JP2002212182A - 1-methylcarbapenem derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a 1-methylcarbapenem compound capable of exhibiting an excellent antimicrobial activity. SOLUTION: This 1-methylcarbapenem compound is represented by the general formula (I) [wherein, R1 denotes a group represented by the formula: COOR3 (R3 denotes hydrogen atom, a 1-6C alkyl group or the like); a group represented by the formula: CONR4R5 (R4 and R5 denote each hydrogen atom, a 1-6C alkyl group which may be substituted or the like), cyano group, a group represented by the formula CH2OR6 (R6 denotes hydrogen atom, a 1-6C alkyl group or the like) or a group represented by the formula CH2NR7R8 (R7 denotes hydrogen atom, a 1-6C alkyl group or the like; and R8 denotes hydrogen atom, a 1-6C alkyl group, a 1-6C alkanoyl group, a 1-6C alkoxycarbonyl group or the like); R2 denotes hydrogen atom or a 1-6C alkyl group; n denotes 1, 2 or 3; and X denotes sulfur atom or oxygen atom] or its pharmacologically acceptable salt or pharmacologically acceptable ester derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a 1-methylcarbapenem compound (I) having excellent antibacterial activity, and a pharmacologically acceptable salt or ester derivative thereof.

[0002]

2. Description of the Related Art There is a demand for the development of carbapenem derivatives having potent and balanced antibacterial activity against a wide range of pathogenic bacteria. JP-A-8-53453 discloses a 1-methylcarbapenem compound having a structure similar to that of the present invention.

[0003]

As a result of various studies on the 1-methylcarbapenem compound for many years, the inventors have found that the compound (I) of the present invention has a stronger antibacterial activity than the conventional 1-methylcarbapenem derivative. Treatment or prevention (especially treatment) of bacterial infections, especially respiratory infections
The present inventors have found that the present invention is effective as an antibacterial agent, and have completed the present invention.

[0004]

[Means for solving the problem] General formula

[0005]

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And a pharmacologically acceptable salt or ester derivative thereof.

In the formula, R ¹ is (1) a group represented by the formula COOR ³ wherein R ³ is a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group, (2) Formula C
A group represented by ONR ⁴ R ⁵ [wherein R ⁴ and R ⁵ are the same or different and are each a hydrogen atom, a C1-C6 alkyl group (one or two same or different groups selected from the following substituent group A) A C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclic group or a C6-C10 aryl group (the same or different ones selected from the following substituent group B)
Or a group which may form a 3- to 6-membered nitrogen-containing heterocycle together with the nitrogen atom to which they are bonded (from the following substituent group B) Or the same or different 1 or 2 groups selected).], (3) a cyano group, (4) a formula C
A group represented by H ₂ OR ⁶ wherein R ⁶ is a hydrogen atom,
A C6 alkyl group or a C3-C6 cycloalkyl group] or (5) a group represented by the formula CH ₂ NR ⁷ R ⁸ [wherein R ⁷
Is hydrogen, C1-C6 alkyl group, a C3-C6 cycloalkyl group, R ⁸ is a hydrogen atom, C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkanoyl group, C6-C10 arylcarbonyl group (May be substituted with one or two same or different groups selected from the following substituent group B), a C1-C6 alkoxycarbonyl group, a 5- or 6-membered aromatic heterocyclic carbonyl group,
Or showing a C1-C6 alkylsulfonyl group or a C6-C10 arylsulfonyl group, or, R ⁷ and R ⁸ (which may be fused with a phenyl group) succinimide group together with the nitrogen atom to which they are attached Shows]
R ² represents a hydrogen atom or a C1-C6 alkyl group,
n represents 1, 2 or 3, and X represents a sulfur atom or an oxygen atom.

The substituent group A includes a hydroxyl group, an amino group (which may be substituted with one or two C1-C6 alkyl groups), a carbamoyl group (where the amino moiety is one or two C1-C6 alkyl groups).
A C1-C6 alkyl group), a carboxyl group, a cyano group, and a C1-C6 alkoxy group, and the substituent group B includes a hydroxy C1-C4 alkyl group and an amino C1-C4 alkyl group. (The amino moiety may be substituted with one or two C1-C6 alkyl groups), a carbamoyl group (the amino moiety is one or two C1-C6 alkyl groups).
A 1-C6 alkyl group, a carboxyl group, a hydroxyl group, an amino group (one or two C1-C6
6-alkyl group), C1-C6 alkoxy group, and C1-C6 alkyl group.
In the above, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
"C1-C6" in the definition of the substituent group A and the substituent group B
"Alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-
Butyl, tert-butyl, n-pentyl, isopentyl,
2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl , 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl group, and the like. R ² , R ³ , R ⁶ ,
In R ⁷ and R ⁸ , Substituent Group A and Substituent Group B, a C1-C3 alkyl group is preferable, and a methyl group is particularly preferable. R ⁴ is preferably a C1-C3 alkyl group, particularly preferably a methyl or isopropyl group. R ⁵ is preferably a C2-C6 alkyl group, most preferably a 1-methyl-2-methylpropyl group.

The "C3-C6 cycloalkyl group" in the definition of R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ represents a cyclic hydrocarbon group having 3 to 6 carbon atoms. , Cyclobutyl, cyclopentyl and cyclohexyl groups, preferably a cyclopropyl group.

The "3- to 6-membered heterocyclic group" in the definition of R ⁴ and R ⁵ is a saturated heterocyclic group containing one or two oxygen, nitrogen and sulfur atoms, such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, Oxylanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, morpholinyl, piperazinyl, thiomorpholinyl group and the like can be mentioned, preferably a 4- to 6-membered nitrogen-containing heterocyclic group, more preferably azetidinyl, pyrrolidinyl or It is a piperidinyl group.

"C6-C10" in the definition of R ⁴ and R ⁵
"C6-C10 in the definition of aryl group" and R ⁸
“Arylcarbonyl group” and “arylsulfonyl group”
Examples of the "C6-C10 aryl" moiety include a phenyl, indenyl and naphthyl group, and a phenyl group is preferred.

The "nitrogen-containing heterocycle" of the "group which forms a 3- to 6-membered nitrogen-containing heterocycle together with the nitrogen atom to which they are bonded" in R ⁴ and R ⁵ includes one or two nitrogen atoms. And a saturated heterocyclic group which may contain an oxygen or sulfur atom, such as aziridino, azetidino, pyrrolidino, piperidino, morpholino, piperazino, and thiomorpholino groups. A heterocyclic ring, more preferably azetidino, piperazino,
A morpholino or thiomorpholino group.

The "C1-C6 alkanoyl group" in the definition of R ⁸ represents a straight-chain or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, Pivaloyl and hexanoyl groups,
Preferably it is a C1-C3 alkanoyl group, most preferably an acetyl group.

In the definition of R ⁸ and the substituent group, “C1-
The "C1-C6 alkoxy" part of the "C1-C6 alkoxycarbonyl group" in the definition of "C6 alkoxy group" represents a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy. , Isopropoxy, butoxy, pentyloxy and hexyloxy groups, preferably a C1-C3 alkoxy group, and most preferably a methoxy group.

In the definition of R ⁸ , the “5- or 6-membered aromatic heterocyclic carbonyl group” of the “5- or 6-membered aromatic heterocyclic carbonyl group” is an aromatic heterocyclic ring containing 1 to 3 oxygen, nitrogen and sulfur atoms. And include, for example, pyrrole, imidazole, thiazole, oxazole, isoxazole, furan, thiophene, triazole, thiadiazole, pyridine, pyrimidine, pyridazine, triazine and the like. Preferably it is furan, thiophene or pyridine.

In the substituent group B, "hydroxy C1-C
Examples of the "4 alkyl group" include a hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl group.
It is a 2-alkyl group, most preferably a hydroxymethyl group.

The "amino C1-C4 alkyl group" in the substituent group B includes, for example, aminomethyl, aminoethyl, aminopropyl and aminobutyl groups, preferably an amino C1-C2 alkyl group. Most preferably, it is an aminomethyl group.

Substituent group A is preferably a group consisting of a hydroxyl group, an amino group (which may be substituted by one or two C1-C3 alkyl groups) and a carbamoyl group, and most preferably an amino group. (Which may be substituted with one or two methyl or ethyl groups).

Substituent group B is preferably hydroxy C1-
C4 alkyl group, amino C1-C4 alkyl group (amino part may be substituted with one or two C1-C3 alkyl groups), carbamoyl group Amino part is substituted with one or two C1-C3 alkyl groups A hydroxyl group, an amino group (which may be substituted with one or two C1-C3 alkyl groups),
More preferably, a hydroxymethyl group, an aminomethyl group (the amino moiety may be substituted by one or two methyl or ethyl groups), a carbamoyl group (the amino moiety is
Or a group consisting of a hydroxyl group and an amino group (which may be substituted with one or two methyl or ethyl groups), more preferably It is an aminomethyl group or an amino group. “Pharmaceutically acceptable ester derivative” of compound (I) refers to a group that is cleaved by chemical or biological methods such as hydrolysis in a human or animal body to form compound (I) or a salt thereof. Refers to an ester derivative in which a carboxyl group or a hydroxyl group of compound (I) is protected, and whether such a derivative is administered orally or intravenously to an experimental animal such as a rat or a mouse, and then the body fluid of the animal Is determined and the original compound (I) or a salt thereof can be detected.

Examples of the protecting group for forming an ester derivative at the carboxyl group include C1-C10 alkyl group, C3-C6 cycloalkyl group, C3-C6 cycloalkyl C1-C4 alkyl group, C2-C10 alkanoyloxy C1-C4 alkyl. Group, C1-C10 alkoxycarbonyloxy C1-C4 alkyl group, phenyl group (the phenyl group is a halogen atom, C1-C4 alkyl group, C1-C4 alkoxy group, methylenedioxy group,
May be substituted with one or two groups selected from a 1-C6 alkanoyloxy group), a C1-C10 alkanoyloxybenzyl group, a phthalidyl group, a 5-methyl-2-oxo-1,3-dioxolene- Examples thereof include a 4-ylmethyl group.

Protecting groups which form ester derivatives at the hydroxyl group include C1-C10 alkanoyl groups, C6-
C10 arylcarbonyl, C1-C10 alkoxycarbonyl group, aminoacyl group and the like can be mentioned.

The above "C1-C10 alkyl group" includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl,
2-pentyl, 3-pentyl, isopentyl, hexyl, 2-hexyl, 3-hexyl, isohexyl, heptyl, octyl, nonyl, decyl group and the like can be mentioned, preferably a C1-C6 alkyl group, more preferably Is a C2-C4 alkyl group, most preferably an ethyl group.

The "C3-C6 cycloalkyl group" includes, for example, a cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl group, preferably a cyclopentyl or cyclohexyl group.

The "C3-C6 cycloalkyl C1-C4 alkyl group" includes, for example, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl,
Cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl and the like can be mentioned, and a cyclopropylmethyl group is preferred.

"C2-10 alkanoyloxy C1-C
Examples of "4 alkyl groups" include acetoxymethyl,
1- (acetoxy) ethyl, 1- (acetoxy) propyl, 1- (acetoxy) butyl, propionyloxymethyl, 1- (propionyloxy) ethyl, isopropionyloxymethyl, 1- (isopropionyloxy)
Ethyl, butyryloxymethyl, 1- (butyryloxy) ethyl, isobutyryloxymethyl, 1- (isobutyryloxy) ethyl, pivaloyloxymethyl, 1-
(Pivaloyloxy) ethyl, valeryloxymethyl,
1- (valeryloxy) ethyl, isovaleryloxymethyl, 1- (isovaleryloxy) ethyl, hexanoyloxymethyl, 1- (hexanoyloxy) ethyl,
Octanoyloxymethyl, 1- (octanoyloxy) ethyl, decanoyloxymethyl, cyclopentylcarbonyloxymethyl, 1-methylcyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-methylcyclohexylcarbonyloxymethyl and the like. And preferably a C2-C6 alkanoyloxymethyl or 1- (C2-C6 alkanoyloxy) ethyl group.

The "C1-C10 alkoxycarbonyloxy C1-C4 alkyl group" includes, for example, methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl,
(Ethoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) butyl, propoxycarbonyloxymethyl, 1- (propoxycarbonyloxy) ethyl, isopropoxycarbonyloxymethyl, 1- (isopropoxy Carbonyloxy) ethyl, butoxycarbonyloxymethyl, 1- (butoxycarbonyloxy) ethyl, isobutoxycarbonyloxymethyl, 1- (isobutoxycarbonyloxy) ethyl, s-butoxycarbonyloxymethyl, 1- (s-butoxycarbonyloxy ) Ethyl, t-butoxycarbonyloxymethyl,
1- (t-butoxycarbonyloxy) ethyl, pentyloxycarbonyloxymethyl, 1- (pentyloxycarbonyloxy) ethyl, (1-methylbutyloxycarbonyloxy) methyl, 1- (1-methylbutyloxycarbonyloxy) ethyl , (2-methylbutyloxycarbonyloxy) methyl, 1- (2-methylbutyloxycarbonyloxy) ethyl, (3-methylbutyloxycarbonyloxy) methyl, 1- (3-methylbutyloxycarbonyloxy) ethyl, ( 1-ethylpropyloxycarbonyloxy) methyl, 1- (1
-Ethylpropyloxycarbonyloxy) ethyl, hexyloxycarbonyloxymethyl, 1- (hexyloxycarbonyloxy) ethyl, (1-methylpentyloxycarbonyloxy) methyl, 1- (1-methylpentyloxycarbonyloxy) ethyl, octyl Oxycarbonyloxymethyl, 1- (octyloxycarbonyloxy) ethyl, decyloxycarbonyloxymethyl, 1- (decyloxycarbonyloxy) ethyl, cyclopentylcarbonyloxymethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, cyclohexylcarbonyloxymethyl , 1- (cyclohexyloxycarbonyloxy) ethyl group and the like, preferably C1-C6 alkoxycarbonyloxymethyl or 1- (cyclohexyloxycarbonyloxy) ethyl group. It is a C1-C6 alkoxycarbonyloxy) ethyl group.

As the "substitutable phenyl group", for example, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxy Phenyl, 3,4-dimethoxyphenyl, 3,4
-Methylenedioxyphenyl, 3-acetoxyphenyl, 4-acetoxyphenyl group and the like,
Preferably, it is an unsubstituted phenyl group.

As the "C2-C10 alkanoyloxybenzyl group", for example, 2-acetoxybenzyl, 3-
Acetoxybenzyl, 4-acetoxybenzyl, 3-propionylbenzyl, 4-propionyloxybenzyl, 4-butyryloxybenzyl, 4-valeryloxybenzyl, 4-hexanoyloxybenzyl, 4-octanoyloxybenzyl, 4-deca A noyloxybenzyl group and the like can be mentioned, and preferably 3- or 4-
(C2-C4 alkanoyloxy) benzyl group.

The "C1-C10 alkanoyl group" includes, for example, formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, octanoyl and decanoyl groups, preferably C2-C6 alkanoyl groups.

The "C6-C10 arylcarbonyl group" includes, for example, a benzoyl, 1-naphthoyl and 2-naphthoyl group, and is preferably a benzoyl group.

"C1-C10 alkoxycarbonyl group"
As, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl,
An octyloxycarbonyl, decyloxycarbonyl group and the like are mentioned, and a C2-C6 alkoxycarbonyl group is preferable.

Examples of the "aminoacyl group" include amino acid groups such as glycyl, alanyl, β-alanyl, leucyl, isoleucyl, phenylalanyl, histidyl, asparagyl, prolyl, and lysyl. It is. The compound (I) of the present invention and a pharmaceutically acceptable ester thereof can form a "pharmaceutically acceptable salt", if necessary.

"Pharmacologically acceptable salt" means the compound (I) of the present invention, which can be converted into a salt, and the salt is preferred. Alkali metal salts such as potassium salts, lithium salts,
Metal salts such as alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts; inorganic salts such as ammonium salts, t-octylamine salts; Dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, Amine salts such as chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, organic salts such as tetramethylammonium salts, tris (hydroxymethyl) aminomethane salts; hydrofluoric acid salts, hydrochloric acid Salt, hydrobromide, iodide water Inorganic acid salts such as hydrohalates, nitrates, perchlorates, sulfates, phosphates and the like; lower alkanes such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate Sulfates, benzenesulfonates, arylsulfonates such as p-toluenesulfonate, acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate Organic acid salts such as acid salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates and aspartates.

The compound (I) of the present invention, its pharmaceutically acceptable salts and ester derivatives include hydrates and solvates thereof. Among the compounds represented by the general formula (I), the following compounds are preferred. (1) Regarding R ¹ (1-1) A compound wherein R ¹ is a group represented by the formula CONR ⁴ R ⁵ , a cyano group or a group represented by the formula CH ₂ NR ⁷ R ⁸ . (1-2) The compound wherein R ¹ is a group represented by the formula CONR ⁴ R ⁵ or a group represented by the formula CH ₂ NR ⁷ R ⁸ . (1-3) The compound wherein R ¹ is a group represented by the formula CONR ⁴ R ⁵ . (2) Regarding R ² (2-1) A compound in which R ² is a hydrogen atom or a C1-C3 alkyl group. (2-2) The compound wherein R ² is a hydrogen atom. (3) Regarding R ³ (3-1) A compound in which R ³ is a hydrogen atom or a C1-C3 alkyl group. (3-2) the compound wherein R ³ is a hydrogen atom, a methyl group or an ethyl group. (4) R ⁴ (4-1) A compound in which R ⁴ is a hydrogen atom or a C1-C3 alkyl group. (4-2) The compound wherein R ⁴ is a hydrogen atom, a methyl or an isopropyl group. (5) Regarding R ⁵ (5-1) R ⁵ is a hydrogen atom, a C1-C6 alkyl group (may be substituted with one or two same or different groups selected from substituent group A) or 4 A compound having from 6 to 6 members of a nitrogen-containing heterocyclic group. (5-2) R ⁵ is a hydrogen atom, a C1-C6 alkyl group (which may be substituted with one or two same or different groups selected from substituent group A), an azetidinyl, pyrrolidinyl or piperidinyl group Certain compounds. (6) Regarding R ⁴ and R ⁵ (6-1) a group in which R ⁴ and R ⁵ form a 4- to 6-membered nitrogen-containing heterocyclic ring together with the nitrogen atom to which they are bonded (from substituent group B) Which may be substituted with one or two selected identical or different groups). (6-2) R ⁴ and R ⁵ are taken together with the nitrogen atom to which they are attached to form an azetidino, piperazino, morpholino or thiomorpholino group (these groups being one or the same or different one selected from substituent group B) Which may be substituted with two groups). (7) Regarding R ⁶ (7-1) A compound in which R ⁶ is a hydrogen atom or a C1-C3 alkyl group. (7-2) The compound wherein R ⁶ is a hydrogen atom. (8) Regarding R ⁷ (8-1) A compound in which R ⁷ is a hydrogen atom or a C1-C3 alkyl group. (8-2) The compound wherein R ⁷ is a hydrogen atom or a methyl group. (8-3) The compound wherein R ⁷ is a hydrogen atom. (9) R ⁸ (9-1) R ⁸ is a hydrogen atom, a C1-C3 alkyl group,
A C1-3 alkanoyl group, a benzoyl group (which may be substituted with one or two same or different groups selected from substituent group B), a C1-C3 alkoxycarbonyl group, a thiophenecarbonyl group, a furancarbonyl group or A compound which is a pyridinecarbonyl group. (9-2) R ⁸ is a hydrogen atom, a benzoyl group (may be substituted with one or two same or different groups selected from substituent group B), a thiophen-2-carbonyl group, a furan- A compound which is a 2-carbonyl group or a pyridine-3-carbonyl group. (10) About n (10-1) The compound wherein n is 1. (11) Regarding X (11-1) Compound wherein X is an oxygen atom.

Compounds obtained by arbitrarily combining two or more of the above preferred substituents are more preferred, and examples thereof include the following compounds. (12) R ¹ is a group represented by the formula CONR ⁴ R ⁵ (wherein R ⁴
A There hydrogen atom or a C1-C3 alkyl group, R ⁵ is a hydrogen atom, (optionally substituted by the same or different 1 or 2 groups selected from Substituent Group A) C1-C6 alkyl group or A 4- to 6-membered nitrogen-containing heterocyclic group), R ² is a hydrogen atom, n is 1, and X is an oxygen atom or a sulfur atom. (13) R ¹ is a group represented by the formula CONR ⁴ R ⁵ (wherein R ⁴
Is a hydrogen atom, a methyl or isopropyl group, R ⁵ is a hydrogen atom, a C1-C6 alkyl group (which may be substituted with one or two same or different groups selected from substituent group A), azetidinyl , A pyrrolidinyl or piperidinyl group), n is 1 and X is an oxygen atom or a sulfur atom. (14) R ¹ is a group represented by the formula CONR ⁴ R ⁵ (wherein R ⁴
And R ⁵ together with the nitrogen atom to which they are attached
And a group forming a 6 to 6-membered nitrogen-containing heterocyclic ring (which may be substituted with one or two same or different groups selected from substituent group B), and R ² is a hydrogen atom ,
A compound wherein n is 1 and X is an oxygen atom or a sulfur atom. (15) R ¹ is a group represented by the formula CONR ⁴ R ⁵ (wherein R ⁴
And R ⁵ together with the nitrogen atom to which they are attached are azetidino, piperazino, morpholino or thiomorpholino groups, which are substituted by one or two identical or different groups selected from substituent group B. R ² is a hydrogen atom, n is 1 and X
Is a compound wherein is an oxygen atom or a sulfur atom. (16) R ¹ is a cyano group, R ² is a hydrogen atom,
A compound wherein n is 1 and X is an oxygen atom or a sulfur atom. (17) R ¹ is a group represented by the formula CH ₂ NR ⁷ R ⁸ (wherein R
⁷ is a hydrogen atom or a C1-3 alkyl group, R ⁸ is,
A hydrogen atom, a C1-C3 alkyl group, a C1-3 alkanoyl group, a benzoyl group (which may be substituted with one or two same or different groups selected from substituent group B),
C1-C3 alkoxycarbonyl group, a thiophene group, a furan group or pyridine carbonyl group), R ² is a hydrogen atom, n is 1, and X represents an oxygen atom or a sulfur atom. (18) R ¹ is a group represented by the formula CH ₂ NR ⁷ R ⁸ (wherein, R
⁷ is a hydrogen atom or a methyl group, and R ⁸ is a hydrogen atom,
A benzoyl group (which may be substituted with one or two same or different groups selected from substituent group B), a thiophene-2-carbonyl group, a furan-2-carbonyl group or a pyridine-3-carbonyl group; And R ²
Is a hydrogen atom, n is 1, and X is an oxygen atom or a sulfur atom.

The compounds (I) of the present invention can be specifically exemplified in Tables 1 to 5. The compound (I) of the present invention is not limited to these exemplified compounds.

In Tables 1 to 5, Me is a methyl group, Et is an ethyl group, Pr is a propyl group, iPr is an isopropyl group,
Is a butyl group, Pen is a pentyl group, Hex is a hexyl group, cPr
Represents a cyclopropyl group, cBu represents a cyclobutyl group, cPen represents a cyclopentyl group, cHex represents a cyclohexyl group, Azt represents an azetidinyl group, Pyr represents a pyrrolidinyl group, Pip represents a piperidinyl group, and Ph represents a phenyl group. Position indicates the bonding position of the sulfur atom. [Table 1]

[0038]

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----------------------------------------------- --------------------- Cpd No. X n position R ² R ³ ------------------- ------------------------------------------------- 1 S 13 HH 2 S 13 HMe 3 S 13 H Et 4 S 13 H Pr 5 S 13 H iPr 6 S 13 H Bu 7 S 13 H Pen 8 S 13 H Hex 9 S 13 H cPr 10 S 13 H cBu 11 S 13 H cPen 12 S 13 H cHex 13 S 13 Me H 14 S 13 Me Me 15 S 13 Me Et 16 S 13 Me Pr 17 S 13 Me iPr 18 S 13 Me Bu 19 S 13 Me Pen 20 S 13 Me Hex 21 S 13 Me cPr 22 S 13 Me cBu 23 S 13 Me cPen 24 S 13 Me cHex 25 S 13 Me cHex 26 S 2 3 HH 27 S 23 H Me 28 S 23 H Et 29 S 23 H Pr 30 S 23 H iPr 31 S 23 H Bu 32 S 23 H Pen 33 S 23 H Hex 34 S 23 H cPr 35 S 23 H cBu 36 S 23 H cPen 37 S 23 H cHex 38 S 23 Me H 39 S 23 Me Me 40 S 23 Me Et 41 S 23 Me Pr 42 S 23 Me iPr 43 S 2 3 Me Bu 44 S 2 3 Me Pen 45 S 2 3 Me Hex 46 S 23 MecPr 47 S 23 MecBu 48 S 23 MecPen 49 S 23 MecHex 50 S 23 MecHex 51 S 3 4 HH 52 S 3 4 H Me 53 S 3 4 H Et 54 S 3 4 H Pr 55 S 3 4 H iPr 56 S 34 H Bu 57 S 34 H Pen 58 S 34 H Hex 59 S 34 H cPr 60 S 34 H cBu 61 S 34 H cPen 62 S 34 H cHex 63 S 34 Me H 64 S 3 4 Me Me 65 S 3 4 Me Et 66 S 3 4 Me Pr 67 S 3 4 Me iPr 68 S 3 4 Me Bu 69 S 3 4 Me Pen 70 S 3 4 Me Hex 71 S 3 4 Me cPr 72 S 3 4 Me cBu 73 S 3 4 Me cPen 74 S 3 4 Me cHex 75 S 34 MecHex 76 O 13 HH 77 O 13 H Me 78 O 13 H Et 79 O 13 H Pr 80 O 13 H iPr 81 O 13 H Bu 82 O 13 H Pen 83 O 13 H Hex 84 O 13 H cPr 85 O 13 H cBu 86 O 13 H cPen 87 O 13 H cHex 88 O 13 Me H 89 O 13 Me Me 90 O 13 Me Et 91 O 13 Me Pr 92 O 13 Me iPr 93 O 13 Me Bu 94 O 13 Me Pen 95 O 13 Me Hex 96 O 13 Me cPr 97 O 1 3 Me cBu 98 O 1 3 Me cPen 99 O 1 3 Me cHex 100 O 1 3 Me cHex 101 O 2 3 HH 102 O 2 3 H Me 103 O 2 3 H Et 104 O 2 3 H Pr 105 O 2 3 H iPr 106 O 2 3 H Bu 107 O 2 3 H Pen 108 O 2 3 H Hex 109 O 2 3 H cPr 110 O 2 3 H cBu 111 O 2 3 H cPen 112 O 2 3 H cHex 113 O 2 3 Me H 114 O 2 3 Me Me 115 O 2 3 Me Et 116 O 2 3 Me Pr 117 O 2 3 Me iPr 118 O 2 3 Me Bu 119 O 2 3 Me Pen 12 0 O 2 3 Me Hex 121 O 2 3 Me cPr 122 O 2 3 Me cBu 123 O 2 3 Me cPen 124 O 2 3 Me cHex 125 O 2 3 Me cHex 126 O 3 4 HH 127 O 3 4 H Me 128 O 3 4 H Et 129 O 34 H Pr 130 O 34 H iPr 131 O 34 H Bu 132 O 34 H Pen 133 O 34 H Hex 134 O 34 H cPr 135 O 34 H cBu 136 O 34 H cPen 137 O 34 H cHex 138 O 34 Me H 139 O 34 Me Me 140 O 34 Me Et 141 O 34 Me Pr 142 O 34 Me iPr 143 O 34 Me Bu 144 O 34 Me Pen 145 O 3 4 Me Hex 146 O 3 4 Me cPr 147 O 3 4 Me cBu 148 O 34 4 Me cPen 149 O 3 4 Me cHex 150 O 3 4 Me cHex --------------- -------------------------------------------------- --- [Table 2]

[0040]

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----------------------------------------------- --------------------- Cpd No. X n position R ^Two R ^Four R ^Five -------------------------------------------------- ------------------ 1 S 13 HHH 2 S 13 HH Me 3 S 13 HH Et 4 S 13 HH Pr 5 S 13 HH iPr 6 S 1 3 HH Bu 7 S 13 H Me Me 8 S 13 H Me Et 9 S 13 H Me Pr 10 S 13 H Me iPr 11 S 13 H Me Bu 12 S 13 H Et Et 13 S 13 H Et Pr 14 S 13 H Et iPr 15 S 13 H Et Bu 16 S 13 H Pr Pr 17 S 13 H Pr iPr 18 S 13 H Pr Bu 19 S 13 H iPr iPr 20 S 13 H iPr Bu 21 S 13 H Bu Bu 22 S 13 HH CH _Two CH _Two OH 23 S 1 3 H Me CH _Two CH _Two OH 24 S 1 3 H Et CH _Two CH _Two OH 25 S 1 3 H Pr CH _Two CH _Two OH 26 S 1 3 H iPr CH _Two CH _Two OH 27 S 1 3 HH CH (CH _Three ) CH _Two OH 28 S 1 3 HH CH (CH _Two OH) CH _Two OH 29 S 1 3 HH CH (CH _Two CH _Three ) CH _Two OH 30 S 1 3 HH CH (CH (CH _Three ) _Two ) CH _Two OH 31 S 1 3 HH CH _Two CH _Two NH _Two 32 S 1 3 HH CH (CH _Three ) CH _Two NH _Two 33 S 1 3 HH CH (CH _Two CH _Three ) CH _Two NH _Two 34 S 1 3 HH CH (CH (CH _Three ) _Two ) CH _Two NH _Two 35 S 1 3 HH CH _Two COOH 36 S 1 3 HH CH (CH _Three ) COOH 37 S 1 3 HH CH (CH _Two OH) COOH 38 S 1 3 HH CH (CH _Two CH _Three ) COOH 39 S 1 3 HH CH (CH (CH _Three ) _Two ) COOH 40 S 1 3 HH CH _Two CONH _Two 41 S 1 3 HH CH (CH _Three ) CONH _Two 42 S 1 3 HH CH (CH _Two OH) CONH _Two 43 S 1 3 HH CH (CH _Two CH _Three ) CONH _Two 44 S 1 3 HH CH (CH (CH _Three ) _Two ) CONH _Two 45 S 13 HH cPr 46 S 13 HH cBu 47 S 13 HH cPen 48 S 13 HH cHex 49 S 13 HH 3-Azt 50 S 13 HH 3-Pyr 51 S 13 HH 3-Pip 52 S 1 3 HH 4-Pip 53 S 1 3 HH 2-COOH-Ph 54 S 1 3 HH 2-CONH _Two -Ph 55 S 13 HH 3-COOH-Ph 56 S 13 HH 3-CONH _Two -Ph 57 S 13 HH 4-COOH-Ph 58 S 13 HH 4-CONH _Two -Ph 59 S 1 3 H -CH _Two CH _Two CH _Two -60 S 1 3 H -CH _Two CH _Two CH _Two CH _Two -61 S 1 3 H -CH _Two CH _Two CH _Two CH _Two CH _Two -62 S 1 3 H -CH _Two CH _Two OCH _Two CH _Two -63 S 1 3 H -CH _Two CH _Two SCH _Two CH _Two -64 S 1 3 H -CH _Two CH _Two NHCH _Two CH _Two -65 S 1 3 H -CH _Two CH (OH) CH _Two -66 S 1 3 H -CH _Two CH (OH) CH _Two CH _Two -67 S 1 3 H -CH _Two CH (OH) CH _Two CH _Two CH _Two -68 S 1 3 H -CH _Two CH _Two CH (OH) CH _Two CH _Two -69 S 1 3 H -CH (COOH) CH _Two CH _Two -70 S 1 3 H -CH (CONH _Two ) CH _Two CH _Two -71 S1 3 H -CH (CH _Two OH) CH _Two CH _Two -72 S 1 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two -73 S 1 3 H -CH (COOH) CH _Two CH _Two CH _Two -74 S 1 3 H -CH (CONH _Two ) CH _Two CH _Two CH _Two -75 S1 3 H -CH (CH _Two OH) CH _Two CH _Two CH _Two -76 S 1 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -77 S1 3 H -CH (COOH) CH _Two CH _Two CH _Two CH _Two -78 S1 3 H -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -79 S 1 3 H -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -80 S 1 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -81 S 1 3 H -CH _Two CH (COOH) CH _Two CH _Two CH _Two -82 S 1 3 H -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -83 S 1 3 H -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -84 S 1 3 H -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -85 S 1 3 H -CH _Two CH _Two CH (COOH) CH _Two CH _Two -86 S 1 3 H -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -87 S 1 3 H -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -88 S 1 3 H -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -89 S 13 Me HH 90 S 13 Me H Me 91 S 13 Me H Et 92 S 13 Me H Pr 93 S 13 Me H iPr 94 S 13 Me H Bu 95 S 13 Me Me Me 96 S 13 Me Me Et 97 S 13 Me Me Pr 98 S 13 Me Me iPr 99 S 13 Me Me Bu 100 S 13 Me Et Et 101 S 13 Me Et Pr 102 S 13 Me Et iPr 103 S 1 3 Me Et Bu 104 S 13 Me Pr Pr 105 S 13 Me Pr iPr 106 S 13 Me Pr Bu 107 S 13 Me iPr iPr 108 S 13 Me iPr Bu 109 S 13 Me Bu Bu 110 S 1 3 Me H CH _Two CH _Two OH 111 S 1 3 Me Me CH _Two CH _Two OH 112 S 1 3 Me Et CH _Two CH _Two OH 113 S 13 Me Pr CH _Two CH _Two OH 114 S 1 3 Me iPr CH _Two CH _Two OH 115 S 1 3 Me H CH (CH _Three ) CH _Two OH 116 S 1 3 Me H CH (CH _Two OH) CH _Two OH 117 S 1 3 Me H CH (CH _Two CH _Three ) CH _Two OH 118 S 1 3 Me H CH (CH (CH _Three ) _Two ) CH _Two OH 119 S 1 3 Me H CH _Two CH _Two NH _Two 120 S 1 3 Me H CH (CH _Three ) CH _Two NH _Two 121 S 1 3 Me H CH (CH _Two CH _Three ) CH _Two NH _Two 122 S 1 3 Me H CH (CH (CH _Three ) _Two ) CH _Two NH _Two 123 S 1 3 Me H CH _Two COOH 124 S 1 3 Me H CH (CH _Three ) COOH 125 S 1 3 Me H CH (CH _Two OH) COOH 126 S 1 3 Me H CH (CH _Two CH _Three ) COOH 127 S 1 3 Me H CH (CH (CH _Three ) _Two ) COOH 128 S 1 3 Me H CH _Two CONH _Two 129 S 1 3 Me H CH (CH _Three ) CONH _Two 130 S 1 3 Me H CH (CH _Two OH) CONH _Two 131 S 1 3 Me H CH (CH _Two CH _Three ) CONH _Two 132 S 1 3 Me H CH (CH (CH _Three ) _Two ) CONH _Two 133 S 13 Me H cPr 134 S 13 Me H cBu 135 S 13 Me H cPen 136 S 13 Me H cHex 137 S 13 Me H 3-Azt 138 S 13 Me 3 H-Pyr 139 S 13 Me H 3-Pip 140 S 13 MeH 4-Pip 141 S 13 Me H 2-COOH-Ph 142 S 13 MeH 2-CONH _Two -Ph 143 S 13 Me H 3-COOH-Ph 144 S 13 Me H 3-CONH _Two -Ph 145 S 1 3 Me H 4-COOH-Ph 146 S 13 Me H 4-CONH _Two -Ph 147 S 1 3 Me -CH _Two CH _Two CH _Two -148 S 1 3 Me -CH _Two CH _Two CH _Two CH _Two -149 S 1 3 Me -CH _Two CH _Two CH _Two CH _Two CH _Two -150 S 1 3 Me -CH _Two CH _Two OCH _Two CH _Two -151 S 1 3 Me -CH _Two CH _Two SCH _Two CH _Two -152 S 1 3 Me -CH _Two CH _Two NHCH _Two CH _Two -153 S 1 3 Me -CH _Two CH (OH) CH _Two -154 S 1 3 Me -CH _Two CH (OH) CH _Two CH _Two -155 S 1 3 Me -CH _Two CH (OH) CH _Two CH _Two CH _Two -156 S 1 3 Me -CH _Two CH _Two CH (OH) CH _Two CH _Two -157 S 1 3 Me -CH (COOH) CH _Two CH _Two -158 S 1 3 Me -CH (CONH _Two ) CH _Two CH _Two -159 S 1 3 Me -CH (CH _Two OH) CH _Two CH _Two -160 S 1 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two -161 S 1 3 Me -CH (COOH) CH _Two CH _Two CH _Two -162 S 1 3 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two -163 S 1 3 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two -164 S 1 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -165 S 1 3 Me -CH (COOH) CH _Two CH _Two CH _Two CH _Two -166 S 1 3 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -167 S 1 3 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -168 S 1 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -169 S 1 3 Me -CH _Two CH (COOH) CH _Two CH _Two CH _Two -170 S 1 3 Me -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -171 S 1 3 Me -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -172 S 1 3 Me -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -173 S 1 3 Me -CH _Two CH _Two CH (COOH) CH _Two CH _Two -174 S 1 3 Me -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -175 S 1 3 Me -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -176 S 1 3 Me -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -177 S 23 HHH 178 S 23 HH Me 179 S 23 HH Et 180 S 23 HH Pr 181 S 23 HH iPr 182 S 23 HH Bu 183 S 23 HMe Me 184 S 23 HMe Et 185 S 23 H Me Pr 186 S 23 H Me iPr 187 S 23 H Me Bu 188 S 23 H Et Et 189 S 23 H Et Pr 190 S 23 H Et iPr 191 S 23 H Et Bu 192 S 2 3 H Pr Pr 193 S 23 H Pr iPr 194 S 23 H Pr Bu 195 S 23 H iPr iPr 196 S 23 H iPr Bu 197 S 23 H Bu Bu 198 S 23 HH CH _Two CH _Two OH 199 S 2 3 H Me CH _Two CH _Two OH 200 S 2 3 H Et CH _Two CH _Two OH 201 S 2 3 H Pr CH _Two CH _Two OH 202 S 2 3 H iPr CH _Two CH _Two OH 203 S 2 3 HH CH (CH _Three ) CH _Two OH 204 S 2 3 HH CH (CH _Two OH) CH _Two OH 205 S 2 3 HH CH (CH _Two CH _Three ) CH _Two OH 206 S 2 3 HH CH (CH (CH _Three ) _Two ) CH _Two OH 207 S 2 3 HH CH _Two CH _Two NH _Two 208 S 2 3 HH CH (CH _Three ) CH _Two NH _Two 209 S 2 3 HH CH (CH _Two CH _Three ) CH _Two NH _Two 210 S 2 3 HH CH (CH (CH _Three ) _Two ) CH _Two NH _Two 211 S 2 3 HH CH _Two COOH 212 S 2 3 HH CH (CH _Three ) COOH 213 S 2 3 HH CH (CH _Two OH) COOH 214 S 2 3 HH CH (CH _Two CH _Three ) COOH 215 S 2 3 HH CH (CH (CH _Three ) _Two ) COOH 216 S 2 3 HH CH _Two CONH _Two 217 S 2 3 HH CH (CH _Three ) CONH _Two 218 S 2 3 HH CH (CH _Two OH) CONH _Two 219 S 2 3 HH CH (CH _Two CH _Three ) CONH _Two 220 S 2 3 HH CH (CH (CH _Three ) _Two ) CONH _Two 221 S 23 HH cPr 222 S 23 HH cBu 223 S 23 HH cPen 224 S 23 HH cHex 225 S 23 HH 3-Azt 226 S 23 HH 3-Pyr 227 S 23 HH 3-Pip 228 S 2 3 HH 4-Pip 229 S 2 3 HH 2-COOH-Ph 230 S 2 3 HH 2-CONH _Two -Ph 231 S 2 3 HH 3-COOH-Ph 232 S 2 3 HH 3-CONH _Two -Ph 233 S 23 HH 4-COOH-Ph 234 S 23 HH 4-CONH _Two -Ph 235 S 2 3 H -CH _Two CH _Two CH _Two -236 S 2 3 H -CH _Two CH _Two CH _Two CH _Two -237 S 2 3 H -CH _Two CH _Two CH _Two CH _Two CH _Two -238 S 2 3 H -CH _Two CH _Two OCH _Two CH _Two -239 S 2 3 H -CH _Two CH _Two SCH _Two CH _Two -240 S 2 3 H -CH _Two CH _Two NHCH _Two CH _Two -241 S 2 3 H -CH _Two CH (OH) CH _Two -242 S 2 3 H -CH _Two CH (OH) CH _Two CH _Two -243 S 2 3 H -CH _Two CH (OH) CH _Two CH _Two CH _Two -244 S 2 3 H -CH _Two CH _Two CH (OH) CH _Two CH _Two -245 S 2 3 H -CH (COOH) CH _Two CH _Two -246 S 2 3 H -CH (CONH _Two ) CH _Two CH _Two -247 S 2 3 H -CH (CH _Two OH) CH _Two CH _Two -248 S 2 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two -249 S 2 3 H -CH (COOH) CH _Two CH _Two CH _Two -250 S 2 3 H -CH (CONH _Two ) CH _Two CH _Two CH _Two -251 S 2 3 H -CH (CH _Two OH) CH _Two CH _Two CH _Two -252 S 2 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -253 S 2 3 H -CH (COOH) CH _Two CH _Two CH _Two CH _Two -254 S 2 3 H -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -255 S 2 3 H -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -256 S 2 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -257 S 2 3 H -CH _Two CH (COOH) CH _Two CH _Two CH _Two -258 S 2 3 H -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -259 S 2 3 H -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -260 S 2 3 H -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -261 S 2 3 H -CH _Two CH _Two CH (COOH) CH _Two CH _Two -262 S 2 3 H -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -263 S 2 3 H -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -264 S 2 3 H -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -265 S 23 Me HH 266 S 23 Me H Me 267 S 23 Me H Et 268 S 23 Me H Pr 269 S 23 Me H iPr 270 S 23 Me H Bu 271 S 23 Me Me Me 272 S 23 Me Me Et 273 S 23 Me Me Pr 274 S 23 Me Me iPr 275 S 23 Me Me Bu 276 S 23 Me Et Et 277 S 23 Me Et Pr 278 S 23 Me Me iPr 279 S 2 3 Me Et Bu 280 S 23 Me Pr Pr 281 S 23 Me Pr iPr 282 S 23 Me Pr Bu 283 S 23 Me iPr iPr 284 S 23 Me iPr Bu 285 S 23 Me Bu Bu 286 S 2 3 Me H CH _Two CH _Two OH 287 S 2 3 Me Me CH _Two CH _Two OH 288 S 2 3 Me Et CH _Two CH _Two OH 289 S 2 3 Me Pr CH _Two CH _Two OH 290 S 2 3 Me iPr CH _Two CH _Two OH 291 S 2 3 Me H CH (CH _Three ) CH _Two OH 292 S 2 3 Me H CH (CH _Two OH) CH _Two OH 293 S 2 3 Me H CH (CH _Two CH _Three ) CH _Two OH 294 S 2 3 Me H CH (CH (CH _Three ) _Two ) CH _Two OH 295 S 2 3 Me H CH _Two CH _Two NH _Two 296 S 2 3 Me H CH (CH _Three ) CH _Two NH _Two 297 S 2 3 Me H CH (CH _Two CH _Three ) CH _Two NH _Two 298 S 2 3 Me H CH (CH (CH _Three ) _Two ) CH _Two NH _Two 299 S 2 3 Me H CH _Two COOH 300 S 2 3 Me H CH (CH _Three ) COOH 301 S 2 3 Me H CH (CH _Two OH) COOH 302 S 2 3 Me H CH (CH _Two CH _Three ) COOH 303 S 2 3 Me H CH (CH (CH _Three ) _Two ) COOH 304 S 2 3 Me H CH _Two CONH _Two 305 S 2 3 Me H CH (CH _Three ) CONH _Two 306 S 2 3 Me H CH (CH _Two OH) CONH _Two 307 S 2 3 Me H CH (CH _Two CH _Three ) CONH _Two 308 S 2 3 Me H CH (CH (CH _Three ) _Two ) CONH _Two 309 S 2 3 Me H cPr 310 S 2 3 Me H cBu 311 S 2 3 Me H cPen 312 S 2 3 Me H cHex 313 S 2 3 Me H 3-Azt 314 S 2 3 Me H 3-Pyr 315 S 2 3 Me H 3-Pip 316 S 2 3 Me H 4-Pip 317 S 2 3 Me H 2-COOH-Ph 318 S 2 3 Me H 2-CONH _Two -Ph 319 S 2 3 Me H 3-COOH-Ph 320 S 2 3 Me H 3-CONH _Two -Ph 321 S 2 3 Me H 4-COOH-Ph 322 S 2 3 Me H 4-CONH _Two -Ph 323 S 2 3 Me -CH _Two CH _Two CH _Two -324 S 2 3 Me -CH _Two CH _Two CH _Two CH _Two -325 S 2 3 Me -CH _Two CH _Two CH _Two CH _Two CH _Two -326 S 2 3 Me -CH _Two CH _Two OCH _Two CH _Two -327 S 2 3 Me -CH _Two CH _Two SCH _Two CH _Two -328 S 2 3 Me -CH _Two CH _Two NHCH _Two CH _Two -329 S 2 3 Me -CH _Two CH (OH) CH _Two -330 S 2 3 Me -CH _Two CH (OH) CH _Two CH _Two -331 S 2 3 Me -CH _Two CH (OH) CH _Two CH _Two CH _Two -332 S 2 3 Me -CH _Two CH _Two CH (OH) CH _Two CH _Two -333 S 2 3 Me -CH (COOH) CH _Two CH _Two -334 S 2 3 Me -CH (CONH _Two ) CH _Two CH _Two -335 S 2 3 Me -CH (CH _Two OH) CH _Two CH _Two -336 S 2 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two -337 S 2 3 Me -CH (COOH) CH _Two CH _Two CH _Two -338 S 2 3 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two -339 S 2 3 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two -340 S 2 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -341 S 2 3 Me -CH (COOH) CH _Two CH _Two CH _Two CH _Two -342 S 2 3 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -343 S 2 3 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -344 S 2 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -345 S 2 3 Me -CH _Two CH (COOH) CH _Two CH _Two CH _Two -346 S 2 3 Me -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -347 S 2 3 Me -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -348 S 2 3 Me -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -349 S 2 3 Me -CH _Two CH _Two CH (COOH) CH _Two CH _Two -350 S 2 3 Me -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -351 S 2 3 Me -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -352 S 2 3 Me -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -353 S 3 4 HHH 354 S 34 HH Me 355 S 34 HH Et 356 S 34 HH Pr 357 S 34 HH iPr 358 S 34 HH Bu 359 S 34 HMe Me 360 S 34 HMe Et 361 S 3 4 H Me Pr 362 S 34 H Me iPr 363 S 34 H Me Bu 364 S 34 H Et Et 365 S 34 H Et Pr 366 S 34 H Et iPr 367 S 34 H Et Bu 368 S 3 4 H Pr Pr 369 S 3 4 H Pr iPr 370 S 3 4 H Pr Bu 371 S 3 4 H iPr iPr 372 S 3 4 H iPr Bu 373 S 3 4 H Bu Bu 374 S 3 4 HH CH _Two CH _Two OH 375 S 3 4 H Me CH _Two CH _Two OH 376 S 3 4 H Et CH _Two CH _Two OH 377 S 3 4 H Pr CH _Two CH _Two OH 378 S 3 4 H iPr CH _Two CH _Two OH 379 S 3 4 HH CH (CH _Three ) CH _Two OH 380 S 3 4 HH CH (CH _Two OH) CH _Two OH 381 S 3 4 HH CH (CH _Two CH _Three ) CH _Two OH 382 S 3 4 HH CH (CH (CH _Three ) _Two ) CH _Two OH 383 S 3 4 HH CH _Two CH _Two NH _Two 384 S 3 4 HH CH (CH _Three ) CH _Two NH _Two 385 S 3 4 HH CH (CH _Two CH _Three ) CH _Two NH _Two 386 S 3 4 HH CH (CH (CH _Three ) _Two ) CH _Two NH _Two 387 S 3 4 HH CH _Two COOH 388 S 3 4 HH CH (CH _Three ) COOH 389 S 3 4 HH CH (CH _Two OH) COOH 390 S 3 4 HH CH (CH _Two CH _Three ) COOH 391 S 3 4 HH CH (CH (CH _Three ) _Two ) COOH 392 S 3 4 HH CH _Two CONH _Two 393 S 3 4 HH CH (CH _Three ) CONH _Two 394 S 3 4 HH CH (CH _Two OH) CONH _Two 395 S 3 4 HH CH (CH _Two CH _Three ) CONH _Two 396 S 3 4 HH CH (CH (CH _Three ) _Two ) CONH _Two 397 S 34 HH cPr 398 S 34 HH cBu 399 S 34 HH cPen 400 S 34 HH cHex 401 S 34 HH 3-Azt 402 S 34 HH 3-Pyr 403 S 34 HH 3-Pip 404 S 3 4 HH 4-Pip 405 S 3 4 HH 2-COOH-Ph 406 S 3 4 HH 2-CONH _Two -Ph 407 S 3 4 HH 3-COOH-Ph 408 S 3 4 HH 3-CONH _Two -Ph 409 S 3 4 HH 4-COOH-Ph 410 S 3 4 HH 4-CONH _Two -Ph 411 S 3 4 H -CH _Two CH _Two CH _Two -412 S 3 4 H -CH _Two CH _Two CH _Two CH _Two -413 S 3 4 H -CH _Two CH _Two CH _Two CH _Two CH _Two -414 S 3 4 H -CH _Two CH _Two OCH _Two CH _Two -415 S 3 4 H -CH _Two CH _Two SCH _Two CH _Two -416 S 3 4 H -CH _Two CH _Two NHCH _Two CH _Two -417 S 3 4 H -CH _Two CH (OH) CH _Two -418 S 3 4 H -CH _Two CH (OH) CH _Two CH _Two -419 S 3 4 H -CH _Two CH (OH) CH _Two CH _Two CH _Two -420 S 3 4 H -CH _Two CH _Two CH (OH) CH _Two CH _Two -421 S 3 4 H -CH (COOH) CH _Two CH _Two -422 S 3 4 H -CH (CONH _Two ) CH _Two CH _Two -423 S 3 4 H -CH (CH _Two OH) CH _Two CH _Two -424 S 3 4 H -CH (CH _Two NH _Two ) CH _Two CH _Two -425 S 3 4 H -CH (COOH) CH _Two CH _Two CH _Two -426 S 3 4 H -CH (CONH _Two ) CH _Two CH _Two CH _Two -427 S 3 4 H -CH (CH _Two OH) CH _Two CH _Two CH _Two -428 S 3 4 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -429 S 3 4 H -CH (COOH) CH _Two CH _Two CH _Two CH _Two -430 S 3 4 H -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -431 S 3 4 H -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -432 S 3 4 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -433 S 3 4 H -CH _Two CH (COOH) CH _Two CH _Two CH _Two -434 S 3 4 H -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -435 S 3 4 H -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -436 S 3 4 H -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -437 S 3 4 H -CH _Two CH _Two CH (COOH) CH _Two CH _Two -438 S 3 4 H -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -439 S 3 4 H -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -440 S 3 4 H -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -441 S 34 Me HH 442 S 34 Me H Me 443 S 34 Me H Et 444 S 34 Me H Pr 445 S 34 Me H iPr 446 S 34 Me H Bu 447 S 34 Me Me Me 448 S 3 4 Me Me Et 449 S 3 4 Me Me Pr 450 S 3 4 Me Me iPr 451 S 3 4 Me Me Bu 452 S 3 4 Me Et Et 453 S 3 4 Me Et Pr 454 S 3 4 Me Et iPr 455 S 3 4 Me Et Bu 456 S 3 4 Me Pr Pr 457 S 3 4 Me Pr iPr 458 S 3 4 Me Pr Bu 459 S 3 4 Me iPr iPr 460 S 3 4 Me iPr Bu 461 S 3 4 Me Bu Bu 462 S 3 4 Me H CH _Two CH _Two OH 463 S 3 4 Me Me CH _Two CH _Two OH 464 S 3 4 Me Et CH _Two CH _Two OH 465 S 3 4 Me Pr CH _Two CH _Two OH 466 S 3 4 Me iPr CH _Two CH _Two OH 467 S 3 4 Me H CH (CH _Three ) CH _Two OH 468 S 3 4 Me H CH (CH _Two OH) CH _Two OH 469 S 3 4 Me H CH (CH _Two CH _Three ) CH _Two OH 470 S 3 4 Me H CH (CH (CH _Three ) _Two ) CH _Two OH 471 S 3 4 Me H CH _Two CH _Two NH _Two 472 S 3 4 Me H CH (CH _Three ) CH _Two NH _Two 473 S 3 4 Me H CH (CH _Two CH _Three ) CH _Two NH _Two 474 S 3 4 Me H CH (CH (CH _Three ) _Two ) CH _Two NH _Two 475 S 3 4 Me H CH _Two COOH 476 S 3 4 Me H CH (CH _Three ) COOH 477 S 3 4 Me H CH (CH _Two OH) COOH 478 S 3 4 Me H CH (CH _Two CH _Three ) COOH 479 S 3 4 Me H CH (CH (CH _Three ) _Two ) COOH 480 S 3 4 Me H CH _Two CONH _Two 481 S 3 4 Me H CH (CH _Three ) CONH _Two 482 S 3 4 Me H CH (CH _Two OH) CONH _Two 483 S 3 4 Me H CH (CH _Two CH _Three ) CONH _Two 484 S 3 4 Me H CH (CH (CH _Three ) _Two ) CONH _Two 485 S 3 4 Me H cPr 486 S 3 4 Me H cBu 487 S 34 Me H cPen 488 S 34 Me H cHex 489 S 34 Me H 3-Azt 490 S 3 4 Me H 3-Pyr 491 S 3 4 Me H 3-Pip 492 S 3 4 Me H 4-Pip 493 S 3 4 Me H 2-COOH-Ph 494 S 3 4 Me H 2-CONH _Two -Ph 495 S 3 4 Me H 3-COOH-Ph 496 S 3 4 Me H 3-CONH _Two -Ph 497 S 3 4 Me H 4-COOH-Ph 498 S 3 4 Me H 4-CONH _Two -Ph 499 S 3 4 Me -CH _Two CH _Two CH _Two -500 S 3 4 Me -CH _Two CH _Two CH _Two CH _Two -501 S 3 4 Me -CH _Two CH _Two CH _Two CH _Two CH _Two -502 S 3 4 Me -CH _Two CH _Two OCH _Two CH _Two -503 S 3 4 Me -CH _Two CH _Two SCH _Two CH _Two -504 S 3 4 Me -CH _Two CH _Two NHCH _Two CH _Two -505 S 3 4 Me -CH _Two CH (OH) CH _Two -506 S 3 4 Me -CH _Two CH (OH) CH _Two CH _Two -507 S 3 4 Me -CH _Two CH (OH) CH _Two CH _Two CH _Two -508 S 3 4 Me -CH _Two CH _Two CH (OH) CH _Two CH _Two -509 S 3 4 Me -CH (COOH) CH _Two CH _Two -510 S 3 4 Me -CH (CONH _Two ) CH _Two CH _Two -511 S 3 4 Me -CH (CH _Two OH) CH _Two CH _Two -512 S 3 4 Me -CH (CH _Two NH _Two ) CH _Two CH _Two -513 S 3 4 Me -CH (COOH) CH _Two CH _Two CH _Two -514 S 3 4 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two -515 S 3 4 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two -516 S 3 4 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -517 S 3 4 Me -CH (COOH) CH _Two CH _Two CH _Two CH _Two -518 S 3 4 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -519 S 3 4 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -520 S 3 4 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -521 S 3 4 Me -CH _Two CH (COOH) CH _Two CH _Two CH _Two -522 S 3 4 Me -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -523 S 3 4 Me -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -524 S 3 4 Me -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -525 S 3 4 Me -CH _Two CH _Two CH (COOH) CH _Two CH _Two -526 S 3 4 Me -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -527 S 3 4 Me -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -528 S 3 4 Me -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -529 O 13 HHH 530 O 13 HH Me 531 O 13 HH Et 532 O 13 HH Pr 533 O 13 HH iPr 534 O 13 HH Bu 535 O 13 HMe Me 536 O 13 HMe Et 537 O 13 H Me Pr 538 O 13 H Me iPr 539 O 13 H Me Bu 540 O 13 H Et Et 541 O 13 H Et Pr 542 O 13 H Et iPr 543 O 13 H Et Bu 544 O 13 H Pr Pr 545 O 13 H Pr iPr 546 O 13 H Pr Bu 547 O 13 H iPr iPr 548 O 13 H iPr Bu 549 O 13 H Bu Bu 550 O 13 HH CH _Two CH _Two OH 551 O 1 3 H Me CH _Two CH _Two OH 552 O 13 H Et CH _Two CH _Two OH 553 O 13 H Pr CH _Two CH _Two OH 554 O 1 3 H iPr CH _Two CH _Two OH 555 O 1 3 HH CH (CH _Three ) CH _Two OH 556 O 1 3 HH CH (CH _Two OH) CH _Two OH 557 O 1 3 HH CH (CH _Two CH _Three ) CH _Two OH 558 O 1 3 HH CH (CH (CH _Three ) _Two ) CH _Two OH 559 O 1 3 HH CH _Two CH _Two NH _Two 560 O 1 3 HH CH (CH _Three ) CH _Two NH _Two 561 O 1 3 HH CH (CH _Two CH _Three ) CH _Two NH _Two 562 O 1 3 HH CH (CH (CH _Three ) _Two ) CH _Two NH _Two 563 O 1 3 HH CH _Two COOH 564 O 1 3 HH CH (CH _Three ) COOH 565 O 1 3 HH CH (CH _Two OH) COOH 566 O 1 3 HH CH (CH _Two CH _Three ) COOH 567 O 1 3 HH CH (CH (CH _Three ) _Two ) COOH 568 O 1 3 HH CH _Two CONH _Two 569 O 1 3 HH CH (CH _Three ) CONH _Two 570 O 1 3 HH CH (CH _Two OH) CONH _Two 571 O 1 3 HH CH (CH _Two CH _Three ) CONH _Two 572 O 1 3 HH CH (CH (CH _Three ) _Two ) CONH _Two 573 O 13 HH cPr 574 O 13 HH cBu 575 O 13 HH cPen 576 O 13 HH cHex 577 O 13 HH 3-Azt 578 O 13 HH 3-Pyr 579 O 13 HH 3-Pip 580 O 1 3 HH 4-Pip 581 O 13 HH 2-COOH-Ph 582 O 13 HH 2-CONH _Two -Ph 583 O 13 HH 3-COOH-Ph 584 O 13 HH 3-CONH _Two -Ph 585 O 1 3 HH 4-COOH-Ph 586 O 1 3 HH 4-CONH _Two -Ph 587 O 1 3 H -CH _Two CH _Two CH _Two -588 O 1 3 H -CH _Two CH _Two CH _Two CH _Two -589 O 1 3 H -CH _Two CH _Two CH _Two CH _Two CH _Two -590 O 1 3 H -CH _Two CH _Two OCH _Two CH _Two -591 O 1 3 H -CH _Two CH _Two SCH _Two CH _Two -592 O 1 3 H -CH _Two CH _Two NHCH _Two CH _Two -593 O 1 3 H -CH _Two CH (OH) CH _Two -594 O 1 3 H -CH _Two CH (OH) CH _Two CH _Two -595 O 1 3 H -CH _Two CH (OH) CH _Two CH _Two CH _Two -596 O 1 3 H -CH _Two CH _Two CH (OH) CH _Two CH _Two -597 O 1 3 H -CH (COOH) CH _Two CH _Two -598 O 1 3 H -CH (CONH _Two ) CH _Two CH _Two -599 O 1 3 H -CH (CH _Two OH) CH _Two CH _Two -600 O 1 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two -601 O 1 3 H -CH (COOH) CH _Two CH _Two CH _Two -602 O 1 3 H -CH (CONH _Two ) CH _Two CH _Two CH _Two -603 O 1 3 H -CH (CH _Two OH) CH _Two CH _Two CH _Two -604 O 1 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -605 O 1 3 H -CH (COOH) CH _Two CH _Two CH _Two CH _Two -606 O 1 3 H -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -607 O 1 3 H -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -608 O 1 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -609 O 1 3 H -CH _Two CH (COOH) CH _Two CH _Two CH _Two -610 O 1 3 H -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -611 O 1 3 H -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -612 O 1 3 H -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -613 O 1 3 H -CH _Two CH _Two CH (COOH) CH _Two CH _Two -614 O 1 3 H -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -615 O 1 3 H -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -616 O 1 3 H -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -617 O 1 3 Me HH 618 O 1 3 Me H Me 619 O 1 3 Me H Et 620 O 1 3 Me H Pr 621 O 1 3 Me H iPr 622 O 1 3 Me H Bu 623 O 1 3 Me Me Me 624 O 13 Me Me Et 625 O 13 Me Me Pr 626 O 13 Me Me iPr 627 O 13 Me Me Bu 628 O 13 Me Et Et 629 O 13 Me Et Pr 630 O 13 Me Et iPr 631 O 1 3 Me Et Bu 632 O 13 Me Pr Pr 633 O 13 Me Pr iPr 634 O 13 Me Pr Bu 635 O 13 Me iPr iPr 636 O 13 Me iPr Bu 637 O 13 Me Bu Bu 638 O 1 3 Me H CH _Two CH _Two OH 639 O 13 Me Me CH _Two CH _Two OH 640 O 1 3 Me Et CH _Two CH _Two OH 641 O 13 Me Pr CH _Two CH _Two OH 642 O 1 3 Me iPr CH _Two CH _Two OH 643 O 13 Me H CH (CH _Three ) CH _Two OH 644 O 1 3 Me H CH (CH _Two OH) CH _Two OH 645 O 1 3 Me H CH (CH _Two CH _Three ) CH _Two OH 646 O 1 3 Me H CH (CH (CH _Three ) _Two ) CH _Two OH 647 O 1 3 Me H CH _Two CH _Two NH _Two 648 O 1 3 Me H CH (CH _Three ) CH _Two NH _Two 649 O 1 3 Me H CH (CH _Two CH _Three ) CH _Two NH _Two 650 O 1 3 Me H CH (CH (CH _Three ) _Two ) CH _Two NH _Two 651 O 1 3 Me H CH _Two COOH 652 O 1 3 Me H CH (CH _Three ) COOH 653 O 13 Me H CH (CH _Two OH) COOH 654 O 1 3 Me H CH (CH _Two CH _Three ) COOH 655 O 1 3 Me H CH (CH (CH _Three ) _Two ) COOH 656 O 1 3 Me H CH _Two CONH _Two 657 O 1 3 Me H CH (CH _Three ) CONH _Two 658 O 1 3 Me H CH (CH _Two OH) CONH _Two 659 O 1 3 Me H CH (CH _Two CH _Three ) CONH _Two 660 O 1 3 Me H CH (CH (CH _Three ) _Two ) CONH _Two 661 O 13 Me H cPr 662 O 13 Me H cBu 663 O 13 Me H cPen 664 O 13 Me H cHex 665 O 13 Me H 3-Azt 666 O 1 3 Me H 3-Pyr 667 O 13 Me H 3-Pip 668 O 13 Me H 4-Pip 669 O 13 Me H 2-COOH-Ph 670 O 13 Me H 2-CONH _Two -Ph 671 O 13 Me H 3-COOH-Ph 672 O 13 Me H 3-CONH _Two -Ph 673 O 1 3 Me H 4-COOH-Ph 674 O 1 3 Me H 4-CONH _Two -Ph 675 O 1 3 Me -CH _Two CH _Two CH _Two -676 O 1 3 Me -CH _Two CH _Two CH _Two CH _Two -677 O 1 3 Me -CH _Two CH _Two CH _Two CH _Two CH _Two -678 O 1 3 Me -CH _Two CH _Two OCH _Two CH _Two -679 O 1 3 Me -CH _Two CH _Two SCH _Two CH _Two -680 O 1 3 Me -CH _Two CH _Two NHCH _Two CH _Two -681 O 1 3 Me -CH _Two CH (OH) CH _Two -682 O 1 3 Me -CH _Two CH (OH) CH _Two CH _Two -683 O 1 3 Me -CH _Two CH (OH) CH _Two CH _Two CH _Two -684 O 1 3 Me -CH _Two CH _Two CH (OH) CH _Two CH _Two -685 O 13 Me -CH (COOH) CH _Two CH _Two -686 O 1 3 Me -CH (CONH _Two ) CH _Two CH _Two -687 O 1 3 Me -CH (CH _Two OH) CH _Two CH _Two -688 O 1 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two -689 O 1 3 Me -CH (COOH) CH _Two CH _Two CH _Two -690 O 1 3 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two -691 O 1 3 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two -692 O 1 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -693 O 13 Me -CH (COOH) CH _Two CH _Two CH _Two CH _Two -694 O 1 3 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -695 O 1 3 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -696 O 1 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -697 O 1 3 Me -CH _Two CH (COOH) CH _Two CH _Two CH _Two -698 O 1 3 Me -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -699 O 1 3 Me -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -700 O 1 3 Me -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -701 O 1 3 Me -CH _Two CH _Two CH (COOH) CH _Two CH _Two -702 O 1 3 Me -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -703 O 1 3 Me -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -704 O 1 3 Me -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -705 O 2 3 HHH 706 O 2 3 HH Me 707 O 2 3 HH Et 708 O 2 3 HH Pr 709 O 2 3 HH iPr 710 O 2 3 HH Bu 711 O 2 3 H Me Me 712 O 2 3 H Me Et 713 O 2 3 H Me Pr 714 O 2 3 H Me iPr 715 O 2 3 H Me Bu 716 O 2 3 H Et Et 717 O 2 3 H Et Pr 718 O 2 3 H Et iPr 719 O 23 H Et Bu 720 O 2 3 H Pr Pr 721 O 23 H Pr iPr 722 O 23 H Pr Bu 723 O 23 H iPr iPr 724 O 23 H iPr Bu 725 O 23 H Bu Bu 726 O 23 HH CH _Two CH _Two OH 727 O 2 3 H Me CH _Two CH _Two OH 728 O 2 3 H Et CH _Two CH _Two OH 729 O 23 H Pr CH _Two CH _Two OH 730 O 2 3 H iPr CH _Two CH _Two OH 731 O 2 3 HH CH (CH _Three ) CH _Two OH 732 O 2 3 HH CH (CH _Two OH) CH _Two OH 733 O 2 3 HH CH (CH _Two CH _Three ) CH _Two OH 734 O 2 3 HH CH (CH (CH _Three ) _Two ) CH _Two OH 735 O 2 3 HH CH _Two CH _Two NH _Two 736 O 2 3 HH CH (CH _Three ) CH _Two NH _Two 737 O 2 3 HH CH (CH _Two CH _Three ) CH _Two NH _Two 738 O 2 3 HH CH (CH (CH _Three ) _Two ) CH _Two NH _Two 739 O 2 3 HH CH _Two COOH 740 O 2 3 HH CH (CH _Three ) COOH 741 O 2 3 HH CH (CH _Two OH) COOH 742 O 2 3 HH CH (CH _Two CH _Three ) COOH 743 O 2 3 HH CH (CH (CH _Three ) _Two ) COOH 744 O 2 3 HH CH _Two CONH _Two 745 O 2 3 HH CH (CH _Three ) CONH _Two 746 O 2 3 HH CH (CH _Two OH) CONH _Two 747 O 23 HH CH (CH _Two CH _Three ) CONH _Two 748 O 2 3 HH CH (CH (CH _Three ) _Two ) CONH _Two 749 O 23 HH cPr 750 O 23 HH cBu 751 O 23 HH cPen 752 O 23 HH cHex 753 O 23 HH 3-Azt 754 O 23 HH 3-Pyr 755 O 23 HH 3-Pip 756 O 2 3 HH 4-Pip 757 O 2 3 HH 2-COOH-Ph 758 O 2 3 HH 2-CONH _Two -Ph 759 O 2 3 HH 3-COOH-Ph 760 O 2 3 HH 3-CONH _Two -Ph 761 O 2 3 HH 4-COOH-Ph 762 O 2 3 HH 4-CONH _Two -Ph 763 O 23 H -CH _Two CH _Two CH _Two -764 O 2 3 H -CH _Two CH _Two CH _Two CH _Two -765 O 2 3 H -CH _Two CH _Two CH _Two CH _Two CH _Two -766 O 2 3 H -CH _Two CH _Two OCH _Two CH _Two -767 O 2 3 H -CH _Two CH _Two SCH _Two CH _Two -768 O 2 3 H -CH _Two CH _Two NHCH _Two CH _Two -769 O 2 3 H -CH _Two CH (OH) CH _Two -770 O 2 3 H -CH _Two CH (OH) CH _Two CH _Two -771 O 2 3 H -CH _Two CH (OH) CH _Two CH _Two CH _Two -772 O 2 3 H -CH _Two CH _Two CH (OH) CH _Two CH _Two -773 O 2 3 H -CH (COOH) CH _Two CH _Two -774 O 2 3 H -CH (CONH _Two ) CH _Two CH _Two -775 O 2 3 H -CH (CH _Two OH) CH _Two CH _Two -776 O 2 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two -777 O 2 3 H -CH (COOH) CH _Two CH _Two CH _Two -778 O 2 3 H -CH (CONH _Two ) CH _Two CH _Two CH _Two -779 O 2 3 H -CH (CH _Two OH) CH _Two CH _Two CH _Two -780 O 2 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -781 O 2 3 H -CH (COOH) CH _Two CH _Two CH _Two CH _Two -782 O 2 3 H -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -783 O 2 3 H -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -784 O 2 3 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -785 O 2 3 H -CH _Two CH (COOH) CH _Two CH _Two CH _Two -786 O 2 3 H -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -787 O 2 3 H -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -788 O 2 3 H -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -789 O 2 3 H -CH _Two CH _Two CH (COOH) CH _Two CH _Two -790 O 2 3 H -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -791 O 2 3 H -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -792 O 2 3 H -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -793 O 2 3 Me HH 794 O 2 3 Me H Me 795 O 2 3 Me H Et 796 O 2 3 Me H Pr 797 O 2 3 Me H iPr 798 O 2 3 Me H Bu 799 O 2 3 Me Me Me 800 O 2 3 Me Me Et 801 O 2 3 Me Me Pr 802 O 2 3 Me Me iPr 803 O 2 3 Me Me Bu 804 O 2 3 Me Et Et 805 O 2 3 Me Et Pr 806 O 2 3 Me Et iPr 807 O 2 3 Me Et Bu 808 O 2 3 Me Pr Pr 809 O 2 3 Me Pr iPr 810 O 2 3 Me Pr Bu 811 O 2 3 Me iPr iPr 812 O 2 3 Me iPr Bu 813 O 2 3 Me Bu Bu 814 O 2 3 Me H CH _Two CH _Two OH 815 O 2 3 Me Me CH _Two CH _Two OH 816 O 2 3 Me Et CH _Two CH _Two OH 817 O 2 3 Me Pr CH _Two CH _Two OH 818 O 2 3 Me iPr CH _Two CH _Two OH 819 O 2 3 Me H CH (CH _Three ) CH _Two OH 820 O 2 3 Me H CH (CH _Two OH) CH _Two OH 821 O 2 3 Me H CH (CH _Two CH _Three ) CH _Two OH 822 O 2 3 Me H CH (CH (CH _Three ) _Two ) CH _Two OH 823 O 2 3 Me H CH _Two CH _Two NH _Two 824 O 2 3 Me H CH (CH _Three ) CH _Two NH _Two 825 O 2 3 Me H CH (CH _Two CH _Three ) CH _Two NH _Two 826 O 2 3 Me H CH (CH (CH _Three ) _Two ) CH _Two NH _Two 827 O 2 3 Me H CH _Two COOH 828 O 2 3 Me H CH (CH _Three ) COOH 829 O 2 3 Me H CH (CH _Two OH) COOH 830 O 2 3 Me H CH (CH _Two CH _Three ) COOH 831 O 2 3 Me H CH (CH (CH _Three ) _Two ) COOH 832 O 2 3 Me H CH _Two CONH _Two 833 O 2 3 Me H CH (CH _Three ) CONH _Two 834 O 2 3 Me H CH (CH _Two OH) CONH _Two 835 O 2 3 Me H CH (CH _Two CH _Three ) CONH _Two 836 O 2 3 Me H CH (CH (CH _Three ) _Two ) CONH _Two 837 O 2 3 Me H cPr 838 O 2 3 Me H cBu 839 O 2 3 Me H cPen 840 O 2 3 Me H cHex 841 O 2 3 Me H 3-Azt 842 O 2 3 Me H 3-Pyr 843 O 2 3 Me H 3-Pip 844 O 2 3 Me H 4-Pip 845 O 2 3 Me H 2-COOH-Ph 846 O 2 3 Me H 2-CONH _Two -Ph 847 O 2 3 Me H 3-COOH-Ph 848 O 2 3 Me H 3-CONH _Two -Ph 849 O 2 3 Me H 4-COOH-Ph 850 O 2 3 Me H 4-CONH _Two -Ph 851 O 2 3 Me -CH _Two CH _Two CH _Two -852 O 2 3 Me -CH _Two CH _Two CH _Two CH _Two -853 O 2 3 Me -CH _Two CH _Two CH _Two CH _Two CH _Two -854 O 2 3 Me -CH _Two CH _Two OCH _Two CH _Two -855 O 2 3 Me -CH _Two CH _Two SCH _Two CH _Two -856 O 2 3 Me -CH _Two CH _Two NHCH _Two CH _Two -857 O 2 3 Me -CH _Two CH (OH) CH _Two -858 O 2 3 Me -CH _Two CH (OH) CH _Two CH _Two -859 O 2 3 Me -CH _Two CH (OH) CH _Two CH _Two CH _Two -860 O 2 3 Me -CH _Two CH _Two CH (OH) CH _Two CH _Two -861 O 2 3 Me -CH (COOH) CH _Two CH _Two -862 O 2 3 Me -CH (CONH _Two ) CH _Two CH _Two -863 O 2 3 Me -CH (CH _Two OH) CH _Two CH _Two -864 O 2 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two -865 O 2 3 Me -CH (COOH) CH _Two CH _Two CH _Two -866 O 2 3 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two -867 O 2 3 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two -868 O 2 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -869 O 2 3 Me -CH (COOH) CH _Two CH _Two CH _Two CH _Two -870 O 2 3 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -871 O 2 3 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -872 O 2 3 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -873 O 2 3 Me -CH _Two CH (COOH) CH _Two CH _Two CH _Two -874 O 2 3 Me -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -875 O 2 3 Me -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -876 O 2 3 Me -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -877 O 2 3 Me -CH _Two CH _Two CH (COOH) CH _Two CH _Two -878 O 2 3 Me -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -879 O 2 3 Me -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -880 O 2 3 Me -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -881 O 3 4 HHH 882 O 3 4 HH Me 883 O 3 4 HH Et 884 O 34 HH Pr 885 O 34 HH iPr 886 O 34 HH Bu 887 O 34 H Me Me 888 O 34 H Me Et 889 O 34 H Me Pr 890 O 34 H Me iPr 891 O 34 H Me Bu 892 O 34 H Et Et 893 O 34 H Et Pr 894 O 34 H Et iPr 895 O 34 H Et Bu 896 O 3 4 H Pr Pr 897 O 34 H Pr iPr 898 O 34 H Pr Bu 899 O 34 H iPr iPr 900 O 34 H iPr Bu 901 O 34 H Bu Bu 902 O 34 HH CH _Two CH _Two OH 903 O 3 4 H Me CH _Two CH _Two OH 904 O 3 4 H Et CH _Two CH _Two OH 905 O 34 H Pr CH _Two CH _Two OH 906 O 3 4 H iPr CH _Two CH _Two OH 907 O 3 4 HH CH (CH _Three ) CH _Two OH 908 O 3 4 HH CH (CH _Two OH) CH _Two OH 909 O 3 4 HH CH (CH _Two CH _Three ) CH _Two OH 910 O 3 4 HH CH (CH (CH _Three ) _Two ) CH _Two OH 911 O 3 4 HH CH _Two CH _Two NH _Two 912 O 3 4 HH CH (CH _Three ) CH _Two NH _Two 913 O 3 4 HH CH (CH _Two CH _Three ) CH _Two NH _Two 914 O 3 4 HH CH (CH (CH _Three ) _Two ) CH _Two NH _Two 915 O 3 4 HH CH _Two COOH 916 O 3 4 HH CH (CH _Three ) COOH 917 O 3 4 HH CH (CH _Two OH) COOH 918 O 3 4 HH CH (CH _Two CH _Three ) COOH 919 O 3 4 HH CH (CH (CH _Three ) _Two ) COOH 920 O 3 4 HH CH _Two CONH _Two 921 O 3 4 HH CH (CH _Three ) CONH _Two 922 O 3 4 HH CH (CH _Two OH) CONH _Two 923 O 3 4 HH CH (CH _Two CH _Three ) CONH _Two 924 O 3 4 HH CH (CH (CH _Three ) _Two ) CONH _Two 925 O 3 4HH cPr 926 O 34 HH cBu 927 O 34 HH cPen 928 O 34 HH cHex 929 O 34 HH 3-Azt 930 O 34 HH 3-Pyr 931 O 34 HH 3-Pip 932 O 3 4 HH 4-Pip 933 O 3 4 HH 2-COOH-Ph 934 O 3 4 HH 2-CONH _Two -Ph 935 O 3 4 HH 3-COOH-Ph 936 O 3 4 HH 3-CONH _Two -Ph 937 O 3 4 HH 4-COOH-Ph 938 O 3 4 HH 4-CONH _Two -Ph 939 O 3 4 H -CH _Two CH _Two CH _Two -940 O 3 4 H -CH _Two CH _Two CH _Two CH _Two -941 O 3 4 H -CH _Two CH _Two CH _Two CH _Two CH _Two -942 O 3 4 H -CH _Two CH _Two OCH _Two CH _Two -943 O 3 4 H -CH _Two CH _Two SCH _Two CH _Two -944 O 3 4 H -CH _Two CH _Two NHCH _Two CH _Two -945 O 3 4 H -CH _Two CH (OH) CH _Two -946 O 3 4 H -CH _Two CH (OH) CH _Two CH _Two -947 O 3 4 H -CH _Two CH (OH) CH _Two CH _Two CH _Two -948 O 3 4 H -CH _Two CH _Two CH (OH) CH _Two CH _Two -949 O 3 4 H -CH (COOH) CH _Two CH _Two -950 O 3 4 H -CH (CONH _Two ) CH _Two CH _Two -951 O 3 4 H -CH (CH _Two OH) CH _Two CH _Two -952 O 3 4 H -CH (CH _Two NH _Two ) CH _Two CH _Two -953 O 3 4 H -CH (COOH) CH _Two CH _Two CH _Two -954 O 3 4 H -CH (CONH _Two ) CH _Two CH _Two CH _Two -955 O 3 4 H -CH (CH _Two OH) CH _Two CH _Two CH _Two -956 O 3 4 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -957 O 3 4 H -CH (COOH) CH _Two CH _Two CH _Two CH _Two -958 O 3 4 H -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -959 O 3 4 H -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -960 O 3 4 H -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -961 O 3 4 H -CH _Two CH (COOH) CH _Two CH _Two CH _Two -962 O 3 4 H -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -963 O 3 4 H -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -964 O 3 4 H -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -965 O 3 4 H -CH _Two CH _Two CH (COOH) CH _Two CH _Two -966 O 3 4 H -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -967 O 3 4 H -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -968 O 3 4 H -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -969 O 3 4 Me HH 970 O 3 4 Me H Me 971 O 3 4 Me H Et 972 O 34 Me H Pr 973 O 34 Me H iPr 974 O 34 MeH Bu 975 O 34 Me Me 976 O 3 4 Me Me Et 977 O 3 4 Me Me Pr 978 O 3 4 Me Me iPr 979 O 3 4 Me Me Bu 980 O 3 4 Me Et Et 981 O 3 4 Me Et Pr 982 O 3 4 Me Et iPr 983 O 3 4 Me Et Bu 984 O 3 4 Me Pr Pr 985 O 3 4 Me Pr iPr 986 O 3 4 Me Pr Bu 987 O 3 4 Me iPr iPr 988 O 3 4 Me iPr Bu 989 O 3 4 Me Bu Bu 990 O 3 4 Me H CH _Two CH _Two OH 991 O 3 4 Me Me CH _Two CH _Two OH 992 O 3 4 Me Et CH _Two CH _Two OH 993 O 3 4 Me Pr CH _Two CH _Two OH 994 O 3 4 Me iPr CH _Two CH _Two OH 995 O 3 4 Me H CH (CH _Three ) CH _Two OH 996 O 3 4 Me H CH (CH _Two OH) CH _Two OH 997 O 3 4 Me H CH (CH _Two CH _Three ) CH _Two OH 998 O 3 4 Me H CH (CH (CH _Three ) _Two ) CH _Two OH 999 O 3 4 Me H CH _Two CH _Two NH _Two 1000 O 3 4 Me H CH (CH _Three ) CH _Two NH _Two 1001 O 3 4 Me H CH (CH _Two CH _Three ) CH _Two NH _Two 1002 O 3 4 Me H CH (CH (CH _Three ) _Two ) CH _Two NH _Two 1003 O 3 4 Me H CH _Two COOH 1004 O 34 Me H CH (CH _Three ) COOH 1005 O 3 4 Me H CH (CH _Two OH) COOH 1006 O 3 4 Me H CH (CH _Two CH _Three ) COOH 1007 O 3 4 Me H CH (CH (CH _Three ) _Two ) COOH 1008 O 3 4 Me H CH _Two CONH _Two 1009 O 3 4 Me H CH (CH _Three ) CONH _Two 1010 O 3 4 Me H CH (CH _Two OH) CONH _Two 1011 O 3 4 Me H CH (CH _Two CH _Three ) CONH _Two 1012 O 3 4 Me H CH (CH (CH _Three ) _Two ) CONH _Two 1013 O 3 4 Me H cPr 1014 O 3 4 Me H cBu 1015 O 3 4 Me H cPen 1016 O 3 4 Me H cHex 1017 O 3 4 Me H 3-Azt 1018 O 3 4 Me H 3-Pyr 1019 O 3 4 Me H 3-Pip 1020 O 3 4 Me H 4-Pip 1021 O 3 4 Me H 2-COOH-Ph 1022 O 3 4 Me H 2-CONH _Two -Ph 1023 O 3 4 Me H 3-COOH-Ph 1024 O 3 4 Me H 3-CONH _Two -Ph 1025 O 3 4 Me H 4-COOH-Ph 1026 O 3 4 Me H 4-CONH _Two -Ph 1027 O 3 4 Me -CH _Two CH _Two CH _Two -1028 O 3 4 Me -CH _Two CH _Two CH _Two CH _Two -1029 O 3 4 Me -CH _Two CH _Two CH _Two CH _Two CH _Two -1030 O 3 4 Me -CH _Two CH _Two OCH _Two CH _Two -1031 O 3 4 Me -CH _Two CH _Two SCH _Two CH _Two -1032 O 3 4 Me -CH _Two CH _Two NHCH _Two CH _Two -1033 O 3 4 Me -CH _Two CH (OH) CH _Two -1034 O 3 4 Me -CH _Two CH (OH) CH _Two CH _Two -1035 O 3 4 Me -CH _Two CH (OH) CH _Two CH _Two CH _Two -1036 O 3 4 Me -CH _Two CH _Two CH (OH) CH _Two CH _Two -1037 O 3 4 Me -CH (COOH) CH _Two CH _Two -1038 O 3 4 Me -CH (CONH _Two ) CH _Two CH _Two -1039 O 3 4 Me -CH (CH _Two OH) CH _Two CH _Two -1040 O 3 4 Me -CH (CH _Two NH _Two ) CH _Two CH _Two -1041 O 3 4 Me -CH (COOH) CH _Two CH _Two CH _Two -1042 O 3 4 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two -1043 O 3 4 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two -1044 O 3 4 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -1045 O 3 4 Me -CH (COOH) CH _Two CH _Two CH _Two CH _Two -1046 O 3 4 Me -CH (CONH _Two ) CH _Two CH _Two CH _Two CH _Two -1047 O 3 4 Me -CH (CH _Two OH) CH _Two CH _Two CH _Two CH _Two -1048 O 3 4 Me -CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two CH _Two -1049 O 3 4 Me -CH _Two CH (COOH) CH _Two CH _Two CH _Two -1050 O 3 4 Me -CH _Two CH (CONH _Two ) CH _Two CH _Two CH _Two -1051 O 3 4 Me -CH _Two CH (CH _Two OH) CH _Two CH _Two CH _Two -1052 O 3 4 Me -CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two CH _Two -1053 O 3 4 Me -CH _Two CH _Two CH (COOH) CH _Two CH _Two -1054 O 3 4 Me -CH _Two CH _Two CH (CONH _Two ) CH _Two CH _Two -1055 O 3 4 Me -CH _Two CH _Two CH (CH _Two OH) CH _Two CH _Two -1056 O 3 4 Me -CH _Two CH _Two CH (CH _Two NH _Two ) CH _Two CH _Two -1057 S 1 3 HH CH (CH _Two (CH _Three ) _Two ) CH _Two OH 1058 S 1 3 HH CH (CH _Two (CH _Three ) _Two ) CH _Two NH _Two 1059 S 1 3 HH CH (CH _Two (CH _Three ) _Two ) COOH 1060 S 1 3 HH CH (CH _Two (CH _Three ) _Two ) CONH _Two 1061 S 1 3 HH CH (CH _Two OH) CH _Two NH _Two 1062 S 1 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two OH 1063 S 1 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two NH _Two 1064 S 1 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) COOH 1065 S 1 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CONH _Two 1066 S 1 3 H Me CH _Two CH _Two NH _Two 1067 S 1 3 H Me CH _Two COOH 1068 S 1 3 H Me CH _Two CONH _Two 1069 S 1 3 H iPr CH _Two CH _Two NH _Two 1070 S 1 3 H iPr CH _Two COOH 1071 S 1 3 H iPr CH _Two CONH _Two 1072 S 1 3 H CH _Two CH (NH _Two ) CH _Two 1073 S 1 3 H CH _Two CH (OCH _Three ) CH _Two 1074 S 1 3 H CH _Two CH (NCH _Three ) CH _Two CH _Two 1075 S2 3 HH CH (CH _Two (CH _Three ) _Two ) CH _Two OH 1076 S 2 3 HH CH (CH _Two (CH _Three ) _Two ) CH _Two NH _Two 1077 S2 3 HH CH (CH _Two (CH _Three ) _Two ) COOH 1078 S2 3 HH CH (CH _Two (CH _Three ) _Two ) CONH _Two 1079 S 2 3 HH CH (CH _Two OH) CH _Two NH _Two 1080 S 2 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two OH 1081 S 2 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two NH _Two 1082 S 2 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) COOH 1083 S 2 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CONH _Two 1084 S 2 3 H Me CH _Two CH _Two NH _Two 1085 S 2 3 H Me CH _Two COOH 1086 S 2 3 H Me CH _Two CONH _Two 1087 S 2 3 H iPr CH _Two CH _Two NH _Two 1088 S 2 3 H iPr CH _Two COOH 1089 S 2 3 H iPr CH _Two CONH _Two 1090 S2 3 H CH _Two CH (NH _Two ) CH _Two 1091 S 2 3 H CH _Two CH (OCH _Three ) CH _Two 1092 S 2 3 H CH _Two CH (NCH _Three ) CH _Two CH _Two 1093 S 3 4 HH CH (CH _Two (CH _Three ) _Two ) CH _Two OH 1094 S 3 4 HH CH (CH _Two (CH _Three ) _Two ) CH _Two NH _Two 1095 S 3 4 HH CH (CH _Two (CH _Three ) _Two ) COOH 1096 S 3 4 HH CH (CH _Two (CH _Three ) _Two ) CONH _Two 1097 S 3 4 HH CH (CH _Two OH) CH _Two NH _Two 1098 S 3 4 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two OH 1099 S 3 4 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two NH _Two 1100 S 3 4 HH CH (CH (CH _Three ) CH _Two CH _Three ) COOH 1101 S 3 4 HH CH (CH (CH _Three ) CH _Two CH _Three ) CONH _Two 1102 S 3 4 H Me CH _Two CH _Two NH _Two 1103 S 3 4 H Me CH _Two COOH 1104 S 3 4 H Me CH _Two CONH _Two 1105 S 3 4 H iPr CH _Two CH _Two NH _Two 1106 S 3 4 H iPr CH _Two COOH 1107 S 3 4 H iPr CH _Two CONH _Two 1108 S 3 4 H CH _Two CH (NH _Two ) CH _Two 1109 S 3 4 H CH _Two CH (OCH _Three ) CH _Two 1110 S 3 4 H CH _Two CH (NCH _Three ) CH _Two CH _Two 1111 O 1 3 HH CH (CH _Two (CH _Three ) _Two ) CH _Two OH 1112 O 1 3 HH CH (CH _Two (CH _Three ) _Two ) CH _Two NH _Two 1113 O 1 3 HH CH (CH _Two (CH _Three ) _Two ) COOH 1114 O 1 3 HH CH (CH _Two (CH _Three ) _Two ) CONH _Two 1115 O 1 3 HH CH (CH _Two OH) CH _Two NH _Two 1116 O 1 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two OH 1117 O 1 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two NH _Two 1118 O 1 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) COOH 1119 O 1 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CONH _Two 1120 O 1 3 H Me CH _Two CH _Two NH _Two 1121 O 1 3 H Me CH _Two COOH 1122 O 1 3 H Me CH _Two CONH _Two 1123 O 1 3 H iPr CH _Two CH _Two NH _Two 1124 O 1 3 H iPr CH _Two COOH 1125 O 1 3 H iPr CH _Two CONH _Two 1126 O 1 3 H CH _Two CH (NH _Two ) CH _Two 1127 O 1 3 H CH _Two CH (OCH _Three ) CH _Two 1128 O 1 3 H CH _Two CH (NCH _Three ) CH _Two CH _Two 1129 O 2 3 HH CH (CH _Two (CH _Three ) _Two ) CH _Two OH 1130 O 2 3 HH CH (CH _Two (CH _Three ) _Two ) CH _Two NH _Two 1131 O 2 3 HH CH (CH _Two (CH _Three ) _Two ) COOH 1132 O 2 3 HH CH (CH _Two (CH _Three ) _Two ) CONH _Two 1133 O 2 3 HH CH (CH _Two OH) CH _Two NH _Two 1134 O 2 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two OH 1135 O 2 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two NH _Two 1136 O 2 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) COOH 1137 O 2 3 HH CH (CH (CH _Three ) CH _Two CH _Three ) CONH _Two 1138 O 2 3 H Me CH _Two CH _Two NH _Two 1139 O 2 3 H Me CH _Two COOH 1140 O 2 3 H Me CH _Two CONH _Two 1141 O 2 3 H iPr CH _Two CH _Two NH _Two 1142 O 2 3 H iPr CH _Two COOH 1143 O 2 3 H iPr CH _Two CONH _Two 1144 O 2 3 H CH _Two CH (NH _Two ) CH _Two 1145 O 23 H CH _Two CH (OCH _Three ) CH _Two 1146 O 2 3 H CH _Two CH (NCH _Three ) CH _Two CH _Two 1147 O 3 4 HH CH (CH _Two (CH _Three ) _Two ) CH _Two OH 1148 O 3 4 HH CH (CH _Two (CH _Three ) _Two ) CH _Two NH _Two 1149 O 3 4 HH CH (CH _Two (CH _Three ) _Two ) COOH 1150 O 3 4 HH CH (CH _Two (CH _Three ) _Two ) CONH _Two 1151 O 3 4 HH CH (CH _Two OH) CH _Two NH _Two 1152 O 3 4 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two OH 1153 O 3 4 HH CH (CH (CH _Three ) CH _Two CH _Three ) CH _Two NH _Two 1154 O 3 4 HH CH (CH (CH _Three ) CH _Two CH _Three ) COOH 1155 O 3 4 HH CH (CH (CH _Three ) CH _Two CH _Three ) CONH _Two 1156 O 3 4 H Me CH _Two CH _Two NH _Two 1157 O 3 4 H Me CH _Two COOH 1158 O 3 4 H Me CH _Two CONH _Two 1159 O 3 4 H iPr CH _Two CH _Two NH _Two 1160 O 3 4 H iPr CH _Two COOH 1161 O 3 4 H iPr CH _Two CONH _Two 1162 O 3 4 H CH _Two CH (NH _Two ) CH _Two 1163 O 3 4 H CH _Two CH (OCH _Three ) CH _Two 1164 O 3 4 H CH _Two CH (NCH _Three ) CH _Two CH _Two -------------------------------------------------- ------------------ [Table 3]

[0042]

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----------------------------------------------- --------------------- Cpd No. X n position R ² --------------------- ----------------------------------------------- 1 S 1 3 H 2 S 1 3 Me 3 S 2 3 H 4 S 2 3 Me 5 S 3 4 H 6 S 3 4 Me 7 O 1 3 H 8 O 1 3 Me 9 O 2 3 H 10 O 2 3 Me 11 O 3 4 H 12 O 3 4 Me ------------------------------------------- ------------------------- [Table 4]

[0044]

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----------------------------------------------- --------------------- Cpd No. X n position R ² R ⁶ ------------------- ------------------------------------------------- 1 S 13 HH 2 S 13 H Me 3 S 13 H Et 4 S 13 H Pr 5 S 13 H iPr 6 S 13 H Bu 7 S 13 H cPr 8 S 13 H cBu 9 S 13 H cPen 10 S 13 H cHex 11 S 13 Me H 12 S 13 Me Me 13 S 13 Me Et 14 S 13 Me Pr 15 S 13 Me iPr 16 S 13 Me Bu 17 S 13 Me cPr 18 S 13 Me cBu 19 S 13 Me cPen 20 S 13 Me cHex 21 S 23 HH 22 S 23 H Me 23 S 23 H Et 24 S 23 H Pr 25 S 23 H iPr 26 S 2 3 H Bu 27 S 2 3 H cPr 28 S 23 H cPen 29 S 23 H cPen 30 S 23 H c Hex 31 S 23 Me H 32 S 23 Me Me 33 S 23 Me Me 34 S 23 Me Pr 35 S 23 Me iPr 36 S 23 Me Bu 37 S 23 Me cPr 38 S 23 Me cBu 39 S 23 Me cPen 40 S 23 Me cHex 41 S 34 HH 42 S 34 H Me 43 S 34 H Et 44 S 34 H Pr45 S 34 H iPr 46 S 34 H Bu 47 S 34 H cPr 48 S 34 H cBu 49 S 34 H cPen 50 S 34 H cHex 51 S 34 Me H 52 S 3 4 Me Me 53 S 3 4 Me Et 54 S 3 4 Me Pr 55 S 3 4 Me iPr 5 6 S 3 4 Me Bu 57 S 3 4 Me cPr 58 S 3 4 Me cBu 59 S 3 4 Me cPen 60 S 3 4 Me cHex 61 O 1 3 HH 62 O 1 3 H Me 63 O 1 3 H Et 64 O 1 3 H Pr 65 O 13 H iPr 66 O 13 H Bu 67 O 13 HcPr 68 O 13 H cBu 69 O 13 H cPen 70 O 13 H cHex 71 O 13 Me H 72 O 13 Me Me 73 O 1 3 Me Et 74 O 1 3 Me Pr 75 O 1 3 Me iPr 76 O 1 3 Me Bu 77 O 1 3 Me cPr 78 O 1 3 Me cBu 79 O 1 3 Me cPen 80 O 1 3 Me cHex 81 O 2 3 HH 82 O 2 3 HMe 83 O 2 3 H Et 84 O 2 3 H Pr 85 O 2 3 H iPr 86 O 2 3 H Bu 87 O 2 3 H cPr 88 O 2 3 H cBu 89 O 2 3 H cPen 90 O 2 3 H cHex 91 O 2 3 Me H 92 O 2 3 Me Me 93 O 2 3 Me Et 94 O 2 3 Me Pr 95 O 2 3 Me iPr 96 O 2 3 Me Bu 97 O 2 3 Me cPr 98 O 2 3 Me cBu 99 O 2 3 Me cPen 100 O 2 3 Me cHex 101 O 3 4 HH 102 O 3 4 H Me 103 O 3 4 H Et 104 O 3 4 H Pr 105 O 3 4 H iPr 106 O 3 4 H Bu 107 O 3 4 H cPr 108 O 34 H cPen 109 O 34 H cPen 110 O 34 H cHex 111 O 34 Me H 112 O 34 Me Me 113 O 34 Me Et 114 O 34 Me Pr 115 O 34 Me iPr 116 O 34 Me Bu 117 O 34 Me cPr 118 O 34 Me cBu 119 O 34 Me c Pen 120 O 34 Me c Hex ------------------------------------------------- ------------------- [Table 5]

[0046]

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----------------------------------------------- --------------------- Cpd No. X n position R ² R ⁷ R ⁸ ----------------- -------------------------------------------------- -1 S 1 3 HHH 2 S 1 3 HH Me 3 S 1 3 HH Et 4 S 1 3 HH COCH ₃ 5 S 1 3 HH COCH ₂ CH ₃ 6 S 1 3 HH COCH ₂ CH ₂ CH ₃ 7 S 1 3 HH COPh 8 S 13 HH COOMe 9 S 13 HH COOEt 10 S 13 H Me Me 11 S 13 H Et Et 12 S 13 H Me COCH ₃ 13 S 13 H Me COPh 14 S 13 H Me COOMe 15 S 13 H Me COOEt 16 S 13 Me HH 17 S 13 Me H Me 18 S 13 Me H Et 19 S 13 Me H COCH ₃ 20 S 13 Me H COCH ₂ CH ₃ 21 S 13 Me H COCH ₂ CH ₂ CH ₃ 22 S 13 Me H COPh 23 S 13 Me H COOMe 24 S 13 Me HCOOEt 25 S 13 Me Me Me 26 S 13 Me Et Et 27 S 13 Me Me COCH ₃ 28 S 1 3 Me Me COPh 29 S 1 3 Me Me COOMe 30 S 1 3 Me Me COOEt 31 S 2 3 HHH 32 S 2 3 HH Me 33 S 2 3 HH Et 34 S 2 3 HH COCH 3 35 S 2 3 HH COCH ₂ CH ₃ 36 S 2 3 HH COCH ₂ CH ₂ CH ₃ 37 S 2 3 HH COPh 38 S 2 3 HH COOMe 39 S 2 3 HH COOEt 40 S 2 3 H Me Me 41 S 2 3 H Et Et 42 S 2 3 H Me COCH ₃ 43 S 2 3 H Me COPh 44 S 2 3 H Me COOMe 45 S 2 3 H Me COOEt 46 S 2 3 Me HH 47 S 2 3 Me H Me 48 S 2 3 Me H Et 49 S 2 3 Me H COCH 3 50 S 2 3 Me H COCH ₂ CH ₃ 51 S 2 3 Me H COCH ₂ CH ₂ CH ₃ 52 S 2 3 Me H COPh 53 S 2 3 Me H COOMe 54 S 2 3 Me H COOEt 55 S 2 3 Me Me Me 56 S 2 3 Me Et Et 57 S 2 3 Me Me COCH ₃ 58 S 2 3 Me Me COPh 59 S 23 Me Me COOMe 60 S 23 Me Me COOEt 61 S 34 HHH 62 S 34 HH Me 63 S 34 HH Et 64 S 3 4 HH COCH ₃ 65 S 3 4 HH COCH ₂ CH ₃ 66 S 3 4 HH COCH ₂ CH ₂ CH ₃ 67 S 3 4 HH COPh 68 S 3 4 HH COOMe 69 S 3 4 HH COOEt 70 S 3 4 H Me Me 71 S 3 4 H Et Et 72 S 3 4 H Me COCH ₃ 73 S 3 4 H Me COPh 74 S 3 4 H Me COOMe 75 S 3 4 H Me COOEt 76 S 3 4 Me HH 77 S 3 4 Me H Me 78 S 3 4 Me H Et 79 S 3 4 Me H COCH 3 80 S 3 4 Me H COCH 2 CH 3 81 S 3 4 Me H COCH 2 CH 2 CH 3 82 S 3 4 Me H COPh 83 S 3 4 Me H COOMe 84 S 3 4 Me H COOEt 85 S 3 4 Me Me Me 86 S 3 4 Me Et Et 87 S 3 4 Me Me COCH ₃ 88 S 3 4 Me Me COPh 89 S 3 4 Me Me COOMe 90 S 3 4 Me Me COOEt 91 O 13 HHH 92 O 13 HH Me 93 O 13 HH Et 94 O 13 HH COCH ₃ 95 O 1 3 HH COCH ₂ CH ₃ 96 O 1 3 HH COCH ₂ CH ₂ CH ₃ 97 O 1 3 HH COPh 98 O 1 3 HH COOMe 99 O 1 3 HH COOEt 100 O 1 3 H Me Me 101 O 1 3 H Et Et 102 O 13 H Me COCH ₃ 103 O 13 H Me COPh 104 O 13 H Me COOMe 105 O 13 H Me COOEt 106 O 13 Me HH 107 O 13 Me H Me 108 O 13 Me H Et 109 O 1 3 Me H COCH ₃ 110 O 1 3 Me H COCH ₂ CH ₃ 111 O 1 3 Me H COCH ₂ CH ₂ CH ₃ 112 O 1 3 Me H COPh 113 O 1 3 Me H COOMe 114 O 1 3 Me H COOEt 115 O 1 3 Me Me Me 116 O 1 3 Me Et Et 117 O 1 3 Me Me COCH ₃ 118 O 1 3 Me Me COPh 119 O 1 3 Me Me COOMe 120 O 1 3 Me Me COOEt 121 O 2 3 HHH 122 O 2 3 HH Me 123 O 2 3 HH Et 124 O 2 3 HH COCH ₃ 125 O 2 3 HH COCH ₂ CH ₃ 126 O 2 3 HH COCH ₂ CH ₂ CH ₃ 127 O 2 3 HH COPh 128 O 2 3 HH COOMe 129 O 2 3 HH COOEt 130 O 2 3 H Me Me 131 O 2 3 H Et Et 132 O 2 3 H Me COCH ₃ 133 O 2 3 H Me COPh 134 O 2 3 H Me COOMe 135 O 2 3 H Me COOEt 136 O 2 3 Me HH 137 O 2 3 Me H Me 138 O 2 3 Me H Et 139 O 2 3 Me H COCH ₃ 140 O 2 3 Me H COCH ₂ CH ₃ 141 O 2 3 Me H COCH ₂ CH ₂ CH ₃ 142 O 2 3 Me H C OPh 143 O 2 3 Me H COOMe 144 O 2 3 Me H COOEt 145 O 2 3 Me Me Me 146 O 2 3 Me Et Et 147 O 2 3 Me Me COCH ₃ 148 O 2 3 Me Me COPh 149 O 2 3 Me Me COOMe 150 O 2 3 Me Me COOEt 151 O 3 4 HHH 152 O 3 4 HH Me 153 O 3 4 HH Et 154 O 3 4 HH COCH ₃ 155 O 3 4 HH COCH ₂ CH ₃ 156 O 3 4 HH COCH ₂ CH ₂ CH ₃ 157 O 3 4 HH COPh 158 O 3 4 HH COOMe 159 O 3 4 HH COOEt 160 O 3 4 H Me Me 161 O 3 4 H Et Et 162 O 3 4 H Me COCH ₃ 163 O 3 4 H Me COPh 164 O 3 4 H Me COOMe 165 O 3 4 H Me COOEt 167 O 3 4 Me HH 168 O 34 Me H Me 169 O 34 Me H Et 170 O 34 Me H COCH ₃ 171 O 34 Me H COCH ₂ CH ₃ 172 O 3 4 Me H COCH ₂ CH ₂ CH ₃ 173 O 3 4 Me H COPh 174 O 3 4 Me H COOMe 175 O 3 4 Me H COOEt 176 O 3 4 Me Me Me 177 O 3 4 Me Et Et 178 O 3 4 Me Me COCH ₃ 179 O 3 4 Me Me COPh 180 O 3 4 Me Me COOMe 181 O 34 4 Me Me COOEt 182 S 13 HH CO-cPr 183 S 13 HH CO-cBu 184 S 13 HH CO- cPen 185 S 13 HH CO-cHex 186 S 13 HH CO-2-thienyl 187 S 13 HH CO-2-furyl 188 S 13 HH CO-2-pyridyl 189 S 13 HH CO-3-pyridyl 190 S 1 3 HH CO-4-pyridyl 191 S 1 3 HH SO ₂ -Ph 192 S 1 3 HH CO-Ph-2-COOH 193 S 1 3 HH CO-Ph-2-CONH ₂ 194 S 1 3 HH CO-Ph-2-CH ₂ OH 195 S 1 3 HH CO-Ph-2-CH ₂ NH ₂ 196 S 13 HH CO-Ph-3-COOH 197 S 13 HH CO-Ph-3-CONH ₂ 198 S 13 HH CO-Ph-3-CH ₂ OH 199 S 1 3 HH CO-Ph-3-CH ₂ NH ₂ 200 S 13 HH CO-Ph-4-COOH 201 S 13 HH CO-Ph-4-CONH ₂ 202 S 13 HH CO-Ph -4-CH ₂ OH 203 S 1 3 HH CO-Ph-4-CH ₂ NH ₂ 204 S 2 3 HH CO-cPr 205 S 2 3 HH CO-cBu 206 S 2 3 HH CO-cPen 207 S 2 3 HH CO-cHex 208 S 23 HH CO-2-thienyl 209 S 23 HH CO-2-furyl 210 S 23 HH CO-2-pyridyl 211 S 23 HH CO-3-pyridyl 212 S 23 HH CO- 4-pyridyl 213 S 2 3 HH SO ₂ -Ph 214 S 23 HH CO-Ph-2-COOH 215 S 23 HH CO-Ph-2-CONH ₂ 216 S 23 HH CO-Ph-2-CH ₂ OH 217 S 23 HH CO-Ph-2-CH ₂ NH ₂ 218 S 23 HH CO-Ph-3-COOH 219 S 23 HH CO-Ph-3-CONH ₂ 220 S 23 HH CO-Ph- 3-CH ₂ OH 221 S 2 3 HH CO-Ph-3-CH ₂ NH ₂ 222 S 2 3 HH CO-Ph-4-COOH 223 S 2 3 HH CO-Ph-4-CONH ₂ 224 S 23 HH CO-Ph-4-CH ₂ OH 225 S 2 3 HH CO-Ph-4-CH ₂ NH ₂ 226 S 3 4 HH CO-cPr 227 S 3 4 HH CO-cBu 228 S 3 4 HH CO-cPen 2 29 S 3 4 HH CO-cHex 230 S 3 4 HH CO-2-thienyl 231 S 34 HH CO-2-furyl 232 S 34 HH CO-2-pyridyl 233 S 34 HH CO-3-pyridyl 234 S 3 4 HH CO-4-pyridyl 235 S 3 4 HH SO ₂ -Ph 236 S 3 4 HH CO-Ph-2-COOH 237 S 3 4 HH CO-Ph-2-CONH ₂ 238 S 3 4 HH CO-Ph -2-CH ₂ OH 239 S 3 4 HH CO-Ph-2-CH ₂ NH ₂ 240 S 3 4 HH CO-Ph-3-COOH 241 S 3 4 HH CO-Ph-3-CONH ₂ 242 S 3 4 HH CO-Ph-3-CH ₂ OH 243 S 3 4 HH CO-Ph-3-CH ₂ NH ₂ 244 S 3 4 HH CO-Ph-4-COOH 245 S 3 4 HH CO-Ph-4-CONH ₂ 246 S 3 4 HH CO-Ph-4-CH ₂ OH 247 S 3 4 HH CO-Ph-4-CH ₂ NH ₂ 248 O 13 HH CO-cPr 249 O 13 HH CO-cBu 250 O 13 HH CO-cPen 251 O 13 HH CO-cHex 252 O 13 HH CO-2-thienyl 253 O 13 HH CO-2-furyl 254 O 13 HH CO-2-pyridyl 255 O 13 HH CO-3- pyridyl 256 O 13 HH CO-4-pyridyl 257 O 13 HH SO ₂ -Ph 258 O 13 HH CO-Ph-2-COOH 259 O 13 HH CO-Ph-2-CONH ₂ 260 O 13 HH CO-Ph-2-CH ₂ OH 261 O 1 3 HH CO-Ph-2-CH ₂ NH ₂ 262 O 1 3 HH CO-Ph-3-COOH 263 O 1 3 HH CO-Ph-3-CONH ₂ 264 O 13 HH CO-Ph-3-CH ₂ OH 265 O 13 HH CO-Ph-3-CH ₂ NH ₂ 266 O 13 HH CO-Ph-4-COOH 26 7 O 13 HH CO-Ph-4-CONH ₂ 268 O 13 HH CO-Ph-4-CH ₂ OH 269 O 13 HH CO-Ph-4-CH ₂ NH ₂ 270 O 23 HH CO-cPr 271 O 23 HH CO-cBu 272 O 23 HH CO-cPen 273 O 23 HH CO-cHex 274 O 23 HH CO-2-thienyl 275 O 23 HH CO-2-furyl 276 O 23 HH CO -2-pyridyl 277 O 2 3 HH CO-3-pyridyl 278 O 2 3 HH CO-4-pyridyl 279 O 2 3 HH SO ₂ -Ph 280 O 2 3 HH CO-Ph-2-COOH 281 O 2 3 HH CO-Ph-2-CONH ₂ 282 O 2 3 HH CO-Ph-2-CH ₂ OH 283 O 2 3 HH CO-Ph-2-CH ₂ NH ₂ 284 O 23 HH CO-Ph-3-COOH 285 O 2 3 HH CO-Ph-3-CONH ₂ 286 O 2 3 HH CO-Ph-3-CH ₂ OH 287 O 2 3 HH CO-Ph-3-CH ₂ NH ₂ 288 O 2 3 HH CO-Ph- 4-COOH 289 O 2 3 HH CO-Ph-4-CONH ₂ 290 O 2 3 HH CO-Ph-4-CH ₂ OH 291 O 2 3 HH CO-Ph-4-CH ₂ NH ₂ 292 O 3 4 HH CO-cPr 293 O 34 HH CO-cBu 294 O 34 HH CO-cPen 295 O 34 HH CO-cHex 296 O 34 HH CO-2-thienyl 297 O 34 HH CO-2-furyl 298 O 3 4 HH CO-2-pyridyl 299 O 3 4 HH CO-3-pyridyl 300 O 34 HH CO-4-pyridyl 301 O 34 HH SO ₂ -Ph 302 O 34 HH CO-Ph-2-COOH 303 O 3 4 HH CO-Ph-2-CONH ₂ 304 O 3 4 HH CO-Ph-2-CH ₂ OH 305 O 3 4 HH CO-Ph-2-CH ₂ NH ₂ 306 O 3 4 HH CO-Ph-3-COOH 307 O 3 4 HH CO-Ph-3-CONH ₂ 308 O 34 HH CO-Ph-3-CH ₂ OH 309 O 34 HH CO-Ph- 3-CH ₂ NH ₂ 310 O 3 4 HH CO-Ph-4-COOH 311 O 3 4 HH CO-Ph-4-CONH ₂ 312 O 3 4 HH CO-Ph-4-CH ₂ OH 313 O 3 4 HH CO-Ph-4-CH ₂ NH ₂ 314 S 1 3 H CO-CH ₂ CH ₂ -CO 315 S 1 3 H CO-1,2-Ph-CO 316 S 2 3 H CO-CH ₂ CH ₂ -CO 317 S 2 3 H CO-1,2-Ph-CO 318 S 3 4 H CO-CH ₂ CH ₂ -CO 319 S 3 4 H CO-1,2-Ph-CO 320 O 1 3 H CO-CH ₂ CH ₂ -CO 321 O 1 3 H CO-1,2-Ph-CO 322 O 2 3 H CO-CH ₂ CH ₂ -CO 323 O 2 3 H CO-1,2-Ph-CO 324 O 3 4 H CO-CH ₂ CH ₂ -CO 325 O 3 4 H CO-1,2-Ph-CO ---------------------------- ---------------------------------------- Of the compounds exemplified in the above table, Table 1: Compound Nos. 1, 2, 3, 13, 14, 15, 2
6, 27, 28, 38, 39, 40, 51, 52, 5
3, 63, 64, 65, 76, 77, 78, 88, 8
9, 90, 101, 102, 103, 113, 114,
115, 126, 127, 128, 138, 139, 1
40 compounds, Table 2: Compound Nos. 1, 2, 7, 22, 26, 31, 3
2, 34, 35, 39, 40, 44, 49, 50, 5,
1, 52, 59, 62, 63, 64, 65, 89, 9
0, 95, 110, 114, 119, 120, 122,
123, 127, 128, 132, 137, 138, 1
39, 140, 147, 150, 151, 152, 15
3, 152, 177, 178, 183, 198, 20
2, 207, 208, 210, 211, 215, 21
6, 220, 225, 226, 227, 228, 23
5, 238, 239, 240, 241, 265, 26
6, 271, 286, 290, 295, 296, 29
8, 299, 303, 304, 308, 313, 31
4, 315, 316, 323, 326, 327, 32
8, 329, 353, 354, 359, 374, 37
8, 383, 384, 386, 387, 391, 39
2,396,401,402,403,404,41
1, 414, 415, 416, 417, 441, 44
2,447,462,466,471,472,47
4, 475, 479, 480, 484, 489, 49
0, 491, 492, 499, 502, 503, 50
4,505,529,530,535,550,55
4, 555, 560, 562, 563, 567, 56
8,572,577,578,579,580,58
7, 590.591, 592, 593, 617, 61
8,623,638,640,647,648,65
0, 651, 655, 656, 660, 665, 66
6, 675, 678, 679, 680, 681, 70
5, 706, 711, 726, 730, 735, 75
3, 754, 755, 756, 763, 766, 76
7,768,769,793,794,799,81
4,818,823,824,826,827,83
1, 832, 836, 841, 851, 854, 85
5,856,857,881,882,887,90
2,906,911,912,914,915,91
9,920,924,929,930,931,93
2,939,942,943,944,945,96
9, 970, 975, 990, 994, 999, 100
0, 1002, 1003, 1007, 1008, 101
2,1017,1018,1019,1020,102
7, 1030, 1031, 1032, 1033, 105
7, 1058, 1059, 1060, 1063, 106
4, 1065, 1066, 1067, 1068, 106
9, 1070, 1071, 1072, 1073, 107
4, 1075, 1076, 1077, 1078, 108
1, 1082, 1083, 1084, 1085, 108
6, 1087, 1088, 1089, 1090, 109
1, 1092, 1093, 1094, 1095, 109
6, 1099, 1100, 1101, 1102, 110
3, 1104, 1105, 1106, 1107, 110
8, 1109, 1110, 1111, 1112, 111
3, 1114, 1117, 1118, 1119, 112
0, 1121, 1122, 1123, 1124, 112
5, 1126, 1127, 1128, 1129, 113
0, 1131, 1132, 1135, 1136, 113
7, 1138, 1139, 1140, 1141, 114
2, 1143, 1144, 1145, 1146, 114
7, 1148, 1149, 1150, 1153, 115
4, 1155, 1156, 1157, 1158, 115
9, 1160, 1161, 1162, 1163, 116
Compound No. 4, Table 3: Compound Nos. 1, 3, 5, 7, 9, 11 Table 4: Compound Nos. 1, 2, 11, 12, 21, 22, 3
1, 32, 41, 42, 51, 52, 61, 62, 7
1, 72, 81, 82, 91, 92, 101, 102,
Compounds 111, 112, and Table 5: Compound Nos. 1, 2, 4, 7, 8, 10, 12, 1
3, 14, 16, 17, 19, 22, 23, 25, 2,
7, 28, 29, 31, 32, 34, 37, 38, 4
0, 42, 43, 44, 46, 47, 49, 52, 5
3, 55, 57, 58, 59, 61, 62, 64, 6
7, 68, 70, 72, 73, 74, 76, 77, 7
9, 82, 83, 85, 87, 88, 89, 91, 9
2,94,97,98,100,102,103,10
4, 106, 107, 109, 112, 113, 11
5, 117, 118, 119, 121, 122, 12
4, 127, 128, 130, 132, 133, 13
4, 136, 137, 139, 142, 143, 14
5, 147, 148, 149, 151, 152, 15
4, 157, 158, 160, 162, 163, 16
4, 167, 168, 170, 173, 174, 17
6, 178, 179, 180, 182, 184, 18
5, 186, 187, 188, 189, 190, 19
1, 192, 193, 194, 195, 196, 19
7, 198, 199, 200, 201, 202, 20
3, 204, 205, 206, 207, 208, 20
9, 210, 211, 212, 213, 214, 21
5, 216, 217, 218, 219, 220, 22
1, 222, 223, 224, 225, 226, 22
7,228,229,230,231,232,23
3, 234, 235, 236, 237, 238, 23
9, 240, 241, 242, 243, 244, 24
5, 246, 247, 248, 249, 250, 25
1, 252, 253, 254, 255, 256, 25
7, 258, 259, 260, 261, 262, 26
3, 264, 265, 266, 267, 268, 26
9, 270, 271, 272, 273, 274, 27
5, 276, 277, 278, 279, 280, 28
1, 282, 283, 284, 285, 286, 28
7,288,289,290,291,292,29
3, 294, 295, 296, 297, 298, 29
9, 300, 301, 302, 303, 304, 30
5, 306, 307, 308, 309, 310, 31
1, 312, 313, 314, 315, 316, 31
7, 318, 319, 320, 321, 322, 32
3, 324, 325 and 326 compounds.

More preferably, Table 1: Compound Nos. 3, 28, 53, 78, 103 and 12
Compound No. 8 Table 2: Compound Nos. 1, 2, 7, 26, 31, 32, and 3
4, 35, 39, 40, 44, 49, 50, 51, 5,
2, 59, 62, 63, 64, 65, 529, 530,
535, 554, 559, 560, 562, 563, 5
67, 568, 572, 577, 578, 579, 58
0, 587, 590, 591, 592, 593, 105
7, 1058, 1059, 1060, 1063, 106
9, 1070, 1071, 1072, 1073, 107
4, 1111, 1112, 1113, 1114, 111
7, 1123, 1124, 1125, 1126, 112
7, 1128, Table 3: Compound No. 1, 3, 7, 11 Table 4: Compound No. 1, 2, 21, 22, 41, 42, 6
Compounds of 1, 62, 81, 82, 101, 102 and Table 5: Compound Nos. 1, 2, 4, 7, 8, 91, 92, 9
4, 97, 98, 182, 183, 184, 185, 1
86, 187, 188, 189, 190, 191, 19
2,193,194,195,196,197,19
8, 199, 200, 201, 202, 203, 24
8, 249, 250, 251, 252, 253, 25
4, 255, 256, 257, 258, 259, 26
0, 261, 262, 263, 264, 265, 26
6, 267, 268, 269, 314, 315, 32
0,321 compounds. Most preferred are the following compounds:

(1R, 5S, 6S) -2- [1- (4-
Carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylic acid (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-oxazol-2-yl) azetidine-3-
Yl] thio-6-[(1R) -1-hydroxyethyl]
-1-Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-hydroxymethyl -1,3-oxazol-2-yl) azetidine-
3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-cyano -1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-cyano-1,
3-oxazol-2-yl) azetidin-3-yl]
Thio-6-[(1R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6 -[(1R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-oxazole -2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em -3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- [4- (4-aminoazetidino) carbonyl-1,3-thiazol-2-yl]
Azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- [4 -(4-Aminoazetidino) carbonyl-1,3-oxazol-2-yl] azetidin-3-yl] thio-6-[(1R) -1-
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- [4- (4-hydroxyazetidino) carbonyl-1,3-thiazole-2 −
Yl] azetidin-3-yl] thio-6-[(1R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
M-3-carboxylic acid (1R, 5S, 6S) -2- [1- [4- (4-hydroxyazetidino) carbonyl-1,3-oxazole-2
-Yl] azetidin-3-yl] thio-6-[(1R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R ) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-
carboxylic acid.

(1R, 5S, 6S) -2- [1- (4-
Thiomorpholinocarbonyl-1,3-oxazole-2
-Yl) azetidin-3-yl] thio-6-[(1R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (piperidin-4-ylcarbamoyl) -1,3-thiazole-2-
Yl] azetidin-3-yl {thio-6-[(R) -1-]
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (piperidin-4-ylcarbamoyl) -1,3-oxazole-2
-Yl] azetidin-3-yl {thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
M-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (azetidin-3-ylcarbamoyl) -1,3-thiazole-2-
Yl] azetidin-3-yl {thio-6-[(R) -1-]
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (azetidin-3-ylcarbamoyl) -1,3-oxazole-2
-Yl] azetidin-3-yl {thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
M-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((3S)-
Pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((3S)-
Pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((3R)-
Pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((3R)-
Pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (piperazine-1-carbonyl) -1 , 3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
-Carboxylic acid (1R, 5S, 6S) -2- {1- [4- (piperazine-1-carbonyl) -1,3-oxazol-2-yl]
Azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-m-
3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [ (R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1 , 3-oxazole-2-
Yl] azetidin-3-yl {thio-6-[(R) -1-]
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((1S)-
1-aminomethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Ill @ thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((1S)-
1-aminomethyl-2-methyl-propylcarbamoyl) -1,3-oxazol-2-yl] azetidine-
3-yl @ thio-6-[(R) -1-hydroxyethyl]
-1-Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- [4-[(2-amino-ethyl) -isopropyl-carbamoyl) -1,3-
Thiazol-2-yl] azetidin-3-yl {thio-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- [4-[(2-amino-ethyl ) -Isopropyl-carbamoyl) -1,3-
Oxazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- [4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl) -1,
3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- [4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl) -1,
3-Oxazol-2-yl] azetidin-3-yl}
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-aminomethyl-1, 3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-aminomethyl-1,3-oxazol-2-yl) azetidine-3-
Yl] thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidine-3- Yl @ thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3
-Carboxylic acid (1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-oxazol-2-yl]
Azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-m-
3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thiazole-2-
Yl] azetidin-3-yl] thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-oxazole-2
-Yl] azetidin-3-yl] thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
Em-3-carboxylic acid (1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidin-3-yl ) Thio-6
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) ) Methyl] -1,3-oxazol-2-yl {azetidin-3-yl) thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- {4-[(furan-2
-Carbonyl-amino) methyl] -1,3-thiazole-
2-yl {azetidin-3-yl) thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid (1R, 5S, 6S) -2- (1- {4-[(furan-2
-Carbonyl-amino) methyl] -1,3-oxazol-2-yl {azetidin-3-yl) thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid

[0051]

BEST MODE FOR CARRYING OUT THE INVENTION The 1-methylcarbapenem derivative represented by the general formula (I) of the present invention can be produced by the methods described in the following methods A and B. [Method A] The method A is a method for producing a compound (I) by reacting a carbapenem compound represented by the formula (II) with a mercapto compound represented by the formula (III) and then subjecting the compound to a deprotection reaction. is there.

[0052]

Embedded image

In the formula, R ¹ , R ² , X and n are as defined above, L ¹ represents a leaving group, P ¹ represents a carboxyl protecting group, and R ¹ p represents a protecting group. R ¹ which may be present is shown.

As the “protecting group for carboxyl group” of P ^1, an optionally substituted benzyl group such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl or 2-nitrobenzyl Is nitro, methyl, chlorine or methoxy); a benzhydryl group;
An allyl group which may have a substituent at the 2-position such as allyl, 2-chloroallyl or 2-methylallyl (the substituent is chlorine or methyl); a group forming the above-mentioned pharmacologically acceptable ester And preferably a benzyl group which may have a substituent (especially 4-nitrobenzyl group).

A “leaving group” for L ¹ is, for example, a group having the formula —OR ¹¹ or —S (O) R ¹² .

R ¹¹ is a C1-C4 alkanesulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl; C6-C6 such as phenylsulfonyl, tolylsulfonyl or naphthylsulfonyl. C10 arylsulfonyl group; diC1-C6 alkylphosphoryl group such as dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoryl, dipentylphosphoryl or dihexylphosphoryl or diC6-C10 such as diphenylphosphoryl or ditolylphosphoryl. It represents an arylphosphoryl group, preferably a diphenylphosphoryl group.

R¹²Is, for example, methyl, ethyl, propyl
Or a C1-C4 alkyl group such as isopropyl;
Fluoromethyl, chloromethyl, fluoroethyl, chloro
Roethyl, fluoropropyl, difluoromethyl, diph
Also fluoroethyl, dichloroethyl, trifluoromethyl
Or halogeno C1-C4 such as trifluoroethyl
Alkyl group; 2-acetylaminoethyl group; 2-acetyl
Aminovinyl group; phenyl optionally having substituent (s)
Or a C6-C10 aryl group such as naphthyl
A group having 1 to 3 identical or different substituents
Is also good. The substituent may be a halogen such as fluorine, chlorine, bromine.
Atom; methyl, ethyl, propyl, isopropyl
C1-C4 alkyl group; methoxy, ethoxy, pro
C1-C4 alkoxy such as oxy, isopropoxy
Groups: methoxycarbonyl, ethoxycarbonyl, t-butyl
(C1-C4 alkoxy) ca such as toxiccarbonyl
Carbonyl group; carbamoyl, mono or di (C1-C
4 alkyl) carbamoyl group; nitro group; hydroxyl group or
And a cyano group. ) Or may have a substituent
One nitrogen atom such as pyridyl or pyrimidinyl
Or a heteroaryl group optionally having two heteroaryl groups
A group having 1 to 3 identical or different substituents
Is also good. The substituent may be a halogen such as fluorine, chlorine, bromine.
Atom; methyl, ethyl, propyl, isopropyl
C1-C4 alkyl group; methoxy, ethoxy, pro
C1-C4 alkoxy such as oxy, isopropoxy
Groups: methoxycarbonyl, ethoxycarbonyl, t-butyl
(C _1-4Alkoxy) carbo
A carbamoyl, mono- or di- (C1-C4
Alkyl) carbamoyl group; nitro group; hydroxyl group or shea
Group. ).

The "hydroxyl-protecting group" contained in R ¹ p includes, for example, substituted benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl and 4-methoxybenzyloxycarbonyl. A benzyloxycarbonyl group (the substituent is nitro, methyl, chlorine or methoxy); and a 2-substituted group such as allyloxycarbonyl, 2-chloroallyloxycarbonyl, or 2-methylallyloxycarbonyl. Allyloxycarbonyl group (the substituent is chlorine or methyl); tri-C1-C4 alkylsilyl group such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl; forming the above-mentioned pharmaceutically acceptable ester Group
Preferably, it is a tri-C1-C4 alkylsilyl group (particularly a t-butyldimethylsilyl group).

The “protecting group for amino group” contained in R ¹ p may be substituted at the 2-position such as allyloxycarbonyl, 2-chloroallyloxycarbonyl, and 2-methylallyloxycarbonyl. Allyloxycarbonyl group (the substituent is chlorine or methyl); such as benzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl An optionally substituted benzyloxycarbonyl group (the substituent is methyl,
Methoxy, chlorine or nitro), preferably an allyloxycarbonyl group or a 4-nitrobenzyloxycarbonyl group, and more preferably a 4-nitrobenzyloxycarbonyl group.

As the “protecting group for carboxyl group” contained in R ¹ p, the above-mentioned protecting group used for P ¹ can be used.

In this method, a compound having the formula (IV) is prepared by reacting a compound having the formula (II) with a compound having the formula (III) in the presence of a base (Step A1). To produce the compound (I) (Step A2). When L ¹ is a group represented by the formula —OR ¹¹ , the compound having the formula (II) as a starting material can be obtained by the method described in DHShih et al., Heterocycles 21,
29 (1984) or a method analogous thereto. When L ¹ is a group represented by the formula —S (O) R ¹² , the starting compound (II) is described in
It is manufactured by the method described in No. 30781 or a method analogous thereto. Hereinafter, each step will be described.

(Step A1) The step A1 is performed according to the general formula (I)
In the step of producing a compound having V), in an inert solvent,
This is achieved by reacting the compound (II) with a mercaptan derivative having the general formula (III) in the presence of a base.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
Halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform; nitriles such as acetonitrile; N, N-dimethylformamide;
Amides such as N, N-dimethylacetamide; esters such as ethyl acetate and methyl acetate;
Ter, tetrahydrofuran, ethers such as dioxane, and preferably acetonitrile,
N, N-dimethylformamide or tetrahydrofuran, particularly preferably acetonitrile.

The base to be used is preferably an organic amine such as triethylamine, diisopropylethylamine, pyridine or dimethylaminopyridine or an inorganic base such as potassium carbonate, sodium carbonate or sodium hydrogencarbonate. Are organic amines (especially diisopropylethylamine).

The reaction is usually carried out at a temperature of -20 ° C to 40 ° C (preferably -10 ° C to 20 ° C). Reaction time is 3
It is 0 minute to 108 hours (preferably 1 hour to 18 hours).

After completion of the reaction, the desired compound (IV) of this step is obtained.
Is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. Further, if desired, the target compound (IV) can be subjected to the next step without isolation.

(Step A2) In step A2, compound (I)
V) to compound (I), wherein compound (I)
This is achieved by removing the protecting group contained in V).

The removal of the protecting group depends on the type of the protecting group, but it is generally a method used in the field of synthetic organic chemistry (for example, TWG Greene, PGMWuts, Protective
Groups in Organic Synthesis, Second Edition, John
Wiley & Sons, Inc. 1991). (1) When the protecting group is a benzyl group, a benzhydryl group which may have a substituent or a benzyloxycarbonyl group which may have a substituent, these protecting groups are present in a solvent in the presence of a catalytic reduction catalyst. It can be removed by the action of hydrogen underneath.

Examples of the catalytic reduction catalyst to be used include a palladium-carbon catalyst, a platinum catalyst, a rhodium-carbon catalyst and the like, and a palladium-carbon catalyst is preferable.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
Preferred are alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and mixed solvents of these organic solvents and water, preferably mixed solvents of tetrahydrofuran and water.

The reaction temperature is usually 0 ° C. to 50 ° C. (preferably 10 ° C. to 40 ° C.). The reaction time varies depending on the type of the starting compound and the catalyst, but is usually 5 minutes to 12 hours (preferably 30 minutes). To 4 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off an insoluble matter such as a catalyst from the reaction mixture and then distilling off the solvent. The obtained compound can be purified, if necessary, by a conventional method, for example, a recrystallization method, a preparative thin-layer chromatography, or a column chromatography. (2) When the protecting group is an allyl group which may be substituted or an allyloxycarbonyl group which may be substituted, these protecting groups may be converted to a tri-C1-C6 alkyltin hydride in a solvent in the presence of palladium. And alkali metal salts of organic carboxylic acids. An organic base or organic substance for capturing an allyl group may be added.

As the palladium, bis (triphenylphosphine) palladium chloride or tetrakis (triphenylphosphine) palladium is preferable.
As the trialkyltin hydride, tributyltin hydride is suitable. As the organic carboxylic acid alkali metal salts, potassium 2-ethylhexanoate or sodium 2-ethylhexanoate is preferable. Morpholine is preferred as the organic base for capturing the allyl group, and dimedone is preferred as the organic substance for capturing the allyl group.

A suitable combination as a deprotecting agent is a combination consisting of bis (triphenylphosphine) palladium chloride and tributyltin hydride or tetrakis (triphenylphosphine) palladium and 2-
It is a combination consisting of potassium ethylhexanoate.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
For example, halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane; esters such as ethyl acetate; ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane; nitriles such as acetonitrile ;methanol,
Alcohols such as ethanol or propanol; water or a mixed solvent thereof, preferably methylene chloride, ethyl acetate or a mixed solvent thereof.

The reaction temperature is not particularly limited, but is usually -20 ° C.
To 100 ° C. (preferably 0 ° C. to 60 ° C.), and the reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles precipitated from the reaction mixture and then distilling off the solvent. The obtained compound can be purified, if necessary, by a conventional method, for example, a recrystallization method, a preparative thin-layer chromatography, or a column chromatography. (3) When the protecting group is a silyl-based protecting group, this protecting group generates a fluoride anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, and potassium fluoride in a solvent. Treated with a compound or acetic acid,
It can be removed by treatment with an organic acid such as methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or an inorganic acid such as hydrochloric acid.

In the case of removal by fluorine anion,
By adding an organic acid such as formic acid, acetic acid or propionic acid, the reaction may proceed under mild conditions.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, it is preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy. Ethers such as ethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; water; organic acids such as acetic acid; and mixed solvents thereof.

The reaction temperature is usually 0 ° C. to 100 ° C. (preferably 10 ° C. to 30 ° C.), and the reaction time is not particularly limited, but is usually 1 to 24 hours (preferably 1 to 4 hours). It is.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (4) When the protecting group is a group that forms a pharmacologically acceptable ester at a carboxyl group or a hydroxyl group, these protecting groups are removed by the action of a hydrolase in water or a mixed solvent of water and an organic solvent. Is done.

The organic solvent mixed with water includes tetrahydrofuran, dioxane, methanol, ethanol,
Ethers or alcohols that are miscible with water, such as propanol, are preferred.

To water or a mixed solvent of water and an organic solvent, an alkali metal salt such as sodium phosphate, sodium acetate or sodium hydrogen carbonate is added, or the pH is adjusted to 6 as a pH buffer such as a phosphate buffer. It is preferably maintained at from 8 to 8.

The hydrolase is not particularly limited as long as it can hydrolyze an ester bond.
For example, pig liver-derived esterase can be mentioned.

The reaction temperature is usually 10 minutes to 8 hours (preferably 30 minutes to 2 hours), and the reaction temperature is 10 to 5 hours.
0 ° C. (preferably 30 to 40 ° C.).

After completion of the reaction, the target compound can be isolated and purified by ion exchange chromatography, reverse phase column chromatography, reprecipitation, recrystallization, and the like.

When compound (IV) contains two or more types of protecting groups, the desired compound (I) can be obtained by carrying out the above deprotection reactions in combination. In addition,
When a pharmacologically acceptable ester derivative of compound (I) is desired, it is not necessary to remove the group that forms a pharmacologically acceptable ester as a protecting group.

The compound (I) thus obtained is
If necessary, the compound can be converted to a pharmacologically acceptable salt or ester derivative according to methods or techniques known in the field of medicinal chemistry, particularly β-lactam antibiotics.

The pharmacologically acceptable ester derivative at the carboxyl group of compound (I) is produced by reacting compound (I) with a halide corresponding to a desired ester residue in a solvent in the presence of a base. be able to.

The halide used can be chloride, bromide or iodide, preferably iodide. When chloride or bromide is used, the reaction can be promoted by adding a catalytic amount of sodium iodide to the reaction solution.

Examples of the base used include organic amines such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and pyridine; and alkali metal carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate. And preferably organic amines (especially 4-dimethylaminopyridine).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. For example, nitriles such as acetonitrile;
Amides such as dimethylformamide; halogenated hydrocarbons such as methylene chloride;
Preferred are amides (especially dimethylacetamide) or nitriles (especially acetonitrile).

The reaction temperature is usually -20 to 50 ° C (preferably -10 to 20 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).

The compound (I) which has been reacted in advance with a base and isolated in advance as a salt can be reacted with a halide as described above.

On the other hand, in the presence of a condensing agent and a base,
It can also be produced by reacting an alcohol corresponding to a desired ester residue.

Examples of the condensing agent include a Mitsunobu reagent such as diethylazodicarboxylate; a phosphoric acid ester condensing agent such as diphenylphosphoryl azide; and dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. Carbodiimide-based condensing agents; onium-based condensing agents such as 2-chloro-1-methylpyridinium iodide;

As the base used, triethylamine, tributylamine, diisopropylethylamine,
Organic amines such as 4-dimethylaminopyridine can be mentioned.

Other additives include phosphines such as triphenylphosphine and tributylphosphine, and alcohols for forming active esters such as 1-hydroxybenztriazole.

Examples of the solvent include halogenated hydrocarbons such as methylene chloride and dichloroethane; amides such as N, N-dimethylformamide; nitriles such as acetonitrile; and ethers such as tetrahydrofuran. .

Preferred combinations thereof include diethyl azodicarboxylate and triphenylphosphine; 2-chloro-1-methylpyridinium iodide and tributylamine or triethylamine; 1-ethyl-3- (3-dimethylaminopropyl ) Carbodiimide and 4-dimethylaminopyridine or 1-hydroxybenztriazole.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. [Method B] Method B is a method for producing compound (III) used as a starting material in method A.

[0102]

Embedded image

In the above, R ¹ p, R ² , X and n have the same meaning as described above. P ² represents a protecting group for a carboxyl group, for example, a C1-C4 alkyl group such as methyl, ethyl, propyl, and butyl; and an optionally substituted benzyl group such as benzyl and 4-methoxybenzyl. And preferably a C1-C4 alkyl group (particularly preferably an ethyl group). P ³ represents a protecting group for a hydroxyl group,
For example, silyl protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl can be mentioned, and a t-butyldiphenylsilyl group is preferable. L ² represents a leaving group,
For example, a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; C1-C4 which may be substituted by fluorine such as a methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and toluenesulfonyloxy group Examples thereof include an alkylsulfonyloxy group and a benzenesulfonyloxy group optionally substituted by alkyl, and a C1-C4 alkylsulfonyloxy group optionally substituted by fluorine. P ⁴ represents a protecting group for a mercapto group, and examples thereof include a C1-C4 alkanoyl group such as formyl, acetyl, propionyl, and butyryl; benzoyl, toluoyl, and an optionally substituted benzoyl group such as anisoyl; Preferably C
1-C4 alkanoyl group (especially acetyl group).

(Step B1) Step B1 is a step of introducing an amide group represented by the formula C (基 X) NH ₂ into a nitrogen atom of compound (V) to produce compound (VI). (1) This step is achieved by reacting compound (V) with a cyanate or thiocyanate in a solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include ethers such as tetrahydrofuran and diethyl ether; halogens such as methylene chloride and dichloroethane. And a mixed solvent of these solvents and water, preferably a mixed solvent of ethers and water (particularly a mixed solvent of tetrahydrofuran and water).

Examples of the salt of cyanic acid or thiocyanic acid include alkali metal salts such as sodium salt and potassium salt or organic ammonium salts such as ammonium salt and triethylammonium salt. Salts (especially potassium salts).

Acids can also be used to convert cyanate or thiocyanate into the corresponding acid in the system. Examples of such an acid include an organic acid such as acetic acid and a mineral acid such as hydrochloric acid, and acetic acid or hydrochloric acid is preferable.

The reaction temperature is usually from -20 to 150 ° C (preferably from -10 to 100 ° C), and the reaction time is usually from 0.1 to 100 ° C.
It is 5 to 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (2) This step can also be achieved by the following method. This method comprises converting the following compound (XII) from compound (V)
It comprises a step of producing I) and a step of producing compound (VI) from compound (XIII).

[0110]

Embedded image

In the formula, X and n are as defined above, and R ⁹
Represents a C1-C4 alkyl group (preferably an ethyl group).

In the step of producing compound (XIII) from compound (V), compound (V) is added to a compound of the formula X = C = N-
COOR ⁹ (wherein, X and R ⁹ are described above and are as defined) is achieved by the action of a compound represented by.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include ethers such as tetrahydrofuran and diethyl ether, and halogens such as methylene chloride and dichloroethane. Hydrocarbons and mixed solvents of these solvents and water can be mentioned, and preferred are ethers or a mixed solvent of ethers and water (particularly tetrahydrofuran or a mixed solvent of tetrahydrofuran and water).

The reaction temperature is usually -20 to 150 ° C (preferably -10 to 50 ° C), and the reaction time is usually 0.5.
To 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The step of producing compound (VI) from compound (XIII) is achieved by reacting compound (XIII) with a base in a solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include alcohols such as methanol and ethanol, and ethers such as tetrahydrofuran and diethyl ether. And a mixed solvent of these solvents and water, preferably alcohols or a mixed solvent of alcohols and water (particularly ethanol or a mixed solvent of ethanol and water).

Examples of the base used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate and potassium carbonate, and organic bases such as sodium methoxide and sodium ethoxide. , Preferably sodium hydroxide.

The reaction temperature is usually -20 to 15 ° C (preferably -10 to 100 ° C), and the reaction time is usually 0.5.
To 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step B2) In step B2, the compound (V)
This is a step of producing a compound (VII) by subjecting the amide group of I) to a ring closure reaction.

[0122] This step is a solvent to the compound (VI), wherein R ² CHL ³ COCOOP ² (wherein the presence of a base, R ² and P ² are as defined above, L ³ is a leaving group This is achieved by acting a compound represented by the following formula: L ³
As the leaving group, a halogen atom is preferable, and a bromine atom is particularly preferable.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, alcohols such as methanol and ethanol, and ethers such as tetrahydrofuran and diethyl ether. And halogenated hydrocarbons such as methylene chloride and dichloroethane, and amides such as N, N-dimethylformamide, preferably alcohols (particularly ethanol).

The base to be used includes, for example, organic bases such as triethylamine and diisopropylamine, and inorganic bases such as sodium carbonate, potassium carbonate and sodium hydrogencarbonate, preferably organic bases (particularly triethylamine). It is.

The reaction temperature is usually from -20 to 150 ° C (preferably from -10 to 100 ° C), and the reaction time is usually from 0.
It is 5 to 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step B3) In step B3, the compound (V)
Hydroxyl group in introducing a protecting group P ³ compound of II) (VII
This is the step of manufacturing I).

This step is carried out by a method usually used in the field of synthetic organic chemistry (for example, TWGreene, PGMWuts,
Protective Groups in Organic Synthesis, Second Edi
, John Wiley & Sons, Inc. 1991).

The introduction of the silyl protecting group can be carried out by the compound (VI)
It is achieved by reacting a silyl halide or silyl triflate having a desired substituent with I) in the presence of a base in a solvent.

Examples of the silyl halides include, for example, trimethylsilyl chloride, triethylsilyl chloride, t-
Examples thereof include butyldimethylsilyl chloride and t-butyldiphenylsilyl chloride, and preferred is t-butyldiphenylsilyl chloride.

Examples of the silyl triflate include, for example, trimethyl silyl triflate, triethyl silyl triflate, t-butyl dimethyl silyl triflate, and t-butyl diphenyl silyl triflate, and preferably t-butyl diphenyl silyl triflate.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include amides such as dimethylformamide and halogenated carbons such as methylene chloride and dichloroethane. Examples thereof include hydrogens, ethers such as tetrahydrofuran and diethyl ether, preferably amides (particularly dimethylformamide) or halogenated hydrocarbons (particularly methylene chloride).

Examples of the base used include organic bases such as imidazole, triethylamine, lutidine, pyridine and dimethylaminopyridine, preferably imidazole or 2,6-lutidine.

The reaction temperature is usually -20 to 50 ° C (preferably -10 to 40 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step B4) In step B4, compound (V)
In this step, compound (IX) is produced by converting the group represented by formula COOP ² in III) into a desired R ¹ p.

This step can be achieved by applying a functional group conversion reaction usually used in the field of synthetic organic chemistry. The details will be described in the following methods C to H.

(Step B5) In step B5, compound (I)
This is a step of producing a compound (X) by removing the protecting group P ³ of the hydroxyl group of X).

This step is carried out by a method usually used in the field of synthetic organic chemistry (for example, TWGreene, PGMWuts,
Protective Groups in Organic Synthesis, Second Edi
, John Wiley & Sons, Inc. 1991).

When the protecting group P ^{3 for the} hydroxyl group is a silyl-based protecting group, the removal is achieved in the same manner as in the method described in Step A2 (3).

(Step B6) In step B6, the hydroxyl group of compound (X) is converted to a leaving group L ² to give compound (XI)
This is the step of manufacturing. (1) When Leaving Group L ² is Various Sulfonyloxy Groups This step is achieved by reacting compound (IX) with a sulfonylating agent in the presence of a base in a solvent.

The sulfonylating agent to be used includes, for example, methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride and the like, and preferably methanesulfonyl chloride.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, halogenated hydrocarbons such as methylene chloride, dichloroethane and chloroform, tetrahydrofuran, diethyl ether Ethers such as ether can be mentioned, and preferred are halogenated hydrocarbons (particularly methylene chloride).

The base to be used includes, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine and dimethylaminopyridine. Triethylamine is preferred.

The reaction temperature is usually -20 to 80 ° C (preferably -10 to 40 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (2) When the leaving group L ² is a halogen atom This step is achieved by reacting compound (IX) with a halogenating agent in a solvent.

Examples of the halogenating agent used include, for example, phosphorus pentachloride, thionyl chloride, phosphorus oxychloride, iodine,
Carbon tetrabromide, carbon tetrachloride, N-chlorosuccinimide, N-
Bromosuccinimide and diethylaminosulfur trifluoride can be mentioned, and carbon tetrabromide is preferred.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include halogenated hydrocarbons such as methylene chloride and dichloroethane, tetrahydrofuran and diethyl ether. Preferred ethers are halogenated hydrocarbons (particularly methylene chloride).

Examples of the additive used include phosphines such as triphenylphosphine and tributylphosphine, and triphenylphosphine is preferred.

The reaction temperature is usually -20 to 100 ° C (preferably -10 to 50 ° C), and the reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step B7) In step B7, the compound (X)
Is converted to a mercapto group protected with a leaving group L ² of I) is a step for preparing the compound (XII).

This step is achieved by reacting compound (XI) with a mercapto agent in a solvent.

The mercapto agent used is, for example, an alkali metal salt of thiocarboxylic acid such as sodium thioacetate, potassium thioacetate, sodium thiopropionate or sodium thiobenzoate or an alkali metal salt of 4-methoxybenzyl mercaptan. And preferably potassium thioacetate.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include ethers such as tetrahydrofuran and dioxane, and acetates such as ethyl acetate and methyl acetate. And amides such as dimethylformamide and dimethylacetamide, preferably amides (particularly dimethylformamide).

The reaction temperature is usually -20 to 150 ° C (preferably 0 to 100 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).

After the completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step B8) In step B8, the compound (X)
This is a step of producing a compound (III) by removing the protecting group P ⁴ of the mercapto group in II). (1) When the protecting group P ⁴ is an alkanoyl group or an arylcarbonyl group This step is achieved by reacting compound (XII) with a salt of a hydrazine compound in a solvent.

As the salt of the hydrazine compound, for example, hydrazine / acetic acid, N, N-dimethylhydrazine / acetic acid can be used, and hydrazine / acetic acid is preferable.

The solvent used in the first step can be used.

Although the reaction temperature is not particularly limited, it is usually -10 ° C to 40 ° C (preferably 10 ° C to 30 ° C), and the reaction time varies depending on the solvent, the reaction temperature and the type of the reaction reagent. Is 30 minutes to 24 hours (preferably 1 hour to 8 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When a salt of a hydrazine compound is used as a deprotecting agent, compound (III) can be used as a raw material in the above-mentioned step A1 without isolation from a reaction solution.

In this step, compound (XIII) is added to a solvent
It can also be achieved by the action of a base.

Examples of the base used include salts of alkali metals such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide and sodium ethoxide. Methoxide.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include alcohols such as methanol and ethanol; and ethers such as tetrahydrofuran and diethyl ether. And amides such as dimethylformamide, and halogenated hydrocarbons such as methylene chloride and dichloroethane, and preferably alcohols (particularly methanol).

The reaction temperature is usually -20 to 100 ° C (preferably -10 to 40 ° C), and the reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (2) When P ⁴ is 4-methoxybenzyl Group This step is achieved by reacting compound (XIII) with an acid in a solvent.

As the acid to be used, sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid can be used, and trifluoromethanesulfonic acid is preferred. The reaction can be promoted by coexisting anisole or thioanisole.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, halogenated hydrocarbons such as methylene chloride and dichloroethane, tetrahydrofuran and diethyl ether Examples thereof include acetic acids such as ethers, acetic acid and trifluoroacetic acid, and acetic acids (particularly, trifluoroacetic acid) are preferred.

The reaction temperature is usually -20 to 100 ° C (preferably -10 to 80 ° C), and the reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. [Method C] Method C is a method for producing a compound (IX-1) having a desired ester residue by converting the protected carboxyl group of compound (VIII).

[0173]

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In the above, R ² , X, n, P ² and P ³
Is as defined above, and R ^3p is an ^optionally protected R
^{Shows 3} . (Step C1) Step C1 is a step of producing a compound (XIV) by reducing the carboxyl ester group of the compound (VIII) to a hydroxymethyl group.

In this step, compound (VIII) is added to a solvent
This is achieved by the action of a reducing agent.

The reducing agent used is not particularly limited as long as it can reduce a carboxyl ester group to a hydroxymethyl group. Examples thereof include alkali metal hydrides such as lithium aluminum hydride, lithium borohydride, sodium borohydride and the like. Alkali metal borohydrides such as borohydride can be mentioned, preferably lithium aluminum hydride.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Examples thereof include ethers such as tetrahydrofuran and diethyl ether. It is tetrahydrofuran.

The reaction temperature is usually -20 to 100 ° C (preferably -10 to 40 ° C), and the reaction time is usually 10 minutes to 24 hours (preferably 0.5 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture, neutralizing and washing with water, and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step C2) Step C2 is a step of oxidizing the hydroxymethyl group of compound (XIV) to produce compound (XV).

This step is accomplished by reacting compound (XIV) with an oxidizing agent in a solvent, and comprises a step of oxidizing a hydroxymethyl group to an aldehyde group and a step of oxidizing an aldehyde group to a carboxyl group. (1) Step of oxidizing a hydroxymethyl group to an aldehyde group The oxidizing agent used is not particularly limited as long as it can oxidize the hydroxymethyl group and convert it to an aldehyde group.
For example, pyridinium chlorochromate, oxalyl chloride-dimethylsulfoxide, trifluoroacetic anhydride-
Examples thereof include dimethyl sulfoxide, active manganese dioxide, and Dess-Martin reagent, preferably active manganese dioxide.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include halogenated hydrocarbons such as methylene chloride and dichloroethane. Preferably it is methylene chloride.

The reaction temperature is usually -100 to 100 ° C (preferably -100 to 50 ° C), and the reaction time is usually 3 to 3.
It is 0 minute to 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the desired compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (2) Step of oxidizing an aldehyde group to a carboxyl group The oxidizing agent used is not particularly limited as long as it can oxidize the aldehyde group and convert it to a carboxyl group. For example, potassium permanganate, ruthenium tetroxide, suboxide Sodium chlorate-sodium (or potassium) dihydrogen phosphate -2
-Methyl-2-butene, and preferably sodium chlorite-sodium dihydrogen phosphate-2-methyl-2-butene.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, halogenated hydrocarbons such as methylene chloride and dichloroethane, tetrahydrofuran and diethyl ether Such as ethers, alcohols such as t-butanol, and a mixed solvent thereof with water, preferably tetrahydrofuran-methylene chloride-water-t.
-A mixed solvent of butanol.

The reaction temperature is usually -20 to 50 ° C (preferably -10 to 40 ° C), and the reaction time is usually 10 minutes to 108 hours (preferably 0.5 to 24 hours).

After completion of the reaction, the desired compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step C3) In step C3, the carboxyl compound (X
This is a step of separately producing V), which is achieved by removing the protecting group of compound (VIII).

This step can be performed in the same manner as in step A2 of method A. (Step C4) Step C4 is a step of producing a compound (XIX-1) by esterifying a carboxyl group of the compound (XV). (1) This step is achieved by reacting a desired alcohol compound represented by the formula R ^3p OH with compound (XV) in a solvent in the presence of a condensing agent.

As the condensing agent to be used, those mentioned in the section of ester formation described in Step A2 of Method A can be used. It can also be achieved via acid chloride using oxalyl chloride.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, halogenated hydrocarbons such as methylene chloride and dichloroethane, tetrahydrofuran and diethyl ether Examples thereof include ethers, amides such as dimethylformamide, and nitriles such as acetonitrile, and preferred are halogenated hydrocarbons (particularly, methylene chloride).

The reaction temperature is usually -50 to 100 ° C (preferably -20 to 50 ° C), and the reaction time is usually 0.5.
To 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (2) This step can also be achieved by allowing compound (XV) to react with a desired compound represented by the formula R ^3p L ³ in a solvent in the presence of a base. L ³ represents a leaving group;
Preferably it is a halogen atom (especially an iodine or bromine atom).

As the base used, an inorganic base or an organic base can be used. As the inorganic base,
Examples thereof include carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; and hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and cesium carbonate is preferred. Examples of the organic base include tertiary amines such as triethylamine and diisopropylethylamine; and bicyclic organic bases such as DBU and DBN. Diisopropylethylamine is preferred.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, halogenated hydrocarbons such as methylene chloride and dichloroethane, tetrahydrofuran, diethyl ether and the like can be used. Examples thereof include ethers, amides such as dimethylformamide, and nitriles such as acetonitrile, and amides (particularly, dimethylformamide) are preferred.

The reaction temperature is usually from -50 to 100 ° C (preferably from -20 to 100 ° C), and the reaction time is usually from 0.1 to 100 ° C.
It is 5 to 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. [Method D] Method D is a method for producing a compound (IX-2) having a desired amide residue by converting a carboxyl group of the compound (XV).

[0196]

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In the above, R ² , X, n and P ³ are as defined above, and R ^4p and R ^5p represent R ⁴ and R ⁵ which may be protected. (Step D1) This step is achieved by reacting compound (XV) with a compound having desired formula HNR ^4p R ^5p in a solvent in the presence of a condensing agent.

In this step, the amino compound HN was used in place of the alcohol compound R ^3p OH in Step C4 of Method C described above.
This can be done by using R ^4p R ^5p .

As the condensing agent, a phosphate condensing agent such as diethylphosphoryl cyanide and a carbonate condensing agent such as carbonyldiimidazole can be used. Preferably, diethyl phosphoryl cyanide,
It is carbonyldiimidazole. [Method E] In the method E, the compound (I) having a desired amide residue by converting the carboxyl ester group of the compound (XIII)
X-2).

[0200]

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In the above, R^Two, X, n, P^Three, R^4pPassing
And R^5pIs as defined above. P^2aIs the carboxy
Protecting group P^TwoRepresents a C1-C4 alkyl group. (Step E1) In this step, compound (VIII) is added to a solvent
In the presence of the catalyst in the presence of the desired formula HNR^4pR ^5pA represented by
This is achieved by acting a mino compound.

As the catalyst to be used, there can be mentioned, for example, C1-C4 aluminum such as trimethylaluminum, and preferably trimethylaluminum.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aromatic solvents such as benzene, toluene and mesitylene, methylene chloride and dichloroethane may be used. Such halogenated hydrocarbons can be mentioned, and an aromatic solvent (particularly, benzene or toluene) is preferable.

The reaction temperature is usually from -20 to 150 ° C (preferably from -10 to 100 ° C), and the reaction time is usually from 0.
It is 5 to 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. [Method F] Method F is a method for producing a cyano compound (IX-3) by converting the carboxyl ester group of compound (XIII).

[0206]

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In the above, R ² , X, n, P ³ and P ^2a
Is as defined above. (Step F1) In this step, an ammonium salt is used in place of the amino compound in the above-mentioned Method E, Step E1,
This is achieved by operating at higher reaction temperatures.

As the ammonium salt, ammonium chloride is preferred, and the reaction is carried out at a reaction temperature of -20 to 150 ° C (preferably -10 to 100 ° C). [Method G] Method G is a method for producing a compound (IX-4) by introducing a desired substituent R ⁶ into a hydroxyl group of the compound (XIV).

[0209]

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In this step, an alkylating agent is allowed to act on compound (XIV) in a solvent in the presence of a base, or a reducing agent is reacted with a desired carbonyl compound in a solvent in the presence of an acid catalyst. Is achieved by (1) Alkylation method under basic conditions Examples of the solvent used include amides such as N, N-dimethylformamide and ethers such as tetrahydrofuran and diethyl ether. Preferred are amides (especially N, N-dimethylformamide).

Examples of the base used include alkali metal hydrides such as sodium hydride and potassium hydride, inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as triethylamine and diisopropylamine. Preferably, it is an alkali metal hydride (especially sodium hydride).

Examples of the alkylating agent used include alkyl halides represented by methyl iodide and ethyl iodide;
Examples thereof include dialkyl sulfates such as dimethyl sulfate and diethyl sulfate. Preferably, it is an alkyl halide (especially alkyl iodide).

The reaction temperature is generally -50 to 100 ° C (preferably -10 to 40 ° C), and the reaction time is generally 10 minutes to 108 hours (preferably 0.5 to 24 hours).

After the completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (2) Alkylation method under acidic conditions The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as methylene chloride and dichloroethane And ethers such as tetrahydrofuran and diethyl ether, and preferred are halogenated hydrocarbons (particularly methylene chloride).

Examples of the acid catalyst include trialkyl silyl triflates such as trimethyl silyl triflate, triethyl silyl triflate, and t-butyl dimethyl silyl triflate. Trimethyl silyl triflate is preferred.

Examples of the desired carbonyl compound include ketones such as acetone, methyl ethyl ketone and cyclohexyl ketone, and alkyl aldehydes such as acetaldehyde and propyl aldehyde, and preferably ketones.

Examples of the reducing agent include trialkylsilanes such as triethylsilane and diphenylmethylsilane, and preferred is trialkylsilane (particularly, triethylsilane).

The reaction temperature is generally -50 to 100 ° C (preferably -10 to 40 ° C), and the reaction time is generally 10 minutes to 108 hours (preferably 0.5 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. [Method H] In the method H, the hydroxyl group of the compound (XIV) is converted to the desired compound of the formula N
This is a method for producing a compound (IX-5) by converting into a group represented by R ^7p R ^8p .

[0220]

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(Step H1) In step H1, the compound (X
This is a step of producing a compound (XV) by introducing a leaving group L ³ into IV), and can be achieved in the same manner as in the above-mentioned Method B, Step B6. (Step H2) Step H2 is a step of producing an amine compound (IX-5a) from the compound (XV) and introducing a substituent as necessary to produce a compound (IX-5b). (A) Step of Producing Amine Compound (IX-5a) This step is achieved by reacting compound (XV) with an aminating agent in a solvent. Alternatively, the compound (X
It is also achieved by producing an azide compound by reacting V) with an azidating agent in a solvent and then reacting with a reducing agent. (1) Method Using Aminating Agent The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, amides such as dimethylformamide, methanol, Examples thereof include alcohols such as ethanol, and ethers such as tetrahydrofuran and diethyl ether, and amides (particularly, dimethylformamide) are preferable.

The aminating agents used include, for example, primary optionally substituted alkylamines such as methylamine and ethylamine; optionally substituted aromatic amines such as aniline and aminothiazole; Examples thereof include secondary alkylamines which may be substituted, such as ethylamine and dimethylamine, and salts of these amines (for example, hydrochloride). Among them, preferred are primary or secondary optionally substituted alkylamines and salts thereof (particularly, methylamine hydrochloride or dimethylamine hydrochloride).

The reaction temperature is generally 0 to 150 ° C. (preferably 10 to 100 ° C.), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (2) Method using azidating agent and reducing agent The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, amides such as dimethylformamide And ethers such as tetrahydrofuran and diethyl ether, and amides (particularly dimethylformamide).

As the azidating agent, sodium azide,
An alkali metal azide such as lithium azide may be mentioned, preferably an alkali metal sodium azide azide (particularly sodium azide).

The reaction temperature is generally 0 to 150 ° C. (preferably 10 to 100 ° C.), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The resulting azide compound is derived into an amine compound (IX-5a) by a reduction reaction.

The reducing agent used is an alkali metal aluminum hydride such as lithium aluminum hydride,
Examples include phosphines such as triphenylphosphine, and catalytic hydrogen reducing agents using metal catalysts such as palladium-carbon and platinum catalysts. Preferably, a catalytic hydrogen reducing agent (particularly,
Palladium-carbon as a catalyst).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include ethers such as tetrahydrofuran and diethyl ether, and alcohols such as methanol and ethanol. And ethers (especially tetrahydrofuran).

In the case of catalytic hydrogen reduction, the solvent to be used includes alcohols such as methanol and ethanol, preferably methanol.

The reaction temperature is usually -10 to 150 ° C (preferably 0 to 100 ° C), and the reaction time is usually 0.5 to 108 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (B) Step of Producing Compound (IX-5b) This step is an optional step, and produces a compound (IX-5b) by introducing a substituent into the amine compound (IX-5a). It is a process.

This step is achieved by reacting a desired acylating agent, sulfonylating agent, phosphorylating agent and chloroformate with an amine compound (IX-5a) in a solvent in the presence of a base.

Examples of the acylating agent include acid anhydrides such as acetic anhydride and benzoic anhydride, and acid chlorides such as acetic chloride and benzoic acid chloride.
Acid chlorides (especially acetic chloride).

Examples of the sulfonylating agent include acid chlorides such as methanesulfonyl chloride and p-toluenesulfonyl chloride, and acid anhydrides such as anhydrous methanesulfonyl and anhydrous p-toluenesulfonyl. Chloride (especially methanesulfonyl chloride)
It is.

Examples of the phosphorylating agent include acid chlorides such as diethyl phosphoryl chloride and dimethyl phosphoryl chloride. Diethyl phosphoryl chloride is preferred.

Examples of the chloroformate include ester compounds such as methyl chloroformate, ethyl chloroformate and benzyl chloroformate, and preferred is a chloroformate (particularly, methyl chloroformate).

Examples of the base used include organic bases such as triethylamine, diisopropylethylamine and pyridine; and inorganic bases such as sodium carbonate, potassium carbonate and sodium hydrogencarbonate. Preferably, organic bases (particularly triethylamine ).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Examples thereof include ethers such as tetrahydrofuran and diethyl ether, and halogenated compounds such as methylene chloride and dichloroethane. Hydrocarbons can be exemplified, and preferred are ethers (particularly, tetrahydrofuran).

The reaction temperature is usually from 0 to 100 ° C. (preferably from 10 to 50 ° C.), and the reaction time is usually from 0.5 to 1 ° C.
08 hours (preferably 1 to 24 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step H3) In the step H3, an amine compound (IX-5a) is produced from the compound (XV) via an azide compound,
This is a step of producing a compound (IX-5b) by introducing a substituent as necessary. (A) Step of Producing Azide Compound This step is carried out by reacting compound (XV) with an azidating agent (particularly diphenylphosphoryl azide), diethyl azodicarboxylate and triphenylphosphine in a solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples thereof include amides such as dimethylformamide, alcohols such as methanol and ethanol, and the like. Examples thereof include ethers such as tetrahydrofuran and diethyl ether, and preferred are ethers (particularly, tetrahydrofuran).

The reaction temperature is usually 0 to 50 ° C. (preferably 1 to 50 ° C.)
0 to 30 ° C.), and the reaction time is usually 0.5 to 10
8 hours (preferably 1 to 24 hours).

After the completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (B) Step of Producing Amine Compound In this step, an azide compound is reduced to form an amine compound (IX)
-5a), which can be carried out in the same manner as in the above-mentioned reduction step of the H2 step (A) (1). (C) Step of Producing Compound (IX-5b) This step is a step performed as necessary, and produces a compound (IX-5b) by introducing a substituent into the amine compound (IX-5a). And the above-mentioned H2
It can be performed in the same manner as in step (B). Method C to H
(IX-1) to (IX-
5) can be converted to compound (III) which is a starting material for the 2-position side chain of compound (I) according to the steps from Method B, Step B5 onward. [Method I] In Method I, a compound (I) which is a synthetic intermediate of Method B
This is a method for separately producing a compound (IX-6) in which X is an oxygen atom in X).

[0246]

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In the above, R ¹ p, R ² , P ³ , and n have the same meanings as described above, and Z represents a protecting group for an amino group, and is preferably a benzyloxycarbonyl group. P ⁵ is a protecting group for a hydroxyl group, preferably an acyl-based protecting group such as acetyl, benzoyl and pivaloyl, and most preferably a benzoyl group.

(Step I-1) Step I-1 is a step of producing a compound (XVI) by converting a carboxyl group of an amino acid compound (XVIa) having an amino group protected to a desired R ¹ p. .

This step can be performed according to a method selected from the above-mentioned methods C to H. In the compound (XVIa) as a starting material, a compound in which R ² is a hydrogen atom can be produced from serine, and a compound in which R ² is a methyl group can be produced from threonine. Compounds in which R2 is other than a hydrogen atom or a methyl group can also be produced by a method well known to those skilled in the art.

(Step 1-2) In step 1-2, a protecting group is introduced into the hydroxyl group of compound (XVI) to give compound (XVI).
This is the step of manufacturing I).

This step can be performed in the same manner as in Method B, Step B3. The silyl-based protecting group for P3 is preferably a t-butyldimethylsilyl group.

(Step I-3) In step I-3, the protecting group for the amino group of compound (XVII) is removed to remove compound (X
VIII).

This step can be carried out according to the method of Method A, Step A2, Step (1). The preferred solvent is methanol.

(Step I-4) Step I-3 is a step of producing a compound (XIX) by converting an amino group of the compound (XVIII) into an isothiocyanate group.

This step is accomplished by reacting compound (XVIII) with a carbon disulfide and a hydrogen sulfide in a solvent in the presence of a base.

As the solvent, halogenated hydrocarbons (particularly methylene chloride) are preferred.

As the dehydrosulfide agent, a halogenated formate (especially ethyl chloroformate) or a quaternary nitrogen-containing reagent (especially 2-chloro-1-methylpyridinium iodide or 2-chloro-1-ethylbenzoxazolium iodide) (Tetrafluoroborate) is preferred.

As the base, tertiary amines such as triethylamine, diisopropylethylamine and tributylamine (particularly triethylamine) are preferred.

The reaction temperature is usually -20 to 100 ° C (preferably 0 to 60 ° C), and the reaction time is usually 0.5 to 48 hours (preferably 1 to 12 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step I-5) In step I-5, compound (XIX) is reacted with a desired cyclic amine to give compound (XX).
X).

This step can be carried out according to Method B, Step B1.

(Step I-6) In step I-6, compound (XXI) was obtained by introducing an acyl protecting group P ⁵ into the hydroxyl group of compound (XX) and then removing silyl protecting group P ^3. This is the manufacturing process. (1) Step of Introducing Acyl-Protecting Group P ⁵ This step can be performed according to the method of Method H, Step H2 (B). (2) Step of Removing Silyl Protecting Group P ³ This step can be performed according to Method A, Step A2.

(Step I-7) Step I-7 is a step of subjecting compound (XXI) to a ring closure reaction to produce compound (XXII).

This step is achieved by reacting compound (XXI) with a cyclizing reagent (hydrogen sulfide reagent) in a solvent in the presence of a base.

Examples of the solvent include amides such as dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as methylene chloride, and nitriles such as acetonitrile, and acetonitrile is preferred.

As the base, tertiary amines such as triethylamine, diisopropylethylamine and tributylamine (particularly triethylamine) are preferred.

Examples of the cyclizing (desulfurizing hydrogen) reagent include mercury salts such as mercury oxide and mercury chloride, and quaternary nitrogen-containing reagents (particularly 2-chloro-1-methylpyridinium iodide or 2-chloro-1-ethylbenzoate). Xazolium tetrafluoroborate) is preferred.

The reaction temperature is usually -20 to 100 ° C (preferably 0 to 60 ° C), and the reaction time is usually 0.5 to 48 hours (preferably 1 to 12 hours).

After the completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, neutralizing and washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step I-8) In step I-8, compound (XXII) is subjected to a dehydrogenation reaction to give compound (XXII)
This is the step of manufacturing I).

In this step, compound (XXII) was added in a solvent,
It is achieved by acting a dehydrogenating reagent.

As the solvent, aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as methylene chloride and dichloroethane are used.

As a dehydrogenating reagent, an oxidizing agent such as manganese dioxide is used.

The reaction temperature is usually 0 to 100 ° C. (preferably 0 to 60 ° C.), and the reaction time is usually 0.5 to 48.
Time (preferably 1 to 12 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is not mixed with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, filtering off insolubles, washing with water, and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

(Step I-9) In Step I-9, the compound (IX-6) is obtained by removing the acyl-protecting group P ⁵ of the compound (XXIII) and then introducing a silyl-protecting group P ^3. This is the manufacturing process. (1) Step of Removing Acyl Protecting Group P ⁵ This step is the same as Method A, Step B1 (2), Compound (VIII)
Can be carried out according to the method for producing compound (VI) from (2) Step of Introducing Silyl-Based Protecting Group P ³ This step can be performed according to Method B, Step B3.

[Method J] The compound (I) can also be produced by the following method J separately from the method A. In particular, the compound (I) wherein R ¹ is represented by the formula COOR ³ or CONR ⁴ R ⁵ -
It can be applied to the production of 1) or (I-2).

[0279]

Embedded image

In the above, R ¹ , R ¹ p, R ² , P ¹ , P
³ , X, L ¹ and n are as defined above. P ³ is preferably a t-butyldimethylsilyl group.

(Step J1) In step J1, the compound (II-1) protected by a silyl protecting group P ³ and the compound (III-) wherein R ¹ p is a carboxyl group protected by an allyl group.
This is a step of producing compound (IV-1) by condensing 1).

This step can be carried out in the same manner as in the above-mentioned Method A, Step A1. The starting compound (II-
1) can be produced by allowing a silylating agent to act on compound (II), and can be carried out according to Method B, step B3. Compound (III-1) can be produced by Method B.

(Step J2) In step J2, compound (IV)
Compound (IV-2) by removing the protecting group allyl group of -1)
This is the step of manufacturing.

This step can be carried out according to the above-mentioned Method A, Step A2, Step (2).

(Step J3) In step J3, compound (IV)
Compound (IV-3) by modifying the carboxyl group of -2)
This is the step of manufacturing.

This step can be carried out according to the above-mentioned Method B, Step B4 (in particular, Method C and Method D).

(Step J4) In step J4, compound (IV)
In this step, compound (I) is produced by removing protective groups P3 and P1 in -3). (1) Removal of protecting group P ³ This step can be carried out according to the above-mentioned Method A, Step A2, Step (3). (2) Removal of protecting group P ¹ This step can be carried out in the same manner as in the above-mentioned Method A, Step A2. The compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof includes, for example, gram-positive bacteria such as staphylococci and Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, Shigella, deformed bacteria, Serratia, Enterobacter, green It has potent and balanced antibacterial activity against a wide range of pathogens, including Gram-negative bacteria such as Pseudomonas aeruginosa and anaerobic bacteria such as Bacteroides fragilis, and is particularly responsible for pneumococcus (penicillin), the causative agent of respiratory infections. Resistant bacteria), Haemophilus
It has strong antibacterial activity against influenza (including β-lactamase producing bacteria). Compound (I) of the present invention
High stability to β-lactamases, including metallo-β-lactamases. The compound (I) of the present invention, when administered orally or parenterally to a recipient, has excellent pharmacokinetics such as giving a high maximum blood concentration and a long half-life in blood. A therapeutic effect on infection can be expected even with a smaller number of administrations and a lower dose compared to drugs. Compound (I) of the present invention also has low kidney toxicity. Therefore, the compound having the general formula (I) of the present invention, or a pharmacologically acceptable salt or ester derivative thereof is useful, for example, as a medicament, and is particularly useful for treating bacterial infections caused by various pathogens, particularly respiratory infections. It is useful as an antibacterial agent for prevention (preferably treatment).

When the compound (I) or a pharmacologically acceptable salt or ester derivative thereof is used as a medicament, particularly as an antibacterial agent, the compound itself or an appropriate pharmacologically acceptable excipient or diluent may be used. And the like, and can be administered orally using tablets, capsules, granules, powders or syrups, or parenterally using injections or the like.

These preparations may contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxy Cellulose derivatives such as propylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked carboxymethylcellulose sodium; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate; Silicate derivatives such as magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; Agent Gelatin; polyvinylpyrrolidone;
Macrogol, etc.), disintegrants (for example, the above-mentioned excipients; croscarmellose sodium, carboxymethyl starch)
Disodium, chemically modified starch such as crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; metal stearate such as calcium stearate, magnesium stearate; colloidal silica) Bee gum; beeswax;
Waxes such as gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfate salts such as sodium sulfate; leucine; sodium lauryl sulfate; Lauryl sulfates such as magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (eg, paraoxybenzoic acid esters such as methylparaben and propylparaben) Chlorobutanol, benzyl alcohol
Alcohols such as phenylethyl alcohol;
Benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.) and flavoring agents (for example, commonly used sweeteners).
Additives such as acidulants, flavors, etc., suspending agents (eg, polysorbate 80, carboxymethyl cellulose sodium, etc.), diluents, formulation solvents (eg, water, ethanol, glycerin, etc.). And manufactured by a well-known method.

The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 2000 mg (preferably 10 mg).
In the case of intravenous administration, the lower limit is 10 mg (preferably 100 mg) and the upper limit is 3000 mg per dose.
(Preferably 2000 mg) is desirably administered to an adult 1 to 6 times a day depending on the symptoms.

[0291]

EXAMPLES The present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples and Formulation Examples, but the scope of the present invention is not limited thereto. For nuclear magnetic resonance spectra in the Examples and Reference Examples, using trimethylsilyl propionic acid sodium -d ₄ to the internal standard for the measurement of the heavy water and measured using tetramethylsilane as an internal standard in the other solvents. When the internal standard substance was not used in the measurement in heavy water, the signal position of proton (HOD) in heavy water was 4.65 ppm.

Example 1 (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0293]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-ethoxycarbonyl-1,3
-Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylate 486 mg (1.71 mmol) of 3-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 1 was added to dimethylformamide 15 m
hydrazine acetate at room temperature under nitrogen atmosphere
171.0 mg (1.86 mmol) was added, and the mixture was stirred as it was for 1.5 hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-) was introduced into the system under ice cooling under a nitrogen atmosphere. Methyl-carbapene-2-em-3-
A solution of 1.02 g (1.72 mmol) of carboxylate in 30 ml of acetonitrile was added dropwise, followed by 1.5 ml (8.61 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction,
Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is purified by silica gel column chromatography (elution solvent: ethyl acetate), and p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazole-) is purified. 2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate as a pale yellow solid (752 mg, yield 75%) I got it.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.6Hz), 7.66 (2H, d, J = 8.6Hz), 7.50 (1H,
S), 5.50 (1H, d, J = 13.7Hz), 5.25 (1H, d, J = 13.7H
z), 4.55 (2H, dd, J = 14.4, 8.0Hz), 4.36 (2H, q, J =
7.1Hz), 4.35-4.20 (3H, m), 4.20-4.05 (2H, m), 3.29
(1H, dd, J = 6.7, 2.4Hz), 3.20 (1H, dq, J = 10.3, 8.3
Hz), 1.82 (1H, br s), 1.42 (3H, d, J = 6.3Hz), 1.40
(3H, t, J = 7.1 Hz), 1.26 (3H, t, J = 7.5 Hz) Mass spectrum (FAB ⁺ ): 589 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [ 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3- Carboxylic acid sodium salt Compound p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine- obtained in Example 1 (1)
3-yl] thio-6-[(R) -1-hydroxyethyl]
744 mg (1.26 mmol) of 1-methyl-carbapene-2-em-3-carboxylate was added to tetrahydrofuran 46 m.
l, Dissolve in 23 ml of distilled water, and add 20% palladium hydroxide 736
In the presence of mg, catalytic hydrogen reduction was performed in a 30 ° C water bath for 1.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 106 mg of sodium hydrogen carbonate was added to the filtrate. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 3% acetonitrile-distilled water to 5% acetonitrile-distilled water to 7% acetonitrile-distilled water) )) And lyophilized to give the desired compound (1R, 5S, 6S) -2- [1- (4-
Ethoxycarbonyl-1,3-thiazol-2-yl)
Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
-Carboxylic acid was obtained as a white solid in 376 mg, 63% yield.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.68
(1H, s), 4.50 (2H, t, J = 12.6Hz), 4.40-4.10 (5H, mi
ncluding q. at 4.30 ppm, J = 8.4Hz), 4.10-3.95 (2H,
m), 3.45-3.35 (1H, m), 3.30-3.25 (1H, m), 1.30 (3H,
t, J = 8.4Hz), 1.25 (3H, d, J = 6.7Hz), 1.15 (3H, d,
J (9.2 Hz). IR (KBr): 1749, 1720, 1602, 1544, 1395, 1316 cm ^-1 Mass spectrum (FAB ⁺ ): 476 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Actual measurement : 476.0938
[M + H] ⁺ , Calculated: 476.0912 (C ₁₉ H ₂₃ O ₆ N ₃ S ₂ Na) Example 2 (1R, 5S, 6S) -2- [1- (4-Carboxyl-1,3-thiazole- 2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylic acid disodium salt

[0297]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-p-
Nitrobenzylcarbonyl-1,3-thiazole-2-
Il) Azetidine (380 mg, 1.0 mmol) was dissolved in dimethylformamide (15 ml), and hydrazine acetate (115 mg, 1.25 mmol) was added at room temperature under a nitrogen atmosphere.
Stirred for hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2 was added to the system under ice cooling under a nitrogen atmosphere.
-(Diphenylphosphoryloxy-6-[(R) -1-
A solution of 695 mg (1.17 mmol) of hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate in 30 ml of acetonitrile was added dropwise, followed by 0.84 ml (4.82 mmol) of diisopropylethylamine, and the mixture was gradually warmed to room temperature. The mixture was stirred overnight while the temperature was raised. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and p-
Nitrobenzyl (1R, 5S, 6S) -2- [1- (4
-P-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a brown foamy solid in a yield of 336 mg in 50%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.6Hz), 8.22 (2H, d, J = 8.6Hz), 7.66 (2H,
d, J = 8.6Hz), 7.59 (2H, d, J = 8.6Hz), 7.57 (1H, s),
5.51 (1H, d, J = 13.7Hz), 5.43 (2H, s), 5.25 (1H,
d, J = 13.7Hz), 4.56 (2H, dd, J = 15.7, 8.7Hz), 4.31-
4.20 (3H, m), 4.19-4.05 (3H, m), 3.29 (1H, dd, J =
7.1, 2.9Hz), 3.20 (1H, dq, J = 9.2, 7.4Hz), 1.38 (3
H, d, J = 6.5 Hz), 1.27 (3H, d, J = 7.2 Hz). Mass spectrum (FAB ⁺ ): 696 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [ 1- (4-carboxyl-1,3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-Methyl-carbapen-2-em-3-carboxylic acid disodium salt The p-nitrobenzyl (1R,
5S, 6S) -2- [1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] Dissolve 330 mg (0.474 mmol) of 1-methyl-carbapen-2-em-3-carboxylate in 16 ml of tetrahydrofuran and 8 ml of distilled water, and contact in a 30 ° C water bath in the presence of 325 mg of 20% palladium hydroxide. Hydrogen reduction was performed for 1.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered and 45 mg of sodium hydrogen carbonate was added to the filtrate. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the mixed solvent described above, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water), and lyophilized to give the target compound (1R, 5S,
6S) -2- [1- (4-Carboxyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-
86 mg of [(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid disodium salt was obtained as a white solid in a yield of 41%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.10
(1H, s), 4.35 (2H, t, J = 8.0Hz), 4.20-4.10 (1H, m),
4.10-4.00 (2H, m), 3.90-3.80 (2H, m), 3.25-3.20 (1
H, m), 3.15-3.00 (1H, m), 1.12 (3H, d, J = 6.0Hz), 1.
00 (3H, d, J = 9.2 Hz). IR (KBr): 1745, 1594, 1541, 1400, 1316, 1282 cm ^-1 . Mass spectrum (FAB ⁺ ): 470 [M + H] ⁺ Example 3 ( 1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0301]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1- (4-carbamoyl-1,3-thiazole-2 obtained in Reference Example 3 -Yl) azetidine
1.13 g (4.39 mmol) was dissolved in dimethylformamide (57 ml), and hydrazine acetate 485 was added at room temperature under nitrogen atmosphere.
mg (5.27 mmol) was added and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl]) was introduced into the system under ice cooling under a nitrogen atmosphere.
-1-Methyl-carbapene-2-em-3-carboxylate 2.61 g (4.39 mmol) of acetonitrile 130 ml
The solution was added dropwise, followed by diisopropylethylamine 3.1
ml (17.6 mmol) was added, and the mixture was stirred for 3 hours while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M brine, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
Purification with methylene chloride to 3% methanol-methylene chloride to 6% methanol-methylene chloride to 9% methanol-methylene chloride) gave p-nitrobenzyl (1R, 5S, 6).
S) -2- [1- (4-Carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6
2.61 g of [(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 94%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.48 (1H,
s), 6.99 (1H, br s), 5.55 (1H, bs), 5.51 (1H, d,
J = 13.9Hz), 5.25 (1H, d, J = 13.9Hz), 4.50 (2H, dd, J
= 16.0, 8.0Hz), 4.31-4.20 (3H, m), 4.10-4.00 (2H,
m), 3.30 (1H, dd, J = 6.6, 2.2Hz), 3.21 (1H, dq, J = 1
0.6, 8.0Hz), 1.83 (1H, br s), 1.38 (3H, d, J = 6.6H
z), 1.28 (3H, d, J = 7.3 Hz) Mass spectrum (FAB ⁺ ): 566 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [1- (4-carbamoyl-1) , 3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-Methyl-carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R,
5S, 6S) -2- [1- (4-carbamoyl-1,3
-Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapene-2-M-3-carboxylate 2.2 g
(3.93 mmol) in tetrahydrofuran 110 ml, distilled water 11
The mixture was dissolved in 0 ml and subjected to catalytic hydrogen reduction for 2 hours at room temperature in the presence of 2.2 g of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 330 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to
Purified with 2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-8% acetonitrile-distilled water) and freeze-dried to be the target compound (1R, 5S, 6S)- 2- [1- (4
-Carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt 1.12 g was obtained as a white solid in a yield of 64%.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.54 (1H, s), 4.56 (2H, t, J = 8.6Hz), 4.40-4.30 (1
H, m), 4.52 (1H, quintet, J = 6.2Hz), 4.21 (1H, dd,
J = 9.1,2.5Hz), 4.07 (2H, m), 3.44 (1H, dd, J = 6.2, 2.
5Hz), 4.07 (2H, dt, J = 8.6,4.2Hz), 3.44 (1H, dd, J =
6.2, 2.5Hz), 3.26 (1H, dd, J = 9.1, 7.2Hz), 1.30 (3
H, d, J = 6.2Hz), 1.20 (3H, d, J = 7.2Hz) IR (KBr): 1749, 1671, 1598, 1546, 1394, 1287 cm ^-1 Mass spectrum (FAB ⁺ ): 447 (M + H] ⁺ High-resolution Mass spectrum (FAB ⁺ ): Found 447.0734 [M
+ H] ^+, calcd _{447.0773 (C 17 H 20 O 5} N 4 S 2 Na) Example 4 (1R, 5S, 6S) -2- [1- (4- cyano-1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0305]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-cyano-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylate 760 mg of 3-acetylthio-1- (4-cyano-1,3-thiazol-2-yl) azetidine obtained in Reference Example 4.
(3.18 mmol) was dissolved in 38 ml of dimethylformamide,
Hydrazine acetate 351 mg (3.8
1 mmol) and stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-) was introduced into the system under ice cooling under a nitrogen atmosphere. Methyl-carbapen-2-em-3-carboxylate
A solution of 1.89 g (3.18 mmol) in 95 ml of acetonitrile was added dropwise, followed by 2.21 ml of diisopropylethylamine (12.
7 mmol) and stirred for 4 hours while gradually raising the temperature to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5M saline, saturated aqueous sodium hydrogen carbonate,
After washing with saturated saline, drying over anhydrous sodium sulfate,
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1/4 to ethyl acetate) to give p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4 -Cyano-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 1.65 g, 96% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.29 (1H,
s), 5.51 (1H, d, 13.9Hz), 5.25 (1H, d, J = 13.9Hz),
4.54 (2H, dd, J = 16.0, 8.0Hz), 4.36-4.24 (3H, m),
4.12-4.04 (2H, m), 3.30 (1H, dd, J = 6.6, 2.9Hz), 3.
20 (1H, dq, J = 9.4, 7.3Hz), 1.80 (1H, br s), 1.38
(3H, d, J = 5.9 Hz), 1.27 (3H, d, J = 7.3 Hz) Mass spectrum (FAB ⁺ ): 542 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [ 1- (4-cyano-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1R,
5S, 6S) -2- [1- (4-cyano-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 600 mg (1.11
mol) was dissolved in 30 ml of tetrahydrofuran and 30 ml of distilled water, and subjected to catalytic hydrogen reduction at room temperature in the presence of 600 mg of 10% palladium on carbon for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 93 mg of sodium hydrogen carbonate was added to the filtrate.
Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water-3% acetonitrile is added-18% acetonitrile-distilled water)
And purified by freeze-drying to obtain the target compound (1R, 5S, 6S) -2- [1- (4-cyano-).
1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
285 mg of methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 60%.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.68 (1H, s), 4.57 (2H, t, J = 8.2Hz), 4.44-4.32 (1
H, m), 4.25 (1H, quintet, J = 6.2Hz), 4.21 (1H, dd,
J = 9.0,2.3Hz), 4.07 (2H, dt, 8.2, 4.7Hz), 3.44 (1H,
dd, J = 6.2, 2.3Hz), 3.25 (1H, dq, J = 9.0, 7.2Hz),
1.31 (3H, d, J = 6.2Hz), 1.20 (3H, d, J = 7.2Hz) IR (KBr): 2231. 1750, 1599, 1549, 1470, 1397, 1307
cm ^-1 Mass spectrum (FAB ⁺ ): 429 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Found: 429.0662
[M + H] ^+, _{calcd: 429.0668 (C 17 H 18 O} 4 N 4 S 2 Na) Example 5 (1R, 5S, 6S) -2- [1- (4-N- methylcarbamoyl -1, 3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0309]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N-methylcarbamoyl-
1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidine 570 mg (2.10 mmol) obtained in Reference Example 5. The dimethylformamide
The solution was dissolved in 28 ml, and 291 mg (3.16 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 2 hours. After confirming the completion of the reaction, put p
-Nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 1.25 g (2.10 mol Acetonitrile 25)
ml solution, followed by diisopropylethylamine
1.83 ml (10.5 mmol) was added, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 3),
p-Nitrobenzyl (1R, 5S, 6S) -2- [1-
(4-N-methylcarbamoyl-1,3-thiazole-
2-yl) azetidin-3-yl] thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylate as a pale yellow solid
mg, 64% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21
(2H, d, J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.43 (1H,
s), 7.14 (1H, s), 5.51 (1H, d, J = 13.8Hz), 5.25 (1
H, d, J = 13.8Hz), 4.48 (2H, dd, J = 17.2, 8.9Hz), 4.35
-4.20 (3H, m), 4.10-4.00 (2H, m), 3.35-3.15 (2H,
m), 2.96 (3H, d, J = 5.1Hz), 1.70 (1H, br s), 1.38
(3H, d, J = 6.2 Hz), 1.27 (3H, d, J = 7.3 Hz) Mass spectrum (FAB ⁺ ): 574 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [ 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em- 3-
Carboxylic acid sodium salt p-Nitrobenzyl (1R,
5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 −
Methyl-carbapen-2-em-3-carboxylate
768 mg (1.34 mmol) was dissolved in 38 ml of tetrahydrofuran and 19 ml of distilled water, and catalytic hydrogen reduction was performed in a water bath at 30 ° C. for 1.5 hours in the presence of 757 mg of 20% palladium hydroxide.
After confirming the completion of the reaction, the reaction mixture was filtered, and 115 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate-
A tetrahydrofuran (1: 1) solution and distilled water were added to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to 3% acetonitrile-distilled water to 5% acetonitrile-distilled water), and frozen. By drying, the target compound (1R, 5S, 6
S) -2- [1- (4-N-methylcarbamoyl-1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt as a white solid 392 mg , With a yield of 64%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.30
(1H, s), 4.40 (2H, t, J = 8.0Hz), 4.30-4.18 (1H, m),
4.18-4.00 (2H, m), 3.90-3.85 (2H, m), 3.30 (1H, d
d, J = 6.3, 3.8 Hz), 3.20-3.05 (1H, m), 1.18 (3H, d,
J = 6.4Hz), 1.06 (3H, d, J = 7.2Hz) IR (KBr): 1749, 1650, 1599, 1552, 1397, 1316 cm ^-1 Mass spectrum (FAB ⁺ ) 461 [M + H] ⁺ Example 6 (1R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0313]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 −
Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-N, N-
563 mg (1.49 mmol) of dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine was dissolved in 28 ml of dimethylformamide, and 264 mg (2.87 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by 3 hours. Stirred. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate) A solution of 1.15 g (1.94 mmol) in 23 ml of acetonitrile was added dropwise, followed by diisopropyl 1.7 ml (9.76 mmol) of ethylamine was added, and the mixture was stirred overnight while gradually warming to room temperature. The obtained organic layer was subjected to liquid extraction at 0.5 M.
After washing sequentially with aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline, the extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 3) to give p-nitrobenzyl (1R, 5S, 6S)-.
2- [1- (4-N, N-dimethylcarbamoyl-1,3
-Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 777 mg, 68% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22
(2H, d, J = 8.2Hz), 7.66 (2H, d, J = 8.2Hz), 7.09 (1H,
s), 5.50 (1H, d, J = 13.5Hz), 5.25 (1H, d, J = 13.5H
z), 4.60-4.40 (2H, m), 4.35-4.20 (3H, m), 4.20-4.00
(2H, m), 3.32-3.25 (1H, m), 3.25-3.12 (4H, m), 3.0
5 (3H, br s), 1.57 (1H, br s), 1.38 (3H, d, J = 6.2H
z), 1.25 (3H, d, J = 7.1 Hz) Mass spectrum (FAB +): 588 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [1- (4-N, N-
Dimethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl obtained in Example 6 (1) (1R,
5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
772 mg (1.31 mmol) of 1-methyl-carbapen-2-em-3-carboxylate was added to 38 ml of tetrahydrofuran,
Dissolve in 19 ml of distilled water and add 20% palladium hydroxide 768
In the presence of mg, catalytic hydrogen reduction was performed in a 30 ° C water bath for 1.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 112 mg of sodium hydrogen carbonate was added to the filtrate. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the mixed solvent described above, concentrated under reduced pressure, purified by chromatography using Cosmoseal, and freeze-dried to give the target compound (1R, 5S, 6S) -2- [1- [1- (4-N,
N-dimethylcarbamoyl-1,3-thiazole-2-
Yl) azetidin-3-yl] thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt as a white solid 3
It was obtained in 75 mg in a yield of 60%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.00
(1H, s), 4.56-4.36 (2H, m), 4.31-4.21 (1H, m), 4.2
1-4.06 (2H, m), 4.01-3.91 (2H, m), 3.41-3.32 (1H,
m), 3.21-3.11 (1H, m), 3.00 (3H, s), 2.91 (3H, s),
1.21 (3H, d, J = 6.4Hz), 1.11 (3H, d, J = 7.1Hz) IR (KBr): 1750, 1610, 1540, 1397, 1305 cm ^-1 Mass spectrum (FAB ⁺ ): 475 (M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): found: 475.1085
[M + H] ^+, _{calcd: 475.1087 (C 19 H 24 O} 5 N 4 S 2 Na) Example 7 (1R, 5S, 6S) -2- [1- (4-N- ethylcarbamoyl -1, 3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0317]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N-ethylcarbamoyl-
1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate 450 mg (1.58 mmol) of 3-acetylthio-1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 7. The dimethylformamide
The solution was dissolved in 23 ml, and 174 mg (1.89 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-) was introduced into the system under ice cooling under a nitrogen atmosphere. Methyl-carbapene-2-m-3
-A solution of 939 mg (1.58 mmol) of carboxylate in 47 ml of acetonitrile was added dropwise, followed by 1.10 ml (6.31 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to 10% methanol-ethyl acetate) to give p-nitrobenzyl (1R, 5S, 6).
S) -2- [1- (4-N-ethylcarbamoyl-1,3
-Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 753 mg, 81% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.43 (1H,
s), 7.12 (1H, t, J = 5.1Hz), 5.51 (1H, d, J = 13.9H
z), 5.25 (1H, d, J = 13.9Hz), 4.49 (2H, dd, J = 16.1,
8.1Hz), 4.32-4.20 (3H, m), 4.10-4.00 (2H, m), 3.44
(2H, dq, J = 7.3, 5.0Hz), 3.29 (1H, dd, J = 7.3, 2.9H
z), 3.21 (1H, dq, J = 8.9, 7.3Hz), 1.38 (3H, d, J = 5.
9Hz), 1.28 (3H, d, J = 7.3Hz), 1.23 (3H, t, J = 7.3Hz) Mass spectrum (FAB ⁺ ): 588 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-
Carboxylic acid sodium salt p-nitrobenzyl (1R,
5S, 6S) -2- [1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 −
Methyl-carbapen-2-em-3-carboxylate
750 mg (1.23 mmol) was dissolved in 38 ml of tetrahydrofuran and 38 ml of distilled water, and subjected to catalytic hydrogen reduction at room temperature in the presence of 750 mg of 10% palladium carbon for 1.7 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and sodium hydrogen carbonate was added to the filtrate.
103 mg was added. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: acetonitrile is added to 3% each of distilled water to 21% acetonitrile-distilled water), and the target compound is obtained by freeze-drying. (1R, 5S, 6S) -2- [1-
(4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
384 mg of -M-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 66%.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.45 (1H, s), 4.60-4.48 (2H, m), 4.40-4,29 (1H, m),
4.25 (1H, quintet, J = 6.2Hz), 4.20 (1H, dd, J = 9.1,
2.3Hz), 4.12-4.00 (2H, m), 3.43 (1H, dd, J = 6.2,
2.3Hz), 3.37 (3H, q, J = 7.2Hz), 3.32-3.18 (1H, m),
1.30 (3H, d, J = 6.2Hz), 1.20 (3H, d, J = 7.2Hz), 1.19
(3H, t, J = 7.2Hz) IR (KBr): 1750, 1659, 1604, 1548, 1394, 1315 cm ^-1 Mass spectrum (FAB ⁺ ): 475 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Observed value: 475.1070
[M + H] ^+, _{calcd: 475.1086 (C 19 H 24 O} 5 N 4 S 2 Na) Example 8 (1R, 5S, 6S) -2- [1- (4-N- isopropylcarbamoyl -1, 3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylic acid sodium salt

[0321]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine-3-
Yl] thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine 460 mg (1.65 mmol) obtained in Reference Example 8. ) Was dissolved in 23 ml of dimethylformamide, 182 mg (1.98 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S)-
2- (diphenylphosphoryloxy-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
A solution of 981 mg (1.65 mmol) of em-3-carboxylate in 49 ml of acetonitrile was added dropwise, followed by 1.15 ml (6.60 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, and then washed.
After drying over anhydrous magnesium sulfate, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2).
To ethyl acetate to 5% methanol-ethyl acetate) to give p-nitrobenzyl (1R, 5S, 6S) -2- [
1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6
-[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 790 mg in a yield of 80%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.42 (1H,
s), 6.95 (1H, d, J = 8.1Hz), 5.51 (1H, d, J = 13.6H
z), 5.25 (1H, d, J = 13.6Hz), 4.49 (2H, dd, J = 14.6,
8.1Hz), 4.32-3.40 (5H, m), 3.30 (1H, dd, J = 7.3, 2.9
Hz), 3.21 (1H, dq, J = 8.8, 7.3Hz), 1.60 (1H, br s),
1.38 (1H, d, J = 6.6 Hz), 1.30-1.20 (9H, m) Mass spectrum (FAB ⁺ ): 602 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3 -Carboxylic acid sodium salt The p-nitrobenzyl (1R,
5S, 6S) -2- [1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapen-2-em-3-carboxylate (790 mg, 1.31 mmol) was added to tetrahydrofuran 40
dissolved in 40 ml of distilled water and 10% palladium on carbon 790 m
In the presence of g, catalytic hydrogen reduction was performed at room temperature for 1.7 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 110 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: acetonitrile is added to distilled water by 4% to 20% acetonitrile-distilled water), and the target compound is obtained by freeze-drying. (1R, 5S, 6S) -2-
[1- (4-N-isopropylcarbamoyl-1,3-
Thiazol-2-yl) azetidin-3-yl] thio-
6-[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 389 mg, yield 61%.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.45 (1H, s), 4.55 (2H, t, J = 8.4Hz), 4.40-4.30 (1
H, m), 4.25 (1H, quintet, J = 6.3Hz), 4.19 (1H, dd,
J = 9.0,2.4Hz), 4.14-4.03 (3H, m), 3.43 (1H, dd, J =
6.3, 2.4Hz), 3.25 (1H, dq, J = 9.0, 7.2Hz), 1.30 (3
H, d, J = 6.3Hz), 1.23 (6H, d, J = 6.7Hz), 1.20 (3H,
d, J = 7.2Hz) IR (KBr): 1751, 1657, 1548, 1492, 1469, 1393, 130
3, 1263 cm ^-1 Mass spectrum (FAB ⁺ ): 489 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: 489.1234
[M + H] ^+, _{calcd: 489.1242 (C 20 H 26 O} 5 N 4 S 2 Na) EXAMPLE 9 (1R, 5S, 6S) -2- [1- (4-N- cyclopentylcarbamoyl -1, 3-thiazol-2-yl)
Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
-Carboxylic acid sodium salt

[0325]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N-Cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-N-cyclopentylcarbamoyl-1,3-thiazole-2- obtained in Reference Example 9.
Il) Azetidine (550 mg, 1.67 mmol) was dissolved in dimethylformamide (28 ml), hydrazine acetate (187 mg, 2.03 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S)-
2- (diphenylphosphoryloxy-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
A solution of 993 mg (1.67 mmol) of em-3-carboxylate in 50 ml of acetonitrile was added dropwise, followed by 1.16 ml (6.68 mmol) of diisopropylethylamine. The mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, and then washed.
The extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and p-nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N-Cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
346 mg of 1-methyl-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 33%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.24
(2H, d, J = 8.0Hz), 7.66 (2H, d, J = 8.0Hz), 7.42 (1H,
S), 7.05 (1H, bd, J = 8.0Hz), 5.51 (1H, d, J = 13.6H
z), 5.26 (1H, d, J = 13.6Hz), 4.49 (2H, dd, J = 15.6,
8.1Hz), 4.38-4.24 (3H, m), 4.10-4.00 (2H, m), 3.30
(1H, dd, J = 6.2, 2.1Hz), 3.22 (1H, dq, J = 9.4, 8.3H
z), 2.12-2.00 (2H, m), 1.81 (1H, br s), 1.78-1.44
(6H, m), 1.38 (3H, d, J = 5.8Hz), 1.28 (3H, d, J = 7.3
Hz) Mass spectrum (FAB ⁺ ): 628 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [1- (4-N-cyclopentylcarbamoyl-1,3-thiazole-2-
Yl) azetidin-3-yl] thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1R,
5S, 6S) -2- [1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 340 mg (0.542 mmol) of -methyl-carbapene-2-em-3-carboxylate was dissolved in 17 ml of tetrahydrofuran and 17 ml of distilled water, and catalytic hydrogen reduction was carried out at room temperature in the presence of 340 mg of 10% palladium on carbon for 2 hours. went. After confirming the completion of the reaction, the reaction mixture was filtered, and 46 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water 44% each of acetonitrile is added to 22
8% acetonitrile-distilled water) and lyophilized to give the desired compound (1R, 5S, 6S).
-2- [1- (4-N-cyclopentylcarbamoyl-
1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 159 mg, in a yield of 57%.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.45 (1H, s), 4.55 (1H, dt, J = 8.1, 1.3Hz), 4.40-4.
30 (1H, m), 4.30-4.16 (3H, m including q at 4.25,
J = 6.3Hz, and dd at 4.19, J = 9.1, 2.6Hz), 4.12-4.00
(2H, m), 3.43 (1H, dd, J = 6.3, 2.6Hz), 3.24 (1H, d
q, J = 9.1, 7.3Hz), 2.06-1.94 (2H, m), 1.80-1.50 (6
H, m), 1.30 (3H, d, J = 6.3Hz), 1.19 (3H, d, J = 7.3H
z) IR (KBr): 1751, 1658, 1605, 1547, 1393, 1315 cm ^-1 Mass spectrum (FAB ⁺ ): 515 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Observed value: 515.1398
[M + H] ^+, _{calcd: 515.1399 (C 22 H 28 O} 5 N 4 S 2 Na) Example 10 (1R, 5S, 6S) -2- [1- ( carboxymethyl-carbamoyl 4-N- cyclohexane - 1,3-thiazol-2-yl)
Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
-Carboxylic acid sodium salt

[0329]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-N-
Cyclohexylcarbamoyl-1,3-thiazole-2
-Yl) azetidine (121 mg, 1.09 mmol) was dissolved in dimethylformamide (19 ml), and hydrazine acetate (121 mg, 1.31 mmol) was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, under a nitrogen atmosphere,
P-Nitrobenzyl (1R, 5S, 6)
S) -2- (Diphenylphosphoryloxy-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 648 mg (1.09
Then, 0.759 ml (4.36 mmol) of diisopropylethylamine was added thereto, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 4 to ethyl acetate to 5% methanol-ethyl acetate) to give p-nitrobenzyl (1R, 5S, 6).
S) -2- [1- (4-N-Cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidine-3-
Yl] thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in an amount of 598 mg in a yield of 86%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.42 (1H,
s), 7.00 (1H, d, J = 8.8Hz), 5.51 (1H, d, J = 13.5H
z), 5.25 (1H, d, J = 13.5Hz), 4.49 (2H, dd, J = 15.4,
8.8Hz), 4.32-4.20 (3H, m), 4.11-4.00 (2H, m), 3.96-
3.80 (1H, m), 3.29 (1H, dd, J = 6.6, 2.2Hz), 3.21 (1
H, dq, J = 8.8, 7.3Hz), 2.01-1.18 (16H, m including
3H, d at 1.38, J = 5.9 Hz and 3H, d at 1.28, J = 7.3 Hz) Mass spectrum (FAB ⁺ ): 642 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [ 1- (4-N-cyclohexylcarbamoyl-1,3-thiazole-2-
Yl) azetidin-3-yl] thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 10 (1)
R, 5S, 6S) -2- [1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapene-2-em-3-carboxylate (590 mg, 0.919 mmol) was dissolved in tetrahydrofuran (30 ml) and distilled water (30 ml), and contact hydrogen was added at room temperature in the presence of 10% palladium carbon (590 mg). Reduction was performed for 3 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 77 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: acetonitrile is added to each of distilled water to 4% to 28% acetonitrile-distilled water), and frozen. By drying, the target compound (1R, 5S, 6S) -2- [1- (4-N-cyclohexylcarbamoyl-1,3-thiazole-2-) is obtained.
Yl) azetidin-3-yl] thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt as a white solid 3
18 mg was obtained in a yield of 66%.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.45 (1H, s), 4.55 (2H, dt, J = 8.5, 1.9Hz), 4.40-4.
30 (1H, m), 4.25 (1H, quintet, J = 6.3Hz), 4.19 (1H,
dd, J = 9.0, 2.4Hz), 4.10-4.00 (2H, m), 3.80-3.70 (1
H, m), 3.43 (1H, dd, J = 6.3, 2.4Hz), 3.24 (1H, dq,
J = 9.0, 7.1Hz), 1.96-1.84 (2H, m), 1.83-1.70 (2H,
m), 1.69-1.58 (1H, m), 1.46-1.10 (11H, m including
3H, d, at 1.30, J = 6.3Hz, and 3H, d, at 1.19, J = 7.
1Hz) IR (KBr): 1751, 1660, 1605, 1545, 1492, 1393, 131
0, 1296 cm ^-1 Mass spectrum (FAB ⁺ ): 529 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Found: 529.1575
[M + H] ^+, _{calcd: 529.1555 (C 23 H 30 O} 5 N 4 S 2 Na) Example 11 (1R, 5S, 6S) -2- [1- (4- morpholinocarbonyl-1,3 Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0333]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-morpholinocarbonyl-1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate Obtained in Reference Example 11. 3-acetylthio-1- (4-morpholinocarbonyl-1,3-thiazol-2-yl)
Azetidine (410 mg, 1.50 mmol) was dissolved in dimethylformamide (20 ml), and hydrazine acetate (138 mg, 1.50 mmol) was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(A solution of 743 mg (1.25 mmol) of diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate in 37 ml of acetonitrile) was added dropwise, followed by Then, 0.873 ml (5.01 mmol) of diisopropylethylamine was added thereto, and the mixture was stirred overnight while gradually warming to room temperature.After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system.
The aqueous layer was separated and extracted with ethyl acetate. Remove the obtained organic layer from 0.
After washing sequentially with 5M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline,
The extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to 10% methanol-ethyl acetate), and p-nitrobenzyl (1R, 5
S, 6S) -2- [1- (4-morpholinocarbonyl-
1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 485 mg, 62% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.19 (1H,
s), 5.51 (1H, d, J = 13.9Hz), 5.25 (1H, d, J = 13.9H
z), 4.50 (2H, ddd, J = 13.9, 8.1, 2.2Hz), 4.35-4.20
(3H, m), 4.10-4.00 (2H, m), 3.95-3.60 (8H, m), 3.2
9 (1H, dd, J = 6.6, 2.2Hz), 3.20 (1H, dq, J = 8.8, 7.3
Hz), 1.38 (3H, d, J = 6.6 Hz), 1.27 (3H, d, J = 7.3 Hz) Mass spectrum (FAB ⁺ ): 630 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2- M-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 11 (1)
R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
480 mg (0.762 mmol) of 1-methyl-carbapene-2-em-3-carboxylate was added to 24 m of tetrahydrofuran.
l, Dissolved in 24 ml of distilled water, 10% palladium on carbon 480 m
In the presence of g, catalytic hydrogen reduction was performed at room temperature for 1.3 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 64 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: acetonitrile is added to each of distilled water to 3% to 15% acetonitrile-distilled water), and the target compound is obtained by freeze-drying. (1R, 5S, 6S) -2- [
1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
236 mg of 2-M-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 60%.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.15 (1H, s), 4.56 (2H, dt, J = 8.4, 0.9Hz), 4.42-4.
32 (1H, m), 4.25 (1H, quintet, J = 6.3Hz), 4.21 (1H,
dd, J = 9.0, 2.3Hz), 4.05 (2H, m), 3.90-3.60 (8H,
m), 3.44 (1H, dd, J = 6.3, 2.3Hz), 3.25 (1H, dq, J =
9.0, 7.3Hz), 1.30 (3H, d, J = 6.3Hz), 1.20 (3H, d, J
= 7.3Hz) IR (KBr): 1799, 1608, 1536, 1392, 1311, 1236, 1113
cm ^-1 Mass spectrum (FAB ⁺ ): 517 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Found: 517.1186
[M + H] ⁺ , Calculated: 517.1192 (C ₂₁ H ₂₆ O ₆ N ₄ S ₂ Na) Example 12 (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3- Thiazol-2-yl) piperidine-
4-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0337]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-Ethoxycarbonyl-3-thiazol-2-yl) piperidin-4-yl] thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 4-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazole obtained in Reference Example 13 -2-yl) piperidine 400 mg (1.27 mmol) in dimethylformamide
The solution was dissolved in 12 ml, and hydrazine acetate (152 mg, 1.65 mmol) was added at room temperature under a nitrogen atmosphere, followed by stirring for 2.5 hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(A solution of 755 mg (1.27 mmol) of diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate in 21 ml of acetonitrile was added dropwise, followed by diisopropyl Ethylamine (1.11 ml, 6.37 mmol) was added, and the mixture was stirred overnight while gradually warming to room temperature.After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated with ethyl acetate. The obtained organic layer was subjected to liquid extraction at 0.5 M.
After washing with aqueous hydrochloric acid, saturated saline and saturated saline, the extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to give p-nitrobenzyl (1R, 5).
S, 6S) -2- [1- (4-ethoxycarbonyl-
1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate 296 mg, obtained as a pale yellow solid, in a yield of 38%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.27
(2H, d, J = 8.7Hz), 7.71 (2H, d, J = 8.7Hz), 7.51 (1H,
s), 5.56 (1H, d, J = 13.7Hz), 5.28 (1H, d, J = 13.7H
z), 4.40 (2H, q, J = 7.1Hz), 4.39-4.30 (2H, m), 4.10-
4.00 (2H, m), 3.60-3.20 (5H, m), 2.20-2.00 (2H,
m), 1.90-1.70 (3H, m), 1.43 (3H, d, J = 6.5Hz), 1.41
(3H, t, J = 7.1 Hz), 1.36 (7.2 Hz) (2) (1R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidine-4 -Yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 12 (1)
R, 5S, 6S) -2- [1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidin-4-
Yl] thio-6-[(R) -1-hydroxyethyl] -1
291 mg (0.578 mmol) of -methyl-carbapene-2-em-3-carboxylate in 14 ml of tetrahydrofuran,
Dissolve in 7 ml of distilled water and 291 mg of 20% palladium hydroxide
In the presence, catalytic hydrogen reduction was performed in a 30 ° C. water bath for 1.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered and 42 mg of sodium hydrogen carbonate was added to the filtrate. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the mixed solvent described above, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to 5% acetonitrile-distilled water to 7% acetonitrile-distilled water), and frozen. By drying, the target compound (1R, 5S,
6S) -2- [1- (4-ethoxycarbonyl-1,3
-Thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 69 mg, yield 29%.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.69 (1H, s), 4.35 (2H, q, J = 7.1Hz), 4.30-4.20 (2
H, m including dd at 4.23, J = 9.2, 2.5Hz), 4.00-3.8
5 (2H, m), 3.55-3.20 (5H, m) 2.20-2.05 (2H, m), 1.75
-1.60 (2H, m), 1.36 (3H, t, J = 7.1Hz), 1.31 (3H, d,
J = 6.4Hz), 1.23 (3H, d, J = 7.2Hz) IR (KBr): 1750, 1729, 1603, 1540, 1448, 1385, 133
7, 1265, 1223, 1210 cm ^-1 Mass spectrum (FAB ⁺ ): 504 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Actual value: 504.1246
[M + H] ⁺ , Calculated: 504.1239 (C ₂₁ H ₂₇ O ₆ N ₃ S ₂ Na) Example 13 (1R, 5S, 6S) -2- [1- (4-Carboxyl-1,3-thiazole) -2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylic acid disodium salt

[0341]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-p-nitrobenzyloxycarbonyl-3-thiazol-2-yl) piperidine-4
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapen-2-em-3-carboxylate 4-acetylthio-1- (4-p
-Nitrobenzylcarbonyl-1,3-thiazole-2
-Yl) Piperidine (150 mg, 0.353 mmol) was dissolved in dimethylformamide (7.5 ml), hydrazine acetate (46 mg, 0.49 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, under a nitrogen atmosphere,
P-Nitrobenzyl (1R, 5S, 6)
S) -2- (Diphenylphosphoryloxy-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 200 mg (0.353
mmol) in 3.0 ml of acetonitrile, followed by 0.09 ml (0.517 mmol) of diisopropylethylamine.
, And the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) was used. ) Piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 220 mg as a pale yellow solid, obtained in 89% yield. .

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.6Hz), 8.22 (2H, d, J = 8.6Hz), 7.66 (2H,
d, J = 8.6Hz), 7.59 (2H, d, J = 8.6Hz), 7.53 (1H, s),
5.51 (1H, d, J = 13.8Hz), 5.43 (2H, s), 5.22 (1H,
d, J = 13.8Hz), 4.35-4.20 (2H, m), 4.05-3.90 (2H,
m), 3.50-3.10 (6H, m), 2.20-1.95 (2H, m), 1.90-1.5
0 (3H, m), 1.38 (3H, d, J = 6.2Hz), 1.31 (3H, d, J =
7.2 Hz) Mass spectrum (FAB ⁺ ): 724 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [1- (4-carboxyl-1,3-thiazol-2-yl) piperidine-
4-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapene-2-em-3-carboxylic acid disodium salt p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-p) obtained in Example 13 (1)
-Nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 570 mg (0.788
(mmol) was dissolved in tetrahydrofuran (38 ml) and distilled water (19 ml) at 30 ° C in the presence of 572 mg of 20% palladium hydroxide.
The catalytic hydrogen reduction was performed in a water bath for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and sodium hydrogen carbonate was added to the filtrate.
mg was added. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to 3% acetonitrile-distilled water), and lyophilized to give the desired compound. There is (1
R, 5S, 6S) -2- [1- (4-carboxyl-
1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylic acid disodium salt was obtained as a white solid, 285 mg, yield 76%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.22
(1H, s), 4.30-4.10 (2H, m), 4.00-3.78 (2H, m), 3.6
0-3.05 (5H, m), 2.15-2.00 (2H, m), 1.80-1.55 (2H,
m), 1.26 (3H, d, J = 6.4 Hz), 1.18 (3H, d, J = 7.2 Hz) IR (KBr): 1747, 1597, 1532, 1397, 1289 cm ^-1 Example 14 (1R, 5S , 6S) -2- [1- (4-Carbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0345]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-Carbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 4-acetylthio-1- (4-carbamoyl-1,3-thiazole-2 obtained in Reference Example 15 -Yl) piperidine (400 mg, 1.40 mmol) was dissolved in dimethylformamide (20 ml), and hydrazine acetate 142 was dissolved at room temperature under a nitrogen atmosphere.
mg (1.54 mmol) was added, and the mixture was stirred for 2 hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl]-
A solution of 1.25 g (2.10 mmol) of 1-methyl-carbapene-2-em-3-carboxylate in 37 ml of acetonitrile was added dropwise, followed by 0.61 ml of diisopropylethylamine.
ml (3.50 mmol) was added, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1), and p-nitrobenzyl (1R, 5S, 6S) -2- [
1- (4-carbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3- 348 mg of carboxylate as pale yellow solid,
Obtained in 42% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22
(2H, d, J = 8.6Hz), 7.66 (2H, d, J = 8.6Hz), 7.44 (1H,
s), 6.99 (1H, br s), 5.56 (1H, br s), 5.51 (1H,
d, J = 13.8Hz), 5.24 (1H, d, J = 13.8Hz), 4.35-4.20 (2
H, m including dd at 4.28, J = 9.7, 2.9Hz), 4.04-3.85
(3H, m), 3.50-3.10 (6H, m), 2.20-2.00 (2H, m), 1.9
5-1.70 (3H, m), 1.39 (3H, d, J = 6.3Hz), 1.31 (3H,
d, J = 7.3 Hz) Mass spectrum (FAB +): 587 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) Piperidine-
4-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 14 (1)
R, 5S, 6S) -2- [1- (4-carbamoyl-
1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate
493 mg (0.839 mmol) in tetrahydrofuran 30 ml,
Dissolve in 15 ml of distilled water and add 0.50 g of 20% palladium hydroxide
In the presence, catalytic hydrogen reduction was performed in a 30 ° C. water bath for 2 hours.
After confirming the completion of the reaction, the reaction mixture was filtered, and 71 mg of sodium hydrogen carbonate was added to the filtrate. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to 3% acetonitrile-distilled water to 5% acetonitrile-distilled water), and frozen. By drying, the target compound (1R, 5S, 6
S) -2- [1- (4-Carbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 127 mg, yield 32%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.70
(1H, s), 4.50-4.35 (2H, m including dd at 4.18, J =
9.2, 2.8Hz), 4.00-3.80 (2H, m), 3.50-3.10 (5H, m),
2.15-1.95 (2H, m), 1.75-1.55 (2H, m), 1.26 (3H,
d, J = 6.5Hz), 1.19 (3H, d, J = 9.0Hz) IR (KBr): 1749, 1667, 1594, 1547, 1386 cm ^-1 Mass spectrum (FAB ⁺ ): 475 [M + H] ⁺ High-resolution mass spectrum (FAB ₊ ): Found: 475.1070
[M + H] ^+, _{calcd: 475.1086 (C 19 H 24 O} 5 N 4 S 2 Na) Example 15 (1R, 5S, 6S) -2- [1- (4-N- methylcarbamoyl -1, 3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0349]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N-methylcarbamoyl-
1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate 4-acetylthio-1- (4-N-
Methylcarbamoyl-1,3-thiazol-2-yl)
1.21 g (4.04 mmol) of piperidine was dissolved in 36 ml of dimethylformamide, 408 mg (4.43 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1.5 hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
A solution of 3.12 g (5.25 mmol) of (diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate in 72 ml of acetonitrile was added dropwise, followed by diisopropyl Ethylamine (1.76 ml, 10.1 mmol) was added, and the mixture was stirred overnight while gradually warming to room temperature.After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated with ethyl acetate. The obtained organic layer was subjected to liquid extraction at 0.5 M.
The extract was washed with aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 20: 1) to give p-nitrobenzyl (1R, 5S, 6S)-.
2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6
-[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 1.336 g, 55% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21
(2H, d, J = 8.0Hz), 7.64 (2H, d, J = 8.0Hz), 7.40 (1H,
s), 7.19 (1H, br s), 5.50 (1H, d, J = 12.8Hz), 5.22
(1H, d, J = 12.8Hz), 4.40-4.20 (2H, m), 4.00-3.80
(2H, m), 3.50-3.10 (5H, m), 2.95 (3H, d, J = 6.4Hz),
2.15-1.90 (3H, m), 1.90-1.70 (2H, m), 1.39 (3H, d,
J = 6.4Hz), 1.20 (3H, d, J = 9.6Hz) Mass spectrum (FAB ⁺ ): 602 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [1- (4- N-methylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 15 (1)
R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine-
4-yl] thio-6-[(R) -1-hydroxyethyl]
857 mg (1.424 mol) of -1-methyl-carbapen-2-em-3-carboxylate was added to 40 m of tetrahydrofuran.
l, Dissolve in 20 ml of distilled water and add 20% palladium hydroxide 853
In the presence of mg, catalytic hydrogen reduction was performed in a 30 ° C water bath for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 120 mg of sodium hydrogen carbonate was added to the filtrate. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the above mixed solvent, concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 3% acetonitrile-distilled water to 2% acetonitrile is added to 9% acetonitrile-distilled water) )) And freeze-dried to give the desired compound (1R, 5S, 6S) -2- [1- (4
-N-methylcarbamoyl-1,3-thiazole-2-
Yl) piperidin-4-yl] thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt as a white solid 31
7 mg, yield 46%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.34
(1H, s), 4.25-4.10 (2H, m including dd at 4.16, J =
9.2, 2.2Hz), 3.95-3.80 (2H, m), 3.50-3.10 (5H, m),
2.84 (3H, s), 2.15-1.95 (2H, m), 1.75-1.50 (2H,
m), 1.24 (3H, d, J = 6.3Hz), 1.17 (3H, d, J = 7.3Hz) IR (KBr): 1750, 1654, 1602, 1553, 1385, 1266 cm ^-1 Mass spectrum (FAB ⁺ ): 489 [M + H] ⁺ high-resolution mass spectrum (FAB +): measured: 489.1255
[M + H] ^+, _{calcd: 489.1242 (C 20 H 26 O} 5 N 4 S 2 Na) EXAMPLE 16 (1R, 5S, 6S) -2- [1- (4-N, N- dimethylcarbamoyl - 1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0353]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1 −
Methyl-carbapen-2-em-3-carboxylate 4-acetylthio-1- (4-N,
620 mg (1.98 mmol) of N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine was dissolved in 35 ml of dimethylformamide, and 201 mg (2.18 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere. 1 as it is
Stirred for hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2 was added to the system under ice cooling under a nitrogen atmosphere.
-(Diphenylphosphoryloxy-6-[(R) -1-
[Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 2.35 g (3.96 mmol) of acetonitrile in 65 ml was added dropwise, followed by 1.40 ml (8.04 mmol) of diisopropylethylamine. The mixture was stirred overnight while the temperature was raised. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, and then washed.
The extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1), and p-nitrobenzyl (1
R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 495 mg in a yield of 41%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22
(2H, d, J = 8.7Hz), 7.66 (2H, d, J = 8.7Hz), 7.09 (1H,
s), 5.51 (1H, d, J = 13.8Hz), 5.23 (1H, d, J = 13.8H
z), 4.35-4.20 (2H, m), 4.00-3.85 (2H, m), 3.50-3.00
(12H, m including 3H x2, each br s at 3.22 and 3.0
7), 2.20-1.95 (2H, m), 1.93-1.70 (3H, m), 1.38 (3H, m
d, J = 6.2 Hz), 1.31 (3H, d, J = 7.3 Hz) Mass spectrum (FAB ⁺ ): 616 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [1- ( 4-N, N-
Dimethylcarbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt P-Nitrobenzyl (1) obtained in Example 16 (1)
R, 5S, 6S) -2- [1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-[(R) -1-hydroxy 487 mg (0.791 mmol) of [ethyl] -1-methyl-carbapen-2-em-3-carboxylate was dissolved in 22 ml of tetrahydrofuran and 11 ml of distilled water. Hydrogen reduction by 1.5
Time went. After confirming the completion of the reaction, the reaction mixture was filtered, and 67 mg of sodium hydrogen carbonate was added to the filtrate. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 5% acetonitrile-distilled water to 7% acetonitrile-distilled water to 9% acetonitrile-distilled water) )) And lyophilized to give the desired compound (1R, 5S, 6S) -2-
[1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) piperidin-4-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 183 mg in a yield of 46%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.00
(1H, s), 4.30-4.10 (2H, m including dd at 4.17, J =
9.0, 2.3Hz), 3.95-3.75 (2H, m), 3.50-3.10 (5H, m),
3.07 (3H, s), 3.00 (3H, s), 2.15-1.95 (2H, m), 1.8
0-1.50 (2H, m), 1.25 (3H, d, J = 6.3Hz), 1.18 (3H, d,
J (7.2 Hz) IR (KBr): 1750, 1612, 1538, 1395 cm ^-1 Mass spectrum (FAB ⁺ ): 503 [M + H] ⁺ Example 17 (1R, 5S, 6S) -2-[(3S ) -1- (4-Carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3 -Carboxylic acid sodium salt

[0357]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2-[(3S) -1- (4-carbamoyl-1,
3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate Obtained in Reference Example 18. (3S) -3-acetylthio-1
210 mg (0.721 mmol) of-(4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine was dissolved in 10 ml of dimethylformamide, and 80 mg (0.865 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere. The mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S)-
2- (diphenylphosphoryloxy-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
A solution of 429 mg (0.721 mmol) of em-3-carboxylate in 20 ml of acetonitrile was added dropwise, followed by 0.502 ml (2.88 mmol) of diisopropylethylamine. The mixture was stirred overnight while gradually warming to room temperature.
After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: methylene chloride to 10% methanol-
Purified with methylene chloride), p-nitrobenzyl (1
R, 5S, 6S) -2-[(3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
412 mg of 1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 100%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22
(2H, d, J = 8.8Hz), 7.65 (2H, d, J = 8.8Hz), 7.40 (1H,
s), 7.03 (1H, br s), 5.50 (1H, d, J = 13.6Hz), 5.48
(1H, br s), 5.22 (1H, d, J = 13.6Hz), 4.36-4.25 (2
H, m including dd at 4.32, J = 9.5, 2.2Hz), 3.71-3.60
(1H, m), 3.60-3.49 (2H, m), 3.40 (1H, dq, J = 9.5,
7.3Hz), 3.30 (1H, dd, J = 6.6, 2.2Hz), 2.60-2.45 (1
H, m), 2.40-2.05 (1H, m), 1.77 (1H, d, J = 4.4Hz),
1.39 (3H, d, J = 6.6 Hz), 1.31 (3H, d, J = 7.3 Hz) Mass spectrum (FAB ⁺ ): 574 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [(3S) -1- (4
-Carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 17 (1)
R, 5S, 6S) -2-[(3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
410 mg (0.715 mmol) of 1-methyl-carbapene-2-em-3-carboxylate was added to 15 m of tetrahydrofuran.
l, Dissolved in 15 ml of distilled water, 10% palladium on carbon 410 mg
In the presence, catalytic hydrogen reduction was performed at room temperature for 1.7 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 60 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water 33% each by adding acetonitrile 〜12% acetonitrile-distilled water), and lyophilized to give the target compound. (1R, 5S, 6S) -2-
[(3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 150 mg, yield 46%.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.41 (1H, s), 4.35-4.20 (2H, m), 4.05 (1H, quintet,
J = 5.2Hz), 3.90 (1H, dd, J = 10.8, 5.9Hz), 3.75-3.65
(1H, m), 3.60-3.40 (4H, m), 2.60-2.45 (1H, m), 2.
20-2.15 (1H, m), 1.31 (3H, d, J = 6.4Hz), 1.25 (3H,
d, J = 8.9Hz) IR (KBr): 1749, 1669, 1599, 1557, 1391, 1289 cm ^-1 Mass spectrum (FAB ⁺ ): 461 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Actual measurement Value: 461.0926
[M + H] ^+, _{calcd: 461.0929 (C 18 H 22 O} 5 N 4 S 2 Na) EXAMPLE 18 (1R, 5S, 6S) -2 - [(3S) - 1- (4- cyano -1 , 3-thiazol-2-yl) pyrrolidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid
Sodium salt

[0361]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2-[(3S) -1- (4-cyano-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (3S) -3-acetylthio-1- obtained in Reference Example 19.
137 mg (0.541 mmol) of (4-cyano-1,3-thiazol-2-yl) pyrrolidine was added to dimethylformamide 7
hydrazine acetate at room temperature under nitrogen atmosphere
60 mg (0.649 mmol) was added, and the mixture was stirred as it was for 1 hour. After confirming the completion of the reaction, put p
-Nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 322 mg (0.541 mmol) ) Of acetonitrile was added dropwise, followed by the addition of 0.376 ml (2.16 mmol) of diisopropylethylamine, and the mixture was stirred for 2 hours while gradually warming to room temperature. A saturated aqueous sodium hydrogen carbonate solution was added, and the aqueous layer was separated and extracted with ethyl acetate.
The extract was washed with aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 3-ethyl acetate) to give p-nitrobenzyl (1R, 5S, 6).
S) -2-[(3S) -1- (4-Cyano-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6
-[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 251 mg, in a yield of 84%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22
(2H, d, J = 8.8Hz), 7.65 (2H, d, J = 8.8Hz), 7.21 (1H,
s), 5.50 (1H, d, J = 13.6Hz), 5.22 (1H, d, J = 13.9H
z), 4.35-4.24 (2H, m), 3.90 (2H, m), 3.74-3.45 (3H,
m), 3.38 (1H, dq, J = 9.4,4.7Hz), 3.30 (1H, dd, J =
7.3, 2.9Hz), 2.60-2.48 (1H, m), 2.24-2.10 (1H, m),
1.62-1.50 (1H, br s), 1.38 (3H, d, J = 5.9Hz), 1.31
(3H, d, J = 7.3Hz) Mass spectrum (FAB +): 556 [M + H] ⁺ (2) (1R, 5S, 6S) -2-[(3S) -1-
Sodium (4-cyano-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate Salt p-Nitrobenzyl (1) obtained in Example 18 (1)
R, 5S, 6S) -2-[(3S) -1- (4-cyano-
1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate
250 mg (0.450 mmol) in tetrahydrofuran 12 ml,
It was dissolved in 12 ml of distilled water and subjected to catalytic hydrogen reduction for 2 hours at room temperature in the presence of 250 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered and the filtrate was treated with sodium hydrogen carbonate 3
8 mg was added. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: acetonitrile is added to each of distilled water to 3% to 15% acetonitrile-distilled water), and the target compound is obtained by freeze-drying. (1R, 5S, 6S) -2-[(3S)
-1- (4-cyano-1,3-thiazol-2-yl)
Pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
128 mg of sodium carboxylate as a white solid,
Obtained in 64% yield.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.56 (1H, s), 4.32-4.22 (2H, m), 4.10-4.00 (1H, m),
3.88 (1H, dd, J = 10.8, 5.9Hz), 3.74-3.62 (1H, m),
3.62-3.53 (1H, m), 3.52-3.38 (3H, m), 2.60-2.48 (1
H, m), 2.19-2.08 (1H, m), 1.31 (3H, d, J = 6.4Hz), 1.
24 (3H, d, J = 7.3Hz) IR (KBr): 2229, 1751, 1604, 1560, 1391, 1310 cm ^-1 Mass spectrum (FAB ⁺ ): 443 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Observed: 443.0799
[M + H] ^+, _{calcd: 443.0824 (C 18 H 20 O} 4 N 4 S 2 Na) Example 19 (1R, 5S, 6S) -2 - [(3R) -1- (4- carbamoyl -1 , 3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0365]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2-[(3R) -1- (4-carbamoyl-1,
3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate Reference Example 20 was obtained ( 3R) -3-acetylthio-1- (4
Carbamoyl-1,3-thiazol-2-yl) pyrrolidine (500 mg, 1.84 mmol) in dimethylformamide 2
The solution was dissolved in 5 ml, and hydrazine acetate (204 mg, 2.21 mmol) was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-) was introduced into the system under ice cooling under a nitrogen atmosphere. Methyl-carbapene-2-em-3-
A solution of 1.09 g (1.84 mmol) of carboxylate in 55 ml of acetonitrile was added dropwise, followed by 1.28 ml (7.36 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction,
Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride to 9% methanol-methylene chloride), and p-nitrobenzyl (1R, 5S,
6S) -2-[(3R) -1- (4-carbamoyl-1,
917 mg of 3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate as a pale yellow solid. , With a yield of 87%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22
(2H, d, J = 8.2Hz), 7.66 (2H, d, J = 8.2Hz), 7.40 (1H,
s), 7.05 (1H, br s), 5.55 (1H, br s), 5.51 (1H,
d, J = 14.1Hz), 5.24 (1H, d, J = 14.1Hz), 4.35-4.25 (2
H, m), 4.05-3.90 (2H, m), 3.70-3.60 (1H, m), 3.60-
3.40 (4H, m), 3.31 (1H, dd, J = 6.9, 2.9Hz), 2.60-2.
40 (1H, m), 2.20-2.05 (1H, m), 1.95 (1H, br s), 1.
39 (3H, d, J = 5.9 Hz), 1.33 (3H, d, J = 6.8 Hz) Mass spectrum (FAB ⁺ ): 574 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [(3R) -1- (4
-Carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl obtained in Example 19 (1) (1
R, 5S, 6S) -2-[(3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
917 mg, (1.60 mmol) of 1-methyl-carbapen-2-em-3-carboxylate was added to tetrahydrofuran 45 m
l, Dissolve in 45 ml of distilled water, 917 mg of 10% palladium on carbon
In the presence, catalytic hydrogen reduction was performed at room temperature for 1.7 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 134 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: acetonitrile is added to distilled water by 2% to 16% acetonitrile-distilled water), and the target compound is obtained by freeze-drying. (1R, 5S, 6S) -2-
[(3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidin-3-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in an amount of 338 mg in a yield of 46%.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.41 (1H, s), 4.35-4.20 (2H, m), 4.10-4.00 (1H, m),
3.89 (1H, dd, J = 11.2, 6.7Hz), 3.70-3.60 (1H, m),
3.58-3.40 (4H, m), 2.60-2.45 (1H, m), 2.20-2.10 (1
H, m), 1.31 (3H, d, J = 6.3Hz), 1.25 (3H, d, J = 7.3H
z) IR (KBr): 1748, 1608, 1597, 1559, 1391, 1289 cm ^-1 Mass spectrum (FAB ⁺ ): 461 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Observed value: 461.0938
[M + H] ^+, _{calcd: 461.0929 (C 18 H 22 O} 5 N 4 S 2 Na) EXAMPLE 20 (1R, 5S, 6S) -2- [1- (4- hydroxymethyl-1,3 Thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid
Sodium salt (4)

[0369]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1- (4-4) obtained in Reference Example 12.
-T-Butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) azetidine (415 mg, 1.16 mmol) was dissolved in dimethylformamide (20.8 ml), and hydrazine acetate 137.0 mg (1.39 mmol) was dissolved at room temperature under a nitrogen atmosphere. )
Was added and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1
R, 5S, 6S) -2- (diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-M-3-carboxylate 690 mg
(1.16 mmol) in 34.4 ml of acetonitrile was added dropwise.
Subsequently, 1.34 ml of diisopropylethylamine (7.69 mmo
l) and gradually raise the temperature to room temperature.
Stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and p-nitrobenzyl (1R, 5S, 6
S) -2- [1- (4-t-Butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 719 mg of 1-methyl-carbapen-2-em-3-carboxylate was obtained as a yellow syrup in a yield of 94%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22
(2H, d, J = 8.3Hz), 7.66 (2H, d, J = 8.8Hz), 6.48 (1H,
s), 5.50 (1H, d, J = 13.9Hz), 5.25 (1H, d, J = 13.9H
z), 4.66 (2H, s), 4.46 (2H, dd, J = 15.4,8.1Hz), 4.3
2-4.20 (3H, m), 4.08-4.00 (2H, m), 3.28 (1H, dd, J =
6.6, 2.2Hz), 3.21 (1H, d, dq, J = 9.1, 7.3Hz), 1.95
(1H, br s), 1.37 (3H, d, J = 5.9Hz), 1.26 (3H, d, J =
(7.3 Hz), 0.94 (9H, s), 0.10 (6H, s) (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
[1- (4-hydroxymethyl-1,3-thiazole-
2-yl) azetidin-3-yl] thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylate p-nitrobenzyl (1) obtained in Example 20 (1)
R, 5S, 6S) -2- [1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl)
Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
-Dissolve 719 mg (1.09 mmol) of carboxylate in 36 ml of anhydrous tetrahydrofuran and add 0.19 ml (3.3 mmo) of acetic acid.
l), 3.3 ml (3.3 mmol) of a tetra-n-butylammonium fluoride-tetrahydrofuran solution were sequentially added under ice-cooling, and the mixture was stirred overnight at room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, liquid separation was performed, and the aqueous layer was further separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 15: 1),
P-Nitrobenzyl (1R, 5S, 6
S) -2- [1- (4-Hydroxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6
-[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate was obtained as a yellow syrup in 426.2 mg in a yield of 72%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.20
(2H, d, J = 8.1Hz), 7.66 (2H, d, J = 8.1Hz), 6.50 (1H,
s), 5.54 (1H, d, J = 13.6Hz), 5.27 (1H, d, J = 13.6H
z), 4.56 (1H, d, J = 13.6Hz), 4.53 (1H, d, J = 13.6Hz),
4.47 (1H, t, J = 8.5Hz), 4.41 (1H, t, J = 8.5Hz), 4.3
2 (1H, quintet, J = 6.4Hz), 4.28-4.20 (2H, m), 4.08
(1H, dd, J = 8.5, 5.4Hz), 3.88 (1H, dd, J = 5.4, 8.5H
z), 3.304 (1H, dd, 6.2, 2.7Hz), 3.204 (1H, dq, J =
9.2, 7.3Hz), 1.35 (3H, d, J = 6.2Hz), 1.25 (3H, d, J
(7.3 Hz) (3) (1R, 5S, 6S) -2- [1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)- 1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt Example 20 (2) p-nitrobenzyl (1R, 5S, 6
S) -2- [1- (4-Hydroxymethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 426.2 mg
(0.78 mmol) in tetrahydrofuran 20 ml, distilled water 10
The resulting mixture was dissolved in ml, and subjected to catalytic hydrogen reduction for 1.5 hours at room temperature in the presence of 530 mg of 20% palladium hydroxide. After confirming the completion of the reaction, the reaction mixture was filtered and the filtrate was treated with sodium hydrogen carbonate 65.
5 mg was added. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to 3% acetonitrile-distilled water), and lyophilized to give the target compound (1R, 5S,
6S) -2- [1- (4-hydroxymethyl-1,3-
Thiazol-2-yl) azetidin-3-yl] thio-
6-[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 156 mg, yield 46%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 6.50
(1H, s), 4.36-4.28 (4H, m), 4.19-4.10 (1H, m), 4.1
0-3.98 (2H, m including 1H, dd at 4.01, J = 8.0, 3.0
Hz), 3.88-3.68 (2H, m), 3.24 (1H, dd, J = 6.6, 2.9H
z), 3.12-3.00 (1H, m), 1.11 (3H, d, J = 5.9Hz), 1.00
(3H, d, J = 7.3Hz) IR (KBr): 3357, 1748, 1600, 1528, 1470, 1396, 1311
cm ^-1 Mass spectrum (FAB ⁺ ): 434 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Found: 434.0796
[M + H] ⁺ , Calculated: 434.0820 (C ₁₇ H ₂₁ O ₅ N ₃ S ₂ Na) Example 21 (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1, 3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0374]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N-methylcarbamoyl-
1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-N obtained in Reference Example 21
142 mg (0.56 mmol) of -methylcarbamoyl-1,3-oxazol-2-yl) azetidine are dissolved in 7 ml of dimethylformamide, and 62 mg (0.67 mmol) of hydrazine acetate at room temperature under a nitrogen atmosphere. And add
The mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S,
6S) -2- (diphenylphosphoryloxy-6-
333 mg of [(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate
(0.56 mmol) in 7 ml of acetonitrile was added dropwise,
Subsequently, 0.39 ml of diisopropylethylamine (2.
24 mmol), and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1), and p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-
Methylcarbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 274 m as a yellow solid
g, 88% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
23 (2H, d, J = 8.8 Hz), 7.77 (1H, s),
7.66 (2H, d, J = 8.8 Hz), 6.78 (1H, b
rs), 5.51 (1H, d, J = 13.9 Hz), 5.2
5 (1H, d, J = 13.2 Hz), 4.51 (2H, q, J =
8.1 Hz), 4.30-4.21 (3H, m), 4.0
8 (2H, dd, J = 5.9, 8.1 Hz), 3.30 (1
H, dd, J = 2.9, 7.3 Hz), 3.24, 3.1
6 (1H, m), 2.94 (3H, d, J = 5.1 Hz),
1.38 (3H, d, J = 5.9 Hz), 1.26 (3H, d, J = 5.9 Hz)
d, J = 7.4 Hz) (2) (1R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl)
Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
-Carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 21 (1)
R, 5S, 6S) -2- [1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] 344 mg (0.62 mmol) of -1-methyl-carbapene-2-em-3-carboxylate were dissolved in 17 ml of tetrahydrofuran and 9 ml of distilled water, and the mixture was placed in a 30 ° C. water bath in the presence of 344 mg of 20% palladium hydroxide. The catalytic hydrogen reduction was performed for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered,
52 mg of sodium hydrogen carbonate were added to the filtrate. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: 5% acetonitrile / distilled water), and lyophilized to give the target compound ( 1R, 5S, 6S) -2- [1-
(4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
166 mg of 2-M-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 60%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.73 (1H,
s), 4.44 (2H, t, J = 8.1 Hz), 4.20−
4.13 (1H, m), 4.10 (1H, t, J = 6.6H
z), 4.05 (1H, d, J = 9.5 Hz), 3.94 (2
H, quint., J = 4.4 Hz), 3.28 (1H, dd,
J = 2.2, 5.9 Hz), 3.09 (1H, quin)
t., J = 7.3 Hz), 2.73 (3H, s), 1.15
(3H, d, J = 6.6 Hz), 1.04 (3H, d, J = 7.
3 Hz) IR (KBr): 3415, 1750, 1625, 1531,
1388 cm ^-1 high resolution mass spectrum (FAB ⁺ ): found: 445.1
162 [M + H] ⁺ , calculated: 445.1157 ( _C18
H ₂₂ O ₆ N ₄ SNa) Example 22 (1R, 5S, 6S) -2- [1- (4- carbamoyl-1,3 Okisazoru 2- yl) azetidin-3
Yl] thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapene-2-m-3-carboxylic acid sodium salt

[0377]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-Carbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-carbamoyl-1,3-oxazole- obtained in Reference Example 22 275 mg (1.14 mmol) of 2-yl) azetidine was dissolved in 14 ml of dimethylformamide, and 126 mg (1.37 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S)-
2- (diphenylphosphoryloxy-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
677 mg of M-3-carboxylate (1.14 mmo
A solution of l) in 14 ml of acetonitrile was added dropwise, followed by 0.79 ml (4.56 mmol) of diisopropylethylamine.
, And the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: toluene: acetonitrile: methanol = 10:
10: 1) and purified with p-nitrobenzyl (1R, 5
S, 6S) -2- [1- (4-carbamoyl-1,3-
Oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in 313 mg, 51% yield.

¹ H-NMR (400 MHz, CD ₃ OD): δ (ppm)
08 (2H, d, J = 8.8 Hz), 7.77 (1H, s),
7.55 (2H, d, J = 8.8 Hz), 5.32 (1H,
d, J = 13.9 Hz), 5.14 (1H, d, J = 13.9)
Hz), 4.43 (2H, t, J = 8.8 Hz), 4.28
-4.20 (1H, m), 4.13 (1H, dd, J = 2.9,
9.5 Hz), 4.00 (1H, t, J = 6.6 Hz),
3.90 (2H, dt, J = 4.4, 9.5 Hz), 3.
23-3.18 (2H, m), 1.18 (3H, d, J = 5.
9 Hz), 1.09 (3H, d, J = 7.3 Hz) (2) (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-oxazol-2-yl) azetidine -3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl obtained in Example 22 (1) (1
R, 5S, 6S) -2- [1- (4-carbamoyl-
1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
313 mg (0.582 mmol) of methyl-carbapene-2-em-3-carboxylate were added to tetrahydrofuran 1
6 ml, dissolved in 8 ml of distilled water, 20% palladium hydroxide 3
In the presence of 13 mg, catalytic hydrogen reduction was performed in a 30 ° C water bath for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 49 mg of sodium hydrogen carbonate was added to the filtrate. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: 5% acetonitrile / distilled water), and lyophilized to obtain the target compound ( 1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in an amount of 110 mg and a yield of 44%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.7
9 (1H, s), 4.46 (2H, t, J = 8.1 Hz),
4.20-4.16 (1H, m), 4.10 (1H, t, J =
5.9 Hz), 4.06 (1H, dd, J = 2.9, 9.5)
Hz), 3.95 (2H, quint., J = 4.4 Hz),
3.28 (1H, dd, J = 2.9, 5.9 Hz), 3.1
2-3.08 (1H, m), 1.15 (3H, d, J = 6.6
Hz), 1.05 (3H, d, J = 7.3 Hz) IR (KBr): 3360, 1749, 1671, 1625,
1384, 1275 cm ^-1 high resolution mass spectrum (FAB ⁺ ): found: 431.1
008 [M + H] ⁺ , calculated: 431.0992 Example 23 (1R, 5S, 6S) -2- [1- (4-cyano-1,
3-oxazol-2-yl) azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0381]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-Cyano-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1- (4-cyano-1,3-oxazole-2 obtained in Reference Example 23 -Yl) azetidine 1
56 mg (0.70 mmol) of dimethylformamide 8 ml
And 77 mg (0.84 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred as it was for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-) was introduced into the system under ice cooling under a nitrogen atmosphere. Methyl-carbapene-2-m-3
-A solution of 416 mg (0.70 mmol) of carboxylate in 8 ml of acetonitrile was added dropwise, followed by 0.49 ml (2.80 mmol) of diisopropylethylamine. Stirred overnight.
After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give p-nitrobenzyl (1R, 5S, 6S)-
2- [1- (4-cyano-1,3-oxazole-2-
Yl) azetidin-3-yl] thio-6-[(R) -1-
[Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate as a pale yellow solid (309 m)
g, 84% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
22 (2H, d, J = 8.8 Hz), 7.74 (1H, s),
7.66 (2H, d, J = 8.8 Hz), 5.51 (1H,
d, J = 13.9 Hz), 5.25 (1H, d, J = 13.2)
Hz), 4.56 (2H, q, J = 8.1 Hz), 4.29
-4.22 (3H, m), 4.15-4.10 (2H, m),
3.30 (1H, dd, J = 2.9, 7.3 Hz), 3.1
9 (1H, dt, J = 7.3, 9.5 Hz), 1.37
(3H, d, J = 6.6 Hz), 1.26 (3H, d, J = 7.
3 Hz) (2) (1R, 5S, 6S) -2- [1- (4-cyano-1,3-oxazol-2-yl) azetidine-3-
Yl] thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 23 (1)
R, 5S, 6S) -2- [1- (4-cyano-1,3-
Oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapene-2-M-3-carboxylate (21)
309 mg (0.59 mmol) in tetrahydrofuran 16
dissolved in 8 ml of distilled water and 20 ml of 30% palladium hydroxide.
In the presence of 9 mg, catalytic hydrogen reduction was performed in a 30 ° C water bath for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 50 mg of sodium hydrogen carbonate was added to the filtrate. An ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: 5% acetonitrile / water), and lyophilized to give the desired compound (1R). , 5S, 6S) -2- [1- (4-cyano-
1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 150 mg in a yield of 60%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.9
2 (1H, s), 4.45 (2H, t, J = 8.8 Hz),
4.20-4.16 (1H, m), 4.09 (1H, t, J =
6.6Hz), 4.05 (1H, d, J = 8.8Hz),
3.95 (2H, quint., J = 4.4 Hz), 3.2
8 (1H, d, J = 6.6 Hz), 3.08 (1H, qui
nt., J = 8.1 Hz), 1.14 (3H, d, J = 6.6)
Hz), 1.03 (3H, d, J = 7.3 Hz) IR (KBr): 3372, 1750, 1628, 1394,
1283 cm ^-1 high resolution mass spectrum (FAB ⁺ ): found: 413.0
921 [M ⁺ H] + _{calcd: 413.0860 (C 17 H 18 O} 5 N 4 SNa) Example 24 (1R, 5S, 6S) -2- [1- (4- azetidinone Gino carbonyl-1,3-thiazole -2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0385]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-azetidinocarbonyl-1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate Obtained in Reference Example 24. 3-acetylthio-1- (4-azetidinocarbonyl-1,3-thiazol-2-yl)
Azetidine (247 mg, 0.83 mmol) was dissolved in dimethylformamide (12 ml), and hydrazine acetate (92 mg, 1.0 mmol) was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate) A solution of 493 mg (0.83 mmol) of 493 mg (0.83 mmol) in 25 ml of acetonitrile was added dropwise, followed by diisopropyl Ethylamine (0.58 ml, 3.32 mmol) was added, and the mixture was stirred overnight while gradually warming to room temperature. The obtained organic layer was washed successively with 0.5M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purified by column chromatography (elution solvent: 10% methanol-ethyl acetate), p-nitrobenzyl (1R, 5S, 6S)-
2- [1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6
[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 321 mg in a yield of 65%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.7Hz), 7.66 (2H, d, J = 8.7Hz), 7.41 (1H, s), 5.5
1 (1H, d, J = 13.7Hz), 5.25 (1H, d, J = 13.7Hz), 4.56
(2H, t, J = 7.4Hz), 4.50-4.40 (2H, m), 4.35-4.10 (5
H, m including2H, t at 4.17, J = 7.4Hz), 4.04 (1H,
t, J = 5.4Hz), 4.02 (1H, t, J = 5.4Hz), 3.29 (1H, dd, J
= 7.0, 2.5Hz), 3.18 (1H, dq, J = 8.9, 7.3Hz), 2.30 (2
H, quintet, J = 7.4Hz), 1.95-1.50 (dull s including
1H of OH group), 1.38 (3H, d, J = 6.3Hz), 1.26 (3H,
d, J = 7.3 Hz) Mass spectrum (FAB ⁺ ): 600 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-thiazole- 2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt Obtained in Example 24 (1). P-nitrobenzyl (1
R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
321 mg (0.54 mmol) of 1-methyl-carbapen-2-em-3-carboxylate was added to 15 ml of tetrahydrofuran,
It was dissolved in 15 ml of distilled water and subjected to catalytic hydrogen reduction for 2 hours at room temperature in the presence of 321 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and sodium hydrogen carbonate was added to the filtrate.
45 mg was added. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer was washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and purified by chromatography using Cosmoseal (elution solvent: distilled water to 5% acetonitrile was added to 15% acetonitrile-distilled water),
The target compound is obtained by freeze-drying (1R, 5
S, 6S) -2- [1- (4-azetidinocarbonyl-
1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
162 mg of methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 65%. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.34 (1H, s),
4.95-4.65 (4H, m), 4.40-4.30 (1H, m), 4.30-4.13 (4
H, m including 1H, quintet at 4.25, J = 6.3Hz, and 1
H, dd, at 4.19, J = 14.4, 7.2Hz), 4.10-4.00 (2H, m),
3.43 (1H, dd, J = 6.3, 2.5Hz), 3.26 (1H, quintet, J
= 7.2Hz), 2.37 (2H, quintet, J = 7.9Hz), 1.30 (3H, d,
J = 6.4Hz), 1.20 (3H, d, J = 7.2Hz) IR (KBr): 1750, 1607, 1538, 1455, 1435, 1393, 130
8, 1292 cm ^-1 Mass spectrum (FAB ⁺ ): 487 [M + H] ⁺ Example 25 (1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-thiazole-2) -Yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0387]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-thiomorpholinocarbonyl-
1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate 207 mg (0.62 mmol) of 3-acetylthio-1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 25 was obtained. It was dissolved in 8 ml of dimethylformamide, and 68.4 mg (0.74 mmol) of hydrazine acetate was added at 0 ° C. under a nitrogen atmosphere.
Stirred for hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2 was added to the system under ice cooling under a nitrogen atmosphere.
-(Diphenylphosphoryloxy-6-[(R) -1-
[Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate A solution of 370.5 mg (0.62 mmol) of acetonitrile in 16 ml was added dropwise, followed by 0.43 ml (2.48 mmol) of diisopropylethylamine, and the mixture was allowed to gradually reach room temperature. The mixture was stirred overnight while the temperature was raised. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: 5% methanol-ethyl acetate).
And purified by p-nitrobenzyl (1R, 5S, 6S)
-2- [1- (1,3-thiazol-4-thiomorpholinocarbonyl-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 246 mg, 61%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.7Hz), 7.67 (2H, d, J = 8.7Hz), 7.12 (1H, s), 5.5
1 (1H, d, J = 13.8Hz), 5.25 (1H, d, J = 13.8Hz), 4.60-
4.40 (2H, m), 4.35-4.22 (3H, m), 4.10-4.00 (2H,
m), 4.00-3.90 (4H, m), 3.29 (1H, dd, J = 6.4, 2.6Hz),
3.21 (1H, dq, J = 9.2, 7.3Hz), 2.80-2.60 (4H, m),
1.80-1.50 (dull s including 1H of OH group), 1.38
(3H, d, J = 6.4 Hz), 1.27 (3H, d, J = 7.3 Hz) Mass spectrum (FAB ⁺ ): 646 [M + H] ⁺ (2) (1R, 5S, 6S) -2- [ 1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)
Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
-Carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 25 (1)
R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 543 mg (0.84 mmol) of 1-methyl-carbapen-2-em-3-carboxylate was added to tetrahydrofuran
Dissolve in 30 ml, 30 ml of distilled water, 10% palladium on carbon 5
In the presence of 43 mg, catalytic hydrogen reduction was performed for 2 hours at room temperature.
After confirming the completion of the reaction, the reaction mixture was filtered, and 70.6 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water-5% each of acetonitrile is added-
The target compound (1R, 5S, 6) is purified by purifying with 20% acetonitrile-distilled water) and freeze-drying.
S) -2- [1- (4-thiomorpholinocarbonyl-
1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 277 mg in a yield of 62%. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.10 (1H, s),
4.56 (2H, t, J = 8.0Hz), 4.42-4.30 (1H, m), 4.25 (1
H, quintet, J = 6.3Hz), 4.21 (2H, dd, J = 7.8,2.4Hz),
4.12-4.02 (2H, m), 3.96-3.85 (2H, m), 3.85-3.75 (2
H, m), 3.44 (1H, dd, J = 6.3, 2.4Hz), 3.26 (1H, dq,
J = 8.9, 7.8Hz), 2.86-2.70 (2H, m), 2.70-2.60 (2H,
m), 1.30 (3H, d, J = 6.3Hz), 1.20 (3H, d, J = 7.8Hz) IR (KBr): 1749, 1608, 1535, 1454 cm ^-1 Mass spectrum (FAB ⁺ ): 533 [ M + H] ⁺ Example 26 ethyl (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapene-2-em-3-carboxylate

[0389]

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(1R, 5S, 6S) obtained in Example 3
-2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid sodium salt 357 mg (0.80
was dissolved in 5 ml of dimethylacetamide, and 374 mg (2.40 mmol) of ethyl iodide was added at 0 ° C under a nitrogen atmosphere.
Was added, and the mixture was stirred for 1 hour as it was, and further stirred for 2 hours while gradually raising the temperature to room temperature. After completion of the reaction, ethyl acetate was added, and the organic layer was washed successively with 10% saline, 10% aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. did. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-20% acetonitrile-ethyl acetate-40% acetonitrile-ethyl acetate-60% acetonitrile-ethyl acetate). After dissolving the obtained purified product in methylene chloride, diethyl ether and hexane are sequentially added to obtain a powder, and ethyl (1R, 5
S, 6S) -2- [1- (4-carbamoyl-1,3-
Thiazol-2-yl) azetidin-3-yl] thio-
6-[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a colorless powder (387 mg, yield 95%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.48 (1H, s), 6.99 (1H, br s), 5.61 (1H, br s), 4.
48 (2H, q, J = 8.5Hz), 4.19-4.43 (4H, m), 4.02-4.13
(2H, m), 3.26 (2H, dd, J = 7.1, 2.7Hz), 3.10 (1H, dq,
J = 9.0, 7.3Hz), 2.07 (1H, d, J = 4.8Hz), 1.37 (3H, d,
J = 6.9Hz), 1.36 (3H, t, J = 7.5Hz), 1.25 (3H, d, J = 7.2
Hz) IR (KBr): 1770, 1669, 1602, 1543, 1324, 1283 cm ^-1 Mass spectrum (FAB ⁺ ): 453 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Observed value: 453.1235
[M + H] ^+, _{calcd: 476.1267 (C 19 H 25 O} 5 N 4 S 2) Example 27 phenyl (1R, 5S, 6S) -2- [1- (4- carbamoyl-1,3-thiazol -2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate

[0392]

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(1R, 5S, 6S) obtained in Example 3
-2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid sodium salt 162 mg (0.36
was dissolved in 1 ml of water and 1 ml of tetrahydrofuran, 0.33 ml (0.33 mmol) of 1M hydrochloric acid was added at 0 ° C., and the reaction solution was concentrated under reduced pressure. The residue obtained is acetonitrile
Dissolve in 10 ml, and add phenol 102 mg (1.1 mmo) at room temperature.
l), dimethylaminopyridine 22 mg (0.18 mmol), 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (139 mg, 0.73 mmol) was added, and after stirring for 30 minutes, 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (139 mg, 0.73 mmol) was added, and the mixture was further stirred for 30 minutes. Ethyl acetate was added to the reaction solution, and the organic layer was washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to 20% acetonitrile-ethyl acetate to 40% acetonitrile-ethyl acetate to 60% acetonitrile-ethyl acetate), and phenyl (1R, 5S,
6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a colorless powder (66 mg, yield 36%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.48 (1H, s), 7.38-7.43 (2H, m), 7.23-7.28 (3H, m),
6.99 (1H, br s), 5.60 (1H, br s), 4.40-4.55 (2H,
m), 4.24-4.36 (3H, m), 4.03-4.13 (2H, m), 3.32 (1H,
dd, J = 7.0, 2.6Hz), 3.25 (1H, dq, J = 9.2, 7.3Hz), 2.
09 (1H, br), 1.39 (3H, d, J = 6.4Hz), 1.30 (3H, d, J =
(7.3Hz) IR (KBr): 1771, 1668, 1542, 1195 cm ^-1 Mass spectrum (FAB ⁺ ): 501 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Actual value: 501.1266
[M + H] ^+, _{calcd: 501.1266 (C 23 H 25 O} 5 N 4 S 2) Example 28 pivaloyloxymethyl (1R, 5S, 6S) -2- [
1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3- Carboxylate

[0395]

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(1R, 5S, 6S) obtained in Example 3
-2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid sodium salt 402 mg (0.90
was dissolved in 5 ml of dimethylacetamide, and 261 mg of methyl pivalate iodide (1.
08 mmol) and stirred for 1 hour. After completion of the reaction, ethyl acetate was added, and the organic layer was washed successively with 10% saline, 10% aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. did. The obtained residue was powdered by adding diethyl ether, and pivaloyloxymethyl (1R,
5S, 6S) -2- [1- (4-carbamoyl-1,3
-Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylate was obtained as a colorless powder at 450 mg in 93% yield.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 7.
47 (1H, s), 7.43 (1H, br s), 7.32 (1H, br s), 5.89
(1H, d, J = 5.9Hz), 5.74 (1H, d, J = 5.9Hz), 5.09 (1H,
d, J = 5.2Hz), 4.42-4.58 (3H, m), 4.20 (1H, dd, J = 9.
4, 2.4Hz), 3.89-4.02 (3H, m), 3.37 (1H, dq, J = 9.1,
7.4Hz), 3.26 (1H, dd, J = 6.3, 2.6Hz), 1.14 (3H, d, J
= 7.4Hz), 1.13 (9H, s), 1.11 (3H, d, J = 6.5Hz) IR (KBr): 1778, 1754, 1602, 1545, 1282, 1118 cm ^-1 Mass spectrum (FAB ⁺ ): 539 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Found: 539.1634
[M + H] ^+, _{calcd: 539.1634 (C 23 H 31 O} 7 N 4 S 2) Example 29 1 - (isopropoxycarbonyloxy) ethyl (1
R, 5S, 6S) -2- [1- (4-carbamoyl-
1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate

[0398]

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(1R, 5S, 6S) obtained in Example 3
-2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid sodium salt 245 mg (0.55
was dissolved in 5 ml of dimethylacetamide, and 317 mg (1.21 mmol) of 1-iodoethyl-isopropyl carbonate was added at 0 ° C. under a nitrogen atmosphere.
Stir for 1.5 hours and gradually raise the temperature to room temperature for 1.5 hours.
Stirred for hours. After the reaction is completed, ethyl acetate is added and the organic layer is separated.
The extract was washed successively with 10% saline, 0.1 M hydrochloric acid, 10% aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-20% acetonitrile-ethyl acetate-40% acetonitrile-ethyl acetate-60% acetonitrile-ethyl acetate). After dissolving the obtained purified product in methylene chloride, diethyl ether and hexane are sequentially added to obtain a powder, and 1- (isopropoxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [
1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3- The carboxylate was obtained as a colorless powder in 266 mg in a yield of 88%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.48 (1H, s), 7.00 (1H, br s), 6.82-6.92 (1H, m),
5.65 (1H, br s), 4.84-4.97 (1H, m), 4.43-4.52 (2H,
m), 4.18-4.39 (3H, m), 4.02-4.07 (2H, m), 3.25 (1
H, dd, J = 7.0, 2.5Hz), 3.17 (1H, dq, J = 9.3, 7.3Hz),
2.16 (1H, br), 1.61, 1.59 (3H, d * 2, J = 5.5Hz), 1.18
-1.39 (12H, m) IR (KBr): 1763, 1669, 1542, 1276, 1074 cm ^-1 Mass spectrum (FAB ⁺ ): 555 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: 555.1570
[M + H] ^+, _{calcd: 555.1584 (C 23 H 31 O} 8 N 4 S 2) Example 30 1- (3-pentyloxycarbonyl-oxy) ethyl
(1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 −
Methyl-carbapen-2-em-3-carboxylate

[0401]

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(1R, 5S, 6S) obtained in Example 3
-2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid sodium salt 402 mg (0.90
was dissolved in 8 ml of dimethylacetamide, and 568 mg (1.98 mmol) of 1-iodoethyl-3-pentylcarbonate was added at 0 ° C. under a nitrogen atmosphere. While stirring for 2 hours. After completion of the reaction, ethyl acetate was added and the organic layer was 10%
Saline, 0.1 M hydrochloric acid, 10% aqueous sodium thiosulfate,
After washing with a saturated aqueous solution of sodium bicarbonate and brine in that order, drying over anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to 20% acetonitrile-ethyl acetate to 40%).
% Acetonitrile-ethyl acetate to 60% acetonitrile-
Ethyl acetate) and purified by 1- (3-pentyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2- [
1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3- Carboxylate as colorless amorphous 506
mg, 96% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.48 (1H, s), 7.00 (1H, br s), 6.85-6.93 (1H, m),
5.58 (1H, br s), 4.57-4.66 (1H, m), 4.42-4.52 (2H,
m), 4.15-4.32 (3H, m), 4.02-4.10 (2H, m), 3.24 (1
H, dd, J = 7.1, 2.6Hz), 3.17 (1H, dq, J = 9.3, 7.4Hz),
2.00 (1H, br), 1.50-1.72 (7H, m), 1.34, 1.36 (3H,
d * 2, J = 6.5Hz), 1.24, 1.25 (3H, d * 2, J = 7.3Hz), 0.
84-0.98 (6H, m) IR (KBr): 1761, 1671, 1542, 1268, 1074 cm ^-1 Mass spectrum (FAB ⁺ ): 583 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value : 583.1907
[M + H] ^+, _{calcd: 583.1896 (C 25 H 35 O} 8 N 4 S 2) Example 31 (1R, 5S, 6S) -2- [1- (4- pyrrolidinocarbonyl 1,3 Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0404]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-pyrrolidinocarbonyl-1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate obtained in Reference Example 26. 3-acetylthio-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)
Azetidine (235 mg, 0.84 mmol) was dissolved in dimethylformamide (12 ml), hydrazine acetate (103 mg, 110 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 3 hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy) -6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 499 mg (0.84 mmol) in 25 ml of acetonitrile was added dropwise, followed by 0.56 ml (3.36 mmol) of diisopropylethylamine and allowed to reach room temperature. The mixture was stirred overnight while gradually raising the temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give p-nitrobenzyl (1: 1).
R, 5S, 6S) -2- [1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-Methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 240 mg, yield 46%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz), 7.28 (1
H, s), 5.51 (1H, d, J = 13.8 Hz), 5.25 (1H, d, J
= 13.8 Hz), 4.49 (2H, dd, J = 14.6, 8.5 Hz), 4.3
5-4.20 (3H, m), 4.05 (1H, t, J = 6.1 Hz), 4.04
(1H, t, J = 6.1 Hz), 3.78 (2H, t, J = 6.5 Hz), 3.
62 (2H, t, J = 6.5 Hz), 3.29 (1H, dd, J = 7.2, 2.
5 Hz), 3.20 (1H, dq, J = 9.0, 7.3 Hz), 1.82-
1.98 (4H, m), 1.38 (3H, d, J = 6.1 Hz), 1.27 (3
(H, d, J = 7.2 Hz) (2) (1R, 5S, 6S) -2- [1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6 -[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt Compound p-nitrobenzyl (1R, 5S, 6S) obtained in Example 31 (1) -2- [1- (4-Pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 240 mg (0.39 mmol) of 2-M-3-carboxylate was dissolved in 12 ml of tetrahydrofuran and 12 ml of distilled water.
Time went. After confirming the completion of the reaction, the reaction mixture was filtered, and 33 mg of sodium hydrogen carbonate was added to the filtrate. Acetic acid and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure and chromatographed using Cosmo Seal (elution solvent: distilled water to 3% acetonitrile-distilled water to 6%).
% Acetonitrile-distilled water) and lyophilized to give the desired compound (1R, 5S, 6S).
-2- [1- (4-Pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6
-[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 113 mg, yield 60%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.40
(1H, s), 4.56 (2H, t, J = 8.6 Hz), 4.43-4.30
(1H, m), 4.25 (1H, quint., J = 6.4 Hz), 4.20 (
1H, dd, J = 8.9, 2.4 Hz), 4.10-3.98 (2H, m), 3.
62 (2H, t, J = 6.6 Hz), 3.54 (2H, t, J = 6.6 Hz
), 3.26 (1H, dq, J = 8.9, 7.4 Hz), 3.43 (1H, d
d, J = 8.9, 2.4 Hz), 2.05-1.85 (4H, m), 1.30
(3H, d, J = 6.4 Hz), 1.27 (3H, d, J = 7.4 Hz) IR (KBr): 3375.7, 1605.9, 1537,4, 1468.9, 1423.6,
1396.6, 1298.2 cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 501 [M + H] ⁺ Example 32 (1R, 5S, 6S) -2- [1- (4-piperidinocarbonyl-1, 3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0407]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-piperidinocarbonyl-1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate obtained in Reference Example 27. 3-acetylthio-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl)
Azetidine (276 mg, 0.85 mmol) was dissolved in dimethylformamide (20 ml), and hydrazine acetate (94.mg, 1.02 mmol) was added at room temperature under a nitrogen atmosphere.
Stirred for hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2 was added to the system under ice cooling under a nitrogen atmosphere.
-(Diphenylphosphoryloxy) -6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
A solution of 505 mg (0.85 mmol) of em-3-carboxylate in 20 ml of acetonitrile was added dropwise, followed by 0.59 ml (3.40 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature.
After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give p-nitrobenzyl (1: 1).
R, 5S, 6S) -2- [1- (4-Piperidinocarbonyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
164-mg of 1-methyl-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 87%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
8.23 (2H, d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz
), 7.02 (1H, s), 5.51 (1H, d, J = 13.7 Hz), 5.
26 (1H, d, J = 13.7 Hz), 4.51 (1H, t, J = 8.1 Hz)
), 4.50 (1H, t, J = 8.1 Hz), 4.32-4.20 (3H, m
including 4.25 (1H, dd, J = 8.0, 2.5 Hz)), 4.07 (
1H, t, J = 5.7 Hz), 4.05 (1H, t, J = 5.7 Hz), 3.72
-3.58 (4H, m), 3.28 (1H, dd, J = 6.8, 2.5 Hz),
3.20 (1H, dq, J = 8.4, 7.3 Hz), 1.80 -1.45 (6H,
m), 1.38 (3H, d, J = 6.8 Hz), 1.26 (3H, d, J = 7.
1 Hz) (2) (1R, 5S, 6S) -2- [1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 32 (1)
R, 5S, 6S) -2- [1- (4-Piperidinocarbonyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
464 mg (0.74 mmol) of 1-methyl-carbapen-2-em-3-carboxylate was added to 20 ml of tetrahydrofuran,
Dissolve in 20 ml of distilled water and add 464 mg of 7.5% palladium on carbon
In the presence, catalytic hydrogen reduction was performed in a water bath at 35 ° C for 2 hours.
After confirming the completion of the reaction, the reaction mixture was filtered, and 62 mg of sodium hydrogen carbonate was added to the filtrate. Acetic acid and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure,
Chromatography using Cosmoseal (elution solvent:
Distilled water to 2% acetonitrile-distilled water to 5% acetonitrile-distilled water to 10% acetonitrile-distilled water to 20
(1R, 5S, 6S) -2- [1- (4-piperidinocarbonyl-1, 3-thiazol-2-yl)
Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
171 mg of carboxylic acid sodium salt as a white solid,
Obtained in a yield of 45%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.04
(1H, s), 4.10-4.00 (2H, m), 4.42-4.30 (1
H, m), 4.25 (1H, quint., J = 6.2 Hz), 4.21 (1H,
dd, J = 9.0, 2.4 Hz), 4.05 (2H, ddd, J = 8.3, 5.4,
2.7 Hz), 3.62 (2H, t, J = 5.3 Hz), 3.49 (2H,
t, J = 5.3 Hz), 3.44 (1H, dd, J = 6.2, 2.4 Hz), 3.
26 (1H, dq, J = 7.7, 7.4 Hz), 1.70-1.60 (4H, m
), 1.60-1.50 (2H, m), 1.30 (3H, d, J = 6.4 Hz
), 1.27 (3H, d, J = 7.2 Hz) IR (KBr): 3382.5, 1747.7, 1605.9, 1538.4, 1400.4,
1310.7, 1249.0 cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 515 [M + H] ⁺ Example 33 (1R, 5S, 6S) -2- [1- (4-N-cyclopropylcarbamoyl-1) , 3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylic acid sodium salt

[0411]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidine-3-
Yl] thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-N-
Cyclopropylcarbamoyl-1,3-thiazole-2
-Yl) azetidine (342 mg, 1.15 mmol) was dissolved in dimethylformamide (12 ml), hydrazine acetate (127 mg, 1.38 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S,
6S) -2- (diphenylphosphoryloxy) -6
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 684 mg (1.15
Then, 0.80 ml (4.60 mmol) of diisopropylethylamine was added thereto, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M brine, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxy 606 mg as a pale yellow solid,
Obtained in a yield of 88%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
8.23 (2H, d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz
), 7.44 (1H, s), 7.23 (1H, br s), 5.51 (1H, s)
d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz), 4.49
(2H, dd, J = 14.3, 7.6 Hz), 4.37-4.19 (3H, m),
3.98-4.12 (3H, m), 3.30 (1H, dd, J = 9.2,7.3
Hz), 3.20 (1H, dq, J = 9.2, 7.3 Hz), 2.80-2.9
4 (1H, m), 1.38 (3H, d, J = 6.4 Hz), 1.27 (3H,
d, J = 7.3 Hz), 0.85 (1H, t, J = 5.5 Hz), 0.83 (
1H, t, J = 5.5 Hz), 0.58-0.70 (2H, m), (2) (1R, 5S, 6S) -2- [1- (4-N-cyclopropylcarbamoyl-1,3-thiazole-2) -Yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt Obtained in Example 33 (1) p-Nitrobenzyl (1
R, 5S, 6S) -2- [1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl ] -1-Methyl-carbapen-2-em-3-carboxylate 606 mg (1.01 mmol) was dissolved in 30 ml of tetrahydrofuran and 30 ml of distilled water, and contacted in a 35 ° C water bath in the presence of 606 mg of 7.5% palladium on carbon. Hydrogen reduction 2.5
Time went. After confirming the completion of the reaction, the reaction mixture was filtered, and 85 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation.
The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to 5% acetonitrile-distilled water to 10% acetonitrile-distilled water), and lyophilized to give the target compound. (1R, 5
S, 6S) -2- [1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapen-2-em-3-carboxylic acid sodium salt as a white solid, 275 mg, yield 56%
I got it.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.46
(1H, s), 4.54 (2H, t, J = 8.2 Hz), 4.38-4.30
(1H, m), 4.25 (1H, quint., J = 6.3 Hz), 4.19 (1
H, dd, J = 8.9, 2.4 Hz), 4.10-4.19 (1H, dd, J =
8.9, 2.4 Hz), 3.43 (1H, dd, J = 6.3, 2.4 Hz), 3.
24 (1H, dq, J = 8.9, 7.3 Hz), 2.78-2.70 (1H, m
), 1.30 (3H, d, J = 6.4 Hz), 1.19 (3H, d, J = 7.
2 Hz), 0.85 (1H, t, J = 5.2 Hz), 0.84 (1H, t, J
= 5.2 Hz), 0.73-0.61 (2H, m) IR (KBr): 3397.0, 1750.1, 1603.5, 1545.7, 1489.7,
1470.5, 1393.3, 1312.3 cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 465 [M + H] ⁺ Example 34 (1R, 5S, 6S) -2- [1- (4-N-cyclobutylcarbamoyl) -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0415]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-N-
Cyclobutylcarbamoyl-1,3-thiazole-2-
Il) Azetidine (398 mg, 1.28 mmol) was dissolved in dimethylformamide (15 ml), hydrazine acetate (141 mg, 1.53 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 2.5 hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S,
6S) -2- (diphenylphosphoryloxy) -6
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 761 mg (1.28
(mmol) of acetonitrile was added dropwise, followed by 0.88 ml (5.12 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5M saline, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate:
Purified with methanol = 9: 1), p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidine-3 -Yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylate as pale yellow solid 578 mg, yield 74
%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
8.23 (2H, d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz
), 7.41 (1H, s), 5.51 (1H, d, J = 13.7 Hz), 5.
25 (1H, d, J = 13.7 Hz), 4.60-4.42 (3H, m inclu
ding 4.52 (2H, quint., J = 7.8 Hz)), 4.36-4 20
(3H, m), 3.30 (1H, dd, J = 6.9, 2.5 Hz), 3.21 (
1H, dq, J = 9.2, 7.4 Hz), 2.47-2.33 (2H, m),
2.10-1.92 (2H, m), 1.85-1.65 (2H, m), 1.39
(3H, d, J = 6.4 Hz), 1.28 (3H, d, J = 7.3 Hz) (2) (1R, 5S, 6S) -2- [1- (4-N-cyclobutylcarbamoyl-1,3 -Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt In Example 34 (1) The resulting p-nitrobenzyl (1
R, 5S, 6S) -2- [1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl ] -1-Methyl-carbapene-2-em-3-carboxylate (578 mg, 0.94 mol) in tetrahydrofuran
Dissolve in 30 ml, 30 ml of distilled water, 7.5% palladium on carbon
In the presence of 578 mg, catalytic hydrogen reduction was performed in a 35 ° C water bath for 2.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 79 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to 5% acetonitrile-distilled water to 10% acetonitrile-distilled water), and lyophilized to give the target compound. There is (1R, 5
S, 6S) -2- [1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid
322 mg of the sodium salt was obtained as a white solid in a yield of 68%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.45
(1H, s), 4.56 (2H, t, J = 8.0 Hz), 4.44-4.29
(2H, m), 4.25 (1H, quint., J = 6.3 Hz), 4.20 (
1H, dd, J = 8.8, 2.4 Hz), 4.12-4.00 (2H, m),
3.44 (1H, dd, J = 6.3, 2.5Hz), 3.26 (1H, dq, J =
8.8, 7.4 Hz), 2.41-2.28 (2H, m), 2.15-2.00
(2H, m), 1.87-1.72 (2H, m), 1.31 (3H, d, J =
6.2 Hz), 1.20 (3H, d, J = 7.2 Hz) IR (KBr): 3395.1, 1750.1, 1659.4, 1604.5, 1545.7,
1490.7, 1470.5, 1393.8, 1310.4, 1251.6 cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 501 [M + H] ⁺ Example 35 (1R, 5S, 6S) -2- [1- [4- ( 4-methylpiperazine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylic acid sodium salt

[0419]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- [4- (4-methylpiperazine-1
-Carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate Reference The 3-acetylthio-1- [4-
(4-methylpiperazine-1-carbonyl) -1,3-
Thiazol-2-yl] azetidine 1.35 g (3.97 mmo
l) was dissolved in 40 ml of dimethylformamide, and hydrazine acetate 438 mg (4.76 mmol) was added at room temperature under a nitrogen atmosphere.
And stirred for 1 hour. After confirming the completion of the reaction,
Under a nitrogen atmosphere, p-nitrobenzyl (1
R, 5S, 6S) -2- (Diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 2.3
A solution of 6 g (3.97 mmol) in 40 ml of acetonitrile was added dropwise, followed by 2.77 ml of diisopropylethylamine (15.
9 mmol), and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 1: 5),
p-Nitrobenzyl (1R, 5S, 6S) -2- [1-
[4- (4-methylpiperazine-1-carbonyl)-
1,3-thiazol-2-yl] azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 828 mg, 60% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
8.23 (2H, d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz
), 7.16 (1H, s), 5.51 (1H, d, J = 13.8 Hz), 5.
25 (1H, d, J = 13.8 Hz), 4.50 (1H, t, J = 4.9 Hz
), 4.49 (1H, t, J = 4.9 Hz), 4.33-4.20 (3H, m
), 4.06 (1H, t, J = 4.9 Hz), 4.05 (1H, t, J = 4.9
Hz) 3.99-3.73 (4H, m), 3.29 (1H, dd, J = 7.
0, 2.5 Hz), 3.20 (1H, dq, J = 9.1, 7.3 Hz), 2.74
-2.48 (4H, m), 1.38 (3H, d, J = 6.3 Hz), 1.27
(3H, d, J = 7.3 Hz) (2) (1R, 5S, 6S) -2- [1- [4- (4-
Methylpiperazine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 35 (1)
R, 5S, 6S) -2- [1- [4- (4-methylpiperazine-1-carbonyl) -1,3-thiazole-2-
Yl] azetidin-3-yl] thio-6-[(R) -1-
[Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 500 mg (0.78 mmol) was dissolved in 25 ml of tetrahydrofuran and 25 ml of distilled water to give 7.5 mg.
% Catalytic hydrogen reduction was performed in a 35 ° C water bath for 2 hours in the presence of 500 mg of palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and acetic acid and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the mixed solvent described above, concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water to 4% acetonitrile-distilled water to 6% acetonitrile-distilled water) ~ 8% acetonitrile-distilled water ~ 10% acetonitrile-distilled water ~ 12% acetonitrile-distilled water) and freeze-dried to obtain the target compound (1).
R, 5S, 6S) -2- [1- [4- (4-methylpiperazine-1-carbonyl) -1,3-thiazole-2-
Yl] azetidin-3-yl] thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt as a white solid 1
It was obtained in 92 mg and a yield of 49%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.24
(1H, s), 4.57 (2H, t, J = 8.4 Hz), 4.39-4.30
(1H, m), 4.25 (1H, quint., J = 6.3 Hz), 4.20 (1
H, dd, J = 9.0, 2.4 Hz), 4.15-3.05 (12H, m inclu
ding 4.04 (2H, dd, J = 8.4, 4.9 Hz), 3.44 (1H,
dd, J = 6.3, 2.6 Hz), 3.25 (1H, dq, J = 9.0, 7.0Hz
)), 2.88 (3H, s), 1.30 (3H, d, J = 6.4 Hz), 1.
20 (3H, d, J = 7.1 Hz) IR (KBr): 3397.0, 1757.8, 1606.4, 1536.0, 1457.9,
1429.0, 1383.7, 1312.3 cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 508 [M + H] ⁺ High resolution mass spectrum (ESI ⁺ ): Observed value: 508.1680 [M + H] ⁺ , Calculated value: 508.1688 (C ₂₂ H ₃₀ N
₅ O ₅ S ₂ Na) Example 36 (1R, 5S, 6S) -2- [1- [4- (3- methoxy-azetidin-1-carbonyl) -1,3-thiazol-2-yl] azetidine - 3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid sodium salt

[0423]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- [4- (3-methoxyazetidine-
1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylate 3-acetylthio-1- [4-
(3-methoxyazetidine-1-carbonyl) -1,3
-Thiazol-2-yl] azetidine 350 mg (1.07 mmol)
Was dissolved in 18 ml of dimethylformamide, 118 mg (1.28 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred as it was for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5
(S, 6S) -2- (diphenylphosphoryloxy) -6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 636 mg (1.07
mmol) in 32 ml of acetonitrile was added dropwise, followed by 746 μl (4.28 mmol) of diisopropylethylamine.
The mixture was stirred for 6 hours while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with 10% brine and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 95: 5-
9: 1) and purified with p-nitrobenzyl (1R, 5
S, 6S) -2- [1- [4- (3-Methoxyazetidine-1-carbonyl) -1,3-thiazol-2-yl]
Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
636 mg of carboxylate as a pale yellow solid, yield 94
%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8Hz), 7.4
4 (1H, s), 5.51 (1H, d, J = 13.9 Hz), 5.25 (1H, d, J
= 13.2 Hz), 4.75−4.69 (1H, m), 4.51−4.43 (2H, m),
4.42−4.37 (1H, m), 4.32−4.20 (5H, m), 4.04 (2H, m
dt, J = 8.1, 5.1 Hz), 3.33 (3H, s), 3.29 (1H, dd,
J = 2.2, 6.6 Hz), 3.20 (1H, dq, J = 9.2, 7.3Hz), 1.38
(3H, d, J = 6.6 Hz), 1.27 (3H, d, J = 7.3 Hz) (2) (1R, 5S, 6S) -2- [1- [4- (3-
Methoxyazetidin-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 36 (1)
R, 5S, 6S) -2- [1- [4- (3-methoxyazetidine-1-carbonyl) -1,3-thiazole-2
-Yl] azetidin-3-yl] thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
630 mg (1.00 mmol) of M-3-carboxylate was dissolved in 32 ml of tetrahydrofuran and 32 ml of distilled water, and subjected to catalytic hydrogen reduction for 2 hours at room temperature in the presence of 630 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 84 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 92: 8), and lyophilized to give the target compound (1R, 5S, 6S) -2- [1- [4-
(3-methoxyazetidine-1-carbonyl) -1,3
-Thiazol-2-yl] azetidin-3-yl] thio-
6-[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 239 mg, yield 46%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.39 (1
H, s), 4.76−4.69 (1H, m), 4.56 (2H, d, J = 8.1 Hz),
4.44−4.31 (4H, m), 4.25 (1H, dq, J = 6.1, 6.4 Hz)
4.20 (1H, dd, J = 2.4, 9.1 Hz), 4.09−3.99 (3H, m),
3.43 (1H, dd, J = 2.4, 6.1Hz), 3.37 (3H, s), 3.26 (1
H, dq, J = 9.1, 7.2 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.20
(3H, d, J = 7.2 Hz) IR (KBr): 1750, 1607, 1538, 1449, 1395, 1306cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 539 [M + Na] ⁺ high-resolution mass spectrum (ESI ⁺ ): Found: 539.1026 [M + Na] ⁺ , Calculated: 539.0111 (C ₂₁ H ₂₅
N ₄ O ₆ S ₂ Na ₂ ) Elemental analysis: Calculated as C ₂₁ H ₂₅ N ₄ O ₆ S ₂ Na ・ 3 / 2H ₂ O Found: C, 46.48% H, 5.53% N, 10.60% S, 11.66% Calculated value: C, 46.40% H, 5.19% N, 10.31% S, 11.80% Example 37 (1R, 5S, 6S) -2- [1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0427]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-phenylcarbamoyl-1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3 obtained in Reference Example 32 -Acetylthio-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl)
893 mg (2.68 mmol) of azetidine was dissolved in 40 ml of dimethylformamide, and 296 mg (3.21 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy) -6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 1.59 g (3.21 mmol) of 53 ml of acetonitrile was added dropwise, followed by 1.87 ml (10.7 mmol) of diisopropylethylamine, and the mixture was gradually allowed to reach room temperature. The mixture was stirred overnight while the temperature was raised. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1), and p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- Phenylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate is pale yellow 1.2 g was obtained as a solid in a yield of 71%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
8.29-8.18 (2H, m), 7.73-7.62 (4H, m), 7.62
-7.50 (1H, m), 7.42-7.82 (2H, m), 7.18-
7.09 (1H, m), 5.51 (1H, d, J = 13.8 Hz), 5.25 (
1H, d, J = 13.8 Hz), 4.54 (2H, dd, J = 15.6, 7.8 Hz
), 4.40-4.21 (3H, m), 4.21-4.08 (2H, m),
3.31 (1H, dd, J = 6.9, 2.5 Hz), 3.23 (1H, dq, J =
9.1, 7.3 Hz), 1.39 (3H, d, J = 6.4 Hz), 1.29 (
(3H, d, J = 7.3 Hz) (2) (1R, 5S, 6S) -2- [1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6- [(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 37 (1)
R, 5S, 6S) -2- [1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
400 mg (0.63 mmol) of 1-methyl-carbapene-2-em-3-carboxylate was added to tetrahydrofuran 120
dissolved in 120 ml of distilled water and 7.5% palladium on carbon 40
The catalytic hydrogen reduction was performed for 2 hours at room temperature in the presence of 0 mg.
After confirming the completion of the reaction, the reaction mixture was filtered, and 53 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmo Seal (elution solvent: distilled water to 4% acetonitrile-distilled water to 8% acetonitrile-distilled water to 12% acetonitrile-distilled water to 16% acetonitrile-distilled water) And the target compound (1R, 5S, 6)
S) -2- [1- (4-Phenylcarbamoyl-1,3
-Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 211 mg in a yield of 64%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.60 −
7.51 (3H, m), 7.54-7.42 (2H, m), 7.36-7.2
7 (1H, m), 4.63 = 4.52 (2H, m), 4.29-4.39 (
1H, m), 4.25 (1H, quint., J = 6.3 Hz), 4.20 (1H,
ddd, J = 9.0, 2.3 Hz), 4.09 (1H, t, J = 8.8 Hz),
4.08 (1H, t, J = 8.8 Hz), 3.44 (1H, ddd, J =
6.6, 1.9 Hz), 3.25 (1H, dq, J = 6.3, 5.9 Hz),
1.3 (3H, d, J = 6.4 Hz), 1.20 (3H, dd, J = 7.2,
2.4 Hz) IR (KBr): 3368.1, 1750.1, 1676.8, 1598.7, 1538.9,
1506.1, 1470.5, 1440.6, 1394.3, 1324.9, 1295.9, 12
45.8 cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 501 [M + H] ⁺ Example 38 (1R, 5S, 6S) -2- [1- [4- (2-hydroxy-ethylcarbamoyl)- 1,3-thiazole-2
-Yl] azetidin-3-yl] thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
M-3-carboxylic acid sodium salt

[0431]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4- [2- (t-butyldiphenylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1- [4- [2
398.2 mg (0.96 mmol) of-(t-butyldiphenylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine are dissolved in 20 ml of dimethylformamide, and hydrazineacetic acid is added at room temperature under a nitrogen atmosphere at room temperature. 110 mg (1.19 mmol) of a salt was added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S)-
2- (diphenylphosphoryloxy) -6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylate 561.4 mg (0.94
(38 mmol) of acetonitrile was added dropwise, followed by 0.7 ml (4.02 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 1), and p-nitrobenzyl (1
R, 5S, 6S) -2- (1- [4- [2- (t-butyldiphenylsilyloxy) -ethylcarbamoyl] -1,3
-Thiazol-2-yl] azetidin-3-yl) thio-
6-[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow syrup in 605.3 mg, 80% yield.

¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm)
8.79 (2H, d, J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.5
4 (1H, t, J = 5.8Hz), 7.42 (1H, s), 5.51 (1H, d, J = 1
3.7Hz), 5.26 (1H, d, J = 13.7Hz), 4.48 (1H, dd, J = 8.
3, 7.3Hz), 4.45 (1H, dd, J = 8.3, 7.3Hz), 4.32-4.23
(3H, m), 4.06 (1H, dd, J = 8.3, 5.9Hz), 4.03 (1H, dd,
J = 8.3, 5.9Hz), 3.76 (2H, t, J = 5.8Hz), 3.52 (2H,
q, J = 5.8Hz), 3.30 (1H, dd, J = 6.8, 2.0Hz), 3.208 (1
H, dq, J = 9.0, 7.4Hz), 1.95 (1H, br s), 1.38 (3H,
d, J = 5.7Hz), 1.27 (3H, d, J = 6.8Hz), 0.91 (9H, s),
0.07 (6H, s) (2) p-nitrobenzyl (1R, 5S, 6S) -2-
[1- [4- (2-hydroxy-ethylcarbamoyl)
-1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylate The p-nitrobenzyl (1) obtained in Example 38 (1)
R, 5S, 6S) -2- (1- [4- [2- (t-butyldiphenylsilyloxy) -ethylcarbamoyl] -1,3
-Thiazol-2-yl] azetidin-3-yl) thio-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 605.3
mg (0.84 mmol) was dissolved in 30 ml of tetrahydrofuran, and 0.15 ml (2.6 mmol) of acetic acid was added under ice cooling.
2.5 ml (2.5 mmol) of a tetrabutylammonium fluoride-tetrahydrofuran solution was sequentially added, followed by stirring at room temperature for 1 day. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 3) to give p-nitrobenzyl (1R, 5S, 6S)-.
2- [1- [4- (2-hydroxy-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
13.7-mg-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in 383.7 mg, 75% yield.

¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm)
8.23 (2H, d, J = 7.9Hz), 7.66 (2H, d, J = 7.9Hz), 7.5
3 (1H, t, J = 5.3Hz), 7.45 (1H, s), 5.508 (1H, d, J =
13.7Hz), 5.255 (1H, d, J = 13.7Hz), 4.50 (1H, t, J =
8.6Hz), 4.48 (1H, t, J = 8.6Hz), 4.32-4.24 (3H, m),
4.07 (1H, dd, J = 8.6, 5.3Hz), 4.05 (1H, dd, J = 8.6,
5.3Hz), 3.807 (2H, t, J = 5.3Hz), 3.58 (2H, q, J = 5.3
Hz), 3.295 (1H, dd, J = 7.6, 2.3Hz), 3.21 (1H, dq, J
= 9.1, 7.6Hz), 2.78 (1H, brs), 1.92 (1H, brs), 1.3
8 (3H, d, J = 6.3 Hz), 1.24 (3H, d, J = 7.6 Hz) (3) (1R, 5S, 6S) -2- [1- [4- (2-
(Hydroxy-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 38 (2)
R, 5S, 6S) -2- [1- [4- (2-hydroxy-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 383.7 mg (0.64 mmol)
Was dissolved in 20 ml of tetrahydrofuran and 9.6 ml of distilled water, and in the presence of 400 mg of 20% palladium hydroxide-carbon,
The catalytic hydrogen reduction was performed in a 30 ° C. water bath for 1 hour. After confirming the completion of the reaction, the reaction mixture was filtered, and 53.4 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 3% acetonitrile-distilled water to 5% acetonitrile-distilled water to 10% acetonitrile-distilled water)
And the target compound (1R, 5S, 6S) -2- [1- [4- (2-hydroxy-ethylcarbamoyl) -1,3-thiazole-] is obtained by freeze-drying.
2-yl] azetidin-3-yl] thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylic acid sodium salt was obtained as a white solid in 152.2 mg, in a yield of 49%.

¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.29
(1H, s), 4.36 (2H, t, J = 8.4Hz), 4.20-4.10 (1H, m),
4.05 (1H, quintet, J = 6.6Hz), 4.00 (1H, dd, J = 10.
9, 2.2Hz), 3.90-3.83 (2H, m), 3.55 (2H, t, J = 5.5H
z), 3.32 (2H, t, J = 5.5Hz), 3.24 (1H, dd, J = 6.6, 2.
2Hz), 3.06 (1H, dq, J = 10.9, 8.6Hz), 1.11 (3H, d, J
= 6.6Hz), 1.00 (3H, d, J = 8.6Hz) IR (KBr): 3396, 1748, 1649, 1599, 1551, 1395, 1315,
1265 cm ^-1 Mass spectrum (FAB ⁺ ): m / z 491 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: 491.1024 [M + H] ⁺ , Calculated value: 491.1035 (C ₁₉ H ₂₃₎ N ₄
S ₂ O ₆ Na) Example 39 (1R, 5S, 6S) -2- [1- [4 - ((1S) -1-
(Hydroxymethyl-propylcarbamoyl) -1,3-
Thiazol-2-yl] azetidin-3-yl] thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0436]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl]-
1,3-thiazol-2-yl] azetidin-3-yl)
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4-
[(1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazole-2
610 mg (1.37 mmol) of [-yl] azetidine was dissolved in 30 ml of dimethylformamide, and 152 mg (1.65 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy) -6-[(R) -1-
A solution of 814 mg (1.37 mmol) of hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate in 40 ml of acetonitrile was added dropwise, followed by the addition of 955 μl (5.48 mmol) of diisopropylethylamine and the temperature was gradually raised to room temperature. The mixture was stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% saline and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to give p-nitrobenzyl (1R, 5S, 6S) -2-
(1- [4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 928 mg, 89% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.
42 (1H, s), 7.42−7.38 (1H, br d, J = 9.5 Hz), 5.51
(1H, d, J = 13.9 Hz), 5.25 (1H, d, J = 13.9 Hz), 4.50
(1H, t, J = 8.1 Hz), 4.45 (1H, t, J = 8.1 Hz), 4.31−
4.23 (2H, m), 4.27 (1H, dd, J = 8.8, 2.6 Hz), 4.07−
1.01 (2H, m), 4.00−3.94 (1H, m), 3.72 (1H, dd, J = 1
0.3, 2.6 Hz), 3.65 (1H, dd, J = 10.3, 4.0 Hz), 3.30
(1H, dd, J = 7.3, 2.6 Hz), 3.21 (1H, dq, J = 8.8, 6.6
Hz), 1.72-1.56 (2H, m), 1.38 (3H, d, J = 5.7 Hz),
1.27 (3H, d, J = 6.6 Hz), 0.95 (3H, t, J = 7.3 Hz), 0.
90 (9H, s), 0.06 (6H, s). (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
[1- [4-((1S) -1-hydroxymethyl-propylcarbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbapen-2-em-3-carboxylate p-nitrobenzyl (1) obtained in Example 39 (1)
R, 5S, 6S) -2- (1- [4-[(1S) -1- (t-
Butyldiphenylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2- 920 mg (1.23 mmol) of M-3-carboxylate in 46 m of tetrahydrofuran
acetic acid under ice-cooling, 208 μl (3.63 mmol) of acetic acid, 1M
3.63 ml (3.63 mmol) of -tetrabutylammonium fluoride-tetrahydrofuran solution was sequentially added, and the mixture was stirred at room temperature for 2 days. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol =
95: 5) and purified with p-nitrobenzyl (1R, 5).
S, 6S) -2- [1- [4-((1S) -1-hydroxymethyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R )
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylate as pale yellow solid
37 mg, yield 56%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
8.23 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.
44 (1H, s), 7.24−7.19 (1H, br d, J = 7.8 Hz), 5.51
(1H, d, J = 13.7 Hz), 5.26 (1H, d, J = 13.7 Hz), 4.50
(2H, dt, J = 8.8, 4.9 Hz), 4.32−4.24 (3H, m), 4.07
(2H, dt, J = 8.8, 5.9 Hz), 4.01−3.93 (1H, m), 3.81
−3.75 (1H, m), 3.71−3.64 (1H, m), 3.30 (1H, dd, J =
6.8, 2.9 Hz), 3.21 (1H, dq, J = 9.0, 6.8 Hz), 1.75−
1.66 (1H, m), 1.65−1.55 (1H, m), 1.38 (3H, d, J = 6.8H
z) 1.28 (3H, d, J = 7.8Hz) 1.00 (3H, t, J = 7.8Hz) (3) (1R, 5S, 6S) -2- [1- [4-((1S)
-1-hydroxymethyl-propylcarbamoyl)-
1,3-thiazol-2-yl] azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 39 (2)
R, 5S, 6S) -2- [1- [4-((1S) -1-hydroxymethyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 430 mg (0.681 m
was dissolved in 22 ml of tetrahydrofuran and 22 ml of distilled water, and subjected to catalytic hydrogen reduction at room temperature in the presence of 430 mg of 10% palladium on carbon for 4 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 57 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (eluent: distilled water to distilled water: acetonitrile = 94: 6), and lyophilized to give the target compound (1R, 5S, 6S) -2-
[1- [4-((1S) -1-hydroxymethyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] 212 mg of sodium 1-methyl-carbapene-2-em-3-carboxylate as a white solid, yield 60
%.

¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm)
7.49 (1H, s), 4.59−4.52 (2H, m), 4.39−4.31 (1H,
m), 4.25 (1H, dq, J = 6.8,6.3 Hz), 4.21 (1H, dd, J =
9.0, 2.4 Hz), 4.10−4.03 (2H, m), 4.01−3.93 (1H,
m), 3.71 (1H, dd, J = 11.7, 4.5 Hz), 3.64 (1H, dd, J
= 11.7, 6.8Hz), 3.43 (1H, dd, J = 6.3, 2.4Hz), 3.26
(1H, dq, J = 8.8, 7.2 Hz), 1.73−1.62 (1H, m), 1.57
−1.44 (1H, m), 1.30 (3H, d, J = 6.4 Hz), 1.20 (3H,
d, J = 7.2 Hz), 0.93 (3H, t, J = 7.4 Hz) .IR (KBr): 1750, 1650, 1602, 1547, 1393, 1313 cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 519 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Found: 519.1339 [M + H] ⁺ , Calculated: 519.1348 Elemental analysis: C ₂₁ H ₂₇ N ₄ O ₆ S ₂ Na ・ 7 / 4H ₂ Calculated as O Observed: C, 46.07% H, 5.78% N, 10.29% S, 11.61% Calculated: C, 45.85% H, 5.59% N, 10.18% S, 11.66% Example 40 (1R, 5S, 6S) ) -2- [1- [4-((1S) -1-
(Hydroxymethyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0441]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4-[(1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine-3-
Yl) thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4- obtained in Reference Example 35
[(1S) -2- (t-butyldimethylsilyloxy)-
645 mg (1.50 mmol) of 1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine was dissolved in 32 ml of dimethylformamide, and 166 mg (1.80 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere. The mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) was introduced into the system under ice cooling under a nitrogen atmosphere.
-2- (diphenylphosphoryloxy) -6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
A solution of 892 mg (1.50 mmol) of 2-em-3-carboxylate in 45 ml of acetonitrile was added dropwise, followed by addition of 1.05 ml (6.0 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction system,
The aqueous layer was separated and extracted with ethyl acetate. Apply the obtained organic layer to 10
After washing with brine and saturated brine, drying over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
Purified with n-hexane: ethyl acetate = 1: 2-ethyl acetate), p-nitrobenzyl (1R, 5S, 6S) -2-
(1- [4-[(1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-
Thiazol-2-yl] azetidin-3-yl) thio-6
-[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in 949 mg in a yield of 86%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.44-7.38 (1H,
br d, J = 5.9Hz), 7.42 (1H, s), 5.51 (1H, d, J = 13.9H)
z), 5.25 (1H, d, J = 13.9Hz), 4.52-4.42 (2H, m), 4.
33-4.22 (3H, m), 4.22-4.14 (1H, m), 4.04 (2H, ddd,
J = 14.0, 5.9, 2.9Hz), 3.67 (1H, dd, J = 10.3, 4.4Hz),
3.62 (1H, dd, J = 10.3, 2.9Hz), 3.30 (1H, dd, J = 6.6,
2.2Hz), 3.21 (1H, dq, J = 7.3, 6.6Hz), 1.38 (3H, d,
J = 5.9Hz), 1.27 (3H, d, J = 7.3Hz), 1.25 (3H, d, J =
(6.6 Hz), 0.92 (9H, s), 0.07 (6H, s). (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
[1- [4-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1- [Hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylate p-Nitrobenzyl (1) obtained in Example 40 (1)
R, 5S, 6S) -2- (1- [4-[(1S) -2- (t-
Butyldiphenylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene 940 mg (1.28 mmol) of 2-M-3-carboxylate in tetrahydrofuran 4
Dissolved in 7 ml, acetic acid 221μl (3.85mmol) under ice cooling,
3.85 ml (3.85 mmol) of a 1M-tetrabutylammonium fluoride-tetrahydrofuran solution was sequentially added, followed by stirring at room temperature for 3 days. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 99: 1 to 1).
9: 1) and purified with p-nitrobenzyl (1R, 5
S, 6S) -2- [1- [4-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6
[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in 462 mg in a yield of 58%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.44 (1H, s), 7.
23-7.19 (1H, br d, J = 7.3Hz), 5.51 (1H, d, J = 13.9H
z), 5.25 (1H, d, J = 13.9Hz), 4.52-4.46 (2H, m), 4.3
1-4.24 (2H, m), 4.27 (1H, dd, J = 9.5, 2.0Hz), 4.22-
4.15 (1H, m), 4.06 (2H, dt, J = 8.1, 5.1Hz), 3.79-3.
71 (1H, m), 3.66-3.59 (1H, m), 3.30 (1H, dd, J = 6.
6, 2.2Hz), 3.21 (1H, dq, J = 9.5, 7.3Hz), 1.38 (3H,
d, J = 5.9Hz), 1.28 (6H, d, J = 7.3Hz). (3) (1R, 5S, 6S) -2- [1- [4-((1S)
-2-hydroxy-1-methyl-ethylcarbamoyl)
-1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 40 (2)
R, 5S, 6S) -2- [1- [4-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-
Thiazol-2-yl] azetidin-3-yl] thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 460 mg (0.745
was dissolved in 23 ml of tetrahydrofuran and 23 ml of distilled water, and catalytic hydrogen reduction was carried out at room temperature for 3 hours in the presence of 460 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 63 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 82:12), and lyophilized to give the target compound (1R, 5S, 6
S) -2- [1- [4-((1S) -2-hydroxy-1-
Methyl-ethylcarbamoyl) -1,3-thiazole-
2-yl] azetidin-3-yl] thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
179 mg of -M-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 48%. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.48 (1H, s),
4.56 (2H, dd, J = 8.3,8.3Hz), 4.39-4.32 (1H, m), 4.
25 (1H, dq, J = 6.3, 6.4Hz), 4.20 (1H, dd, J = 9.1, 2.
4Hz), 4.18-4.11 (1H, m), 4.10-4.03 (2H, m), 3.68
(1H, dd, J = 11.6,4.8Hz), 3.61 (1H, dd, J = 11.6, 6.7H
z), 3.44 (1H, dd, J = 6.3, 2.4Hz), 3.26 (1H, dq, J = 9.
1, 6.6Hz), 1.30 (3H, d, J = 6.4Hz), 1.22 (3H, d, J =
6.7Hz), 1.20 (3H, d, J = 6.6Hz) .IR (KBr): 1749, 1650, 1602, 1547, 1393, 1313, 1295
cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 505 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: 505.1196 [M + H] ⁺ , Calculated value: 505.1191 (C ₂₀ H ₂₆ N
₄ O ₆ S ₂ Na) Elemental analysis: Calculated as C ₂₀ H ₂₅ N ₄ O ₆ S ₂ Na ・ 4 / 3H ₂ O Measured value: C, 45.63% H, 5.35% N, 10.66% S, 11.91% Calculated value : C, 45.45% H, 5.28% N, 10.60% S, 12.13% Example 41 (1R, 5S, 6S) -2- [1- [4-((1S) -1
-Hydroxymethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid
Sodium salt

[0443]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl] azetidine-3- Yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4-
[(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-
Thiazol-2-yl] azetidine 500 mg (1.09 mmol)
Was dissolved in 25 ml of dimethylformamide, 121 mg (1.31 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred as it was for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R,
5S, 6S) -2- (diphenylphosphoryloxy)-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 648 mg (1.
Then, 759 μl (4.36 mmol) of diisopropylethylamine was added, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% saline and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-
1: 4) and purified with p-nitrobenzyl (1R, 5
S, 6S) -2- (1- [4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl] azetidine- 3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
Carboxylate as a pale yellow solid 694 mg, yield 8
Obtained at 4%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.47-7.52 (1H, br
d, J = 9.8Hz), 7.43 (1H, s), 5.52 (1H, d, J = 13.7Hz),
5.25 (1H, d, J = 13.7Hz), 4.51 (1H, t, J = 7.8Hz), 4.4
5 (1H, t, J = 7.8Hz), 4.28 (1H, dd, J = 9.3, 2.0Hz),
4.31-4.25 (2H, m), 4.05 (2H, ddd, J = 7.8, 5.6, 1.2H
z), 3.86-3.80 (2H, m), 3.62 (1H, dd, J = 9.8, 3.9H
z), 3.30 (1H, dd, J = 6.8, 2.0Hz), 3.22 (1H, dq, J = 9.
3, 6.8Hz), 2.05-1.95 (1H, m), 1.39 (3H, d, J = 5.9H
z), 1.28 (3H, d, J = 6.8Hz), 0.99 (3H, d, J = 6.8Hz),
0.97 (3H, d, J = 6.8 Hz), 0.91 (9H, s), 0.06 (6H, s). (2) p-Nitrobenzyl (1R, 5S, 6S) -2
-[1- [4-((1S) -1-hydroxymethyl-2-
Methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylate p-nitrobenzyl (1) obtained in Example 41 (1)
R, 5S, 6S) -2- (1- [4-[(1S) -1- (t-
(Butyldiphenylsilyloxymethyl) -2-methyl-
Propylcarbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 690 mg (0.914 mmol) was dissolved in 35 ml of tetrahydrofuran, and 157 μl of acetic acid (2.
74 mmol), and 1.74 ml (2.74 mmol) of a 1 M solution of tetrabutylammonium fluoride-tetrahydrofuran were sequentially added.
Thereafter, the mixture was stirred at room temperature for 2 days. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate:
Purified with methanol = 9: 1), p-nitrobenzyl (1R, 5S, 6S) -2- [1- [4-((1S) -1)
-Hydroxymethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-Methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 388 mg, 66% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.44 (1H, s), 7.
33-7.28 (1H, br d, J = 8.8Hz), 5.51 (1H, d, J = 13.9H
z), 5.25 (1H, d, J = 13.9Hz), 4.50 (2H, ddd, J = 8.1,
8.1, 3.7Hz), 4.32-4.24 (2H, m), 4.27 (1H, dd, J = 9.
2, 2.5Hz), 3.88-3.76 (2H, m), 3.74 (1H, dd, J = 11.0,
6.6Hz), 3.30 (1H, dd, J = 7.0, 2.5Hz), 3.22 (1H, d
q, J = 7.2, 7.3Hz), 2.06-1.95 (1H, m), 1.38 (3H, d, J
= 6.6Hz), 1.28 (3H, d, J = 7.3Hz), 1.02 (3H, d, J = 7.3
Hz), 0.99 (3H, d, J = 6.6 Hz). (3) 1R, 5S, 6S) -2- [1- [4-((1S)
-1-hydroxymethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene -2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 41 (2)
R, 5S, 6S) -2- [1- [4-((1S) -1-hydroxymethyl-2-methyl-propylcarbamoyl)-
1,3-thiazol-2-yl] azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 380
mg (0.588 mmol) in tetrahydrofuran 19 ml, distilled water 1
The mixture was dissolved in 9 ml and subjected to catalytic hydrogen reduction for 2 hours at room temperature in the presence of 380 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 49 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 76:24), and lyophilized to give 1R, 5S, 6 as the target compound.
S) -2- [1- [4-((1S) -1-hydroxymethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 164 mg, in a yield of 52%. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.49 (1 H, s),
4.61-4.53 (2H, m), 4.39-4.31 (1H,, 4.25 (1H, dq, J =
6.2, 6.3Hz), 4.20 (1H, dd, J = 2.4, 9.1Hz), 4.11-4.0
4 (2H, m), 3.87-3.83 (1H, m), 3.80 (1H, dd, J = 3.8, 1
1.7Hz), 3.71 (1H, dd, J = 7.5, 11.7Hz), 3.43 (1H, dd,
J = 2.4, 6.2Hz), 3.26 (1H, dq, J = 9.1, 7.2Hz), 1.97-
1.84 (1H, m), 1.30 (3H, d, J = 6.3Hz), 1.20 (3H, d,
J = 7.2Hz), 0.97 (3H, d, J = 6.8Hz), 0.93 (3H, d, J = 6.
9Hz). IR (KBr): 1749, 1651, 1600, 1547, 1493, 1470, 139
3, 1315cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 555 [M + Na] ⁺ High-resolution mass spectrum (FAB ⁺ ): Observed value: 533.1497
[M + H] ^+, _{calcd: 533.1505 (C 22 H 30 N} 4 O 6 S 2 Na) Elemental _{Analysis: C 22 H 29 N 4 O} 6 S 2 Na · 5 / 3H 2 O Calculated Found: C , 46.89% H, 5.86% N, 10.41% S, 11.15% Calculated: C, 46.96% H, 5.79% N, 9.96% S, 11.40% Example 42 (1R, 5S, 6S) -2- [1- [4-((1S) -1-
Hydroxymethyl-3-methyl-butylcarbamoyl)
-1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0445]

[Of 60]

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidine-3- Yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- {4-} obtained in Reference Example 37
[(1S) -1- (t-Butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl−１azetidine (450 mg, 0.954 mmol) was dissolved in dimethylformamide (23 ml). Under an atmosphere, at room temperature, 105 mg (1.14 mmol) of hydrazine acetate was added,
The mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S,
6S) -2- (diphenylphosphoryloxy) -6
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 567 mg (0.954 m
mol) in 28 ml of acetonitrile was added dropwise, followed by 665 μl (3.82 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% saline and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-
1: 4) and purified with p-nitrobenzyl (1R, 5
S, 6S) -2- (1- {4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl} azetidine- 3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
645 mg of carboxylate as pale yellow solid, yield 8
7%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d, J
= 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.41 (1H, s), 7.35-
7.30 (1H, br d, J = 9.5Hz), 5.51 (1H, d, J = 13.9Hz),
5.25 (1H, d, J = 13.9Hz), 4.50 (1H, dd, J = 8.1Hz), 4.
45 (1H, dd, J = 8.1Hz), 4.31-4.24 (3H, m), 4.21-4.13
(1H, m), 4.06 (1H, dd, J = 5.9, 2.9Hz), 4.03 (1H, d
d, J = 5.9, 2.2Hz), 3.66 (2H, d, J = 2.9Hz), 3.30 (1H,
dd, J = 7.3, 2.9Hz), 3.21 (1H, dq, J = 6.6, 7.3Hz),
1.68-1.57 (1H, m), 1.52 (1H, ddd, J = 14.6, 8.8, 5.9
Hz), 1.44 (1H, ddd, J = 14.6, 8.8, 5.9Hz), 1.38 (3H,
d, J = 5.9Hz), 1.28 (3H, d, J = 7.3Hz), 0.95 (6H, t, J
= 6.6Hz), 0.91 (9H, s), 0.05 (6H, s). (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
[1- [4-((1S) -1-hydroxymethyl-3-methyl-butylcarbamoyl) -1,3-thiazole-2-
Yl] azetidin-3-yl] thio-6-[(R) -1-
[Hydroxyethyl] -1-methyl-carbapen-2-em-3carboxylate The p-nitrobenzyl (1) obtained in Example 42 (1)
R, 5S, 6S) -2- (1- {4-[(1S) -1- (t
-Butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl {azetidin-3-yl) thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (640 mg, 0.827 mmol) was dissolved in tetrahydrofuran (32 ml), and 142 μl of acetic acid was added under ice-cooling.
(2.48 mmol), 2.48 ml (2.48 mmol) of a 1 M solution of tetrabutylammonium fluoride-tetrahydrofuran were sequentially added, and the mixture was stirred at room temperature for 2 days. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- [1- [4- ((1S) −
1-hydroxymethyl-3-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-Methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 302 mg in a yield of 55%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.44 (1H, s), 7.
18-7.14 (1H, br d, J = 7.8Hz), 5.51 (1H, d, J = 13.7H
z), 5.26 (1H, d, J = 13.7Hz), 4.53-4.47 (2H, m), 4.3
1-4.25 (3H, m), 4.20-4.13 (1H, m), 4.07 (2H, ddd,
J = 8.8, 4.9, 4.9Hz), 3.80-3.74 (1H, m), 3.66-3.60 (1
H, m), 3.30 (1H, dd, J = 6.8, 2.9Hz), 3.22 (1H, dq,
J = 6.8, 6.8Hz), 2.79-2.74 (1H, bt, J = 5.9Hz), 1.74-
1.65 (1H, m), 1.51 (1H, ddd, J = 14.7, 8.8, 5.9Hz),
1.43 (1H, ddd, J = 14.7, 8.8, 5.9Hz), 1.38 (3H, d, J
= 6.8Hz), 1.28 (3H, d, J = 6.8Hz), 0.96 (3H, d, J = 4.9
Hz), 0.95 (3H, d, J = 4.9 Hz). (3) (1R, 5S, 6S) -2- [1- [4-((1S)
-1-hydroxymethyl-3-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapen-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 42 (2)
R, 5S, 6S) -2- [1- [4-((1S) -1-hydroxymethyl-3-methyl-butylcarbamoyl)-
1,3-thiazol-2-yl] azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 300
mg (0.455mmol) in tetrahydrofuran 15ml, distilled water 1
It was dissolved in 5 ml and subjected to catalytic hydrogen reduction at room temperature for 2.5 hours in the presence of 300 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 38 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution,
A liquid separation operation was performed. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 76:24), and lyophilized to give the target compound (1R, 5S, 6
S) -2- [1- [4-((1S) -1-hydroxymethyl-3-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6
[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 131 mg, yield 53%. ^{1 H-NMR (400MHz, D} 2 O, TSP): δ (ppm) 7.45 (1H, s)
4.60-4.53 (2H, m), 4.39-4.31 (1H, m), 4.25 (1H, dq,
J = 6.0, 6.4Hz), 4.19 (1H, dd, J = 2.0, 9.1Hz), 4.19-
4.13 (1H, m), 4.06 (2H, dd, J = 4.9, 8.4Hz), 3.68 (1
H, dd, J = 4.7, 11.6Hz), 3.59 (1H, dd, J = 6.7, 11.6H)
z), 3.43 (1H, dd, J = 2.0, 6.0Hz), 3.26 (1H, dq, J =
9.1, 7.2Hz), 1.69-1.57 (1H, m), 1.50 (1H, ddd, J = 4.
5, 9.2, 14.1Hz), 1.39 (1H, ddd, J = 4.5, 9.2, 14.1H
z), 1.39 (3H, d, J = 6.4Hz), 1.20 (3H, d, J = 7.2Hz),
0.91 (6H, t, J = 6.2Hz) .IR (KBr): 1750, 1651, 1604, 1547, 1492, 1470, 139
0, 1311cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 547 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Observed value: 547.1674
[M + H] ⁺ , calculated: 547.1661 Example 43 (1R, 5S, 6S) -2- [1- [4-((1S, 2S)
-1-hydroxymethyl-2-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0447]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4-[(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl] azetidine- 3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4-
[(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,
3-thiazol-2-yl] azetidine 910mg (1.93mmo
l) was dissolved in dimethylformamide (46 ml), hydrazine acetate (213 mg, 2.31 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R,
5S, 6S) -2- (diphenylphosphoryloxy)-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 1.15 g (1.
A solution of (93 mmol) in acetonitrile (58 ml) was added dropwise, followed by the addition of 1.34 ml (7.72 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% saline and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to 1).
1: 4) and purified with p-nitrobenzyl (1R, 5
S, 6S) -2- (1- [4-[(1S, 2S) -1- (t-
(Butyldiphenylsilyloxymethyl) -2-methyl-
Butylcarbamoyl] -1,3-thiazol-2-yl]
Azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
765 mg of carboxylate as a pale yellow solid, yield 5
Obtained at 1%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.50-7.45 (1H, b
rd, J = 9.5Hz), 7.42 (1H, s), 5.66 (1H, d, J = 13.9H
z), 5.25 (1H, d, J = 13.9Hz), 4.50 (1H, t, J = 8.1Hz),
4.44 (1H, t, J = 8.1Hz), 4.32-4.24 (2H, m), 4.27 (1
H, dd, J = 2.6, 9.7Hz), 4.07-4.02 (2H, m), 3.91-3.85
(1H, m), 3.83 (1H, dd, J = 2.9, 10.3Hz), 3.63 (1H,
dd, J = 3.7,10.3Hz), 3.30 (1H, dd, J = 2.6, 7.0Hz), 3.
21 (1H, dq, J = 9.7, 6.6Hz), 1.88-1.84 (1H, br s),
1.80-1.70 (1H, m), 1.58-1.50 (1H, m), 1.38 (3H, d,
J = 6.6Hz), 1.27 (3H, d, J = 7.3Hz), 1.22-1.10 (1H,
m), 0.95 (3H, d, J = 7.3Hz), 0.90 (3H, t, J = 7.4Hz),
0.91 (9H, s), 0.05 (6H, s). (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
[1- [4-((1S, 2S) -1-hydroxymethyl-2
-Methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylate p-nitrobenzyl (1) obtained in Example 43 (1)
R, 5S, 6S) -2- (1- [4-[(1S, 2S) -1-
(T-butyldiphenylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazole-2
-Yl] azetidin-3-yl) thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
760 mg (0.982 mmol) of M-3-carboxylate was dissolved in 38 ml of tetrahydrofuran, and 169 μl of acetic acid was added under ice cooling.
(2.95 mmol), 2.95 ml (2.95 mmol) of a 1 M solution of tetrabutylammonium fluoride-tetrahydrofuran were sequentially added, and the mixture was stirred at room temperature for 3 days. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- [1- [4- ((1S, 2
S) -1-Hydroxymethyl-2-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 390 mg in a yield of 60%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.44 (1H, s), 7.3
3-7.29 (1H, br d, J = 8.8Hz), 5.51 (1H, d, J = 13.8H
z), 5.25 (1H, d, J = 13.8Hz), 4.53-4.46 (2H, m), 4.3
1-4.28 (2H, m), 4.28 (1H, dd, J = 9.5, 2.2Hz), 4.10-
4.03 (2H, m), 3.94-3.87 (1H, m), 3.85-3.79 (1H,
m), 3.78-3.72 (1H, m), 3.30 (1H, dd, J = 7.0, 2.2H
z), 3.21 (1H, dq, J = 9.5, 7.3Hz), 1.83-1.72 (1H,
m), 1.61-1.48 (1H, m), 1.38 (3H, d, J = 6.6Hz), 1.28
(3H, d, J = 7.3Hz), 1.26-1.14 (1H, m), 0.99 (3H, d,
J = 6.6Hz), 0.93 (3H, t, J = 7.3Hz). (3) (1R, 5S, 6S) -2- [1- [4-((1S,
2S) -1-Hydroxymethyl-2-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 43 (2)
R, 5S, 6S) -2- [1- [4-((1S, 2S) -1
-Hydroxymethyl-2-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
390 mg (0.591 mmol) of 1-methyl-carbapene-2-em-3-carboxylate was added to 20 ml of tetrahydrofuran,
It was dissolved in 20 ml of distilled water and subjected to catalytic hydrogen reduction for 2 hours at room temperature in the presence of 390 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and sodium hydrogen carbonate 5
0 mg was added. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 76:24), and lyophilized to give the target compound (1).
R, 5S, 6S) -2- [1- [4-((1S, 2S) -1
-Hydroxymethyl-2-methyl-butylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid
136 mg of the sodium salt was obtained as a white solid in a yield of 42%. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.49 (1H, s),
4.61-4.53 (2H, m), 4.39-4.31 (1H, m), 4.25 (1H, d
q, J = 6.2, 6.3Hz), 4.20 (1H, dd, J = 9.0, 2.3Hz), 4.1
1-4.04 (2H, m), 3.91 (1H, ddd, J = 7.4, 3.6, 3.6Hz),
3.81 (1H, dd, J = 11.8, 3.6Hz), 3.72 (1H, dd, J = 11.
8, 7.4Hz), 3.43 (1H, dd, J = 6.2, 2.3Hz), 3.25 (1H,
dq, J = 9.0, 7.2Hz), 1.76-1.64 (1H, m), 1.55-1.44 (1
H, m), 1.30 (3H, d, J = 6.3Hz), 1.20 (3H, d, J = 7.2H
z), 1.22-1.11 (1H, m), 0.95 (3H, d, J = 6.9Hz), 0.88
(3H, t, J = 7.4Hz). IR (KBr): 1750, 1651, 1602, 1547, 1493, 1470, 139
4, 1311cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 547 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Observed value: 547.1647
[M + H] ⁺ , calculated: 547.1661 Example 44 (1R, 5S, 6S) -2- [1- [4- (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl)-
1,3-thiazol-2-yl] azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0449]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4-[(2-t-butyldiphenylsilyloxy)-(1-t-butyldiphenylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine -3-yl) thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4- obtained in Reference Example 39
[(2-t-butyldiphenylsilyloxy)-(1-t
-Butyldiphenylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine
770 mg (1.45 mmol) was dissolved in dimethylformamide 39 ml, and hydrazine acetate 160 mg at room temperature under a nitrogen atmosphere.
(1.74 mmol) was added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]-was introduced into the system under ice cooling under a nitrogen atmosphere.
A solution of 862 mg (1.45 mmol) of 1-methyl-carbapen-2-em-3-carboxylate in 43 ml of acetonitrile was added dropwise, followed by 1.01 ml of diisopropylethylamine (5.
79 mmol), and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% saline and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
1: 2 to 1: 4) and purified with p-nitrobenzyl (1
R, 5S, 6S) -2- (1- [4-[(2-t-butyldiphenylsilyloxy)-(1-t-butyldiphenylsilyloxymethyl) -ethylcarbamoyl] -1,
3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 951 mg, 76%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.57-7.52 (1H, b
rd, J = 8.8Hz), 7.42 (1H, s), 5.52 (1H, d, J = 13.9H
z), 5.25 (1H, d, J = 13.9Hz), 4.47 (1H, t, J = 8.1Hz),
4.44 (1H, t, J = 8.1Hz), 4.26 (1H, dd, J = 3.6, 9.2H
z), 4.31-4.23 (2H, m), 4.09-3.99 (3H, m), 3.86-3.8
1 (1H, m), 3.61 (1H, dd, J = 6.6, 9.5Hz), 3.30 (1H,
dd, J = 2.6, 7.0Hz), 3.21 (1H, dq, J = 9.2, 6.6Hz), 1.
38 (3H, d, J = 5.9Hz), 1.27 (3H, d, J = 6.6Hz), 0.91 (9
H, s), 0.07 (6H, s). (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
[1- [4- (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate p-nitrobenzyl (1) obtained in Example 44 (1)
R, 5S, 6S) -2- (1- [4-[(2-t-butyldiphenylsilyloxy)-(1-t-butyldiphenylsilyloxymethyl) -ethylcarbamoyl] -1,3
-Thiazol-2-yl] azetidin-3-yl) thio-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 950 mg (1.1 mg)
0 mmol) was dissolved in 48 ml of tetrahydrofuran, and under ice-cooling, 378 μl (6.60 mmol) of acetic acid and 6.60 ml (6.60 ml) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran were added.
mmol), followed by stirring at room temperature for 3 days. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1 to 85:15),
p-Nitrobenzyl (1R, 5S, 6S) -2- [1-
[4- (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- Methyl-carbapene-2-em-3-
499mg carboxylate as pale yellow solid, yield 72%
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.73 (2H, d, J = 8.8Hz), 7.49 (1H, s), 7.
45 (1H, d, J = 8.1Hz), 5.46 (1H, d, J = 13.9Hz), 5.31
(1H, d, J = 13.9Hz), 5.09 (1H, d, J = 4.4Hz), 4.85-4.7
7 (2H, m), 4.57-4.42 (3H, m), 4.22 (1H, dd, J = 1.7,
8.8Hz), 4.01-3.95 (2H, m), 3.89-3.82 (1H, m), 3.56
-3.50 (2H, m), 3.49-3.41 (2H, m), 3.41-3.27 (2H,
m), 1.16 (3H, d, J = 6.6 Hz), 1.14 (3H, d, J = 6.6 Hz). (3) (1R, 5S, 6S) -2- [1- [4- (2-
(Hydroxy-1-hydroxymethyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid
Sodium salt p-nitrobenzyl (1) obtained in Example 44 (2)
R, 5S, 6S) -2- [1- [4- (2-hydroxy-
1-hydroxymethyl-ethylcarbamoyl) -1,3
-Thiazol-2-yl] azetidin-3-yl] thio-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 490 mg (0.
773 mmol) was dissolved in 25 ml of tetrahydrofuran and 25 ml of distilled water, and subjected to catalytic hydrogen reduction in the presence of 490 mg of 10% palladium carbon at room temperature for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 65 mg of sodium hydrogen carbonate was added to the filtrate.
Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 9: 1), and lyophilized to give the target compound (1R, 5S, 6S) -2-
[1- [4- (2-hydroxy-1-hydroxymethyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt as a white solid
mg, 47% yield. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.51 (1H,
s), 4.56 (2H, t, J = 8.2Hz), 4.39-4.31 (1H, m), 4.25
(1H, dq, J = 6.3, 6.4Hz), 4.20 (1H, dd, J = 2.4,9.0H
z), 4.19-4.14 (1H, m), 4.06 (2H, ddd, J = 3.6, 4.9,
8.6Hz), 3.78 (2H, dd, J = 5.1, 11.7Hz), 3.72 (2H, dd,
J = 6.6, 11.7Hz), 3.43 (1H, dd, J = 2.4, 6.3Hz), 3.25
(1H, dq, J = 9.0, 7.2Hz), 1.30 (3H, d, J = 6.4Hz), 1.
20 (3H, d, J = 7.2Hz). IR (KBr): 1748, 1649, 1599, 1547, 1393, 1313cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 521 [M + H] ⁺ high resolution mass spectrum (FAB ⁺ ): found: 521.1155
[M + H] ⁺ , Calculated: 521.1141 (C ₂₀ H ₂₆ N ₄ O ₇ S ₂ Na) Elemental analysis: Calculated as C ₂₀ H ₂₅ N ₄ O ₇ S ₂ Na ・ 4 / 3H ₂ O Observed: C , 44.21% H, 5.12% N, 10.31% S, 11.46% Calculated: C, 44.11% H, 5.12% N, 10.29% S, 11.78% Example 45 (1R, 5S, 6S) -2- (1- [4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0451]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4- [2-[(t-butyldiphenylsilyloxy) ethyl] -methyl-carbamoyl] -1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylate The 3-acetylthio-1- (4- [2
-[(T-butyldiphenylsilyloxy) ethyl] -methyl-carbamoyl] -1,3-thiazol-2-yl)
Azetidine (384 mg, 0.89 mmol) was dissolved in dimethylformamide (11 ml), and hydrazine acetate (99 mg, 1.07 mmol) was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy) -6-[(R) -1-
[Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate A solution of 5.29 mg (0.89 mmol) of acetonitrile in 22 ml was added dropwise, followed by 0.62 ml (3.56 mmol) of diisopropylethylamine, and gradually added to room temperature. The mixture was stirred overnight while the temperature was raised. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, and then washed.
After drying over anhydrous magnesium sulfate, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give p-nitrobenzyl (1
R, 5S, 6S) -2- [1- (4- [2-[(t-butyldiphenylsilyloxy) ethyl] -methyl-carbamoyl] -1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-Methyl-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 263 mg in a yield of 50%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H,
d, J = 8.7 Hz), 7.63 (2H, d, J = 8.7 Hz), 7.14 (0.
6H, s), 7.03 (0.4H, s), 5.48 (1H, d, J = 1.3 Hz
), 5.25 (1H, d, J = 1.3 Hz), 4.50 (1H, t, J = 8.
0 Hz), 4.23 (2H, t, J = 9.0 Hz), 4.31-4.18 (3
H, m), 4.05 (1H, dd., J = 8.3, 5.4 Hz), 3.89-
3.80 (1H, m), 3.80-3.72 (1H, m), 3.72-3.63
(1H, m), 3.63-3.51 (1H, m), 3.26 (1H, dd, J
= 7.1, 2.5 Hz), 3.26 (1.8H, s), 3.18 (1H, dq, J
= 8.3, 7.5 Hz), 3.07 (1.2H, s), 1.35 (3H, d, J =
6.4 Hz), 1.22 (3H, d, J = 6.9 Hz), 0.86 (9H, d
d, J = 7.8, 1.4 Hz), 0.27 (6H, dd, J = 12.4, 3.2 Hz
) (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
(1- [4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapen-2-em-3-carboxylate p-nitrobenzyl (1) obtained in Example 45 (1)
R, 5S, 6S) -2- [1- (4- [2-[(t-butyldiphenylsilyloxy) ethyl] -methyl-carbamoyl] -1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
622 mg (0.85 mmol) of 1-methyl-carbapene-2-em-3-carboxylate was added to 30 parts of tetrahydrofuran.
acetic acid 0.15 ml (2.55 mmo) under ice-cooling.
l) 2.55 ml (2.55 mmol) of a 1M-tetrabutylammonium fluoride-tetrahydrofuran solution was sequentially added,
Thereafter, the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1), and p-nitrobenzyl (1R, 5S, 6S) -2- (1- [4- [(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-
[263] [(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 50%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz), 7.25 (1
H, s), 5.50 (1H, d, J = 1.4 Hz), 5.26 (1H, d, J
= 1.4 Hz), 4.62-4.40 (2H, m), 4.36-4.20 (
3H, m), 4.08 (1H, t., J = 9.1 Hz), 4.06 (1H, t.,
J = 9.1 Hz), 3.84 (2H, t., J = 4.9 Hz), 3.63 (2
H, dd., J = 4.9 Hz), 3.29 (1H, dd, J = 6.4, 2.6 Hz
), 3.21 (1H, quint., J = 7.5 Hz), 3.08 (3H, s),
1.38 (3H, d, J = 6.2 Hz), 1.26 (3H, d, J = 7.3 Hz)
) (3) (1R, 5S, 6S) -2- (1- [4-[(2-
Hydroxyethyl) -methyl-carbamoyl] -1,3
-Thiazol-2-yl] azetidin-3-yl) thio-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 45 (2)
R, 5S, 6S) -2- (1- [4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 401 mg (0.65 m
was dissolved in 20 ml of tetrahydrofuran and 20 ml of distilled water, and subjected to catalytic hydrogen reduction in a water bath at 35 ° C. for 2 hours in the presence of 401 mg of 7.5% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 5 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution,
A liquid separation operation was performed. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 2%
The target compound (1R, 5S, 6S) -2- (1- [4-[(2
-Hydroxyethyl) -methyl-carbamoyl] -1,
3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-
134 mg of carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 41%. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.31 (0.6H,
s), 7.11 (0.4H, s), 4.56 (2H, t, J = 8.2 Hz),
4.41-4.31 (2H, m), 4.25 (1H, quint., J = 6.2 Hz
), 4.21 (1H, dd, J = 9.1, 2.4 Hz), 4.12-4.00
(2H, m), 3.85 (1H, t, J = 5.4 Hz), 3.74 (1H, t,
J = 5.4 Hz), 3.70-3.60 (2H, m), 3.44 (1H, dd,
J = 6.2, 2.4 Hz), 3.26 (1H, dq, J = 9.1, 7.4 Hz
), 3.07 (1.2H, s), 3.08 (1.8H, s), 1.30 (3H,
d, J = 6.5 Hz), 1.20 (3H, d, J = 7.3 Hz) IR (KBr): 3397.0, 1749.1, 1606.4, 1538.9, 1469.5,
1398.1, 1311.4, 1266.0cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 505 [M + H] ⁺ High-resolution mass spectrum (ESI ⁺ ): Observed value: 505.1185
[M + Na] ^+, _{calcd: 505.1191 (C 20 H 25 N} 4 O 6 S 2 Na 2) Example 46 (1R, 5S, 6S) -2- [1- [4- ( carboxymethyl - carbamoyl) -1,3-thiazole-2-
Yl] azetidin-3-yl] thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid disodium salt

[0453]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- [4- (p-nitrobenzyloxycarbonylmethyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylate p-nitrobenzyl (1) obtained in Reference Example 41 (10)
R, 5S, 6S) -2- [1- [4- (p-nitrobenzyloxycarbonylmethyl-carbamoyl) -1,3-
Thiazol-2-yl] azetidin-3-yl] thio-6
Dissolve 209.7 mg (0.24 mmol) of-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapene-2-em-3-carboxylate in 10 ml of tetrahydrofuran and cool under ice-cooling. Acetic acid 0.04
2 ml (0.7 mmol), 1M tetrabutylammonium fluoride-tetrahydrofuran solution 0.72 ml (0.7
2 mmol) was added in sequence, and then the mixture was stirred at room temperature for 4 days. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 1), and p-nitrobenzyl (1R, 5S, 6S) -2- [1- [4- (p-
Nitrobenzyloxycarbonylmethyl-carbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
14.5 mg of 1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 53%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 7.9Hz), 8.22 (2H, d, J = 7.9Hz), 7.66 (2H, d, J =
7.9Hz), 7.60 (1H, t, J = 6.6Hz), 7.54 (2H, d, J = 7.9H
z), 7.47 (1H, s), 5.505 (1H, d, J = 13.8Hz), 5.30 (2
H, s), 5.255 (1H, d, J = 13.8Hz), 4.50 (1H, t, J = 8.3H
z), 4.40 (1H, t, J = 8.3Hz), 4.32-4.24 (4H, m), 4.06
(1H, dd, J = 8.3, 6.2Hz), 4.05 (1H, dd, J = 8.3, 6.2H)
z), 3.30 (1H, dd, J = 7.0, 3.1Hz), 3.21 (1H, dq, J =
9.0, 7.4Hz), 1.98 (1H, br s), 1.38 (3H, J = 5.7Hz),
1.27 (3H, d, J = 7.4 Hz) (2) (1R, 5S, 6S) -2- [1- [4- (carboxylmethyl-carbamoyl) -1,3-thiazol-2-yl] azetidine-3 -Yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid disodium salt p-nitrobenzyl (1) obtained in Example 46 (1)
R, 5S, 6S) -2- [1- [4- (p-nitrobenzyloxycarbonylmethyl-carbamoyl) -1,3-
Thiazol-2-yl] azetidin-3-yl] thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 330.4 mg
(0.38 mmol) in 16.5 ml of tetrahydrofuran,
It was dissolved in 8.3 ml of distilled water and subjected to catalytic hydrogen reduction for 2 hours at room temperature in the presence of 350 mg of 20% palladium hydroxide-carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 63.9 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation.
The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water), and lyophilized to give the desired compound (1R, 5S, 6S).
-2- [1- [4- (Carboxymethyl-carbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid
158.7 mg of disodium salt as a white solid, yield
79%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.83 (1H, s), 4.45
(1H, t, J = 8.3Hz), 4.43 (1H, t, J = 8.3Hz), 4.28-4.2
1 (1H, m), 4.124 (1H, quintet, J = 5.8Hz), 4.08 (1H,
dd, J = 8.8, 2.0Hz), 3.99-3.92 (2H, m), 3.80 (2H,
s), 3.31 (1H, dd, J = 5.9, 2.0Hz), 3.14 (1H, dq, J = 8.
8, 6.8Hz), 1.18 (3H, d, J = 5.9Hz), 1.08 (3H, d, J = 6.
8Hz) IR (KBr): 3388, 1748, 1602, 1550, 1398, 1314, 1267
cm ^-1 Mass spectrum (FAB ⁺ ): 527 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: [M + H] ⁺ ,
_{Calculated: (C 19 H 21 N 4} O 7 S 2 Na) Example 47 (1R, 5S, 6S) -2- [1- [4- (3- hydroxyazetidine-l-carbonyl) -1,3 -Thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0455]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- [4- (3-Hydroxyazetidine-1-carbonyl) -1,3-thiazol-2-yl]
Azetidin-3-yl] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate Obtained in Reference Example 42 (2). p-Nitrobenzyl (1
R, 5S, 6S) -2- (1- [4- [3- (t-butyldiphenylsilyloxy) azetidine-1-carbonyl] -1,3-thiazol-2-yl] azetidine-3-
Il) Thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 850 mg (0.878 mmol) was dissolved in tetrahydrofuran 43 ml and cooled with ice. In the bottom, acetic acid 301μl (5.
27 mmol), and 5.27 ml (5.27 mmol) of a 1 M solution of tetrabutylammonium fluoride-tetrahydrofuran were sequentially added.
Thereafter, the mixture was stirred at room temperature for one day. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol =
95: 5 methylene chloride: methanol = 9: 1), and purified by p-nitrobenzyl (1R, 5S, 6S) -2-
[1- [4- (3-Hydroxyazetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine-
3-yl] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-
355 mg of M-3-carboxylate as a pale yellow solid,
Obtained in 66% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.7Hz), 7.66 (2H, d, J = 8.7Hz), 7.44 (1H, s), 5.
51 (1H, d, J = 13.7Hz), 5.25 (1H, d, J = 13.7Hz), 4.82
-4.77 (1H, m), 4.71-4.65 (1H, m), 4.51-4.36 (4H,
m), 4.31-4.23 (3H, m), 4.07-3.96 (3H, m), 3.29 (1H,
(dd, J = 2.4, 7.0Hz), 3.20 (1H, dq, J = 9.2,7.1Hz), 1.3
8 (3H, d, J = 6.3 Hz), 1.27 (3H, d, J = 7.1 Hz). (2) (1R, 5S, 6S) -2- [1- [4- (3-
Hydroxyazetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 47 (1)
R, 5S, 6S) -2- [1- [4- (3-hydroxyazetidine-1-carbonyl) -1,3-thiazole-
2-yl] azetidin-3-yl] thio-6-[(R)-
1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 350 m
g (0.568 mmol) in 18 ml of tetrahydrofuran, 18 m of distilled water
and catalytic hydrogen reduction was performed for 2 hours at room temperature in the presence of 10% palladium carbon (350 mg). After confirming the completion of the reaction, the reaction mixture was filtered, and 48 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 9: 1), and lyophilized to give the target compound (1R, 5S, 6S)
-2- [1- [4- (3-hydroxyazetidine-1-
Carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt As a white solid, 118 mg, yield 4
Obtained at 2%. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.33 (1H, s),
4.78-4.67 (2H, m), 4.56 (2H, t, J = 8.0Hz), 4.45-4.
31 (3H, m), 4.25 (1H, dq, J = 6.3, 6.3Hz), 4.20 (1H,
dd, J = 2.3, 9.0Hz), 4.10-4.03 (2H, m), 3.97 (1H, dd,
J = 3.7, 11.5Hz), 3.44 (1H, dd, J = 2.3, 6.3Hz), 3.25
(1H, dq, J = 9.0, 7.2Hz), 1.30 (3H, d, J = 6.3Hz), 1.20
(3H, d, J = 7.2Hz). IR (KBr): 1749, 1603, 1540, 1452, 1394, 1306cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 503 ([M + H] ⁺ high resolution mass spectrum (FAB ⁺ ): Found: 503.1040
[M + H] ⁺ , Calculated: 503.1035 (C ₂₀ H ₂₄ N ₄ O ₆ S ₂ Na) Elemental analysis: C ₂₀ H ₂₃ N ₄ O ₆ S ₂ Na ・ 8 / 3H ₂ O Calculated Actual: C, 44.04% H, 4.93% N, 9.86% S, 11.30% Calculated: C, 43.63% H, 5.19% N, 10.18% S, 11.65% Example 48 (1R, 5S, 6S) -2- [1- [ 4- (Carboxymethyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid disodium salt

[0457]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- [4- (methyl-p-nitrobenzyloxycarbonylmethyl-carbamoyl) -1,3-
Thiazol-2-yl] azetidin-3-yl] thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate p-nitrobenzyl (1) obtained in Reference Example 43 (3)
R, 5S, 6S) -2- [1- [4- (methyl-p-nitrobenzylcarbonylmethyl-carbamoyl) -1,3
-Thiazol-2-yl] azetidin-3-yl] thio-
997 mg (1.15 mmol) of 6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapene-2-em-3-carboxylate in tetrahydrofuran
Dissolve in 50 ml and add acetic acid 0.2 ml (3.44 mmo) under ice-cooling.
l) 3.44 ml (3.44 mmol) of a 1 M solution of tetrabutylammonium fluoride-tetrahydrofuran was added sequentially,
Thereafter, the mixture was stirred at room temperature for 2 days. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate:
Purified with methanol = 19: 1), p-nitrobenzyl (1R, 5S, 6S) -2- [1- [4- (methyl-p
-Nitrobenzylcarbonylmethyl-carbamoyl)-
1,3-thiazol-2-yl] azetidin-3-yl]
Thio-6-[(R) -l-hydroxyethyl] -l-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 413 mg, 47% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.32-8.10
(4H, m), 7.75-7.60 (2H, m), 7.60-7.45 (2H,
m), 7.75 (0.5H, s), 7.41 (0.5H, s), 5.51 (1
H, d, J = 13.6 Hz), 5.38-5.20 (3H, m including
5.26 (1H, d, J = 13.6 Hz)), 4.75-3.71 (9H, min
cluding 4.36 (1H, s), 4.56-4.46 (1H.m), 3.93
-3.83 (1H, m)), 3.45-3.05 (4H, m including
3.36 (0.9H, s), 3.16 (2.1H, s)), 3.29 (1H, d,
J = 6.3 Hz), 1.38 (3H, d, J = 6.1 Hz), 1.33-1.2
0 (3H, m) (2) (1R, 5S, 6S) -2- [1- [4- (carboxylmethyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] Thio-6
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid disodium salt The p-nitrobenzyl (1) obtained in Example 48 (1)
R, 5S, 6S) -2- [1- [4- (methyl-p-nitrobenzylcarbonylmethyl-carbamoyl) -1,3
-Thiazol-2-yl] azetidin-3-yl] thio-
413 mg of 6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (0.
54 mmol) in 20 ml of tetrahydrofuran and 20 ml of distilled water
And subjected to catalytic hydrogen reduction at room temperature in the presence of 413 mg of 7.5% palladium carbon for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 91 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water)
And lyophilized to give the desired compound (1R, 5S, 6S) -2- [1- [1- (carboxylmethyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidine. -3-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid disodium salt was obtained as a white solid in 126 mg, 43% yield. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.18 (0.6H,
s), 7.03 (0.4H, s), 4.41-4.32 (0.2H.m), 4.2
5 (1H, quint., J = 6.3 Hz), 4.15-3.98 (4H, m),
3.43 (1H, dd, J = 6.3, 2.2 Hz), 3.26 (1H, quin
t., J = 8.2 Hz), 3.11 (1.2H, s), 3.06 (1.8H, s
), 1.30 (3H, d, J = 6.4 Hz), 1.20 (3H, d, 7.1 Hz
) IR (KBr): 3389.3, 1748.2, 1605.4, 1541.8, 1469.5,
1394.3 cm ^-1 Mass spectrum (ESI ⁺ ): m / z: 519 [M-Na + 2H] ⁺ high-resolution mass spectrum (ESI ⁺ ): Found: 519.0956
^{[M-Na + 2H] +} , _{calcd: 519.0984 (C 20 H 24 N} 4 O 7 S 2 Na) Example 49 (1R, 5S, 6S) -2- [1- (4-N - carbamoylmethyl - N'-methylcarbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0459]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- [4- (carbamoylmethyl-methyl-carbamoyl) -1,3-thiazol-2-yl]
Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylate p-nitrobenzyl (1) obtained in Reference Example 44 (2)
R, 5S, 6S) -2- [1- [4- (carbamoylmethyl-methyl-carbamoyl) -1,3-thiazole-2
-Yl] azetidin-3-yl] thio-6-[(R) -1
-T-butyldimethylsilyloxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 932 mg
(1.27 mmol) in 50 ml of tetrahydrofuran,
Under ice-cooling, acetic acid 0.22 ml (3.81 mmol), 1 M tetrabutylammonium fluoride-tetrahydrofuran solution
3.81 ml (3.81 mmol) was added sequentially, and then at room temperature.
Stirred for a day. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol =
10: 1) and purified with p-nitrobenzyl (1R, 5
S, 6S) -2- [1- [4- (carbamoylmethyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in 424 mg, in a yield of 53%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 7.8 Hz), 7.66 (2H, d, J = 7.8 Hz), 7.36 (
0.2H, s), 7.24 (0.8H, s), 5.51 (1H, d, J = 13.7
Hz), 5.25 (1H, d, J = 13.7 Hz), 4.59-4.39 (
2H, m), 4.39 -3.94 (7H, m), 3.36 (0.6H, s), 3.
29 (1H, dd, J = 6.9, 3.3 Hz), 3.25 -3.14 (1H, m
), 3.11 (2.4H, s), 1.38 (3H, d, J = 6.1 Hz),
1.26 (3H, d, J = 7.1 Hz) (2) (1R, 5S, 6S) -2- [1- [4- (carbamoylmethyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidine -3-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid disodium salt The p-nitrobenzyl (1) obtained in Example 49 (1)
R, 5S, 6S) -2- [1- [4- (carbamoylmethyl-methyl-carbamoyl) -1,3-thiazole-2
-Yl] azetidin-3-yl] thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
Dissolve 424 mg (0.67 mmol) of M-3-carboxylate in 20 ml of tetrahydrofuran and 20 ml of distilled water to obtain 7.5
In the presence of 424 mg of palladium carbon, catalytic hydrogen reduction was performed at room temperature for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 57 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water to 4% acetonitrile-distilled water), and lyophilized to give the target compound. (1R, 5S, 6S) -2- [1- [4- (carbamoylmethyl-methyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 115 mg, 33% yield. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.22 (0.5H,
s), 7.20 (0.5H, s), 4.55 (2H, dd, J = 17.4, 8.4
Hz), 4.41-4.32 (1H, m), 4.25 (1H, quint., J =
6.3 Hz), 4.23-4.18 (3H, m including 4.22 (2
H, s)), 4.05 (2H, ddd, J = 17.3, 8.8, 4.9 Hz), 3.
44 (1H, dd, J = 6.2, 2.4 Hz), 3.31 -3.20 (1H, m
), 3.18 (1.5H, s), 3.09 (1.5H, s), 1.30 (3H,
d, J = 6.4 Hz), 1.20 (3H, d, 7.1 Hz) IR (KBr): 3384.5, 1748.2, 1681.6, 1603.5, 1539.9,
1469.5, 1397 2, 1310.4cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 518 [M + H] ⁺ High-resolution mass spectrum (ESI ⁺ ): Observed value: 518.1168
[M + H] ^+, _{calcd: 518.1144 (C 20 H 25 N} 5 O 6 S 2 Na) Example 50 (1R, 5S, 6S) -2- [1- [4- ( carbamoylmethyl - carbamoyl) - 1,3-thiazole-2-
Yl] azetidin-3-yl] thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0461]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- [4- (carbamoylmethyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1 -Methyl-carbapen-2-em-3-carboxylate p-nitrobenzyl (1) obtained in Reference Example 45 (2)
R, 5S, 6S) -2- [1- [4- (carbamoylmethyl-carbamoyl) -1,3-thiazol-2-yl]
Azetidin-3-yl] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 428.6 mg
(0.6 mmol) was dissolved in 21 ml of tetrahydrofuran, and 0.11 ml (1.9 mmol) of acetic acid was added under ice-cooling.
1.8 ml (1.8 mmol) of a solution of M-tetrabutylammonium fluoride-tetrahydrofuran was sequentially added, followed by stirring at room temperature for 3 days. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 8: 1).
And purified by p-nitrobenzyl (1R, 5S, 6S)
-2- [1- [4- (carbamoylmethyl-carbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
There was obtained 310.5 mg of 1-methyl-carbapene-2-em-3-carboxylate as a pale yellow solid in a yield of 85%. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 8.24 (2H, d, J
= 8.8Hz), 7.96 (1H, t, J = 5.7Hz), 7.72 (2H, d, J = 8.8H
z), 7.50 (1H, s), 7.40 (1H, br s), 7.08 (1H, br)
s), 5.46 (1H, d, J = 13.9Hz), 5.32 (1H, d, J = 13.9H
z), 5.09 (1H, d, J = 5.1Hz), 4.58-4.40 (3H, m), 4.22
(1H, dd, J = 9.2, 2.7Hz), 4.01-3.96 (3H, m), 3.81
(2H, d, J = 5.7Hz), 3.44-3.30 (2H, m), 1.16 (3H, d,
J = 6.6 Hz), 1.14 (3H, d, J = 7.3 Hz) (2) (1R, 5S, 6S) -2- [1- [4- (carbamoylmethyl-carbamoyl) -1,3-thiazole-2 -Yl] azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 50 (1)
R, 5S, 6S) -2- [1- [4- (carbamoylmethyl-carbamoyl) -1,3-thiazol-2-yl]
Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
A carboxylate (310.5 mg, 0.5 mmol) was dissolved in tetrahydrofuran (15.5 ml) and distilled water (7.8 ml), and dissolved in 20% palladium hydroxide-carbon (360 mg).
Catalytic hydrogen reduction was performed for 2 hours in a 5 ° C. water bath. After confirming the completion of the reaction, the reaction mixture was filtered, and sodium hydrogen carbonate was added to the filtrate.
42.3 mg were added. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to 5% acetonitrile-distilled water to 10% acetoyl-distilled water), and lyophilized to give the desired compound. (1R, 5S, 6S) -2- [
1- [4- (carbamoylmethyl-carbamoyl)-
1,3-thiazol-2-yl] azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 157 mg, yield 62%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.43 (1H, s), 4.45
(2H, t, J = 7.8Hz), 4.28-4.18 (1H, m), 4.13 (1H, qu
intet, J = 5.9Hz), 4.08 (1H, dd, J = 9.3, 2.3Hz), 4.00
-3.92 (4H, m), 3.31 (1H, dd, J = 5.9, 2.3Hz), 3.14
(1H, dq, J = 9.3, 7.8Hz), 1.13 (3H, d, J = 5.9Hz), 1.0
8 (3H, d, J = 7.8Hz) IR (KBr): 3384, 1748, 1660, 1600, 1549, 1492, 147
1, 1394, 1315, 1264 cm ^{- 1} Mass spectrum (FAB ⁺ ): 504 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Actual value: 504.1018
[M + H] ^+, _{calcd: 504.0988 (C 19 H 23 O} 6 N 5 S 2 Na) Example 51 (1R, 5S, 6S) -2- [1- [4 - ((1S) -
1-carboxyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid
Disodium salt

[0463]

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P-Nitrobenzyl (1R, 5S, 6S)
-2- (1- [4-[(1S) -2-methyl-1- (p-
Nitrobenzyloxycarboxyl) -propylcarbamoyl] -1,3-thiazol-2-yl] azetidine-
3-yl) thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapene-2-em-3-carboxylate p-nitrobenzyl (1) obtained in Reference Example 46 (3)
R, 5S, 6S) -2- (1- [4-[(1S) -2-methyl-1- (p-nitrobenzyloxycarboxyl)]
-Propylcarbamoyl] -1,3-thiazole-2-
Yl] azetidin-3-yl) thio-6-[(R) -1-
t-butyldimethylsilyloxyethyl] -1-methyl-
Carbapen-2-M-3-carboxylate 1.15 g
(1.29 mmol) was dissolved in 58 ml of tetrahydrofuran and, under ice-cooling, 222 μl (3.87 mmol) of acetic acid and 3.87 ml of a 1 M tetrabutylammonium fluoride-tetrahydrofuran solution
(3.87 mmol) was added sequentially, and the mixture was stirred at room temperature for 2 days. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to give p-nitrobenzyl (1R, 5).
S, 6S) -2- (1- [4-[(1S) -2-methyl-1- (p-nitrobenzyloxycarboxyl) -propylcarbamoyl] -1,3-thiazol-2-yl]
Azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-
377 mg of 3-carboxylate as pale yellow solid, yield
37%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 8.22 (2H, d, J = 8.8Hz), 7.66 (2H, d, J =
8.8Hz), 7.58-7.55 (1H, br s), 7.54 (2H, d, J = 8.8H
z), 7.45 (1H, s), 5.51 (1H, d, J = 13.5Hz), 5.28 (2
H, s), 5.26 (1H, d, J = 13.5Hz), 4.74 (1H, dd, J = 5.1,
8.8Hz), 4.53-4.47 (2H, m), 4.32-4.26 (3H, m), 4.1
0-4.05 (2H, m), 3.30 (1H, dd, J = 2.9, 6.6Hz), 3.22
(1H, dq, J = 9.5, 6.6Hz), 2.32-2.24 (1H, m), 1.39 (3
H, d, J = 5.8Hz), 1.28 (3H, d, J = 6.6Hz), 1.00 (3H,
d, J = 7.3 Hz), 0.97 (3H, d, J = 7.3 Hz). (2) (1R, 5S, 6S) -2- [1- [4-((1
S) -1-Carboxy-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylic acid disodium salt p-nitrobenzyl (1) obtained in Example 51 (1)
R, 5S, 6S) -2- (1- [4-[(1S) -2-methyl-1- (p-nitrobenzyloxycarboxyl)]
-Propylcarbamoyl] -1,3-thiazole-2-
Yl] azetidin-3-yl) thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (370 mg, 0.465 mmol) was dissolved in tetrahydrofuran (19 ml) and distilled water (19 ml), and subjected to catalytic hydrogen reduction at room temperature in the presence of 10% palladium carbon (370 mg). For 3 hours. After checking the completion of the reaction, the reaction mixture was filtered, and 80 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure and chromatographed using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile =
96: 4) and freeze-dried to give the desired compound (1R, 5S, 6S) -2- [1- [4-
((1S) -1-carboxyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1- 165 mg of methyl-carbapene-2-em-3-carboxylic acid disodium salt as a white solid,
Obtained in 63% yield. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.51 (1H, s),
4.59 (2H, dt, J = 8.0,5.6Hz), 4.40-4.34 (1H, m), 4.
29-4.23 (2H, m), 4.20 (1H, dd, J = 2.4, 9.0Hz), 4.10
(2H, dt, J = 9.0, 5.2Hz), 3.44 (1H, dd, J = 2.4, 6.4H
z), 3.27 (1H, dq, J = 9.0, 7.2Hz), 2.28-2.16 (1H,
m), 1.30 (3H, d, J = 6.2Hz), 1.20 (3H, d, J = 7.2Hz),
0.98 (3H, d, J = 6.8Hz), 0.95 (3H, d, J = 6.8Hz) .IR (KBr): 1749, 1599, 1547, 1491, 1471, 1400, 131
4, 1292, 1264cm ^-1 Mass spectrum (ESI ⁺ ): m / z: 591 [M + Na] ⁺ High-resolution mass spectrum (ESI ⁺ ): Actual value: 591.0952
[M + Na] ^+, _{calcd: 591.0936 (C 22 H 26 N} 4 O 7 S 2 Na 2) Elemental _{analysis: C 22 H 26 N 4 O} 7 S 2 Na 2 · 8 / 3H 2 O Calculated Found : C, 42.78% H, 5.33% N, 9.14% S, 10.12% Calculated value: C, 42.85% H, 5.12% N, 9.09% S, 10.40% Example 52 (1R, 5S, 6S) -2- [ 1- [4-((1S)-
1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid
Sodium salt

[0465]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate The p-nitrobenzyl (1) obtained in Reference Example 47 (3)
R, 5S, 6S) -2- [1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl)-
1,3-thiazol-2-yl] azetidin-3-yl]
Thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-
930 mg (1.20 mmol) of carboxylate was dissolved in 47 ml of tetrahydrofuran and, under ice-cooling, 206 μl of acetic acid (3.60 mmo)
l) 3.60 ml (3.60 mmol) of a 1M-tetrabutylammonium fluoride-tetrahydrofuran solution was sequentially added, followed by stirring at room temperature for 2 days. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give p-nitrobenzyl (1R, 5S, 6S) -2- [1- [4- ((1S)-
1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
383 mg of 1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 48%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.61-7.56 (1H, b
rd, J = 9.5Hz), 6.05-6.01 (1H, br s), 5.51 (1H, d,
J = 13.5Hz), 5.43-5.39 (1H, br s), 5.26 (1H, d, J = 1
3.5Hz), 4.54-4.47 (2H, m), 4.38-4.33 (1H, m), 4.32-
4.25 (2H, m), 4.10-4.04 (2H, m), 3.30 (1H, dd, J = 6.
6, 2.9Hz), 3.22 (1H, dq, J = 9.5, 7.3Hz), 2.33-2.24
(1H, m), 1.38 (3H, d, J = 5.9Hz), 1.28 (3H, d, J = 7.3H
z), 1.03 (3H, d, J = 6.6 Hz), 10.1 (3H, d, J = 6.6 Hz). (2) (1R, 5S, 6S) -2- [1- [4-((1
S) -1-Carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 52 (1)
R, 5S, 6S) -2- [1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl)-
1,3-thiazol-2-yl] azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 380
mg (0.577 mmol) in tetrahydrofuran 19 ml, distilled water
It was dissolved in 19 ml and subjected to catalytic water reduction for 3 hours at room temperature in the presence of 380 mg of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 48 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution,
A liquid separation operation was performed. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (eluent: distilled water to distilled water: acetonitrile = 81: 9), and lyophilized to give the target compound (1R, 5S, 6
S) -2- [1- [4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
170 mg of [(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 54%. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.55 (1H, s),
4.58 (2H, t, J = 8.2Hz), 4.40-4.34 (1H, m), 4.29 (1
(H, d, J = 6.9Hz), 4.25 (1H, dq, J = 6.2, 6.4Hz), 4.20
(1H, dd, J = 2.4, 9.0Hz), 4.09 (2H, dt, J = 9.0, 4.6H
z), 3.43 (1H, dd, J = 2.4, 6.2Hz), 3.26 (1H, dq, J = 9.
0, 7.2Hz), 2.26-2.16 (1H, m), 1.30 (3H, d, J = 6.4Hz),
0.20 (3H, d, J = 7.2Hz), 1.02 (6H, d, J = 6.8Hz) .IR (KBr): 1749, 1662, 1603, 1545, 1490, 1471, 139
4, 1316, 1293, 1260 cm ^{- 1} Mass spectrum (FAB ⁺ ): m / z: 546 [M + H] ⁺ high-resolution mass spectrum (ESI ⁺ ): Observed value: 568.1271
[M + Na] ⁺ , Calculated: 568.1276 (C ₂₂ H ₂₈ N ₅ O ₆ SNa ₂ ) Elemental analysis: Calculated as C ₂₂ H ₂₈ N ₅ O ₆ SNa ・ 3H ₂ O Actual: C, 44.17% H, 6.18% N, 11.84% S, 10.67% Calculated: C, 44.07% H, 5.72% N, 11.68% S, 10.69% Example 53 (1R, 5S, 6S) -2- [1- [4- (carboxyl) Methyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid disodium salt

[0467]

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(1) 3-acetylthio-1- [4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3- obtained in Reference Example 48
Thiazol-2-yl] azetidine 312 mg (0.63 mmol)
Was dissolved in 9 ml of dimethylformamide, 70 mg (0.76 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1
R, 5S, 6S) -2- (Diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 452
mg (0.76 mmol) in 20 ml of acetonitrile was added dropwise, followed by 0.44 ml of diisopropylethylamine (2.5
2 mmol) and stirred for 4 hours. After confirming the completion of the reaction,
Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 2).
0: 1) and purified with p-nitrobenzyl (1R, 5
S, 6S) -2- (1- [4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl] azetidine-3-
Yl) thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapene-2-em-3-carboxylate was obtained as a pale-yellow solid in 193 mg, yield 39%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (4H,
d, J = 8.9 Hz), 7.66 (2H, d, J = 8.9 Hz), 7.56 (1
H, d, J = 8.0 Hz), 7.43-7.32 (1.4H, m), 7.15
(0.6H, br s), 5.51 (1H, d, J = 13.8 Hz), 5.28 (
1.2H, br s), 5.25 (1H, d, J = 13.8 Hz), 5.20 (
0.8H, br s), 5.05-4.65 (0.4H, m), 4.85-4.65
(0.6H, m), 4.65-3.95 (8H, m including 4.50
(2H, t., J = 7.4 Hz), 4.11 (2H, t., J = 7.4 Hz)),
3.93-3.75 (1H, m), 3.29 (1H, dd, J = 6.6, 2.
0 Hz), 3.25-3.08 (1H, m), 1.38 (3H, d, J = 6.
4 Hz), 1.35 (3H, d, J = 7.2 Hz), 1.20 (6H, br s
(2) (1R, 5S, 6S) -2- [1- [4- (carboxylmethyl-isopropyl-carbamoyl) -1,3
-Thiazol-2-yl] azetidin-3-yl] thio-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid disodium salt The compound p-nitrobenzyl (1R, 5S, 6S) -2-1- [4- [isopropyl-
(P-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 193 mg (0.24 mmol) of 2-M-3-carboxylate was added to tetrahydrofuran 9
dissolved in 9 ml of distilled water and 7.5 ml of palladium on carbon 193
In the presence of mg, catalytic hydrogen reduction was performed in a 35 ° C water bath for 3 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 40 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water), and lyophilized to give the target compound (1).
R, 5S, 6S) -2- [1- [4- (Carboxymethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid disodium salt was obtained as a white solid in 63 mg, yield 45%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.08 (0.6H, br s
), 7.04 (0.4H, br s), 4.70-4.69 (0.2H.m), 4.
53 (2H, d, J = 8.0 Hz), 4.42-4.31 (1H, m), 4.1
8-4.09 (0.8H, m), 4.25 (1H, quint., J = 6.4 Hz
), 4.20 (1H, d, J = 9.1 Hz), 4.09-4.02 (2H, m
), 3.95 (2H, d, J = 5.8 Hz), 3.43 (1H, dd, J = 6.
4, 0.8 Hz), 3.26 (1H, quint., J = 7.6 Hz), 1.31
(3H, d, J = 6.4 Hz), 1.26-1.10 (9H, m) IR (KBr): 3398.0, 1749.1, 1603.5, 1539.9, 1467., 1
453.1, 1392.4, 1310.4, 1277.6cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 569 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Observed value: 569.1119
[M + H] ^+, _{calcd: 569.1116 (C 22 H 27 O} 7 N 4 S 2 Na 2) Example 54 (1R, 5S, 6S) -2- [1- [4- ( carbamoylmethyl - isopropyl - Carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0469]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4- (carbamoylmethyl-isopropyl-carbamoyl)-obtained in Reference Example 49
1,3-thiazol-2-yl] azetidine 347 mg (0.9
7 mmol) was dissolved in 10 ml of dimethylformamide, and hydrazine acetate 108 mg (1.17
mmol) and stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 was introduced into the system under ice cooling under a nitrogen atmosphere. −
Methyl-carbapen-2-em-3-carboxylate
A solution of 696 mg (1.17 mmol) in 20 ml of acetonitrile was added dropwise, followed by 0.68 ml of diisopropylethylamine.
(3.88 mmol) was added, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1), and p-nitrobenzyl (1R, 5S, 6S) -2- [1- [4-
(Carbamoylmethyl-isopropyl-carbamoyl)-
1,3-thiazol-2-yl] azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 359 mg, yield 56%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 7.05-6.
72 (1H, m) 5.51 (1H, d, J = 13.8 Hz), 5.25 (11H,
d, J = 13.8 Hz), 4.80-4.45 (1H, m), 4.45-4.
35 (2H, m), 4.35-4.17 (3H, m), 4.03 (4H, m
), 3.29 (1H, dd, J = 7.0, 2.5 Hz), 3.25-3.05
(1H, m), 1.38 (3H, d, J = 6.3 Hz), 1.33 -0.98
(9H, m including 1.25 (3H, d, J = 7.1 Hz)) (2) (1R, 5S, 6S) -2- [1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3
-Thiazol-2-yl] azetidin-3-yl] thio-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt Compound p-nitrobenzyl (1R, 5S, 6S) obtained in Example 54 (1) ) -2- [1- [4- (Carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 359 mg (0.55 m
was dissolved in 12 ml of tetrahydrofuran and 12 ml of distilled water, and subjected to catalytic hydrogen reduction in a 35 ° C water bath for 3 hours in the presence of 359 mg of 7.5% palladium hydroxide. After confirming the completion of the reaction,
The reaction mixture was filtered, and the filtrate was treated with sodium hydrogen carbonate (46 mg).
Was added. Acetic acid and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water), and lyophilized to give the target compound (1R, 5S, 6S). -2-
[1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapene-2-M-3-carboxylic acid sodium salt as a white solid 195 mg, yield 65
%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.17 (0.2H, br s
), 7.12 (0.8H, br s), 4.56 (2H, dd, J = 17.4,
9.0 Hz), 4.42-4.16 (4H, m including 4.25 (1H,
quint., J = 6.3 Hz), 4.21 (1H, dd, J = 8.4, 2.3 Hz
), 4.09-3.97 (2H, m), 3.44 (1H, dd, J = 6.3, 2.
5 Hz), 3.26 (1H, quint., J = 8.4 Hz), 1.30 (3H,
d, J = 6.4 Hz), 1.25-1.08 (9H, m including 1.1
9 (3H, d, J = 6.7 Hz)) IR (KBr): 3404.7, 1749.1, 1681.6, 1605.4, 1538.0,
1468.5, 1448.3, 1395.2, 1306.5, 1277.6 cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 546 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Observed value: 546.1458
[M + H] ^+, _{calcd: 546.1457 (C 22 H 29 N} 5 O 6 S 2 Na) Example 55 (1R, 5S, 6S) -2- [1- [4- ( cyanomethyl - isopropyl - carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid sodium salt

[0471]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- [4- (Cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3- obtained in Reference Example 50.
Thiazol-2-yl] azetidine 344 mg (1.01 mmol)
Was dissolved in 10 ml of dimethylformamide, and hydrazine acetate 112 mg (1.22 mmol) was added at room temperature under a nitrogen atmosphere.
And stirred for 1 hour. After confirming the completion of the reaction,
Under a nitrogen atmosphere, p-nitrobenzyl (1
R, 5S, 6S) -2- (Diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 725
mg (1.22 mmol) of acetonitrile in 20 ml was added dropwise, followed by diisopropylidipropylethylamine.
0.70 ml (4.04 mmol) was added, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was treated with 0.5 M hydrochloric acid aqueous solution,
After washing with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, drying over anhydrous magnesium sulfate, filtration, and the filtrate were concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1).
) And purified with p-nitrobenzyl (1R, 5S, 6).
S) -2- [1- [4- (cyanomethyl-isopropyl-
Carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate Obtained as a yellow solid in 245 mg, 39% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.7 Hz), 7.6 (2H,, J = 8.7 Hz), 7.48-7.
15 (1H, m), 5.51 (1H, d, J = 14.0 Hz), 5.26 (
1H, d, J = 14.0 Hz), 4.86 (1H, quint., J = 6.5 Hz)
) 4.72-3.76 (9H, m including 4.52 (2H, t J =
8.1 Hz), 4.27 (2H, dd, J = 6.6, 2.5 Hz)), 3.29 (
1H, dd, J = 6.9, 2.5 Hz), 3.21 (1H, quint., J = 9.
3, 7.3 Hz), 1.38 (3H, d, J = 6.2 Hz), 1.35-1.20
(9H, m including 1.25 (3H, d, J = 7.3 Hz)) (2) (1R, 5S, 6S) -2- [1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazole- 2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt Compound p-nitrobenzyl (1R, 5S, 6S)-obtained in Example 55 (1)- 2- [1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
245 mg (0.39 mmol) of 2-M-3-carboxylate
Was dissolved in 12 ml of tetrahydrofuran and 12 ml of distilled water,
In the presence of 245 mg of 7.5% palladium on carbon, catalytic hydrogen reduction was performed in a water bath at 35 ° C for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 33 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water to 4%).
(1R, 5S, 6S) -2- [1- [4- (cyanomethyl-isopropyl-carbamoyl)]. -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
87 mg of [(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 42%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.20 (1H, br s),
4.58 (2H, t, J = 8.0Hz), 4.49-4.31 (3H, m incl
uding 4.41 (2H, s)), 4.25 (1H, quint., J = 6.3 H
z), 4.21 (1, dd, J = 9.0, 2.3 Hz), 4.19-3.80
(3H, m including 4.07 (2H, dd, J = 8.6, 4.9 Hz),
3.44 (1H, dd, J = 6.3, 2.4 Hz), 3.26 (1H, dq, J =
9.0, 7.2 Hz), 1.43-1.25 (9H, m including 1.31
(3H, d, J = 6.4 Hz), 1.20 (3H, d, J = 7.2 Hz)) IR (KBr): 3398.0, 1750.1, 1606.4, 1537.0, 1468.5,
1426.1, 1401.0, 1373.1, 1332.6, 1311.4, 1274.7 cm
^-1 Mass spectrum (FAB ⁺ ): m / z: 550 [M + Na] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: 550.1179
[M + Na] ^+, _{calcd: 550.1171 (C 22 H 26 N} 5 O 5 S 2 Na 2) Example 56 (1R, 5S, 6S) -2- {1- [4- ( piperidin-4-y Rucarbamoyl) -1,3-thiazole-2-
Yl] azetidin-3-yl {thio-6-[(R) -1-]
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid

[0473]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4- [1- (p-nitrobenzyl)
Oxycarbonyl) -piperidin-4-ylcarbamoy
[-1,3-thiazol-2-yl] azetidine-3-
Yl @ thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapene-2-m-3-carboxylate
G The 3-acetylthio-1- [4- [1
-(P-nitrobenzyloxycarbonyl) -piperidi
4-N-ylcarbamoyl] -1,3-thiazole-2
-Yl] azetidine (260 mg, 0.500 mmol) in dimethylform
Dissolve in 13 ml of amide, and add hydra
Add 55 mg (0.600 mmol) of gin acetate and leave for 1 hour
Stirred. After confirming the completion of the reaction, cool the system under ice in a nitrogen atmosphere.
In the p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy) -6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapen-2-e
297 mg (0.500 mmol) of acetic acid
15 ml of tonitrile solution is added dropwise, followed by diisopropyl
Add 348 μl (2.00 mmol) of ethylamine and leave it at room temperature.
The mixture was stirred overnight while the temperature was gradually raised until the reaction was completed. Reaction completion confirmation
Then, add ethyl acetate and saturated aqueous sodium bicarbonate to the reaction
Was extracted with ethyl acetate. 0.5M of the obtained organic layer
Wash sequentially with aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, then anhydrous
Dry over sodium sulfate, filter and concentrate the filtrate under reduced pressure.
Was. The obtained residue is subjected to silica gel column chromatography.
-(Elution solvent: ethyl acetate to ethyl acetate: methanol =
9: 1) and purified with p-nitrobenzyl (1R, 5
S, 6S) -2- (1- [4- [1- (p-nitroben
(Diloxycarbonyl) -piperidin-4-ylcarba
Moyl] -1,3-thiazol-2-yl] azetidine-
3-yl @ thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapene-2-em-3-carboxy
The rate was obtained as pale yellow solid in 348 mg, 85% yield. ¹ H-NMR (400 MHz, CDCl _Three ): δ (ppm) 8.23 (4H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.52 (2H, d, J =
8.8Hz), 7.43 (1H, s), 7.05-7.01 (1H, br d, J = 8.8H
z), 5.51 (1H, d, J = 13.7Hz), 5.25 (1H, d, J = 13.7H
z), 5.23 (2H, s), 4.52-4.46 (2H, m), 4.31-4.25 (3
H, m), 4.23-4.04 (3H, m), 4.05 (2H, dt, J = 8.8, 5.9
Hz), 3.30 (1H, dd, J = 2.4, 7.3Hz), 3.21 (1H, dq, J =
6.8,8.8Hz), 3.11-2.95 (2H, m), 2.07-2.00 (2H, m),
1.55-1.41 (2H, m), 1.38 (3H, d, J = 6.8Hz), 1.28 (3
(H, d, J = 5.9Hz). (2) (1R, 5S, 6S) -2- ｛1- [4- (pipe
Lysin-4-ylcarbamoyl) -1,3-thiazole
-2-yl] azetidin-3-yl {thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylate carboxylic acid sodium
P-Nitrobenzyl obtained in Example 56 (1)
(1R, 5S, 6S) -2-｛(1- [4- [1- (p
-Nitrobenzyloxycarbonyl) -piperidine-4
-Ylcarbamoyl] -1,3-thiazol-2-yl]
Azetidin-3-yl {thio-6-[(R) -1-hydride]
Roxyethyl] -1-methyl-carbapene-2-m-
340 mg (0.414 mmol) of 3-carboxylate in tetrahydro
Dissolve in 17ml of lofuran and 17ml of distilled water and add 10% paradigm
Catalytic hydrogen reduction for 4.5 hours at room temperature in the presence of 340 mg of carbon
Was. After confirming the completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated with ethyl acetate.
Chill and distilled water were added, and a liquid separation operation was performed. Water layer
Concentrate under reduced pressure and chromatograph using Cosmo Seal
-(Elution solvent: distilled water to distilled water: acetonitrile 8:
Purify in 2) and freeze-dry to obtain the target compound
(1R, 5S, 6S) -2- ｛1- [4- (pipe
Lysin-4-ylcarbamoyl) -1,3-thiazole
-2-yl] azetidin-3-yl {thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
70 mg of 2-M-3-carboxylic acid as a white solid, yield
33%. ¹ H-NMR (400MHz, D _Two O): δ (ppm) 7.50 (1H, s), 4.55
(2H, t, J = 8.2Hz), 4.36-4.29 (1H, m), 4.24 (1H, dq,
J = 6.2, 6.4Hz), 4.17 (1H, dd, J = 2.2, 9.1Hz), 4.17-
4.08 (1H, m), 4.03 (1H, dd, J = 5.0, 8.3Hz), 3.53 (2
H, dt, J = 13.3, 3.1Hz), 3.43 (1H, dd, J = 2.2, 6.2H
z), 3.25 (1H, dq, J = 9.1, 7.2Hz), 3.17 (2H, dt, J = 1
2.8, 2.9Hz), 2.20 (1H, dd, J = 2.9, 14.2Hz), 1.93-1.
80 (2H, m), 1.30 (3H, d, J = 6.4Hz), 1.19 (3H, d, J =
7.2Hz) .IR (KBr): 1754, 1658, 1602, 1545, 1385, 1315cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 508 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Found: 508.1693
[M + H] ⁺ , Calculated: 508.1688 (C _{twenty two} H ₃₀ N _Five O _Five S _Two ) Elemental analysis: C _{twenty two} H ₂₉ N _Five O _Five S _Two ・ 3H _Two Calculated as O Observed: C, 47.07% H, 6.38% N, 12.37% S, 11.14% Calculated: C, 47.05% H, 6.28% N, 12.47% S, 11.42% Example 57 (1R, 5S, 6S) ) -2- ｛1- [4-((3S)-
Pyrrolidin-3-ylcarbamoyl) -1,3-thiazo
-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carba
Pen-2-M-3-carboxylic acid

[0475]

[Of 75]

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl ] Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4-
[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-
Thiazol-2-yl diazetidine 280 mg (0.554 mmol)
Was dissolved in 14 ml of dimethylformamide, 61 mg (0.665 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred as it was for 2 hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5
(S, 6S) -2- (diphenylphosphoryloxy) -6
329 g of [[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (0.554 m
mol) of acetonitrile in 16 ml was added dropwise, followed by 356 μl (2.22 mmol) of diisopropylethylamine.
The mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate:
Purified with methanol = 9: 1), p-nitrobenzyl (1R, 5S, 6S) -2- (1- [4-[(3S) -1]
-(P-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole-2
-Yl {azetidin-3-yl] thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
399 mg of M-3-carboxylate as a pale yellow solid,
Obtained in 89% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 8.20 (2H, d, J = 8.8Hz), 7.66 (2H, d, J =
8.8Hz), 7.53 (2H, dd, J = 8.8, 13.7Hz), 7.45 (1H,
s), 7.17-7.12 (1H, brt, J = 7.8Hz), 5.51 (1H, d, J =
13.7Hz), 5.25 (1H, d, J = 13.7Hz), 5.30-5.18 (2H, m),
4.68-4.59 (1H, m), 4.54-4.46 (2H, m), 4.32-4.24
(3H, m), 4.09-4.00 (2H, m), 3.84-3.76 (1H, m), 3.6
5-3.53 (2H, m), 3.46-3.40 (1H, m), 3.30 (1H, dd, J
= 2.9, 6.8Hz), 3.22 (1H, dq, J = 8.8,6.6Hz), 2.32-2.22 (1
H, m), 2.09-1.94 (1H, m), 1.38 (3H, d, J = 6.8Hz), 1.
28 (3H, d, J = 6.8 Hz). (2) (1R, 5S, 6S) -2- ｛1- [4-((3
S) -Pyrrolidin-3-ylcarbamoyl) -1,3-
Thiazol-2-yl] azetidin-3-yl {thio-
6-[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid Compound p-nitrobenzyl (1R, 5S, 6S) obtained in Example 57 (1)- 2- (1- [4-[(3S) -1
-(P-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole-2
-Yl {azetidin-3-yl] thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
390 mg (0.483 mmol) of M-3-carboxylate was dissolved in 20 ml of tetrahydrofuran and 20 ml of distilled water, and subjected to catalytic hydrogen reduction at room temperature in the presence of 390 mg of 20% palladium hydroxide.
I went for 4.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 76:24), and lyophilized to give the target compound (1R, 5S, 6S) -2-
１− 1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidine-
3-yl @ thio-6-[(R) -1-hydroxyethyl]
90 mg of -1-methyl-carbapene-2-em-3-carboxylic acid was obtained as a white solid in a yield of 38%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.52 (1H, s), 4.69
-4.62 (1H, m), 4.59-4.50 (2H, m), 4.37-4.39 (1H,
m), 4.22 (1H, dq, J = 6.4, 6.4Hz), 4.11 (1H, dd, J =
2.4, 9.0Hz), 4.07-4.01 (2H, m), 3.65-3.55 (2H, m),
3.48-3.39 (3H, m), 3.21 (1H, dq, J = 9.0, 7.2Hz),
2.50-2.40 (1H, m), 2.23-2.14 (1H, m), 1.30 (3H, d,
J = 6.4Hz), 1.18 (3H, d, J = 7.2Hz) .IR (KBr): 1754, 1654, 1597, 1545, 1386, 1313cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 494 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): found: 494.1529
[M + H] ^+, _{calcd: 494.1532 (C 21 H 28 N} 5 O 5 S 2) Elemental _{analysis: C 21 H 27 N 5 O} 5 S 2 · 7 / 3H 2 O Calculated Found: C, 47.04 % H, 5.95% N, 13.04% S, 11.83% Calculated value: C, 47.09% H, 5.96% N, 13.08% S, 11.97% Example 58 (1R, 5S, 6S) -2- ｛1- [4] -((3R)-
Pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid

[0477]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl ] Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 3-acetylthio-1- [4-
[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-
Thiazol-2-yl diazetidine 280 mg (0.554 mmol)
Was dissolved in 14 ml of dimethylformamide, 61 mg (0.665 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred as it was for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5
(S, 6S) -2- (diphenylphosphoryloxy) -6
-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 329 mg (0.554
mmol) in 16 ml of acetonitrile was added dropwise, followed by 386 μl (2.22 mmol) of diisopropylethylamine.
The mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate:
Purified with methanol = 9: 1), p-nitrobenzyl (1R, 5S, 6S) -2- (1- [4-[(3R) -1-]
(P-Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole-2-
Il @ azetidin-3-yl] thio-6-[(R) -1-
4.6 mg of hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate as a pale yellow solid,
Obtained in 93% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 8.19 (2H, d, J = 8.8Hz), 7.66 (2H, d, J =
8.8Hz), 7.53 (2H, dd, J = 8.8, 15.6Hz), 7.45 (1H,
s), 7.17-7.11 (1H, br s), 5.51 (1H, d, J = 13.8H
z), 5.30-5.18 (3H, m), 4.67-4.58 (1H, m), 4.53
-4.47 (2H, m), 4.32-4.23 (3H, m), 4.06 (2H, dt,
J = 8.8, 5.9Hz), 3.81-3.76 (1H, m), 3.65-3.53 (2
H, m), 3.47- 3.40 (1H, m), 3.30 (1H, dd, J = 2.9, 6.
8Hz), 3.22 (1H, dq, J = 8.8, 7.8Hz), 2.32-2.25 (1
H, m), 2.09-1.95 (1H, m), 1.39 (3H, d, J = 5.9Hz),
1.28 (3H, d, J = 7.8 Hz) (2) (1R, 5S, 6S) -2- ｛1- [4-((3
R) -Pyrrolidin-3-ylcarbamoyl) -1,3-
Thiazol-2-yl] azetidin-3-yl {thio-
6-[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid Compound p-nitrobenzyl (1R, 5S, 6S) -obtained in Example 58 (1) 2- (1- [4-[(3R) -1-
(P-Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole-2-
Il @ azetidin-3-yl] thio-6-[(R) -1-
[Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 410 mg (0.508 mmol) was dissolved in tetrahydrofuran 21 ml and distilled water 21 ml, and contact hydrogen was added at room temperature in the presence of 20% palladium hydroxide 410 mg. Reduction
I went for 4.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 76:24), and lyophilized. Is a compound (1
R, 5S, 6S) -2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[( R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid was obtained as a white solid in 101 mg in a yield of 41%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.52 (1H, s), 4.69
-4.62 (1H, m), 4.60-4.52 (2H, m), 4.38-4.30 (1H, m
m), 4.24 (1H, dq, J = 6.3, 6.3Hz), 4.16 (1H, dd, J =
2.3, 8.9Hz), 4.09-4.02 (2H, m), 3.67-3.54 (2H, m),
3.49-3.40 (3H, m), 3.24 (1H, dq, J = 8.9, 7.2Hz),
2.49-2.40 (1H, m), 2.24-2.14 (1H, m), 1.30 (3H, d,
J = 6.3Hz), 1.20 (3H, d, J = 7.2Hz) .IR (KBr): 1756, 1656, 1598, 1544, 1384, 1313cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 494 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): found: 494.1519
[M + H] ^+, _{calcd: 494.1532 (C 21 H 28 N} 5 O 5 S 2) Elemental _{analysis: C 21 H 27 N 5 O} 5 S 2 · 3H 2 O Calculated Found: C, 46.35% H , 5.75% N, 12.82% S, 11.68% Calculated: C, 46.06% H, 6.07% N, 12.79% S, 11.71% Example 59 (1R, 5S, 6S) -2- ｛1- [4- ( Azetidin-3-ylcarbamoyl) -1,3-thiazole-2-
Yl] azetidin-3-yl {thio-6-[(R) -1-]
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid

[0479]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4- [1- (p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl] azetidin-3-
Yl) thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4- [1
-(P-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazole-2
[-Yl] azetidine (400 mg, 0.814 mmol) was dissolved in dimethylformamide (20 ml), hydrazine acetate (90 mg, 0.977 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy) -6-[(R) -1-
A solution of 484 mg (0.814 mmol) of hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate in 25 ml of acetonitrile was added dropwise, followed by 568 μl (3.26 mmol) of diisopropylethylamine and the temperature was gradually raised to room temperature. The mixture was stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. 0.5M of the obtained organic layer
After washing sequentially with aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline, the extract was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol =
9: 1) and purified with p-nitrobenzyl (1R, 5
S, 6S) -2- (1- [4- [1- (p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl] azetidine-3
-Yl) thio-6-[(R) -1-hydroxyethyl]-
496 mg of 1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in a yield of 77%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.54 (1H,
s), 8.23 (4H, d, J = 8.8Hz), 8.22 (2H, d, J = 8.8Hz),
7.66 (2H, d, J = 8.8Hz), 7.52 (2H, d, J = 8.8Hz), 7.52-
7.47 (1H, m), 7.45 (1H, s), 5.51 (1H, d, J = 13.9H
z), 5.25 (1H, d, J = 13.9Hz), 4.90-4.80 (1H, m), 4.5
4-4.47 (2H, m), 4.47-4.38 (2H, m), 4.42 (2H, dd, J
= 8.8, 8.8Hz), 4.13-4.25 (2H, m), 4.27 (1H, dd, J =
2.2, 9.5Hz), 4.09-3.96 (4H, m), 3.30 (1H, dd, J = 2.
2, 7.0Hz), 3.21 (1H, dq, J = 9.5, 6.6Hz), 1.38 (3H,
d, J = 6.6 Hz), 1.28 (3H, d, J = 5.9 Hz). (2) (1R, 5S, 6S) -2- ｛1- [4- (azetidin-3-ylcarbamoyl) -1, 3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid Compound p-nitrobenzyl (1R, 5S, 6S) -2- (1- [4- [1- (p-nitrobenzyloxycarbonyl)) obtained in Example 59 (1) -Azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em- 3-
A solution of 490 mg (0.617 mmol) of carboxylate in 25 ml of tetrahydrofuran and 25 ml of distilled water was subjected to catalytic hydrogen reduction at room temperature in the presence of 490 mg of 20% palladium hydroxide for 4.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 76:
The target compound (1R, 5S, 6S) -2- ｛1- [4- (azetidin-3-ylcarbamoyl) -1,3-thiazol-2-yl is purified by lyophilization and purification in 24). ] Azetidin-3-yl @ thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid as a white solid
mg, yield 49%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.54 (1H, s), 4.9
7-4.87 (1H, m), 4.60-4.54 (2H, m), 4.44 (2H, dd, J = 1
1.9, 8.4Hz), 4.39-4.30 (3H, m), 4.23 (1H, qd, J = 6.
4, 6.2Hz), 4.15 (1H, dd, J = 9.0, 2.4Hz), 4.10-4.03
(2H, m), 3.43 (1H, dd, J = 6.3, 2.4Hz), 3.23 (1H, d
q, J = 9.0, 7.2Hz), 1.30 (3H, d, J = 6.4Hz), 1.19 (3H,
d, J = 7.2Hz) .IR (KBr): 1753, 1655, 1600, 1545, 1387, 1314cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 480 [M + H] ⁺ High-resolution mass spectrum (FAB) ⁺ ): Observed: 480.1391
[M + H] ^+, _{calcd: 480.1375 (C 20 H 26 N} 5 O 5 S 2) Elemental _{analysis: C 20 H 25 N 5 O} 5 S 2 · 9 / 4H 2 O Calculated Found: C, 46.06 % H, 5.38% N, 13.70% S, 12.33% Calculated value: C, 46.19% H, 5.72% N, 13.47% S, 12.33% Example 60 (1R, 5S, 6S) -2- ｛1- [4 -(Piperazine-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em- 3
-Carboxylic acid

[0481]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4-[(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] -1,
3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate obtained in Reference Example 55. 3-acetylthio-1- [4-
546 mg (1.07 mmol) of [(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] -1,3-thiazol-2-yl] azetidine was dissolved in 15 ml of dimethylformamide, and the solution was dissolved in ice under a nitrogen atmosphere. Add 118 mg (1.29 mmol) of hydrazine acetate with cooling
Stir for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S)-
2- (diphenylphosphoryloxy) -6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylate 636 mg (1.07 mmol)
Of acetonitrile was added dropwise, followed by the addition of 0.22 ml (1.29 mmol) of diisopropylethylamine.
The mixture was stirred for 1 hour while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 1: 20) to give p-nitrobenzyl (1R, 5S, 6S) -2- (1- [4- [(4-
(p-nitrobenzyloxycarbonyl) -piperazine-
1-carbonyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylate as pale yellow solid 215 mg, yield 29
%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (4H, d
d, J = 8.5, 5.2 Hz), 7.66 (2H, d, J = 8.7 Hz), 7.
52 (2H, d, J = 8.7 Hz) 7.22 (1H, s), 5.51 (1H,
d, J = 13.8 Hz), 5.25 (1H, d, J = 13.8 Hz), 5.25
(2H, s), 4.50 (1H, t, J = 8.0 Hz), 4.49 (1H, t,
J = 8.0 Hz), 4.35-4.20 (3H, m), 4.04 (1H, t,
J = 8.5 Hz), 4.31 (1H, t, J = 8.5 Hz), 3.98-3.6
9 (4H, m), 3.69-3.48 (4H, m), 3.29 (1H, dd, J
= 6.8, 2.6 Hz), 3.20 (1H, dq, J = 9.2, 7.2 Hz),
1.36 (3H, d, J = 6.3 Hz), 1.26 (3H, d, J = 7.5 H)
z) (2) (1R, 5S, 6S) -2- {1- [4- (piperazino-1-ylcarbonyl) -1,3-thiazole-
2-yl] azetidin-3-yl {thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylic acid Compound p-nitrobenzyl (1R, 5S, 6S) -2- (1- [4-[(4-p-nitrobenzyloxycarbonyl)-) obtained in Example 60 (1) Piperazine-1-carbonyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3- 539 mg (0.79 mmol) of carboxylate was dissolved in 30 ml of tetrahydrofuran and 30 ml of distilled water, and subjected to catalytic hydrogen reduction in a water bath at 35 ° C for 2 hours in the presence of 539 mg of 7.5% palladium carbon. After confirming the completion of the reaction, add ethyl acetate,
And distilled water were added to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-
8% acetonitrile-distilled water to 10% acetonitrile-
Purified with distilled water to 13% acetonitrile-distilled water to 16% acetonitrile-distilled water to 20% acetonitrile-distilled water) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- ｛1. -[4- (piperazino-1-ylcarbonyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene- 2-M-3-carboxylic acid as a white solid 107 mg, yield 27
%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.23 (1H, s), 4.
56 (2H, t, J = 8.4 Hz), 4.40-4.30 (1H, m), 4.24
(1H, quint., J = 6.2 Hz), 4.20 (1H, dd, J = 8.7,
2.2 Hz), 4.03 (2H, dd, J = 8.7, 2.2 Hz), 3.95 (4
H, t, J = 5.2 Hz), 3.43 (1H, dd, J = 6.2, 2.4 Hz
), 3.40-3.29 (4H, m), 3.24 (1H, dq, J = 8.7,
7.3 Hz), 1.29 (3H, d, J = 6.3 Hz), 1.19 (3H, d,
J = 7.9 Hz) IR (KBr): 3415.3, 1759.7, 1620.9, 1536.0, 1456.0,
1431.9, 1384.6, 1313.3, 1246.8cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 494 [M + H] ⁺ High-resolution mass spectrum (ESI ⁺ ): Observed: 494.1529
[M + H] ⁺ , calculated: 494.2532 (C ₂₁ H ₂₈ N ₅ O ₅ S ₂ ) Example 61 (1R, 5S, 6S) -2- ｛1- [4- (2-amino-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid

[0483]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl]-
1,3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4- [2
330.6 mg (0.68 mmol) of-(p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine is dissolved in 17 ml of dimethylformamide, and the mixture is dissolved at room temperature under a nitrogen atmosphere. Hydrazine acetate (82 mg, 0.89 mmol) was added, and the mixture was stirred as it was for 1 hour. After confirming the completion of the reaction, under a nitrogen atmosphere,
P-Nitrobenzyl (1R, 5S, 6)
S) -2- (Diphenylphosphoryloxy) -6
426 mg of [(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate
(0.72 mmol) in 21 ml of acetonitrile was added dropwise, followed by 0.5 ml of diisopropylethylamine.
(2.9 mmol), and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 2), and p-nitrobenzyl (1R, 5S, 6S) -2- (1- [4-
[2- (p-nitrobenzyloxycarbonylamino)
-Ethylcarbamoyl] -1,3-thiazol-2-yl] azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 348. as a pale yellow solid.
1 mg, yield 66%. ¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 7.8Hz), 8.14 (2H, d, J = 8.8Hz), 7.66 (2H, d, J =
(7.8Hz), 7.47 (2H, d, J = 8.8Hz), 7.43 (1H, s), 7.38
(1H, t, J = 6.3Hz), 5.51 (1H, d, J = 13.7Hz), 5.51 (1
H, t, J = 6.3Hz), 5.25 (1H, d, J = 13.7Hz), 5.18 (2H,
s), 4.48 (1H, t, J = 8.3Hz), 4.46 (1H, t, J = 8.3Hz),
4.32-4.24 (3H, m), 4.05 (1H, dd, J = 8.3, 5.6Hz), 4.
03 (1H, dd, J = 8.3, 5.6Hz), 3.55 (2H, d, 6.3Hz), 3.4
4 (2H, q, 6.3Hz), 3.30 (1H, dd, J = 6.9, 1.9Hz), 3.2
2 (1H, dq, J = 8.8, 6.5Hz), 1.73 (1H, br s), 1.38 (3
H, d, J = 6.5 Hz), 1.28 (3H, d, J = 6.5 Hz) (2) (1R, 5S, 6S) -2- ｛1- [4- (2-
(Amino-ethylcarbamoyl) -1,3-thiazole-
2-yl] azetidin-3-yl {thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylic acid p-nitrobenzyl (1) obtained in Example 61 (1)
R, 5S, 6S) -2- (1- [4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine-3-
Yl) thio-6-[(R) -1-hydroxyethyl] -1
328.4 mg (0.42 mmol) of -methyl-carbapene-2-em-3-carboxylate was dissolved in 16.4 ml of tetrahydrofuran and 8.2 ml of distilled water, and dissolved in 328.4 mg of 20% palladium hydroxide-carbon. Catalytic hydrogen reduction was performed for 2 hours in a water bath at ℃. After confirming the completion of the reaction, the reaction mixture was filtered, and an ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 5% acetonitrile-distilled water to 10% acetonitrile-distilled water to 15% acetonitrile-distilled water) ) And the target compound (1)
R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbapene-2-em-3
96.4 mg of carboxylic acid as a white solid, 49% yield
I got it. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.37 (1H, s), 4.42
(1H, t, J = 8.4Hz), 4.42 (1H, t, J = 8.4Hz), 4.24-4.1
6 (1H, m), 4.10 (1H, quintet, J = 6.6Hz), 4.00 (1H, d
d, J = 8.9, 2.4Hz), 3.94 (1H, dd, J = 8.4, 4.8Hz), 3.9
0 (1H, dd, J = 8.4, 4.8Hz), 3.57 (2H, t, J = 5.9Hz),
3.26 (1H, dd, J = 6.6, 2.4Hz), 3.12 (2H, t, J = 5.9Hz),
3.08 (1H, dq, J = 8.9, 7.3Hz), 1.16 (3H, d, J = 6.6H
z), 1.05 (3H, d, J = 7.3Hz) IR (KBr): 3383, 1755, 1652, 1599, 1547, 1387, 1314
cm ^-1 Mass spectrum (FAB ⁺ ): m / z 468 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Found: 468.1365
[M + H] ⁺ , Calculated: 468.1366 (C ₁₉ H ₂₆ O ₅ N ₅ S ₂ ) Example 62 (1R, 5S, 6S) -2- ｛1- [4- (3-Amino-azetidine-1 -Carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid

[0485]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl] azetidine-3-
Yl @ thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4- [3
-(P-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazole-2
390 mg (0.793 mmol) of [-yl] azetidine was dissolved in 20 ml of dimethylformamide, and 88 mg (0.952 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy) -6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 471 mg (0.793 mmol) in 24 ml of acetonitrile was added dropwise, followed by 552 μl (3.17 mmol) of diisopropylethylamine, and the temperature was gradually raised to room temperature. The mixture was stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with 10% brine and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 93: 7), and p-nitrobenzyl (1R, 5S, 6S) -2- (1- [4-
[3- (p-nitrobenzyloxycarbonylamino)
-Azetidin-1-carbonyl] -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylate as a pale yellow solid
7 mg, 93% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (4H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.51 (2H, d, J =
8.8Hz), 7.46 (2H, s), 5.51 (1H, d, J = 13.9Hz), 5.40-
5.37 (1H, m), 5.25 (1H, d, J = 13.9Hz), 5.21 (2H,
s), 4.92-4.86 (1H, m), 4.59-4.42 (4H, m), 4.40-4.32
(1H, m), 4.30-4.23 (3H, m), 4.04-3.92 (3H, m), 3.3
0 (1H, dd, J = 2.2, 6.6Hz), 3.21 (1H, dq, J = 7.3, 9.0
Hz), 1.38 (3H, d, J = 6.6 Hz), 1.27 (3H, d, J = 7.3 Hz). (2) (1R, 5S, 6S) -2- ｛1- [4- (3-
Amino-azetidino-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid p-nitrobenzyl (1) obtained in Example 62 (1)
R, 5S, 6S) -2-{(1- [4- [3- (p-nitrobenzyloxycarbonyl) -azetidin-1-carbonyl] -1,3-thiazol-2-yl] azetidin-3-yl 580 mg (0.731 mmol) of thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate were added to tetrahydrofuran 3
0 ml, dissolved in 30 ml of distilled water, 580 mg of 10% palladium on carbon
In the presence, catalytic hydrogen reduction was performed at room temperature for 5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 8: 2), and lyophilized to obtain the desired product. Compound (1R, 5S, 6S) -2- ｛
1- [4- (3-amino-azetidine-1-carbonyl)
-1,3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-
135 mg of methyl-carbapen-2-em-3-carboxylic acid was obtained as a white solid in a yield of 39%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.45 (1H, s), 4.9
8-4.85 (1H, m), 4.64-4.49 (4H, m), 4.38-4.30 (1H,
m), 4.31-4.17 (4H, m), 4.07-4.00 (2H, m), 3.44 (1
H, dd, J = 2.0, 5.9Hz), 3.24 (1H, qd, J = 7.2, 8.5Hz),
1.30 (3H, d, J = 6.4Hz), 1.20 (3H, d, J = 7.2Hz) .IR (KBr): 1756, 1607, 1537, 1449, 1387, 1309, 129
1, 1261cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 50 [M + Na] ⁺ High-resolution mass spectrum (ESI ⁺ ): Observed value: 502.1179
[M + Na] ^+, _{calcd: 502.1195 (C 20 H 25 N} 5 O 5 S 2 Na) Elemental _{Analysis: C 20 H 25 N 5 O} 5 S 2 · 3H 2 O Calculated Found: C, 44.27% H, 5.28% N, 13.26% S, 12.68% Calculated: C, 45.02% H, 5.86% N, 13.12% S, 12.02% Example 63 (1R, 5S, 6S) -2- (1- [4- [(2-amino-ethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl {azetidin-3-yl) thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid

[0487]

Embedded image

(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4- [Methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4- [methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl obtained in Reference Example 58 {-1,3-thiazol-2-yl) azetidine 348.9 mg (0.71 mmol)
Was dissolved in 17.5 ml of dimethylformamide, and 85.2 mg of hydrazine acetate (0.
93 mmol) and stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 was introduced into the system under ice cooling under a nitrogen atmosphere.
-Methyl-carbapene-2-em-3-carboxylate 420.3 mg (0.71 mmol) of acetonitrile 2
1 ml of the solution was added dropwise, followed by 0.49 ml (2.8 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 2) to give p-nitrobenzyl (1R, 5S, 6S)-
2- [1- (4- [methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl}-
1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 267.5 mg, 47% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (4H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.56-7.46 (3H, m
including 2H, d, at 7.49 ppm, J = 8.8Hz), 7.22 (0,7
H, s), 7.21 (0.3H, s), 5.52 (1H, d, J = 13.9Hz), 5.2
5 (1H, d, J = 13.9Hz), 5.172 (2H, s), 4.52-4.38 (2H,
m), 4.32-4.10 (3H, m), 4.10-3.98 (2H, m), 3.74-3.5
8 (2H, m), 3.56-3.40 (2H, m), 3.30-3.26 (1H, m),
3.16-3.06 (1H, m), 3.24 (0.9H, s), 3.04 (2.1H, s),
1.77 (1H, d, J = 4.4Hz), 1.38 (3H, d, J = 5.9Hz), 1.22
(3H, J = 7.3Hz) (2) (1R, 5S, 6S) -2- (1- [4-[(2-
Amino-ethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl {azetidin-3-yl) thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid p-nitrobenzyl (1) obtained in Example 63 (1)
R, 5S, 6S) -2- [1- (4- [methyl- [2- (p
-Nitrobenzyloxycarbonylamino) -ethyl]
Carbamoyl {-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 267. 5 mg (0.33 mmol) was dissolved in 14 ml of tetrahydrofuran and 6.7 ml of distilled water.
20% palladium hydroxide-carbon 300mg, 30 ℃
Catalytic hydrogen reduction was performed in a water bath for 1.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and an ethyl acetate-tetrahydrofuran (1: 1) solution and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 5% acetonitrile-distilled water to 10%).
The target compound (1R, 5S, 6S) -2- (1- [4-[(2-
Amino-ethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl {azetidin-3-yl) thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid as a white solid
81.6 mg was obtained in a yield of 51%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.11 (0.4H, s), 7.
05 (0.6H, s), 4.43 (2H, .t, J = 8.8Hz), 4.26-4.18 (1H,
m), 4.12 (1H, quintet, J = 5.9Hz), 4.08 (1H, dd, J =
8.8, 2.3Hz), 3.91 (2H, dd, J = 8.8, 4.9Hz), 3.70 (2
H, t, 5.9Hz), 3.31 (1H, dd, J = 5.9, 2.3Hz), 3.23-3.
16 (2H, m), 3.12 (1H, dq, J = 8.8, 7.8Hz), 3.00 (1.8
H, s), 2.94 (1.2H, s), 1.17 (3H, d, J = 5.9Hz), 1.07
(3H, d, J = 7.8Hz) IR (KBr): 3419, 2966, 1754, 1607, 1540, 1470, 139
1, 1315 cm ^-1 Mass spectrum (FAB ⁺ ): m / z 482 [M + H] ⁺ Example 64 (1R, 5S, 6S) -2- (1- {4-[(2-hydroxy-ethyl) -Isopropyl-carbamoyl] -1,
3-thiazol-2-yl {azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid

[0489]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-
｛[2- (t-butyldimethylsilyloxy) -ethyl]
-Isopropyl-carbamoyl {-1,3-thiazol-2-yl) azetidine (618 mg, 1.35 mmol) was dissolved in dimethylformamide (30 ml), and hydrazine acetate (149 mg, 1.62 mmol) was added at room temperature under a nitrogen atmosphere. ,
The mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5
(S, 6S) -2- (diphenylphosphoryloxy) -6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 963 mg (1.
(62 mmol) in 60 ml of acetonitrile was added dropwise, followed by 0.94 ml (5.40 mmol) of diisopropylethylamine.
Was added, and the mixture was stirred for 8 hours while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate.
The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1), and p-nitrobenzyl (1R, 5S, 6S) -2-{[1- (4
-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3-thiazol-2-yl) azetidin-3-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 310 mg, yield 30%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H,
d, J = 8.4 Hz), 7.64 (2H, d, J = 8.4 Hz), 7.12-6.
90 (1H, m), 5.45 (1H, d, J = 13.7 Hz), 5.25 (1
H, d, J = 13.7 Hz), 4.69-4.18 (6H, minluding
4.45 (2H, dd, J = 7.9, 6.5 Hz), 4.24 (1H, quin
t., J = 6.3 Hz), 4.22 (1H, dd., J = 9.0,2.5 Hz)),
3.89-3.72 (1H, m), 3.72-3.46 (2H, m), 3.46
-3.32 (1H, m), 3.26 (1H, dd, J = 6.3, 2.5 Hz),
3.17 (1H, dq, J = 9.0, 7.3 Hz), 1.36 (3H, d, J =
6.3 Hz), 1.31-1.09 (9H, m including 1.25 (3H,
d, J = 7.2 Hz)), 0.87 (9H, s), 0.06 (6H, d, J =
2.9 Hz) (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
(1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl}
Azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-
3-carboxylate p-nitrobenzyl (1) obtained in Example 64 (1)
R, 5S, 6S) -2- [1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-
Carbamoyl {-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 4.47 g (5.88 mmol) was dissolved in 220 ml of tetrahydrofuran, and 0.40 ml of acetic acid was added under ice cooling (0.40 ml).
7.06 mmol) and 1 M-tetrabutylammonium fluoride-tetrahydrofuran solution (7.06 ml, 7.06 mmol) were sequentially added, followed by stirring at room temperature for 1 day. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 10: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- (1- ｛4).
-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl {azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl- Carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 1.79 g, 47% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz), 7.20 (0.
6H, br s), 7.09 (0.4H, br s), 5.50 (1H, d, J = 1
3.8 Hz), 5.26 (1H, d, J = 13.8 Hz), 4.62-4.18
(6H, m including 4.49 (2H, t., J = 8.4 Hz), 4.26
(1H, dd, J = 9.3, 2.6 Hz)), 4.04 (2H, dd, J = 8.
4, 5.4 Hz), 3.80 (2H, br s), 3.56 (2H, br s),
3.28 (1H, dd, J = 7.5, 2.5 Hz), 3.19 (1H, br s
), 1.38 (3H, d, J = 6.2 Hz), 1.35 (3.6H, br s),
1.26 (3H, d, J = 7.3 Hz), 1.21 (2.4H, brs) (3) (1R, 5S, 6S) -2- (1- （4-[(2
-Hydroxy-ethyl) -isopropyl-carbamoyl]
-1,3-thiazol-2-yl {azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylic acid p-nitrobenzyl (1) obtained in Example 64 (2)
R, 5S, 6S) -2- (1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,3-
Thiazol-2-yl {azetidin-3-yl) thio-
1.79 g of 6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (
2.77 mmol) in tetrahydrofuran 90 ml, distilled water 90
Dissolved in 7.5 ml of palladium on carbon in the presence of 1.79 g of 7.5%
Catalytic hydrogen reduction was performed in a water bath at ℃ for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and sodium hydrogen carbonate 2 was added to the filtrate.
3 mg was added. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water to 4% acetonitrile-
(1R, 5S, 6S) -2- (1- {4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl] -1,
897 mg of 3-thiazol-2-yl {azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid as a white solid, Obtained in 61% yield. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.08 (0.2H, s),
7.02 (0.8H, s), 4.56 (2H, t, J = 8.0 Hz), 4.50-
4.40 (0.3H, m), 4.40-4.30 (1H, m), 4.25 (1
H, quint., J = 6.5 Hz), 4.21 (1H, dd, J = 8.4, 2.2
Hz), 4.16-4.06 (0.7H, m), 4.05 (2H, dd, J =
8.0, 4.8 Hz), 3.69-3.60 (0.5H, m), 3.60-3.52
(0.5H, m), 3.52 (2H, t, J = 6.3 Hz), 3.43 (1
H, dd, J = 6.5, 2.4 Hz), 3.25 (1H, quint., J = 8.4
Hz), 1.42-1.07 inclding 1.30 (3H, d, J = 6.3 Hz
), 1.20 (3H, d, J = 7.1 Hz)) IR (KBr): 3382.5, 1750.1, 1603.5, 1537.0, 1468.5,
1452.1, 1396.2, 1312.3, 1284.4cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 533 [M + H] ⁺ High-resolution mass spectrum (ESI ⁺ ): Observed value: 533.1489
[M + H] ^+, _{calcd: 533.1504 (C 22 H 29 N} 4 O 5 S 2 Na) Example 65 (1R, 5S, 6S) -2- (1- {4 - [(2- Amino - ethyl ) -Isopropyl-carbamoyl] -1,3-
Thiazol-2-yl {azetidin-3-yl) thio-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid

[0490]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4- {isopropyl- [2- (p
-Nitrobenzyloxyamino) -ethyl] -carbamoyl {-1,3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-
746 mg (1.43 mmol) of {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) azetidine are dissolved in 22 ml of dimethylformamide, and the mixture is dissolved in a nitrogen atmosphere. At room temperature, 158 mg (1.72 mmol) of hydrazine acetate was added,
The mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5
(S, 6S) -2- (diphenylphosphoryloxy) -6
-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 1.02 g (1.7
A solution of 2 mmol) in 45 ml of acetonitrile was added dropwise, followed by 1.00 ml (5.72 mmol) of diisopropylethylamine, and the mixture was stirred for 3 hours while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-
{Isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) azetidin-3-yl] thio-6
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 610 mg in a yield of 52%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (4H, d
d, J = 11.0, 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 7.5
0 (2H, d, J = 8.6Hz), 7.25-6.95 (1H, m), 5.51 (
1H, d, J = 13.7 Hz), 5.25 (1H, d, J = 13.7 Hz),
5.19 (2H, s), 4.63-3.88 (8H, m), 3.91-3.35
(4H, m), 3.29 (1H, dd, J = 6.8, 2.2 Hz), 3.25-
3.08 (1H, m), 1.38 (3H, d, J = 6.2 Hz), 1.31
(3H, brs), 1.25 (3H, d, J = 7.3 Hz), 1.21 (3H,
br s) (2) (1R, 5S, 6S) -2- (1- {4-[(2
-Amino-ethyl) -isopropyl-carbamoyl]-
1,3-thiazol-2-yl {azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylic acid p-nitrobenzyl (1) obtained in Example 65 (1)
R, 5S, 6S) -2- [1- (4- {isopropyl-
[2- (p-nitrobenzyloxyamino) -ethyl]-
Carbamoyl {-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 610 mg (0.74 mmol) was dissolved in 30 ml of tetrahydrofuran and 30 ml of distilled water, and subjected to catalytic hydrogen reduction in a water bath at 35 ° C. in the presence of 610 mg of 7.5% palladium carbon.
I went for 2 hours. After confirming the completion of the reaction, ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water-
4% acetonitrile-distilled water-6% acetonitrile-distilled water-8% acetonitrile-distilled water-10% acetonitrile-distilled water-12% acetonitrile-distilled water-14%
Purified with acetonitrile-distilled water to 16% acetonitrile-distilled water-18% acetonitrile-distilled water) and freeze-dried to obtain the target compound (1R, 5S,
6S) -2- (1- {4-[(2-amino-ethyl) -isopropyl-carbamoyl] -1,3-thiazole-2
-Yl {azetidin-3-yl) thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylic acid was obtained as a white solid in 104 mg, yield 28%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.06 (1H, s), 4.
56 (2H, t, J = 8.4 Hz), 4.41-4.31 (1H, m), 4.2
9-4.09 (3H, m including 4.24 (1H, quint., J =
6.3 Hz), 4.20 (1H, dd, J = 8.9, 2.4 Hz)), 4.03
(2H, dd, J = 8.4, 4.8 Hz), 3.43 (1H, dd, J = 6.3,
2.4 Hz), 3.37-3.16 (3H, m including 3.25 (1
H, dq, J = 8.9, 7.4 Hz)), 1.29 (3H, d, J = 6.4 Hz
), 1.25-1.15 (9H, m including 1.19 (3H, d, J =
7.0 Hz)) IR (KBr): 3381.6, 1759.7, 1597.7, 1537.0, 1469.5,
1424.2, 1388.5, 1371.1, 1314.3, 1282.4cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 510 [M + H] ⁺ High-resolution mass spectrum (ESI ⁺ ): Actual value: 510.1826
[M + H] ^+, _{calcd: 510.1845 (C 22 H 32 N} 5 O 5 S 2 Na) Example 66 (1R, 5S, 6S) -2- {1- [4 - ((1S) -
1-aminomethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Ill @ thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid

[0493]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-{(1S) -2-methyl- [1
-(P-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl] -1,3-thiazole-2
-Yl) azetidin-3-yl] thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
M-3-carboxylate 3-acetylthio-1- (4-
｛(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl] -1,3-thiazol-2-yl) azetidine 780 mg
(1.50 mmol) was dissolved in 40 ml of dimethylformamide, and 166 mg (1.80 mm
ol) and stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 was introduced into the system under ice cooling under a nitrogen atmosphere. -Methyl-carbapene-2-em-3-carboxylate 89
A solution of 2 mg (1.50 mmol) in 45 ml of acetonitrile was added dropwise, followed by 1.05 ml of diisopropylethylamine (6.00 mm
ol), and gradually raise the temperature to room temperature.
Stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with 10% brine and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 98: 2), and p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- ｛(1S) -2
-Methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl] -1,3-
Thiazol-2-yl) azetidin-3-yl] thio-6
-[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in 950 mg, in a yield of 77%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 8.09 (2H, d, J = 8.8Hz), 7.66 (2H, d, J
= 8.8Hz), 7.43 (1H, s), 7.40 (2H, d, J = 8.8Hz), 7.12
(1H, br d, J = 8.8Hz), 5.51 (1H, d, J = 13.2Hz), 5.25
(1H, d, J = 13.2Hz), 5.23 (1H, d, J = 13.2Hz), 5.05
(1H, d, J = 13.2Hz), 4.51 (1H, t, J = 8.1Hz), 4.44 (1
H, t, J = 8.1Hz), 4.32-4.25 (3H, m), 4.06-3.96 (3H,
m), 3.45-3.32 (2H, m), 3.30 (1H, dd, J = 2.2, 6.6H
z), 3.21 (1H, dq, J = 7.3, 9.5Hz), 1.93-1.84 (1H,
m), 1.38 (3H, d, J = 5.9Hz), 1.28 (3H, d, J = 7.3Hz),
1.00 (3H, d, J = 6.6 Hz), 0.98 (3H, d, J = 7.3 Hz). (2) (1R, 5S, 6S) -2- ｛1- [4-((1
S) -1-Aminomethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl -Carbapene-2-em-3-carboxylic acid p-nitrobenzyl (1) obtained in Example 66 (1)
R, 5S, 6S) -2- [1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl] -1,3-thiazole-2 -Yl) azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 950 mg (1.15 mmol
l) was dissolved in tetrahydrofuran (48 ml) and distilled water (48 ml), and subjected to catalytic hydrogen reduction in the presence of 950 mg of 10% palladium carbon at room temperature for 3 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and ethyl acetate- and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer is washed with the above-mentioned mixed solvent, concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 76:24).
And the target compound (1R, 5S, 6S) -2- ｛1- [4-((1S)
-1-aminomethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Ill @ thio-6-[(R) -1-hydroxyethyl]-
103 mg of 1-methyl-carbapene-2-em-3-carboxylic acid was obtained as a white solid in a yield of 18%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 8.18-8.03 (1H,
m), 7.51 (1H, s), 4.47 (2H, t, J = 8.1Hz), 4.24-4.14
(1H, m), 3.99-3.85 (4H, m), 3.84-3.77 (1H, m), 3.
09-2.88 (4H, m), 1.94-1.84 (1H, m), 1.14 (3H, d, J =
6.2Hz), 1.03 (3H, d, J = 7.0Hz), 0.89 (3H, d, J = 6.6H
z), 0.84 (3H, d, J = 6.6Hz). IR (KBr): 1752, 1660, 1605, 1545, 1494, 1471cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 510 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Found: 510.1846
[M + H] ⁺ , Calculated: 510.1845 (C ₂₂ H ₃₂ N ₅ O ₆ S ₂ ) Elemental analysis: Calculated as C ₂₂ H ₃₁ N ₅ O ₆ S ₂・ 13 / 7H ₂ O Observed: C, 48.92 % H, 6.29% N, 12.60% S, 12.04% Calculated: C, 48.65% H, 6.44% N, 12.90% S, 11.81% Example 67 (1R, 5S, 6S) -2- [1- (4 -Aminomethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylic acid

[0495]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- {1- [4- (p-nitrobenzylcarbonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4-
(P-nitrobenzylcarbonylamino-methyl)-
1,3-thiazol-2-yl] azetidine 265.2
mg (0.63 mmol) was dissolved in 14 ml of dimethylformamide, and hydrazine acetate 7 was dissolved at room temperature under a nitrogen atmosphere.
6.4 mg (0.5 mmol) was added, and the mixture was stirred as it was for 0.5 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 was introduced into the system under ice cooling under a nitrogen atmosphere. -Methyl-carbapene-2-m-
A solution of 390 mg (0.66 mmol) of 3-carboxylate in 19 ml of acetonitrile was added dropwise, followed by 0.44 ml (2.5 mmol) of diisopropylethylamine.
The mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 3), and p-nitrobenzyl (1R,
5S, 6S) -2- {1- [4- (p-nitrobenzylcarbonylamino-methyl) -1,3-thiazole-2
-Yl] azetidin-3-yl] thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
Em-3-carboxylate as pale yellow solid 26
8.4 mg, 59% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (4H, d,
J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.51 (2H, d, J =
8.8Hz), 6.45 (1H, s), 5.51 (1H, d, J = 13.9Hz), 5.37
(1H, br s), 5.25 (1H, d, J = 13.9Hz), 5.21 (2H, s),
4.48 (1H, t, J = 7.8Hz), 4.46 (1H, t, J = 7.8Hz), 4.35
-4.20 (5H, m), 4.03 (2H, dd, J = 7.8, 4.9Hz), 3.29
(1H, dd, J = 6.2, 2.5Hz), 3.22 (1H, dq, J = 8.9, 7.3H
z), 1.80 (1H, d, J = 4.4Hz), 1.38 (3H, d, J = 5.9Hz),
1.27 (3H, d, J = 7.3 Hz) (2) (1R, 5S, 6S) -2- [1- (4-aminomethyl-1,3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-Methyl-carbapen-2-em-3-carboxylic acid p-nitrobenzyl (1) obtained in Example 67 (1)
R, 5S, 6S) -2-1- [4- (p-nitrobenzylcarbonylamino-methyl) -1,3-thiazole-
2-yl] azetidin-3-yl] thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylate 660 mg (0.89 mmol)
Was dissolved in 30 ml of tetrahydrofuran and 30 ml of distilled water, and subjected to catalytic hydrogen reduction in a water bath at 35 ° C. for 2 hours in the presence of 606 mg of 7.5% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-8% acetonitrile-distilled water- 10% acetonitrile-distilled water ~ 13
% Acetonitrile-distilled water to 15% acetonitrile-distilled water) and freeze-dried to give the desired compound (1R, 5S, 6S) -2- [1- (4-aminomethyl-1,3- Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid as a white solid 123 mg, yield. 34%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 6.85 (1H, s), 4.
54 (2H, t, J = 8.1 Hz), 4.38-4.30 (1H, m), 4.25
(1H, quint., J = 6.3 Hz), 4.25 (1H, dd, J = 8.9,
2.5 Hz), 4.07 (2H, s), 4.02 (2H, dd, J = 8.1, 4.
0 Hz), 3.44 (1H, dd, J = 6.3, 2.5 Hz), 3.25 (1H,
dq, J = 8.9, 7.3 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.2
0 (3H, d, J = 7.2 Hz) IR (KBr): 3362.3, 1756.8, 1589.1, 1527.3, 1469.5,
1386.6, 1309.4, 1286.3, 1259.3cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 411 [M + H] ⁺ High-resolution mass spectrum (ESI ⁺ ): Actual value: 411.1173
[M + H] ⁺ , calculated: 411.4161 (C ₁₇ H ₂₃ N ₄ O ₄ S ₂ ) Example 68 (1R, 5S, 6S) -2-−２ 1- [4- (methoxycarbonylamino-methyl)- 1,3-thiazole-2-
Yl] azetidin-3-yl {thio-6-[(R) -1-]
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0497]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- {1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4-
(Methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine (441 mg, 1.39 mmol) was dissolved in dimethylformamide (13 ml), and hydrazine acetate 154 mg (1.67 mmol) was added at room temperature under a nitrogen atmosphere.
And stirred for 1 hour. After confirming the completion of the reaction,
Under a nitrogen atmosphere, p-nitrobenzyl (1
R, 5S, 6S) -2- (Diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 993
mg (1.67 mmol) in 26 ml of acetonitrile was added dropwise, followed by 0.97 ml of diisopropylethylamine (5.5
6 mmol), and the mixture was stirred for 30 minutes while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and p-nitrobenzyl (1R, 5S, 6
S) -2- {1- [4- (methoxycarbonylamino-
Methyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 307 mg was obtained as a yellow solid in a yield of 53%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz), 6.45 (1
H, s), 5.51 (1H, d, J = 13.7 Hz), 5.26 (1H, d,
J = 13.7 Hz), 4.48 (2H, t, J = 8.0 Hz), 4.43-4.
18 (5H, m), 4.09-3.99 (2H, m), 4.09-3.99 (
2H, m), 3.69 (3H, s), 3.29 (1H, dd, J = 6.7, 2.7
Hz), 3.21 (1H, dq, J = 9.0, 7.3 Hz), 1.38 (3H,
d, J = 6.1 Hz), 1.25 (3H, d, J = 7.3 Hz), (2) (1R, 5S, 6S) -2- ｛1- [4- (methoxycarbonylamino-methyl) -1,3 -Thiazol-2-yl] azetidin-3-yl {thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 68 (1)
R, 5S, 6S) -2- {1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1- [Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 307 mg (0.52 mmol) was dissolved in 15 ml of tetrahydrofuran and 15 ml of distilled water. The catalytic hydrogen reduction was performed for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 44 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate- and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmo Seal (elution solvent: distilled water to 2% acetonitrile-distilled water to 4% acetonitrile-distilled water to 6% acetonitrile-distilled water), and freeze-dried. The desired compound (1R, 5S, 6S) -2-
｛1- [4- (methoxycarbonylamino-methyl)-
1,3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 135 mg and a yield of 53%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 6.59 (1H, s), 4.
51 (2H, t, J = 8.1 Hz), 4.38-4.29 (1H, m), 4.25
(1H, quint., J = 6.2 Hz), 4.20 (1H, dd, J = 9.1,
2.5 Hz), 4.19 (2H, s), 4.05-3.98 (2H, m),
3.68 (3H, s), 3.43 (1H, dd, J = 6.2, 2.4 Hz), 3.2
5 (1H, dq, J = 9.1, 7.4 Hz), 1.30 (3H, d, J = 6.2 H
z), 1.20 (3H, d, J = 7.2 Hz) IR (KBr): 3355.5, 1748.2, 1725.1, 1600.6, 1525.4,
1470.5, 1395.2, 1311.4, 1290.1, 1254.5cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 513 [M + Na] ⁺ High-resolution mass spectrum (FAB ⁺ ): Observed value: 513.0850
[M + Na] ^+, _{calcd: 513.0855 (C 19 H 23 N} 4 O 5 S 2 Na 2) Example 69 (1R, 5S, 6S) -2- {1- [4- ( benzoylamino-methyl) - -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
-Carboxylic acid sodium salt

[0499]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- {1- [4- (Benzoylamino-methyl) -1,3-thiazol-2-yl] azetidine-3
-Ill @ thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4- obtained in Reference Example 64
(Benzoylamino-methyl) -1,3-thiazole-
698 mg (2.01 mmol) of 2-yl] azetidine was dissolved in 20 ml of dimethylformamide, and 222 mg (2.41 mmol) of hydrazine acetate was added thereto at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S,
6S) -2- (diphenylphosphoryloxy) -6
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 1.43 g (2.41
Then, 1.40 ml (8.94 mmol) of diisopropylethylamine was added thereto, and the mixture was stirred for 2.5 hours while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate.
The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 20: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4-
(Benzoylamino-methyl) -1,3-thiazole-
2-yl] azetidin-3-yl {thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylate as a pale yellow solid 851
mg, yield 65%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H,
d, J = 8.7 Hz), 7.81 (2H, d, J = 7.3 Hz), 7.66 (2
H, d, J = 8.7 Hz) 7.56-7.38 (3H, m), 6.79 (1H, b
s), 6.52 (1H, s), 5.51 (1H, d, J = 13.7 Hz),
5.25 (1H, d, J = 13.7 Hz), 4.53 (2H, dd, J = 5.3,
2.9 Hz), 4.47 (2H, t, J = 8.3 Hz), 4.33-4.22 (
3H, m), 4.10-3.95 (2H, m), 3.28 (1H, dd, J =
6.7, 2.6Hz), 3.19 (1H, dq, J = 7.9, 6.4 Hz), 1.3
7 (3H, d, J = 6.4 Hz), 1.26 (3H, d, J = 7.3 Hz) (2) (1R, 5S, 6S) -2- ｛1- [4- (benzoylamino-methyl) -1 , 3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt Example 69 ( P-Nitrobenzyl (1) obtained in 1)
R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapen-2-em-3-carboxylate (851 mg, 1.31 mmol) was dissolved in tetrahydrofuran (40 ml) and distilled water (40 ml), and a water bath at 35 ° C. was used in the presence of 85% of 7.5% palladium carbon. Catalytic hydrogen reduction 2
Time went. After confirming the completion of the reaction, the reaction mixture was filtered, and 110 mg of sodium hydrogen carbonate was added to the filtrate. Acetic acid and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water-4% acetonitrile-distilled water-6% acetonitrile-distilled water-8% acetonitrile-distilled water- Purified with 10% acetonitrile-distilled water to 15% acetonitrile-distilled water) and freeze-dried to obtain the target compound (1).
R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxy Ethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 144 mg, yield 20%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.81 (2H, d, J =
7.4 Hz), 7.70-7.55 (3H, m), 6.62 (1H, d, J =
8.6 Hz), 4.52 (2H, t, J = 7.9 Hz), 4.47 (2H, s
), 4.37-4.28 (1H, m), 4.24 (1H, quint., J =
6.2 Hz), 4.19 (1H, dd, J = 8.8, 2.2 Hz), 4.05-
3.97 (2H, m), 3.43 (1H, dd, J = 6.2, 2.2 Hz),
3.26 (1H, dq, J = 8.8, 7.2 Hz), 1.29 (3H, d, J =
6.4 Hz), 1.19 (3H, d, J = 7.2 Hz) IR (KBr): 3336.2, 1750.2, 1645.9, 1601.6, 1526.4,
1488.8, 1470.5, 1396.2, 1308.5, 1294.0cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 537 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: 537.1246
[M + H] ^+, _{calcd: 537.1243 (C 24 H 26 N} 4 O 5 S 2 Na) Example 70 (1R, 5S, 6S) -2- {1- [4- ( benzenesulfonylamino-methyl) - -1,3-thiazole-2-
Yl] azetidin-3-yl] thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0501]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl]- 1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4- obtained in Reference Example 65
1.00 g (2.68 mmol) of (benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidine was dissolved in 30 ml of dimethylformamide, and 296 mg (3.21 mmol) of hydrazine acetate at room temperature under a nitrogen atmosphere.
And stirred for 1 hour. After confirming the completion of the reaction,
Under a nitrogen atmosphere, p-nitrobenzyl (1
R, 5S, 6S) -2- (Diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 1.7
A solution of 5 g (2.94 mmol) in 60 ml of acetonitrile was added dropwise, followed by 1.87 ml of diisopropylethylamine (10.
7 mmol), and the mixture was stirred for 3 hours while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was treated with 0.5M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate,
After sequentially washing with saturated saline, drying over anhydrous magnesium sulfate, filtration, and the filtrate were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- {1- [4- (benzenesulfonyl). Amino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylate as pale yellow solid
1.13 g, yield 61%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H,
d, J = 8.7 Hz), 7.83 (2H, d, J = 7.5 Hz), 7.66 (2
H, d, J = 8.7 Hz) 7.60-7.43 (3H, m), 6.33 (1H, s
), 5.58 (1H, br s), 5.51 (1H, d, J = 13.7 Hz),
5.26 (1H, d, J = 13.7 Hz), 4.48 (2H, t, J = 7.8 H
z), 4.44 (2H, t, J = 7.8 Hz), 4.36- 4.18 (3H, m
), 4.13 (1H, quint., J = 7.2 Hz), 4.08 (1H, dd,
J = 12.7, 6.0 Hz), 4.01 (1H, dd, J = 8.6, 5.6 Hz
), 3.94 (1H, dd, J = 8.6, 5.6 Hz), 3.30 (1H, d
d, J = 6.7, 2.6 Hz), 3.21 (1H, dq, J = 8.9, 7.4 Hz
), 1.37 (3H, d, J = 6.2 Hz), 1.23 (3H, dd, J =
7.2, 1.2 Hz) (2) (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio- 6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 70 (1)
R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1- Dissolve 1.13 g (1.65 mmol) of [hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate in 55 ml of tetrahydrofuran and 55 ml of distilled water, and add 7.5%
In the presence of 1.13 g of palladium carbon, catalytic hydrogen reduction was performed in a water bath at 35 ° C for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 139 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water-4% acetonitrile-distilled water-8% acetonitrile-distilled water-12% acetonitrile-distilled water- Purified with 16% acetonitrile-distilled water to 20% acetonitrile-distilled water) and freeze-dried to obtain the target compound (1R, 5S, 6S) -2- {1- [1-
-(Benzenesulfonylamino-methyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 627 mg, yield 66%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.71-7.68 (3H,
m), 7.61-7.52 (2H, m)., 6.52 (1H, s), 4.35-
4.18 (5H, m including 4.22 (1H, dd, J = 9.1, 2.4
Hz)), 4.12 (2H, s), 3.78-3.65 (2H, m), 3.
36 (1H, dd, J = 6.2, 2.4 Hz), 3.23 (1H, dq, J = 8.
8, 7.2 Hz), 1.31 (3H, d, J = 6.4 Hz), 1.21 (3H,
d, J = 7.2 Hz) IR (KBr): 3293.8, 1748.2, 1597.7, 1528.3, 1470.5,
1447.3, 1397.2, 1314.3cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 573 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Observed value: 573.0911
[M + H] ^+, _{calcd: 573.0093 (C 23 H 26 N} 4 O 5 S 2 Na) Example 71 (1R, 5S, 6S) -2- (1- {4 - [( thiophene-2-carbonyl -Amino) methyl] -1,3-thiazol-2-yl {azetidin-3-yl) thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0503]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl}
Azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-
3-carboxylate 3-acetylthio-1- {4-} obtained in Reference Example 66
[(Thiophen-2-carbonyl-amino) methyl] -1,
3-thiazol-2-yl diazetidine 490 mg (1.52 m
mol) was dissolved in 15 ml of dimethylformamide, and 169 mg (1.83 mmo) of hydrazine acetate was dissolved in a nitrogen atmosphere at room temperature.
l) was added and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 was introduced into the system under ice cooling under a nitrogen atmosphere. -Methyl-carbapene-2-em-3-carboxylate
A solution of 1.09 g (1.83 mmol) in 30 ml of acetonitrile was added dropwise, followed by 1.06 ml of diisopropylethylamine (
0.68 mmol), and the mixture was stirred for 2.5 hours while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
Purified with ethyl acetate), p-nitrobenzyl (1R,
5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazole-2-
Il @ azetidin-3-yl) thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
997m as M-3-carboxylate as pale yellow solid
g, 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.0 Hz), 8.02 (2H, s), 7.66 (2H, d, J = 8.
0 Hz) 7.47 (1H, d, J = 5.2 Hz), 7.07 (1H, d, J =
4.2 Hz), 6.55 (1H, s), 5.50 (1H, d, J = 13.7 Hz
), 5.26 (1H, d, J = 13.7 Hz), 4.67-4.55 (2H, m
), 4.51 (2H, d, J = 5.3 Hz), 4.35-4.22 (2H, m
), 4.22-4.03 (3H, m), 3.29 (1H, dd, J = 6.8,
2.6 Hz), 3.18 (1H, dq, J = 9.0, 7.5 Hz), 1.37 (
3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.3 Hz) (2) (1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino)) Methyl] -1,3-thiazol-2-yl {azetidin-3-yl) thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1
R, 5S, 6S) -2- (1- {4-[(thiophene-2)
-Carbonyl-amino) methyl] -1,3-thiazole-
2-yl {azetidin-3-yl) thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
997 mg (1.52 mmol) of 2-M-3-carboxylate
Was dissolved in 35 ml of tetrahydrofuran and 35 ml of distilled water, and subjected to catalytic hydrogen reduction in a water bath at 35 ° C. for 2 hours in the presence of 997 mg of 7.5% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered, and 128 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to
4% acetonitrile-distilled water-8% acetonitrile-distilled water-12% acetonitrile-distilled water-15% acetonitrile-distilled water-20% acetonitrile-distilled water)
The target compound is obtained by freeze-drying (1R, 5
(S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt as a white solid
87 mg was obtained in a yield of 35%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.73 (2H, d, J =
2.7 Hz), 7.19 (1H, t, J = 4.4 Hz), 6.59 (1H, d,
J = 0.7 Hz), 4.49 (2H, t, J = 7.5 Hz), 4.43 (2H,
s), 4.35-4.27 (1H, m), 4.24 (1H, quint., J =
6.3 Hz), 4.18 (1H, dd, J = 8.3, 2.4 Hz), 3.99 (1
H, t, J = 4.7 Hz), 3.97 (1H, t, J = 4.7 Hz), 3.42
(1H, dd, J = 6.3, 2.4 Hz), 3.22 (1H, quint., J =
8.3Hz), 1.30 (3H, d, J = 6.4Hz), 1.18 (3H, d, J
= 7.1 Hz) IR (KBr): 3324.7, 1749.1, 1599.7, 1530.2, 1469.5,
1418.4, 1396.2cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 521 [M-Na + 2H] ⁺ high-resolution mass spectrum (ESI ⁺ ): Actual value: 521.0992
^{[M-Na + 2H] +} , _{calcd: 521.0942 C 22 H 25 N 4} O 5 S 3) Example 72 (1R, 5S, 6S) -2- (1- {4 - [( furan -2
-Carbonyl-amino) methyl] -1,3-thiazole-
2-yl {azetidin-3-yl) thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid sodium salt

[0505]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- {4-[(furan-2-carbonyl-
Amino) methyl] -1,3-thiazol-2-yl {azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylate 3-acetylthio-1- {4-} obtained in Reference Example 67
[(Furan-2-carbonyl-amino) methyl] -1,3-
Thiazol-2-yl diazetidine 341 mg (1.12 mmo
l) was dissolved in 10 ml of dimethylformamide, and 123 mg (1.34 mmol) of hydrazine acetate at room temperature under a nitrogen atmosphere.
And stirred for 1 hour. After confirming the completion of the reaction,
Under a nitrogen atmosphere, p-nitrobenzyl (1
R, 5S, 6S) -2- (Diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 797
mg (1.34 mmol) in 20 ml of acetonitrile was added dropwise, followed by 0.78 ml of diisopropylethylamine (4.4
8 mmol), and the mixture was stirred for 3 hours while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was treated with 0.5M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate,
After sequentially washing with saturated saline, drying over anhydrous magnesium sulfate, filtration, and the filtrate were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and p-nitrobenzyl (1R, 5S,
6S) -2- (1- {4-[(furan-2-carbonyl-
Amino) methyl] -1,3-thiazol-2-yl {azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
641 mg of carboxylate as pale yellow solid, yield 89
%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 7.8 Hz), 7.66 (2H, d, J = 7.8 Hz) 7.45 (1H,
s), 7.13 (1H, d, J = 3.5 Hz), 6.53 (1H, s), 6.4
9 (1H, d, J = 5.1 Hz), 5.48 (1H, d, J = 13.7 Hz),
5.26 (1H, d, J = 13.7 Hz), 4.60-4.40 (4H, min
cluding 4.51 (2H, d, J = 5.6 Hz)), 4.35-4.20 (
2H, m), 4.20-4.00 (3H, m), 3.29 (1H, dd, J =
6.9, 2.5Hz), 3.19 (1H, dq, J = 9.3, 7.3 Hz), 1.3
7 (3H, d, J = 6.4 Hz), 1.26 (3H, d, J = 7.3 Hz) (2) (1R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl- Amino) methyl] -1,3-thiazol-2-yl {azetidin-3-yl) thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 72 (1)
R, 5S, 6S) -2- (1- {4-[(furan-2-carbonyl-amino) methyl] -1,3-thiazole-2-
Il @ azetidin-3-yl) thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
Dissolve 640 mg (1.00 mmol) of M-3-carboxylate in 32 ml of tetrahydrofuran and 32 ml of distilled water,
In the presence of 640 mg of 7.5% palladium carbon, catalytic hydrogen reduction was performed in a water bath at 35 ° C for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 84 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water to 4% acetonitrile-distilled water to
Purified with 6% acetonitrile-distilled water-8% acetonitrile-distilled water-10% acetonitrile-distilled water-15% acetonitrile-distilled water) and freeze-dried to be the target compound (1R, 5S, 6S)- 2- (1-
{4-[(furan-2-carbonyl-amino) methyl]-
1,3-thiazol-2-yl {azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 218 mg, yield 41%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.69 (1H, dd, J =
1.7, 0.8 Hz), 7.19 (1H, dd, J = 3.6, 0.7 Hz), 6.6
4 (1H, dd, J = 3.6, 1.7 Hz), 4.51 (2H, t, J = 8.2
Hz), 4.44 (2H, s), 4.38-4.28 (1H, m), 4.25
(1H, quint., J = 6.3 Hz), 4.19 (1H, dd, J = 8.9, 2.
2 Hz), 4.02 (1H, dd, J = 5.0, 3.2Hz), 4.00 (1H,
dd, J = 5.0, 2.9 Hz), 3.43 (1H, dd, J = 6.3, 2.5
Hz), 3.24 (1H, dq, J = 8.9, 7.1 Hz), 1.30 (3H, d,
J = 6.4 Hz), 1.19 (3H, d, J = 7.1 Hz) IR (KBr): 3367.1, 1749.1, 1653.7, 1594.8, 1524.5,
1472.4, 1395.2cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 505 [M-Na + 2H] ⁺ High-resolution mass spectrum (ESI ⁺ ): Actual value: 505.1208
^{[M-Na + 2H] +} , _{calcd: 505.1216 (C 22 H 25 N} 4 O 6 S 2) Example 73 (1R, 5S, 6S) -2- [1- (4- phthalimidomethyl-1,3 -Thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid
Sodium salt

[0507]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-phthalimidomethyl-1,3
-Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylate 599 mg (1.60 mmol) of 3-acetylthio-1- (4-phthalimidomethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 68 was converted to dimethylformamide
The solution was dissolved in 18 ml, and 177 mg (1.92 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy) -6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate A solution of 1.14 g (1.92 mmol) in 36 ml of acetonitrile was added dropwise, followed by 1.11 ml (6.40 mmol) of diisopropylethylamine, and the mixture was allowed to gradually reach room temperature. The mixture was stirred for 30 minutes while being heated. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and p-
Nitrobenzyl (1R, 5S, 6S) -2- [1- (4
-Phthalimidomethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 640 mg as a pale yellow solid,
Obtained in a yield of 59%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.7 Hz), 7.88 (2H, dd, J = 5.5, 3.1 Hz), 7.
73 (2H, dd, J = 5.5, 3.1 Hz), 7.65 (2H, d, J = 8.7
Hz), 6.41 (1H, s), 5.49 (1H, d, J = 13.7 Hz),
5.25 (1H, d, J = 13.7 Hz), 4.80 (2H, s), 4.46
(1H, t, J = 8.1 Hz), 4.43 (1H, t, J = 8.1 Hz),
4.32-4.18 (3H, m, including 4.24 (1H, dd, J =
9.2, 2.4 Hz)), 4.02 (1H, dd, J = 5.5, 2.8 Hz), 4.0
0 (1H, dd, J = 5.5, 2.8 Hz), 3.26 (1H, dd, J = 6.
9, 2.5 Hz), 3.19 (1H, dq, J = 9.2, 7.3 Hz), 1.3
8 (3H, d, J = 6.2 Hz), 1.25 (3H, dd, J = 7.3, 2.1
Hz) (2) (1R, 5S, 6S) -2- [1- (4-phthalimidomethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1 -Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 73 (1)
R, 5S, 6S) -2- [1- (4-phthalimidomethyl-1,3-thiazol-2-yl) azetidine-3-
Yl] thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapene-2-em-3-carboxylate (640 mg, 0.95 mmol) in tetrahydrofuran (32 ml,
Dissolve in 32 ml of distilled water, 640 mg of 7.5% palladium on carbon
In the presence, catalytic hydrogen reduction was performed in a water bath at 35 ° C for 2 hours.
After checking the completion of the reaction, the reaction mixture was filtered, and 80 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate,
And distilled water were added to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water to 4% acetonitrile-distilled water to 6% acetonitrile-distilled water to 8%
Acetonitrile-distilled water ~ 10% acetonitrile-distilled water ~ 15% acetonitrile-distilled water ~ 20% acetonitrile-
Purified with distilled water) and lyophilized to give the desired compound ((1R, 5S, 6S) -2- [1- (4-phthalimidomethyl-1,3-thiazol-2-yl) azetidine-3). -Yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
202 mg of sodium carboxylate as a white solid,
Yield 38%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.90-7.78 (4H,
m), 6.56 (1H, d, J = 2.7 Hz), 4.70 (2H, s), 4.4
3 (1H, t, J = 7.9 Hz), 4.42 (1H, t, J = 7.9 Hz),
4.31-4.19 (2H, m including 4.24 (1H, quint., J
= 6.3 Hz)), 4.17 (1H, dd, J = 8.7, 2.0 Hz), 3.94
(1H, t, J = 7.9 Hz), 3.92 (1H, t, J = 7.9 Hz),
3.18 (1H, dq, J = 8.7, 7.2 Hz), 1.29 (3H, d, J =
6.4 Hz), 1.15 (3H, d, J = 7.2 Hz) IR (KBr): 3409.5, 1768.4, 1750.1, 1717.3, 1601.6,
1528.3, 1425.1, 1393.3, 1313.3 cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 563 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: 585.0865
[M + Na] ^+, _{calcd: 585.0864 (C 25 H 23 N} 4 O 6 S 2 Na 2) Example 74 (1R, 5S, 6S) -2- [1- (4- succinate imide methyl -1, 3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapene-2-em-3-carboxylic acid
Sodium salt

[0509]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-succinimidomethyl-1,3
-Thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylate 238 mg (0.73 mmol) of 3-acetylthio-1- (4-succinimidomethyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 69 was converted to dimethylformamide.
The mixture was dissolved in 7 ml, and hydrazine acetate (81 mg, 0.88 mmol) was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 was introduced into the system under ice cooling under a nitrogen atmosphere. -Methyl-carbapene-2-m-
A solution of 523 mg (0.88 mmol) of 3-carboxylate in 14 ml of acetonitrile was added dropwise, followed by 0.51 ml (2.92 mmol) of diisopropylethylamine, and the mixture was stirred for 2 hours while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 20: 1), and p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4- Succinimidomethyl-1,3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-Methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 211 mg, 46% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz), 6.42 (1
H, s), 5.50 (1H, d, J = 13.8 Hz), 5.25 (1H, d,
J = 13.8 Hz), 4.61 (2H, s), 4.46 (1H, t, J = 8.0
Hz), 4.45 (1H, t, J = 8.0 Hz), 4.32-4.18 (3
H, m, including 4.25 (1H, dd, J = 9.1, 2.3 Hz)), 4.
02 (1H, t, J = 4.8 Hz), 4.00 (1H, dd, J = 4.8, 3.7
Hz), 3.28 (1H, dd, J = 6.9, 2.5 Hz), 3.20 (1H, d
q, J = 9.1, 7.3 Hz), 2.76 (4H, s), 1.38 (3H,
d, J = 6.2 Hz), 1.27 (3H, d, J = 7.3 Hz) (2) (1R, 5S, 6S) -2- [1- (4-succinimidomethyl-1,3-thiazole-2-) Yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt p obtained in Example 74 (1) -Nitrobenzyl (1
R, 5S, 6S) -2- [1- (4-Succinimidomethyl-1,3-thiazol-2-yl) azetidine-3-
Yl] thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapene-2-em-3-carboxylate 211 mg (0.34 mmol) in tetrahydrofuran 10 ml,
Dissolve in 10 ml of distilled water and add 211 mg of 7.5% palladium on carbon
In the presence, catalytic hydrogen reduction was performed in a water bath at 35 ° C for 2 hours.
After confirming the completion of the reaction, the reaction mixture was filtered, and 29 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate,
And distilled water were added to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to 2% acetonitrile-distilled water to 4% acetonitrile-distilled water), and lyophilized to give the target compound. ((1R, 5S, 6S) -2
-[1- (4-Succinimidomethyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
115 mg of 2-M-3-carboxylic acid sodium salt was obtained as a white solid in a yield of 66%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 6.59 (1H, s), 4.
57 (2H, s), 4.50 (2H, t, J = 8.1 Hz), 4.38-4.2
9 (1H, m), 4.25 (1H, quint., J = 6.3 Hz), 4.20
(1H, dd, J = 8.7, 2.3 Hz), 4.01 (1H, t, J = 4.2 H
z), 3.99 (1H, t, J = 4.2 Hz), 3.43 (1H, dd, J =
6.3, 2.4 Hz), 3.24 (1H, dq, J = 8.7,7.4 Hz), 2.4
8 (4H, s), 1.30 (3H, d, J = 6.4 Hz), 1.19 (3H,
d, J = 7.2 Hz) IR (KBr): 3381.6, 1749.1, 1794.8, 1601.6, 1526.4,
1470.5, 1424.2, 1399.1, 1312.3, 1295.0, 1168.7cm- ¹ Mass spectrum (FAB ⁺ ): m / z: 515 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: 515.1034
[M + H] ^+, _{calcd: 515.1035 (C 21 H 24 N} 4 O 6 S 2 Na) Example 75 (1R, 5S, 6S) -2- [1- (4- azetidinone Gino carbonyl-1,3 -Oxazo-ru-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0511]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-azetidinocarbonyl-1,
3-Oxazol-2-yl) azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-azetidinocarbonyl-1) obtained in Reference Example 71 330 mg (1.17 mmol) of 1,3-oxazol-2-yl) azetidine were dissolved in 17 ml of dimethylformamide, 130 mg (1.41 mmol) of hydrazine acetate were added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy) -6-[(R) -1-
A solution of 696 mg (1.17 mmol) of hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate in 35 ml of acetonitrile was added dropwise, followed by 815 μl (4.68 mmol) of diisopropylethylamine, and the temperature was gradually raised to room temperature. The mixture was stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with 10% brine and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl). -1,3-Oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 605 mg as a yellow solid, 89% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d, J =
8.8Hz), 7.71 (1H, s), 7.66 (2H, d, J = 8.8Hz), 5.5
1 (1H, d, J = 13.9Hz), 5.25 (1H, d, J = 13.9Hz), 4.54-
4.47 (4H, m), 4.29-4.12 (2H, m), 4.26 (1H, dd, J =
2.2, 9.5Hz), 4.09 (2H, t, J = 8.8Hz), 4.07 (2H, t, J =
8.8Hz), 3.29 (1H, dd, J = 2.2, 6.6Hz), 3.19 (1H, dq,
J = 9.5, 7.3Hz), 2.37-2.27 (2H, m), 1.38 (3H, d, J =
(5.9 Hz), 1.26 (3H, d, J = 7.3 Hz). (2) (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) ) Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 75 (1)
R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
600 mg (1.03 mmol) of -1-methyl-carbapen-2-em-3-carboxylate was dissolved in 30 ml of tetrahydrofuran and 30 ml of distilled water, and subjected to catalytic hydrogen reduction for 2 hours at room temperature in the presence of 600 mg of 10% palladium carbon. . After confirming the completion of the reaction,
The reaction mixture was filtered, and 86 mg of sodium hydrogen carbonate was added to the filtrate. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, and chromatographed using Cosmoseal (elution solvent: distilled water to
Purified with distilled water: acetonitrile = 9: 1) and lyophilized to give the desired compound (1R, 5S, 6)
S) -2- [1- (4-azetidinocarbonyl-1,3
-Oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt as a white solid 278 mg, yield 58%. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.80 (1H, s),
4.59 (2H, t, J = 8.3Hz), 4.45 (2H, t, J = 7.8Hz), 4.3
5-4.27 (1H, m), 4.25 (1H, dq, J = 6.2, 6.4Hz), 4.20
(1H, dd, J = 2.4, 9.1Hz), 4.16 (2H, t, J = 7.8Hz), 4.0
8 (2H, dt, J = 9.2, 4.6Hz), 3.43 (1H, dd, J = 2.4, 6.2
Hz), 3.24 (1H, dq, J = 9.1, 7.2Hz), 2.39 (1H, quinte
t, J = 7.8Hz), 1.30 (3H, d, J = 6.4Hz), 1.19 (3H, d, J
IR (KBr): 1750, 1619, 1468, 1443, 1383cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 493 [M + Na] ⁺ High-resolution mass spectrum (ESI ⁺ ): Actual value : 493.1167
[M + Na] ⁺ , Calculated: 493.1133 (C ₂₀ H ₂₃ N ₄ O ₆ SNa ₂ ) Elemental analysis: Calculated as C ₂₀ H ₂₃ N ₄ O ₆ Sna ・ H ₂ O Actual: C, 49.04% H, 5.46% N, 11.57% S, 6.29% Calculated: C, 49.18% H, 5.16% N, 11.47% S, 6.56% Example 76 (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl) -1,3-oxazo-ru-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt

[0513]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- (4-morpholinocarbonyl-1,
3-Oxazol-2-yl) azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- (4-morpholinocarbonyl-1, obtained in Reference Example 72, 260 mg (0.835 mmol) of 3-oxazol-2-yl) azetidine was dissolved in 13 ml of dimethylformamide, and 92 mg (1.00 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1 was introduced into the system under ice cooling under a nitrogen atmosphere. -Methyl-carbapene-2-m-
A solution of 496 mg (0.835 mmol) of 3-carboxylate in 25 ml of acetonitrile was added dropwise, followed by the addition of 582 μl (3.34 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% saline,
After washing successively with a saturated saline solution, the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-). 1,3-Oxazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate is pale yellow It was obtained as a solid in 552 mg, 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.73 (1H, s), 7.66 (2H, d, J = 8.8Hz), 5.
51 (1H, d, J = 13.2Hz), 5.25 (1H, d, J = 13.2Hz), 4.52
(2H, q, J = 8.1Hz), 4.31-4.20 (3H, m), 4.13-4.06 (2
H, m), 3.76-3.65 (8H, br s), 3.29 (1H, dd, J2.5,7.0
Hz), 3.19 (1H, dq, J = 9.5, 7.3Hz), 1.38 (3H, d, J =
(5.9Hz), 1.26 (3H, d, J = 7.3Hz). (2) (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) Azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylic acid sodium salt p-nitrobenzyl (1) obtained in Example 76 (1)
R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapen-2-em-3-carboxylate 550 mg (0.835 mmol) was added to tetrahydrofuran 28 ml,
Dissolved in distilled water 28ml, in the presence of 10% palladium carbon 550mg,
Catalytic hydrogen reduction was performed at room temperature for 2.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 70 mg of sodium hydrogen carbonate was added to the filtrate.
Was added. Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 9: 1), and lyophilized to give the target compound (1R, 5S,
6S) -2- [1- (4-morpholinocarbonyl-1,
3-Oxazol-2-yl) azetidin-3-yl]
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 193 mg, yield 46%. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.77 (1H, s),
4.60 (2H, t, J = 8.2Hz), 4.36-4.28 (1H, m), 4.25 (1
H, dq, J = 6.1, 6.3Hz), 4.21 (1H, dd, J = 2.2, 9.0Hz),
4.09 (1H, dt, J = 8.9, 4.5Hz), 3.90-3.66 (8H, m),
3.43 (1H, dd, J = 2.2, 6.1Hz), 3.25 (1H, dq, J = 9.0,
7.2Hz), 1.30 (3H, d, J = 6.3Hz), 1.19 (3H, d, J = 7.2H
z). IR (KBr): 1750, 1618, 1459, 1443, 1385, 1304 cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 523 [M + Na] ⁺ High-resolution mass spectrum (ESI ⁺ ): Actual measurement Value: 523.1238
[M + Na] ⁺ , Calculated: 523.1240 (C ₂₁ H ₂₅ N ₄ O ₇ SNa ₂ ) Elemental analysis: Calculated as C ₂₁ H ₂₅ N ₄ O ₇ SNa / H ₂ O Actual: C, 48.45% H, 5.41% N, 10.45% S, 5.55% Calculated: C, 48.64% H, 5.25% N, 10.81% S, 6.18% Example 77 (1R, 5S, 6S) -2- [1- [4- (3 -Methoxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0515]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- [1- [4- (3-methoxyazetidine-
1-carbonyl) -1,3-oxazol-2-yl]
Azetidin-3-yl] thio 6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-
Carboxylate 3-acetylthio-1- [4- obtained in Reference Example 73
(3-methoxyazetidine-1-carbonyl) -1,3
-Oxazol-2-yl] azetidine 330mg (1.06mmo
l) was dissolved in 17 ml of dimethylformamide, and 117 mg (1.27 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R,
5S, 6S) -2- (diphenylphosphoryloxy)-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 630 g (1.0
6 mmol) in 32 ml of acetonitrile was added dropwise, followed by addition of 739 μml (4.24 mmol) of diisopropylethylamine.
The mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with 10% brine and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 95: 5-
9: 1) and purified with p-nitrobenzyl (1R, 5
S, 6S) -2- [1- [4- (3-Methoxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl] thio-6-[(R)- 1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate was obtained as a pale yellow solid in 550 mg, 85% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 7.74 (1H, s), 7.66 (2H, d, J = 8.8Hz),
5.55 (1H, d, J = 13.2Hz), 5.25 (1H, d, J = 13.2Hz), 4.
71-4.63 (1H, m), 4.51 (2H, q, J = 8.1Hz), 4.38-4.20
(6H, m), 4.10-4.05 (2H, m), 4.04-3.98 (1H, m), 3.3
2 (3H, s), 3.29 (1H, dd, J = 2.2, 6.6Hz), 3.20 (1H, d
q, J = 9.2, 7.3Hz), 1.38 (3H, d, J = 5.9Hz), 1.26 (3H,
d, J = 7.3 Hz). (2) (1R, 5S, 6S) -2- [1- [4- (3-
Methoxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl] thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 77 (1)
R, 5S, 6S) -2- [1- [4- (3-methoxyazetidine-1-carbonyl) -1,3-oxazole-
2-yl] azetidin-3-yl] thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-Dissolve 550 mg (0.896 mmol) of M-3-carboxylate in 28 ml of tetrahydrofuran and 28 ml of distilled water and add 10%
Perform catalytic hydrogen reduction at room temperature in the presence of 550 mg of palladium carbon.
I went for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and 75 mg of sodium hydrogen carbonate was added to the filtrate. Acetic acid and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 92: 8), and lyophilized to give the target compound (1R, 5S, 6S) -2- [1- [4- (3
-Methoxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl] thio-6
-[(R) -1-Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 276 mg, yield 62%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.84 (1H, s), 4.66
(1H, dd, J = 6.4, 10.3Hz), 4.60 (2H, t, J = 8.3Hz),
4.46-4.30 (4H, m), 4.25 (1H, dq, J = 6.2, 6.4Hz), 4.
20 (1H, dd, J = 2.4, 9.0Hz), 4.09 (2H, quintet, J = 4.
5Hz), 4.04-3.98 (1H, m), 3.43 (1H, dd, J = 2.4, 6.2H
z), 3.37 (3H, s), 3.25 (1H, dq, J = 9.0,7.2Hz), 1.30
(3H, d, J = 6.4Hz), 1.19 (3H, d, J = 7.2Hz) .IR (KBr): 1750, 1622, 1457, 1385cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 523 [ M + Na] ⁺ high-resolution mass spectrum (ESI ⁺ ): found: 523.1227
[M + Na] ⁺ , Calculated: 523.1239 (C ₂₁ H ₂₅ N ₄ O ₇ SNa ₂ ) Elemental analysis: Calculated as C ₂₁ H ₂₅ N ₄ O ₇ Sna ・ 4 / 3H ₂ O Observed: C, 48.07% H, 5.61% N, 10.78% S, 6.03% Calculated value: C, 48.09% H, 5.32% N, 10.68% S, 6.11% Example 78 (1R, 5S, 6S) -2- ｛1- [4- (3-Hydroxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid sodium salt

[0517]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- {4- [3- (t-butyldiphenylsilyloxy) -azetidin-1-ylcarbonyl]
-1,3-Oxazol-2-yl {azetidine-3-
Yl) thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- {4-} obtained in Reference Example 74
[3- (t-butyldiphenylsilyloxy) -azetidin-1-ylcarbonyl] -1,3-oxazole-2
860 mg (1.61 mmol) of -yldiazetidine was dissolved in 43 ml of dimethylformamide, and 178 mg (1.93 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -2-
(Diphenylphosphoryloxy) -6-[(R) -1-
A solution of 957 mg (1.61 mmol) of hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate in 48 ml of acetonitrile was added dropwise, followed by the addition of 1.12 ml (6.44 mmol) of diisopropylethylamine, and the mixture was gradually warmed to room temperature. Stir overnight while warming. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% saline and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give p-nitrobenzyl (1R, 5S, 6S) -2-.
(1- {4- [3- (t-butyldiphenylsilyloxy) -azetidin-1-ylcarbonyl] -1,3-oxazol-2-yl} azetidin-3-yl) thio-
6-[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 1.20 g, 89% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.69 (1H, s), 7.66 (2H, d, J = 8.8Hz), 7.
64-7.59 (4H, m), 7.47-7.36 (6H, m), 5.51 (1H, d, J
= 13.5Hz), 5.25 (1H, d, J = 13.5Hz), 4.65-4.59 (1H,
m), 4.69-4.50 (1H, m), 4.50 (2H, q, J = 8.1Hz), 4.39
-4.32 (1H, m), 4.30-4.20 (2H, m), 4.26 (1H, dd, J =
2.9, 9.5Hz), 4.18-3.99 (4H, m), 3.29 (1H, dd, J = 2.
9, 7.3Hz), 3.20 (1H, dq, J = 9.5, 7.3Hz), 1.38 (3H,
d, J = 6.5 Hz), 1.27 (3H, d, J = 7.3 Hz), 1.06 (9H, s). (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
１− 1- [4- (3-hydroxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine-
3-yl @ thio-6-[(R) -1-hydroxyethyl]
-1-methyl-carbapen-2-em-3-carboxylate The p-nitrobenzyl (1) obtained in Example 78 (1)
R, 5S, 6S) -2- (1- {4- [3- (t-butyldiphenylsilyloxy) -azetidin-1-ylcarbonyl] -1,3-oxazol-2-yl} azetidine-3 -Yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate (1.20 g, 1.43 mmol) was dissolved in tetrahydrofuran (60 ml) and cooled under ice-cooling. , Acetic acid 240μl (4.30mmo
l) 4.30 ml (4.30 mmol) of a 1 M solution of tetrabutylammonium fluoride-tetrahydrofuran were added sequentially, and the mixture was stirred at room temperature for 4 days. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 95: 5 to 9: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- ｛1- [4. -(3-hydroxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 325 mg, yield 38%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.74 (1H, s), 7.66 (2H, d, J = 8.8Hz), 5.
51 (1H, d, J = 13.7Hz), 5.25 (1H, d, J = 13.7Hz), 4.80
-4.68 (2H, m), 4.50 (2H, q, J = 8.0Hz), 4.43-4.29 (2
H, m), 4.29-4.20 (3H, m), 4.13-4.05 (2H, m), 4.02-
3.95 (1H, m), 3.29 (1H, dd, J = 2.7, 6.9Hz), 3.20 (1
H, dq, J = 9.3, 7.3Hz), 1.38 (3H, d, J = 6.3Hz), 1.26
(3H, d, J = 7.3 Hz). (3) (1R, 5S, 6S) -2- ｛1- [4- (3-
(Hydroxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid sodium salt The p-nitrobenzyl (1) obtained in Example 78 (2)
R, 5S, 6S) -2- {1- [4- (3-hydroxyazetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6- [ (R)
-1-hydroxyethyl] -1-methyl-carbapene-
320 mg (0.534 mmol) of 2-M-3-carboxylate
Is dissolved in 16 ml of tetrahydrofuran and 16 ml of distilled water, and 1
Catalytic hydrogen reduction was performed at room temperature for 5 hours in the presence of 320 mg of 0% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered,
To the filtrate was added sodium hydrogencarbonate (45 mg). Ethyl acetate and distilled water were added to the reaction solution to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 9: 1), and lyophilized to give the target compound (1R, 5S, 6S) -2- ｛1-
[4- (3-hydroxyazetidine-1-carbonyl)-
1,3-Oxazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapene-2-em-3-carboxylic acid sodium salt was obtained as a white solid in 144 mg, yield 56%. ¹ H-NMR (400 MHz, D ₂ O, TSP): δ (ppm) 7.84 (1H,
s), 4.75-4.66 (2H, m), 4.60 (2H, t, J = 8.2Hz), 4.44
-4.38 (1H, m), 4.35-4.23 (3H, m), 4.20 (1H, dd, J =
2.4, 9.0Hz), 4.09 (2H, dt, J = 8.9, 4.5Hz), 3.98-3.9
3 (1H, m), 3.43 (1H, dd, J = 2.4, 6.2Hz), 3.24 (1H,
dq, J = 9.0, 7.2Hz), 1.30 (3H, d, J = 6.4Hz), 1.19 (3
H, d, J = 7.2Hz). IR (KBr): 1750, 1621, 1470, 1385, 1294, 1277cm ^-1 Mass spectrum (ESI ⁺ ): m / z: 509 [M + Na] ⁺ High-resolution mass spectrum (ESI ⁺ ): Found: 509.1102
[M + Na] ⁺ , Calculated: 509.1083 Elemental analysis: Found: C, 46.25% H, 6.23% N, 11.07% S, 5.90% Calculated: C, 49.38% H, 4.77% N, 11.52% S, 6.59% Example 79 (1R, 5S, 6S) -2- {1- [4- (3-Amino-azetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio -6
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid

[0519]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- {1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidin-1-ylcarbonyl] -1,3-oxazol-2-yl {azetidin-3-yl} Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- {4-} obtained in Reference Example 75
[3- (p-nitrobenzyloxycarbonylamino)-
Azetidin-1-ylcarbonyl] -1,3-oxazo-
190 mg (0.383 mmol) of ru-2-yl diazetidine was dissolved in 10 ml of dimethylformamide, and 42 mg (0.460 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) was introduced into the system under ice cooling under a nitrogen atmosphere.
-2- (diphenylphosphoryloxy-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
A solution of 228 mg (0.383 mmol) of -M-3-carboxylate in 11 ml of acetonitrile was added dropwise, followed by 268 μl (1.53 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction system,
The aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer is
After washing with a 0% saline solution and a saturated saline solution sequentially, the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 93: 7),
p-Nitrobenzyl (1R, 5S, 6S) -2- {1
-{4- [3- (p-nitrobenzyloxycarbonylamino) -azetidin-1-ylcarbonyl] -1,3-
Oxazol-2-yl {azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylate was obtained as a pale yellow solid in 257 mg, 86% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (4H, d,
J = 8.8Hz), 7.75 (1H, s), 7.66 (2H, d, J = 8.8Hz), 7.
51 (2H, d, J = 8.8Hz), 5.51 (1H, d, J = 13.7Hz), 5.34-
5.31 (1H, m), 5.25 (1H, d, J = 13.7Hz), 5.21 (2H,
s), 4.87-4.82 (1H, m), 4.60-4.42 (2H, m), 4.49 (2H,
q, J = 8.8Hz), 4.38−4.30 (1H, m), 4.28-4.20 (3H,
m), 4.06 (2H, dt, J = 8.8, 4.9Hz), 4.00-3.93 (1H,
m), 3.29 (1H, dd, J = 2.9, 6.8Hz), 3.18 (1H, dq, J = 9.
0, 6.8Hz), 1.38 (3H, d, J = 5.9Hz), 1.26 (3H, d, J =
(6.8Hz). (2) (1R, 5S, 6S) -2- ｛1- [4- (3-
Amino-azetidin-1-carbonyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6
-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid p-nitrobenzyl (1) obtained in Example 79 (1)
R, 5S, 6S) -2- {1- {4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1
-Ylcarbonyl] -1,3-oxazol-2-yl}
Azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-m-
250 mg (0.321 mmol) of 3-carboxylate was dissolved in 13 ml of tetrahydrofuran and 13 ml of distilled water, and subjected to catalytic hydrogen reduction in the presence of 250 mg of 10% palladium carbon at room temperature for 3.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure and chromatographed using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile =
82:18) and freeze-dried to give the desired compound (1R, 5S, 6S) -2- ｛1- [4.
-(3-amino-azetidine-1-carbonyl) -1,3
-Oxazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid as a white solid, 68 mg, yield Obtained at 46%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.88 (1H, s), 4.60
(2H, t, J = 8.2Hz), 4.57-4.49 (2H, m), 4.35-4.16 (6
H, m), 4.08 (2H, dt, J = 8.6, 4.5Hz), 3.44 (1H, dd,
J = 2.5, 6.2Hz), 3.24 (1H, dq, J = 9.0, 7.2Hz), 1.30
(3H, d, J = 6.4Hz), 1.19 (3H, d, J = 7.2Hz). IR (KBr): 1754, 1624, 1457, 1380cm ^-1 Mass spectrum (ESI ⁺ ): m / z: 486 [ M + Na] ⁺ high-resolution mass spectrum (ESI ⁺ ): found: 464.1609
[M + H] ⁺ , Calculated: 464.1603 (C ₂₀ H ₂₆ N ₅ O ₆ S) Elemental analysis: Calculated as C ₂₀ H ₂₅ N ₅ O ₆ S ・ 10 / 3H ₂ O Actual: C, 45.85% H , 5.69% N, 13.62% S, 6.18% Calculated: C, 45.88% H, 6.10% N, 13.38% S, 6.12% Example 80 (1R, 5S, 6S) -2- ｛1- [4- ( (3S)-
Pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid

[0521]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- (1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl} azetidin-3-yl ) Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- {4-} obtained in Reference Example 76
[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl diazetidine (530 mg, 1.08 mmol) is dissolved in dimethylformamide (27 ml), and the mixture is dissolved in a nitrogen atmosphere under,
At room temperature, hydrazine acetate 120 mg (1.30 mmol) was added,
The mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S,
6S) -2- (diphenylphosphoryloxy) -6
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate 642 g (1.08 mmo
A solution of l) in 32 ml of acetonitrile was added dropwise, followed by the addition of 753 μl (4.32 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature.
After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with 10% brine and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9).
5: 5) and purified with p-nitrobenzyl (1R, 5).
S, 6S) -2- (1- {4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl}
Azetidin-3-yl) thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
652 mg of carboxylate as a pale yellow solid, yield 76
%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (4H, d,
J = 8.8Hz), 7.77 (1H, s), 7.66 (2H, d, J = 8.8Hz), 7.
53 (2H, t, J = 8.8Hz), 6.82-6.78 (1H, m), 5.51 (1H,
d, J = 13.6Hz), 5.25 (1H, d, J = 13.6Hz), 5.30−5.18
(2H, m), 4.66-4.58 (1H, m), 4.57-4.46 (2H, m), 4.1
1-4.20 (2H, m), 4.26 (1H, dd, J = 2.2, 8.8Hz), 4.14-
4.04 (2H, m), 3.82-3.74 (1H, m), 3.64-3.55 (2H,
m), 3.46-3.40 (1H, m), 3.29 (1H, dd, J = 2.2, 6.6Hz),
3.20 (1H, dq, J = 8.8, 7.2Hz), 2.30-2.20 (1H, m),
2.10-1.92 (1H, m), 1.38 (3H, d, J = 6.6Hz), 1.27 (3
(H, d, J = 7.2 Hz). (2) (1R, 5S, 6S) -2- ｛1- [4-((3
S) -Pyrrolidin-3-ylcarbamoyl) -1,3-
Oxazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylic acid Compound p-nitrobenzyl (1R, 5S, 6S) -2- (1- {4-[(3S)-) obtained in Example 80 (1)
1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole-
2-yl {azetidin-3-yl) thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapene-2
Dissolve 650 mg (0.821 mmol) of M-3-carboxylate in 33 ml of tetrahydrofuran and 33 ml of distilled water, and add 10%
Catalytic hydrogen reduction at room temperature in the presence of 650 mg of palladium carbon
I went for 4.5 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 76:24), and lyophilized to give the target compound (1R, 5S, 6S) -2
-{1- [4-((3S) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl] 129 mg of -1-methyl-carbapene-2-em-3-carboxylic acid was obtained as a white solid in a yield of 33%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.94 (1H, s), 4.68
-4.60 (1H, m), 4.60 (2H, t, J = 8.2Hz), 4.35-4.28 (1
H, m), 4.25 (1H, dq, J = 6.2, 6.4Hz), 4.19 (1H, dd,
J = 2.4, 9.1Hz), 4.09 (2H, dt, J = 8.9, 4.4Hz), 3.63
(1H, dd, J = 7.0, 12.6Hz), 3.58 (1H, dt, J = 12.0, 7.6
Hz), 3.50-2.98 (3H, m), 3.24 (1H, dq, J = 9.1, 7.2H
z), 2.49-2.39 (1H, m), 2.22-2.13 (1H, m), 1.30 (3
H, d, J = 6.4Hz), 1.19 (3H, d, J = 7.2Hz) .IR (KBr): 1755, 1626, 1543, 1386cm ^-1 Mass spectrum (FAB ⁺ ): m / z: 478 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): found: 478.1768
[M + H] ⁺ , Calculated: 478.1761 (C ₂₁ H ₂₈ N ₅ O ₆ S) Elemental analysis: Calculated as C ₂₁ H ₂₇ N ₅ O ₆ S ・ 3H ₂ O Actual: C, 47.33% H, 5.52 % N, 12.9% S, 5.97% Calculated value: C, 47.45% H, 6.26% N, 13.17% S, 6.06% Example 81 (1R, 5S, 6S) -2- ｛1- [4-((3R ) ―
Pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid

[0523]

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(1) p-Nitrobenzyl (1R, 5S,
6S) -2- ｛1- [4-((3R) -pyrrolidine-3
-Ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- [4-
((3R) -pyrrolidin-3-ylcarbamoyl) -1,
3-Oxazol-2-yl] azetidine 280 mg (0.572 mm
ol) was dissolved in 14 ml of dimethylformamide, 63 mg (0.686 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, p-nitrobenzyl (1R,
5S, 6S) -2- (diphenylphosphoryloxy)-
340 g of 6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylate (0.57
2 mmol) in 17 ml of acetonitrile was added dropwise, followed by 399 μl (2.29 mmol) of diisopropylethylamine.
The mixture was stirred for 4.5 hours while gradually warming to room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with 10% brine and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol =
95: 5) and purified with p-nitrobenzyl (1R, 5).
S, 6S) -2-1- [4-((3R) -pyrrolidine-3
-Ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate Was obtained as a pale yellow solid in 323 mg, 73% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 8.22 (2H, dd, J = 8.8, 12.7Hz), 7.77 (1H,
s), 7.66 (2H, d, J = 8.8Hz), 7.52 (2H, dd, J = 8.8, 1
2.7Hz), 6.82-6.78 (1H, bt, J = 6.8Hz), 5.51 (1H, d,
J = 13.7Hz), 5.23 (1H, d, J = 13.7Hz), 5.25-5.19 (2H,
m), 4.66-4.58 (1H, m), 4.56-4.49 (2H, m), 4.30-4.21
(3H, m), 4.13-4.04 (2H, m), 3.80-3.74 (1H, m), 3.
64-3.53 (2H, m), 3.44-3.39 (1H, m), 3.29 (1H, dd,
J = 2.9, 6.8Hz), 3.20 (1H, dq, J = 7.8,7.8Hz), 2.30-2.20
(1H, m), 2.10-1.94 (1H, m), 1.38 (3H, d, J = 5.9H
z), 1.27 (3H, d, J = 7.8 Hz). (2) (1R, 5S, 6S) -2- ｛1- [4-((3
R) -Pyrrolidin-3-ylcarbamoyl) -1,3-
Oxazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylic acid Compound p-nitrobenzyl (1R, 5S, 6S) -2-1- [4-((3R) -pyrrolidine-3-i] obtained in Example 81 (1). Rucarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 320 mg (0.404 mm
ol) was dissolved in 16 ml of tetrahydrofuran and 16 ml of distilled water, and subjected to catalytic hydrogen reduction at room temperature in the presence of 320 mg of 10% palladium carbon for 4 hours. After confirming the completion of the reaction, the reaction mixture was filtered, and ethyl acetate and distilled water were added to the filtrate to carry out a liquid separation operation. The aqueous layer is concentrated under reduced pressure, purified by chromatography using Cosmoseal (elution solvent: distilled water to distilled water: acetonitrile = 79: 21), and lyophilized to give the target compound (1R, 5S, 6S)-
2- {1- [4-((3R) -pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl} thio-6-[(R) -1-hydroxyethyl ] -1-Methyl-carbapen-2-em-3-carboxylic acid was obtained as a white solid in 88 mg, yield 46%. ¹ H-NMR (400 MHz, D ₂ O): δ (ppm) 7.94 (1H, s), 4.67
-4.60 (1H, m), 4.60 (2H, t, J = 8.3Hz), 4.35-4.28 (1
H, m), 4.25 (1H, dq, J = 6.2, 6.4Hz), 4.20 (1H, dd,
J = 2.4, 9.1Hz), 4.08 (2H, dt, J = 8.8, 4.5Hz), 3.63
(1H, dd, J = 7.0, 12.6Hz), 3.57 (1H, dt, J = 12.0, 7.6
Hz), 3.49-3.37 (3H, m), 3.24 (1H, dq, J = 9.1, 7.2H
z), 2.49-2.38 (1H, m), 2.22−2.13 (1H, m), 1.30 (3H,
d, J = 6.4Hz), 1.19 (3H, d, J = 7.2Hz) IR (KBr): 1758, 1625, 1543, 1385cm ^-1 Mass spectrum (ESI ⁺ ): m / z: 478 [M + H] ⁺ High-resolution mass spectrum (ESI ⁺ ): Found: 478.1739
[M + H] ⁺ , Calculated: 478.1760 (C ₂₁ H ₂₈ N ₅ O ₆ S) Elemental analysis: Calculated as C ₂₁ H ₂₇ N ₅ O ₆ S ・ 3H ₂ O Actual: C, 47.30% H, 5.88 % N, 13.14% S, 6.01% Calculated value: C, 47.45% H, 6.26% H, 13.17% S, 6.03% Reference Example 1 3-acetylthio-1- (4-ethoxycarbonyl-
1,3-thiazol-2-yl) azetidine

[0525]

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(1) (3-Hydroxyazetidine-1-
Carbothioyl) carbamic acid ethyl ester N-benzhydryl-3-hydroxyazetidine 20 g (83.6
was dissolved in 600 ml of methanol and subjected to catalytic hydrogen reduction in a water bath at 1 atm and 50 ° C for 2 hours in the presence of 20 g of 10% palladium carbon. After confirming the completion of the reaction, the reaction mixture was filtered to remove the catalyst, and the obtained filtrate was concentrated under reduced pressure.
Ethyl acetate and distilled water were added to the residue, liquid separation and extraction were performed, and the organic layer was extracted again with distilled water. The obtained aqueous layer was concentrated under reduced pressure to obtain a reddish brown oily product. Subsequently, the above compound was dried under reduced pressure, dissolved in 180 ml of tetrahydrofuran and 60 ml of distilled water, and 19.7 ml (167 mmol) of ethoxycarbonylisothiocyanate was added under ice-cooling.
After 0 minutes, the temperature was returned to room temperature, and the mixture was stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the reaction solution, and the mixture was separated and extracted. The organic layer was dried over anhydrous sodium sulfate, filtered,
The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to ethyl acetate) to give (3) as a yellow oil.
-Hydroxyazetidine-1-carbothioyl) carbamic acid ethyl ester was obtained in 7.4 g with a yield of 43%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.63
(1H, br s), 4.80-4.50 (3H, m), 4.40-4.00 (4H, min in
cluding 2H, q, at 4.18, J = 7.3Hz), 2.28 (1H, br s),
1.29 (3H, t, 7.3 Hz) (2) 1- (4-Ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine (3-Hydroxyazetidine obtained in Reference Example 1 (1)) Azetidine-1-carbotic oil) carbamic acid ethyl ester 1
4.4 g (70.5 mmol) of ethanol 72 ml, distilled water 72 ml
And dissolved in sodium hydroxide 14.1 g (353 mm
ol), and the mixture was heated under reflux for 16 hours. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and then 88 ml of a 4N hydrochloric acid gas-dioxane solution was added under ice cooling. Subsequently, 17.7 ml (141 mmol) of ethyl-2-bromopyruvate and 19.8 ml (141 mmol) of triethylamine were added to the system, and the mixture was refluxed again for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and the aqueous layer was separated and extracted with ethyl acetate.
The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1 to 1: 1) to give 1- (4-ethoxycarbonyl-) as a light brown solid.
8.5 g of 1,3-thiazol-2-yl) -3-hydroxyazetidine was obtained in a yield of 53%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.46
(1H, s), 4.88-4.78 (1H, m), 4.42-4.32 (4H, m), 4.
02 (2H, ddd, J = 10.3, 5.6, 1.5Hz), 2.05 (1H, br s),
1.37 (3H, t, 7.3 Hz) (3) 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- obtained in Reference Example 1 (2) 676 mg (2.96 mmol) of (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine was treated with methylene chloride (20.5).
methanesulfonyl chloride under ice-cooling.
28 ml (3.63 mmol), triethylamine 0.495 ml (3.5
After 6 minutes, the reaction system was returned to room temperature and stirred for 2 hours. After confirming the completion of the reaction, ethanol was added to the system under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered,
The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2) to give a light brown solid, 1- (4-ethoxycarbonyl-1,3-thiazole-2-). Il)-
748 mg of 3-methanesulfonyloxyazetidine was obtained in a yield of 82%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.52
(1H, s), 5.50-5.30 (1H, m), 4.51 (2H, dd, J = 9.9,
6.7Hz), 4.37 (2H, q, J = 7.1Hz), 4.32 (2H, dd, J = 10.
1, 3.7 Hz), 3.09 (3H, s), 1.37 (3H, t, J = 7.1 Hz) (4) 3-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine 742 mg (2.42 mmol) of 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 1 (3) was dissolved in 37 ml of dimethylformamide. At room temperature, 1.11 g (9.72 mmol) of potassium thioacetate was added, and the mixture was added
Stirred for hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 1) to give 3-acetylthio-1- (4-ethoxycarbonyl-1,3-ethoxycarbonyl) as a light brown solid. Thiazol-2-yl) azetidine was obtained in a yield of 494 mg and a yield of 71%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.49
(1H, s), 4.58 (2H, t, J = 8.3Hz), 4.50-4.30 (3H, m,
including 2H, q, at 4.36, J = 7.2Hz), 4.03 (2H, dd,
J = 8.3, 5.7 Hz), 2.36 (3H, s), 1.37 (3H, t, J = 7.2 Hz) Mass spectrum (FAB ⁺ ): 287 [M + H] ⁺ Reference example 2 3-acetylthio-1- ( 4-p-nitrobenzylcarbonyl-1,3-thiazol-2-yl) azetidine

[0531]

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(1) 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine 1- (4-ethoxy) obtained in Reference Example 1 (2) 8.5 g (37.2 mmol) of carbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine was dissolved in 255 ml of dimethylformamide, and 19.4 ml (74.5 mmol) of t-butyldiphenylsilyl chloride was added under ice cooling. , Imidazole 5.
07 g (74.5 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2.5 hours. After confirming the completion of the reaction, 2.59 ml of ethanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and 1
0% brine was added, and the aqueous layer was separated and extracted with ethyl acetate.
The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and then washed.
The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1 to 2:
Purified in 1), a light brown solid of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,
14.85 g of 3-thiazol-2-yl) azetidine was obtained in a yield of 86%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.64
-7.58 (4H, m), 7.50-7.36 (6H, m), 7.43 (1H, s), 4.
79-4.50 (1H, m), 4.35 (2H, q, J = 7.3Hz), 4.13 (2H,
dd, J = 9.0, 6.6Hz), 4.06 (2H.dd, J = 9.0, 5.1Hz), 1.3
6 (3H, t, J = 7.1 Hz), 1.06 (9H, s) (2) 3-t-butyldiphenylsilyloxy-1-
(4-Hydroxymethyl-1,3-thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-ethoxypropyl) obtained in Reference Example 2 (1)
Thiazol-2-yl) azetidine 5.0 g (10.7 mmol)
Was dissolved in 100 ml of anhydrous tetrahydrofuran, and 1.22 g (32.1 mmol) of lithium aluminum hydride prepared in advance was prepared.
Was added dropwise to a suspension of 250 ml of anhydrous tetrahydrofuran under ice-cooling under a nitrogen atmosphere, and after completion of the dropwise addition, the mixture was stirred for 1.5 hours under the same conditions. After confirming the completion of the reaction, magnesium sulfate decahydrate was gradually added to the system under the same conditions, and when the foaming from the system had subsided, the mixture was stirred at room temperature for 1 hour. Thereafter, ethyl acetate was gradually added to the system, and then saturated saline was added.
After separating and extracting the aqueous layer with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1).
To 1: 2) to give 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-
3.88 g of 1,3-thiazol-2-yl) azetidine
Obtained in 86% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.66
-7.58 (4H, m), 7.50-7.38 (6H, m), 6.40 (1H, s), 4.
78-4.70 (1H, m), 4.53 (2H, s), 4.10 (2H, dd, J = 9.
2, 6.6Hz), 4.01 (2H, ddd, J = 9.2, 5.1, 1.3Hz), 2.24
(1H, br s), 1.06 (9H, s) (3) 3-t-butyldiphenylsilyloxy-1-
(4-formyl-1,3-thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-thiazol-2) obtained in Reference Example 2 (2) -Yl) azetidine 3.88 g (9.15 mmol)
Was dissolved in 194 ml of anhydrous methylene chloride, 19.4 g of activated manganese dioxide was added to the solution, and the mixture was stirred at room temperature for 7 hours. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1 to
1: 1) to obtain 3.54 g of 3-t-butyldiphenylsilyloxy-1- (4-formyl-1,3-thiazol-2-yl) azetidine as a white solid in a yield of 92%.・¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.69 (1H, s), 7.
64-7.59- (4H,, m), 7.50-7.36 (7H, m), 4.80-4.72 (1
H, m), 4.16 (2H, dd, J = 9.5, 6.6Hz), 4.08 (2H, ddd,
J = 9.5, 5.1, 1.5Hz), 1.06 (9H, s) (4) 3-t-butyldiphenylsilyloxy-1-
(4-Carboxy-2-yl) azetidine 3-tert-butyldiphenylsilyloxy-1- (4-formyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (3) 3.5 g ( 8.28 mmol) was dissolved in 21 ml of anhydrous methylene chloride, and 105 m of t-butanol was added to the system.
41.4 ml of l, 2M 2-methyl-2-butene tetrahydrofuran solution was added. Then sodium chlorite 1.88
g (16.6 mmol), sodium dihydrogen phosphate 1.99 g (16.6
(mmol) was added dropwise to the system under ice-cooling, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and 1M-
Hydrochloric acid solution (pH: 2 to 3) was added. After separating and extracting the aqueous layer with ethyl acetate, the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to 5% methanol-ethyl acetate) to give a brown syrup-like 3-t.
-Butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine
2.43 g, 67% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.62
-7.56 (4H, m), 7.50 (1H, s), 7.49-7.36 (6H, m), 4.
81-4.72 (1H, m), 4.16-4.08 (2H, m), 4.04 (2H, dd,
J = 9.5, 5.1Hz), 2.00 (1H, br s), 1.07 (9H, s) (5) 3-t-butyldiphenylsilyloxy-1-
(4-p-nitrobenzylcarbonyl-1,3-thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-) obtained in Reference Example 2 (4) 224.8 mg (0.51 mmol) of thiazol-2-yl) azetidine were dissolved in 11.2 ml of anhydrous methylene chloride, and 0.067 ml (0.76 mmol) of oxalyl chloride in 0.02 ml of a catalytic amount of dimethylformamide was added to the system under ice-cooling. . Two hours later,
The reaction solution was concentrated under reduced pressure, and the residue was dried under reduced pressure for 1 hour.
This residue was dissolved again in 11.2 ml of anhydrous methylene chloride, and 157 mg (1.0 mmo) of p-nitrobenzyl alcohol was added under ice cooling.
l) and 0.14 ml (1.0 mmol) of triethylamine.
Stirred for hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3: 1) to give 3-butyldiphenylsilyloxy- as a pale yellow syrup.
93 mg of 1- (4-p-nitrobenzylcarbonyl-1,3-thiazol-2-yl) azetidine, yield 32%
I got it.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22
(2H, d, J = 8.8Hz), 7.64-7.56 (4H, m), 7.50 (1H,
s), 7.48-7.36 (6H, m), 5.42 (2H, s), 4.79-4.72 (1
H, m), 4.16 (2H, dd, J = 8.8, 6.8Hz), 4.07 (2H, dd, J
= 8.8, 4.8 Hz), 1.06 (9H, s) (6) 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine Reference Example 2 (5) 3-butyldiphenylsilyloxy-1- (4-p-nitrobenzylcarbonyl-
1,3-thiazol-2-yl) azetidine 93 mg (0.1
6 mmol) in 4.7 ml of anhydrous tetrahydrofuran.
Acetic acid 0.028 ml (0.49 mmol), 1M tetrabutylammonium fluoride-tetrahydrofuran solution 0.48 ml
(0.48 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 1) to give 1- (4-p-nitrobenzyloxycarbonyl-) as a pale yellow solid.
1,4-Thiazol-2-yl) -3-hydroxyazetidine was obtained in an amount of 42.4 mg in a yield of 81%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.8Hz), 7.59 (2H, d, J = 8.8Hz), 7.53 (1H,
s), 5.40 (2H, s), 4.90-4.78 (1H, m), 4.39- (2H, d
d, J = 9.7, 7.2Hz), 4.03 (2H, dd, J = 9.7, 5.1Hz), 2.2
8 (1H, d, J = 6.2 Hz). (7) 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine Reference Example 2 (6 1)-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) obtained in
648 mg (1.93 mmol) of -3-hydroxyazetidine was dissolved in 20 ml of anhydrous methylene chloride, and 0.31 ml (3.95 mmol) of methanesulfonyl chloride and 0.55 ml (3.95 mmol) of triethylamine were added under ice-cooling, and 10 minutes later. Then, the reaction system was returned to room temperature and stirred for 3 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered,
The filtrate was concentrated under reduced pressure. The obtained residue is n-hexane-
Recrystallization with a mixed solvent of ethyl acetate gave 1- (4) as a white solid.
This gave 789 mg of -p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine in a yield of 99%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.7Hz), 7.59 (1H, s), 7.59 (2H, d, J = 8,7
Hz), 5.50-5.40 (3H, m including 1H, s at 5.44), 4.
52 (2H, dd, J = 10.3, 6.6Hz), 4.32 (2H, dd, J = 10.3,
4.1Hz), 3.10 (3H, s) (8) 3-acetylthio-1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)
Azetidine 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) obtained in Reference Example 2 (7)
-3-methanesulfonyloxyazetidine 776 mg (1.88
was dissolved in 35 ml of dimethylformamide, and 860 mg (7.53 mmol) of potassium thioacetate was added at room temperature to give 9
The mixture was stirred in a 0 ° C. oil bath for 4 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
1: 1) to give 3-acetylthio-
1- (4-p-nitrobenzyloxycarbonyl-1,
73.8 mg of 3-thiazol-2-yl) azetidine were obtained in a yield of 11%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23
(2H, d, J = 8.6Hz), 7.59 (2H, d, J = 8.6Hz), 7.55 (1H,
s), 5.43 (2H, s), 4.59 (2H, t, J = 8.5Hz), 4.50-4.4
0 (1H, m), 4.04 (2H, dd, J = 8.5, 5.7Hz), 2.36 (3H,
s) Reference Example 3 3-acetylthio-1- (4-carbamoyl-1,3-
Thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-thiazole-
2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-ethoxycarbonyl) obtained in Reference Example 2 (1)
Thiazol-2-yl) azetidine 5.85 g (12.5 mmo
l) was dissolved in 290 ml of benzene, 56.4 ml of a 0.67 M ammonium chloride-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was stirred in a 40 ° C water bath for 17 hours. After confirming the completion of the reaction, 100 ml of 10% aqueous acetic acid and 50 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 2 hours. Subsequently, ethyl acetate was added to the reaction system, a liquid separation operation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1 to 1:
Purified in 2), 4.97 g of 3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-thiazol-2-yl) azetidine as a light brown solid was obtained in a yield of 91%.
I got it.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.66
-7.58 (4H, m), 7.50-7.38 (7H, m), 6.99 (1H, bs),
5.48 (1H, br s), 4.80-4.72 (1H, m), 4.10 (2H, dd,
J = 8.8, 6.6Hz), 4.01 (2H, dd, J = 8.8, 5.1Hz), 1.07
(9H, s) (2) 1- (4-carbamoyl-1,3-thiazole-
2-yl) -3-hydroxyazetidine 6.7 g of 3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 3 (1) ( (15.3 mmol) was dissolved in 200 ml of anhydrous tetrahydrofuran.
18.4 ml of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to 10% methanol-ethyl acetate).
-(4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine as a white solid, 2.
78 g, 91% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.43
(1H, s), 7.05 (1H, br s), 5.47 (1H, br s), 4.90-4.
80 (1H, m), 4.35 (2H, dd, J = 9.5, 6.6Hz), 3.97 (2H,
dd, J = 9.5, 4.4Hz), 2.31 (1H, d, J = 9.6Hz) (3) 1- (4-carbamoyl-1,3-thiazole-
2-yl) -3-methanesulfonyloxyazetidine 1- (4-carbamoyl- obtained in Reference Example 3 (2)
1.0 g (5.02 mmol) of 1,3-thiazol-2-yl) -3-hydroxyazetidine was dissolved in 30 ml of methylene chloride and 5 ml of pyridine, and 0.967 ml (12.5 mmol) of methanesulfonyl chloride was added under ice cooling. Triethylamine 1.75 m
l (12.5 mmol) was added and 10 minutes later, the reaction system was returned to room temperature and stirred for 2.5 hours. After confirming the completion of the reaction, 0.405 ml of methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Isopropyl ether was added to the obtained residue, and the mixture was filtered and light yellow solid 1- (4-carbamoyl-1,3-thiazole-2-
Yl) -3-methanesulfonyloxyazetidine
0 g, 94% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.50
(1H, s), 6.99 (1H, br s), 5.60-5.40 (2H, m), 4.46
(2H, ddd, J = 9.5, 6.6, 1.5Hz), 4.28 (2H, ddd, J = 9.
5, 4.4, 1.5 Hz), 3.11 (1H, s) (4) 3-acetylthio-1- (4-carbamoyl-
1,3-thiazol-2-yl) azetidine 1- (4-carbamoyl- obtained in Reference Example 3 (3)
3.04 g (11.0 mmol) of 1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine was dissolved in 152 ml of dimethylformamide, and 7.5 g (65.8 mmol) of potassium thioacetate was added at room temperature. ℃ oil bath 10
Stirred for hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to 4% methanol-
The residue was purified with ethyl acetate) to give 3-acetylthio-1- (4-carbamoyl-1,3-thiazole-2) as a light brown solid.
1.97 g of -yl) azetidine was obtained in a yield of 70%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.46
(1H, s), 7.00 (1H, br s), 5.55 (1H, br s), 4.53 (2
H, t, J = 8.1Hz), 4.50-4.40 (1H, m), 3.99 (2H, dd, J
= 8.1, 5.1Hz), 2.37 (3H, S) Reference Example 4 3-acetylthio-1- (4-cyano-1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-cyano-1,3-thiazol-2-yl) azetidine 3-t-butyldiphenylsilyl obtained in Reference Example 2 (1) Oxy-1- (4-ethoxycarbonyl-1,3-
7.73 g of thiazol-2-yl) azetidine (16.6 mmo
l) was dissolved in 370 ml of benzene, and 75 ml of a 0.67 M ammonium chloride-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, followed by stirring in a 50 ° C water bath for 17 hours. After confirming the completion of the reaction, add 10% aqueous acetic acid
Then, ethyl acetate was added to the reaction system, and the mixture was stirred at room temperature for 30 minutes. A liquid separation operation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1) to give 3-t-butyldiphenylsilyloxy-1 as a pale yellow solid.
6.98 g of-(4-cyano-1,3-thiazol-2-yl) azetidine was obtained in a yield of 76%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.64 (4H,
m), 7.50-7.37 (6H, m), 7.20 (1H, s), 4.80-4.74 (1
H, m), 4.13 (2H, dd, J = 8.8, 6.8Hz), 4.04 (2H, dd,
J = 8.8, 4.9Hz), 1.07 (9H, s) IR (KBr): 2230, 1535, 1465, 1310, 1114 cm ^-1 Mass spectrum (FAB ⁺ ): 420 [M + H] ⁺ (2) 1- (4-cyano-1,3-thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-cyano-1,3) obtained in Reference Example 4 (1) -Thiazole-
Dissolve 2.36 g (5.62 mmol) of 2-yl) azetidine in 115 ml of anhydrous tetrahydrofuran, and add 1.0 M
6.7 ml (6.7 mmol) of a tetra-n-butylammonium fluoride-tetrahydrofuran solution was added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, the reaction solution is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (elution solvent:
Purification with toluene: ethyl acetate = 1: 2) yielded 1- (4
-Cyano-1,3-thiazol-2-yl) -3-hydroxyazetidine as a white solid, 0.78 g, yield 77%
I got it.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.26
(1H, s), 4.92-4.86 (1H, m), 4.37 (2H, dd, J = 9.8,
6.8Hz), 4.02 (2H, dd, J = 9.8, 4.9Hz), 2.34 (1H, d,
J = 5.9 Hz) (3) 1- (4-cyano-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- (4-cyano- obtained in Reference Example 4 (2) 1, 3-
Thiazol-2-yl) -3-hydroxyazetidine
0.78 g (4.3 mmol) was dissolved in methylene chloride (40 ml), and methanesulfonyl chloride 1.0 ml (12.9 mmo
l), triethylamine 1.8 ml (12.9 mmol)
After 0 minute, the reaction system was returned to room temperature and stirred for 40 minutes. After confirming the completion of the reaction, methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate = 1: 1) to give a white solid, 1- (4-nitryl-1,3-thiazol-2-yl) -3. -1.12 g of methanesulfonyloxyazetidine was obtained in a yield of 100%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.31
(1H, s), 5.50-5.40 (1H, m), 4.50 (2H, dd, J = 9.9,
(6.6Hz), 4.31 (2H, dd, J = 9.9, 4.4Hz), 3.11 (3H, s) (4) 3-acetylthio-1- (4-cyano-1,3-thiazol-2-yl) azetidine Reference Example 1- (4-cyano-1,3- obtained in 3 (3)
1.12 g (4.32 mmol) of thiazol-2-yl) -3-methanesulfonyloxyazetidine were dissolved in 56 ml of dimethylformamide, and potassium thioacetate was added at room temperature at 3.89 g.
g (27.0 mmol) was added, and the mixture was stirred in an 80 ° C. oil bath for 4 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-
Hexane: ethyl acetate = 2: 1) to give 0.767 g of 3-acetylthio-1- (4-cyano-1,3-thiazol-2-yl) azetidine as a brown solid in a yield of 75%. Was.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.28
(1H, s), 4.57 (2H, t, J = 8.3Hz), 4.50-4.40 (1H, m),
4.03 (2H, dd, J = 8.3, 5.5 Hz), 2.39 (3H, s) Reference Example 5 3-acetylthio-1- (4-N-methylcarbamoyl-
1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-N-methylcarbamoyl-1,2-thiazol-2-yl) azetidine 3-t-butyl obtained in Reference Example 2 (1) Butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-
Thiazol-2-yl) azetidine (5) 500 mg (1.07
mmol) in 25 ml of benzene, and 0.61 M methylamine hydrochloride-trimethylaluminum-benzene solution 3.21 ml
Was added at room temperature under a nitrogen atmosphere, and the mixture was heated under reflux for 1.5 hours. After confirming the completion of the reaction, 10% aqueous acetic acid 25
ml and 50 ml of ethyl acetate were added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate was added to the reaction system, a liquid separation operation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1), and 3-t-butyldiphenylsilyloxy-1- (4-N- Methylcarbamoyl-1,3-thiazol-2-yl) azetidine (479 mg, yield 99%)
I got it.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.65
-7.59 (4H, m), 7.50-7.34 (7H, m), 7.14 (1H, br s),
4.80-4.70 (1H, m), 4.09 (2H, t, J = 8.8Hz), 4.00 (2
H, dd, J = 8.8, 5.1Hz), 2.95 (3H, d, J = 5.1Hz), 1.06
(9H, s) (2) 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenyl obtained in Reference Example 5 (1) Silyloxy-1- (4-N-methylcarbamoyl-1,3
-Thiazol-2-yl) azetidine 4.74 g (10.5 mmo
l) was dissolved in 240 ml of anhydrous tetrahydrofuran, and cooled to 1.0 M tetra-n-butylammonium fluoride- under ice-cooling.
12.6 ml (12.6 mmol) of a tetrahydrofuran solution was added, and the mixture was stirred as it was for 30 minutes. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10:
Purified in 1), 1- (4-N-methylcarbamoyl-
1,3-thiazol-2-yl) -3-hydroxyazetidine was obtained as a white solid in 2.10 g, 96% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.34
(2H, s), 7.20 (1H, br s), 4.85-4.75 (1H, m), 4.31
(2H, dd, J = 9.7, 6.4Hz), 3.94 (2H, dd, J = 9.7, 5.5H
z), 3.10 (1H, brs), 2.96 (3H, d, J = 5.1 Hz) Mass spectrum: 213 [M ⁺ ] (3) 1- (4-N-methylcarbamoyl-1,3-thiazole-2 -Yl) -3-methanesulfonyloxyazetidine 2.15 g of 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 5 (2) ( 10.1 mmol) in methylene chloride 45 m
methanesulfonyl chloride under ice-cooling 3.12
ml (40.3 mmol), triethylamine 7.04 ml (50.5 mm
ol), and after 10 minutes, the reaction system is returned to room temperature, and
Stir for 1.5 hours. After confirming the completion of the reaction, methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate: methanol = 10: 1) to give a pale yellow foamy solid, 1-.
(4-N-methylcarbamoyl-1,3-thiazole-2
-Yl) -3-methanesulfonyloxyazetidine (11
2.95 g of c) was obtained in a yield of 100%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.44
(1H, s), 7.18 (1H, br s), 5.50-5.39 (1H, m), 4.45
82H, dd, J = 9.7, 6.6Hz), 4.26 (2H, dd, J = 9.7, 4.3H
z), 3.11 (3H, s), 2.97 (3H, d, J = 5.1 Hz) Mass spectrum (FAB ⁺ ): 292 [M + H] ⁺ (4) 3-acetylthio-1- (4-N-methyl Carbamoyl-1,3-thiazol-2-yl) azetidine 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 5 (3) Gin (3.0 g, 10.3 mmol) was dissolved in dimethylformamide (150 ml), and potassium thioacetate (7.07 g, 61.9 mmol) was added at room temperature.
Stirred for hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 4 to 1: 1).
0), and purified as a light brown solid 3-acetylthio-1-
(4-N-methylcarbamoyl-1,3-thiazole-2
-Yl) azetidine in 2.41 g, 86% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.44
(1H, s), 7.18 (1H, br s), 4.53 (2H, t, J = 8.0Hz),
4.50-4.40 (1H, m), 4.50-3.95 (2H, m), 2.95 (3H, d,
J = 6.0 Hz), 2.38 (3H, s) Mass spectrum (FAB ⁺ ): 272 [M + H] ⁺ Reference Example 6 3-acetylthio-1- (4-N, N-dimethylcarbamoyl-1,3-thiazole -2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-N, N-dimethylcarbamoyl-1,3-
Thiazol-2-yl) azetidine The 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-ethoxypropyl) obtained in Reference Example 2 (1).
Thiazol-2-yl) azetidine 500 mg (1.07 mmo
l) in 25 ml of benzene, and a solution of 0.67 M dimethylamine hydrochloride-trimethylaluminum-benzene in 3.21 ml
Was added at room temperature under a nitrogen atmosphere, and the mixture was heated under reflux for 2 hours. After confirming the completion of the reaction, 50 ml of 10% aqueous acetic acid and 50 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1 to 1:
Purified in 3), light brown solid 3-t-butyldiphenylsilyloxy-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine was obtained for 500 m.
g, 100% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.70
-7.60 (4H, m), 7.52-7.40 (6H, m), 7.00 (1H, s), 4.
79-4.70 (1H, m), 4.11 (2H, dd, J = 9.5, 7.5Hz), 4.02
(2H, dd, J = 9.5, 5.0Hz), 3.19 (3H, s), 3.05 (3H,
s), 1.06 (9H, s) (2) 1- (4-N, N-dimethylcarbamoyl-1,3-
Thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-N, N-dimethylcarbamoyl- obtained in Reference Example 6 (1)
1,3-thiazol-2-yl) azetidine 5.13 g (1
(0.7 mmol) was dissolved in 250 ml of anhydrous tetrahydrofuran, and under ice-cooling, 12.0 ml (12.0 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was dissolved.
Was added and stirred for 30 minutes as it was. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 1- (4-N, N-dimethylcarbamoyl-1,3).
-Thiazol-2-yl) -3-hydroxyazetidine was obtained as a colorless transparent syrup in 2.42 g, 100% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.03
(1H, s), 4.90-4.70 (1H, m), 4.32 (2H, t, J = 8.2H
z), 3.95 (2H, dd, J = 8.2, 4.5Hz), 3.20 (3H, br s),
3.05 (3H, br s), 2.85 (1H, br s) Mass spectrum: 227 [M ⁺ ] (3) 1- (4-N, N-dimethylcarbamoyl-1,3-
Thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxy obtained in Reference Example 6 (2) Azetidine 2.56 g (10.7 mmol) in methylene chloride
Dissolve in 50 ml and cool under ice-cooling to methanesulfonyl chloride
2.4 ml (31.0 mmol), triethylamine 7.4 ml (53.1 m
mol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2.5 hours. After confirming the completion of the reaction, methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered,
The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1) to give a light brown oily 1- (4-N, N-dimethylcarbamoyl-1, 3- Thiazol-2-yl) -3-methanesulfonyloxyazetidine was obtained in an amount of 3.28 g and a yield of 100%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.13
(1H, s), 5.50-5.38 (1H, m), 4.46 (2H, dd, J = 9.7,
6.6Hz), 4.26 (2H, dd, J = 9.7, 4.3Hz), 3.21 (3H, br
s), 3.10 (3H, s), 3.07 (3H, brs) Mass spectrum (FAB ⁺ ): 306 [M + H] ⁺ (4) 3-Acetylthio-1- (4-N, N-methylcarbamoyl- 1,3-thiazol-2-yl) azetidine 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in Reference Example 6 (3) 3.40 g (11.1 mmol) of gin was dissolved in 170 ml of dimethylformamide, and 7.62 g (66.7 mmol) of potassium thioacetate was added at room temperature, followed by stirring in an oil bath at 80 ° C. for 3 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 4: 1 to 5: 1 to
7: 1) to give 2.71 g of 3-acetylthio-1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine as a brown syrup in 85% yield.
I got it.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.09
(1H, s), 4.53 (2H, dd, J = 9.0, 7.9Hz), 4.50-4.40
(1H, m), 3.99 (2H, dd, J = 9.0, 5.5Hz), 3.20 (3H, br
s), 3.06 (3H, brs), 2.36 (3H, s) Reference Example 7 3-acetylthio-1- (4-N-ethylcarbamoyl-
1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidine 3-t-butyl obtained in Reference Example 2 (1) Butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-
Thiazol-2-yl) azetidine 1.0 g (2.14 mmol)
Was dissolved in 50 ml of benzene, and 0.67 M ethylamine hydrochloride was added.
6.42 ml of -trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 2 hours. After confirming the completion of the reaction, 50 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 5: 1 to 1:
Purified in 1), and a light brown solid of 3-t-butyldiphenylsilyloxy-1- (4-N-ethylcarbamoyl-
997 mg of 1,3-thiazol-2-yl) azetidine
Obtained in 100% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.66
-7.58 (4H, m), 7.50-7.37 (6H, m), 7.35 (1H, s), 7.
14 (1H, br s), 4.80-4.76 (1H, m), 4.16-4.06 (2H,
m), 4.01 (2H, dd, J = 8.8, 5.1Hz), 3.43 (2H, dq, J =
7.3, 5.6 Hz), 1.22 (3H, t, J = 7.3 Hz), 1.07 (9H, s) (2) 1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) -3- Hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-N-ethylcarbamoyl-1,3 obtained in Reference Example 7 (1)
-Thiazol-2-yl) azetidine 990 mg (2.14 mmo
l) was dissolved in 30 ml of anhydrous tetrahydrofuran, and under ice cooling, 2.56 ml (2.56 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added.
The mixture was stirred for 1.3. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate-
5% methanol-ethyl acetate) to give 1- (4-
N-ethylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine as a white solid, 46
1 mg, yield 95%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.36
(1H, s), 7.20 (1H, br s), 4.90-4.78 (1H, m), 4.32
(2H, dd, J = 9.0, 7.3Hz), 3.96 (2H, dd, J = 9.0, 4.3H
z), 3.44 (2H, dq, J = 7.2, 5.4Hz), 2.61 (1H, d, J = 6.6
Hz), 1.22 (3H, t, J = 7.2 Hz) (3) 1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine Reference Example 7 (2 460 mg (2.02 mmol) of 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in the above) was treated with methylene chloride (23 m).
methanesulfonyl chloride 0.46 under ice-cooling
9 ml (6.06 mmol), triethylamine 0.849 ml (6.06
After 10 minutes, the reaction system was returned to room temperature and stirred for 1.3 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 3-ethyl acetate), and 1- (4-N-ethylcarbamoyl-1,3-thiazole-2) as a pale yellow solid. -Yl) -3-methanesulfonyloxyazetidine was obtained in an amount of 598 mg in a yield of 97%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.44
(1H, s), 7.13 (1H, br s), 5.48-5.38 (1H, m), 4.46
(2H, ddd, J = 9.5, 6.6, 1.5Hz), 4.27 (2H, ddd, J = 9.
5, 4.4, 1.5Hz), 3.45 (2H, dq, J = 7.3, 5.0Hz), 3.10
(3H, s), 1.24 (3H, t, J = 7.3 Hz) (4) 3-acetylthio-1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidine Reference Example 7 (3 590 mg (1.93 mmol) of 1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in the above was dissolved in 30 ml of dimethylformamide, and the solution was dissolved at room temperature. Then, 1.32 g (11.6 mmol) of potassium thioacetate was added thereto, and the mixture was stirred overnight in an oil bath at 80 ° C. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to
1: 2) to give a light brown solid, 3-acetylthio-
453 mg of 1- (4-N-ethylcarbamoyl-1,3-thiazol-2-yl) azetidine was obtained at a yield of 82%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.40
(1H, s), 7.14 (1H, br s), 4.53 (2H, t, J = 8.8Hz),
4.48-4.38 (1H, m), 3.98 (2H, dd, J = 8.8, 5.6Hz), 3.
44 (2H, dq, J = 7.3, 5.9Hz), 2.37 (3H, s), 1.23 (3H,
(t, J = 7.3 Hz) Reference Example 8 3-acetylthio-1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-N-isopropylcarbamoyl-1,3
-Thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-ethoxypropyl) obtained in Reference Example 2 (1)
Thiazol-2-yl) azetidine 1.0 g (2.14 mmol)
Was dissolved in 50 ml of benzene, and 6.42 ml of 0.67 M isopropylamine hydrochloride-trimethylaluminum-benzene solution was dissolved.
Was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 2.5 hours. After confirming the completion of the reaction, 50 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate were added to the system under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 3-t-butyldiphenylsilyloxy-1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine as a light brown solid in 1.01.
g, 99% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.66
-7.58 (4H, m), 7.50-7.36 (6H, m), 7.34 (1H, s), 6.
98 (1H, br d, J = 8.1Hz), 4.80-4.70 (1H, m), 4.26-4.
16 (1H, m), 4.11 (2H, dd, J = 8.8, 7.3Hz), 4.02 (2H,
dd, J = 8.8, 4.4Hz), 1.24 (6H, d, J = 6.6Hz), 1.07 (9
H, s) (2) 1- (4-N-isopropylcarbamoyl-1,3
-Thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-N-isopropylcarbamoyl- obtained in Reference Example 8 (1)
1,3-thiazol-2-yl) azetidine 1.01 g
(2.11 mmol) was dissolved in 30 ml of anhydrous tetrahydrofuran, and under ice-cooling, 2.53 ml of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution (2.53 mmol)
Was added and stirred for 30 minutes as it was. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. And the residue was subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 3-
The residue was purified by ethyl acetate) to give 1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine as a white solid, 681 mg, yield.
Obtained at 100%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.36
(1H, s), 7.00 (1H, br d, J = 8.0Hz), 4.90-4.78 (1H,
m), 4.32 (2H, dd, J = 9.9, 8.7Hz), 3.97 (2H, ddd, J
= 9.9, 7.3, 1.7Hz), 2.55 (1H, d, J = 8.0Hz), 1.25 (6
(H, d, J = 6.6 Hz) (3) 1- (4-N-isopropylcarbamoyl-1,3
-Thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 8 (2) Gin 490 mg (2.03 mmol) was dissolved in methylene chloride (15 ml), and methanesulfonyl chloride 0.471 ml (6.09 mmol), triethylamine 0.854 ml was added under ice cooling.
(6.09 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature,
The mixture was stirred for 1.5 hours as it was. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 3).
To ethyl acetate) to give 1- (4-N-
Isopropylcarbamoyl-1,3-thiazole-2-
Yl) -3-methanesulfonyloxyazetidine
mg, 100% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.44
(1H, s), 7.00 (1H, br d, J = 8.0Hz), 5.48-5.38 (1H,
m), 4.46 (2H, dd, J = 9.5, 6.6Hz), 4.32-4.18 (3H, m
including 2H, dd, at 4.28, J = 9.5, 5.1Hz), 3.11 (3
H, s), 1.25 (6H, d, J = 6.6 Hz) (4) 3-acetylthio-1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) azetidine Reference Example 8 (3) 680 mg (2.03 mmol) of 1- (4-N-isopropylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in
Was dissolved in 35 ml of dimethylformamide, and 1.39 g (12.2 mmol) of potassium thioacetate was added at room temperature.
Stirred overnight in oil bath. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 3-acetylthio-1- (4-N-isopropylcarbamoyl-1,3
-Thiazol-2-yl) azetidine 461 mg, in yield
81%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.40
(1H, s), 6.98 (1H, br s), 4.54 (2H, t, J = 8.8Hz),
4.50-4.40 (1H, m), 4.26-4.16 (1H, m), 3.99 (2H, d
d, J = 8.8, 5.9Hz), 2.37 (3H, s), 1.24 (6H, d, J = 5.9
Hz) Reference Example 9 3-acetylthio-1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine

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(1) 3-tert-butyldiphenylsilyloxy-1- (4-N-cyclopentylcarbamoyl-1,
3-Thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-ethoxypropyl) obtained in Reference Example 2 (1)
Thiazol-2-yl) azetidine 1.0 g (2.14 mmol)
Was dissolved in 50 ml of benzene, 6.42 ml of a 0.67 M cyclopentylamine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 5 hours. After confirming the completion of the reaction, 50 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 30 minutes.
Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 3-t-butyldiphenylsilyloxy-1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine as a light brown solid 1.07
g, was obtained in a yield of 99%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.66
-7.60 (4H, m), 7.50-7.38 (6H, m), 7.34 (1H, s), 7.
08 (1H, br d, J = 8.1Hz), 4.80-4.70 (1H, m), 4.38-4.
26 (1H, m), 4.11 (2H, dd, J = 8.8, 5.6Hz), 4.02 (2H,
dd, J = 8.8, 4.4Hz), 2.12-2.20 (2H, m), 1.80-1.40
(6H, m), 1.07 (9H, s) (2) 1- (4-N-cyclopentylcarbamoyl-1,
3-thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-N-cyclopentylcarbamoyl-1,3-thiazole-2 obtained in Reference Example 9 (1) -Yl) azetidine 1.07 g
(2.12 mmol) was dissolved in 32 ml of anhydrous tetrahydrofuran and, under ice-cooling, 2.54 ml (2.54 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution
Was added and the mixture was stirred as it was for 40 minutes. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction solution, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to ethyl acetate) to give 1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl). ) -3-Hydroxyazetidine as a white solid, 528 mg, yield 9
Obtained at 3%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.36
(1H, s), 7.11 (1H, d, J = 4.4Hz), 4.88-4.78 (1H,
m), 4.40-4.25 (3H, m), 3.96 (2H, dd, J = 9.5, 4.4H
z), 2.54 (1H, d, J = 6.0Hz), 2.12-2.00 (2H, m), 1.80
-1.44 (6H, m) (3) 1- (4-N-cyclopentylcarbamoyl-1,
3-thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) -3- obtained in Reference Example 9 (2)
520 mg (1.95 mmol) of hydroxyazetidine was dissolved in 16 ml of methylene chloride, and 0.452 ml (5.84 mmol) of methanesulfonyl chloride and 0.818 ml of triethylamine were added under ice-cooling.
(5.84 mmol) and 10 minutes later, the reaction system was returned to room temperature.
The mixture was stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to give 1- (4-N-cyclopentylcarbamoyl-1,3) as a pale yellow solid. -Thiazol-2-yl) -3-methanesulfonyloxyazetidine
m, 100% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.43
(1H, s), 7.07 (1H, br d, J = 8.1Hz), 5.48-5.38 (1H,
m), 4.46 (2H, ddd, J = 9.9, 6.6, 1.5Hz), 4.40-4.20
(3H, m including 2H, ddd, J = 9.9, 4.9, 1.5Hz), 3.11
(3H, s), 2.15-1.98 (2H, m), 1.80-1.40 (6H, m) (4) 3-acetylthio-1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) Azetidine 1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) -3- obtained in Reference Example 9 (3)
Methanesulfonyloxyazetidine 670 mg (1.95 mmol)
Was dissolved in 34 ml of dimethylformamide, and 1.34 g (11.7 mmol) of potassium thioacetate was added at room temperature.
Stirred overnight in oil bath. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
2: 1 to 1: 2) to give 3-acetylthio-1- (4-N-cyclopentylcarbamoyl-) as a light brown solid.
550 mg of 1,3-thiazol-2-yl) azetidine were obtained with a yield of 87%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.40
(1H, s), 7.10 (1H, d, J = 8.0Hz), 4.53 (2H, dd, J = 9.
2, 6.9Hz), 4.48-4.38 (1H, m), 4.38-4.26 (1H, m),
3.99 (2H, dd, J = 9.2, 4.6Hz), 2.36 (3H, s), 2.12-2.0
6 (2H, m), 1.80-1.40 (6H, m) Reference Example 10 3-acetylthio-1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-N-cyclohexylcarbamoyl-1,
3-Thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-ethoxypropyl) obtained in Reference Example 2 (1)
Thiazol-2-yl) azetidine 1.0 g (2.14 mmol)
Was dissolved in 50 ml of benzene, 6.42 ml of a 0.67 M cyclohexylamine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 2 hours. After confirming the completion of the reaction, 50 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 30 minutes.
Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 5: 1 to 1:
Purified in 1) to give 3-t-butyldiphenylsilyloxy-1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidine as a light brown solid.
1.09 g was obtained in a yield of 99%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.66
-7.58 (4H, m), 7.50-7.38 (6H, m), 7.34 (1H, s), 7.
04 (1H, br d, J = 8.8Hz), 4.80-4.70 (1H, m), 4.11 (2
H, dd, J = 8.8, 6.6Hz), 4.02 (2H, dd, J = 8.8, 5.1Hz),
3.98-3.80 (1H, m), 2.02-1.94 (2H, m), 1.80-1.70
(2H, m), 1.70-1.10 (6H, m), 1.07 (9H, s) (2) 1- (4-N-cyclohexylcarbamoyl-1,
3-thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-N-cyclohexylcarbamoyl-1,3-thiazole obtained in Reference Example 10 (1) -2-yl) azetidine 1.09
g (2.10 mmol) was dissolved in 55 ml of anhydrous tetrahydrofuran.
Was added and stirred for 1.5 hours as it was. After confirming the completion of the reaction,
Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction solution, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate,
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to ethyl acetate) to give 1
-(4-N-Cyclohexylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine was obtained as a white solid in 570 mg, 97% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.36
(1H, s), 7.07 (1H, d, J = 8.1Hz), 4.99-4.78 (1H, m),
4.33 (2H, dd, J = 9.0, 7.3Hz), 4.00-3.80 (3H, m inc
luding 2H, dd, J = 9.0, 4.4Hz), 2.56 (1H, d, J = 8.3H
z), 2.02-1.92 (2H, m), 1.80-1.70 (2H, m), 1.70-1.1
0 (6H m) (3) 1- (4-N-cyclohexylcarbamoyl-1,
3-thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) -3 obtained in Reference Example 10 (2)
-570 mg (2.03 mmol) of hydroxyazetidine was dissolved in 17 ml of methylene chloride, and 0.471 ml (6.08 mmol) of methanesulfonyl chloride and 0.85 ml of triethylamine were added under ice cooling.
2 ml (6.08 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 17 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Isopropyl ether was added to the obtained residue, and the mixture was filtered, and light yellow solid 1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl)-was obtained.
739 mg of 3-methanesulfonyloxyazetidine was obtained in a yield of 100%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.43
(1H, s), 7.02 (1H, br d, J = 8.1Hz), 5.48-5.39 (1H,
m), 4.46 (2H, ddd, J = 9.5, 6.6, 1.5Hz), 4.27 (2H,
dd, J = 9.5, 5.1Hz), 3.98-3.84 (1H, m), 3.11 (3H, s),
2.01-1.94 (2H, m), 1.80-1.70 (2H, m), 1.70-1.10
(6H, m) (4) 3-acetylthio-1- (4-N-cyclohexylcarbamoyl-1,3-thiazol-2-yl) azetidine 1- (4-N-) obtained in Reference Example 10 (3) Cyclohexylcarbamoyl-1,3-thiazol-2-yl) -3
-Methanesulfonyloxyazetidine 730 mg (2.03 mmo
l) was dissolved in 37 ml of dimethylformamide, and 1.39 g (12.2 mmol) of potassium thioacetate was added at room temperature.
The mixture was stirred in an oil bath for 15 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1 to 1: 2) to give 3-acetylthio-1- (4-N-cyclohexane) as a light brown solid. Hexylcarbamoyl-1,3-thiazol-2-yl) azetidine was treated with 372 m
g, 54% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.40
(1H, s), 7.06 (1H, br d, J = 8.0Hz), 4.53 (1H, dd,
J = 9.5, 8.2Hz), 4.48-4.40 (1H, m), 3.99 (2H, dd, J =
(9.5,3.7Hz), 3.95-3.85 (1H, m), 2.37 (3H, s), 2.01-
1.96 (2H, m), 1.80-1.10 (8H, m) Reference Example 11 3-acetylthio-1- (4-morpholinocarbonyl-
1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-N-morpholinocarbonyl-1,3-thiazol-2-yl) azetidine 3-t- obtained in Reference Example 2 (1) Butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-
Thiazol-2-yl) azetidine 1.0 g (2.14 mmol)
Was dissolved in 50 ml of benzene, 6.42 ml of a 0.67 M morpholine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 2 hours. After confirming the completion of the reaction, 50 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate were added under ice cooling.
l was added and stirred at room temperature for 30 minutes. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-
Hexane: ethyl acetate—3: 1 to 1: 3)
3-t-butyldiphenylsilyloxy- as a light brown solid
1.05 g of 1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidine was obtained at a yield of 97%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.64
-7.58 (4H, m), 7.50-7.36 (6H, m), 7.12 (1H, s), 4.
80-4.70 (1H, m), 4.10 (2H, dd, J = 9.6, 8.0Hz), 4.00
(2H, dd, J = 9.6, 4.8Hz), 3.96-3.60 (8H, m), 1.06
(9H, s) (2) 1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy obtained in Reference Example 11 (1) -1- (4-morpholinocarbonyl-1,
3-thiazol-2-yl) azetidine 1.05 g (2.07 m
mol) was dissolved in 32 ml of anhydrous tetrahydrofuran, and 2.48 ml (2.48 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, followed by stirring for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to 10% methanol-ethyl acetate) to give 1- (4-morpholinocarbonyl-
1,3-Thiazol-2-yl) -3-hydroxyazetidine was obtained as a white solid in 542 mg in a yield of 97%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.15
(1H, s), 4.90 (1H, m), 4.32 (2H, dd, J = 8.8, 7.3H
z), 3.95 (2H, dd, J = 8.8, 4.4Hz), 4.00-3.60 (8H,
m), 2.45 (1H, brs) (3) 1- (4-N-morpholinocarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine Obtained in Reference Example 11 (2). 540 mg (2.01 mmol) of 1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine was treated with methylene chloride 27
methanesulfonyl chloride under ice cooling.
467 ml (6.03 mmol), triethylamine 0.845 ml (6.03
After 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: 5% methanol-ethyl acetate) to give a light yellow solid, 1- (4-morpholinocarbonyl-).
1,688- (1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine was obtained in a yield of 99%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.23 (1H, s), 5.
45-5.40 (1H, m), 4.45 (2H, dd, J = 9.5, 6.6Hz), 4.26
(2H, ddd, J = 9.5, 4.4, 1.5Hz), 4.00-3.60 (8H, m),
3.10 (3H, s) (4) 3-acetylthio-1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidine 1- (4-morpholinocarbonyl- obtained in Reference Example 11 (3) 680 mg (1.96 mmol) of 1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine was dissolved in 20 ml of dimethylformamide, and 671 mg (5.87 mmol) of potassium thioacetate was added at room temperature. The mixture was stirred in an oil bath for 18 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
1: 3-ethyl acetate) to give 3-acetylthio-1- (4-morpholinocarbonyl-1,3) as a light brown solid.
-Thiazol-2-yl) azetidine in 411 mg, yield
64% gained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.20 (1H, s), 4.
52 (2H, t, J = 8.8Hz), 4.48-4.38 (1H, m), 3.98 (2H, d
d, J = 8.8, 5.1 Hz), 4.00-3.60 (8H, m), 2.36 (3H, s) Reference Example 12 3-acetylthio-1- (4-4-t-butyldimethylsilyloxymethyl-1,3 -Thiazol-2-yl)
Azetidine

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(1) 1- (4-hydroxymethyl-1,
3-Thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-thiazol-2-yl) obtained in Reference Example 2 (2) ) Azetidine 548.9 mg (1.29 mmo
l) was dissolved in 28 ml of anhydrous tetrahydrofuran, and 1.56 ml (1.56 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling.
The mixture was stirred for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to obtain 1- (4-hydroxymethyl-1,3-thiazole). -2-yl) -3-hydroxyazetidine was obtained as a white solid in 230 mg, 96% yield.

¹ H-NMR (400 MHz, CD ₃ OD): δ (ppm) 6.54
(1H, s), 4.76-4.68 (1H, m), 4.46 (2H, s), 4.32-4.
24 (2H, m), 3.88-3.82 (2H, m) (2) 1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) -3-hydroxyazetidine Reference Example 12 226.5 mg (1.22 mmol) of 1- (4-hydroxymethyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in (1) was dissolved in 11.5 ml of dimethylformamide and cooled under ice-cooling. T-butyldimethylsilyl chloride 220 mg (1.46 mmol), imidazole
120 mg (1.76 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 5 hours. After confirming the completion of the reaction, add 2 ml of methanol to the system under ice-cooling, and add
Stirred for 0 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
n-hexane: ethyl acetate = 1: 1) to give 1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) -3-hydroxyazetidine as a white solid. 300.4 mg, yield 82%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.43
(1H, s), 4.86-4.78 (1H, m), 4.66 (2H, s), 4.30 (2
H, dd, J = 9.5, 7.0Hz), 3.93 (2H, dd J = 9.5, 4.4Hz),
2.80 (1H, brs), 0.94 (9H, S), 0.10 (6H, s) (3) 1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) -3- Methanesulfonyloxyazetidine 1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 12 (2) 300.4 mg (1.00 mmo
l) was dissolved in 15 ml of methylene chloride, and 0.2 ml (2.49 mmol) of methanesulfonyl chloride and 0.35 ml (2.51 mmol) of triethylamine were added under ice cooling, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane-ethyl acetate = 1: 1) to give 1- (4-t-butyldimethylsilyloxymethyl-1,3) as a yellow syrup. -Thiazol-2-yl) -3-methanesulfonyloxyazetidine 326.5 mg, yield 86
%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.50
(1H, s), 5.44-5.38 (1H, m), 4.43 (2H, dd, J = 9.9,
5.5Hz), 4.23 (2H, dd, J = 9.9, 4.1Hz), 3.10 (3H, s),
0.90 (9H, s), 0.10 (6H, s) (4) 3-acetylthio-1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) azetidine Reference Example 12 (3) 326.5 mg of 1- (4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in
(0.86 mmol) was dissolved in 16 ml of dimethylformamide, and 780 mg (5.41 mmol) of potassium thioacetate was added at room temperature.
Was added and stirred in an oil bath at 80 ° C. for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered,
The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1) to give 3-acetylthio-1- (4-t-butyldimethylsilyloxymethyl) as a brown syrup. -1,3-thiazol-2-yl) azetidine
Obtained in a yield of 191 mg, 62%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.45
(1H, s), 4.66 (2H, s), 4.50 (2H, t, J = 8.6Hz), 3.9
5 (2H, dd, J = 8.6, 5.1Hz), 2.35 (3H, s), 0.93 (9H,
s), 0.10 (6H, s) Reference Example 13 4-acetylthio-1- (4-ethoxycarbonyl-
1,3-thiazol-2-yl) piperidine

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(1) (4-hydroxypiperidine-1-
Carbothioyl) carbamic acid ethyl ester 1.0 g (9.89 mmol) of 3-hydroxypiperidine was dissolved in 50 ml of tetrahydrofuran, and 1.4 ml (11.9 mmol) of ethoxycarbonylisothiocyanate was added under ice-cooling. After 10 minutes, the temperature was returned to room temperature. And the mixture was stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the reaction solution, and the mixture was separated and extracted. After drying the organic layer over anhydrous magnesium sulfate,
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: toluene:
Ethyl acetate = 1: 2) to give 2.3 g of yellow oily (4-hydroxypiperidine-1-carbothioyl) carbamic acid ethyl ester in a yield of 100%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 4.26
(1H, br s), 4.19 (2H, q, J = 8.3Hz), 4.06 (1H, m),
4.0-3.4 (3H, dull s), 2.10 (2H, m), 1.80-1.60 (4H,
m), 1.29 (3H, t, J = 8.3 Hz) (2) 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -4-hydroxypiperidine Obtained in Reference Example 13 (1). (4-Hydroxypiperidine-1-carbothioyl) carbamic acid ethyl ester
2.3 g (9.89 mmol) of ethanol 23 ml, distilled water 23 ml
In sodium hydroxide solution 1.98 g (49.5 m
mol), and the mixture was heated under reflux for 15 hours. After confirming the completion of the reaction,
The reaction solution was cooled to room temperature, and then 12.4 ml of a 4N hydrochloric acid gas-dioxane solution was added under ice cooling. Subsequently, 2.5 ml (19.8 mmol) of ethyl-2-bromopyruvate was introduced into the system,
2.8 ml (20.1 mmol) of triethylamine were added, and
Heated to reflux for an hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate = 2: 1) to give 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) as a pale yellow syrup. 0.99 g of 4-hydroxypiperidine was obtained in a yield of 39%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.46 (1H, s), 4.35 (2H, q, J = 7.8Hz), 3.96 (1H, m),
3.88 (2H, dt, J = 13.5, 3.0Hz), 3.31 (2H, ddd, J = 1
3.5,9.0, 3.0Hz), 2.04-1.96 (2H, m), 1.74-1.56 (3H,
m), 1.37 (3H, t, J = 7.8Hz) Mass spectrum: 256
[M ⁺ ] (3) 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -4-methanesulfonyloxypiperidine 1- (4-ethoxycarbonyl- obtained in Reference Example 13 (2) 128 mg (0.50 mmol) of 1,3-thiazol-2-yl) -4-hydroxypiperidine was added to methylene chloride 6.5
methanesulfonyl chloride under ice-cooling.
0.043 ml (0.56 mmol), triethylamine 0.084 ml (0.6
(0 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 30 minutes. After confirming the completion of the reaction, 1 ml of ethanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system,
The aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate.
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-n-hexane = 5: 1 to give a white solid 1-.
(4-ethoxycarbonyl-1,3-thiazole-2-
Yl) -4-methanesulfonyloxypiperidine.
0 mg was obtained in a yield of 49%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.49 (1H, s), 5.01-4.90 (1H, m), 4.45 (2H, q, J =
8.0Hz), 3.80 (2H, ddd, J = 12.6, 8.4, 4.2Hz), 3.52
(2H, ddd, J = 12.6, 8.4, 4.2Hz), 3.05 (3H, s), 2.20-
1.90 (4H, m), 1.36 (3H, t, J = 8.0 Hz) Mass spectrum: 334 [M ⁺ ] (4) 4-acetylthio-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl ) Piperidine 76 mg (0.23 mmol) of 1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -4-methanesulfonyloxypiperidine obtained in Reference Example 13 (3) was dissolved in 4.0 ml of dimethylformamide. Then, 145 mg (1.3 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in a 90 ° C oil bath for 8 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate.
The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 1) to give 4-acetylthio-1- (4-ethoxycarbonyl-1,3-ethoxycarbonyl) as a light brown solid. Thiazol-2-yl) piperidine was obtained in 67 mg in a yield of 94%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.45 (1H, s), 4.34 (2H, q, J = 7.1Hz) 3.88 (2H, dt,
J = 13.4, 3.2Hz), 3.80-3.60 (1H, m), 3.33 (ddd, J = 1
3.6,8.5, 3.2Hz), 2.33 (3H, s), 2.15-1.95 (2H, m),
1.85-1.65 (2H, m), 1.37 (3H, t, 7.1 Hz) Mass spectrum: 314 [M ⁺ ] Reference Example 14 4-acetylthio-1- (4-p-nitrobenzylcarbonyl-1,3-thiazole- 2-yl) piperidine

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(1) 4-t-butyldimethylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) piperidine 1- (4-ethoxy) obtained in Reference Example 13 (2) 1.00 g (3.90 mmol) of carbonyl-1,3-thiazol-2-yl) -4-hydroxypiperidine was dissolved in 50 ml of dimethylformamide, and 1.2 g (7.96 mmol) of t-butyldimethylsilyl chloride was added under ice cooling. Imidazole 0.6
g (8.8 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred as it was for 18 hours. After confirming the completion of the reaction, ethanol was added to the system under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 4: 1) to give 4-t-butyldimethylsilyloxy-1- (4-ethoxy) as a pale yellow oil. 1.38 g of carbonyl-1,3-thiazol-2-yl) azetidine was obtained in a yield of 95%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.42 (1H, s), 4.35 (2H, q, J = 7.1Hz), 4.03-3.89 (1
H, m), 3.70 (2H, ddd, J = 12.4, 8.5, 3.7Hz), 3.46 (2
H, ddd, 12.4, 8.5, 3.7Hz), 1.90-1.77 (2H, m), 1.71
-1.59 (2H, m), 1.37 (3H, t, J = 7.1Hz), 0.90 (9H, s),
0.08 (6H, s) Mass spectrum: 370 [M ⁺ ] (2) 4-t-butyldimethylsilyloxy-1- (4
-Carboxyl-1,3-thiazol-2-yl) piperidine 4-t-butyldimethylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) obtained in Reference Example 14 (1) ) 1.0 g (2.7 mmol) of piperidine was dissolved in 20 ml of ethanol, and 5.4 ml (5.4 mmol) of a 1N aqueous solution of sodium hydroxide was added under ice-cooling, followed by stirring at room temperature for 3.5 hours. After confirming the completion of the reaction, 1.8 ml of 2N hydrochloric acid aqueous solution was added under ice cooling. (Intrasystem pH: 6-5) Thereafter, ethyl acetate was gradually added into the system, and then saturated saline was added. After separating and extracting the aqueous layer with ethyl acetate, the obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from methanol-ethyl acetate to obtain 471 mg of primary crystals as white crystals. Next, the residue obtained by concentrating the mother liquor was subjected to silica gel column chromatography (elution solvent: ethyl acetate: 2-propano-
To 10: 4: 1 to 5: 2: 1) to give 4-t-butyldimethylsilyloxy-1- (4
-Carboxyl-1,3-thiazol-2-yl) piperidine was obtained in an amount of 440 mg, and a total of 911 mg in a yield of 99%.

¹ H-NMR (400 MHz, CDCl ₃ + D ₂ O): δ (p
pm) 7.35 (1H, s), 4.10-3.85 (1H, m), 3.75-3.50 (2H,
m), 3.50-3.25 (2H, m), 1.90-1.70 (2H, m), 1.70-1.
50 (2H, m), 0.90 (9H, s), 0.07 (6H, m) Mass spectrum (FAB ⁺ ): 343 [M + H] ⁺ (3) 4-t-butyldimethylsilyloxy-1- (4
-P-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) piperidine 4-t-butyldimethylsilyloxy-1- (4-carboxyl-1,3-thiazole obtained in Reference Example 14 (2) 902 mg (2.63 mmol) of -2-yl) piperidine was dissolved in 40 ml of anhydrous methylene chloride, and 710 mg (5.3 mmo) of hydroxybenzotriazole was cooled under ice in a nitrogen atmosphere.
l), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) 1.254 g (6.6 mmol),
788 mg (5.2 mmol) of p-nitrobenzyl alcohol was added, and the mixture was stirred at room temperature for 4 hours. After confirming the completion of the reaction and after confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 4-yellow solid.
t-butyldimethylsilyloxy-1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazole-2
-Yl) piperidine was obtained in 916 mg, 73% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
8.23 (2H, d, J = 8.5Hz), 7.60 (2H, d, J = 8.5Hz), 7.49
(1H, s), 5.42 (2H, s), 4.05-3.95 (1H, m), 3.70 (2
H, ddd, J = 12.6, 8.6, 3.9Hz), 3.48 (2H, ddd, J = 12.
6, 6.2, 4.2Hz), 1.92-1.76 (2H, m), 1.75-1.50 (2H,
m), 0.90 (9H, s), 0.07 (6H, s) Mass spectrum (FAB ⁺ ): 478 [M + H] ⁺ (4) 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazole -2-yl) -4-hydroxypiperidine 4-butyldimethylsilyloxy-1- (4-p-nitrobenzylcarbonyl- obtained in Reference Example 14 (3)
1,3-thiazol-2-yl) piperidine 300 mg (0.
628 mmol) in anhydrous tetrahydrofuran (15 ml), acetic acid (0.22 ml, 3.84 mmol), 1M tetrabutylammonium fluoride-tetrahydrofuran solution (3.76 ml)
(3.76 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 21 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1- (4-p-nitrobenzyloxycarbonyl-) as a pale yellow solid.
1,3-Thiazol-2-yl) -4-hydroxypiperidine was obtained in 123 mg in a yield of 54%.

¹ H-NMR (400 MHz, CDCl ₃ + D ₂ O): δ
(ppm) 8.22 (2H, d, J = 8.0Hz), 7.60 (2H, d, J = 8.0Hz),
7.50 (1H, s), 5.42 (2H, s), 4.02-3.94 (1H, m), 3.
89 (2H, dt, J = 12.0, 4.0Hz), 3.33 (2H, ddd, J = 12.0,
8.0, 4.0Hz), 2.05-1.94 (2H, m), 1.75-1.55 (2H, m) Mass spectrum: 363 [M ⁺ ] (5) 4-Methanesulfonyloxy-1- (4-p-nitrobenzyloxy) Carbonyl-1,3-thiazole-
2-yl) piperidine 0.75 g (2.06 mmol) of 1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl) -4-hydroxypiperidine obtained in Reference Example 14 (4) Was dissolved in 38 ml of anhydrous methylene chloride, and 0.18 ml (2.33 mmol) of methanesulfonyl chloride and 0.35 ml (2.51 mmol) of triethylamine were added under ice-cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour. did. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 2: 1) to give 4-methanesulfonyloxy-1- (4-p-nitrobenzyloxycarbonyl) as a colorless solid. 0.87 g of (-1,3-thiazol-2-yl) piperidine was obtained in a yield of 96%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
8.23 (2H, d, J = 8.5Hz), 7.59 (2H, d, J = 8.5Hz), 7.54
(1H, s), 5.42 (2H, s), 5.05-4.95 (1H, m), 3.79 (2
H, ddd, J = 12.2, 7.6, 4.0Hz), 3.55 (2H, ddd, J = 12.
2, 7.2, 4.0Hz), 3.07 (3H, s), 2.18-2.06 (2H, m),
2.00-1.80 (2H, m) Mass spectrum (FAB ⁺ ): 441 [M + H] ⁺ (6) 4-acetylthio-1- (4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl )
Piperidine 4-methanesulfonyloxy-1- (4-p-nitrobenzyloxycarbonyl) obtained in Reference Example 14 (5)
1,3-thiazol-2-yl) piperidine 1.2 g (2.7
2 mmol) was dissolved in 60 ml of dimethylformamide, and 625 mg (5.47 mmol) of potassium thioacetate was added at room temperature.
The mixture was stirred in a 90 ° C. oil bath for 3.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
1: 1) to give 4-acetylthio-
1- (4-p-nitrobenzyloxycarbonyl-1,
769 mg of 3-thiazol-2-yl) piperidine were obtained in a yield of 88%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
8.23 (2H, d, J = 8.4Hz), 7.59 (2H, d, J = 8.4Hz), 7.51
(1H, s), 5.42 (2H, s), 3.95-3.80 (2H, m), 3.80-3.6
0 (1H, m), 3.34 (2H, ddd, J = 13.1, 9.9, 3.1Hz), 2.3
4 (3H, s), 2.25-1.95 (2H, m), 1.85-1.65 (2H, m) Mass spectrum (FAB ⁺ ): 422 [M + H] ⁺ Reference Example 15 4-acetylthio-1- (4- Carbamoyl-1,3-
Thiazol-2-yl) piperidine

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(1) 4-tert-butyldimethylsilyloxy-1- (4-carbamoyl-1,3-thiazole-2
-Yl) piperidine 4.99 g (14.6 mmol) of 4-t-butyldimethylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 14 (2) was methylene chloride. Dissolve in 150 ml and add carbonyldiimidazo-
2.80 g (17.3 mmol) was added at room temperature under a nitrogen atmosphere.
The mixture was stirred under the same conditions for 1.5 hours. After confirming the disappearance of raw materials, 8.7 ml of 28% aqueous ammonia was added to the system, and the mixture was added at room temperature for 3 hours.
Stirred for 0 minutes. Subsequently, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated saline were added to the residue to carry out a liquid separation operation. The aqueous layer was subjected to liquid separation extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give 4-t-butyldimethylsilyloxy-1- (4-carbamoyl-) as a pale yellow solid. 1.90 g (1,3-thiazol-2-yl) piperidine was obtained in a yield of 59%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.39 (1H, s), 7.03 (1H, br s), 5.50 (1H, br s), 4.
05-3.95 (1H, m), 3.66 (2H, ddd, J = 12.5, 8.6, 3.7H
z), 3.43 (2H, ddd, J = 12.5, 6.5, 4.2Hz), 1.92-1.75
(2H, m), 1.75-1.55 (2H, m), 0.90 (9H, s), 0.08 (6H,
s) Mass spectrum (FAB ⁺ ): 342 [M + H] ⁺ (2) 1- (4-carbamoyl-1,3-thiazole-
2-yl) -4-hydroxypiperidine 4-t-butyldimethylsilyloxy-1- (4-carbamoyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 15 (1) 1.226 g (3.59 was dissolved in 30 ml of anhydrous tetrahydrofuran, and under ice-cooling 1.85 ml of acetic acid (32.3 mmol), 32.3 ml of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution
2.3 mmol) and stirred for 24 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1- (4-carbamoyl-1,3-thiazol-2-yl) -4-hydroxypiperidine as a white solid. , 0.82 g, 100% yield
I got it.

¹ H-NMR (400 MHz, CD ₃ OD): δ (ppm) 7.38
(1H, s), 3.95-3.80 (1H, m), 3.40-3.20 (2H, m), 2.
00-1.85 (2H, m), 1.75-1.50 (2H, m) Mass spectrum (FAB ⁺ ): 228 [M + H] ⁺ (3) 1- (4-carbamoyl-1,3-thiazole-
2-yl) -4-methanesulfonyloxypiperidine 1- (4-carbamoyl- obtained in Reference Example 15 (2)
1.93 g (8.49 mmol) of 1,3-thiazol-2-yl) -4-hydroxypiperidine was dissolved in 100 ml of methylene chloride, and 10.0 ml of methanesulfonyl chloride was added under ice cooling.
(129 mmol) and 18.0 ml (129 mmol) of triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 24 hours. After confirming the completion of the reaction, methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 1).
0: 1) to give 1.59 g of 1- (4-carbamoyl-1,3-thiazol-2-yl) -4-methanesulfonyloxypiperidine (31a) as a pale yellow solid in 61% yield. Was.

¹ H-NMR (400 MHz, CD ₃ OD): δ (ppm) 7.42
(1H, s), 5.10-4.90 (1H, m), 3.77 (2H, ddd, J = 13.0,
7.4, 4.0Hz), 3.53 (2H, ddd, J = 13.0, 7.7, 4.0Hz),
3.12 (3H, s), 2.18-2.07 (2H, m), 2.00-1.89 (2H, m) Mass spectrum: 305 [M ⁺ ] (4) 4-acetylthio-1- (4-carbamoyl-
1,3-thiazol-2-yl) piperidine 1- (4-carbamoyl- obtained in Reference Example 15 (3)
1.59 g (5.21 mmol) of 1,3-thiazol-2-yl) -4-methanesulfonyloxypiperidine (31a) was dissolved in 80 ml of dimethylformamide, and 1.19 g (10.4 mmol) of potassium thioacetate was added at room temperature. In a 90 ° C oil bath
Stirred for 2.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 10: 1) to obtain 4-acetylthio-1- (4-carbamoyl-1,3-thiazole-) as a brown solid. 1.01 g of 2-yl) piperidine was obtained in a yield of 68%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.41 (1H, s), 7.00 (1H, br s), 5.55 (1H, br s), 3.
90-3.78 (2H, m), 3.78-3.64 (1H, m), 3.35-3.25 (2H,
m), 2.32 (3H, s), 2.10-2.00 (2H, m), 1,80-1.65 (2H
, m) Mass spectrum (FAB ⁺ ): 285 [M + H] ⁺ Reference Example 16 4-acetylthio-1- (4-N-methylcarbamoyl-
1,3-thiazol-2-yl) piperidine

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(1) 4-t-butyldimethylsilyloxy-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine 4-t-butyl obtained in Reference Example 14 (2) 200 mg (0.584 mmol) of butyldimethylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) piperidine was dissolved in 6.0 ml of dimethylformamide, and 114 mg (0.703 mmol) of carbonyldiimidazole was dissolved in nitrogen. Under an atmosphere, the mixture was added at room temperature and stirred in a 50 ° C. oil bath for 3 hours. After confirming the disappearance of the raw materials, 0.23 ml of a 40% aqueous solution of methylamine was added to the system, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated saline were added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 5: 4).
And purified as light brown solid 4-t-butyldimethylsilyloxy-1- (4-N-methylcarbamoyl-1,3
-Thiazol-2-yl) piperidine in 202.5 mg, yield
97%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.36 (1H, s), 7.20 (1H, br s), 4.10-3.98 (1H, m),
3.68 (2H, ddd, J = 12.6, 8.5, 3.7Hz), 3.45 (2H, ddd,
J = 12.6, 6.4, 4.2Hz), 2.99 (3H, d, J = 4.8Hz), 1.95-
1.78 (2H, m), 1.78-1.60 (2H, m), 0.93 (H, s), 0.11
(6H, s) Mass spectrum (FAB ⁺ ): 356 [M + H] ⁺ (2) 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine Reference Example 4-t-butyldimethylsilyloxy-1- (4-N-methylcarbamoyl-1,3) obtained in 16 (1)
-Thiazol-2-yl) piperidine 1.69 g (4.75 mmo
l) was dissolved in 85 ml of anhydrous tetrahydrofuran, and under ice-cooling, 1.36 ml (23.8 mmol) of acetic acid, 2M solution of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran
ml (23.8 mmol) was added, and the mixture was stirred in a 50 ° C oil bath for 14.5 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1- (4-
N-methylcarbamoyl-1,3-thiazol-2-yl) -4-hydroxypiperidine as a white solid, 1.
48 g, 97% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.35
(1H, s), 7.18 (1H, br s), 4.05-3.90 (1H, m), 3.74
(2H, ddd, J = 12.7, 4.7Hz) ,. 3.28 (2H, ddd, J = 12.7,
9.0,3.6Hz), 2.10-1.90 (2H, m), 1.80-1.50 (3H, m) Mass spectrum: 241 [M ⁺ ] (3) 4-Methanesulfonyloxy-1- (4-N-methylcarbamoyl- 1,3-thiazol-2-yl) piperidine 1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) -4-hydroxypiperidine obtained in Reference Example 16 (2) 1.143 g (4.74 mmol) in methylene chloride 3
Dissolve in 5 ml and methanesulfonyl chloride under ice-cooling
0.44 ml (5.68 mmol), triethylamine 0.86 ml (5.6
8 mmol), and after 10 minutes, the reaction system was returned to room temperature and stirred for 4 hours. After confirming the completion of the reaction, methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered,
The filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was filtrated to give 4-methanesulfonyloxy-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine as a pale yellow solid (1.438 g, yield). 95%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.38 (1H, s), 7.14 (1H, br s), 5.06-4.93 (1H, m),
3.74 (2H, ddd, J = 13.2, 7.5, 4.2Hz), 3.48 (2H, ddd,
J = 13.2, 7.2, 4.2Hz), 3.07 (3H, s), 2.97 (3H, d, J
= 5.1Hz), 2.20-1.90 (4H, m) Mass spectrum (FAB ⁺ ): 320 [M + H] ⁺ (4) 4-acetylthio-1- (4-N-methylcarbamoyl-1,3-thiazole- 2-yl) piperidine 1.438 g (4.50 mmol) of 4-methanesulfonyloxy-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 16 (3) was added to dimethyl It was dissolved in 72 ml of formamide, and 1.03 g (9.00 mmol) of potassium thioacetate was added at room temperature, followed by stirring in a 90 ° C. oil bath for 2.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 10: 1 to 1).
The residue was purified with ethyl acetate to obtain 1.22 g of 4-acetylthio-1- (4-N-methylcarbamoyl-1,3-thiazol-2-yl) piperidine as a light brown solid in a yield of 91%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.38 (1H, s), 7.15 (1H, br s), 3.82 (2H, dt, J = 12.
7, 4.8Hz), 3.78-3.63 (1H, m), 3.30 (2H, ddd, J = 12.
7, 11.1, 4.7Hz), 2.95 (3H, d, J = 6.4Hz), 2.35 (3H,
s), 2.15-1.95 (2H, m), 1.85-1.35 (2H, m) Mass spectrum (FAB ⁺ ): 300 [M + H] ⁺ Reference Example 17 4-acetylthio-1- (4-N, N- Dimethylcarbamoyl-1,3-thiazol-2-yl) azetidine

[0624]

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(1) 4-t-butyldimethylsilyloxy-1- (4-N, N-dimethylcarbamoyl-1,3-
Thiazol-2-yl) piperidine 0.98 g (2.86 mmol) of 4-t-butyldimethylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) piperidine obtained in Reference Example 14 (2) Was dissolved in 30 ml of dimethylformamide, 559 mg (3.45 mmol) of carbonyldiimidazole was added at room temperature under a nitrogen atmosphere, and the mixture was stirred in a 50 ° C oil bath for 3 hours. After confirming the disappearance of the raw materials, subsequently, 100 ml of a 50% aqueous dimethylamine solution was added to the system, and the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate was added to the reaction system to carry out a liquid separation operation. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 3), and 4-t-butyldimethylsilyloxy-1- (4-N ,
N-dimethylcarbamoyl-1,3-thiazole-2-
Il) piperidine) was obtained in 995 mg, 94% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.04 (1H, s), 4.05-3.95 (1H, m), 3.67 (2H, ddd, J = 1
2.6, 8.4, 4.3Hz), 3.41 (2H, ddd, J = 12.6, 7.0, 4.3H
z), 3.26 (3H, br s), 3.07 (3H, br s), 1.92-1.75 (2
H, m), 1.72-1.50 (2H, m), 0.90 (9H, s), 0.08 (6H,
s) Mass spectrum (FAB ⁺ ): 370 [M + H] ⁺ (2) 1- (4-N, N-dimethylcarbamoyl-1,3
-Thiazol-2-yl) -4-hydroxypiperidine 4-t-butyldimethylsilyloxy-1- (4-N, N-dimethylcarbamoyl- obtained in Reference Example 17 (1)
1,13-thiazol-2-yl) piperidine 2.13 g
(5.76 mmol) was dissolved in 85 ml of anhydrous tetrahydrofuran, and under ice-cooling, 1.65 ml (28.8 mmol) of acetic acid and 28.8 ml (28.8 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution were added thereto. The mixture was stirred in an oil bath for 1.5 hours. After confirming the completion of the reaction, the reaction solution is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (elution solvent:
Purification with ethyl acetate: methanol = 10: 1) yielded 1-
1.47 g of (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -4-hydroxypiperidine was obtained as a white solid in a yield of 100%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.07 (1H, s), 4.03-3.89 (1H, m), 3.83 (2H, ddd, J = 1
2.0, 5.0Hz), 3.35-3.20 (5H, m), 3.08 (3H, br s),
2.05-1.90 (2H, m), 1.90-1.55 (3H, m) Mass spectrum: 255 [M ⁺ ] (3) 1- (4-N, N-dimethylcarbamoyl-1,3
-Thiazol-2-yl) -4-methanesulfonyloxypiperidine 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -4- obtained in Reference Example 17 (2).
Hydroxypiperidine 1.47 g (5.76 mmol) was dissolved in methylene chloride 60 ml, and methanesulfonyl chloride 0.82 ml (10.6 mmol), triethylamine 1.48 ml under ice-cooling.
(10.6 mmol) was added and 10 minutes later, the reaction system was returned to room temperature and stirred for 2 hours. After confirming the completion of the reaction, methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to obtain a light yellow solid 1
1.38 g of-(4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -4-methanesulfonyloxypiperidine was obtained at a yield of 72%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.12 (1H, s), 5.05-4.90 (1H, m), 3.85-3.65 (2H, m),
3.60-3.40 (2H, m), 3.23 (3H, br s), 3.08 (6H, br
s) 2.20-1.90 (4H, m) Mass spectrum (FAB ⁺ ): 334 [M + H] ⁺ (4) 4-acetylthio-1- (4-N, N-methylcarbamoyl-1,3-thiazole-2 -Yl) piperidine 1- (4-N, N-dimethylcarbamoyl-1,3-thiazol-2-yl) -4- obtained in Reference Example 17 (3)
Methanesulfonyloxypiperidine 1.33 g (3.99 mmo
l) was dissolved in 66 ml of dimethylformamide, and 940 mg (8.23 mmol) of potassium thioacetate was added at room temperature.
The mixture was stirred in an oil bath for 3.0 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 5:
1 to 7: 1) to give 4-acetylthio-1- (4-N, N-dimethylcarbamoyl-1,3-
Thiazol-2-yl) piperidine in 629 mg, yield 50.
%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.07 (1H, s), 3.90-3.78 (3H, m), 3.75-3.60 (2H, m),
3.40-3.15 (5H, m), 3.08 (3H, br s), 2.32 (3H, s),
2.12-1.98 (2H, m), 1.82-1.60 (2H, m) Mass spectrum (FAB ⁺ ): 314 [M + H] ⁺ Reference Example 18 (3S) -3-acetylthio-1- (4-carbamoyl-1 , 3-thiazol-2-yl) pyrrolidine

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(1) {(3R) -3-hydroxypyrrolidine-1-carbothioyl} carbamic acid ethyl ester (3R) -3-hydroxypyrrolidine hydrochloride 15 g (121.4 mmo
l) was dissolved in 450 ml of tetrahydrofuran, 15.7 ml of ethoxycarbonylisothiocyanate was added under ice-cooling, the temperature was returned to room temperature after 10 minutes, and the mixture was stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the reaction solution, and the mixture was separated and extracted. After drying the organic layer over anhydrous sodium sulfate,
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized with a mixed solvent of ethyl acetate-n-hexane and then collected by filtration to obtain yellow crystal {(3R) -3-hydroxypyrrolidine-1-carbothioyl} carbamic acid ethyl ester (24.62 g, yield).
93%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.38
-7.25 (1H, br s), 4.35-3.63 (5H, m), 4.16 (2H, q, J
= 6.8Hz), 2.19-2.05 (2H, m), 1.30 (3H ,, t, J = 6.8Hz) (2) (3R) -1- (4-ethoxycarbonyl-1,3-
Thiazol-2-yl) -3-hydroxypyrrolidine 24.6 g (113 mmol) of {(3R) -3-hydroxypyrrolidine-1-carbothioyl} carbamic acid ethyl ester obtained in Reference Example 18 (1) was dissolved in 125 ml of ethanol. Dissolve in 125 ml of distilled water.
g (789 mmol) was added and the mixture was refluxed overnight. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and then 4N
-Hydrochloric acid gas-dioxane solution was added until pH7. Subsequently, 28.4 m of ethyl-2-bromopyruvate was added to the system.
l (226 mmol), triethylamine 31.7 ml (226 mmol)
Was added and the mixture was refluxed again for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 1)
~ 1: 2) and purified as a light brown solid (3R) -1- (4
-Ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine (19.26 g, yield 70%)
I got it.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.39
(1H, s), 4.66-4.61 (1H, m), 4.36 (2H, q, J = 7.3H
z), 3.72-3.65 (2H, m), 3.62-3.56 (2H, m), 2.23-2.1
5 (1H, m), 2.14-2.07 (1H, m), 1.37 (3H, t, J = 7.3Hz) (3) (3R) -3-t-butyldiphenylsilyloxy-1
-(4-ethoxycarbonyl-1,3-thiazole-2
-Yl) pyrrolidine 3.0 g (12.4 mmol) of (3R) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine obtained in Reference Example 18 (2) was treated with dimethylformamide. The mixture was dissolved in 90 ml, and under ice cooling, 6.45 ml (24.8 mmol) of t-butyldiphenylsilyl chloride and 1.69 g (24.8 mmol) of imidazole were added. After 10 minutes, the reaction system was returned to room temperature and stirred overnight. . After confirming the completion of the reaction,
Under ice-cooling, 0.86 ml of ethanol was added to the system, and the mixture was stirred at room temperature for 2 hours. Subsequently, ethyl acetate and 10%
A saline solution was added, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1 to 1:
Purification was performed in 1), and (3R) -3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine as a light brown solid was obtained in an amount of 5.85.
g, 90% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.69
-7.60 (4H, m), 7.48-7.35 (6H, m), 7.39 (1H, s), 4.
56-4.50 (1H, m), 4.12 (2H, q, J = 7.3Hz), 3.77-3.70
(1H, m), 3.56-3.46 (3H, m), 2.06-1.90 (2H, m), 1.38
(3H, t, J = 7.3 Hz), 1.05 (9H, s) (4) (3R) -3-t-butyldiphenylsilyloxy-1
-(4-Carboxyl-1,3-thiazol-2-yl) pyrrolidine (3R) -3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-) obtained in Reference Example 18 (3).
1,3-thiazol-2-yl) pyrrolidine 300 mg (0.
624 mmol) was dissolved in 12 ml of ethanol and 3 ml of distilled water, and 1.56 ml of a 1N aqueous sodium hydroxide solution (1.56 mmo
l) was added at room temperature, followed by stirring at room temperature for 6 hours. After confirming the completion of the reaction, 1N aqueous hydrochloric acid was added under ice cooling. (In the system
pH: 4-5) Thereafter, ethyl acetate was gradually added to the system, and then saturated saline was added. After the aqueous layer was separated and extracted with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid (3R) -3.
There was obtained 305 mg of -t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) pyrrolidine in a yield of 97%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.68
-7.60 (4H, m), 7.48-7.35 (6H, m), 7.40 (1H, s), 4.
57-4.50 (1H, m), 3.72-3.62 (1H, m), 3.50-3.36 (3H,
m), 2.10-1.92 (2H, m), 1.05 (9H, s) (5) (3R) -3-t-butyldiphenylsilyloxy-1
-(4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine (3R) -3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3) obtained in Reference Example 18 (4). −
Thiazol-2-yl) pyrrolidine 910 mg (2.01 mmo
l) was dissolved in 30 ml of dimethylformamide, 652 mg (4.02 mmol) of carbonyldiimidazole was added at room temperature under a nitrogen atmosphere, and the mixture was stirred in a 50 ° C oil bath for 4 hours. After confirming the disappearance of the raw materials, 2.7 ml of 28% aqueous ammonia was added to the system, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and 10% saline were added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and (3R) -3-t-butyldiphenylsilyloxy-1- (4-N-carbamoyl-1,3-thiazol-2-yl) was obtained as a light brown solid. Pyrrolidine was obtained in 730 mg in a yield of 80%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.71
-7.64 (4H, m), 7.48-7.38 (6H, m), 7.09-7.05 (1H, b
rs), 5.50-5.44 (1H, br s), 4.57-4.52 (1H, m), 3.7
2-3.66 (1H, m), 3.51-3.45 (1H, m), 3.45-3.43 (2H,
m), 2.09-2.02 (1H, m), 2.08-1.93 (1H, m), 1.08 (9
H, s) (6) (3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine (3R) -3-t obtained in Reference Example 18 (5) -Butyldimethylsilyloxy-1- (4-carbamoyl-1,3-
Thiazol-2-yl) piperidine 950 mg (2.10 mmol)
Was dissolved in 20 ml of anhydrous tetrahydrofuran, 2.52 ml (2.52 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and the mixture was returned to room temperature and stirred for 1.3 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to ethyl acetate to 10% methanol-ethyl acetate).
(3R) -1- (4-carbamoyl-1,3-thiazole-
428 mg of 2-yl) -3-hydroxypyrrolidine was obtained as a white solid in a yield of 96%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 7.
42-7.36 (1H, br s), 7.30-7.23 (1H, br s), 7.27 (1
H, s), 5.08 (1H, d, J = 3.7Hz), 4.42-4.37 (1H, m),
3.51 (1H, dd, J = 11.0, 4.4Hz), 3.90-3.43 (2H, m),
3.30-3.27 (1H, m), 2.14-2.01 (1H, m), 1.99-1.86 (1
H, m) (7) (3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine and (3R) -1- (4-cyano-1,3 -Thiazole-
2-yl) -3-methanesulfonyloxypyrrolidine 290 mg of (3R) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine obtained in Reference Example 18 (6) ( 1.36 mmol) in methylene chloride 9 m
methanesulfonyl chloride under ice cooling.
684 ml (8.85 mmol), triethylamine 1.24 ml (8.85 mmol
After 10 minutes, the reaction system was returned to room temperature and stirred as it was overnight. After confirming the completion of the reaction, 0.33 ml of methanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: 5% methanol-ethyl acetate to 10% methanol-ethyl acetate) to give (3R) -1- ( 4-carbamoyl-1,
3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine in 130 mg, 45% yield, (3R) -1-
(4-cyano-1,3-thiazol-2-yl) -3-
Methanesulfonyloxypyrrolidine as a pale yellow solid 148
mg, yield 40%. (3R) -1- (4-carbamoyl-1,3-thiazole-
2-yl) -3-methanesulfonyloxypyrrolidine
(a) ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.41 (1H,
s), 7.10-6.98 (1H, bs), 5.60-5.52 (1H, br s), 5.50
-5.40 (1H, m), 3.88-3.76 (2H, m), 3.65-3.60 (2H,
m), 3.08 (3H, s), 2.50-2.41 (1H, m), 2.39-2.32 (1
H, m) (3R) -1- (4-cyano-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine (b) ¹ H-
NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.23 (1H, s), 5.45
5.42 (1H, m), 3.88-3.76 (2H, m), 3.69-3.62 (2H,
m), 3.08 (3H, s), 2.55-2.47 (1H, m), 2.43-2.32 (1H,
m) (8) (3S) -3-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine (3R) -1- (4-) obtained in Reference Example 18 (7). 190 mg (0.652 mmol) of carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine was dissolved in 6 ml of acetonitrile, and 223 mg (1.96 mmol) of potassium thioacetate was added at room temperature. Heated to reflux for an hour.
After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to ethyl acetate to 2% methanol-
The residue was purified by ethyl acetate to give 135 mg of (3S) -3-acetylthio-1- (4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine as a light brown solid in a yield of 77%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.37
(1H, s), 7.08-7.02 (1H, br s), 5.50-5.44 (1H, br
s), 4.26-4.12 (1H, m), 3.94 (1H, dd, J = 11.0, 6.6H
z), 3.62-3.50 (2H, m), 3.44 (1H, dd, J = 11.0, 5.1H
z), 2.54-2.45 (1H, m), 2.36 (3H, s), 2.13-2.04 (1H,
m) Reference Example 19 (3S) -3-acetylthio-1- (4-cyano-1,3-
Thiazol-2-yl) pyrrolidine

[0639]

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(3R) -1- obtained in Reference Example 18 (7)
(4-cyano-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine 300 mg (1.10 mmol)
Was dissolved in 9 ml of acetonitrile, 376 mg (3.30 mmol) of potassium thioacetate was added at room temperature, and the mixture was heated under reflux for 5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 5: 1 to 1: 1) to give (3S) -3-acetylthio-1- (4) as a light brown solid. -Cyano-
137 mg of 1,3-thiazol-2-yl) pyrrolidine,
Obtained in 50% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.19
(1H, s), 4.19-4.12 (1H, m), 3.94 (1H, dd, J = 11.0,
6.6Hz), 3.64-3.53 (2H, m), 3.43 (1H, dd, J = 11.0,
5.1Hz), 2.55-2.48 (1H, m), 2.36 (3H, s), 2.15-2.06
(1H, m) Reference Example 20 (3R) -3-acetylthio-1- (4-carbamoyl-
1,3-thiazol-2-yl) pyrrolidine

[0642]

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(1) (3R) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine (3R) -1 obtained in Reference Example 18 (2) 970 mg (4.00 mmol) of-(4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine is dissolved in 30 ml of methylene chloride, and methanesulfonyl chloride 1.24 ml (16.0 mmol) is dissolved under ice-cooling. ), Triethylamine 2.24 ml
(16.0 mmol) was added and the mixture was stirred for 1 hour. After confirming the completion of the reaction, 0.81 ml of ethanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: toluene: acetonitrile = 4: 1 to 1:
Purified in 1), and a pale yellow solid of (3R) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-
1.00g methanesulfonyloxypyrrolidine, 78% yield
I got it.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.43
(1H, s), 5.44-5.41 (1H, m), 4.36 (2H, q, J = 7.0H
z), 3.92 (1H, dd, J = 12.5, 1.5Hz), 3.85 (1H, dd, J =
12.5,3.7Hz), 3.72-3.65 (2H, m), 3.06 (3H, s), 2.52-
2.46 (1H, m), 2.40-2.31 (1H, m), 1.38 (3H, t, J = 7.0H
z), (2) (3S) -3-acetyl-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine (3R) -1- (obtained in Reference Example 20 (1). 1.0 g (3.12 mmol) of 4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine was dissolved in 30 ml of dimethylformamide, and 919 mg (9.36 mmol) of potassium acetate was added at room temperature. At 80 ℃ oil bath
Stir for 5.5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: toluene: acetonitrile =
3: 1 to 1: 1) to give a light brown solid (3S) -3-
Acetyl-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine was used in an amount of 877 mg and a yield of 99%.
I got it.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.41
(1H, s), 5.45-5.41 (1H, m), 4.36 (2H, q, J = 7.3H
z), 3.44 (1H, dd, J = 11.7, 5.1Hz), 3.70-3.60 (3H,
m), 2.35-2.17 (2H, m), 2.05 (3H, s), 1.38 (3H, t,
(7.3 Hz) (3) (3S) -1- (4-ethoxycarbonyl-1,3-
Thiazol-2-yl) -3-hydroxypyrrolidine (3S) -3-acetyl-1 obtained in Example 20 (2)
-(4-ethoxycarbonyl-1,3-thiazole-2
-Yl) pyrrolidine 5.0 g (17.6 mmol) in ethanol 1
The solution was dissolved in 50 ml, 60 mg (0.879 mmol) of sodium ethoxide was added to the system at room temperature, and the mixture was stirred overnight under the same conditions. After confirming the completion of the reaction, the system was neutralized by adding 4N-hydrochloric acid gas-1,2-dioxane (0.22 ml), ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel chromatography (elution solvent: toluene:
After purification with acetonitrile = 1: 1 to 1: 2), white solid (3S) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine was converted to 4.1.
6 g, 98% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.39
(1H, s), 4.67-4.61 (1H, m), 4.36 (2H, q, J = 7.3H
z), 3.72-3.56 (4H, m), 2.24-2.07 (2H, m), 1.37 (3
(H, t, J = 7.3 Hz) (4) (3S) -3-t-butyldiphenylsilyloxy-
1- (4-ethoxycarbonyl-1,3-thiazole-
2-yl) pyrrolidine 4.1 g (16.9 mmol) of (3S) -1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine obtained in Reference Example 20 (3) was dissolved in dimethyl. After dissolving in 120 ml of formamide and adding 8.8 ml (33.8 mmol) of t-butyldiphenylsilyl chloride and 2.3 g (33.8 mmol) of imidazole under ice cooling, the reaction system was returned to room temperature after 10 minutes and stirred overnight. did. After confirming the completion of the reaction, 1.18 ml of ethanol was added to the system under ice cooling, followed by stirring at room temperature for 30 minutes. Subsequently, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane-ethyl acetate = 4: 1)
To 1: 1) to give (3S) -3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) pyrrolidine as a light brown solid.
7.60 g, 94% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.68
-7.61 (4H, m), 7.52-7.35 (6H, m), 7.37 (1H, s), 4.
56-4.51 (1H, m), 4.36 (2H, q, J = 7.0Hz), 3.77-3.69
(1H, m), 3.58-3.48 (3H, m), 2.05-1.88 (2H, m), 1.38
(3H, t, J = 7.0Hz), 1.05 (9H, s) (5) (3S) -3-t-butyldiphenylsilyloxy-1
-(4-Carboxyl-1,3-thiazol-2-yl) pyrrolidine (3S) -3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-) obtained in Reference Example 20 (4).
5.0 g of (1,3-thiazol-2-yl) pyrrolidine (10.4
was dissolved in 200 ml of ethanol and 50 ml of distilled water, and 26.0 ml (26.0 mmol) of a 1N aqueous solution of sodium hydroxide was dissolved.
Was added at room temperature, and the mixture was stirred as it was for 7.5 hours. After confirming the completion of the reaction, 1N aqueous hydrochloric acid was added under ice cooling. (System pH: 4-
5) Thereafter, ethyl acetate was gradually added to the system, and then saturated saline was added. After the aqueous layer was separated and extracted with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (3S) -3-t-butyldiphenylsilyl as a white solid. Oxy-1- (4-carboxyl-1,3-thiazol-2-yl) pyrrolidine was converted to 4.71
g, 100% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.70
-7.52 (4H, m), 7.52-7.25 (6H, m), 7.40 (1H, s), 4.
57-4.40 (1H, m), 3.68-3.55 (1H, m), 3.48-3.24 (3H,
m), 2.04-1.86 (2H, m), 1.07 (9H, s) (6) (3S) -3-t-butyldiphenylsilyloxy-1
-(4-carbamoyl-1,3-thiazol-2-yl) pyrrolidine (3S) -3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3) obtained in Reference Example 20 (5) −
Thiazol-2-yl) pyrrolidine 4.7 g (10.4 mmol)
Was dissolved in 140 ml of dimethylformamide, and 3.37 g (20.8 mmol) of carbonyldiimidazole was added under a nitrogen atmosphere.
The mixture was added at room temperature and stirred in a 50 ° C. oil bath for 3.5 hours. After confirming the disappearance of the raw materials, 14 ml of 28% aqueous ammonia was added to the system, followed by stirring at room temperature for 1 hour. Subsequently, ethyl acetate and 10% saline were added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 4: 1 to 2: 1),
A pale brown solid of (3S) -3-t-butyldiphenylsilyloxy-1- (4-N-carbamoyl-1,3-thiazol-2-yl) pyrrolidine was obtained in 3.14 g, 67% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.68
-7.62 (4H, m), 7.48-7.36 (6H, m), 7.34 (1H, s), 7.
08-7.05 (1H, br s), 5.49-5.44 (1H, br s), 4.57-4.5
1 (1H, m), 2.10-1.93 (2H, m), 1.06 (9H, s) (7) (3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxy Pyrrolidine (3S) -3-t-butyldimethylsilyloxy-1- (4-carbamoyl-1,3) obtained in Reference Example 20 (6)
-Thiazol-2-yl) piperidine 3.1 g (6.86 mmo
l) was dissolved in 90 ml of anhydrous tetrahydrofuran, 8.24 ml (8.24 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice cooling, and the mixture was stirred for 1.5 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate to 10% methanol-ethyl acetate) to give (3S) -1- (4-carbamoyl-1). ,
There was obtained 1.42 g of 3-thiazol-2-yl) -3-hydroxypyrrolidine as a white solid in a yield of 98%.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 7.
43-7.36 (1H, br s), 7.74-7.22 (1H, br s), 7.27 (1
H, s), 5.09 (1H, d, J = 3.7Hz), 4.44-4.38 (1H, m),
3.51 (1H, dd, J = 11.0, 4.4Hz), 3.49-3.42 (2H, m),
3.33-3.28 (1H, m), 2.15-2.02 (1H, m), 1.97-1.89 (1
(H, m) (8) (3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine (3S) -1 obtained in Reference Example 20 (7). 1.42 g (6.66 mmol) of-(4-carbamoyl-1,3-thiazol-2-yl) -3-hydroxypyrrolidine was treated with methylene chloride (40 m).
l, suspended in 9 ml of pyridine, and 2.58 ml (33.3 mmol) of methanesulfonyl chloride under ice-cooling, triethylamine
4.67 ml (33.3 mmol) was added, and the mixture was stirred as it was for 1 hour. After confirming the completion of the reaction, add methanol 1.2
Then, the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: 5% methanol-ethyl acetate to 1%).
0% methanol-ethyl acetate) to give a pale yellow solid.
(3S) -1- (4-carbamoyl-1,3-thiazole-
2-yl) -3-methanesulfonyloxypyrrolidine
1.15 g, yield 60%.

[0651] ^{1 H-NMR (400MHz, CDCl} 3): δ (ppm) 7.41
(1H, s), 7.08-7.02 (1H, br s), 5.57-5.46 (1H, br
s), 5.45-5.43 (1H, m), 3.86 (1H, dd, J = 12.5Hz), 3.
80 (1H, dd, J = 12.5, 4.4Hz), 3.68-3.60 (2H, m), 3.0
8 (3H, s), 2.52-2.40 (1H, m), 2.39-2.31 (1H, m) (9) (3R) -3-acetylthio-1- (4-carbamoyl-1,3-thiazole-2- Yl) pyrrolidine 1.15 g of (3S) -1- (4-carbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxypyrrolidine obtained in Reference Example 20 (7) (acetonitrile
Dissolve in 35 ml, and add potassium thioacetate (1.35 g) at room temperature.
(11.8 mmol) was added, and the mixture was heated under reflux for 6 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to 2% methanol-ethyl acetate) to give a light brown solid (3R)-
3-acetylthio-1- (4-carbamoyl-1,3-
962 mg of thiazol-2-yl) pyrrolidine in a yield of 90
% Obtained.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.37
(1H, s), 7.13-6.99 (1H, br s), 5.59-5.45 (1H, br
s), 4.19-4.09 (1H, m), 3.94 (1H, dd, J = 11.0, 6.6H
z), 3.61-3.50 (2H, m), 3.44 (1H, dd, J = 11.0, 5.1H
z), 2.54 ^ 2.45 (1H, m), 2.37 (3H, s), 2.14-2.05 (1H,
m) Reference Example 21 3-acetylthio-1- (4-N-methylcarbamoyl-
1,3-oxazol-2-yl) azetidine

[0653]

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(1) 1-carbamoyl-3-hydroxyazetidine N-benzhydryl-3-hydroxyazetidine 5.36 g
(22.4 mmol) was dissolved in 250 ml of methanol.
1 atmosphere, 5 pressure in the presence of 5.36 g of 0% palladium hydroxide
Catalytic hydrogen reduction was performed in a 0 ° C. water bath for 1 hour. After confirming the completion of the reaction, the reaction mixture was filtered to remove the catalyst, and the obtained filtrate was concentrated under reduced pressure. Ethyl acetate and distilled water were added to the residue, liquid separation and extraction were performed, and the organic layer was extracted again with distilled water.
The obtained aqueous layer was concentrated under reduced pressure to obtain a reddish brown oily product. Subsequently, after drying the above compound under reduced pressure, acetic acid 10
The mixture was dissolved in 20 ml of distilled water and 20 ml of an aqueous solution of 2.91 g of sodium cyanate at room temperature, and stirred for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated, and the obtained residue was subjected to silica gel column chromatography (elution solvent:
Purification with dichloromethane / methanol = 5: 1) gave 1-carbamoyl-3-hydroxyazetidine as a colorless oil.

¹ H-NMR (500 MHz, CD ₃ OD): δ (ppm)
4.54-4.50 (1H, m), 4.16-4.12 (2
H, m), 3.74 (2H, dd, J = 4.4, 9.7 Hz) (2) 3-t-butyldiphenylsilyloxy-1-carbamoylazetidine Obtained in Reference Example 21 (1). 1-carbamoyl-3-hydroxyazetidine was added to 100 ml of dimethylformamide
And 18.0 ml (66.9 mmol) of t-butyldiphenylsilyl chloride and imidazole under ice-cooling.
55 g (66.9 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred as it was overnight. After confirming the completion of the reaction,
Under ice-cooling, 1 ml of ethanol was added to the system, and the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1),
3-t-butyldiphenylsilyloxy-1 as a white solid
1.45 g of carbamoylazetidine was obtained in a total yield of 18% over two steps.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.60 (4H, d, J = 8.1 Hz), 7.46-7.3
6 (6H, m), 4.59-4.54 (1H, m), 4.26
(2H, brs), 3.96 (2H, t, J = 8.8 Hz),
3.91 (2H, dd, J = 5.1, 8.8 Hz), 1.0
6 (9H, s) (3) 3-t-butyldiphenylsilyloxy-1-
(4-ethoxycarbonyl-1,3-oxazole-2
-Yl) azetidine 3.47 g of 3-t-butyldiphenylsilyloxy-1-carbamoylazetidine obtained in Reference Example 21 (2)
(9.79 mmol) was dissolved in 170 ml of tetrahydrofuran, and 4.11 g (48.
95 mmol), 2.5 ml of ethyl-2-bromopyruvate (1
(9.58 mmol) and heated to reflux for 8 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 5: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3) as a white solid. 2.96 g of-(oxazol-2-yl) azetidine was obtained in a yield of 45%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.76 (1H, s), 7.60 (4H, d, J = 7.8H
z), 7.46-7.37 (6H, m), 4.71-4.6
7 (1H, m), 4.34 (2H, q, J = 6.8 Hz),
14 (2H, t, J = 8.8 Hz), 4.09 (2H, dd,
J = 5.9, 9.8 Hz), 1.34 (3H, t, J = 6.
8 Hz), 1.05 (9H, s) (4) 3-t-butyldiphenylsilyloxy-1-
(4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3) obtained in Reference Example 21 (3).
-Oxazol-2-yl) azetidine 325 mg
(0.72 mmol) was dissolved in 7 ml of benzene, and 0.67 M methylamine-trimethylaluminum-benzene solution was added.
7 ml was added at room temperature under a nitrogen atmosphere, and the mixture was heated under reflux for 1 hour. After confirming the completion of the reaction, add 10% aqueous acetic acid 2
0 ml was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate was added to the reaction system, a liquid separation operation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3 as a white solid.
-T-butyldiphenylsilyloxy-1- (4-N-
236 mg of methylcarbamoyl-1,3-oxazol-2-yl) azetidine was obtained in a yield of 75%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.72 (1H, s), 7.61 (4H, d, J = 7.8H
z), 7.47-7.38 (6H, m), 6.88 (1H, b
rs), 4.74-4.68 (1H, m), 4.10 (2H,
t, J = 8.7 Hz), 4.04 (2H, dd, J = 5.6,
8.8 Hz), 2.92 (3H, d, J = 5.0 Hz),
1.06 (9H, s) (5) 1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy obtained in Reference Example 21 (4) -1- (4-N-methylcarbamoyl-
1,3-oxazol-2-yl) azetidine 662 m
g (1.52 mmol) was dissolved in 33 ml of tetrahydrofuran, and under ice cooling, 1.5 ml (1.5 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was dissolved.
Was added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction,
The reaction solution is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 1).
0: 1) to give 210 mg of 1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine as a white solid in a yield of 70%.

¹ H-NMR (400 MHz, CD ₃ OD): δ (ppm)
83 (1H, s), 4.86-4.66 (1H, m), 4.3
3 (2H, dd, J = 6.6, 8.1 Hz), 3.93 (2
H, dd, J = 5.1, 8.8 Hz), 2.85 (3H,
s) (6) 1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) -3-methanesulfonyloxyazetidine 1- (4-N-) obtained in Reference Example 21 (5) 209 mg (1.06 mmol) of methylcarbamoyl-1,3-oxazol-2-yl) azetidine was dissolved in 5 ml of methylene chloride and 15 ml of pyridine, and 0.41 ml (5.30 mmol) of methanesulfonyl chloride was cooled under ice-cooling. ), 0.74 ml (5.30 mmol) of triethylamine and 10 minutes later
The reaction system was returned to room temperature and stirred for 2 hours. After confirming the completion of the reaction, add 1 ml of methanol to the system under ice-cooling.
The mixture was stirred at room temperature for 30 minutes. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10:
Purified in 1), 1- (4-N-methylcarbamoyl-
1,3-Oxazol-2-yl) -3-methanesulfonyloxyazetidine as a white solid, 253 m
g, 86% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.78 (1H, s), 6.80 (1H, brs), 5.41
−5.35 (1H, m), 4.48 (2H, dd, J = 6.6,
10.3 Hz), 4.30 (2H, dd, J = 4.4, 1
0.3 Hz), 3.10 (3H, s), 2.94 (3H,
d, J = 5.1 Hz) (7) 3-acetylthio-1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine 1- (obtained in Reference Example 21 (6). 4-N-methylcarbamoyl-1,3-oxazol-2-yl) -3-methanesulfonyloxyazetidine 252 mg (0.92
mmol) was dissolved in 12 ml of dimethylformamide, and 0.63 g (5.52 mmol) of potassium thioacetate was added at room temperature, followed by stirring in an oil bath at 80 ° C for 7 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-acetylthio-1- (4-N-methylcarbamoyl-1,3-oxazol-2-yl) azetidine as a white solid. 136 mg, yield 58%.

¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm)
7.75 (1H, s), 6.79 (1H, brs), 4.5
5 (2H, t, J = 8.4 Hz), 4.43-4.37 (1
H, m), 4.02 (2H, dd, J = 5.8, 8.9 H
z), 2.94 (3H, d, J = 5.1 Hz), 2.36
(3H, s) Reference Example 22 3-acetylthio-1- (4-carbamoyl-1,3-
Oxazol-2-yl) azetidine

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(1) 3-tert-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-oxazol-2-yl) azetidine 3-tert-butyldiphenylsilyl obtained in Reference Example 21 (3) Oxy-1- (4-ethoxycarbonyl-1,3
-Oxazol-2-yl) azetidine 1.70 g
(3.77 mmol) was dissolved in 38 ml of benzene, and 0.67 M
Methylamine-trimethylaluminum-benzene solution 1
3.7 ml was added at room temperature under a nitrogen atmosphere, and the mixture was stirred in a 50 ° C water bath for 4 hours. After confirming the completion of the reaction, put 1
100 ml of 0% acetic acid aqueous solution was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate was added to the reaction system, a liquid separation operation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give a white solid 3-
0.83 g of t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3-oxazol-2-yl) azetidine was obtained at a yield of 52%.

¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm)
7.75 (1H, s), 7.61 (4H, d, J = 6.7
Hz), 7.47-7.36 (6H, m), 6.72 (1H,
brs), 5.69 (1H, brs), 4.74-4.69.
(1H, m), 4.12 (2H, t, J = 6.7 Hz), 4.0
5 (2H, dd, J = 5.0, 7.8 Hz), 1.06 (9
H, s) (2) 1- (4-carbamoyl-1,3-oxazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-carbamoyl-1,3- 1.30 g (3.08 mmol) of oxazol-2-yl) azetidine was dissolved in 60 ml of tetrahydrofuran, and the mixture was dissolved in 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice-cooling.
1 ml was added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1- (4-carbamoyl-
1,3-Oxazol-2-yl) -3-hydroxyazetidine was obtained as a white solid in 0.43 g in a yield of 75%.

¹ H-NMR (400 MHz, CD ₃ OD): δ (ppm)
7.87 (1H, s), 4.70-4.65 (1H, m),
4.34 (2H, dd, J = 6.6, 9.5 Hz), 3.9
4 (2H, dd, J = 5.9, 9.5 Hz) (3) 1- (4-carbamoyl-1,3-oxazol-2-yl) -3-methanesulfonyloxyazetidine Reference Example 22 (2 1)-(4-carbamoyl-)
423 mg (2.31 mmol) of 1,3-oxazol-2-yl) -3-hydroxyazetidine was added to methylene chloride 1
0 ml and 30 ml of pyridine, 0.90 ml (11.55 mmol) of methanesulfonyl chloride and 1.60 ml (11.55 mmol) of triethylamine were added under ice-cooling, and after 10 minutes, the reaction system was returned to room temperature. The mixture was stirred for 2 hours. After confirming the completion of the reaction, 1 ml of methanol was added to the system under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1- (4-carbamoyl-1,3-oxazole-). 2-yl) -3-methanesulfonyloxyazetidine as a white solid, 470 m
g, 78% yield.

¹ H-NMR (400 MHz, CD ₃ OD): δ (ppm)
7.91 (1H, s), 5.45-5.42 (1H, m),
4.51 (2H, dd, J = 6.6, 9.5 Hz), 4.2
8 (2H, dd, J = 4.4, 9.5 Hz), 3.16 (3
H, s) (4) 3-acetylthio-1- (4-carbamoyl-
1,3-Oxazol-2-yl) azetidine 1- (4-carbamoyl- obtained in Reference Example 22 (3)
469 mg (1.80 mmol) of 1,3-oxazol-2-yl) -3-methanesulfonyloxyazetidine were dissolved in 23 ml of dimethylformamide, and 1.23 g (10.80) of potassium thioacetate was added at room temperature. mmol) and add 8
The mixture was stirred in a 0 ° C. oil bath for 8 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 1).
0: 1) to give 275 mg of 3-acetylthio-1- (4-carbamoyl-1,3-oxazol-2-yl) azetidine as a white solid in a yield of 63%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.79 (1H, s), 6.69 (1H, brs), 5.6
0 (1H, brs), 4.56 (2H, t, J = 8.8 Hz),
4.44-4.37 (1H, m), 4.03 (2H, dd,
J = 5.1, 8.8 Hz), 2.36 (3H, s) Reference Example 23 3-acetylthio-1- (4-cyano-1,3-oxazol-2-yl) azetidine

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(1) 3-tert-butyldiphenylsilyloxy-1- (4-cyano-1,3-oxazole-2-
Il) azetidine 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3) obtained in Reference Example 21 (3)
-Oxazol-2-yl) azetidine 357 mg
(0.79 mmol) was dissolved in 8 ml of benzene, and 0.67 M methylamine-trimethylaluminum-benzene solution was dissolved.
8 ml was added at room temperature under a nitrogen atmosphere, and the mixture was stirred in a 60 ° C water bath for 7 hours. After confirming the completion of the reaction, add 10%
10 ml of aqueous acetic acid was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate was added to the reaction system, a liquid separation operation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 5: 1) to give 3-t-butyldiphenylsilyloxy-1-colorless oil.
130 mg of (4-cyano-1,3-oxazol-2-yl) azetidine were obtained in a yield of 41%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.66 (1H, s), 7.60 (4H, d, J = 8.1)
Hz), 7.48-7.38 (6H, m), 4.73-4.
70 (1H, m), 4.14 (2H, dd, J = 6.6, 8.
8 Hz), 4.08 (2H, dd, J = 5.1, 9.5H
z), 1.06 (9H, s) (2) 1- (4-cyano-1,3-oxazole-2-
Yl) -3-hydroxyazetidine 0.61 g of 3-t-butyldiphenylsilyloxy-1- (4-cyano-1,3-oxazol-2-yl) azetidine obtained in Reference Example 23 (1) ( 1.51 mmol)
Was dissolved in 30 ml of tetrahydrofuran, and 1.5 ml of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, followed by stirring for 1 hour. After confirming the completion of the reaction, the reaction solution is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (elution solvent:
The residue was purified with ethyl acetate) to give 1- (4-cyano-1,3-
Oxazol-2-yl) -3-hydroxyazetidine was obtained as a white solid in 0.21 g, 86% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (pp
m) 7.70 (1H, s), 4.83-4.81 (1H,
m), 4.40 (2H, dd, J = 6.6, 9.5 Hz),
4.06 (2H, dd, J = 4.4, 8.8 Hz), 2.2
6 (1H, d, J = 5.9 Hz) (3) 1- (4-cyano-1,3-oxazole-2-
Yl) -3-methanesulfonyloxyazetidine 1- (4-cyano-1,3 obtained in Reference Example 23 (2)
-Oxazol-2-yl) azetidine 214 mg
(1.30 mmol) in 10 ml of methylene chloride and 5 ml of pyridine
In methanesulfonyl chloride under ice cooling.
0 ml (6.50 mmol), triethylamine 0.90 ml
(6.50 mmol) was added and 10 minutes later, the reaction system was returned to room temperature and stirred for 2 hours. After confirming the completion of the reaction, add 1 ml of methanol to the system under ice-cooling, and add
Stirred for minutes. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give a colorless oil of 1- (4-
310 mg of cyano-1,3-oxazol-2-yl) -3-methanesulfonyloxyazetidine, yield 9
Obtained at 8%.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.76 (1H, s), 5.42-5.36 (1H, m),
4.53 (2H, dd, J = 6.6, 11.0 Hz);
34 (2H, dd, J = 4.4, 11.0 Hz), 3.11
(3H, s) (4) 3-acetylthio-1- (4-cyano-1,3-
Oxazol-2-yl) azetidine 1- (4-cyano-1,3 obtained in Reference Example 23 (3)
309 mg (1.27 mmol) of -oxazol-2-yl) -3-methanesulfonyloxyazetidine were dissolved in 15 ml of dimethylformamide, and 0.87 g (7.62 mmol) of potassium thioacetate was added at room temperature. And stirred at 80 ° C. oil bath for 5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1) to give colorless oily 3-acetylthio-1- (4-cyano-1,3-oxazol-2-yl). ) 15 azetidine
7 mg, 55% yield.

¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm)
7.72 (1H, s), 4.60 (2H, t, J = 8.8H
z), 4.45-4.38 (1H, m), 4.07 (2H, d
d, J = 5.9, 8.8 Hz), 2.37 (3H, s). Reference Example 24 3-acetylthio-1- (4-azetidinocarbonyl-
1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidine 3-t-butyl obtained in Reference Example 2 (1) Diphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-
Thiazol-2-yl) azetidine 1.0 g (2.14 mmol)
Was dissolved in 50 ml of benzene, 4.6 ml of a 0.67 M azetidine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 4 hours. After confirming the completion of the reaction, 50 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate were added to the system under ice cooling.
Then, the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
n-Hexane: ethyl acetate = 1: 1) and purified as a light brown solid 3-t-butyldiphenylsilyloxy-1-.
(4-azetidinocarbonyl-1,3-thiazole-2
-Yl) azetidine in 0.60 g, 55% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.62 (4H, dd, J =
8.0, 1.4Hz), 7.51-7.36 (6H, m), 7.42 (1H, s), 4.80
-4.68 (1H, m), 4.56 (2H, t, J = 7.7Hz), 4.16 (2H, t,
J = 7.7Hz), 4.09 (2H, t, J = 8.7Hz), 4.00 (2H, dd, J = 8.
7, 4.9Hz), 2.28 (2H, quintet, J = 7.7Hz), 1.06 (9H,
s) (2) 1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1 obtained in Reference Example 24 (1) -(4-azetidinocarbonyl-1,
3-thiazol-2-yl) azetidine 0.60 g (1.18 m
mol) was dissolved in 25 ml of anhydrous tetrahydrofuran, and 1.42 ml (1.42 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, followed by stirring for 30 minutes. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction solution, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: 5% methanol-ethyl acetate) to give 1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine. Was obtained as a white solid in 242 mg in a yield of 86%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.35 (1H, s), 4.
86-4.78 (2H, t, J = 7.7Hz), 4.30 (2H, dd, J = 9.5, 6.6
Hz), 4.16 (2H, t, J = 7.7Hz), 3.93 (2H, dd, J = 9.5, 5.
0Hz), 2.29 (2H, quintet, J = 7.7Hz) 1.95-1.5 (dulls including 1H of OH group) (3) 1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) -3 -Methanesulfonyloxyazetidine 242 mg (1.01 mmol) of 1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 24 (2) was treated with methylene chloride. 1
Dissolve in 0 ml and add methanesulfonyl chloride under ice-cooling.
0.43 ml (3.04 mmol), triethylamine 0.24 ml (3.04
After 10 minutes, the reaction was returned to room temperature and stirred for 30 minutes. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Isopropyl ether was added to the obtained residue, and the mixture was filtered and 1- (4-azetidinocarbonyl-) as a pale yellow solid was obtained.
1,3-Thiazol-2-yl) -3-methanesulfonyloxyazetidine was obtained in 302 mg at a yield of 94%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.44 (1H, s), 5.
46-5.38 (1H, m), 4.58 (2H, t, J = 7.8Hz), 4.43 (2H,
ddd, J = 9.6, 6.6, 1.0Hz), 4.24 (1H, ddd, J = 9.6, 4.
6, 1.0Hz), 4.17 (2H, t, J = 7.8Hz), 3.10 (3H, s), 2.
30 (2H, quintet, J = 7.8 Hz) (4) 3-acetylthio-1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidine 1- obtained in Reference Example 24 (3) Dissolve 302 mg (0.95 mmol) of (4-azetidinocarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine in 10 ml of dimethylformamide, and add 0.65 g of potassium thioacetate at room temperature ( 5.70 mmol) and stirred in an oil bath at 80 ° C. for 6 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
2: 1) to give 3-acetylthio-
1- (4-Azetidinocarbonyl-1,3-thiazol-2-yl) azetidine was obtained at 247 mg in a yield of 87%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.40 (1H, s), 4.
57 (2H, t, J = 7.8Hz), 4.51 (2H, t, J = 8.4Hz), 4.46-4.
36 (1H, m), 4.16 (2H, t, J = 7.8Hz), 3.96 (2H, dd, J
= 8.4, 5.3Hz), 2.36 (3H, s), 2.29 (2H, quintet, J =
7.8 Hz) Reference Example 25 3-acetylthio-1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidine

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(1) 3-tert-butyldiphenylsilyloxy-1- (4-thiomorpholinocarbonyl-1,3-
Thiazol-2-yl) azetidine The 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-ethoxypropyl) obtained in Reference Example 2 (1).
Thiazol-2-yl) azetidine 1.0 g (2.14 mmol)
Was dissolved in 50 ml of benzene, 4.6 ml of a 0.67 M thiomorpholine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 4 hours. After confirming the completion of the reaction, add 50 ml of 10% aqueous acetic acid and ethyl acetate
100 ml was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, ethyl acetate was further added to the reaction system, and a liquid separation operation was performed.
The aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1),
3-t-butyldiphenylsilyloxy- as a light brown solid
There was obtained 1.16 g of 1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidine in a yield of 98%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.32 (4H, dd, J =
(7.9, 1.4Hz), 7.54-7.35 (6H, m), 7.07 (1H, s), 4.80
-4.70 (1H, m), 4.10 (2H, dd, J = 8.8, 6.5Hz), 4.10-
3.86 (6H, m including 2H, dd at 4.00, J = 8.8, 4.8H
z), 2.80-2.55 (4H, m), 1.06 (9H, s) (2) 1- (4-thiomorpholinocarbonyl-1,3-
Thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- (1,3-thiazol-4-thiomorpholinocarbonyl-2-yl) obtained in Reference Example 25 (1) Azetidine 1.16 g
(2.10 mmol) was dissolved in 35 ml of anhydrous tetrahydrofuran, and under ice-cooling, 2.52 ml (2.52 mmol) of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution
Was added and stirred for 30 minutes as it was. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate).
599 mg of (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine was obtained as a white solid in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.09 (1H, s), 4.
89-4.77 (1H, m), 4.32 (2H, dd, J = 9.1, 6.7Hz), 4.10
-3.90 (6H, m including 2H, dd at 3.96, J = 9.1, 4.3H
z), 2.80-2.58 (4H, m), 2.50 (1H, brs) (3) 1- (4-thiomorpholinocarbonyl-1,3-
Thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 25 (2) 599 mg (2.50 mmol) was dissolved in methylene chloride (30 ml) and methanesulfonyl chloride 0.49 ml (6.30 mmol), triethylamine 0.88 ml under ice cooling
(6.30 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature.
The mixture was stirred for 30 minutes as it was. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. After washing the obtained organic layer with saturated saline,
The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: 5% methanol-ethyl acetate) to give a pale yellow solid, 1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) -3. -Methanesulfonyloxyazetidine was obtained in a yield of 709 mg and a yield of 93%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.17 (1H, s), 5.
46-5.38 (1H, m), 4.45 (2H, ddd, J = 9.8, 6.7, <1.1H
z), 4.26 (2H, ddd, J = 9.8, 4.4, 1.1Hz), 4.08-3.93
(4H, m), 3.11 (3H, s), 2.80-2.60 (4H, m) (4) 3-acetylthio-1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidine Reference Example 709 mg (1.95 mmol) of 1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in 25 (3)
Was dissolved in 20 ml of dimethylformamide, 1.34 g (11.7 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in an oil bath at 80 ° C. for 5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: n-hexane: methylene chloride = 1: 1: 1), and 3-acetylthio-1- (4-thiomorpholino) as a light brown solid was obtained. Carbonyl-1,3-thiazol-2-yl) azetidine
It was obtained in 413 mg in a yield of 64%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.13 (1H, s), 4.
53 (2H, t, J = 8.4Hz), 4.48-4.40 (1H, m), 4.13-3.86
(6H, m including 2H, dd at 3.98, J = 8.4, 5.2Hz), 2.
80-2.60 (4H, m), 2.36 (3H, s) Reference Example 26 3-acetylthio-1- (4-pyrrolidinocarbonyl-
1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine 3-t-butyl obtained in Reference Example 2 (1) Diphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-
Thiazol-2-yl) azetidine 1.00 g (2.14 mmo
l) was dissolved in 50 ml of benzene, 7.6 ml of a 0.67 M pyrrolidine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 6 hours. After confirming the completion of the reaction,
Under ice-cooling, 50 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate
Then, the mixture was stirred at room temperature for 2 hours. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4) as a light brown solid.
-Pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine was obtained at 775 mg in a yield of 78%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.70-7.56
(4H, m), 7.35-7.50 (6H, m), 7.21 (1H, s),
4.80-4.70 (1H, m), 4.18-4.06 (2H, m), 4.00
(2H, dd, J = 8.6. 5.1 Hz), 3.80 (2H, t, J = 6.5 H
z), 3.60 (2H, t, J = 6.5 Hz), 1.83-1.98 (4H, m
), 1.06 (9H, s) (2) 3-hydroxy-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine 3-t-butyl obtained in Reference Example 26 (1) Diphenylsilyloxy-1- (4-pyrrolidinocarbonyl-1,
3-thiazol-2-yl) azetidine 775 mg (1.58
was dissolved in 30 ml of anhydrous tetrahydrofuran, and cooled to 1.0 M tetra-n-butylammonium fluoride- under ice-cooling.
2.01 ml (2.01 mmol) of a tetrahydrofuran solution was added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 20: 1) to give 3-hydroxy-1- (4
-Pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine as a white solid, 290 mg, yield 72%
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.42 (1H, s
), 4.88-4.78 (1H, m), 4.32 (2H, dd, J = 9.0, 6.
8 Hz), 3.95 (2H, dd, J = 9.0, 4.3 Hz), 3.82 (2
H, t, J = 6.5 Hz), 3.61 (2H, t, J = 6.5 Hz), 2.43
(1H, d, J = 6.8Hz), 1.83-1.97 (4H, m) (3) 3-Methanesulfonyloxy-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine Reference Example 3-hydroxy-1- (4) obtained in 26 (2)
-Pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine (290 mg, 1.14 mmol) was treated with methylene chloride 9
methanesulfonyl chloride under ice cooling.
30 ml (5.12 mmol), triethylamine 0.70 ml (5.1
2 mmol) and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: methylene chloride:
(Ethyl acetate = 1: 1 to ethyl acetate), and 335 mg of 3-methanesulfonyloxy-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine as a pale yellow solid was collected. Obtained at a rate of 89%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.33 (1H, s
), 5.48-5.38 (1H, m), 4.45 (2H, ddd, J = 10.1,
6.6, 1.2 Hz), 4.26 (2H, ddd, J = 10.1, 4.4, 1.1
Hz), 3.82 (2H, t, J = 6.6 Hz), 3.62 (2H, t, J =
6.6 Hz), 3.10 (3H, s), 2.00-1.83 (4H, m) (4) 3-acetylthio-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine Reference Example 26 ( 335 mg (1.01 mmol) of 3-methanesulfonyloxy-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine obtained in 3) was dissolved in 15 ml of dimethylformamide, and the mixture was dissolved at room temperature. 1.10 g (8.80 mmol) of potassium thioacetate was added thereto, and the mixture was stirred in a 90 ° C. oil bath for 5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-acetylthio-1- (4-pyrrolidinocarbonyl-1,3-thiazol-2-yl) azetidine as a light brown solid. 235 mg, yield 75%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.28 (1H, s
), 4.52 (2H, dd, J = 8.4, 8.4 Hz), 4.39-4.48 (1
H, m), 3.98 (2H, dd, J = 8.4, 5.2 Hz), 3.82 (2H,
t, J = 6.5 Hz), 3.61 (2H, t, J = 6.5 Hz), 2.36 (
3H, s), 1.98 -1.82 (4H, m) Reference Example 27 3-acetylthio-1- (4-piperidinocarbonyl-
1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine 3-t-butyl obtained in Reference Example 2 (1) Butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-
Thiazol-2-yl) azetidine 1.00 g (2.14 mmo
l) was dissolved in 50 ml of benzene, 7.3 ml of a 0.67 M piperidino-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 5 hours. After confirming the completion of the reaction, add 50 ml of 10% aqueous acetic acid and ethyl acetate
100 ml was added, and the mixture was stirred at room temperature for 2 hours. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 3-t-butyldiphenylsilyloxy-1 as a light brown solid.
-(4-piperidinocarbonyl-1,3-thiazole-
607 mg of 2-yl) azetidine were obtained in a yield of 56%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.61 (4H, d
d, J = 6.2 Hz), 7.35 -7.50 (6H, m), 6.95 (1H, s
), 4.78-4.70 (1H, m), 4.17-4.05 (2H, m), 4.
01 (2H, dd, J = 8.6.4.9 Hz), 3.64 (4H, t, J = 5.
4 Hz), 1.75-1.48 (6H, m), 1.06 (9H, s) (2) 3-hydroxy-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine Reference Example 27 3-t-butyldiphenylsilyloxy-1- (4-piperidinocarbonyl-1, obtained in (1),
3-thiazol-2-yl) azetidine 607 mg (1.20
mmol) was dissolved in 25 ml of anhydrous tetrahydrofuran, and cooled to 1.0 M with tetra-n-butylammonium fluoride- under ice-cooling.
1.40 ml (1.40 mmol) of a tetrahydrofuran solution was added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give 3-hydroxy-1- (4
-Piperidinocarbonyl-1,3-thiazol-2-yl) azetidine as a white solid, 310 mg, yield 97%
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.97 (1H, s
), 4.87-4.77 (1H, m), 4.33 (2H, ddd, J = 9.8,
6.6, 1.1 Hz), 3.96 (2H, dd, J = 9.8, 4.4 Hz), 3.
57-3.72 (4H, t, J = 5.4 Hz), 1.81-1.45 (6H, m
(3) 3-Methanesulfonyloxy-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine 3-hydroxy-1- (4) obtained in Reference Example 27 (2).
-Piperidinocarbonyl-1,3-thiazol-2-yl) azetidine (310 mg, 1.16 mmol) in methylene chloride 1
Dissolve in 0 ml and add methanesulfonyl chloride under ice-cooling.
0.27 ml (3.48 mmol), triethylamine 0.49 ml (3.
48 mmol) and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-methanesulfonyloxy- as a pale yellow solid.
346 mg of 1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine was obtained in a yield of 86%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.06 (1H, s
), 5.37-5.47 (1H, m), 4.46 (2H, dd, J = 9.8,
6.7 Hz), 4.27 (2H, dd, J = 9.8, 4.3 Hz), 3.65 (
4H, t, J = 5.2 Hz), 3.10 (3H, t, J = 5.2 Hz), 1.
78-1.47 (6H, m) (4) 3-Acetylthio-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine 3-methanesulfonyl obtained in Reference Example 27 (3) 346 mg (1.00 mmol) of oxy-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine was dissolved in 15 ml of dimethylformamide, and 687 mg (6.01 mmol) of potassium thioacetate was added at room temperature. ) And stirred in a 90 ° C. oil bath for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (elution solvent: ethyl acetate), and 3-acetylthio-1- (4-piperidinocarbonyl-1,3-thiazol-2-yl) azetidine as a light brown solid is obtained. Was obtained in a yield of 276 mg and 85%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.02 (1H, s
), 4.54 (2H, dd, J = 8.5 Hz), 4.39-4.49 (1H, m
), 3.99 (2H, dd, J = 8.5, 5.4 Hz), 3.65 (4H, t,
J = 5.4 Hz), 2.36 (3H, s), 1.90-1.40 (6H, m) Reference Example 28 3-acetylthio-1- (4-N-cyclopentylcarbamoyl-1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-N-cyclopropylcarbamoyl-1,
3-Thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-ethoxypropyl) obtained in Reference Example 2 (1)
Thiazol-2-yl) azetidine 1.00 g (2.14 mmo
l) was dissolved in 50 ml of benzene, and 7.20 ml of 0.67 M cyclopropylamine-trimethylaluminum-benzene solution was dissolved.
Was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 2 hours. After confirming the completion of the reaction, 50 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate were added to the system under ice cooling, and the mixture was stirred at room temperature for 2 hours. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 3-t-butyldiphenylsilyloxy-1- (4-N-cyclopropylcarbamoyl) as a light brown solid. −
1,79-thiazol-2-yl) azetidine 979 mg,
Was obtained in a yield of 90%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.62-7.62
(4H, m), 7.33-7.50 (6H, m), 7.36 (1H, s),
4.80-4.68 (1H, m), 4.18-4.06 (3H, m), 4.02
(2H, dd, J = 8.2, 5.8 Hz), 3.80-3.70 (1H, m),
1.06 (9H, s), 0.83 (1H, t, J = 6.9 Hz), 0.82 (
1H, t, J = 6.9 Hz), 0.70-0.58 (2H, m) (2) 1- (4-N-cyclopropylcarbamoyl-1,
3-thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-N-cyclopropylcarbamoyl-1,3-thiazole- obtained in Reference Example 28 (1) 2-yl) azetidine 907 m
g (1.94 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml), and cooled under ice-cooling to a 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution (2.30 ml (2.30 mmo).
l) was added and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction solution, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. And the residue was purified by silica gel column chromatography (eluent: ethyl acetate).
-(4-N-Cyclopropylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine was obtained as a white solid in 367 mg, 81% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.37 (1H, s
), 7.23 (1H, s), 4.67-4.80 (1H, m), 4.32 (
2H, dd, J = 9.0, 6.7 Hz), 3.96 (2H, dd, J = 9.0, 4.
3 Hz), 2.82-2.70 (1H, m), 0.84 (1H, t, J = 7.1
Hz), 0.83 (1H, t, J = 7.1 Hz), 0.55-0.70 (2
H, m) (3) 1- (4-N-cyclopropylcarbamoyl-1,
3-thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) -3 obtained in Reference Example 28 (2).
-Dissolve 376 mg (1.57 mmol) of hydroxyazetidine in 10 ml of methylene chloride and 0.36 ml (4.71 mmol) of methanesulfonyl chloride and 0.66 ml of triethylamine under ice cooling.
ml (4.71 mmol) was added, and the mixture was stirred for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give a pale yellow solid 1
-(4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine was obtained in 343 mg in a yield of 88%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.45 (1H, s
), 7.18 (1H, s), 5.48-5.36 (1H, m), 4.44 (
2H, dd, J = 10.2, 6.6 Hz), 4.26 (2H, dd, J = 10.2,
4.4 Hz), 3.11 (3H, s), 2.91-2.79 (1H, m),
0.85 (1H, d, J = 6.9 Hz), 0.84 (1H, d, J = 6.9 Hz
), 0.72-0.66 (2H, m) (4) 3-acetylthio-1- (4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) azetidine 1 obtained in Reference Example 28 (3) -(4-N-cyclopropylcarbamoyl-1,3-thiazol-2-yl) -3
-Methanesulfonyloxyazetidine 433 mg (1.31 mm
ol) was dissolved in 20 ml of dimethylformamide, and 895 mg (7.84 mmol) of potassium thioacetate was added at room temperature to give 9
The mixture was stirred in a 0 ° C. oil bath for 5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-acetylthio-1- (4-N-cyclopropylcarbamoyl-1) as a light brown solid.
343 mg of 3-thiazol-2-yl) azetidine were obtained in a yield of 88%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.14 (1H, s
), 7.20 (1H, br s), 4.52 (2H, t, J = 8.6 Hz),
4.49-4.38 (1H, m), 3.98 (2H, dd, J = 8.6,5.9 Hz
), 3.98 (2H, dd, J = 8.6, 5.9 Hz), 2,90-2.82
(1H, m), 2.36 (3H, s), 0.84 (1H, t, J = 7.0 Hz
), 0.83 (1H, t, J = 7.0 Hz), 0.70 -0.56 (2H, m
Reference Example 29 3-Acetylthio-1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-N-cyclobutylcarbamoyl-1,3
-Thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-ethoxypropyl) obtained in Reference Example 2 (1)
Thiazol-2-yl) azetidine 1.00 g (2.14 mmo
l) was dissolved in 50 ml of benzene, 7.30 ml of a 0.67 M cyclobutylamine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 2 hours. After confirming the completion of the reaction, 50 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate were added to the system under ice cooling, and the mixture was stirred at room temperature for 2 hours.
Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-N-cyclobutylcarbamoyl) as a light brown solid. -1,
965 mg of 3-thiazol-2-yl) azetidine were obtained in a yield of 87%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.62 (4H,
d, J = 8.0 Hz), 7.28 -7.39 (6H, m), 7.34 (1H, s
), 4.70-4.80 (1H, m), 4.58-4.46 (1H, m), 4.
11 (2H, dd, J = 8.8, 6.5 Hz), 4.02 (2H, dd, J =
8.8, 4.0 Hz), 2.35-2.20 (2H, m), 2.05-1.92
(2H, m), 1.69-1.80 (2H, m), 1.07 (9H, s), (2) 1- (4-N-cyclobutylcarbamoyl-1,3
-Thiazol-2-yl) -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-N-cyclobutylcarbamoyl-1,3-thiazole-2 obtained in Reference Example 29 (1) -Yl) azetidine 966 mg
(1.86 mmol) was dissolved in 40 ml of anhydrous tetrahydrofuran, and under ice-cooling, a 1.0 M solution of tetra-n-butylammonium fluoride-tetrahydrofuran 2.20 ml (2.20 mmol)
Was added and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction solution, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. And the residue is purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1-
Ethyl acetate), and 433 mg of 1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) -3-hydroxyazetidine as a white solid was obtained in a yield of 9
Obtained at 5%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.35 (1H, s
), 4.89-4.78 (1H, m), 4.60-4.45 (1H, m),
4.34 (2H, dd, J = 9.3, 6.7 Hz), 3.96 (2H, dd, J =
9.3, 6.7 Hz), 2.32-2.48 (2H, m), 2.48-2.32
(1H, m), 1.72- 1.68 (2H.m) (3) 1- (4-N-cyclobutylcarbamoyl-1,3
-Thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) -3- obtained in Reference Example 29 (2)
Hydroxyazetidine 433 mg (1.71 mmol) was dissolved in methylene chloride 10 ml, and methanesulfonyl chloride 0.30 ml (5.12 mmol), triethylamine 0.70 ml was added under ice cooling.
(5.12 mmol) was added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction system,
The aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate.
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate).
567 mg of 1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine as a pale yellow solid, yield 100
%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.43 (1H, s
), 5.48-5.38 (1H, m), 4.60-4.38 (3H, m incl
uding 4.47 (2H, dd, J = 9.6, 6.6 Hz)), 4.28 (2
H, dd, J = 9.6, 4.6 Hz), 3.11 (3H, s), 2.48-2 3
3 (2H, m), 2.07-1.92 (2H, m), 1.85-1.68 (
2H, m) (4) 3-acetylthio-1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidine 1- (4-N-) obtained in Reference Example 29 (3). Cyclobutylcarbamoyl-1,3-thiazol-2-yl) -3-
Methanesulfonyloxyazetidine 567 mg (1.71 mmo
l) was dissolved in 10 ml of dimethylformamide, and at room temperature, 1.17 g (10.3 mmol) of potassium thioacetate was added.
Stirred overnight in an oil bath. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate =
1: 3) to give 318 mg of 3-acetylthio-1- (4-N-cyclobutylcarbamoyl-1,3-thiazol-2-yl) azetidine as a light brown solid, in a yield of 75%.
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.33 (1H, s
), 4.62-4.37 (4H, m including 4.54 (2H, t, J =
8.6 Hz), 4.00 (2H, dd, J = 8.6, 2.5 Hz)), 2,31-
2.48 (5H, m including 2.37 (3H, s)), 2.07-1.93
(2H, m), 1.84-1.67 (2H, m) <Reference Example 30> 3-acetylthio-1- [4- (4-methylpiperazine-
1-carbonyl) -1,3-thiazol-2-yl] azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- [4- (4-methylpiperazine-1-carbonyl) -1,3-thiazol-2-yl] azetidine Obtained in Reference Example 2 (1). 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-
Thiazol-2-yl) azetidine 1.00 g (2.14 mmo
l) was dissolved in 50 ml of toluene, and 7.40 ml of 0.67M 1-methylpiperazine-trimethylaluminum-toluene solution was dissolved.
Was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 3 hours. After confirming the completion of the reaction, 50 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate were added to the system under ice cooling, and the mixture was stirred at room temperature for 2 hours.
Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 3-t-butyldiphenylsilyloxy-1- [4- (4-methylpiperazine) as a light brown solid. -1-carbonyl) -1,3-thiazol-2-yl] azetidine
41 mg was obtained in a yield of 85%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.62 (4H, d
d, J = 8.0, 1.4 Hz), 7.50-7.36 (6H, m), 7.08
(1H, s), 4.10 (2H, dd, J = 10.3, 6.9 Hz), 4.00
(2H, dd, J = 10.3, 5.0 Hz)), 3.98-3.65 (4H, m
), 2.63-2.42 (4H, m), 2.37 (3H, m), 1.06 (9
H, s) (2) 3-hydroxy-1- [4- (4-methylpiperazine-1-carbonyl) -1,3-thiazol-2-yl]
Azetidine 3-t-butyldiphenylsilyloxy-1- [4- (4-methylpiperazine-1-) obtained in Reference Example 30 (1).
Carbonyl) -1,3-thiazol-2-yl] azetidine (941 mg, 1.81 mmol) was added to anhydrous tetrahydrofuran 47
dissolved in 1.0 ml of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice-cooling.
2.17 mmol) and stirred for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 3: 1) to give 3-hydroxy-1-
[4- (4-methylpiperazine-1-carbonyl) -1,
3-thiazol-2-yl] azetidine was obtained as a white solid in 422 mg, in a yield of 83%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.01 (1H, s
), 4.88-4.80 (1H, m), 4.26 (2H, dd, J = 8.6,
7.1 Hz), 3.96 (2H, dd, J = 8.6, 4.8 Hz), 3.89-
3.68 (4H, m), 2.80-2.58 (4H, m), 2.31 (3H,
s) (3) 3-Methanesulfonyloxy-1- [4- (4-methylpiperazine-1-carbonyl) -1,3-thiazol-2-yl] azetidine 3- obtained in Reference Example 30 (2) Hydroxy-1-1-1
[4- (4-methylpiperazine-1-carbonyl) -1,
3-thiazol-2-yl] azetidine 422 mg (1.49 m
mol) was dissolved in 21 ml of methylene chloride, and 0.14 ml (1.79 mmol) of methanesulfonyl chloride and 0.25 ml (1.79 mmol) of triethylamine were added under ice-cooling.
Stirred for hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: methanol = 3: 1) to give 3-methanesulfonyloxy-1- as a pale yellow solid.
[4- (4-methylpiperazine-1-carbonyl) -1,
3-thiazol-2-yl] azetidine in 537 mg, yield
Obtained at 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.36 (1H, s
), 5.47-5.40 (1H, m), 4.46 (2H, dd, J = 10.0,
6.6 Hz), 4.27 (2H, dd, J = 10.0, 4.3 Hz), 3.56-
3.47 (4H, m), 3.11 (3H, s), 2.96-2.86 (4H, m
), 2.81 (3H, s) (4) 3-acetylthio-1- [4- (4-methylpiperazine-1-carbonyl) -1,3-thiazol-2-yl] azetidine Obtained in Reference Example 26 (3). 337 mg of the obtained 3-methanesulfonyloxy-1- [4- (4-methylpiperazine-1-carbonyl) -1,3-thiazol-2-yl] azetidine
(1.49 mmol) was dissolved in 16 ml of dimethylformamide, and 1.02 g (8.94 mmol) of potassium thioacetate was added at room temperature.
Was added and stirred in a 90 ° C. oil bath for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 3-acetylthio-1- [4- (4-methylpiperazine-1-carbonyl) as a light brown solid. [1,3-thiazol-2-yl] azetidine was obtained in a yield of 261 mg and 51%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.15 (1H, s
), 4.53 (2H, t, J = 8.5 Hz), 4.48-4.38 (1H, m
), 3.98 (2H, dd, J = 8.5, 5.4 Hz), 3.96-3.74 (
4H, m), 2.63-2.42 (4H, m), 3.49 (6H, s) Reference Example 31 3-acetylthio-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-thiazole- 2-yl]
Azetidine

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(1) 1-t-butoxycarbonyl-3-
Methoxyazetidine 1-benzhydryl-3-hydroxyazetidine 10.0 g
(41.8 mmol) was dissolved in 300 ml of methanol and subjected to catalytic hydrogen reduction at room temperature in the presence of 10.0 g of 10% palladium on carbon for 3 hours. After confirming the completion of the reaction, the reaction solution was filtered, and 18.2 g (83.6 mmol) of di-t-butoxycarbonyl anhydride was added to the filtrate.
Was added and stirred at room temperature for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated, and the obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
1: 1 to 1: 2) to obtain 1-t-butoxycarbonyl-3-hydroxyazetidine (7.05 g, 97% yield). Subsequently, 2.5 g (14.4 mmol) of 1-t-butoxycarbonyl-3-hydroxyazetidine was added to dimethylformamide.
Dissolve in 125ml and cool with sodium hydride (55% oil
Dispersion) 1.27 g (28.8 mmol) was added, 10 minutes later, the temperature was returned to room temperature, and the mixture was stirred for 0.5 hour. Next, 1.79 ml (28.8 mmol) of methyl iodide was added to the reaction system under ice cooling, and after 10 minutes, the temperature was returned to room temperature, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, a 10% acetic acid aqueous solution was added under ice cooling, and the mixture was stirred for 30 minutes as it was. Subsequently, ethyl acetate and 10% saline were added to the system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2:
Purification was performed in 1) to obtain 2.18 g of colorless oily 1-t-butoxycarbonyl-3-methoxyazetidine in a yield of 81%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 4.16-4.10
(1H, m), 4.09-4.03 (2H, m), 3.82 (2H, dd, J = 10.
2, 4.4Hz), 3.28 (3H, s), 1.44 (9H, s) (2) 3-t-butyldiphenylsilyloxy-1-
[4- (3-Methoxy-azetidine-1-carbonyl)-
1,3-thiazol-2-yl] azetidine 1.60 g (13.9 mmol) of 1-t-butoxycarbonyl-3-methoxyazetidine obtained in Reference Example 31 (1) was added to 1,4
-Dissolved in 26 ml of dioxane and 4N-hydrochloric acid gas under ice-cooling-
26 ml of 1,4-dioxane was added, followed by stirring at room temperature overnight. After confirming the completion of the reaction, the reaction solution was filtered, and ethyl acetate and diisopropyl ether were added to the obtained residue, followed by filtration. 1.84 g of gin hydrochloride was obtained with a yield of 100%. Subsequently, Reference Example 2 (1)
3-tert-butyldiphenylsilyloxy-1 obtained in
-(4-ethoxycarbonyl-1,3-thiazole-2
-Yl) azetidine 500 mg (1.07 mmol) in toluene 25 ml
And 3.21 ml of a 0.67 M 3-methoxyazetidine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was stirred in a water bath at 80 ° C. for 1 hour. After confirming the completion of the reaction, 20 ml of 10% aqueous acetic acid and 50 ml of ethyl acetate were added to the system under ice cooling.
ml was added and the mixture was stirred at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- [4- (3-methoxy-azetidine-1-carbonyl) as a light brown solid. [1,3-thiazol-2-yl] azetidine was obtained in a yield of 366 mg and a yield of 67%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.64-7.60
(4H, m), 7.49-7.38 (6H, m), 7.36 (1H, s), 4.78-
4.70 (2H, m), 4.42-4.36 (1H, m), 4.32 -4.25 (1
H, m), 4.24-4.18 (1H, m), 4.09 (2H, t, J = 7.3Hz),
4.03 to 3.96 (3H, m), 3.33 (3H, s), 1.07 (9H, s) (3) 3-hydroxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3- Thiazole-2-
[Ill] azetidine 3-t-butyldiphenylsilyloxy-1- [4- (3-methoxy-azetidine-) obtained in Reference Example 31 (2)
870 mg (1.71 mmol) of 1-carbonyl) -1,3-thiazol-2-yl] azetidine was added to anhydrous tetrahydrofuran 45
dissolved in ice-cold solution, and 2.06 ml of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice-cooling (2.06 m
mol) was added and the mixture was stirred as it was for 0.5 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1) to give 3-hydroxy-1- [4- (3
-Methoxy-azetidine-1-carbonyl) -1,3-
Thiazol-2-yl] azetidine as a white solid, 4
81 mg, 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.38 (1H,
s), 4.85-4.79 (1H, m), 4.75 (1H, dd, J = 10.3, 5.9
Hz), 4.41 (1H, dd, J = 11.0, 2.9 Hz), 4.34-4.25 (3
H, m), 4.22 (1H, tt, J = 6.6, 4.4 Hz), 4.01 (1H, dd,
J = 10.3, 2.9 Hz), 3.93 (2H, dd, J = 8.8, 4.4 Hz), 3.3
2 (3H, s) (4) 3-Methanesulfonyloxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine In Reference Example 31 (3). The obtained 3-hydroxy-1- [4
-(3-methoxy-azetidine-1-carbonyl) -1,
3-thiazol-2-yl] azetidine 480 mg (1.71 mmol
l) was dissolved in methylene chloride (25 ml), and methanesulfonyl chloride (397 μl (5.13 mmol), triethylamine 7
19 μl (5.13 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9).
5: 5) to give 3-methanesulfonyloxy-1- [4- (3-methoxy-azetidine-1-) as a pale yellow solid.
568 mg of carbonyl) -1,3-thiazol-2-yl] azetidine were obtained in a yield of 96%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.46 (1H,
s), 5.45-5.39 (1H, m), 4.74 (1H, dd, J = 10.6, 6.2
Hz), 4.47-4.37 (3H, m), 4.33-4.19 (4H, m), 4.
04-3.99 (1H, m), 3.33 (3H, s), 3.10 (3H, s) (5) 3-acetylthio-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3- Thiazole-2
-Yl] azetidine 3-Methanesulfonyloxy-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-thiazol-2-yl] azetidine 560m obtained in Reference Example 31 (4).
g (1.61 mmol) in 28 ml of dimethylformamide,
1.10 g (9.67 mmol) of potassium thioacetate was added at room temperature,
The mixture was stirred in an 80 ° C. oil bath for 4.5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 97: 3) to give 3-acetylthio-1- [4- (3-methoxy-azetidine-) as a light brown solid. 1-carbonyl) -1,3-thiazole-2
356 mg of [-yl] azetidine was obtained in a yield of 68%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.43 (1H,
s), 4.73 (1H, dd, J = 10.3, 5.1Hz), 4.51 (2H, t, J =
8.1Hz), 4.46-4.37 (2H, m), 4.32-4.26 (1H, m),
4.21 (1H, tt, J = 6.6, 4.4Hz), 4.00-3.93 (2H, m),
3.78-3.72 (1H, m), 3.32 (3H, s), 2.36 (3H, s) Reference Example 32 3-acetylthio-1- (4-phenylcarbamoyl-
1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine 3-t-butyldiphenyl obtained in Reference Example 2 (1) Silyloxy-1- (4-ethoxycarbonyl-1,3-
Thiazol-2-yl) azetidine 2.00 g (4.29 mmo
l) was dissolved in 100 ml of toluene, 14.6 ml of a 0.67 M aniline-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 3 hours. After confirming the completion of the reaction, 100 ml of 10% aqueous acetic acid and 200 ml of ethyl acetate were added to the system under ice cooling, and the mixture was stirred at room temperature for 3 hours. Subsequently, ethyl acetate was further added to the reaction system, and a liquid separation operation was performed.
The aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1) to give 3-t-butyldiphenylsilyloxy-1 as a light brown solid.
-(4-phenylcarbamoyl-1,3-thiazole-
2.20 g of 2-yl) azetidine was obtained in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.73-7.61
(6H, m), 7.51-7.30 (9H, m), 7.14-7.08 (1H,
m), 4.82-4.76 (1H, m), 4.14 (2H, dd, J = 15.2,
8.2 Hz), 4.06 (2H, dd, J = 8.9, 4.6 Hz), 1.08
(9H, s) (2) 3-Hydroxy-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy- obtained in Reference Example 32 (1) 1- (4-phenylcarbamoyl-1,
3-thiazol-2-yl) azetidine 2.20 g (4.29
(mmol) was dissolved in 110 ml of anhydrous tetrahydrofuran, and 1.0M tetra-n-butylammonium fluoride was added under ice-cooling.
-Tetrahydrofuran solution (5.15 ml, 5.15 mmol) was added, and the mixture was stirred for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to give 3-hydroxy-1- (4-phenylcarbamoyl-1,3-phenyl-3- (3-phenylcarbamoyl).
Thiazol-2-yl) azetidine as a white solid
1.18 g, 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.04 (1H, b
rs), 7.76-7.65 (2H, m), 7.51-7.37 (3H, m
), 7.18-7.08 (1H, m), 4.90-4.80 (1H, m), 4.3
6 (2H, dd, J = 9.1, 6.6 Hz), 3.99 (2H, dd, J = 9.
1, 4.3 Hz) (3) 3-Methanesulfonyloxy-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine 3-hydroxy-1- (obtained in Reference Example 32 (2) 4
-Phenylcarbamoyl-1,3-thiazol-2-yl) azetidine 1.18 mg (4.29 mmol) in methylene chloride
Dissolve in 60 ml and mix with methanesulfonyl chloride under ice-cooling
0.50 ml (6.44 mmol), triethylamine 0.90 ml (6.
44 mmol) and stirred for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: methylene chloride:
Purified with ethyl acetate = 9: 1) to give a pale yellow solid 3-
Methanesulfonyloxy-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine
1.36 g, yield 89%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.98 (1H, b
rs), 7.68 (2H, d, J = 7.6 Hz), 7.55 (1H, s),
7.36 (2H, d, J = 8.0 Hz), 7.18-7.08 (1H, m),
5.50-5.40 (1H, m), 4.51 (2H, ddd, J = 9.6, 6.
6, 1.0 Hz), 4.32 (2H, ddd, J = 9.6, 4.3, 1.0 Hz),
3.12 (3H, s) (4) 3-Acetylthio-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine 3-methanesulfonyloxy-1- obtained in Reference Example 32 (3) 1.28 g (3.85 mmol) of (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine was dissolved in 40 ml of dimethylformamide, and 2.60 g (23.1 mmol) of potassium thioacetate was added at room temperature. The mixture was stirred in an oil bath for 3 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate =
1: 2) to give 893 mg of 3-acetylthio-1- (4-phenylcarbamoyl-1,3-thiazol-2-yl) azetidine as a light brown solid in a yield of 70%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.01 (1H, b
rs), 7.68 (2H, d, J = 8.6 Hz), 7.35 (2H, t, J
= 7.5 Hz), 7.20-7.28 (1H, m), 4.58 (2H, t, J =
8.5 Hz), 4.52-4.02 (1H, m), 4.04 (2H, dd, J =
8.5, 5.3 Hz), 2.83 (3H, s) Reference Example 33 3-acetylthio-1- {4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} Azetidine

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(1) [2- (t-Butyldiphenylsilyloxy) -ethyl] -carbamic acid benzyl ester 2.0 g (32.7 mmol) of aminoethanol was dissolved in 60 ml of methylene chloride, and benzyl chloroformate 5.6 was obtained.
ml (41.3 mmol), triethylamine 5.5 ml (3
9.5 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: toluene: acetonitrile = 3: 2), and 5.37 g of (2-hydroxyethyl) -carbamic acid benzyl ester as a white solid was obtained in a yield of 84%. Obtained. Subsequently, 5.37 g (27.5 mmol) of the obtained (N-benzyloxycarbonyl) -2-aminoethanol was dissolved in 160 ml of dimethylformamide, and 8.6 ml of tert-butyldiphenylsilane chloride (33. 0 mmol) and 2.3 g (33.8 mmol) of imidazole, followed by stirring at room temperature overnight. After confirming the completion of the reaction, ethanol was added to the system, and the mixture was stirred for 2 hours. Next, ethyl acetate is added to the system.
A saturated aqueous sodium hydrogen carbonate solution was added, and liquid separation operation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 5: 1).
To give 11.93 g of [2- (t-butyldiphenylsilyloxy) -ethyl] -carbamic acid benzyl ester as a colorless transparent syrup in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.64 (4H, d,
J = 6.8Hz), 7.46-7.28 (12H, m), 5.10 (2H, s), 3.73
(2H, t, J = 4.9Hz), 3.35 (2H, q, J = 4.9Hz), 1.05 (9H,
s) (2) 3-tert-butyldiphenylsilyloxy-1-
{4-[(2- (t-butyldiphenylsilyloxy)-
Ethylcarbamoyl] -1,3-thiazol-2-yl diazetidine 3.01 g (6.0 g) of [2- (t-butyldiphenylsilyloxy) -ethyl] -carbamic acid benzyl ester obtained in Reference Example 33 (1). 9 mmol) in methanol 15
Dissolve in 0 ml, 20% palladium hydroxide-carbon.
Catalytic hydrogen reduction was performed at room temperature in the presence of 0 g. After confirming the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent:
Purification was performed using methylene chloride: methanol = 10: 1) to obtain 1.49 g of 2- (t-butyldiphenylsilyloxy) -ethylamine as a light brown syrup in a yield of 72%. Subsequently, 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1).
16 g (2.49 mmol) was dissolved in 58 ml of benzene,
0.67M 2- (t-butyldiphenylsilyloxy) -ethylamine-trimethylaluminum-benzene solution
8.5 ml was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 5 hours. After confirming the completion of the reaction, add 10% aqueous acetic acid
Add 50 ml and 200 ml of ethyl acetate, and add 1 ml at room temperature.
Stirred for hours. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3:
Purified in 1), and a light brown solid 3-t-butyldiphenylsilyloxy-1- {4- [2- (t-butyldiphenylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl 1.68 g of azetidine, yield
Obtained at 94%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.74 (1H, br
t, J = 4.6Hz), 7.67 (4H, d, J = 7.5Hz), 7.60 (4H, d,
J = 7.5Hz), 7.42-7.32 (13H, m), 4.78-4.68 (1H, m), 4.
08 (2H, t, J = 7.8Hz), 4.03-3,98 (2H, m), 3.79 (2H,
t, J = 4.6Hz), 3.56 (2H, t, J = 4.6Hz), 1.08 (9H, s),
1.06 (9H, s) (3) 3-Hydroxy-1- (4-hydroxyethylcarbamoyl-1,3-thiazol-2-yl) azetidine 3-t-butyldiphenylsilyl obtained in Reference Example 33 (2) Oxy-1- {4- [2- (t-butyldiphenylsilyloxy) -ethylcarbamoyl] -1,3-thiazol-2-yl} azetidine 1.68 g (2.33 m
mol) was dissolved in 75 ml of anhydrous tetrahydrofuran, and cooled to 1.0 M tetra-n-butylammonium fluoride under ice-cooling.
5.6 ml (5.6 mmol) of a tetrahydrofuran solution was added, and the mixture was stirred as it was for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10:
Purification was performed in 1) to obtain 481.2 mg of 3-hydroxy-1- (4-hydroxyethylcarbamoyl-1,3-thiazol-2-yl) azetidine as a white solid in a yield of 85%. ¹ H-NMR (400 MHz, MeOH-d ₄ ): δ (ppm) 7.39 (1H, s),
4.78 (1H, m), 4.31 (2H, dd, J = 8.4, 7.0Hz), 3.89 (2
H, dd, J = 8.4, 4.8Hz), 3.67 (2H, t, J = 5.9Hz), 3.46
(2H, t, J = 5.9 Hz) (4) 1- [4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1,3-thiazole-2-
Yl] -3-hydroxyazetidine 3-hydroxy-1- (4) obtained in Reference Example 33 (3).
-Hydroxyethylcarbamoyl-1,3-thiazol-2-yl) azetidine 481.2 mg (1.98 mmol)
l) was dissolved in 24.0 ml of dimethylformamide, and 352 mg of t-butyldimethylsilane chloride was added under ice cooling.
(2.3 mmol), 116.3 mg of imidazole (2.4 m
mol), and the mixture was stirred under ice cooling for 4 hours. After confirming the completion of the reaction, methanol was added to the system and stirred for 30 minutes. Next, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 3), and 1- [4- [2- (t-butyldimethylsilyloxy) -ethyl) was obtained as a colorless transparent syrup. Carbamoyl] -1,3-thiazole-2-
531.1 mg of yl] -3-hydroxyazetidine,
Yield 75%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.60 (1H, t,
J = 5.9Hz), 7.35 (1H, s), 4.88-4.76 (1H, m), 4.30
(2H, dd, J = 9.8, 7.8Hz), 3.93 (2H, dd, J = 9.8,4.9H
z), 3.75 (2H, t, J = 5.9Hz), 3.52 (2H, q, J = 5.9Hz),
2.85 (1H, d, J = 6.8 Hz), 0.92 (9H, s), 0.08 (6H, s) (5) 1- [4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1 , 3-thiazole-2-
Yl] -3-methanesulfonyloxyazetidine 1- [4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1, obtained in Reference Example 33 (4),
3-thiazol-2-yl] -3-hydroxyazetidine 531.1 mg (1.49 mmol) was treated with methylene chloride 2
The solution was dissolved in 6.6 ml, and under ice-cooling, methanesulfonyl chloride 0.3 ml (3.9 mmol), triethylamine 0.5
2 ml (3.7 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for an hour. After confirming the completion of the reaction, methanol was added to the reaction system, followed by stirring for 30 minutes. Thereafter, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: toluene: ethyl acetate = 1:
Purified in 1) to give 1- [4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl]-as a pale yellow solid.
1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine (647.1 mg, yield: 100%)
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.54 (1H, br
t, J = 5.9Hz), 7.44 (1H, s), 5.46-5.39 (1H, m), 4.4
3 (2H, dd, J = 9.7, 6.8Hz), 4.24 (2H, dd, J = 9.7, 3.9
Hz), 3.76 (2H, t, J = 5.9Hz), 3.53 (2H, t, J = 5.9Hz),
3.11 (3H, s), 0.93 (9H, s), 0.08 (6H, s) (6) 3-acetylthio 1- [4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1,3 −
Thiazol-2-yl] azetidine 1- [4- [2- (t-butyldimethylsilyloxy) -ethylcarbamoyl] -1, obtained in Reference Example 33 (5),
3-thiazol-2-yl] -3-methanesulfonyloxyazetidine (647.1 mg, 1.49 mmol) was dissolved in dimethylformamide (32.0 ml), and potassium thioacetate (1.28 mg, 8.9 mmol) was added at room temperature. ) And add 80
The mixture was stirred in an oil bath for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 2) to give 3-acetylthio-1- [4- [2- (t-butyldimethylsilyl) as a light brown solid. Oxy) -ethylcarbamoyl] -1,3-thiazole-2-
[Ill] azetidine was obtained in 398.2 mg, 65% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.55 (1H, br
t, J = 5.4Hz), 7.40 (1H, s), 4.51 (2H, dd, J = 8.8,
7.8Hz), 4.48-4.40 (1H, m), 3.96 (2H, dd, J = 8.8, 4.
9Hz), 3.75 (2H, t, J = 5.4Hz), 3.52 (2H, q, J = 5.4H
z), 2.37 (3H, s), 0.92 (9H, s), 0.08 (6H, s) Reference Example 34 3-acetylthio-1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) ) -Propylcarbamoyl] -1,3-thiazol-2-yl] azetidine

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(1) [(1S) -1- (t-Butyldiphenylsilyloxymethyl) -propyl] -carbamic acid benzyl ester 2.00 g (22.4 mmol) of L-ethylglycinol was dissolved in 60 ml of methylene chloride, and 3.84 ml of benzyl formate (26.9 m
mol) and 3.77 ml (26.9 mmol) of triethylamine were added under ice-cooling, followed by stirring at room temperature for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 2: 1 to 1: 2) to give [(1S) -1- (hydroxymethyl) -propyl] as a colorless oil.
4.27 g of carbamic acid benzyl ester was obtained in a yield of 85%. Subsequently, [(1S) -1- (hydroxymethyl) -propyl] -carbamic acid benzyl ester 4.27 g (19.1 m
mol) was dissolved in 128 ml of dimethylformamide, and 5.97 ml (22.9 mmol) of t-butyldiphenylsilane chloride was dissolved under ice cooling.
l) and 1.56 g (22.9 mmol) of imidazole were added, followed by stirring at room temperature overnight. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was saturated with aqueous sodium hydrogen carbonate,
After washing with saturated saline and drying over anhydrous sodium sulfate,
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1 to 4: 1), and white crystals of [(1S) -1- (t-butyldiphenylsilyloxy) were obtained. 9.48 g of methyl) -propyl] -carbamic acid benzyl ester was obtained in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.65-7.60
(4H, m), 7.44-7.29 (11H, m), 5.09 (2H, s), 4.92
-4.86 (1H, br d, J = 8.8Hz), 3.71-3.47 (3H, m),
1.68-1.60 (2H, m), 1.05 (9H, s), 0.88 (3H, t, J =
(7.3 Hz) (2) 3-t-butyldiphenylsilyloxy-1-
[4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl] azetidine [(1S)-obtained in Reference Example 34 (1). 3.70 g (8.00 mmol) of 1- (t-butyldiphenylsilyloxymethyl) -propyl] -carbamic acid benzyl ester is dissolved in 185 ml of methanol, and catalytic hydrogen reduction is carried out at room temperature for 4 hours at room temperature in the presence of 3.70 g of 10% palladium carbon. Was done. After confirming the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 9: 1).
2.32 g (88%) of colorless oily (1S) -1- (t-butyldiphenylsilyloxymethyl) -propylamine was obtained. Subsequently, 2.00 g of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1).
(4.29 mmol) was dissolved in 100 ml of benzene, and 0.67 M (1
S) -1- (t-Butyldiphenylsilyloxymethyl)-
Propylamine-trimethylaluminum-benzene solution
12.9 ml was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed overnight.
After confirming the completion of the reaction, add 100 ml of 10% aqueous acetic acid
And 200 ml of ethyl acetate were added, and the mixture was stirred at room temperature for 1 hour.
Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1 to 2:
Purified in 1), and a light brown solid 3-t-butyldiphenylsilyloxy-1- [4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl] -1,3- Thiazol-2-yl] azetidine.
52 g, 79% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.57-7.69
(8H, m), 7.28-7.46 (12H, m), 7.36 (1H, s), 4.69
-4.74 (1H, m), 3.76-4.11 (5H, m), 3.74 (1H, dd,
J = 10.3, 2.9Hz), 3.70 (1H, dd, J = 10.3, 4.1Hz), 1.0
8 (9H, s), 1.05 (9H, s), 0.93 (3H, t, J = 7.3 Hz) (3) 3-hydroxy-1- [4-[(1S) -1- (hydroxymethyl) -propyl Carbamoyl] -1,3-
Thiazol-2-yl] azetidine 3-t-butyldiphenylsilyloxy-1- [4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -propylcarbamoyl obtained in Reference Example 34 (2) ] -1,3-thiazol-2-yl] azetidine 2.52 g
(3.50 mmol) was dissolved in 126 ml of anhydrous tetrahydrofuran,
Under ice-cooling, 8.40 ml (8.40 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added, and the mixture was stirred overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give 3-hydroxy- as a pale yellow oil.
1- [4-[(1S) -1- (hydroxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl] azetidine was obtained in 947 mg in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.36 (1H,
s), 4.86-4.75 (1H, m), 4.33 (2H, dd, J = 8.1, 6.6H
z), 4.02-3.91 (3H, m), 3.79 (1H, dd, J = 11.0, 1.2
Hz), 3.67 (1H, dd, J = 11.0, 6.6Hz), 3.19-3.10 (1
H, br s), 3.02-2.97 (1H, br s), 1.73-1.64 (2H,
m), 1.00 (3H, t, J = 7.3 Hz) (4) 1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -propylcarbamoyl] -1,
3-thiazol-2-yl] -3-hydroxyazetidine 3-hydroxy-1- [4 obtained in Reference Example 34 (3)
-[(1S) -1- (hydroxymethyl) -propylcarbamoyl] -1,3-thiazol-2-yl] azetidine
940 mg (3.50 mmol) was dissolved in 47 ml of dimethylformamide, and 633 mg of t-butyldimethylsilane chloride was added under ice cooling.
(4.20 mmol) and 286 mg (4.20 mmol) of imidazole were added, and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
Purified with n-hexane: ethyl acetate = 2: 1 to 1: 3), and pale yellow oily 1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -propylcarbamoyl]- 1.00 g of 1,3-thiazol-2-yl] -3-hydroxyazetidine was obtained at a yield of 74%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.50-7.44
(1H, m), 7.36 (1H, s), 4.86-4.79 (1H, m), 4.33-
4.27 (2H, m), 4.01-3.92 (3H, m), 3.72 (1H, dd, J
= 9.9, 2.6Hz), 3.65 (1H, dd, J = 9.9, 4.0Hz), 1.70-
1.60 (2H, m), 0.95 (3H, t, J = 7.3Hz), 0.92 (9H, s),
0.06 (6H, s) (5) 1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -propylcarbamoyl-]-
1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine 1- [4-[(1S) -1- obtained in Reference Example 34 (4).
(T-butyldimethylsilyloxymethyl) -propylcarbamoyl-]-1,3-thiazol-2-yl] -3
-Hydroxyazetidine (1.00 mg, 2.59 mmol) was dissolved in methylene chloride (50 ml), and methanesulfonyl chloride (602 μl (7.78 mmol), triethylamine 1.09 ml (7.78 m
mol) was added and 10 minutes later, the reaction system was returned to room temperature and stirred for 3 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1 to 1:
Purified in 2), 1- [4-[(1S) -1] as a pale yellow oil
-(T-butyldimethylsilyloxymethyl) -propylcarbamoyl-]-1,3-thiazol-2-yl]-
1.02 g of 3-methanesulfonyloxyazetidine, yield
85%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.44 (1H,
s), 7.44-7.38 (1H, m), 5.45-5.39 (1H, m), 4.47
-4.40 (2H, m), 4.29-4.21 (2H, m), 4.02 -3.95
(1H, m), 3.73 (1H, dd, J = 10.3, 2.9Hz), 3.65 (1H, d
d, J = 10.3, 4.4Hz), 3.11 (3H, s), 0.95 (3H, t, J = 7.
3Hz), 0.92 (9H, s), 0.06 (6H, s) (6) 3-acetylthio-1- [4-[(1S) -1-
(T-butyldimethylsilyloxymethyl) -propylcarbamoyl-]-1,3-thiazol-2-yl] azetidine 1- [4-[(1S) -1-] obtained in Reference Example 34 (5).
(T-butyldimethylsilyloxymethyl) -propylcarbamoyl-]-1,3-thiazol-2-yl] -3
-1.02 g (2.20 mmol) of methanesulfonyloxyazetidine
Was dissolved in 50 ml of dimethylformamide, 1.51 mg (13.2 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred overnight in an oil bath at 80 ° C. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4:
1-2: 1) to give a light brown oily 3-acetylthio-1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -propylcarbamoyl-]-1,
618 g of 3-thiazol-2-yl] azetidine, yield 63.
%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.43-7.39
(1H, m), 7.40 (1H, s), 4.53-4.47 (2H, m), 4.46
-4.41 (1H, m), 4.00-3.93 (3H, m), 3.74 -3.70 (1
H, m), 3.67-3.62 (1H, m), 2.37 (3H, s), 1.72-
1.56 (2H, m), 0.95 (3H, t, J = 7.3Hz), 0.91 (9H, s),
0.06 (6H, s) Reference Example 35 3-Acetylthio-1- [4-[(1S) -2- (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazole-2- Il] azetidine

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(1) [(1S) -2- (t-Butyldiphenylsilyloxy) -1-methyl-ethyl] -carbamic acid benzyl ester L-alaninol 2.00 g (26.6 mmol) was treated with methylene chloride 60 m
benzyl chloroformate 4.57 ml (32.0 mmol),
4.48 ml (32.0 mmol) of triethylamine was added under ice-cooling, followed by stirring at room temperature overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane:
(Ethyl acetate = 2: 1 to 1: 2) to give white crystals.
4.61 g of [(1S) -2-hydroxy-1-methyl-ethyl] -carbamic acid benzyl ester was obtained in a yield of 83%. Subsequently, [(1S) -1- (hydroxymethyl) -ethyl] -carbamic acid benzyl ester 4.61 g (22.0 mmol)
l) was dissolved in 140 ml of dimethylformamide, and 6.87 ml (26.4 mmol) of t-butyldiphenylsilane chloride was dissolved under ice-cooling.
l) and 1.80 g (26.4 mmol) of imidazole were added, followed by stirring at room temperature for 6 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 8: 1-6: 1) to give [(1S) -2- (t-butyldiphenylsilyloxy) as a colorless oil. ) -1-Methyl-ethyl] -carbamic acid benzyl ester (10.7 g, yield 100%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.67-7.60
(4H, m), 7.42-7.29 (11H, m), 5.10 (2H, s), 4.96
-4.85 (1H, br s), 3.91-3.80 (1H, m), 3.67 (1H,
dd, J = 10.3, 2.6Hz), 3.56 (1H, dd, J = 10.3, 3.7Hz),
1.55 (3H, d, J = 11.7Hz), 1.09 (9H, s) (2) 3-t-butyldiphenylsilyloxy-1-
[4-[(1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-
Thiazol-2-yl] azetidine [(1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethyl] obtained in Reference Example 35 (1).
6.71 g (15.0 mmol) of carbamic acid benzyl ester was dissolved in 340 ml of methanol, and 6.71 g of 10% palladium carbon was dissolved.
In the presence, catalytic hydrogen reduction was performed at room temperature for 2.5 hours. After confirming the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: methylene chloride to methylene chloride: methanol = 8).
5:15) and purified as a pale yellow oil (1S) -2-
(T-butyldiphenylsilyloxy) -1-methyl-
3.93 g of ethylamine was obtained in a yield of 84%. Subsequently, 2.0 g (4.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) was added to 100 ml of benzene. And 12.9 ml of a 0.67M (1S) -2- (t-butyldiphenylsilyloxy) -1-methyl-ethylamine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed overnight. After confirming the completion of the reaction, 100 ml of 10% aqueous acetic acid and 200 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
n-Hexane: ethyl acetate = 6: 1 to 2: 1) to give 3-t-butyldiphenylsilyloxy-1- [4-[(1S) -2- (t-butyldiphenyl) as a light brown solid. Silyloxy) -1-methyl-ethylcarbamoyl]-
1.77 g of [1,3-thiazol-2-yl] azetidine was obtained in a yield of 88%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.69-7.65
(4H, m), 7.61-7.57 (4H, m), 7.46-7.30 (12H,
m), 7.35 (1H, s), 4.75-4.68 (1H, m), 4.28 -4.18
(1H, m), 4.10-4.03 (H, m), 4.03-3.97 (2H, m),
3.72 (1H, dd.J = 9.9, 4.1Hz), 3.64 (1H, dd.J = 9.9,
(3.3Hz), 1.31 (3H, d, J = 6.6Hz), 1.09 (9H, s), 1.05
(9H, s) (3) 3-hydroxy-1- [4-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-
Thiazol-2-yl] azetidine 3-t-butyldiphenylsilyloxy-1- [4-[(1S) -2- (t-butyldiphenylsilyloxy) -1-methyl obtained in Reference Example 35 (2) -Ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine 2.
77 g (3.77 mmol) was dissolved in 140 ml of anhydrous tetrahydrofuran, 9.06 ml (9.06 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice cooling, and the mixture was stirred for 3.5 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give 3-hydroxy-1-
[4-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidine was obtained as a white solid in 911 mg in a yield of 94%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.34 (1H,
s), 7.26-7.10 (1H, brs), 4.86-4.77 (1H, m), 4.
32 (2H, dd, J = 8.8, 6.6Hz), 4.24-4.12 (1H, m), 3.9
9-3.92 (2H, m), 3.79-3.71 (1H, m), 3.66-3.58
(1H, m), 3.28 -3.21 (1H, br s), 2.99-2.92 (1H,
br d, J = 5.1 Hz), 1.25 (3H, d, J = 7.2 Hz) (4) 1- [4-[(1S) -2- (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl ]-
1,3-thiazol-2-yl] -3-hydroxyazetidine 3-hydroxy-1- [4 obtained in Reference Example 35 (3)
910 mg (3.54 mmol) of-((1S) -2-hydroxy-1-methyl-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidine was added to 46 ml of dimethylformamide.
Tert-butyldimethylsilane chloride under ice cooling.
6 mg (3.89 mmol) and 265 mg (3.89 mmol) of imidazole were added, and the mixture was stirred at room temperature for 6 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n
-Hexane: ethyl acetate = 1: 1 to 1: 4) to give 1- [4-[(1S) -1- (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] as a pale yellow oil. ] -1,3-thiazol-2-yl] -3-hydroxyazetidine was obtained in 935 mg in a yield of 71%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.48-7.42
(1H, br d, J = 8.8Hz), 7.36 (1H, s), 4.86-4.79 (1
H, m), 4.30 (2H, ddd, J = 15.6, 5.9, 2.9Hz), 4.34-
4.27 (1H, m), 3.97-3.91 (2H, m), 3.68 (1H, dd, J
= 9.5, 4.4Hz), 3.63 (1H, dd, J = 9.5, 2.9Hz), 1.25 (3
H, d, J = 7.3 Hz), 0.93 (9H, s), 0.07 (6H, s) (5) 1- [4-[(1S) -2- (t-butyldimethylsilyloxy) -1-methyl -Ethylcarbamoyl]-
1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine 1- [4-[(1S) -2- obtained in Reference Example 35 (4).
(T-butyldimethylsilyloxy) -1-methyl)-
Ethylcarbamoyl] -1,3-thiazol-2-yl]
930 mg (2.50 mmol) of -3-hydroxyazetidine was dissolved in 47 ml of methylene chloride, and 480 μl (6.20 mmol) of methanesulfonyl chloride and 869 μl of triethylamine (6.2
(0 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1 to 1:
Purified in 2), 1- [4-[(1S) -2] as a pale yellow oil
-(T-butyldimethylsilyloxy) -1-methyl-
Ethylcarbamoyl] -1,3-thiazol-2-yl]
1.16 g of -3-methanesulfonyloxyazetidine was obtained at a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.43 (1H,
s) 7.43-7.39 (1H, brs), 5.44-5.39 (1H, m), 4.43
(2H, ddd, J = 6.6, 5.9, 1.5Hz), 4.27-4.21 (2H,
m), 4.21-4.13 (1H, m), 3.68 (1H, dd, J = 9.5, 4.4H
z), 3.63 (1H, dd, J = 9.5, 2.9Hz), 3.11 (3H, s), 1.25
(3H, d, J = 6.6 Hz), 0.93 (9H, s), 0.07 (6H, s) (6) 3-acetylthio-1- [4-[(1S) -2-
(T-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine 1- [4-[(1S) -2- obtained in Reference Example 35 (5).
(T-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] -1,3-thiazol-2-yl]-
3-methanesulfonyloxyazetidine 1.16 g (2.50 mmo
l) was dissolved in 60 ml of dimethylformamide, 1.71 mg (15.0 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred overnight in an oil bath at 80 ° C. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
4: 1 to 2: 1) to give 3-acetylthio-1- [4-[(1S) -2- (t-butyldimethylsilyloxy) -1-methyl-ethylcarbamoyl] as a pale brown oil.
709 mg of [1,3-thiazol-2-yl] azetidine,
Obtained in 60% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.45-7.40
(1H, br s), 7.39 (1H, s), 4.54-4.47 (2H, m), 4.46
-4.41 (1H, m), 4.20-4.15 (1H, m), 4.00- 3.93
(2H, m), 3.67 (1H, dd, J = 10.3, 4.4Hz), 3.62 (1H, d
d, J = 10.3, 3.7Hz), 2.37 (3H, s), 1.24 (3H, d, J =
6.6 Hz), 0.92 (9H, s), 0.07 (6H, s) Reference Example 36 3-acetylthio-1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl- Propylcarbamoyl] -1,3-thiazol-2-yl] azetidine

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(1) [(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propyl]-
2.00 g (19.4 mmol) of carbamic acid benzyl ester L-valinol in 60 ml of methylene chloride
Benzyl chloroformate 3.32 ml (23.3 mmol), triethylamine 3.27 ml (23.3 mmol) was added under ice cooling,
Thereafter, the mixture was stirred at room temperature for 4.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane:
(Ethyl acetate = 2: 1 to 1: 2) to give white crystals.
4.56 g of [(1S) -1- (hydroxymethyl) -2-methyl-propyl] -carbamic acid benzyl ester was obtained at a yield of 99%. Subsequently, 4.56 g (19.2 mmol) of [(1S) -1- (hydroxymethyl) -2-methyl-propyl] -carbamic acid benzyl ester was added to dimethylformamide 14
0 ml, and under ice cooling, 6.00 ml (23.1 mmol) of t-butyldiphenylsilane chloride and 1.57 g of imidazole (23.
1 mmol) and then stirred at room temperature for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system.
A liquid separation operation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate = 8: 1 to 1).
6: 1), and purified as white crystals [(1S) -1- (t-
(Butyldiphenylsilyloxymethyl) -2-methyl-
Propyl] -carbamic acid benzyl ester, 10.1 g,
Obtained in 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.65-7.60
(4H, m), 7.45-7.29 (11H, m), 5.09 (2H, s), 4.92
-4.84 (1H, br d, J = 9.5Hz), 3.71 (1H, dd, J = 10.3,
4.4Hz), 3.66 (1H, dd, J = 10.3, 4.4Hz), 3.55-3.46
(1H, m), 1.99 -1.87 (1H, m), 1.05 (9H, s), 0.89 (6
(H, d, J = 7.3 Hz) (2) 3-t-butyldiphenylsilyloxy-1-
[4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl]-
1,3-thiazol-2-yl] azetidine [(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propyl] -carbamic acid benzyl ester obtained in Reference Example 36 (1) 7.14 g (15.0m
mol) was dissolved in 215 ml of methanol and subjected to catalytic hydrogen reduction in the presence of 7.14 g of 10% palladium carbon at room temperature for 3 hours. After confirming the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: methylene chloride: methanol = 98: 2-
9: 1) to give a colorless oily (1S) -1- (t-
(Butyldiphenylsilyloxymethyl) -2-methyl-
3.73 g of propylamine was obtained at a yield of 73%. Subsequently, 2.0 g (4.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in Reference Example 2 (1) was added to 100 ml of benzene. Dissolved in 0.67M (1S) -1- (t-
(Butyldiphenylsilyloxymethyl) -2-methyl-
Propylamine-trimethylaluminum-benzene solution
12.9 ml was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed overnight.
After confirming the completion of the reaction, add 100 ml of 10% aqueous acetic acid
And 200 ml of ethyl acetate were added, and the mixture was stirred at room temperature for 1 hour.
Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1 to 4:
Purified in 1), and a light brown solid 3-t-butyldiphenylsilyloxy-1- [4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl]- 1.98 g of [1,3-thiazol-2-yl] azetidine was obtained in a yield of 61%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.69-7.56
(8H, m), 7.44-7.31 (12H, m), 7.37 (1H, s), 4.74-
4.67 (1H, m), 4.09-3.94 (4H, m), 3.87-3.78 (1
H, m), 3.85 (1H, dd, J = 10.3, 2.1Hz), 3.67 (1H, dd,
J = 10.3, 3.9Hz), 2.17-2.05 (1H, m), 1.09 (9H, s),
1.06 (9H, s), 0.99 (3H, d, J = 6.9Hz), 0.97 (3H, d,
(J = 6.8 Hz) (3) 3-hydroxy-1- [4-[(1S) -1- (hydroxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl] azetidine Reference Example 3-t-butyldiphenylsilyloxy-1- [4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3 obtained in 36 (2) -Thiazol-2-yl] azetidine (1.98 g, 2.60 mmol) was added to anhydrous tetrahydrofuran 100
and dissolved under ice-cooling in a solution of 6.23 ml of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution (6.23 ml).
3 mmol), and the mixture was stirred overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give a colorless oil.
-Hydroxy-1- [4-[(1S) -1- (hydroxymethyl) -2-methyl-propylcarbamoyl] -1,
755 mg of 3-thiazol-2-yl] azetidine, yield 100
%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.34 (1H,
s), 7.35-7.31 (1H, brs), 4.84-4.75 (1H, m), 4.3
2 2H, dd, J = 8.8, 6.8Hz), 3.97 (1H, dd, J = 8.8, 4.4H
z), 3.94 (1H, dd, J = 8.8, 4.4Hz), 3.87-3.77 (2H,
m), 3.73 (1H, dd, J = 10.7, 6.8Hz), 3.33-3.21 (1H,
br s), 3.24-2.94 (1H, br s), 1.98 (1H, septet,
J = 6.8Hz), 1.01 (3H, d, J = 6.8Hz), 0.98 (3H, d, J = 6.
8 Hz) (4) 1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl] -3-hydroxyazeti Gin 3-hydroxy-1- [4 obtained in Reference Example 36 (3)
-[(1S) -1- (hydroxymethyl) -2-methyl-
Propylcarbamoyl] -1,3-thiazol-2-yl] azetidine (750 mg, 2.60 mmol) was dissolved in dimethylformamide (38 ml), and under ice cooling, tert-butyldimethylsilane chloride (470 mg, 3.12 mmol) and imidazole (212 mg, 3.12 mmol).
mmol), and the mixture was stirred under ice cooling for 2 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2:
1-1: 3) to give 1- [4-[(1
S) -1- (t-Butyldimethylsilyloxymethyl)
700 m of 2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl] -3-hydroxyazetidine.
g, 67% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.54-7.50
(1H, br d, J = 9.8Hz), 7.37 (1H, s), 4.86-4.80 (1
H, m), 4.35-4.27 (2H, m), 3.98-3.92 (2H, m), 3.
84 (1H, dd, J = 9.8, 2.9Hz), 3.84-3.79 (1H, m), 3.
62 (1H, dd, J = 9.8, 3.9Hz), 2.00 (1H, septet, J = 6.8
Hz), 0.98 (3H, d, J = 6.8Hz), 0.96 (3H, d, J = 6.8Hz),
0.91 (9H, s), 0.06 (6H, s) (5) 1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3- Thiazol-2-yl] -3-methanesulfonyloxyazetidine 1- [4-[(1S) -1- obtained in Reference Example 36 (4).
(T-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazole-2
-Yl] -3-hydroxyazetidine 700 mg (1.75 mmol)
Was dissolved in 35 ml of methylene chloride, and 406 μl (5.25 mmol) of methanesulfonyl chloride and triethylamine 7 were added under ice-cooling.
36 μl (5.25 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate-2: 1 to 1: 2) to give 1- [4-
[(1S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-
Thiazol-2-yl] -3-methanesulfonyloxyazetidine was obtained in a yield of 895 mg in 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.50-7.45
(1H, br d, J = 9.5Hz), 7.44 (1H, s), 5.45-5.39 (1
H, m), 4.43 (2H, ddd, J = 11.0, 6.6, 1.5Hz), 4.24 (2
H, ddd, J = 11.0, 4.4, 1.5Hz), 3.83 (1H, dd, J = 10.7,
2.6Hz), 3.84 -3.79 (1H, m), 3.62 (1H, dd, J = 10.7,
4.8Hz), 3.11 (3H, s), 2.04-1.94 (1H, m), 0.98
(3H, d, J = 7.3Hz), 0.96 (3H, d, J = 6.6Hz), 0.91 (9H,
s), 0.06 (6H, s) (6) 3-acetylthio-1- [4-[(1S) -1-
(T-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazole-2
-Yl] azetidine 1- [4-[(1S) -1-] obtained in Reference Example 36 (5).
(T-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazole-2
-Yl] -3-methanesulfonyloxyazetidine 890 mg
(1.75 mmol) in 45 ml of dimethylformamide,
At room temperature, 1.20 g (10.5 mmol) of potassium thioacetate was added,
The mixture was stirred overnight in an oil bath at 80 ° C. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1 to 1: 1) to give a light brown oily 3-
502 mg of acetylthio-1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-propylcarbamoyl] -1,3-thiazol-2-yl] azetidine, 63% yield. I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.50-7.45
(1H, br d, J = 9.5Hz), 7.40 (1H, s), 4.54-4.43 (2
H, m), 4.47-4.40 (1H, m), 4.00-3.93 (2H, m), 3.
86-3.78 (2H, m), 3.64-3.59 (1H, m), 2.04-1.9
4 (1H, m), 0.98 (3H, d, J = 6.6Hz), 0.96 (3H, d, J = 6.
6Hz), 0.91 (9H, s), 0.05 (6H, s) Reference Example 37 3-acetylthio-1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -3-methyl-butyi] Rucarbamoyl] -1,3-thiazol-2-yl] azetidine

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(1) [(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butyl] -carbamic acid benzyl ester L-leucinol 1.00 g (8.53 mmol) was treated with methylene chloride 30 m
1.46 ml (10.2 mmol) of benzyl chloroformate,
1.43 ml (10.2 mmol) of triethylamine was added under ice-cooling, followed by stirring at room temperature for 3 days. After confirming the completion of the reaction,
Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane:
Ethyl acetate = 2: 1 to 1: 1) to give a colorless oil
2.31 g of [(1S) -1- (hydroxymethyl) -3-methyl-butyl] -carbamic acid benzyl ester in a yield of 1
Obtained at 00%. Subsequently, 4.84 g (19.3 mmol) of [(1S) -1- (hydroxymethyl) -3-methyl-butyl] -carbamic acid benzyl ester was added to 145 ml of dimethylformamide.
And cooled under ice-cooling to obtain t-butyldiphenylsilane chloride.
6.01 ml (23.1 mmol), imidazole 1.57 g (23.1 mmol)
Was added thereto, followed by stirring at room temperature for 8 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 19: 1 to 7:
Purified in 1), 9.22 g of [(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butyl] -carbamic acid benzyl ester as a colorless oil was obtained in a yield of 98.
%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.65-7.61
(4H, m), 7.45-7.32 (11H, m), 5.09 (2H, d, J = 2.9H
z), 4.85-4.80 (1H, br d, J = 8.8Hz), 3.86 -3.77 (1
H, m), 3.70 (1H, dd, J = 9.8, 2.9Hz), 3.59 (1H, dd,
J = 9.8, 2.9Hz), 1.63-1.54 (1H, m), 1.43-1.37 (2
H, m), 1.06 (9H, s), 0.91 (3H, d, J = 6.8Hz), 0.89
(3H, d, J = 6.8 Hz) (2) 3-t-butyldiphenylsilyloxy-1-
[4-[(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylcarbamoyl]-
1,3-thiazol-2-yl] azetidine 7.35 [(1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butyl] -carbamic acid benzyl ester obtained in Reference Example 37 (1) g (15.0 mmol)
Was dissolved in 220 ml of methanol, and 10% palladium on carbon 7.35 was dissolved.
In the presence of g, catalytic hydrogen reduction was performed at room temperature for 4 hours. After confirming the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: methylene chloride: methanol = 98: 2 to 9: 1).
To give 4.50 g of (1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylamine as a colorless oil in a yield of 84%. Subsequently, Reference Example 2
2.00 g (4.29 mmol) of 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1,3-thiazol-2-yl) azetidine obtained in (1) was added to benzene.
The mixture was dissolved in 100 ml, and 12.9 ml of a 0.67 M (1S) -1- (t-butyldiphenylsilyloxymethyl) -3-methyl-butylamine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, followed by refluxing overnight. After confirming the completion of the reaction, 100 ml of 10% acetic acid aqueous solution and ethyl acetate 2
After adding 00 ml, the mixture was stirred at room temperature for 0 hour. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n
-Hexane: ethyl acetate = 6: 1 to 4: 1) to give 3-t-butyldiphenylsilyloxy-1- [4-[(1S) -1- (t-butyldiphenylsilyl) as a light brown solid. Oxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl] azetidine is converted to 2.14.
g, yield 64%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.68-7.62
(4H, m), 7.62-7.56 (4H, m), 7.46-7.28 (12H,
m), 7.37 (1H, s), 4.74-4.69 (1H, m), 4.24 -4.16
(1H, m), 4.11-4.03 (2H, m), 1.00 (1H, dd, J = 10.
7, 4.9Hz), 3.98 (1H, dd, J = 11.7, 4.9Hz), 3.72 (1H,
dd, J = 9.8, 3.9Hz), 3.67 (1H, dd, J = 9.8, 2.9Hz),
1.65-1.46 (3H, m), 1.08 (9H, s), 1.05 (9H, s),
0.94 (3H, d, J = 5.9 Hz), 0.92 (3H, d, J = 5.9 Hz) (3) 3-hydroxy-1- [4-[(1S) -1- (hydroxymethyl) -3-methyl -Butylcarbamoyl]
-1,3-thiazol-2-yl] azetidine 3-t-butyldiphenylsilyloxy-1- [4-[(1S) -1- (t-butyldiphenylsilyloxy) obtained in Reference Example 37 (2) Methyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl] azetidine (2.14 g, 3.72 mmol) in 107 ml of anhydrous tetrahydrofuran
Under ice-cooling, and a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution 8.94 ml (8.94 m
mol) was added and the mixture was stirred for 4 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give a pale yellow oil.
-Hydroxy-1- [4-[(1S) -1- (hydroxymethyl) -3-methyl-butylcarbamoyl] -1,3
-Thiazol-2-yl] azetidine (825 mg, yield 74%)
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.36 (1H,
s), 7.24-7.17 (1H, brd, J = 8.8Hz), 4.85-4.77 (1
H, m), 4.32 (2H, dd, J = 8.8, 7.3Hz), 4.20-4.12 (1
H, m), 3.96 (2H, ddd, J = 8.8, 8.8, 4.4Hz), 3.77 (1
H, dd, J = 10.9, 1.3Hz), 3.61 (1H, dd, J = 10.9, 5.9H
z), 3.17-3.08 (1H, br s), 3.08-2.95 (1H, br s),
1.75-1.65 (1H, m), 1.55-1.46 (1H, m), 1.46-
1.37 (1H, m), 0.95 (3H, d, J = 6.6Hz), 0.94 (3H, d, J
= 6.6 Hz) (4) 1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl] -3- Hydroxyazetidine 3-hydroxy-1- [4 obtained in Reference Example 37 (3)
-[(1S) -1- (hydroxymethyl) -3-methyl-
Butylcarbamoyl] -1,3-thiazol-2-yl]
Azetidine (820 mg, 2.74 mmol) in dimethylformamide 4
The solution was dissolved in 1 ml, and under ice cooling, 495 mg (3.29 mmol) of t-butyldimethylsilane chloride and 224 mg of imidazole (3.29 mm).
ol) and stirred overnight under ice-cooling. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1 to 1:
Purified in 2), 1- [4-[(1S) -1] as a pale yellow oil
-(T-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazole-2
-Yl] -3-hydroxyazetidine 731 mg, 65% yield
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.40-7.37
(1H, br s), 7.36 (1H, s), 4.87-4.79 (1H, m), 4.3
1 (2H, dd, J = 15.0, 8.4Hz), 4.21-4.12 (1H, m), 3.9
8-3.92 (2H, m), 3.68-3.65 (2H, m), 1.68-1.60
(1H, m), 1.56- 1.40 (2H, m), 0.95 (3H, d, J = 6.6H
z), 0.94 (3H, d, J = 6.6Hz), 0.92 (9H, s,), 0.06 (6H,
s) (5) 1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl] -3-methanesulfonyl Oxyazetidine 1- [4-[(1S) -1-] obtained in Reference Example 36 (4)
(T-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazole-2-
Yl] -3-hydroxyazetidine (730 mg, 1.76 mmol) was dissolved in methylene chloride (37 ml), and methanesulfonyl chloride (409 μl, 5.29 mmol) and triethylamine, 741 μm were added under ice-cooling.
l (5.29 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
2: 1 to 1: 2) to give 1- [4-
846 mg of [(1S) -1- (t-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine, 98% yield. I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.43 (1H,
s), 7.36-7.30 (1H, brd, J = 9.5Hz), 5.45-5.39 (1
H, m), 4.47-4.39 (2H, m), 4.28-4.20 (2H, m), 4.
20-4.14 (1H, m), 3.66 (2H, d, J = 3.7Hz), 3.11 (3
H, s), 1.70-1.58 (1H, m), 1.53 (1H, ddd, J = 13.9,
8.8, 5.9Hz), 1.44 (1H, ddd, J = 13.9, 8.8, 5.9Hz),
0.95 (6H, t, J = 6.3 Hz), 0.92 (9H, s), 0.09 (6H, s) (6) 3-acetylthio-1- [4-[(1S) -1-
(T-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazole-2-
1- [4-[(1S) -1-] obtained in Reference Example 37 (5).
(T-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazole-2-
Yl] -3-methanesulfonyloxyazetidine 840mg
(1.71 mmol) was dissolved in 42 ml of dimethylformamide, and 1.17 mg (10.2 mmol) of potassium thioacetate was added at room temperature to give 8
The mixture was stirred overnight in a 0 ° C. oil bath. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1 to 1: 1) to give a light brown oily 3-
452 mg of acetylthio-1- [4-[(1S) -1- (t-butyldimethylsilyloxymethyl) -3-methyl-butylcarbamoyl] -1,3-thiazol-2-yl] azetidine, 56% yield. I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.39 (1H,
s), 7.36 7.31 (1H, brd, J = 9.5Hz), 4.54-4.39 (3
H, m), 4.20-4.12 (1H, m), 3.97 (1H, dd, J = 8.8H
z), 3.96 (1H, dd, J = 8.8Hz), 3.66 (2H, d, J = 3.7Hz),
1.70-1.60 (1H, m), 1.58-1.40 (2H, m), 0.95 (3
H, d, J = 6.6Hz), 0.94 (3H, d, J = 6.6Hz), 0.91 (9H,
s), 0.05 (6H, s) <Reference Example 38> 3-acetylthio-1- [4-[(1S, 2S) -1- (t
-Butyldimethylsilyloxymethyl) -2-methyl-
Butylcarbamoyl] -1,3-thiazol-2-yl]
Azetidine

[0702]

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(1) [(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butyl] -carbamic acid benzyl ester L-isoleucinol 2.20 g (18.8 mmol) was treated with methylene chloride. 66
benzyl chloroformate 3.22 ml (22.5 mmo
l) and 3.15 ml (22.5 mmol) of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 2: 1 to 1: 1) to give [(1S, 2S) -1- (hydroxymethyl) -2 as a colorless oil. −
Methyl-butyl] -carbamic acid benzyl ester
7 g, 88% yield. Subsequently, (2S)-(N-benzyloxycarbonyl) -2-amino-3-methylbutano-
4.17 g (16.6 mmol) of dimethylformamide was dissolved in 125 ml of dimethylformamide.
18 ml (19.9 mmol), 1.35 g (19.9 mmol) of imidazole
Was added thereto, followed by stirring at room temperature for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 19: 1 to 5:
Purified in 1), colorless crystals of [(1S, 2S) -1- (t)
-Butyldiphenylsilyloxymethyl) -2-methyl-butyl] -carbamic acid benzyl ester, 6.72 g,
Obtained in 83% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.65-7.60
(4H, m), 7.45-7.30 (11H, m), 5.09 (2H, m), 4.93
-4.84 (1H, br d, J = 8.8Hz), 3.74-3.60 (2H, m),
3.60-3.52 (1H, m), 1.74-1.64 (1H, m), 1.53-
1.44 (1H, m), 1.14-1.06 (1H, m), 1.04 (9H, s),
0.92 to 0.8 (6H, m) (2) 3-tert-butyldiphenylsilyloxy-1-
[4-[(1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylcarbamoyl]
[-1,3-thiazol-2-yl] azetidine [(1S, 2S) -1- (t) obtained in Reference Example 38 (1)
-Butyldiphenylsilyloxymethyl) -2-methyl-butyl] -carbamic acid benzyl ester 6.72 g (13.
Was dissolved in 200 ml of methanol and subjected to catalytic hydrogen reduction in the presence of 6.72 g of 10% palladium carbon at room temperature for 2 hours. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
~ 9: 1) to give a colorless oily (1S, 2S) -1-
4.04 g of (t-butyldiphenylsilyloxymethyl) -2-methyl-butylamine was obtained at a yield of 83%. Subsequently, 3-t-butyldiphenylsilyloxy-1- (4-ethoxycarbonyl-1, obtained in Reference Example 2 (1),
2.00 g of 3-thiazol-2-yl) azetidine (4.29 mmo
l) is dissolved in 100 ml of benzene, and 0.67M (1S, 2S)
-1- (t-butyldiphenylsilyloxymethyl)-
12.9 ml of a 2-methyl-butylamine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed overnight. After confirming the completion of the reaction, 200 ml of 10% aqueous acetic acid and 200 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 0.5 hour. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
6: 1-1: 3), and purified as a light brown solid 3-t-butyldiphenylsilyloxy-1- [4-[(1S, 2S)
-1- (t-butyldiphenylsilyloxymethyl)-
1.89 g of 2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl] azetidine was obtained in a yield of 57%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.70-7.57
(8H, m), 7.46-7.26 (12H, m), 7.36 (1H, s), 4.73
-4.67 (1H, m), 4.09-3.94 (4H, m), 3.93 -3.86 (1
H, m), 3.84 (1H, dd, J = 10.7, 2.0Hz), 3.67 (1H, dd,
J = 10.7, 3.4Hz), 1.90-1.82 (1H, m), 1.22-1.11
(1H, m), 1.07 (9H, s), 1.04 (9H, s), 0.93 (3H, d, J
= 6.9Hz), 0.90 (3H, t, J = 7.3Hz) (3) 3-Hydroxy-1- [4-[(1S, 2S) -1-
(Hydroxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl] azetidine 3-t-butyldiphenylsilyloxy-1- [4-[(-) obtained in Reference Example 38 (2). 1.89 g (2.45 mmol) of 1S, 2S) -1- (t-butyldiphenylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl] azetidine in anhydrous tetrahydrofuran 9
5 ml, and cooled under ice-cooling to a 5.87 ml (5.8 M solution of 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran).
7 mmol), and the mixture was stirred overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give a pale yellow oil.
-Hydroxy-1- [4-[(1S, 2S) -1- (hydroxymethyl) -2-methyl-butylcarbamoyl]-
1,3-thiazol-2-yl] azetidine in 811 mg,
Obtained in 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.37 (1H,
s), 7.35-7.31 (1H, brs), 4.87-4.78 (1H, m), 4.
33 (2H, dd, J = 10.3, 6.6Hz), 4.00-3.93 (2H, m), 3.
92-3.86 (1H, m), 3.86-3.78 (1H, m), 3.78-3.7
0 (1H, m), 3.05- 2.98 (1H, br s), 2.75-2.71 (1H,
br d, J = 7.3Hz), 1.80-1.70 (1H, m), 1.59-1.50
(1H, m), 1.27-1.13 (1H, m), 0.98 (3H, d, J = 7.3H
z), 0.93 (3H, t, J = 7.3 Hz) (4) 3-hydroxy-1- [4-[(1S, 2S) -1-
(T-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazole-2-
[Il] azetidine 3-hydroxy-1- [4] obtained in Reference Example 38 (3)
-[(1S, 2S) -1- (hydroxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazole-2
1.34 g (4.48 mmol) of [-yl] azetidine were dissolved in 67 ml of dimethylformamide, and under ice cooling, 810 mg (5.37 mmol) of t-butyldimethylsilane chloride and 527 mg of imidazole.
(5.37 mmol), and the mixture was stirred under ice cooling for 2.5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: toluene: acetonitrile =
5: 1 to 3: 1) to give 3-hydroxy-1- [4-[(1S, 2S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-butyl] as a pale yellow oil. Rucarbamoyl] -1,3-thiazol-2-yl] azetidine
1.35 g, 97% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.57-7.51
(1H, br d, J = 8.8Hz), 7.36 (1H, s), 4.86-4.79 (1
H, m), 4.34-4.26 (2H, m), 3.98-3.91 (2H, m), 3.
90-3.84 (1H, m), 3.84 (1H, dd, J = 9.8, 2.4Hz), 3.
63 (1H, dd, J = 9.8, 3.9Hz), 2.63-2.59 (1H, br d,
J = 5.9Hz), 1.80-1.71 (1H, m), 1.60 -1.51 (1H, m),
1.20-1.12 (1H, m), 0.95 (3H, d, J = 6.8Hz), 0.91
(9H, s), 0.90 (2H, t, J = 6.8 Hz), 0.05 (6H, s) (5) 1- [4-[(1S, 2S) -1- (t-butyldimethylsilyloxymethyl) -2-Methyl-butylcarbamoyl] -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine 3-hydroxy-1- [4 obtained in Reference Example 38 (4).
-[(1S, 2S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl]-
1,3-thiazol-2-yl] azetidine 1.35 g (3.26
was dissolved in 68 ml of methylene chloride, and 758 μl (9.79 mmol) of methanesulfonyl chloride and 1.37 ml (9.79 mmol) of triethylamine were added under ice-cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours. . After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 2: 1 to 1: 2) to give a pale yellow oil, 1-.
[4-[(1S, 2S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl]-
1.53 g of 1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine was obtained at a yield of 97%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.50-7.46
(1H, br d, J = 9.8Hz), 7.43 (1H, s), 5.45-5.39 (1
H, m), 4.45 (1H, dd, J = 8.8, 6.8Hz), 4.42 (1H, dd,
J = 8.8, 6.8Hz), 4.26 (1H, dd, J = 9.8, 3.9Hz), 4.23
(1H, dd, J = 9.8, 3.9Hz), 3.91-3.85 (1H, m), 3.84
(1H, dd, J = 10.3, 2.4Hz), 3.63 (1H, dd, J = 10.3, 3.4H
z), 3.11 (3H, s), 1.80-1.71 (1H, m), 1.59-1.51
(1H, m), 1.22-1.12 (1H, m), 0.95 (3H, d, J = 3.8H
z), 0.91 (9H, s), 0.91 (3H, t, J = 6.8Hz), 0.05 (6H,
s) (6) 3-acetylthio-1- [4-[(1S, 2S) -1
-(T-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazole-2
-Yl] azetidine 1- [4-[(1S, 2S)-obtained in Reference Example 38 (5).
1- (t-butyldimethylsilyloxymethyl) -2-
Methyl-butylcarbamoyl] -1,3-thiazole-
2-yl] -3-methanesulfonyloxyazetidine 1.5
5 g (3.15 mmol) was dissolved in 78 ml of dimethylformamide,
At room temperature, 2.16 g (18.9 mmol) of potassium thioacetate was added,
The mixture was stirred overnight in an oil bath at 80 ° C. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3: 1 to 2: 1) to give a light brown oily 3-
910 mg of acetylthio-1- [4-[(1S, 2S) -1- (t-butyldimethylsilyloxymethyl) -2-methyl-butylcarbamoyl] -1,3-thiazol-2-yl] azetidine, yield 61%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.52-7.46
(1H, br d, J = 9.5Hz), 7.39 (1H, s), 4.54-4.40 (3
H, m), 4.00-3.92 (2H, m), 3.91-3.84 (1H, m), 3.
83 (1H, dd, J = 10.3, 2.2Hz), 3.63 (1H, dd, J = 10.3,
3.7Hz), 2.37 (3H, s), 1.81-1.70 (1H, m), 1.58-
1.50 (1H, m), 1.20-1.09 (1H, m), 0.95 (3H, d, J =
6.6Hz), 0.91 (9H, s), 0.90 (3H, t, J = 7.3Hz), 0.05
(6H, s) Reference Example 39 3-acetylthio-1- {4- [2- (t-butyldimethylsilyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazole -2-yl] azetidine

[0704]

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(1) t-butyldiphenylsilyloxy-N-carbobenzyloxy-L-serine methyl ester N-carbobenzyloxy-L-serine 4.0 g (16.7 mmol)
Was dissolved in 200 ml of benzene and 50 ml of methanol, and 10.9 ml (21.7 mmol) of a hexane solution of 2M-trimethylsilyldiazomethane was added under ice-cooling, followed by stirring at room temperature for 3 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 1 to 1: 3) to give 4.40 g of N-carbobenzyloxy-L-serine methyl ester as a colorless oil. Obtained in 100% yield. Subsequently, 4.40 g (16.7 mmol) of N-carbobenzyloxy-L-serine methyl ester was added to dimethylformamide 210.
ml, and cooled under ice-cooling to 5.20 ml (20.0 mmol) of t-butyldiphenylsilane chloride and 1.36 g of imidazole (20.0 ml).
mol) was added, followed by stirring at room temperature for 3 days. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 8: 1-6: 1).
And purified with t-butyldiphenylsilyloxy-N-carbobenzyloxy-L-serine methyl ester to 8.18.
g, 99% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.61-7.56
(4H, m), 7.45-7.31 (11H, m), 5.69-5.62 (1H, br
d, J = 8.8Hz), 5.12 (2H, s), 4.45 (1H, dt, J = 8.1, 2.
9Hz), 4.09 (1H, dd, J = 10.3, 2.9Hz), 3.90 (1H, dd,
J = 10.3, 2.9Hz), 3.74 (3H, s) (2) [2- (t-butyldiphenylsilyloxy) -1
-(T-butyldiphenylsilyloxymethyl) -ethyl] -carbamic acid benzyl ester 11.5 g (24.8 g) of the t-butyldiphenylsilyloxy-N-carbobenzyloxy-L-serine methyl ester obtained in Reference Example 39 (1). mmol) in tetrahydrofuran
Dissolved in 115 ml of ethanol and 230 ml of ethanol, 1.88 g (49.6 mmol) of sodium borohydride under ice cooling, lithium chloride
2.10 g (49.6 mmol) was added, followed by stirring at room temperature overnight. After confirming the completion of the reaction, methylene chloride and 10% aqueous acetic acid were added to the system, and a liquid separation operation was performed. The aqueous layer was separated and extracted with methylene chloride, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
3: 1 to 1: 1) to give 9.26 of colorless oily benzyl ester of [2- (t-butyldiphenylsilyloxy) -1- (hydroxymethyl) -ethyl] -carbamic acid.
g, 81% yield. Subsequently, 9.26 g (20.0 mmol) of [2- (t-butyldiphenylsilyloxy) -1- (hydroxymethyl) -ethyl] -carbamic acid benzyl ester
l) was dissolved in 280 ml of dimethylformamide, and 7.79 ml (30.0 mmol) of t-butyldiphenylsilane chloride was dissolved under ice-cooling.
l) and 2.04 g (30.0 mmol) of imidazole were added, followed by stirring at room temperature for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 19: 1 to 9: 1) to give [2- (t-butyldiphenylsilyloxy) as a colorless oil.
-1- (t-butyldiphenylsilyloxymethyl)-
Ethyl] -carbamic acid benzyl ester (13.6 g, 97% yield) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.65-7.60
(8H, m), 7.44-7.29 (17H, m), 5.05 (2H, s), 4.99
-4.93 (1H, br d, J = 8.8Hz), 3.94-3.87 (1H, m),
3.85 (2H, dd, J = 9.8, 3.9Hz), 3.76 (2H, dd, J = 9.8,
5.9 Hz), 1.02 (18H, s) (3) 3-t-butyldiphenyloxy-1- {4- [2
-(T-butyldiphenylsilyloxy) -1- (t-butyldiphenylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine [2-] obtained in Reference Example 39 (2). 13.6 g (19.5 mmol) of (t-butyldiphenylsilyloxy) -1- (t-butyldiphenylsilyloxymethyl) -ethyl] -carbamic acid benzyl ester was dissolved in 410 ml of methanol, and 13.6 g of 10% palladium carbon was dissolved. The catalytic hydrogen reduction was performed at room temperature for 3.5 hours. After confirming the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 98: 2 to 9: 1) to give a colorless oil. 2- (t-butyldiphenylsilyloxy) -1- (t
-Butyldiphenylsilyloxymethyl) -ethylamine (9.34 g, yield 84%) was obtained. Subsequently, Reference Example 2 (1)
3-tert-butyldiphenylsilyloxy-1 obtained in
-(4-ethoxycarbonyl-1,3-thiazole-2
−yl) azetidine (2.00 g, 4.29 mmol) in benzene (100 ml)
And 12.9 ml of a 0.67M solution of 2- (t-butyldiphenylsilyloxy) -1- (t-butyldiphenylsilyloxymethyl) -ethylamine-trimethylaluminum-benzene was added at room temperature under a nitrogen atmosphere and refluxed overnight. did. After confirming the completion of the reaction, add 10% aqueous acetic acid
200 ml and 200 ml of ethyl acetate were added, and the mixture was stirred at room temperature for 3 hours. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate.
After washing the obtained organic layer with saturated aqueous sodium hydrogen carbonate and saturated saline,
The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1 to 1).
4: 1) and purified as pale yellow solid 3-t-butyldiphenyloxy-1- {4- [2- (t-butyldiphenylsilyloxy) -1- (t-butyldiphenylsilyloxymethyl)- 3.19 g of ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine was obtained in a yield of 75%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.70-7.65
(8H, m), 7.59-7.55 (4H, m), 7.44-7.28 (18H,
m), 7.33 (1H, s), 4.71-4.64 (1H, m), 4.31 -4.22
(1H, m), 4.04-3.97 (4H, m), 3.94 (2H, dd, J = 9.2,
4.4Hz), 3.82 (2H, dd, J = 9.2, 6.2Hz) (4) 3-hydroxy-1-−１4- [2-hydroxy-
1- (hydroxymethyl) -ethylcarbamoyl]-
1,3-thiazol-2-yl] azetidine 3-t-butyldiphenyloxy-1- {4- [2- (t-butyldiphenylsilyloxy) -1- (t) obtained in Reference Example 39 (3). -Butyldiphenylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazole-
Dissolve 3.19 g (3.23 mmol) of 2-yl] azetidine in 160 ml of anhydrous tetrahydrofuran, add 11.6 ml (11.6 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice-cooling, and leave for 2 hours. Stirred. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1 to 8: 2) to give 3-
Hydroxy-1- {4- [2-hydroxy-1- (hydroxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine was obtained as a white solid at 1.21%.
g, 100% yield. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 7.47-7.41 (1
H, br d, J = 8.8Hz), 7.42 (1H, s), 5.84 (1H, d, J = 6.
6Hz), 4.80 (2H, t, J = 5.5Hz), 4.66-4.58 (1H, m),
4.28-4.21 (2H, m), 3.88-3.81 (1H, m), 3.80 (2
H, dd, J = 8.8, 4.4 Hz), 3.53 (2H, m), 3.45 (2H, m) (5) 1- {4- [2- (t-butyldimethylsilyloxy) -1- (t- Butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazole-2
-Yl] -3-hydroxyazetidine 3-hydroxy-1- {4 obtained in Reference Example 39 (4)
-[2-hydroxy-1- (hydroxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine (750 mg, 2.74 mmol) is added to dimethylformamide 38.
951 mg (6.31 mmol) of t-butyldimethylsilane chloride and 430 mg of imidazole (6.31 mmol) under ice-cooling.
l) was added, and the mixture was stirred overnight under ice-cooling. After confirming the completion of the reaction, ethyl acetate and 10% ethyl acetate were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3:
1-1: 1) to give 1- {4- [2] as pale yellow crystals.
970 mg of-(t-butyldimethylsilyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl] -3-hydroxyazetidine in 71% yield. Obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 7.62-7.57 (1
H, br d, J = 8.1Hz), 7.38 (1H, s), 4.87-4.78 (1H,
m), 4.30 (2H, dd, J = 10.3, 6.6Hz), 4.12-4.04 (1H,
m), 3.93 (2H, dd, J = 9.5, 4.4Hz), 3.84 (2H, dd, J =
9.5, 3.7Hz), 3.62 (2H, dd, J = 9.5, 6.6Hz), 2.26-
2.22 (1H, br d, J = 6.6Hz), 0.92 (18H, s), 0.08 (12
H, s) (6) 1- {4- [2- (t-butyldimethylsilyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazole-2
-Yl] -3-methanesulfonyloxyazetidine 1- {4- [2- (t-butyldimethylsilyloxy) -1- (t-butyldimethylsilyloxymethyl)-obtained in Reference Example 39 (5). Ethylcarbamoyl] -1,
1.27 g (2.53 mmol) of 3-thiazol-2-yl] -3-hydroxyazetidine was dissolved in 64 ml of methylene chloride, and 587 μl (7.59 mmol) of methanesulfonyl chloride was added under ice-cooling.
1.06 ml (7.59 mmol) of triethylamine was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours.
After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1 to 1: 2), and 1- {4- [2- (t-butyldimethyl) as pale yellow crystals was obtained. Silyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazole-2
-Yl] -3-methanesulfonyloxyazetidine in 1.5
6 g, 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.58-7.53
(1H, br d, J = 8.8Hz), 7.44 (1H, s), 5.43-5.38 (1
H, m), 4.41 (2H, dd, J = 9.5, 6.6Hz), 4.23 (2H, dd,
J = 9.5, 5.9Hz), 4.12-4.03 (1H, m), 3.84 (1H, dd,
J = 9.5, 2.9Hz), 3.64 (2H, dd, J = 9.5, 5.9Hz), 3.11
(3H, s), 0.91 (18H, s), 0.07 (12H, s) (7) 3-acetylthio-1- {4- [2- (t-butyldimethylsilyloxy) -1- (t-butyldimethyl) Silyloxymethyl) -ethylcarbamoyl] -1,3
-Thiazol-2-yl] azetidine 1- {4- [2- (t-butyldimethylsilyloxy) -1- (t-butyldimethylsilyloxymethyl) -ethylcarbamoyl] obtained in Reference Example 39 (6). -1,
3-thiazol-2-yl] -3-methanesulfonyloxyazetidine (1.56 g, 2.53 mmol) was dissolved in dimethylformamide (78 ml), and potassium thioacetate (1.73 g) was added at room temperature.
g (15.2 mmol) was added, and the mixture was stirred overnight in an oil bath at 80 ° C. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 4: 1 to 2: 1) to give 3-acetylthio-1- {4-} 4 as a light brown solid.
[2- (t-butyldimethylsilyloxy) -1- (t-
Butyldimethylsilyloxymethyl) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine
3 mg, yield 57%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.59-7.53
(1H, br d, J = 8.8Hz), 7.40 (1H, s), 4.52-4.42 (3
H, m), 4.11-4.06 (1H, m), 3.94 (2H, dd, J = 8.4,
4.8Hz), 3.83 (2H, dd, J = 9.5, 3.3Hz), 3.61 (2H, dd,
J = 9.5, 6.6Hz), 2.37 (3H, s), 0.91 (18H, s), 0.07
(12H, s) Reference Example 40 3-Acetylthio-1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3-thiazol-2-yl) azetidine

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(1) [2- (t-Butyldiphenylsilyloxy) -ethyl] -methyl-carbamic acid benzyl ester 1.20 ml (15.0 mmol) of N-methylaminoethanol was dissolved in 36 ml of methylene chloride, and benzyl chloroformate was dissolved.
2.56 ml (18.0 mmol), triethylamine 2.52 ml (
18.0 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 2.8 g of (2-hydroxy-ethyl) -methyl-carbamic acid benzyl ester as a pale yellow oil in a yield of 90%. . Subsequently, 2.82 g (13.5 mmol) of (2-hydroxy-ethyl) -methyl-carbamic acid benzyl ester was dissolved in 85 ml of dimethylformamide, and 4.21 ml (16.2 mmol) of t-butyldiphenylsilane chloride and imidazole were dissolved under ice cooling. 1.10 g (16.2 mmol) was added and then at room temperature
Stirred for hours. After confirming the completion of the reaction, methanol was added to the system and stirred for 30 minutes. Next, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 9: 1) to give [2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-carbamic acid as a pale yellow solid The benzyl ester was obtained in a yield of 5.7 g and a yield of 94%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.72 (1H, d
d, J = 7.4, 1.6 Hz), 7.47-7.20 (11H, m), 7.64
(4H, t, J = 6.1 Hz), 5.12 (1H, s), 5.05 (1H, s
), 3.80 (1H, t, J = 5.5 Hz), 3.73 (1H, t, J = 5.
5 Hz), 3.45 (1H, t, J = 5.6 Hz), 3.41 (1H, t, J =
5.6 Hz) 2.99 (3H, s), 1.03 (9H, s) (2) 3-t-butyldiphenylsilyloxy-1-
(4-｛[2- (t-butyldiphenylsilyloxy)
-Ethyl] -methyl-carbamoyl {-1,3-thiazol-2-yl) azetidine [2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-benzylcarbamate obtained in Reference Example 40 (1) 5.7 g (12.7 mmol) of the ester in methanol 28
It was dissolved in 5 ml and subjected to catalytic hydrogen reduction at room temperature in the presence of 5.7 g of 10% palladium hydroxide. After confirming the completion of the reaction,
The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 19: 2 to ethyl acetate: methanol =
1: 1) to give [2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-amine as a clear oil.
2.67 g, 69% yield. Subsequently, 3-t-butyldiphenylsilyloxy-1- obtained in Reference Example 2 (1).
(4-ethoxycarbonyl-1,3-thiazole-2-
Il) 1.91 g (4.09 mmol) of azetidine in 100 parts of benzene
Then, 13.6 ml of a 0.67 M [2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-amine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was refluxed overnight. After confirming the completion of the reaction, 100 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate were added to the system under ice cooling.
The mixture was stirred at room temperature for 2 hours. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was saturated with aqueous sodium bicarbonate,
After washing with saturated saline, drying over anhydrous sodium sulfate,
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give a light brown solid, 3-t.
-Butyldiphenylsilyloxy-1- (4-｛[2-
(T-Butyldiphenylsilyloxy) -ethyl] -methyl-carbamoyl {-1,3-thiazol-2-yl) azetidine was obtained in a yield of 2.54 g and a yield of 85%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.74-7.55
(8H, m), 7.50-7.31 (12H, m), 7.00 (1H, s),
4.79-4.64 (1H, m), 4.08-3.59 (7H, m, incl
uding 4.80-4.00 (2H, m), 3.85-3.73 (2H, m
)), 3.27 (0.3 H, s), 3.07 (0.7 H, s), 1.06 (
9H, s), 1.02 (9H, s) (3) 3-hydroxy-1- {4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} azetidine Reference Example 40 3-t-butyldiphenylsilyloxy-1- (4-{[2- (t-butyldiphenylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3-thiazole-2- obtained in (2). Il) azetidine 2.2
4 g (3.05 mmol) was dissolved in 70 ml of anhydrous tetrahydrofuran, and under ice-cooling, a solution of 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran 7.32 ml (7.32 m
mol) was added and the mixture was stirred for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: methanol = 20: 1 to ethyl acetate: methanol = 15: 1) to give 3-hydroxy- 1- {4-[(2-hydroxyethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl} azetidine as a white solid, 833 m
g, 94% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.18 (1H, s
), 4.86-4.74 (1H, m), 4.29 (2H, t, J = 8.4 Hz
), 3.94 (2H, dd, J = 8.4, 4.9 Hz), 3.86 (2H, t,
J = 5.0 Hz), 3.65 (2H, t, J = 5.0 Hz), 3.07 (3
H, s) (4) 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3
-Thiazol-2-yl) -3-hydroxyazetidine 3-hydroxy-1- {4 obtained in Reference Example 40 (3)
-[(2-hydroxyethyl) -methyl-carbamoyl]
-1,3-thiazol-2-yl diazetidine 576 mg
(2.24 mmol) was dissolved in 29 ml of dimethylformamide, and 354 mg of t-butyldimethylsilane chloride was added under ice cooling.
(2.35 mmol), imidazole 160 mg (2.35 mmol)
Was added and the mixture was stirred under ice cooling for 2 hours. After confirming the completion of the reaction, methanol was added to the system and stirred for 30 minutes. Next, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1 to ethyl acetate) to obtain 1- (4-{[2- (t-butyldimethylsilyloxy) as a pale yellow solid. ) -Ethyl] -methyl-carbamoyl {-1,3-
Thiazol-2-yl) -3-hydroxyazetidine
489 mg was obtained in a yield of 60%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.11 (0.7H,
s), 7.01 (0.3H, s), 4.87-4.76 (1H, m), 4.3
1 (2H, t, J = 8.3 Hz), 3.96 (2H, dd, J = 8.3, 4.5
Hz), 3.91-3.83 (1H, m), 3.79 (1H, d, J = 4.5
Hz), 3.74 (1H, d, J = 4.5 Hz), 3.66-3.52 (1H, m
), 3.28 (0.9H, s), 3.11 (2.1H, s), 0.88 (9H, s)
), 0.05 (6H, d, J = 14.0 Hz) (5) 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3
-Thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- (4-｛[2- (t-) obtained in Reference Example 40 (4).
Butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl {-1,3-thiazol-2-yl) -3-
Hydroxyazetidine (442 mg, 1.19 mmol) was dissolved in methylene chloride (15 ml).
l (1.49 mmol) was added and the mixture was stirred for 1 hour.
After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl) as a pale yellow solid. ] -Methyl-carbamoyl {-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine in 517 mg, 97% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.18 (0.6H,
s), 7.08 (0.4H, s), 5,45-5.35 (1H, m), 4.42
(2H, t, J = 8.7 Hz), 4.23 (2H, dd, J = 8.7, 3.7
Hz), 3.91-3.81 (1H, m), 3.81-3.74 (1H, m
), 3.74-3.67 (1H, m), 3.62-3.53 (1H, m),
3.26 (1.2H, s), 3.09 (1.8H, s), 0.85 (9H, s)
), 0.01 (6H, s) (6) 3-acetylthio-1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl} -1,3-thiazol-2-yl ) Azetidine 1- (4-｛[2- (t-) obtained in Reference Example 40 (5)
Butyldimethylsilyloxy) -ethyl] -methyl-carbamoyl {-1,3-thiazol-2-yl) -3-
Methanesulfonyloxyazetidine 516 mg (1.14 mm
ol) was dissolved in 15 ml of dimethylformamide, and 815 mg (7.14 mmol) of potassium thioacetate was added at room temperature to give 9
The mixture was stirred in a 0 ° C. oil bath for 3 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 3-acetylthio-1- (4-｛[2- (t-butyldimethylsilyl) as a light brown solid. Oxy) -ethyl] -methyl-carbamoyl｝-
279 mg of 1,3-thiazol-2-yl) azetidine
Obtained in 57% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.08 (0.7H,
s), 7.16 (0.4H, s), 4.52 (2H, t, J = 7.3 Hz),
4.48-4.39 (1H, m), 3.97 (2H, t, J = 7.3 Hz) 3.
92-3.82 (1H, m), 3.78 (1H, d, J = 4.1 Hz), 3.
75 (1H, d, J = 4.1 Hz), 3.66-3.50 (1H, m), 3.5
9 (0.9H, s), 3.92 (2.1H, s), 2.39 (3H, s),
0.88 (9H, d, J = 4.7 Hz), 0.04 (6H, d, J = 1.5 Hz
) Reference Example 41 p-Nitrobenzyl (1R, 5S, 6S) -2- [1-
[4- (p-nitrobenzyloxycarbonylmethyl) carbamoyl-1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl]- 1-methyl-carbapene-
2-M-3-carboxylate

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(1) 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine 3-t- obtained in Reference Example 2 (4) 6.73 g (15.3 mmol) of butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine was dissolved in 330 ml of dimethylformamide, and 1.59 ml (18.4 mmol) of allyl bromide and diisopropyl were dissolved at room temperature. Ethylamine 3.
21 ml (18.4 mmol) was added to the system, and the mixture was stirred in an 80 ° C. oil bath for 10 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 5: 1), and brown oily 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) was obtained. ) -3-t-Butyldiphenylsilyloxyazetidine (5.31 g, yield 73%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.63-7.59
(4H, m), 7.46 (1H, s), 7.47-7.36 (6H, m), 6.04
-5.95 (1H, m), 5.40-5.35 (1H, m), 5.28 -5.24 (1
H, m), 4.80-4.78 (2H, m), 4.77-4.71 (1H, m),
4.16 (2H, dd, J = 8.8, 6.6Hz), 4.06 (2H, dd, J = 8.8,
4.4 Hz), 1.06 (9H, s) (2) 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine 1- obtained in Reference Example 41 (1) (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-t-
Butyldiphenylsilyloxyazetidine 5.31 g (11.1m
mol) was dissolved in 266 ml of anhydrous tetrahydrofuran.
13.3 ml (13.3 mmol) of a tetrabutylammonium fluoride-tetrahydrofuran solution was added under ice-cooling, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give pale brown crystalline 1- (4-allyloxycarbonyl-1). 3-thiazol-2-yl) -3-hydroxyazetidine to 2.
91 g was obtained with a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.49 (1H,
s), 6.06-5.96 (1H, m), 5.42-5.35 (1H, m), 5.29
-5.24 (1H, m), 4.87-4.80 (1H, m), 4.79 (2H, d,
J = 5.9Hz), 4.38 (2H, t, J = 8.8Hz), 4.02 (2H, dd, J =
9.8, 3.9 Hz), 2.52- 2.37 (1H, brs) (3) 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine Reference Example 41 (2) 2.91 g (11.1 mmol) of 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-hydroxyazetidine obtained in the above was dissolved in 146 ml of anhydrous methylene chloride and cooled under ice-cooling. Methanesulfonyl chloride 2.58ml (33.3mmol), triethylamine 4.67ml (33.
3 mmol), and after 10 minutes, the reaction system was returned to room temperature and stirred for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, and the mixture was filtered. The residue was washed with diisopropyl ether to give pale brown crystals of 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3. 2.71 g of methanesulfonyloxyazetidine was obtained at a yield of 77%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.55 (1H,
s), 6.07-5.96 (1H, m), 5.45-5.35 (2H, m), 5.30
-5.25 (1H, m), 4.81 (2H, dt, J = 5.9, 1.5Hz), 4.51
(2H, dd, J = 11.0, 6.6, 1.5Hz), 4.31 (2H, ddd, J = 11.
0, 4.4, 1.5 Hz), 3.10, (3H, s) (4) 3-acetylthio-1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidine Obtained in Reference Example 41 (3). 2.70 g (8.51 mmol) of 1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine thus obtained was dissolved in 135 ml of dimethylformamide, and potassium thioacetate was added at room temperature. 5.83 g (51.1 mmol) was added, and the mixture was stirred in an oil bath at 80 ° C for 10 hours. After confirming the completion of the reaction, ethyl acetate and 10
% Saline was added, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1),
1.61 g (63% yield) of 3-acetylthio-1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidine as a light brown solid was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.51 (1H,
s), 6.06-5.96 (1H, m), 5.41-5.35 (1H, m), 5.29
-5.26 (1H, m), 4.58 (2H, t, J = 8.1Hz), 4.47- 4.40
(1H, m), 4.04 (2H, dd, J = 9.5, 5.9Hz), 2.36 (3H,
s) (5) p-Nitrobenzyl (1R, 5S, 6S) -6
[(R) -1-t-butyldimethylsilyloxyethyl]
-2- (diphenylphosphoryloxy) -1-methyl-
Carbapen-2-em-3-carboxylate p-nitrobenzyl (1R, 5S, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2 -M-3
5.00 g (8.41 mmol) of carboxylate was dissolved in 250 ml of dimethylformamide, and 2.54 g (16.8 mmol) of t-butyldimethylsilane chloride and 1.14 imidazole were dissolved under ice-cooling.
g (16.8 mmol) was added, and the mixture was stirred under ice-cooling for 7 hours. After confirming the completion of the reaction, methanol was added to the system and stirred for 30 minutes. Next, ethyl acetate and 10% saline were added to the system.
A liquid separation operation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3: 1) to give p-nitrobenzyl (1R, 5) as a pale yellow oil.
5.27 g of (S, 6S) -6-[(R) -1-tert-butyldimethylsilyloxyethyl] -2- (diphenylphosphoryloxy) -1-methyl-carbapen-2-em-3-carboxylate were obtained. Obtained at a rate of 88%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.14 (2H,
d, J = 8.8Hz), 7.56 (2H, d, J = 8.8Hz), 7.39-7.29 (4
H, m), 7.28-7.17 (6H, m), 5.34 (1H, d, J = 13.9H
z), 5.23 (1H, d, J = 13.9Hz), 4.24 (1H, dq, J = 5.9,
5.9Hz), 4.20 (1H, dd, J = 10.3, 2.9Hz), 3.43 (1H, d
q, J = 10.3,7.3Hz), 3.28 (1H, dd, J = 5.9, 2.9Hz), 1.2
3 (3H, d, J = 5.9Hz), 1.20 (3H, d, J = 7.3Hz), 0.86 (9
H, s), 0.06 (6H, d, J = 3.7 Hz) (6) p-Nitrobenzyl (1R, 5S, 6S) -2-
[1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-
[(R) -1-t-butyldimethylsilyloxyethyl]
-1-Methyl-carbapen-2-em-3-carboxylate 3-acetylthio-1- obtained in Reference Example 41 (4)
(4-allyloxycarbonyl-1,3-thiazole-
1.61 g (5.40 mmol) of 2-yl) azetidine was dissolved in 80 ml of dimethylformamide, and 596 mg (6.47 mmol) of hydrazine acetate was added at room temperature under a nitrogen atmosphere, followed by stirring for 1.5 hours. After confirming the completion of the reaction, p-nitrobenzyl (1R, 5S, 6S) -6-[(R) -1-t-butyl obtained in Reference Example 41 (5) was introduced into the system under ice cooling under a nitrogen atmosphere. Dimethylsilyloxyethyl] -2- (diphenylphosphoryloxy) -1-methyl-carbapen-2-em-3
-A solution of 3.83 g (5.40 mmol) of carboxylate in 190 ml of acetonitrile was added dropwise, followed by addition of 3.76 ml (21.6 mmol) of diisopropylethylamine, and the mixture was stirred overnight while gradually warming to room temperature. After confirming the completion of the reaction,
Ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was saturated with aqueous sodium bicarbonate,
After washing successively with a saturated saline solution, the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1) to give p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-allyl). Oxycarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3 3.73 g of carboxylate was obtained as a pale yellow solid in 97% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H,
d, J = 8.8Hz), 7.65 (2H, d, J = 8.8Hz), 7.53 (1H, s),
6.07-5.96 (1H, m), 5.45 (1H, d, J = 13.9Hz), 5.42-
5.35 (1H, m), 5.30-5.25 (1H, m), 5.26 (1H, d, J
= 13.9Hz), 4.80 (2H, d, J = 5.1Hz), 4.55 (2H, q, J = 8.
1Hz), 4.32-4.22 (3H, m), 4.15-4.09 (3H, m), 3.2
6 (1H, dd, J = 5.1, 2.9Hz), 3.13 (1H, J = 9.5, 7.3Hz),
1.25 (3H, d, J = 5.9Hz), 1.24 (3H, d, J = 7.3Hz), 0.8
7 (9H, s), 0.08 (6H, d, J = 5.1 Hz) (7) p-Nitrobenzyl (1R, 5S, 6S) -2-
[1- (4-Carboxy-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-t
-Butyldimethylsilyloxyethyl] -1-methyl-
Carbapen-2-em-3-carboxylate p-nitrobenzyl (1) obtained in Reference Example 41 (6)
R, 5S, 6S) -2- [1- (4-allyloxycarbonyl-1,3-thiazol-2-yl) azetidine-
3-yl] thio-6-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-
3.73 g (5.2 mmol) of M-3-carboxylate are dissolved in 180 ml of methylene chloride, and 1.46 g (10.4 mmol) of dimedone, 603 m of palladium (0) tetrakistriphenylphosphine are dissolved.
g (0.522 mmol), triphenylphosphine 205 mg (0.783
mmol) and stirred at room temperature under a nitrogen atmosphere for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1 to methylene chloride: methanol = 1).
0: 1), and p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carboxy-) as a light brown solid.
1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-
1.91 g of 3-carboxylate was obtained in a yield of 54%. Mass spectrum (FAB ⁺ ): m / z: 675 [M + H] ⁺ (8) N- (t-butoxycarbonyl) glycine p-nitrobenzyl ester N- (t-butoxycarbonyl) glycine 1.51 g
(8.62 mmol) was dissolved in 75 ml of anhydrous methylene chloride, and 2.63 ml of p-nitrobenzyl alcohol (1
7.2 mmol), 1-ethyl 3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (hereinafter referred to as WSC)
3.3 g (17.2 mmol) and 106 mg (0.87 mmol) of 4-dimethylaminopyridine were added under ice cooling, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. After confirming the completion of the reaction,
Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1) to give N- (t-
2.67 g (butoxycarbonyl) glycine p-nitrobenzyl ester was obtained in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 7.5Hz), 7.53 (2H, d, J = 7.5Hz), 5.28 (2H, s), 5.
02 (1H, brt, J = 3.3Hz), 4.00 (2H, d, J = 3.3Hz), 1.4
6 (9H, s) (9) p-Nitrobenzyl (1R, 5S, 6S) -2-
[1- [4- (p-nitrobenzyloxycarbonylmethyl) carbamoyl-1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-t-butyldimethylsilyloxy Ethyl] -1-methyl-carbapen-2-em-3-carboxylate N- (t-butoxycarbonyl) glycine p-nitrobenzyl ester obtained in Reference Example 41 (8) 2.6
7 g (8.62 mmol) was dissolved in 27 ml of 1,4-dioxane, 27 ml of a 4N hydrochloric acid gas-1,4-dioxane solution was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. After confirming the completion of the reaction, diethyl ether was added to the system, the mixture was stirred for 30 minutes, the reaction solution was filtered, and the residue was washed with diethyl ether and dried to obtain glycine p-white crystals.
1.59 g of nitrobenzyl ester hydrochloride, yield 75
%. Next, p-nitrobenzyl (1R, 5S, 6S) -2- [1- (4-carboxy-1,3-thiazol-2-yl) azetidin-3-yl obtained in Reference Example 41 (7). ] Thio-6-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-methyl-carbapene-2
-M-3-carboxylate 207.4 mg (0.3
1 mmol) and 116 mg (0.47 mmol) of the above-mentioned glycine p-nitrobenzyl ester hydrochloride were suspended in 10.5 ml of dimethylformamide, and 0.072 ml (0.4 ml) of diethyl phosphoryl cyanide was cooled under ice-cooling under a nitrogen atmosphere.
7 mmol), 0.14 ml (1.00 mmol) of triethylamine
l) was added and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1) to give p-nitrobenzyl (1R, 5S, 6S)-
2- [1- [4- (p-nitrobenzyloxycarbonylmethyl) carbamoyl-1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-t
-Butyldimethylsilyloxyethyl] -1-methyl-
Carbapene-2-em-3-carboxylate was obtained as a pale yellow syrup in 209.7 mg, 77% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 8.22 (2H, d, J = 8.8Hz), 7.65 (2H, d, J =
8.8Hz), 7.59 (1H, t, J = 3.3Hz), 7.54 (2H, d, J = 8.8H
z), 7.47 (1H, s), 5.46 (1H, d, J = 13.9Hz), 5.30 (2
H, s), 5.27 (1H, d, J = 13.9Hz), 4.51 (1H, t, J = 8.3H
z), 4.47 (1H, t, J = 8.3Hz), 4.37-4.23 (5H, m), 4.08
(1H, dd, J = 8.3, 3.3Hz), 4.06 (1H, dd, J = 8.3, 3.3H
z), 3.27 (1H, dd, J = 6.2, 3.6Hz), 3.16 (1H, dq, J = 1
1.5, 8.8Hz), 1.27 (3H, d, J = 8.8Hz), 1.25 (3H, d, J
= 8.8 Hz), 0.87 (9H, s), 0.09 (3H, s), 0.08 (3H, s) Reference Example 42 p-Nitrobenzyl (1R, 5S, 6S) -2- [1-
[4- (3-t-butyldiphenylsilyloxyazetidin-1-carbonyl) -1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-t
-Butyldimethylsilyloxyethyl] -1-methyl-
Carbapen-2-M-3-carboxylate

[0710]

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(1) 1-benzyloxycarbonyl-3
-T-butyldiphenylsilyloxyazetidine 1-benzhydryl-3-hydroxyazetidine 10 g (4
(1.8 mmol) was dissolved in 300 ml of methanol and subjected to catalytic hydrogen reduction in a 50 ° C water bath for 3 hours in the presence of 10 g of 10% palladium carbon. After confirming the completion of the reaction, the reaction solution was filtered, the residue was washed with methanol, and the filtrate was concentrated under reduced pressure. Ethyl acetate and distilled water were added to the obtained residue to carry out a liquid separation operation. The water tank was washed with ethyl acetate, concentrated under reduced pressure, and the obtained residue was dried under reduced pressure. The crude product was methylene chloride 120 ml, methanol 1
Dissolve in 20 ml and benzyl chloroformate 8.95 ml (62.7 mmo
l) and 8.79 ml (62.7 mmol) of triethylamine were added, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction solution, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
1: 1 to ethyl acetate) to give 1-benzyloxycarbonyl-3-hydroxyazetidine (1.91 g, yield 22).
%. Subsequently, 1-benzyloxycarbonyl-3
1.91 g (9.22 mmol) of -hydroxyazetidine was dissolved in 96 ml of dimethylformamide, and 2.88 ml (11.1 mmol) of t-butyldiphenylsilane chloride and imidazole were added under ice-cooling.
756 mg (11.1 mmol) was added, and the mixture was stirred under ice cooling for 6 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 6: 1) to give 1-benzyloxycarbonyl-3-t as a colorless oil.
-4.04 g of butyldiphenylsilyloxyazetidine,
Obtained in 98% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.73-7.70
(1H, m), 7.60-7.56 (4H, m), 7.46-7.29 (10H,
m), 5.07 (2H, s), 4.58-4.52 (1H, m), 4.01 (2H,
m), 3.95 (2H, dd, J = 9.8, 4.9 Hz), 1.05 (9H, s) (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
[1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) -1,3-thiazole-
2-yl] azetidin-3-yl] thio-6-[(R)-
1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 1-benzyloxycarbonyl-3-t-butyldiphenylsilyloxyase obtained in Reference Example 42 (2) Dissolve 4.04 g (9.07 mmol) of carbon in 200 ml of methanol,
Catalytic hydrogen reduction was performed at room temperature for 1.5 hours in the presence of 4.04 g of 10% palladium carbon. After confirming the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was dried under reduced pressure to give 3-t-butyldiphenylsilyloxyazetidine as a colorless oil.
2.70 g, 96% yield. Subsequently, p-nitrobenzyl (1R, 5S, 6S) -2- obtained in Reference Example 41 (7).
[1- (4-Carboxy-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-t
-Butyldimethylsilyloxyethyl] -1-methyl-
Carbapen-2-M-3-carboxylate 1.71 g
(2.53 mmol) and 947 mg (3.04 mmol) of the above-mentioned 3-t-butyldiphenylsilyloxyazetidine were dissolved in 86 ml of dimethylformamide. Under a nitrogen atmosphere, 461 μl (3.04 mmol) of diethylphosphoryl cyanide and 426 μl of triethylamine were cooled on ice under a nitrogen atmosphere. (3.04 mmol), and the mixture was stirred at room temperature for 5.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 4: 1), and p-nitrobenzyl (1
R, 5S, 6S) -2- [1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)
-1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -1-methyl-carbapen-2-em-3 789 mg of carboxylate were obtained in a yield of 32%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.8Hz), 7.66 (2H, d, J = 8.8Hz), 7.62 (2H, d, J =
8.8Hz), 7.47-7.36 (6H, m), 7.39 (1H, s), 5.46 (1
(H, d, J = 13.7Hz), 5.27 (1H, d, J = 13.7Hz), 4.65-4.
52 (2H, m), 4.50- 4.42 (2H, m), 4.40-4.34 (1H,
m), 4.32-4.26 (3H, m), 4.19-4.11 (1H, m), 4.06
-4.00 (3H, m), 3.28 (1H, dd, J = 4.9, 2.9Hz), 3.18
(1H, dq, J = 8.8,7.8Hz), 1.27 (3H, d, J = 7.8Hz), 1.26
(3H, d, J = 5.9Hz), 1.07 (9H, s), 0.87 (9H, s), 0.09
(6H, d, J = 5.9 Hz) Reference Example 43 p-Nitrobenzyl (1R, 5S, 6S) -2- (1
-{4- [methyl- (p-nitrobenzyloxycarbonyl) methyl-carbamoyl] -1,3-thiazole-
2-yl {azetidin-3-yl) thio-6-[(R)
-1-tert-butyldimethylsilyloxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylate

[0712]

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(T-Butoxycarbonyl-methyl-amino) -acetic acid p-nitrobenzyl ester 3.56 g (40 mmol) of sarcosine was added to 180 m of methanol.
l, dissolve in 90 ml of distilled water, add 9.6 g (44.0 mmol) of di-t-butoxycarbonyl anhydride, 80 ml of 1 M aqueous sodium hydroxide solution, add to the system under ice-cooling, and add 1.5 hours at room temperature. Stirred. After confirming the completion of the reaction, Dowex-50W was added to the system under ice cooling, and the pH of the reaction solution was adjusted to 5-4.
Was adjusted. Thereafter, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 7.57 g of a crude product of (t-butoxycarbonyl-methyl-amino) -acetic acid. continue,
The obtained (t-butoxycarbonyl-methyl-amino)
-2.52 g (13.3 mmol) of acetic acid and 4.07 g (26.6 mmol) of p-nitrobenzyl alcohol in 125 ml of methylene chloride
In a nitrogen atmosphere under ice-cooling and 5.10 g of WSC (2
6.6 mmol), 252 mg of 4-dimethylaminopyridine (1.3
3 mmol), and then returned to room temperature and stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give (t-butoxycarbonyl-methyl-amino) -acetic acid p-nitrobenzyl ester as a pale yellow oil (4.30). g, 88% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.28-8.29
(2H, m), 7.58-7.47 (2H, m), 5.72 (2H, d, J =
2.2 Hz), 4.07 (1.2H, s), 3.99 (0.8H, s), 2.95
(3H, d, J = 5.8 Hz), 1.47 (5.4H, s), 1.39 (3.6
H, s) (2) Sarcosine p-nitrobenzyl ester hydrochloride 4.30 g (133 mmol) of (t-butoxycarbonyl-methyl-amino) -acetic acid p-nitrobenzyl ester obtained in Reference Example 43 (1). It was dissolved in 43 ml of 1,4-dioxane, and 4.3 ml of a 4N hydrochloric acid gas-1,4-dioxane solution was added under ice-cooling, followed by stirring at room temperature for 2.5 hours. After confirming the completion of the reaction, diethyl ether was added to the system, and the mixture was stirred for 30 minutes. A yield of 88% was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.32-8.23
(2H, m), 7.72-7.60 (2H, m), 5.42 (2H, s),
4.08 (2H, s), 2.77 (3H, s) (3) p-Nitrobenzyl (1R, 5S, 6S) -2-
(1- {4- [methyl- (p-nitrobenzyloxycarbonyl) methyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6
[(R) -1- (t-butyldimethylsilyloxy) ethyl] -1-methyl-carbapen-2-em-3-carboxylate The p-nitrobenzyl (1) obtained in Reference Example 41 (7)
R, 5S, 6S) -2- [1- (4-carboxy-1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-
1.00 g (1.51 mmol) of carboxylate and Reference Example 43
590 mg (2.26 mmol) of sarcosine p-nitrobenzyl ester hydrochloride obtained in (2) was suspended in 30 ml of dimethylformamide, and 0.37 ml (2.26 mmol) of diethylphosphoryl cyanide and triethylamine were cooled under ice-cooling under a nitrogen atmosphere. Add 0.95 ml (6.80 mmol) and add 3
Stirred for hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1 to ethyl acetate).
-Nitrobenzyl (1R, 5S, 6S) -2- (1-
{4- [methyl- (p-nitrobenzyloxycarbonyl) methyl-carbamoyl] -1,3-thiazole-2
-Yl {azetidin-3-yl) thio-6-[(R)-
1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate
It was obtained in 997 mg, 76% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.29-8.15
(4H, m), 7.71-7.62 (2H, m), 7.58-7.42 (2H,
m), 7.40 (0.6H, s), 7.25 (0.4H, s), 5.46 (1
H, d, J = 13.8 Hz), 5.34-5.22 (3H, m including
5.26 (1H, d, J = 13.9 Hz)), 4.63 (1H, s), 4.57
-4.45 (1H, m), 4.27 (2H, t, J = 9.6 Hz), 4.26
(2H, t, J = 9.6 Hz), 3.89 (1H, dd, J = 7.7, 5.8
Hz), 3.36 (1.2H, s), 3.15 (1.8H, s), 3.26 (1
H, dd, J = 5.0, 2.6 Hz), 1.25 (6H, d, J = 7.2 Hz),
0.86 (9H, s), 0.08 (6H, d, J = 5.0 Hz) Reference Example 44 p-Nitrobenzyl (1R, 5S, 6S) -2- (1
-{4- [methyl- (carbamoyl) methyl-carbamoyl] -1,3-thiazol-2-yl} azetidine-
3-yl) thio-6-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-methyl-carbapene-2
-M-3-carboxylate

[0714]

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(1) Carbamoylmethyl-methyl-carbamic acid t-butyl ester 5.03 g (26.6 mmol) of (t-butoxycarbonyl-methyl-amino) -acetic acid obtained in Reference Example 43 (1) was added to anhydrous methylene chloride 250 dissolved in 1 ml, 1-hydroxybenzotriazole 7.19 g (53.2 mmol), WSC 10.2
g (53.2 mmol), 4-dimethylaminopyridine 325 m
g (2.66 mmol) was added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 days. After confirming the disappearance of raw materials, 2
8% aqueous ammonia was added and stirred for 30 minutes. After confirming the completion of the reaction, ethyl acetate and a saturated saline solution were added, and a liquid separation operation was performed. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: methylene chloride: methanol = 10: 1).
Then, 848 mg of carbamoylmethyl-methyl-carbamic acid t-butyl ester as a pale yellow oil was obtained in a yield of 1
Obtained at 7%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 3.87 (2H, s
), 2.96 (3H, s), 1.47 (9H, s) (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
(1- {4- [methyl- (carbamoyl) methyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1-t-butyldimethylsilyloxy Ethyl] -1-methyl-carbapen-2-em-3-carboxylate carbamoylmethyl-methyl-carbamic acid t-butyl ester obtained in Reference Example 44 (1) 848 mg (4.50 m
mol) was dissolved in 8.50 ml of 1,4-dioxane, and 8.50 ml of a 4N hydrochloric acid gas-1,4-dioxane solution was added under ice-cooling, followed by stirring at room temperature for 2.5 hours. After confirming the completion of the reaction, diethyl ether was added to the system, the mixture was stirred for 30 minutes, the reaction solution was filtered, the residue was washed with diethyl ether, and dried to obtain 421 mg of 2-methylamino-acetamide hydrochloride. A yield of 75% was obtained. Subsequently, Reference Example 41
P-Nitrobenzyl (1R, 5S, 6) obtained in (7)
S) -2- [1- (4-Carboxy-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-
[(R) -1-t-butyldimethylsilyloxyethyl]
1.00 g (1.51 mmol) of -1-methyl-carbapen-2-em-3-carboxylate and 282 mg (2.26 mmol) of 2-methylamino-acetamide hydrochloride described above are suspended in 30 ml of dimethylformamide, and the nitrogen atmosphere is applied. Under ice-cooling, diethyl phosphoryl cyanide 0.37 ml (2.26 mmo
l) and 0.95 ml (6.80 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 3.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 10: 1).
And purified by p-nitrobenzyl (1R, 5S, 6S)
-2- (1- {4- [methyl- (carbamoyl) methyl-carbamoyl] -1,3-thiazol-2-yl} azetidin-3-yl) thio-6-[(R) -1- (t-
Butyldimethylsilyloxy) ethyl] -1-methyl-
932 m of carbapene-2-m-3-carboxylate
g, 84% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 7.9 Hz), 7.65 (2H, d, J = 7.9), 7.35 (0.7
H, s), 7.23 (0.3H, s), 5.46 (1H, d, J = 13.9 Hz
), 5.26 (1H, d, J = 13.9 Hz), 4.62 = 4.40 (2
H, m), 4.40-4.22 (3H, m), 4.20 (1H, s), 4.12
(2H, dd, J = 14.2, 7.1 Hz), 4.07-3.97 (1H, m),
4.04 (0.6H, br s), 3.27 (1H, dd, J = 5.0, 2.8 Hz
), 3.15 (1H, dq, J = 9.5, 7.3 Hz), 3.11 (2.4H,
br s), 1.25 (6H, d, J = 5.8 Hz), 0.87 (9H, s),
0.08 (6H, d, J = 5.0 Hz) Reference Example 45 p-Nitrobenzyl (1R, 5S, 6S) -2- [1-
[4- (carbamoylmethyl) carbamoyl-1,3-
Thiazol-2-yl] azetidin-3-yl] thio-6
-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate

[0716]

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(1) Carbamoylmethyl-carbamic acid
t-butyl ester N- (t-butoxycarbonyl) glycine 3.01 g
(17.2 mmol) was dissolved in 150 ml of anhydrous methylene chloride, and 4.63 g of 1-hydroxybenzotriazole was dissolved.
(34.3 mmol), 6.60 g (34.4 mmol) of WSC
l), 210 mg of 4-dimethylaminopyridine (1.7
2 mmol) under ice-cooling, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. After confirming the disappearance of the raw materials, 28% aqueous ammonia was added to the reaction system, followed by stirring for 15 minutes. After confirming the completion of the reaction, methylene chloride and saturated saline were added, and liquid separation was performed. The aqueous layer was separated and extracted with methylene chloride, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1), and 717.7 mg of carbamoylmethyl-carbamic acid t-butyl ester as a colorless transparent syrup was obtained at a yield of 24%.
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.202 (1H, b
rs), 5.763 (1H, br s), 5.267 (1H, br t, J-5.1Hz),
3.820 (2H, d, J = 5.1Hz), 1.456 (9H, s) (2) p-Nitrobenzyl (1R, 5S, 6S) -2-
[1- [4- (carbamoylmethyl) carbamoyl-
1,3-thiazol-2-yl] azetidin-3-yl]
Thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3
-Carboxylate 717.2 mg (4.12) of carbamoylmethyl-carbamic acid t-butyl ester obtained in Reference Example 45 (1)
mmol) was dissolved in 7.2 ml of 1,4-dioxane and 7.2 ml of a 4N hydrochloric acid gas-1,4-dioxane solution under ice-cooling.
Was added and stirred at room temperature overnight. After the completion of the reaction was confirmed, diethyl ether was added to the system, and the mixture was stirred for 30 minutes.
9 mg was obtained in a yield of 86%. Subsequently, p-nitrobenzyl (1R, 5S, 6S) -2 obtained in Reference Example 41 (7).
-[1- (4-carboxy-1,3-thiazole-2-
Yl) azetidin-3-yl] thio-6-[(R) -1-
t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate 56
6.6 mg (0.85 mmol) and 154.3 mg (1.40 mmol) of the above-mentioned glycinamide hydrochloride were suspended in 28.0 ml of dimethylformamide, and 0.2 ml of diethylphosphoryl cyanide was cooled under ice-cooling under a nitrogen atmosphere. 1.32m
mol) and 0.36 ml (2.6 mmol) of triethylamine, and the mixture was stirred at room temperature for 5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 3),
Light yellow solid p-nitrobenzyl (1R, 5S, 6S)
-2- [1- [4- (carbamoylmethyl) carbamoyl-1,3-thiazol-2-yl] azetidine-3-
428.6 mg of yl] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate, yield 70%
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H, d,
J = 8.4Hz), 7.70 (1H, t, J = 5.3Hz), 7.65 (2H, d, J =
8.4Hz), 7.46 (1H, s), 6.15 (1H, br s), 5.46 (1H,
d, J = 13.4Hz), 5.43 (1H, br s), 5.27 (1H, d, J = 13.4
Hz), 4.52 (1H, t, J = 8.3Hz), 4.50 (1H, t, J = 8.3Hz),
4.345-4.24 (3H, m), 4.12-4.04 (4H, m), 3.265 (1H, d
d, J = 5.1, 2.7Hz), 3.155 (1H, dq, J = 9.4, 7.0Hz), 1.
264 (3H, d, J = 7.0Hz), 1.22 (3H, d, J = 4.8Hz), 0.86
(9H, s), 0.09 (3H, s), 0.08 (3H, s) Reference Example 46 p-Nitrobenzyl (1R, 5S, 6S) -2- [1-
[4-((1S) -2-methyl-1- (p-nitrobenzyloxycarbonyl) -propylcarbamoyl] -1,
3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate

[0718]

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(1) N- (t-butoxycarbonyl) -L
-Valine p-nitrobenzyl ester N- (t-butoxycarbonyl) -L-valine 2.50 g (1
1.5 mmol) in 125 ml of anhydrous methylene chloride, and 3.52 g (23.0 mmol) of p-nitrobenzyl alcohol, WSC 4.41
g (23.0 mmol), 140 mg of 4-dimethylaminopyridine
(1.15 mmol) was added under ice-cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 4.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
The product was purified with n-hexane: ethyl acetate = 2: 1) to give N- (t-butoxycarbonyl) -L-valine p as white crystals.
3.07 g of -nitrobenzyl ester was obtained in a yield of 76%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 7.53 (2H, d, J = 8.8Hz), 5.26 (2H, d, J =
5.1Hz), 5.00-4.94 (1H, m), 2.21-2.10 (1H, m),
1.45 (9H, s), 0.97 (3H, d, J = 7.3Hz), 0.88 (3H, d,
J = 6.6 Hz) (2) L-valine p-nitrobenzyl ester hydrochloride 3.07 g of N- (t-butoxycarbonyl) -L-valine p-nitrobenzyl ester obtained in Reference Example 46 (1)
(8.71 mmol) was dissolved in 31 ml of 1,4-dioxane, 31 ml of a 4N hydrochloric acid gas-1,4-dioxane solution was added under ice cooling, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue, followed by filtration.
By washing the residue with ethyl acetate and drying,
2.21 L-valine p-nitrobenzyl ester hydrochloride
g, yield 88%. Elemental analysis: Actual value: C, 48.77% H, 5.63% N, 9.49% Cl, 12.38% Calculated value: C, 49.92% H, 5.93% N, 9.70% Cl, 12.28% (3) p-Nitrobenzyl (1R) , 5S, 6S) -2-
[1- [4-((1S) -2-methyl-1- (p-nitrobenzyloxycarbonyl) -propylcarbamoyl]]
-1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-
3-carboxylate p-nitrobenzyl (1) obtained in Reference Example 41 (7)
R, 5S, 6S) -2- [1- (4-carboxy-1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-
1.00 g (1.48 mmol) of carboxylate and Reference Example 46
514 mg (1.78 mmol) of L-valine p-nitrobenzyl ester hydrochloride obtained in (2) was treated with dimethylformamide
The mixture was dissolved in 50 ml, and under a nitrogen atmosphere, 275 μl (1.78 mmol) of diethylphosphoryl cyanide and 620 μl (3.56 mmol) of diisopropylethylamine were added thereto under ice cooling, followed by stirring at room temperature for 2 hours. After confirming the completion of the reaction, ethyl acetate and 10
% Saline was added, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2:
1-1: 1: 1) and purified with p-nitrobenzyl (1R,
5S, 6S) -2- [1- [4-((1S) -2-methyl-1- (p-nitrobenzyloxycarbonyl) -propylcarbamoyl] -1,3-thiazol-2-yl]
Azetidin-3-yl] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate was obtained in 1.15 g, 86% yield. Was. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 8.21 (2H, d, J = 8.8Hz), 7.65 (2H, d, J =
8.8Hz), 7.58-7.55 (1H, br s), 7.54 (2H, d, J = 8.8H
z), 7.45 (1H, s), 5.46 (1H, d, J = 13.9Hz), 5.28 (2
H, s), 5.27 (1H, d, J = 13.9Hz), 4.74 (1H, dd, J = 9.5,
5.9Hz), 4.51 (2H, t, J = 8.8Hz), 4.33- 4.24 (3H,
m), 4.08 (2H, dd, J = 8.8, 5.9Hz), 3.27 (1H, dd, J =
5.1, 2.9Hz), 3.17 (1H, dq, J = 9.5, 7.3Hz), 2.33-
2.24 (1H, m), 1.26 (3H, d, J = 7.3Hz), 1.25 (3H, d,
J = 5.9Hz), 1.01 (3H, d, J = 6.6Hz), 0.97 (3H, d, J = 7.
3 Hz), 0.87 (9H, s), 0.09 (6H, d, J = 5.1 Hz) Reference Example 47 p-Nitrobenzyl (1R, 5S, 6S) -2- [1-
[4-((1S) -1-carbamoyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl]
Azetidin-3-yl] thio-6-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate

[0720]

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(1) (1S) -1-carbamoyl-2-
Methyl-carbamic acid t-butyl ester N- (t-butoxycarbonyl) -L-valine 3.00 g
(13.8 mmol) was dissolved in 150 ml of anhydrous methylene chloride.
3.73 g (27.6 mmol) of hydroxybenzotriazole, W
SC 5.29 g (27.6 mmol), 4-dimethylaminopyridine
169 mg (1.38 mmol) was added under ice-cooling, and under a nitrogen atmosphere,
The mixture was stirred at room temperature for 3 hours. After confirming the disappearance of the raw materials, 28% ammonia water was added to the reaction system, and the mixture was stirred for 30 minutes. After confirming the completion of the reaction, ethyl acetate and saturated saline were added, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 9: 1) to give 2.81 t-butyl (1S) -1-carbamoyl-2-methyl-carbamic acid as white crystals. g, yield 94
%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 5.93-5.84
(1H, br s), 5.45-5.36 (1H, br s), 5.06-5.00
(1H, br s), 3.98-3.91 (1H, m), 2.21-2.12 (1H,
m), 1.45 (9H, s), 0.99 (3H, d, J = 6.6Hz), 0.94 (3H,
d, J = 6.6 Hz) (2) 2-amino-3-methyl-butylamide hydrochloride 2.81 g (13.0 mm) of 1-carbamoyl-2-methyl-carbamic acid t-butyl ester obtained in Reference Example 47 (1)
ol) was dissolved in 28 ml of 1,4-dioxane, and cooled with ice.
28 ml of 4N-hydrochloric acid gas-1,4-dioxane solution was added, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the system, the mixture was filtered, and the residue was washed with ethyl acetate and dried to give (2S) -2-amino-3-methyl-butyramide hydrochloride. 1.94 g of salt, yield 9
8% was obtained. Elemental analysis: Actual value: C, 39.21% H, 8.34% N, 18.31% Cl, 23.38% Calculated value: C, 39.35% H, 8.59% N, 18.35% Cl, 23.23% (3) p-Nitrobenzyl (1R) , 5S, 6S) -2-
[1- [4-((1S) -1-carbamoyl-2methyl-propylcarbamoyl) -1,3-thiazole-2-
Yl] azetidin-3-yl] thio-6-[(R) -1-
t-Butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-carboxylate The p-nitrobenzyl (1) obtained in Reference Example 41 (7)
R, 5S, 6S) -2- [1- (4-carboxy-1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-tert-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-3-
1.00 g (1.48 mmol) of carboxylate and Reference Example 47
272 mg (1.78 mg) of L-valinamide hydrochloride obtained in (2)
was dissolved in 50 ml of dimethylformamide, and 275 μl of diethylphosphoryl cyanide was cooled under ice-cooling under a nitrogen atmosphere.
(1.78 mmol), 620 μl of diisopropylethylamine (3.
56 mmol) and stirred at room temperature for 2.5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
Purification with n-hexane: ethyl acetate = 1: 3 to methylene chloride: ethyl acetate = 3: 1) and p-nitrobenzyl (1R, 5S, 6S) -2- [1- [4-((1S) −
1-carbamoyl-2methyl-propylcarbamoyl)
-1,3-thiazol-2-yl] azetidin-3-yl] thio-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-carbapen-2-em-
934 mg of 3-carboxylate were obtained in a yield of 82%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H, d,
J = 8.8Hz), 7.65 (2H, d, J = 8.8Hz), 7.61-7.56 (1H,
br d, J = 9.5Hz), 7.43 (1H, s), 6.06-6.00 (1H, br
s), 5.46 (1H, d, J = 13.9Hz), 5.42-5.37 (1H, br
s), 5.27 (1H, d, J = 13.9Hz), 4.50 (1H, dt, J = 8.1,4.4
Hz), 4.36 (1H, dd, J = 8.8, 6.6Hz), 4.32- 4.25 (3H,
m), 4.08 (2H, dd, J = 8.1, 5.1Hz), 3.27 (1H, dd, J =
5.1, 2.2Hz), 3.16 (1H, dq, J = 9.5, 7.3Hz), 2.34-
2.24 (1H, m), 1.26 (3H, d, J = 7.3Hz), 1.25 (3H, d,
J = 6.6Hz), 1.03 (3H, d, J = 6.6Hz), 1.01 (3H, d, J = 6.
6 Hz), 0.87 (9H, s), 0.08 (6H, d, J = 4.4 Hz) Reference Example 48 3-acetylthio-1- [4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1 , 3-thiazol-2-yl] azetidine

[0722]

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(1) (t-butoxycarbonyl-isopropyl-amino) -acetic acid methyl ester glycine methyl ester hydrochloride 3.03 g (24.1)
mmol) was dissolved in 150 ml of methanol, and 3.4 ml (24.4 mmol) of triethylamine and acetone 1 were added to the system.
7.7 ml (241.1 mmol) was added, and the mixture was stirred in a 50 ° C water bath for 1.5 hours. Subsequently, 3.03 g (48.2 mmol) of sodium cyanoborohydride was added to the reaction system under ice cooling, and then a 10% hydrochloric acid gas-methanol solution was added to adjust the system to pH 3 to 4, Stir for 30 minutes. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was dried under reduced pressure. Subsequently, this crude product was subjected to methanol 45m
l, suspended in 90 ml of methylene chloride, and di-t
-Butoxycarbonyl anhydride 10.5 g (4
8.1 mmol) and 13.5 ml of triethylamine (96.
9 mmol) and stirred at room temperature overnight. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate 5: 1) to obtain 3.93 g of (t-butoxycarbonyl-isopropyl-amino) -acetic acid methyl ester as a colorless transparent syrup. Obtained at a rate of 70%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 4.54-4.40
(0.6H, m), 4.24-4.10 (0.4H, m), 3.86 (0.8H, s), 3.
74 (1.2H, s), 3.72 (3H, s), 1.48 (3.6H, s), 1.42
(5.4H, s), 1.11 (2.4H, d, J = 7.7Hz), 1.09 (3.6H, d,
J = 7.7 Hz) (2) (t-butoxycarbonyl-isopropyl-amino) -acetic acid p-nitrobenzyl ester (t-butoxycarbonyl-isopropyl-amino) -acetic acid methyl ester 5 obtained in Reference Example 48 (1) .
59 g (24.2 mmol) was dissolved in 112 ml of methanol and 56 ml of distilled water, and 37 m of 1M aqueous sodium hydroxide solution was dissolved.
l was added to the system under ice cooling, and the mixture was stirred at room temperature for 7 hours. After confirming the completion of the reaction, Dowex-50W was added to the system under ice cooling, and the pH of the reaction solution was adjusted to 5 to 4. Thereafter, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 5.25 g of a crude product of (t-butoxycarbonyl-isopropyl-amino) -acetic acid. Subsequently, the obtained (t-butoxycarbonyl-isopropyl-amino) -acetic acid.
05 g (9.44 mmol) and 2.89 g (18.9 mmol) of p-nitrobenzyl alcohol in methylene chloride 100
of WSC 3.62 under ice-cooling and nitrogen atmosphere.
g (18.9 mmol), 4-dimethylaminopyridine 12
0 mg (0.98 mmol) was added and then allowed to come to room temperature and stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the reaction system to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 5: 2), and (t-butoxycarbonyl-isopropyl-amino) -acetic acid p-nitrobenzyl ester of a pale yellow transparent syrup was obtained. 1.93
g, 58% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.24 (1H, d,
J = 8.0Hz), 8.22 (1H, d, J = 8.0Hz), 7.53 (2H, d, J =
8.0Hz), 5.26 (2H, s), 4.54-4.42 (0.5H, m), 4.28-4.
16 (0.5H, m), 3.94 (1H, s), 3.84 (1H, s), 1.48 (4.
5H, s), 1.36 (4.5H, s), 1.12 (3H, d, J = 7.7Hz), 1.1
0 (3H, d, J = 7.7 Hz) (3) isopropylamino-acetic acid p-nitrobenzyl ester hydrochloride (t-butoxycarbonyl-isopropyl-amino) -p-nitroacetic acid obtained in Reference Example 48 (2) 1.93 g (5.48 mmo) of benzyl ester
l) was dissolved in 20 ml of 1,4-dioxane, and cooled under ice-cooling.
20 ml of 4N hydrochloric acid gas-1,4-dioxane solution was added,
Stirred overnight at room temperature. After confirming the completion of the reaction, diethyl ether was added to the system, the mixture was stirred for 30 minutes, the reaction solution was filtered, the residue was washed with diethyl ether, and dried to obtain isopropylamino-acetic acid p-nitrobenzyl ester as white crystals. 1.50 g of the hydrochloride was obtained in a yield of 95%. ¹ H-NMR (500 MHz, MeOH-d ₄ ): δ (ppm) 8.26 (2H, d ,.
J = 8.8Hz), 7.67 (2H, d, J = 8.8Hz), 5.43 (2H, s), 4.11
(2H, s), 3.50-3.40 (1H, m), 1.34 (6H, d, J = 5.9Hz) (4) 3-t-butyldiphenylsilyloxy-1-
[4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl] azetidine Isopropylamino-acetic acid p-nitrobenzyl ester hydrochloride obtained in Reference Example 48 (3) 500 mg of salt (1.73
mmol) and the 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3) obtained in Reference Example 2 (4).
-Thiazol-2-yl) azetidine 506 mg (1.15 m
mol) was suspended in 15 ml of dimethylformamide, and cooled under ice-cooling under a nitrogen atmosphere with 0.28 ml of diethylphosphoryl cyanide.
ml (1.73 mmol), triethylamine 0.60 ml (4.32 m
mol), and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give a pale yellow oil of 3-t-butyldiphenylsilyloxy-1- [4- [isopropyl- (p -Nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3
-Thiazol-2-yl] azetidine in a yield of 578 mg.
Obtained at 5%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.28-8.18
(2H, m), 7.70-7.30 (12H, m), 7.38 (0.4H, br
s), 7.10 (0.6H, br s), 5.29 (0.8H, br s), 5.16
(1.2H, br s), 5.04-4.44 (3H, m), 4.20-3.85
(5H, m), 1.17 (6H, brs), 1.06 (9H, brs) (5) 3-hydroxy-1- [4- [isopropyl- (p
-Nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl] azetidine 3-t-butyldiphenylsilyloxy-1- [4- [isopropyl- () obtained in Reference Example 48 (4). p-Nitrobenzyloxycarbonylmethyl) -carbamoyl]-
1,3-thiazol-2-yl] azetidine 1.81 g (
2.69 mmol) was dissolved in 90 ml of anhydrous tetrahydrofuran, and 0.18 ml (3.23 mmol) of acetic acid and 3.23 ml (3.23 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution were added under ice-cooling. Stirred for hours. After confirming the completion of the reaction, the reaction solution is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (elution solvent:
Purify with methylene chloride: ethyl acetate = 1: 1)
-Hydroxy-1- [4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl]-
[1,3-thiazol-2-yl] azetidine was obtained as a white solid in 968 mg, in a yield of 83%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.22 (2H,
d, J = 8.0 Hz), 7.55 (1H, d, J = 8.0 Hz), 7.42 (1
H, d, J = 8.0 Hz), 7.39 (0.4H, s), 7.12 (0.6H, s
), 5.29 (1.2H, br s), 5.22 (0.8H, br s), 5.03-
4.89 (0.5H, m), 4.89-4.76 (1H, m), 4.59 (1
H, br s), 4.32 (1H, t, J = 7.3 Hz), 4.22-4.02
(2H, m), 4.02-3.85 (1H, m), 3.85 (1H, m), 1.
10-1.03 (6H, m) (6) 1- [4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-
Thiazol-2-yl] -3-methanesulfonyloxyazetidine 3-hydroxy-1- [4 obtained in Reference Example 48 (5).
-[Isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazole-2
-Yl] azetidine 968 mg (2.23 mmol) in methylene chloride
Dissolve in 50 ml and cool under ice-cooling to methanesulfonyl chloride
0.42 ml (5.34 mmol), triethylamine 0.37 ml (
2.67 mmol) and stirred for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction system,
The aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: methylene chloride:
Ethyl acetate = 1: 1) to give a pale yellow solid 1-
835 mg of [4- [isopropyl- (p-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine was obtained in a yield of 73%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 7.9 Hz), 7.55 (1H, d, J = 7.9 Hz), 7.48 (
0.4H, br s), 7.43 (1H, d, J = 7.9 Hz), 7.26 (0.6
H, br s), 5.51-5.16 (3H, m including 5.29 (
1.2H, s), 5.22 (0.8H, s)), 5.04-4.89 (0.4H, m
), 4.89-4.72 (1H, m), 4.59-4.48 (1H, m),
4.48-4.37 (1H, m), 4.37-4.18 (2H, m), 4.18
-3.96 (2H, m), 3.11 (3H, s), 1.30-1.17 (6
H, m) (7) 3-acetylthio-1- [4- [isopropyl-
(P-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl] azetidine 1- [4- [isopropyl-] obtained in Reference Example 48 (6).
(P-nitrobenzyloxycarbonylmethyl) -carbamoyl] -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine 835 mg (1.63 mmol)
Was dissolved in 42 ml of dimethylformamide, and at room temperature, 1.12 g (9.77 mmol) of potassium thioacetate was added, and the mixture was heated at 90 ° C.
The mixture was stirred in an oil bath for 7 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-acetylthio-1- [4- [isopropyl- (p-nitrobenzyloxycarbonyl) as a light brown solid. Methyl) -carbamoyl] -1,3-thiazol-2-yl] azetidine in 312 mg, 39% yield
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H,
d, J = 6.9 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.44 (
0.6H, br s), 7.43 (1H, d, J = 8.3 Hz), 7.17 (0.6
H, br s), 5.19 (1.2H, s), 5.22 (0.8H, br s),
5.02-4.90 (0.6H, m), 4.90-4.78 (0.4H, m),
4.65-3.65 (7H, m), 2.36 (3H, br s), 1.40-1.
18 (6H, m) Reference Example 49 3-acetylthio-1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazole-2
-Yl] azetidine

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(1) Carbamoylmethyl-isopropyl-carbamic acid t-butyl ester Reference Example 48 (2) The obtained (t-butoxycarbonyl-
3.20 g (14.7 mm) of isopropyl-amino) -acetic acid
ol) and 4.0 g of 1-hydroxybenzotriazole (2
9.6 mmol) was dissolved in 150 ml of methylene chloride, and 5.6 g (29.2 mmol) of WSC was added under ice cooling and a nitrogen atmosphere.
l), 200 mg (1.64) of 4-dimethylaminopyridine
mmol) and then allowed to come to room temperature and stirred overnight. After confirming the disappearance of the raw materials, 40 ml of 28% ammonia water was added to the system,
Stir for 30 minutes. After confirming the completion of the reaction, methylene chloride and saturated saline were added to the reaction system, and a liquid separation operation was performed. The aqueous layer was separated and extracted with methylene chloride, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 10: 1), and 2.67 g of carbamoylmethyl-isopropyl-carbamic acid t-butyl ester as a white solid was obtained at a yield of 8;
Obtained at 4%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 5.434 (1H, b
rs), 4.25 (1H, br s), 3.735 (2H, s), 1.478 (9H,
s), 1.14 (6H, d, J = 6.6 Hz) (2) 2-isopropylamino-acetamide hydrochloride carbamoylmethyl-isopropyl-carbamic acid t-butyl ester 2.6 obtained in Reference Example 49 (1)
7 g (12.3 mmol) was dissolved in 1,4-dioxane (30 ml), 4N-hydrochloric acid gas-1,4-dioxane solution (30 ml) was added under ice cooling, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, diethyl ether was added to the system, and the mixture was stirred for 30 minutes. The reaction solution was filtered, the residue was washed with diethyl ether, and dried to give 2-isopropylamino-acetamide hydrochloride as white crystals. 1.82 g, yield 97
%. ¹ H-NMR (500 MHz, MeOH-d ₄ ): δ (ppm) 3.80 (2H, s),
3.46-3.38 (1H, m), 1.34 (6H, d, J = 6.8 Hz) (3) 3-t-butyldiphenylsilyloxy-1-
[4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine 2-isopropylamino- obtained in Reference Example 49 (2)
Acetamide hydrochloride 500 mg (3.28 mmol) and Reference Example 2
3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazole-2) obtained in (4)
-Yl) azetidine (961 mg, 2.19 mmol) was suspended in dimethylformamide (29 ml), and cooled under ice-cooling under a nitrogen atmosphere to 0.54 ml (3.29 mmol) of diethylphosphoryl cyanide.
l), 1.15 ml (8.19 mmol) of triethylamine,
The mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
Ethyl acetate), and 1.18 g of 3-t-butyldiphenylsilyloxy-1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine as pale yellow oil, Obtained in 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.62 (4H,
d, J = 6.6 Hz), 7.52 -7.36 (6H, m), 7.21-6.85
(1H, m), 4.80-4.72 (1H, m), 4.28 (1H, t, J =
7.3 Hz), 4.24 (1H, t, J = 7.3 Hz), 4.16-4.01
(2H, m), 4.01- 3.88 (2H, m), 1.25 (6H, d, J =
6.7 Hz), 1.07 (9H, brs) (4) 1- [4- (carbamoylmethyl-isopropyl-
Carbamoyl) -1,3-thiazol-2-yl] -3-
Hydroxyazetidine 6.52 g of 3-t-butyldiphenylsilyloxy-1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 49 (3) ( (11.8 mmol) was dissolved in 326 ml of anhydrous tetrahydrofuran.
-Butylammonium fluoride-tetrahydrofuran solution
14.2 ml (14.2 mmol) was added, and the mixture was stirred as it was for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to obtain 1- [4
-(Carbamoylmethyl-isopropyl-carbamoyl)
[1,3-thiazol-2-yl] -3-hydroxyazetidine was obtained as a white solid in 2.35 g in a yield of 67%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.20-7.02
(0.6H, m), 7.02-6.80 (0.6H, m), 5.86-5.62
(0.4H, m), 5.62-5.32 (0.6H, m), 5.25 -5.14
(0.3H, m), 4.90-4.75 (0.7H, m), 4.67 (0.7H,
quint., J = 6.6 Hz), 4.43-4.34 (0.4H, m), 4.34
-4.22 (0.6H, m), 4.03 (2H, s), 4.00-3.91 (
2H, m), 3.89 (0.3H, quint., J = 6.0 Hz), 1.26
(6H, dd, J = 6.7, 2.4 Hz) (5) 1- [4- (carbamoylmethyl-isopropyl-
Carbamoyl) -1,3-thiazol-2-yl] -3-
Methanesulfonyloxyazetidine and 1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine 1- [obtained in Reference Example 49 (4) 4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] -3-hydroxyazetidine 2.35 g
(7.88 mmol) was dissolved in 120 ml of methylene chloride and 0.91 ml (11.8 mmol) of methanesulfonyl chloride was added under ice cooling.
1.66 ml (11.8 mmol) of triethylamine was added, and the mixture was stirred for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazole as a pale yellow solid. 516 mg, 17% yield of 2-yl] -3-methanesulfonyloxyazetidine and 1- [4- (cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl]-as a pale yellow solid. 634 mg of 3-methanesulfonyloxyazetidine was obtained in a yield of 22%. 1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.15-6.72
(1H, m), 5.65-5.15 (1H, m), 4.79-4.62 (1H,
m), 4.44 (2H, t, J = 6.7 Hz), 4.26 (2H, d, J =
6.7 Hz), 4.05 (2H, m), 3.11 (3H, s), 1.26 (6
H, m) 1- [4- (Cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.55-7.10
(1H, m), 5.50-5.38 (1H, m), 4.93-4.78 (1H, m
m), 4.60-4.00 (6H, m including 4.51 (2H, t, J
= 9.6 Hz), 4.32 (2H, dd, J = 9.6, 3.7 Hz)), 3.11
(3H, s), 1.31 (6H, d, J = 6.8 Hz) (6) 3-acetylthio-1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine Reference 516 mg (1.37 mmol) of 1- [4- (carbamoylmethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine obtained in Example 49 (5) was treated with dimethylformamide. 15
and 939 mg of potassium thioacetate at room temperature (
8.22 mmol), and the mixture was stirred in a 90 ° C. oil bath for 3 hours.
After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 20: 1).
And a light brown solid of 3-acetylthio-1- [4
-(Carbamoylmethyl-isopropyl-carbamoyl)
-1,3-thiazol-2-yl] azetidine in 347 m
g, yield 71%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.45-6.72
(1H, m), 4.76-4.61 (1H, m), 4.51 (2H, t, J =
7.4 Hz), 4.47-4.40 (1H, m), 4.40 (2H, s), 3.
98 (2H, t, J = 7.4 Hz), 2.37 (3H, s), 1.26 (6
(H, d, J = 6.8 Hz) Reference Example 50 3-acetylthio-1- [4- (cyanomethylisopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine

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(1) 3-acetylthio-1- [4- (cyanomethylisopropyl-carbamoyl) -1,3-thiazol-2-yl] azetidine 1- [4- () obtained in Reference Example 49 (5) Cyanomethyl-isopropyl-carbamoyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine
635 mg (1.77 mmol) in dimethylformamide 19 ml
At room temperature and potassium thioacetate 1.21 g (10.6
mmol) and stirred in a 90 ° C. oil bath for 3 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1 to ethyl acetate) to give a light brown solid, 3-acetylthio-1- [4-.
(Cyanomethylisopropyl-carbamoyl) -1,3
[Thiazol-2-yl] azetidine in 344 mg, yield 5
Obtained at 7%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.58-7.18
(1H, m), 4.96-4.82 (1H, m), 4.82-4.10 (5H,
m including 4.54 (2H, t, J = 8.4 Hz), 4.50-4.4
0 (1H, m)), 4.01 (2H, t, J = 8.4 Hz), 2.36 (3H,
s), 1.30 (6H, d, J = 6.8 Hz) Reference Example 51 3-acetylthio-1- [4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3- Thiazol-2-yl] azetidine

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4-Hydroxy-1- (p-nitrobenzyloxycarbonyl) -piperidine 3.0 g (21.8 mmol) of 4-hydroxypiperidine hydrochloride was dissolved in 90 ml of methylene chloride and 15 ml of pyridine. 15.4 g (72.0 mmol) of -nitrobenzyl and 13.1 ml (93.8 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 3 days. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
n-hexane: ethyl acetate = 1: 1 to ethyl acetate), and 2.96 g of 4-hydroxy-1- (p-nitrobenzyloxycarbonyl) -piperidine as pale yellow crystals,
Obtained in a yield of 48%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.1Hz), 8.51 (2H, d, J = 8.1Hz), 5.23 (2H, s),
3.98-3.87 (3H, m), 3.30-3.15 (2H, m), 1.96-
1.85 (2H, m), 1.59-1.48 (2H, m) (2) 4-Methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -piperidine 4-hydroxy- obtained in Reference Example 51 (1) 1- (p
-Nitrobenzyloxycarbonyl) -piperidine 2.96
g (14.8 mmol) was dissolved in 90 ml of methylene chloride, and 1.15 ml (14.8 mmol) of methanesulfonyl chloride and 2.07 ml (14.8 mmol) of triethylamine were added thereto under ice cooling. After 10 minutes, the reaction system was returned to room temperature and left as it was. Stirred for 6 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane:
Purification was performed with ethyl acetate = 1: 1) to obtain 3.31 g of 4-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -piperidine as pale yellow crystals in a yield of 87%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 7.51 (2H, d, J = 8.8Hz), 5.23, (2H, s), 4.
96-4.90 (1H, m), 3.79-3.72 (2H, m), 3.51- 3.44
(2H, m), 3.05 (3H, s), 2.10-1.96 (2H, m), 1.92
-1.84 (2H, m) (3) 4-azido-1- (p-nitrobenzyloxycarbonyl) -piperidine 4-methanesulfonyloxy-1- (p-nitrobenzyloxy) obtained in Reference Example 51 (2) Carbonyl) -piperidine (3.31 g, 9.24 mmol) in dimethylformamide 100
Dissolve in sodium chloride and add 660 mg of sodium azide (10.2 mmo
l) was added and the mixture was stirred in a 100 ° C. oil bath for 3 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered,
The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3: 1 to 1: 1) to give pale yellow crystals.
-Azido-1- (p-nitrobenzyloxycarbonyl) -piperidine was obtained in 2.81 g at a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 7.51 (2H, d, J = 8.8Hz), 5.22 (2H, s),
3.86 (2H, dt, J = 13.9, 5.1Hz), 3.68-3.62 (1H, m),
3.32-3.20 (2H, m), 1.98-1.85 (2H, m), 1.68-
1.61 (2H, m) 4-amino-1- (p-nitrobenzyloxycarbonyl) -piperidine 2.81 g of 4-azido-1- (p-nitrobenzyloxycarbonyl) -piperidine obtained in Reference Example 51 (3)
(9.17 mmol) was dissolved in 84 ml of acetonitrile, 2.53 g (9.63 mmol) of triphenylphosphine was added to the system, and the mixture was heated at 70 ° C.
The mixture was stirred in an oil bath for 3 hours. After confirming the disappearance of the raw materials, 3.10 g (9.63 mmol) of sodium sulfate decahydrate was added to the system, and the mixture was stirred for 3 hours. After the completion of the reaction was confirmed, the reaction solution was filtered, and methylene chloride and 0.1 M aqueous hydrochloric acid were added to the filtrate, followed by separation and extraction. Methylene chloride and sodium hydrogen carbonate were added to the obtained water tank, and the water tank was separated and extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
After drying under reduced pressure, 2.33 g of 4-amino-1- (p-nitrobenzyloxycarbonyl) -piperidine as pale yellow crystals,
Obtained in 91% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, 8.8Hz), 7.51 (2H, d, 8.8Hz), 5.22 (2H, s), 4.18
-4.06 (2H, m), 3.01-2.83 (2H, m), 1.88 -1.80 (2
H, m), 1.34-1.22 (2H, m) (5) 3-t-butyldiphenyloxy-1- [4- [1
-(P-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazole-2
-Yl] azetidine 382 mg of 4-amino-1- (p-nitrobenzyloxycarbonyl) -piperidine obtained in Reference Example 51 (4).
(1.37 mmol) and the 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-) obtained in Reference Example 2 (4).
500 mg of 1,3-thiazol-2-yl) azetidine (1.
14 mmol) was dissolved in 25 ml of dimethylformamide, and 208 μl of diethylphosphoryl cyanide was cooled under ice-cooling under a nitrogen atmosphere.
(1.37 mmol) and 192 μl (1.37 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to 1: 3), and 3-t-butyldiphenyloxy-1- [4-
574 mg of [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl] azetidine was obtained at a yield of 72%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.24 (2H,
d, J = 8.8Hz), 7.62 (4H, d, J = 8.8Hz), 7.54-7.38 (6
H, m), 7.36 (1H, s), 7.09-7.04 (1H, br d, J = 8.8H
z), 5.23 (2H, s), 4.79-4.72 (1H, m), 4.22-4.04
(5H, m), 4.01 (2H, dd, J = 8.8, 5.1Hz), 3.08-2.97
(2H, m), 2.08-2.00 (2H, m), 1.55-1.42 (2H, m
m), 1.07 (9H, s) (6) 3-hydroxy-1- [4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl ] Azetidine 3-t-butyldiphenyloxy-1- [4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl]-obtained in Reference Example 51 (5).
1,3-thiazol-2-yl] azetidine 570 mg (0.8
20 mmol) was dissolved in 17 ml of anhydrous tetrahydrofuran, and under ice-cooling, 56 μl of acetic acid, (0.984 mmol), 1.0 M tetra-n-
Butyl ammonium fluoride-tetrahydrofuran solution 9
84 μl (0.984 mmol) were sequentially added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 3 to ethyl acetate:
Purified with methanol = 95: 5), 3-hydroxy-
1- [4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-
Thiazol-2-yl] azetidine as a white solid, 3
60 mg was obtained in a yield of 95%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.51 (2H, d, J = 8.8Hz), 7.39 (1H, s), 7.
11-7.06 (1H, br d, J = 8.1Hz), 5.23 (2H, s), 4.88-
4.80 (1H, m), 4.32 (2H, dd, J = 8.8, 6.6Hz), 4.24-
4.04 (3H, m), 3.96 (2H, dd, J = 9.5, 4.4Hz), 3.12-
2.95 (2H, m), 2.37-2.32 (1H, d, J = 5.9Hz), 2.04-
1.99 (2H, m), 1.55-1.43 (2H, m) (7) 3-Methanesulfonyloxy-1- [4- [1-
(P-Nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazole-2-
[Il] azetidine 3-hydroxy-1- [4] obtained in Reference Example 51 (6).
360 mg (0.780 mmol) of-[1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazol-2-yl] azetidine is dissolved in 18 ml of methylene chloride and cooled with ice. 181 μl (2.34 mmol) of methanesulfonyl chloride, 328 μl of triethylamine (2.3
After 4 minutes, the reaction system was returned to room temperature and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol =
98: 2) to give 3-methanesulfonyloxy-1- [4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] as a pale yellow solid.
-1,3-thiazol-2-yl] azetidine 390 mg,
Obtained in 93% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 7.52 (2H, d, J = 8.8Hz), 7.52 (1H, s), 7.
06-7.02 (1H, br d, J = 7.7Hz), 5.45-5.40 (1H,
m), 5.23 (2H, s), 4.45 (2H, dd, J = 10.3, 6.8Hz), 4.
27 (2H, dd, J = 10.3, 4.3Hz), 4.24-4.06 (3H, m),
3.11 (3H, s), 3.10-2.95 (2H, m), 2.07 -2.00 (2H,
m), 1.56-1.44 (2H, m) (8) 3-acetylthio-1- [4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3-thiazole-2 -Yl] azetidine 3-methanesulfonyloxy-1- [4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl] -1,3 obtained in Reference Example 51 (7).
-Thiazol-2-yl] azetidine 390 mg (0.723 mmo
l) was dissolved in dimethylformamide (20 ml), potassium thioacetate (496 mg, 4.34 mmol) was added at room temperature, and the mixture was stirred in an oil bath at 80 ° C overnight. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1).
2-ethyl acetate) to give 3-acetylthio-1- [4- [1- (p-nitrobenzyloxycarbonyl) -piperidin-4-ylcarbamoyl]-as a light brown solid.
[262] [1,3-thiazol-2-yl] azetidine was obtained in a yield of 70%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.1Hz), 7.51 (2H, d, J = 8.1Hz), 7.41 (1H, s),
7.08-7.04 (1H, br d, J = 7.8Hz), 5.23 (2H, s), 4.5
3 (2H, t, J = 8.8Hz), 4.46-4.40 (1H, m), 4.22-4.
04 (3H, m), 3.98 (2H, dd, J = 8.8, 5.9Hz), 3.12-2.9
6 (2H, m), 2.37 (3H, s), 2.06-2.00 (2H, m), 1.55
-1.43 (2H, m) <Reference Example 52> 3-acetylthio-1- [4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole -2-yl @ azetidine

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(1) (3R) -3-hydroxy-1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine (3R) -3-hydroxypyrrolidine hydrochloride 7.00 g (56.6 g)
mmol) were suspended in 210 ml of methylene chloride, 13.4 g (62.3 mmol) of p-nitrobenzyl chloroformate and 17.4 ml (125 mmol) of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n
-Hexane: ethyl acetate = 1: 1 to ethyl acetate) to give (3R) -3-hydroxy-1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine
3.6 g, 90% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.1Hz), 7.53 (2H, d, J = 8.1Hz), 5.24 (2H, s),
4.55-4.50 (1H, m), 3.63-3.53 (3H, m), 3.51-
3.44 (1H, m), 2.09-1.93 (2H, m) (2) (3R) -3-methanesulfonyloxy-1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine 9.0 g (33.8 mmol) of (3R) -3-hydroxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine obtained in Reference Example 52 (1) is dissolved in 270 ml of methylene chloride. Methanesulfonyl chloride under ice-cooling 2.88 ml (37.2
mmol) and 5.21 ml (37.2 mmol) of triethylamine.
After 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n
-Hexane: ethyl acetate = 1: 2-ethyl acetate) to give (3R) -3-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl)-as a pale yellow solid.
11.5 g of pyrrolidine was obtained in a yield of 99%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.1Hz), 7.53 (2H, m) 5.33-5.23 (1H, m) 5.24
(2H, s), 3.82 (1H, dd, J = 12.5,5.1Hz), 3.72 -3.53
(3H, m), 3.06 (3H, s), 2.42-2.26 (1H, m), 2.26-
2.11 (1H, m) (3) (3S) -3-azido-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine (3R) -3-methanesulfonyloxy-1 obtained in Reference Example 52 (2) 4.00 g (11.6 mmol) of-(p-nitrobenzyloxycarbonyl) -pyrrolidine is dissolved in 120 ml of dimethylformamide, and 831 m of sodium azide is added to the system.
g (12.8 mmol) was added, and the mixture was stirred in a 100 ° C. oil bath for 2 hours.
After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1 to 1: 2) to give (3S) -3-azido-1- (p-) as pale yellow crystals. 3.43 g of nitrobenzyloxycarbonyl) -pyrrolidine, 100% yield
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.7Hz), 7.54 (2H, d, J = 8.7Hz), 5.18 (2H, s),
4.24-4.38 (1H, m), 3.62-3.48 (4H, m), 2.19-
2.11 (2H, m) (4) (3S) -3-amino-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine (3S) -3-azido-1 obtained in Reference Example 52 (3)
Dissolve 3.43 g (11.6 mmol) of-(p-nitrobenzyloxycarbonyl) -pyrrolidine in 103 ml of acetonitrile,
3.19 g (12.2 mmol) of triphenylphosphine was added to the system, and the mixture was stirred in a 70 ° C oil bath for 2 hours. After confirming the disappearance of the raw materials, 3.93 g (12.2 mmol) of sodium sulfate decahydrate was added to the system, and the mixture was stirred for 5 hours. After confirming the completion of the reaction, the reaction solution is filtered,
Methylene chloride and 0.1 M aqueous hydrochloric acid were added to the filtrate, and the mixture was separated and extracted. Methylene chloride and sodium hydrogen carbonate were added to the obtained water tank, and the water tank was separated and extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain pale yellow crystals of (3S) -3-.
Amino-1- (p-nitrobenzyloxycarbonyl)
-2.83 g of pyrrolidine were obtained in a yield of 92%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.7Hz), 7.52 (2H, d, J = 8.7Hz), 5.23 (2H, s),
3.68-3.57 (3H, m), 3.52-3.44 (1H, m), 3.19-
3.11 (1H, m), 2.14-2.04 (1H, m), 1.77-1.64 (1
H, m) (5) 3-t-butyldiphenylsilyloxy-1- [4
-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3
-Thiazol-2-yl} azetidine (3S) -3-amino-1 obtained in Reference Example 52 (4)
363 mg (1.37 mmol) of-(p-nitrobenzyloxycarbonyl) -pyrrolidine and 3 obtained in Reference Example 2 (4)
-T-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine
500 mg (1.14 mmol) were suspended in 25 ml of dimethylformamide, and 208 μl (1.37 mmol) of diethylphosphoryl cyanide and 192 μl of triethylamine (1.
37 mmol) and stirred at room temperature for 2 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n
-Hexane: ethyl acetate = 1: 1 to 1: 3) to give 3-t-butyldiphenylsilyloxy-1- [4-[(3S) -1- (p-nitrobenzyloxy) as a pale yellow solid. Carbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine
mg, 72% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
m), 7.61 (4H, d, J = 8.8Hz), 7.53 (2H, m), 7.48-7.
38 (6H, m), 7.37 (1H, s), 7.22-7.15 (1H, brt, J =
8.3Hz), 5.24 (2H, d, J = 10.7Hz), 4.80-4.74 (1H,
m), 4.67-4.59 (1H, m), 4.11 (2H, t, J = 7.3Hz), 4.
07-4.00 (2H, m), 3.81 (1H, dt, J = 10.7, 5.9Hz),
3.67-3.52 (2H, m), 3.40 (1H, dd, J = 11.2, 5.4Hz),
2.33-2.22 (1H, m), 2.08-1.92 (1H, m), 1.07 (9
H, s) (6) 3-hydroxy-1- [4-[(3S) -1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine-3
-Ylcarbamoyl] -1,3-thiazol-2-yl} azetidine 3-t-butyldiphenylsilyloxy-1- [4-[(3S) -1- (p-) obtained in Reference Example 52 (5). Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl {azetidine (560 mg, 0.816 mmol) in anhydrous tetrahydrofuran 17m
acetic acid 56 μl, (0.980 mmol),
980 μl (0.980 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was sequentially added, and the mixture was stirred as it was for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give 3-hydroxy-1-.
[4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,
3-Thiazol-2-yl diazetidine was obtained as a white solid in 359 mg, 98% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
m), 7.53 (2H, m), 7.40 (1H, s), 7.24-7.17 (1H, br
s), 5.30-5.18 (2H, m), 4.89-4.82 (1H, m), 4.6
6-4.58 (1H, m), 4.33 (2H, t, J = 7.8Hz), 3.96 (2H,
dd, J = 8.8, 3.9Hz), 3.80 (1H, dt, J = 11.2, 5.8Hz),
3.66-3.52 (2H, m), 3.46-3.39 (1H, m), 2.44-
2.37 (1H, br s), 2.33-2.22 (1H, m), 2.10-1.95
(1H, m) (7) 3-methanesulfonyloxy-1- [4-[(3
S) -1- (p-Nitrobenzyloxycarbonyl)-
Pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl {azetidine 3-hydroxy-1- [4 obtained in Reference Example 52 (6).
-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3
-Thiazol-2-yl diazetidine 350 mg (0.782 mmo
l) was dissolved in 18 ml of methylene chloride, and 182 μl (2.35 mmol) of methanesulfonyl chloride and triethylamine 3 were added under ice cooling.
29 μl (2.35 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 98: 2) to give 3-methanesulfonyloxy-1- [4-[(3S)-) as a pale yellow solid. 1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine-3
-Ylcarbamoyl] -1,3-thiazol-2-yl} azetidine was obtained in 410 mg in a yield of 99%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H,
m), 7.53 (2H, m), 7.46 (1H, s), 7.20-7.14 (1H, b
rs), 5.45-5.40 (1H, m), 5.24 (2H, d, J = 8.8Hz),
4.66-4.59 (1H, m), 4.46 (2H, t, J = 8.1Hz), 4.27
(2H, dd, J = 9.9, 4.0Hz), 3.81 (1H, dt, J = 11.0, 6.3H
z), 3.67-3.52 (2H, m), 3.42 (1H, dd, J = 11.0, 5.1
Hz), 3.12 (3H, s), 2.31-2.24 (1H, m), 2.07-1.9
5 (1H, m) (8) 3-acetylthio-1- [4-[(3S) -1-
(P-Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole-2-
Ill-azetidine 3-methanesulfonyloxy-1- [4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1, obtained in Reference Example 52 (7); 3-thiazol-2-yl azetidine 410mg
(0.780 mmol) was dissolved in 21 ml of dimethylformamide,
At room temperature, 534 mg (4.68 mmol) of potassium thioacetate was added, and the mixture was stirred overnight in an oil bath at 80 ° C. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane:
Ethyl acetate = 1: 2-ethyl acetate) to give 3-acetylthio-1- [4-[(3S) -1-] as a light brown solid.
(P-Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole-2-
287 mg of irdiazetidine was obtained at a yield of 73%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
m), 7.52 (2H, m), 7.42 (1H, s), 7.20-7.15 (1H, br
s), 5.24 (2H, d, J = 10.7Hz), 4.66-4.59 (1H, m),
4.53 (2H, t, J = 8.3Hz), 4.47-4.41 (1H, m), 3.99
(2H, t, J = 6.4Hz), 3.84-3.76 (1H, m), 3.65-3.53
(2H, m), 3.41 (1H, dd, J = 11.7, 4.9Hz), 2.37 (3H,
s), 2.33-2.20 (1H, m), 2.07-1.93 (1H, m) Reference Example 53 3-acetylthio-1- [4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidine- 3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine

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(1) (3S) -3-acetoxy-1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine 7.50 g (21.8 mmol) of (3R) -3-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine obtained in Reference Example 52 (2) was dissolved in 225 ml of dimethylformamide. Dissolved in potassium acetate 6.41g (65.3mmo
l) was added into the system, and the mixture was stirred in an 80 ° C. oil bath overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% saline and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 2: 1 to 1: 2) to give (3S) -3-acetoxy-1- (p) as white crystals.
-Nitrobenzyloxycarbonyl) -pyrrolidine in 5.
51 g, 82% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.1Hz), 7.53 (2H, d, J = 8.1Hz), 5.33-5.29 (1
H, m), 5.24 (2H, s), 3.68-3.50 (4H, m), 2.19- 2.0
2 (2H, m), 2.04 (3H, s) (2) (3S) -3-hydroxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine (3S)-obtained in Reference Example 53 (1) 5.51 g (17.8 mmol) of 3-acetoxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine was dissolved in 200 ml of methanol,
Add a catalytic amount of sodium methoxide to the system and add at room temperature
Stir for 4.5 hours. After confirming the completion of the reaction, the system was neutralized by adding a 4N-hydrochloric acid gas-1,4-dioxane solution, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction solution, and the aqueous solution was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 2-ethyl acetate) to give white crystals (3S) -3-hydroxy-.
4.00 g of 1- (p-nitrobenzyloxycarbonyl) -pyrrolidine was obtained at a yield of 84%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.1Hz), 7.53 (2H, d, J = 8.1Hz), 5.24 (2H, s),
4.55-4.50 (1H, m), 3.63-3.52 (3H, m), 3.52-
3.44 (1H, m), 2.09-1.92 (2H, m) (3) (3S) -3-methanesulfonyloxy-1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine 4.00 g (15.0 mmol) of (3S) -3-hydroxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine obtained in Reference Example 53 (2) was added to 120 ml of methylene chloride. Dissolve and cool under ice-cooling 1.28 ml of methanesulfonyl chloride (1
6.5 mmol) and 2.31 ml (16.5 mmol) of triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate).
To give 5.33 g (100%) of colorless oily (3S) -3-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 7.53 (2H, dd, J = 8.1, 3.7Hz), 5.33-5.
23 (1H, m), 5.24 (2H, s), 3.82 (1H, dd, J = 12.5, 5.1
Hz), 3.72-3.53 (3H, m), 3.06 (3H, s), 2.42-2.2
6 (1H, m), 2.26- 2.11 (1H, m) (4) (3R) -3-azido-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine (3S) obtained in Reference Example 53 (3). ) -3-Methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine (5.33 g, 15.0 mmol) was dissolved in 159 ml of dimethylformamide, and 1.07 g of sodium azide was added to the system.
(16.5 mmol), and the mixture was stirred in a 100 ° C. oil bath for 3.5 hours.
After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 10% saline and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1 to 1: 2) to give (3R) -3-azido-1- (p-nitro) as a colorless oil. (Benzyloxycarbonyl) -pyrrolidine to 4.48
g, 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 7.53 (2H, d, J = 8.8Hz), 5.24 (2H, s),
4.24-4.18 (1H, m), 3.62-3.48 (4H, m), 2.19-
2.02 (2H, m) (5) (3R) -3-amino-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine (3R) -3-azido-1 obtained in Reference Example 53 (4).
Dissolve 4.48 g (15.4 mmol) of-(p-nitrobenzyloxycarbonyl) -pyrrolidine in 134 ml of acetonitrile,
4.22 g (16.1 mmol) of triphenylphosphine was added to the system, and the mixture was stirred in a 70 ° C oil bath for 1.5 hours. After confirming the disappearance of raw materials,
5.19 g (16.1 mmol) of sodium sulfate decahydrate was added to the system, and the mixture was stirred for 5 hours. After confirming the completion of the reaction, the reaction solution was filtered, methylene chloride and 0.1 M aqueous hydrochloric acid were added to the filtrate, and the mixture was separated and extracted. Methylene chloride and sodium hydrogen carbonate were added to the obtained water tank, and the water tank was separated and extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain light yellow crystals of (3R) -3.
3.53 g of -amino-1- (p-nitrobenzyloxycarbonyl) -pyrrolidine was obtained at a yield of 86%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.8Hz), 7.52 (2H, d, J = 8.8Hz), 5.23 (2H, s), 3.
66-3.58 (3H, m), 3.52-3.45 (1H, m), 3.19- 3.12
(1H, m), 2.13-2.04 (1H, m), 1.76-1.66 (1H, m) (6) 3-t-butyldiphenylsilyloxy-1- [4
-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-
Thiazol-2-yl diazetidine (3R) -3-amino-1 obtained in Reference Example 53 (5)
363 mg (1.37 mmol) of-(p-nitrobenzyloxycarbonyl) -pyrrolidine and 3- (obtained in Reference Example 2 (4))
t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine 50
0 mg (1.14 mmol) was suspended in 25 ml of dimethylformamide, and 208 μl (1.37 mmol) of diethylphosphoryl cyanide and 192 μl of triethylamine (1.37 mmol) were cooled under ice-cooling under a nitrogen atmosphere.
mmol) and stirred at room temperature for 2 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-
Hexane: ethyl acetate = 1: 1 to 1: 3)
3-t-butyldiphenylsilyloxy as a pale yellow solid
1- [4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl]-
598 mg of 1,3-thiazol-2-yl} azetidine,
Obtained in a yield of 51%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.8Hz), 7.62 (4H, d, J = 8.1Hz), 7.56-7.38 (8
H, m), 7.37 (1H, s), 7.22-7.16 (1H, br s) 5.24 (2
H, d, J = 8.8Hz), 4.76 (1H, ddd, J = 6.6, 5.1Hz), 4.67
-4.58 (1H, m), 4.15-4.07 (2H, m), 4.06-3.98
(2H, m), 3.86-3.78 (1H, m), 3.67 -3.52 (2H, m),
3.40 (1H, dd, J = 11.0, 5.1Hz), 2.34-2.20 (1H, m),
2.02 -1.90 (1H, m), 1.07 (9H, s) (7) 3-hydroxy-1- [4-[(3R) -1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine-3
-Ylcarbamoyl] -1,3-thiazol-2-yl} azetidine 3-t-butyldiphenylsilyloxy-1- [4-[(3R) -1- (p-) obtained in Reference Example 53 (6). Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yldazetidine (590 mg, 0.860 mmol) in anhydrous tetrahydrofuran 18 m
acetic acid under ice-cooling, 59 μl of acetic acid, (1.03 mmol),
1.03 ml (1.03 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was sequentially added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol =
95: 5) to give 3-hydroxy-1- [4-
[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-
Thiazol-2-yl diazetidine as a white solid,
It was obtained in a yield of 378 mg and 98%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H,
m), 7.53 (2H, m), 7.40 (1H, s), 7.24-7.18 (1H, br
s), 5.30-5.18 (2H, m), 4.88-4.81 (1H, m), 4.66
-4.58 (1H, m), 4.32 (2H, t, J = 7.8Hz), 3.96 (2H,
dd, J = 8.8, 4.9Hz), 3.80 (1H, dt, J = 12.2, 6.8Hz),
3.66-3.52 (2H, m), 3.46-3.40 (1H, m), 2.49-
2.41 (1H, br s), 2.33-2.22 (1H, m), 2.09-1.95
(1H, m) (8) 3-methanesulfonyloxy-1- [4-[(3
R) -1- (p-Nitrobenzyloxycarbonyl)-
Pyrrolidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine 3-hydroxy-1- [4 obtained in Reference Example 53 (7)
-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-
Thiazol-2-yl diazetidine 370mg (0.827mmol)
Was dissolved in 19 ml of methylene chloride, and 192 μl (2.48 mmol) of methanesulfonyl chloride and 348 of triethylamine were added under ice-cooling.
μl (2.48 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours. 192 ml (2.48 mmol) of methanesulfonyl chloride, 348 ml of triethylamine (2.48
After 10 minutes, the reaction system was returned to room temperature and stirred for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol =
98: 2) to give 3-methanesulfonyloxy-1- [4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1, a pale yellow solid. 422 mg of 3-thiazol-2-yl diazetidine were obtained in a yield of 97%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H,
m), 7.53 (2H, m), 7.46 (1H, s), 7.19-7.13 (1H, br
s), 5.45-5.40 (1H, m), 5.24 (2H, d, J = 10.7Hz),
4.66-4.59 (1H, m), 4.46 (2H, t, J = 7.8Hz), 4.27
(2H, dd, J = 9.8, 2.9Hz), 3.81 (1H, dt, J = 13.7,5.9H
z), 3.66-3.54 (2H, m), 3.43 (1H, dd, J = 11.2, 4.4
Hz), 3.12 (3H, s), 2.30-2.22 (1H, m), 2.09-1.9
5 (1H, m) (9) 3-acetylthio-1- [4-[(3R) -1-
(P-Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-thiazole-2-
Ill-azetidine 3-methanesulfonyloxy-1- [4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1, obtained in Reference Example 53 (8); 420 mg of 3-thiazol-2-yl diazetidine
(0.799 mmol) was dissolved in 21 ml of dimethylformamide, 548 mg (4.79 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in an oil bath at 80 ° C. overnight. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane:
Ethyl acetate = 1: 2-ethyl acetate: methanol = 99:
Purified in 1) to give a light brown solid 3-acetylthio-1-
[4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,
280 mg of 3-thiazol-2-yl diazetidine, yield 6
9%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
m), 7.3 (2H, m), 7.42 (1H, s), 7.21-7.15 (1H, br
s), 5.24 (2H, d, J = 10.7Hz), 4.66-4.58 (1H, m),
4.53 (2H, dd, J = 8.8, 7.8Hz), 4.47-4.41 (1H, m),
3.99 (2H, dd, J = 6.8, 5.9Hz), 3.84-3.76 (1H, m),
3.66-3.53 (2H, m), 3.41 (1H, dd, J = 11.7, 4.9Hz),
2.37 (3H, s), 2.33-2.23 (1H, m), 2.03-1.94 (1
H, m) Reference Example 54 3-acetylthio-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl} azetidine

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3-hydroxy-1- (p-nitrobenzyloxycarbonyl) -azetidine 1-benzhydryl-3-hydroxyazetidine (9.00 g, 37.6 mmol) was dissolved in methanol (270 ml), and the mixture was dissolved in 10% palladium carbon (9.00 g). Catalytic hydrogen reduction was performed in a 50 ° C water bath for 5.5 hours. After confirming the completion of the reaction, the reaction solution was filtered, the residue was washed with methanol, and the filtrate was concentrated under reduced pressure. Ethyl acetate to the obtained residue,
Distilled water was added, liquid separation was performed, and the aqueous layer was washed with ethyl acetate, concentrated under reduced pressure, and the obtained residue was dried under reduced pressure. This crude product was dissolved in 82 ml of methylene chloride and 55 ml of methanol, and 8.90 g of p-nitrobenzyl chloroformate (4.
1.3 mmol) and 5.79 ml (41.3 mmol) of triethylamine, and the mixture was stirred at room temperature for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1).
1-ethyl acetate) to give 3-hydroxy-1- (p-nitrobenzyloxycarbonyl) as pale yellow crystals
3.52 g of azetidine was obtained in a yield of 37%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.8Hz), 7.50 (2H, d, J = 8.8Hz), 5.19 (2H, s),
4.71-4.64 (1H, m), 4.27 (2H, dd, J = 9.9, 7.0Hz),
3.93 (2H, dd, J = 9.9, 4.0Hz), 2.20-2.16 (1H, br
d, J = 5.9 Hz) (2) 3-Methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -azetidine 3-hydroxy-1- (p) obtained in Reference Example 54 (1)
-Nitrobenzyloxycarbonyl) -azetidine 3.52
g (14.0 mmol) was dissolved in 106 ml of methylene chloride, and 1.19 ml (15.4 mmol) of methanesulfonyl chloride and 2.16 ml (15.4 mmol) of triethylamine were added under ice-cooling. After 10 minutes, the reaction system was returned to room temperature. Stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered,
The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to 1: 3) to give pale yellow crystals of 3
4.63 g of -methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -azetidine was obtained at a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.8Hz), 7.50 (2H, d, J = 8.8Hz), 5.29-5.22 (1
H, m), 5.20 (2H, s), 4.40 (2H, dd, J = 10.2, 6.2Hz),
4.22 (2H, dd, J = 10.2, 4.0 Hz), 3.08 (3H, s) (3) 3-azido-1- (p-nitrobenzyloxycarbonyl) -azetidine 3 obtained in Reference Example 54 (2) -Methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) -azetidine (4.63 g, 14.0 mmol) was added to dimethylformamide 140
Dissolve in water and add sodium azide 1.37g (21.0mmo
l) was added and the mixture was stirred in a 100 ° C. oil bath for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered,
The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 2: 1 to 1: 1) to give pale yellow crystals of 3
-Azido-1- (p-nitrobenzyloxycarbonyl) -azetidine was obtained in 2.15 g at a yield of 55%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.8Hz), 7.50 (2H, d, J = 8.8Hz), 5.19 (2H, s),
4.33-4.28 (3H, m), 4.03-3.96 (2H, m) (4) 3-Amino-1- (p-nitrobenzyloxycarbonyl) -azetidine 3-azido- obtained in Reference Example 54 (3) 2.15 g of 1- (p-nitrobenzyloxycarbonyl) -azetidine
(7.76 mmol) was dissolved in 65 ml of acetonitrile, 2.14 g (8.14 mmol) of triphenylphosphine was added to the system, and the mixture was heated at 70 ° C.
The mixture was stirred in an oil bath for 2 hours. After confirming the disappearance of the raw materials, 2.62 g (8.14 mmol) of sodium sulfate decahydrate was added to the system, and the mixture was stirred for 3 hours. After the completion of the reaction was confirmed, the reaction solution was filtered, and methylene chloride and 0.1 M aqueous hydrochloric acid were added to the filtrate, followed by separation and extraction. Methylene chloride and sodium hydrogen carbonate were added to the obtained water tank, and the water tank was separated and extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
1.87 g of 3-amino-1- (p-nitrobenzyloxycarbonyl) -azetidine as pale yellow crystals was obtained in a yield of 96%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.8Hz), 7.50 (2H, d, J = 8.8Hz), 5.18 (2H, s),
4.27 (2H, dd, J = 8.6, 8.6Hz), 3.87 (1H, tt, J = 5.1,
(7.3Hz), 3.70 (2H, dd, J = 8.8,5.1Hz) (5) 3-t-butyldiphenylsilyloxy-1-
{4-[(1-p-nitrobenzyloxycarbonyl)-
Azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl] azetidine 549 mg of 3-amino-1- (p-nitrobenzyloxycarbonyl) -azetidine obtained in Reference Example 54 (4)
(2.18 mmol) and the 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-) obtained in Reference Example 2 (4).
800 mg of 1,3-thiazol-2-yl) azetidine (1.
82 mmol) was dissolved in 40 ml of dimethylformamide, and 331 μl of diethylphosphoryl cyanide was cooled with ice under a nitrogen atmosphere.
(2.18 mmol) and 306 μl (2.18 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate.
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 1 to 1: 3) to give 3-t-butyldiphenylsilyloxy-1- as a pale yellow solid.
{4-[(1-p-nitrobenzyloxycarbonyl)-
Azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl] azetidine was obtained in a yield of 1.06 g and a yield of 49%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.1Hz), 7.62 (4H, d, J = 8.1Hz), 7.54-7.39 (8
H, m), 7.37 (1H, s), 5.21 (2H, s), 4.89-4.81 (1
H, m), 4.81-4.73 (1H, m), 4.41 (2H, dd, J = 8.8,
8.8Hz), 4.12 (2H, dd, J = 8.8, 8.8Hz), 4.05-3.98 (4
H, m), 1.07 (9H, s) (6) 3-hydroxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazole-2 -Yl] azetidine 3-t-butyldiphenylsilyloxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1, obtained in Reference Example 54 (5); 3-thiazol-2-yl] azetidine 1.06 g
(1.58 mmol) in 53 ml of anhydrous tetrahydrofuran,
Under ice cooling, 109 μl of acetic acid, (1.90 mmol), 1.0 M tetra-
1.90 ml (1.90 mmol) of an n-butylammonium fluoride-tetrahydrofuran solution was sequentially added, and the mixture was stirred for 2 hours. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 95: 5).
To give 3-hydroxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl] azetidine as a white solid. 649 mg, yield 95%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.8Hz), 7.58-7.50 (1H, br s), 7.52 (2H, d,
J = 8.8Hz), 7.40 (1H, s), 5.20 (2H, s), 4.90 -4.80
(1H, m), 4.42 (2H, dd, J = 8.8, 8.8Hz), 4.34 (2H, d
d, J = 9.5, 6.6Hz), 4.02 (2H, dd, J = 9.5, 5.2Hz), 4.00
-3.96 (2H, m) (7) 3-Methanesulfonyloxy-1- {4-[(1
-P-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazole-2-
[Il] azetidine 3-Hydroxy-1- {4} obtained in Reference Example 54 (6)
640 mg (1.48 mmol) of-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazol-2-yl] azetidine is dissolved in 20 ml of methylene chloride and cooled with ice. Methanesulfonyl chloride 343 μml (4.43 mmol), triethylamine 621 μml (4.
After 10 minutes, the reaction system was returned to room temperature and stirred as it was overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9).
8: 2) to give 3-methanesulfonyloxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl]-as a pale yellow solid.
[1,3-thiazol-2-yl] azetidine was obtained in 611 mg in a yield of 81%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.8Hz), 7.51 (2H, d, J = 8.8Hz), 7.50-7.46 (1
H, br s), 7.46 (1H, s), 5.46-5.41 (1H, m), 5.20
(2H, s), 4.89-4.80 (1H, m), 4.49-4.38 (4H, m),
4.28 (2H, dd, J = 11.8, 4.4Hz), 4.01 (2H, dd, J = 9.
5, 5.3 Hz), 3.12 (3H, s) (8) 3-acetylthio-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3-thiazole- 2-yl] azetidine 3-methanesulfonyloxy-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl] -1,3 obtained in Reference Example 54 (7).
-Thiazol-2-yl] azetidine 610 mg (1.19 mmol)
Was dissolved in 81 ml of dimethylformamide, 817 mg (7.15 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred overnight in an oil bath at 80 ° C. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1).
2-ethyl acetate) to give 3-acetylthio-1- {4-[(1-p-nitrobenzyloxycarbonyl) -azetidin-3-ylcarbamoyl]-as a light brown solid.
405 mg of 1,3-thiazol-2-yl] azetidine
Obtained in 69% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
d, J = 8.8Hz), 7.53-7.49 (1H, m), 7.51 (2H, d, J = 8.
8Hz), 7.43 (1H, s), 5.20 (2H, s), 4.89-4.79 (1H,
m), 4.54 (2H, dd, J = 8.1, 8.1Hz), 4.48-4.18 (3H,
m), 4.04-3.97 (2H, m), 2.37 (3H, s) Reference Example 55 3-acetylthio-1- [4-[(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl]-
1,3-thiazol-2-yl] azetidine

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(1) 4- (p-Nitrobenzyloxycarbonyl) -piperazine hydrochloride 1.50 g of 4- (t-butoxycarbonyl) -piperazine
(8.05 mmol) was suspended in 68 ml of methylene chloride, and 1.90 g (8.86 mm) of p-nitrobenzyl chloroformate was cooled under ice-cooling.
ol) and 1.24 ml (8.86 mmol) of triethylamine, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 3
) And 1- (t-butoxycarbonyl) -4- (p-nitrobenzyloxycarbonyl) as pale yellow oil
2.60 g of piperazine were obtained in a yield of 89%. continue,
2.60 g (7.12 mmol) of this product was added to acetonitrile 10
The mixture was dissolved in 0 ml, and 15.0 ml of a 4N hydrochloric acid gas-ethyl acetate solution was added under ice-cooling, followed by stirring for 2 hours. After confirming the completion of the reaction, diethyl ether was added to the system and stirred for 30 minutes. The reaction system was filtered, and the residue was washed with diethyl ether, and 2.4 g of 4- (p-nitrobenzyloxycarbonyl) -piperazine hydrochloride as a white solid was obtained in a yield of 86.
%. (2) 3-t-butyldiphenylsilyloxy-1- [4
-[(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] -1,3-thiazole-2-
[Il] azetidine 4-p-nitrobenzyloxycarbonylpiperazine hydrochloride 874 mg (2.19 mmo) obtained in Reference Example 55 (1)
l) and the 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-carboxyl) obtained in Reference Example 2 (4).
Thiazol-2-yl) azetidine 800 mg (1.82 mmo
l) is suspended in 40 ml of dimethylformamide, and cooled under ice-cooling under a nitrogen atmosphere to 0.33 ml of diethyl phosphoryl cyanide
(2.19 mmol), triethylamine 0.30 ml (2.19 mm
ol) and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- [4-[(4-p -Nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] -1,3-thiazol-2-yl] azetidine (915 mg, yield 73%)
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.24 (2H,
d, J = 8.7 Hz), 7.61 (4H, dd, J = 7.9, 1.4 Hz), 7.
52 (2H, d, J = 8.7 Hz), 7.49-7.37 (6H, m), 7.1
4 (1H, s), 5.25 (2H, s), 4.80-4.71 (1H, m
), 4.11 (2H, dd, J = 8.7, 6.6 Hz), 4.01 (2H, dd,
J = 8.7, 4.9 Hz), 3.95-3.66 (4H, m), 3.65-3.5
2 (4H, m), 1.06 (9H, s) (3) 3-hydroxy-1- [4-[(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl]
-1,3-thiazol-2-yl] azetidine 3-t-butyldiphenylsilyloxy-1- [4-[(4-p-nitrobenzyloxycarbonyl) -piperazine- obtained in Reference Example 55 (2). 1-carbonyl] -1,
3-thiazol-2-yl] azetidine 1.77 g (1.71
was dissolved in 35 ml of anhydrous tetrahydrofuran, and 0.11 ml (1.88 mmol) of acetic acid and 1.0 M tetra-
1.88 ml (1.88 mmol) of an n-butylammonium fluoride-tetrahydrofuran solution was sequentially added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate.
The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol = 9: 1).
) To purify 3-hydroxy-1- [4-[(4-p-
(Nitrobenzyloxycarbonyl) -piperazine-1-
Carbonyl] -1,3-thiazol-2-yl] azetidine was obtained as a white solid in 726 mg, in a yield of 95%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.24 (2H,
d, J = 8.6 Hz), 7.52 (2H, d, J = 8.6 Hz), 7.17 (1
H, s), 5,25 (2H, s), 4.89-4.79 (1H, m), 4.3
2 (2H, dd, J = 9.1, 6.7 Hz), 3.96 (2H, dd, J = 9.
1, 4.5 Hz), 3.93-3.68 (4H, m), 3.66-3.52 (
4H, m) (4) 3-Methanesulfonyloxy-1- [4-[(4-
(p-nitrobenzyloxycarbonyl) -piperazine-
1-carbonyl] -1,3-thiazol-2-yl] azetidine 3-hydroxy-1- [4 obtained in Reference Example 55 (3)
-[(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] -1,3-thiazole-2-
[Il] azetidine 804 mg (1.80 mmol) in methylene chloride
Dissolve in 40 ml and methanesulfonyl chloride under ice-cooling
0.30 ml (2.15 mmol), triethylamine 0.17 ml (2.
15 mmol) and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 9: 1) to give 3-methanesulfonyloxy-1- [4-[(4-
(p-nitrobenzyloxycarbonyl) -piperazine-
1-carbonyl] -1,3-thiazol-2-yl] azetidine was obtained in 550 mg in a yield of 58%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.5 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.25 (1
H, s), 5.50-5.39 (1H, m), 5.26 (2H, s), 4.49
(2H, t, J = 9.6 Hz), 4.26 (2H, dd, J = 9.6, 4.2 H
z), 4.00-3.66 (4H, m), 3.66-3.47 (4H, m),
3.11 (3H, s), (5) 3-acetylthio-1- [4-[(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] -1,3-thiazol-2-yl] azetidine Reference 3-methanesulfonyloxy-1- [4-[(4-p-nitrobenzyloxycarbonyl) -piperazine-1-carbonyl] -1,3-thiazol-2-yl] azetidine obtained in Example 55 (4) 550 mg (1.05 mmol) was dissolved in 40 ml of dimethylformamide, 717 mg (6.28 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in a 90 ° C oil bath for 3 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1).
: 1) to give a light brown solid 3-acetylthio-
1- [4-[(4-p-nitrobenzyloxycarbonyl)
-Piperazine-1-carbonyl] -1,3-thiazol-2-yl] azetidine was obtained in 345 mg in a yield of 64%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.7 Hz), 7.53 (2H, d, J = 8.7 Hz), 7.22 (1
H, s), 5.25 (2H, s), 4.52 (2H, t, J = 8.4 Hz),
4.48-4.39 (1H, m), 3.98 (2H, dd, J = 8.4, 5.3 H
z), 3.95-3.68 (4H, m), 3.45-3.68 (4H, m),
2.33 (3H, s) Reference Example 56 3-acetylthio-1- [4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl]-
1,3-thiazol-2-yl] azetidine

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(1) (2-Hydroxy-ethyl) -carbamic acid t-butyl ester 2.51 g (41.1 mmol) of aminoethanol were dissolved in 50 ml of methylene chloride and 50 ml of methanol, and di-t was added under ice-cooling. -Butoxycarbonyl anhydride 1
3.5 g (61.9 mmol), triethylamine 8.6 ml
(61.7 mmol) was added and stirred at room temperature for 3 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate and saturated saline were added to the residue, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give (2-hydroxy-ethyl) -carbamic acid t-colorless transparent syrup.
6.18 g of butyl ester was obtained in 93% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 5.01 (1H, br
s), 3.70 (2H, br s), 3.29 (2H, q, J = 5.1Hz), 2.65
(1H, brs), 1.45 (9H, s) (2) (2-azido-ethyl) -carbamic acid t-butyl ester (2-hydroxy-ethyl) -carbamic acid t-butyl ester 1.5 g (6. 2 mmol) was dissolved in 75 ml of tetrahydrofuran, and under ice cooling, 3.0 ml (13.9 mmol) of diphenylphosphoryl azide, 3.7 g (14.1 mmol) of triphenylphosphine, and a 40% solution of diethyl azodicarboxylate in 40% toluene 5 .1g (1
3.9 mmol) was added under a nitrogen atmosphere, and the mixture was stirred as it was for 4 hours. After confirming the completion of the reaction, ethyl acetate and saturated saline were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1) to obtain 1.24 g of (2-azido-ethyl) -carbamic acid t-butyl ester as a colorless transparent syrup. , 72% yield. ¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) 4.85 (1H, br
s), 3.42 (2H, t, J = 4.8Hz), 3.31 (2H, t, J = 4.8Hz),
1.45 (9H, s) IR (liquid film): 2103, 1697, 1521, 1368, 1272, 12
53 cm ^-1 Mass spectrum (FAB ⁺ ): 187 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: 187.1186
[M + H] ^+, _{calcd: 187.1195 (C 7 H 15 O} 2 N 4) (3) (2-t- butoxycarbonylamino-ethyl) - -
1.22 g (6.55 mmol) of carbamic acid p-nitrobenzyl ester (2-azido-ethyl) -carbamic acid t-butyl ester in methanol 60 m
dissolved in 20% palladium hydroxide-carbon 1.22 g
In the presence, catalytic hydrogen reduction was performed at room temperature. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 60 ml of methylene chloride and 2.12 g (9.8 mmol) of p-nitrobenzyl chloroformate was cooled under ice-cooling.
l) and 1.37 ml (9.8 mmol) of triethylamine were added, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, ethyl acetate and saturated saline were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1), and (2-t-butoxycarbonylamino-ethyl) -carbamic acid p-nitrobenzyl ester as a white solid was added to 1 residue. .46 g, 66% yield. ¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H, d,
J = 9.0Hz), 7.51 (2H, d, J = 9.0Hz), 5.37 (1H, br s),
5.20 (2H, s), 4.82 (1H, br s), 3.35-3.25 (4H, m),
1.45 (9H, s) IR (KBr): 3355, 1708, 1692, 1534, 1350, 1263, 1170
cm ^-1 Mass spectrum (FAB ⁺ ): 340 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Actual value: 340.1512
[M + H] ⁺ , Calculated: 340.1508 (C ₁₅ H ₂₂ O ₆ N ₃ ) (4) 3-t-butyldiphenylsilyloxy-1-
[4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazole-2
-Yl] azetidine (2-t-butoxycarbonylamino-ethyl) -carbamic acid p-nitrobenzyl ester 1.46 g (4.
3 mmol) was dissolved in 15 ml of 1,4-dioxane, and 15 ml of a 4N hydrochloric acid gas-1,4-dioxane solution was added under ice-cooling.
Was added and stirred at room temperature for 5.5 hours. After confirming the completion of the reaction, diethyl ether was added to the system and stirred for 30 minutes.
The reaction system was filtered, and the residue was washed with diethyl ether to obtain 1.18 g of 1- (p-nitrobenzyloxycarbonylamino) ethylamine hydrochloride as a white solid, yield 100.
%. Subsequently, the obtained 2- (p-nitrobenzyloxycarbonylamino) -ethylamine hydrochloride 490 m
g (1.77 mmol) and 3-t obtained in Reference Example 2 (4)
-Butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine 5
30 mg (1.21 mmol) of dimethylformamide 2
The mixture was suspended in 6.5 ml, and under a nitrogen atmosphere, 0.3 ml (1.98 mmol) of diethylphosphoryl cyanide and 0.5 ml (3.59 mmol) of triethylamine were added under ice-cooling, followed by stirring at room temperature for 1.5 hours. . After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 1) to give 3-t-butyldiphenylsilyloxy-1- as a pale yellow solid.
[4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazole-2
630 mg of [-yl] azetidine was obtained in a yield of 79%. ¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) 8.16 (2H, d,
J = 8.8Hz), 7.62 (4H, d, J = 6.8Hz), 7.50-7.38 (9H,
m), 7.35 (1H, s), 5.62 (1H, brt, J = 5.9Hz), 5.17
(2H, s), 4.79-4.72 (1H, m), 4.09 (2H, dd, J = 8.8,
6.6Hz), 4.00 (2H, dd, J = 8.8, 4.9Hz), 3.55 (2H, q,
J = 5.9Hz), 3.43 (2H, q, J = 5.9Hz), 1.07 (9H, s) IR (KBr): 1724, 1660, 1547, 1523, 1346, 1318, 125
5, 1113 cm ^-1 Mass spectrum (FAB ⁺ ): 660 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: 660.2324
[M + H] ^+, _{calcd: 660.2312 (C 33 H 38 N} 5 O 6 SSi) (5) 3- hydroxy -1- [4- [2- (p- nitrobenzyloxycarbonyl amino) - ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine 3-t-butyldiphenylsilyloxy-1- [4- [2- (p-nitrobenzyloxycarbonylamino) -ethyl obtained in Reference Example 56 (4) Carbamoyl] -1,
3-thiazol-2-yl] azetidine 1.21 g
(1.84 mmol) in 60.6 m of anhydrous tetrahydrofuran
l, and cooled under ice-cooling to 0.13 ml of acetic acid, (2.2
7 mmol), 1.0 M tetra-n-butylammonium fluoride
2.2 mL (2.2 mmol) of a tetrahydrofuran solution was sequentially added, and the mixture was stirred for 2.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered,
The filtrate was concentrated under reduced pressure. Isopropyl ether was added to the obtained residue, and the mixture was washed with stirring, filtered, and 3-hydroxy-
667 mg of 1- [4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine was obtained as a yellow solid.
Obtained in 86% yield. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 8.21 (2H, d, J
= 8.8Hz), 8.03 (1H, t, J = 5.9Hz), 7.59 (2H, d, J = 8.8H
z), 7.50 (1H, t, J = 5.9Hz), 7.41 (1H, s), 5.83 (1H,
d, J = 5.9Hz), 5.17 (2H, s), 4.66-4.58 (1H, m), 4.23
(2H, dd, J = 8.8, 7.0Hz), 3.79 (2H, dd, J = 8.8, 4.9H
z), 3.31 (2H, q, J = 5.9Hz), 3.16 (2H, q, J = 5.9Hz) IR (KBr): 1698.1655, 1552, 1520, 1343, 1279 cm ^-1 Mass spectrum (FAB ⁺ ): 422 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): measured value: 444.0952
[M + Na] ⁺ , Calculated: 444.0953 (C ₁₇ H ₁₉ O ₆ N ₅ SNa) (6) 3-Methanesulfonyloxy-1- [4- [2-
(P-Nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine 3-hydroxy-1- [4 obtained in Reference Example 56 (5).
-[2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazole-2
658.4 mg (1.56 mmol) of [-yl] azetidine was dissolved in 33 ml of methylene chloride and 5 ml of pyridine, and 0.31 ml (4.0 ml) of methanesulfonyl chloride was cooled under ice-cooling.
0 mmol), 0.57 ml of triethylamine (4.09 mm
ol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 4 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was 0.5 M hydrochloric acid aqueous solution, saturated aqueous sodium hydrogen carbonate,
After washing with saturated saline, drying over anhydrous sodium sulfate,
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 2) to give a light yellow solid 3-
Methanesulfonyloxy-1- [4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine was converted to 6
07.3 mg, 78% yield. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 8.21 (2H, d, J
= 8.8Hz), 8.10 (1H, t, J = 5.9Hz), 7.59 (2H, d, J = 8.8H
z), 7.51 (1H, t, J = 5.9Hz), 7.50 (1H, s), 5.46-5.41
(1H, m), 5.17 (2H, s), 4.45 (2H, dd, J = 9.9, 6.6H
z), 4.17 (2H, dd, J = 9.9, 4.0Hz), 3.29 (3H, s) IR (KBr): 1720, 1658, 1547, 1523, 1348, 1255, 118
4, 1169 cm ^-1 Mass spectrum (FAB ⁺ ): 500 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Actual value: 500.0910
[M + H] ⁺ , calculated: 500.0910 (C ₁₈ H ₂₂ O ₈ N ₅ S ₂ ) (7) 3-acetylthio-1- [4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl ] -1,3-thiazol-2-yl] azetidine 3-methanesulfonyloxy-1- [4- [2- (p-nitrobenzyloxycarbonylamino) -ethylcarbamoyl] obtained in Reference Example 56 (6). [1,3-thiazol-2-yl] azetidine 607.3 mg (1.22 mmol
l) was dissolved in 33 ml of dimethylformamide, and 1.06 g (7.35 mmol) of potassium thioacetate was added at room temperature, followed by stirring in an oil bath at 80 ° C for 7 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. 0.5M of the obtained organic layer
The extract was washed with aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 2), and 3-acetylthio-1- [4- [2-] as a light brown solid was obtained.
(P-Nitrobenzyloxycarbonylamino) -ethylcarbamoyl] -1,3-thiazol-2-yl] azetidine was obtained in 335.8 mg in a yield of 58%. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 8.21 (2H, d, J
= 8.3Hz), 8.05 (1H, t, J = 5.9Hz), 7.58 (2H, d, J = 8.3H
z), 7.50 (1H, t, J = 5.9Hz), 7.47 (1H, s), 5.17 (2H,
s), 4.50 (2H, t, J = 8.8Hz), 4.42-4.36 (1H, m), 3.9
2 (2H, dd, J = 8.8, 4.6Hz), 3.305 (2H, q, J = 5.9Hz),
3.16 (2H, q, J = 5.9Hz), 2.36 (3H, s) IR (KBr): 3368, 1690, 1677, 1543, 1520, 1494, 134
9, 1255, 1239, 1108 cm ^{- 1} Mass spectrum (FAB ⁺ ): 480 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Actual value: 480.1002
[M + H] ⁺ , calculated: 480.1011 (C ₁₉ H ₂₂ O ₆ N ₅ S ₂ ) Reference Example 57 3-acetylthio-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine- 1-carbonyl] -1,3-thiazol-2-yl] azetidine

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1-t-butoxycarbonyl-3- (methanesulfonyloxy) -azetidine 3.24 g (18.7 mmol) of 1-t-butoxycarbonyl-3-hydroxyazetidine obtained in Reference Example 31 (1) was methylene chloride. Dissolved in 160 ml, methanesulfonyl chloride 1.59 ml (20.6 mmol), triethylamine 2.89 ml under ice cooling
(20.6 mmol) was added and 10 minutes later, the reaction system was returned to room temperature.
The mixture was stirred for 6 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. After washing the obtained organic layer with saturated saline,
The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to 1).
1: 2) to give 4.71 mg of 1-t-butoxycarbonyl-3- (methanesulfonyloxy) -azetidine as a pale yellow oil in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 5.23-5.17
(1H, m), 4.28 (2H, dd, J = 6.6,1.5Hz), 4.10 (2H, m),
3.07 (3H, s), 1.46 (9H, s) (2) 3-azido-1- (t-butoxycarbonyl)-
Azetidine 1-t-butoxycarbonyl-3- (methanesulfonyloxy) -azetidine 4.71 obtained in Reference Example 57 (1)
g (18.7 mmol) in 140 ml of dimethylformamide,
3.65 g (56.1 mmol) of sodium azide was added to the system, and 9
Stirred in a 0 ° C. oil bath overnight. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 4: 1) to give 3-azido-1 as a colorless oil.
3.44 g of-(t-butoxycarbonyl) -azetidine was obtained at a yield of 93%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 4.25-4.15
(3H, m), 3.92-3.87 (2H, m), 1.45 (9H, s) (3) 1-t-butoxycarbonyl-3- (p-nitrobenzyloxycarbonylamino) -azetidine Reference Example 57 (2) Dissolve 3.44 g (17.4 mmol) of 3-azido-1- (t-butoxycarbonyl) -azetidine obtained in Step 2 in 170 ml of methanol, and in the presence of 3.44 g of 10% palladium carbon, contact hydrogen at room temperature for 2 hours. Reduction was performed. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of 3-amino-1-t-butoxycarbonylazetidine. This product is dissolved in 170 ml of methylene chloride,
5.63 g (26.1 mm) of p-nitrobenzyl chloroformate under ice cooling
ol) and 3.66 ml (26.1 mmol) of triethylamine, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to 1:
Purification was performed in 2) to obtain 4.84 g of colorless oily 1-t-butoxycarbonyl-3- (p-nitrobenzyloxycarbonylamino) -azetidine in a yield of 79%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.1Hz), 7.50 (2H, d, J = 8.1Hz), 5.26-5.18 (1
H, br s), 5.26 (2H, s), 5.84 (1H, d, J = 5.1Hz), 4.5
0-4.40 (1H, m), 4.24 (2H, t, J = 9.5Hz), 3.76 (2H,
dd, J = 9.5, 5.1 Hz), 1.43 (9H, s) (4) 3-t-butyldiphenylsilyloxy-1-
[4- [3- (p-Nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl] azetidine Reference Example 57 (3) 1-t-butoxycarbonyl-3- ( p
-Nitrobenzyloxycarbonylamino) -azetidine (4.84 g, 13.8 mmol) was dissolved in 1,4-dioxane (50 ml), and 4N hydrochloric acid gas-1,4-dioxane solution (50 ml) was added thereto under ice-cooling. Stirred for hours. After confirming the completion of the reaction, the reaction system was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the mixture was filtered. The residue was washed with ethyl acetate, and 2.31 g of pale yellow crystalline 3- (p-nitrobenzyloxycarbonylamino) -azetidine hydrochloride was obtained at a yield of 58%. Obtained. Subsequently, 944 mg (3.28 mmol) of 3- (p-nitrobenzyloxycarbonylamino) -azetidine hydrochloride and Reference Example 2
3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazole-2) obtained in (4)
-Yl) azetidine (1.2 g, 2.74 mmol) was suspended in dimethylformamide (60 ml). Under a nitrogen atmosphere, 498 μl (3.28 mmol) of diethylphosphoryl cyanide and 922 μl (6.58 mmol) of triethylamine were added under ice-cooling. Stirred overnight. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- [4- [3- [3] as a pale yellow solid.
-(P-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazole-2
[-Yl] azetidine was obtained at 853 mg in a yield of 53%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 7.64-7.59 (4H, m), 7.52 (2H, d, J =
8.8Hz), 7.48-7.37 (6H, m), 7.37 (1H, s), 5.58-
5.51 (1H, br d, J = 8.1Hz), 5.22 (2H, s), 4.93-4.8
4 (1H, m), 4.76 -4.70 (1H, m), 4.60-4.50 (1H,
m), 4.50-4.41 (1H, m), 4.39-4.30 (1H, m), 4.11
-4.03 (2H, m), 3.97 (2H, dd, J = 8.1, 5.1Hz), 4.00
-3.92 (1H, m), 1.06 (9H, s) (5) 3-Hydroxy-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3- Thiazol-2-yl] azetidine 3-t-butyldiphenylsilyloxy-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] obtained in Reference Example 57 (4). -1,3-thiazol-2-yl] azetidine 850 mg
(1.27 mmol) was dissolved in 43 ml of anhydrous tetrahydrofuran, and 87 μl of acetic acid, (1.52 mmol), 1.52 ml (1.52 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution were sequentially added under ice cooling, and the mixture was added as it was. Stirred for 0.5 hours. After confirming the completion of the reaction, ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, and the mixture was filtered. The residue was washed with diisopropyl ether, and 3-hydroxy-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-) was added. Carbonyl]-
[1,3-thiazol-2-yl] azetidine was obtained as a white solid in 486 mg in a yield of 88%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.25 (2H,
d, J = 8.8Hz), 8.14 (1H, d, J = 7.3Hz), 7.61 (2H, d, J =
8.8Hz), 7.43 (1H, s), 5.83 (1H, d, J = 5.9Hz), 5.19
(2H, s), 4.74-4.67 (1H, m), 4.66-4.58 (1H, m),
4.40-4.34 (1H, m), 4.32-4.26 (1H, m), 4.24-
4.17 (3H, m), 3.86-3.80 (1H, m), 3.79- 3.71 (2H,
m) (6) 3-Methanesulfonyloxy-1- [4- [3-
(P-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazole-2-
[Il] azetidine 3-hydroxy-1- [4] obtained in Reference Example 57 (5)
630 mg (1.45 mmol) of-[3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl] azetidine are dissolved in 32 ml of methyl chloride and 12 ml of pyridine, and cooled with ice. Under the conditions, 377 μl (4.36 mmol) of methanesulfonyl chloride and 611 μl (4.36 mmol) of triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 4 hours. After confirming the completion of the reaction,
Ethyl acetate and saturated saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, followed by filtration. The residue was washed with diisopropyl ether, and 3-methanesulfonyloxy-1- [4- [3- (p-
Nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl] azetidine was obtained in a yield of 766 mg and 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.25 (2H,
d, J = 8.8Hz), 8.15 (2H, d, J = 7.3Hz), 7.61 (2H, d, J =
8.8Hz), 7.52 (1H, s), 5.50-5.43 (1H, m), 5.19 (2
H, s), 4.72 (1H, t, J = 8.8Hz), 4.46-4.27 (4H, m),
4.25-4.11 (3H, m), 3.85 (1H, dd, J = 9.9, 5.5Hz),
3.29 (3H, s) (7) 3-acetylthio-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-
Carbonyl] -1,3-thiazol-2-yl] azetidine 3-methanesulfonyloxy-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine- obtained in Reference Example 57 (6). 1-carbonyl] -1, 3
-Thiazol-2-yl] azetidine 760 mg (1.45 mmol)
Was dissolved in 38 ml of dimethylformamide, 993 mg (8.70 mmol) of potassium thioacetate was added at room temperature, and the mixture was heated at 80 ° C. in an oil bath.
Stirred for 9 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-acetylthio-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1 as a light brown solid. −
Carbonyl] -1,3-thiazol-2-yl] azetidine was obtained in an amount of 397 mg in a yield of 56%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 7.52 (2H, d, J = 8.8Hz), 7.44 (1H, s),
5.36-5.30 (1H, m), 5.21 (2H, s), 4.74-4.83 (1
H, m), 4.60-4.34 (6H, m), 3.95 (3H, m), 2.37 (3
H, s) Reference Example 58 3-acetylthio-1- (4- [methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- {4- [methyl- (2-hydroxyethyl) carbamoyl] -1,3-thiazol-2-yl} azetidine N-methylaminoethanol 0ml (12.4mmo
l) and the 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-carboxyl) obtained in Reference Example 2 (4).
3.64 g of thiazol-2-yl) azetidine (8.
3 mmol) was suspended in 180 ml of dimethylformamide, and 1.9 ml (12.5 mmol) of diethylphosphoryl cyanide and 1.19 ml of triethylamine were cooled under ice-cooling under a nitrogen atmosphere.
73 ml (12.4 mmol) was added, and the mixture was stirred at room temperature for 7 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 1) to give 3-t of pale yellow transparent syrup.
3.41 g of -butyldiphenylsilyloxy-1- {4- [methyl- (2-hydroxyethyl) carbamoyl] -1,3-thiazol-2-yl} azetidine, yield 8
Obtained at 3%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.61 (4H, d,
J = 7.0Hz), 7.48-7.36 (6H, m), 7.17 (1H, s), 4.79-
4.71 (1H, m), 4.17 (2H, t, J = 6.8Hz), 4.05 (2H, dd,
J = 6.8, 2.7Hz), 3.84 (2H, t, J = 5.4Hz), 3.64 (2H,
t, J = 5.4Hz), 3.28 (1H, br s), 3.05 (3H, s), 1.06 (9
H, s) (2) 3-tert-butyldiphenylsilyloxy-1-
{4-[(2-azidoethyl) -methyl-carbamoyl]
-1,3-thiazol-2-yl} azetidine 3-t-butyldiphenylsilyloxy-1- {4- [methyl- (2-hydroxyethyl) carbamoyl] -1, obtained in Reference Example 58 (1), 997.5 mg (2.0 mmol) of 3-thiazol-2-yl diazetidine is dissolved in 50 ml of tetrahydrofuran, and 0.65 ml (3.02 mmol) of diphenylphosphoryl azide and 793 mg (3.02 mmol) of triphenylphosphine are dissolved under ice-cooling. ),
1.12 g (3.04 mmol) of a 40% solution of diethyl azodicarboxylate in toluene was added under a nitrogen atmosphere, and the mixture was stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and liquid separation was performed.
The aqueous layer was separated and extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: toluene: ethyl acetate = 1:
Purified in 1), 3-t-butyldiphenylsilyloxy-1- {4-[(2-azidoethyl) -methyl-carbamoyl] -1,3-thiazole-2 as a colorless transparent syrup.
1.05 g of -Ildazetidine was obtained in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.80-7.00 (1
1H, m), 4.90-3.00 (11H, m), 1.06 (9H, s) (3) 3-t-butyldiphenylsilyloxy-1- (4
-[Methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine 3-t-butyldiphenylsilyl obtained in Reference Example 58 (2) Oxy-1- {4-[(2-azidoethyl) -methyl-carbamoyl] -1,3-thiazol-2-yl}
1.05 g (2.02 mmol) of azetidine in methanol
Dissolved in 60 ml, 20% palladium hydroxide-carbon.
Catalytic hydrogen reduction was performed at room temperature in the presence of 05 g. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in methylene chloride (52.3 ml) and p-nitrobenzyl chloroformate (650.7 mg) was added under ice cooling.
(3.02 mmol), 0.42 ml of triethylamine
(3.01 mmol) and the mixture was stirred at room temperature for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated saline were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: toluene: acetonitrile = 2: 1) to give a pale yellow solid, 3-t-butyldiphenylsilyloxy-1- (4-.
699.5 mg of [methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine, yield 5
2%. ¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) 8.12 (2H, d,
J = 7.8Hz), 7.78 (1H, br s), 7.68-7.30 (13H, m), 5.
18 (0.5H, s), 5.13 (1.5H, s), 4.80-4.64 (1H, m), 4.
10 (2H, t, J = 7.3Hz), 4.01 (2H, dd, J = 7.3, 5.4Hz),
3.72 (2H, m), 3.50 (2H, m), 3.25 (0.75H, s), 3.02
(2.25H, s), 1.03 (9H, s) Mass spectrum (FAB ⁺ ): 674 [M + H] ⁺ High-resolution mass spectrum (FAB ⁺ ): Measured value: 674.2490
[M + H] ^+, _{calcd: 674.2468 (C 34 H 40 O} 6 N 5 SSi) (4) 3- hydroxy-1- (4- [methyl - [2-(p
-Nitrobenzyloxycarbonylamino) -ethyl]
Carbamoyl {-1,3-thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4- [methyl- [2- (p-nitrobenzyloxy) obtained in Reference Example 58 (3). Carbonylamino) -ethyl] carbamoyl {-1,3-thiazol-2-yl) azetidine
806.9 mg (1.20 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml), and acetic acid (0.09 ml) was added under ice-cooling.
l, (1.57 mmol), 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution 1.44 ml
(1.44 mmol) were sequentially added, and the mixture was stirred as it was for 4 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 15: 1) to give 3-hydroxy-1- (4- [methyl- [2- (p-nitrobenzyloxycarbonylamino)]. ) -Ethyl] carbamoyl {-1,3-thiazol-2-yl) azetidine was obtained as a white solid in 428.2 mg, 84% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H, d,
J = 8.8Hz), 7.71 (1H, t, J = 5.5Hz), 7.49 (2H, d, J =
8.8Hz), 7.17 (1H, s), 5.18 (2H, s), 4.88-4.70 (1H,
m), 4.27 (2H, dd, J = 9.1, 7.8Hz), 3.93 (2H, dd, J =
9.1, 4.8Hz), 3.68 (2H, t, J = 5.5Hz), 3.47 (2H, q, J =
5.5Hz), 3.25 (0.8H, s), 3.03 (2.2H, s), 2.40 (1H,
d, J = 5.9 Hz) (5) 3-methanesulfonyloxy-1- (4- [methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazole-
2-yl) azetidine 3-hydroxy-1- (4) obtained in Reference Example 56 (5)
-[Methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine 428.2 mg (1.0
1 mmol) was dissolved in 21.4 ml of methylene chloride, and 0.25 ml of methanesulfonyl chloride (3.23 ml) was added under ice cooling.
mmol), triethylamine 0.45 ml (3.23 mmol
l) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred as it was for 6 hours. After confirming the completion of the reaction, methanol was added to the reaction system, followed by stirring for 30 minutes. Subsequently, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 15: 1) to give 3-methanesulfonyloxy-1- as a pale yellow solid.
(4- [Methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl} -1,3-thiazol-2-yl) azetidine was obtained in 480.1 mg in 93% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H, d,
J = 8.1Hz), 7.60-7.44 (3H, m including d, at 7.50 p
pm, J = 8.1Hz), 7.26 (0.3H, s), 7.24 (0.7H, s), 5.41
(0.3H, m), 5.34 (0.7H, m), 5.18 (2H, s), 4.42 (2
H, dd, J = 9.0, 7.4Hz), 4.25 (2H, dd, J = 9.0, 3.2Hz),
3.66 (2H, t, J = 5.2Hz), 3.60-3.42 (2H, m), 3.26 (0.
9H, br s), 3.10 (0.9H, br s), 3.08 (2.1H, s), 3.03
(2.1H, s), (7) 3-acetylthio-1- (4- [methyl- [2-
(P-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl {-1,3-thiazol-2-yl)
Azetidine 3-methanesulfonyloxy-1- (4- [methyl- [2- (p-nitrobenzyloxycarbonylamino) -ethyl] carbamoyl}-obtained in Reference Example 56 (6).
1,3-thiazol-2-yl) azetidine 480.
1 mg (0.93 mmol) of dimethylformamide 24 ml
820 mg potassium thioacetate at room temperature
(5.69 mmol), and the mixture was stirred in an oil bath at 80 ° C. for an hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. . The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 15: 1), and 3-acetylthio-1- (4- [methyl- [2- (p-nitro) as a light brown solid was obtained. Benzyloxycarbonylamino) -ethyl] carbamoyl {-1,3-thiazol-2-yl) azetidine was obtained in 348.9 mg at a yield of 76%. ¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H, d,
J = 8.8Hz), 7.73 (1H, br s), 7.49 (2H, d, J = 8.8Hz),
7.29 (0.4H, s), 7.20 (0.6H, s), 5.18 (2H, s), 4.4
7 (2H, t, J = 8.8Hz), 4.40-4.28 (1H, m), 3.92 (2H, d
d, J = 8.8, 5.7Hz), 3.66 (2H, t, J = 5.4Hz), 3.52-3.44
(2H, m), 3.26 (1.2H, s), 3.03 (1.8H, s), 2.36 (1.2
H, s), 2.34 (1.8H, s) Reference Example 59 3-acetylthio-1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl} -1,3-thiazole -2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- {4-[(2-hydroxyethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine N-isopropylaminoethanol 0.61 ml (1.38 mm
ol) and the 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-carboxyl) obtained in Reference Example 2 (4).
Thiazol-2-yl) azetidine 500 mg (1.14 mmo
l) was suspended in 15 ml of dimethylformamide, and cooled under ice-cooling under a nitrogen atmosphere to 0.23 ml of diethyl phosphoryl cyanide
(1.38 mmol), 0.19 ml of triethylamine (0.23 mm
ol) and stirred for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 3-t-butyldiphenylsilyloxy-1- {4-} 4-light oil as a pale yellow oil.
[(2-hydroxyethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine
318 mg was obtained in a yield of 56%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.57 (4H,
d, J = 6.5 Hz), 7.50- 7.30 (6H, m), 7.07 (0.6
H, s), 6.92 (0.4H, s), 4.81-4.63 (1H, m),
4.49 (0.5 H, s), 4.33 (0.5H, s), 4.22-3.88
(4H, m, including 4.06 (2H, dd, J = 14.3, 7.7 Hz
)), 3.88-3.62 (2H, m), 1.39-1.08 (6H, m),
1.02 (9H, s) (2) 3-hydroxy-1- {4-[(2-hydroxyethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine Obtained in Reference Example 59 (1). 3-t-butyldiphenylsilyloxy-1- {4-[(2-hydroxyethyl)
-Isopropyl-carbamoyl] -1,3-thiazol-2-yldiazetidine (2.49 g, 4.75 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml), and dissolved under ice-cooling.
5.70 ml (5.70 mmol) of M-tetra-n-butylammonium fluoride-tetrahydrofuran solution was added.
Stirred for hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 3-hydroxy-1- {4-[(2- Hydroxyethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl {azetidine as a white solid, 1.3
3 g, 98% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.13 (0.7H,
s), 7.03 (0.3H, s), 4.62-4.48 (1H, m), 4.48
-4.36 (1H, m), 4.29 (2H, t, J = 8.0 Hz), 3.94
(2H, dd, J = 8.0, 4.1 Hz), 3.80 (2H, br s), 3.
57 (2H, br s), 1.35 (3H, br s), 1.20 (3H, br s)
) (3) 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl}-
1,3-thiazol-2-yl) -3-hydroxyazetidine 3-hydroxy-1- {4 obtained in Reference Example 59 (2).
-[(2-hydroxyethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine
1.33 g (4.66 mmol) in 40 m of dimethylformamide
l-t-butyldimethylsilane under ice-cooling.
738 mg (4.89 mmol), imidazole 333 mg (4.89
mmol), and the mixture was stirred under ice cooling for 2 hours.
After confirming the completion of the reaction, methanol was added to the system and stirred for 30 minutes. Next, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the system, and liquid separation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1 to ethyl acetate) to give 1- (4-{[2- (t-butyldimethylsilyloxy) as a pale yellow oil. ) -Ethyl] -isopropyl-carbamoyl {-1,3-thiazol-2-yl) -3-hydroxyazetidine in 1.26 g, 69% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.99 (0.2H,
s), 6.91 (0.8H, s), 4.84-4.72 (1H, m), 4.7
2-4.35 (1H, m), 4.72-4.35 (1H, m), 4.27 (
2H, dd, J = 9.4, 6.8 Hz), 3.91 (2H, dd, J = 9.4, 4.
8 Hz), 3.71-3.35 (1H, m), 3.71-3.50 (2H, m
), 3.50-3.28 (1H, m), 1.17 (6H, br s), 0.87
(9H, brs), 0.06 (6H, d, J = 2.8 Hz) (4) 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl}-
1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl obtained in Reference Example 59 (3). -Carbamoyl {-1,3-thiazol-2-yl)-
1.24 g (3.23 mmol) of 3-hydroxyazetidine was dissolved in 62 ml of methylene chloride, and 0.30 ml (3.88 mmol) of methanesulfonyl chloride was added under ice cooling.
0.54 ml (3.88 mmol) was added, and the mixture was stirred for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1-ethyl acetate) to give 1- (4-{[2- (t-butyldimethylsilyloxy) as a pale yellow solid. ) -Ethyl] -isopropyl-carbamoyl {-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine in 649 mg, 42% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.16-6.95
(1H, m), 5,46-5.36 (1H, m), 4.49-3.68 (3
H, m including 4.41 (2H, ddd, J = 9.6, 6.6, 1.0 Hz
)), 4.23 (2H, dd, J = 9.6, 4.4 Hz), 3.91-3.72
(1H, m), 3.72 -3.51 (2H, m), 3.51-3.30 (1H,
m), 3.07 (3H, s), 1.24 (6H, br s), 0.83 (9
H, s), 0.06 (6H, d, J = 3.4 Hz) (5) 3-acetylthio-1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-
Carbamoyl {-1,3-thiazol-2-yl) azetidine 1- (4-{[2- (t-butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl}-obtained in Reference Example 59 (4). 1,3-thiazol-2-yl)-
3-methanesulfonyloxyazetidine 649 mg (1.35
was dissolved in 19 ml of dimethylformamide, and 930 mg (8.14 mmol) of potassium thioacetate was added at room temperature to give 9
The mixture was stirred in a 0 ° C. oil bath for 3 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1 to ethyl acetate), and 3-acetylthio-1- (4-{[2- (t- Butyldimethylsilyloxy) -ethyl] -isopropyl-carbamoyl {-1,3-thiazol-2-yl) azetidine was obtained in 618 mg in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.20 -6.89
(1H, m), 4.68-4.18 (4H, m including 4.48 (2H,
t, J = 8.5 Hz)), 3.94 (2H, dd, J = 8.5, 5.3 Hz),
3.88-3.23 (4H, m), 2.39 (3H, s), 1.16 (6H,
br s), 0.86 (9H, s), 0.04 (6H, d, J = 1.4 Hz) Reference Example 60 3-acetylthio-1- (4-diisopropyl- [2-
(P-nitrobenzyloxyamino) -ethyl] -carbamoyl {-1,3-thiazol-2-yl) azetidine

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(1) 1- {4-[(2-azido-ethyl) -isopropyl-carbamoyl] -1,3-thiazol-2-yl} azetidine-3-t-butyldiphenylsilyloxyazetidine Reference Example 59 3-t-butyldiphenylsilyloxy-1- {4-[(2-hydroxyethyl) obtained in (1)
-Isopropyl-carbamoyl] -1,3-thiazol-2-yl diazetidine (1.46 g, 2.79 mmol) was dissolved in tetrahydrofuran (73 ml), and under ice-cooling, diphenylphosphoryl azide (0.90 ml (4.18 mmol), triphenylphosphine) 1.10 g (4.18 mmol), diethyl azodicarboxylate-40% toluene solution 1.54 g (4.
18 mmol) was added under a nitrogen atmosphere, and the mixture was stirred as it was for 3 hours. After confirming the completion of the reaction, ethyl acetate and saturated saline were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1) to give 1- {4-[(2-azido-ethyl) -isopropyl- as a pale yellow oil.
Carbamoyl] -1,3-thiazol-2-yl {azetidine-3-t-butyldiphenylsilyloxyazetidine was obtained in 1.33 g, 87% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.62 (4H,
dd, J = 8.0, 1.4 Hz), 7.36-7.26 (6H, m), 7.26
-6.90 (1H, m), 4.80-4.76 (1H, m), 4.75-4.
61 (1H, m), 4.13 (1H, t, J = 7.4 Hz), 4.10 (1
H, t, J = 7.4 Hz), 4.01 (2H, dd, J = 8.7, 4.0 Hz),
3.80-3.33 (4H, m including 3.56 (2H, br s)),
1.20 (6H, br s), 1.06 (9H, s) (2) 3-t-butyldiphenylsilyloxy-1- (4
-{Isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) azetidine 1- {4-[(obtained in Reference Example 60 (1). 2-azido-ethyl) -isopropyl-carbamoyl] -1,3-
Thiazol-2-yl diazetidine-3-t-butyldiphenylsilyloxyazetidine 1.33 g (2.42 mmo
l) was dissolved in 65 ml of methanol, and subjected to catalytic hydrogen reduction at room temperature in the presence of 1.33 g of 20% palladium hydroxide. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
The obtained crude product was dissolved in 63 ml of methylene chloride, and 627 mg of p-nitrobenzyl chloroformate (2.90 mmol
l) and 0.41 ml (2.90 mmol) of triethylamine were added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated saline were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol =
10: 1) to give 3-t-butyldiphenylsilyloxy-1- (4- {isopropyl-isopropyl) as a pale yellow oil.
[2- (p-nitrobenzyloxyamino) -ethyl]-
Carbamoyl {-1,3-thiazol-2-yl) azetidine was obtained in 945 mg in a yield of 56%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.60 (4H,
d, J = 1.0 Hz), 7.55- 7.32 (10H, m), 7.12 (0.4
H, br s), 6.95 (0.6H, br s), 5.28-5.18 (2H, m
), 4.81-4.67 (1H, m), 4.24-4.06 (2H, m),
4.00 (2H, dd, J = 8.7, 4.9 Hz), 3.70- 3.18 (4H,
m), 1.20 (6H, brs), 1.06 (9H, d, J = 1.6 Hz) (3) 3-hydroxy-1- (4-diisopropyl-
[2- (p-nitrobenzyloxyamino) -ethyl]-
Carbamoyl {-1,3-thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4- {isopropyl- [2- (p) obtained in Reference Example 60 (2).
-Nitrobenzyloxyamino) -ethyl] -carbamoyl {-1,3-thiazol-2-yl) azetidine 9
45 mg (1.38 mmol) in anhydrous tetrahydrofuran 50 ml
Acetic acid 0.10 ml under ice-cooling, (1.66 mmo
l), 1.66 ml (1.66 mmol) of a 1.0 M solution of tetra-n-butylammonium fluoride-tetrahydrofuran were sequentially added, and the mixture was stirred for 3 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate ;:
Methanol = 10: 1) to give 3-hydroxy-
1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3
-Thiazol-2-yl) azetidine was obtained as a white solid in 433 mg, in a yield of 66%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H, d,
J = 8.5 Hz), 7.49 (2H, d, J = 8.5 Hz), 7.11 (0.
4H, s), 6.95 (0.6H, s), 5.18 (2H, s), 4.88-
4.62 (1H, m), 4.62-4.18 (3H, m), 3.93 (2H,
dd, J = 8.8, 4.4Hz), 3.72-3.36 (4H, m), 1.30
(3H, brs), 1.20 (3H, brs) (4) 1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl}-
1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine 3-hydroxy-1- (4) obtained in Reference Example 60 (3).
Dissolve 1.43 g (3.09 mmol) of-{isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] -carbamoyl} -1,3-thiazol-2-yl) azetidine in 72 ml of methylene chloride and cool on ice. Under methanesulfonyl chloride 0.29 ml (3.70 mmol), triethylamine
0.52 ml (3.70 mmol) was added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 20: 1) to give 1- (4- {isopropyl}-[2-
(P-Nitrobenzyloxyamino) -ethyl] -carbamoyl {-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine 776 mg, yield 46%
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.20 (2H,
d, J = 8.4 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.20 (
0.4H, br s), 7.07 (0.6H, br s), 5.41 (1H, br
s), 5.19 (2H, s), 4.66-4.18 (5H, m including
4.44 (2H, t, J = 8.8 Hz), 4.25 (2H, t, J = 8.8 Hz
)), 3.68-3.36 (4H, m), 3.10 (3H, s), 1.31 (3
H, brs), 1.22 (3H, brs) (5) 3-acetylthio-1- (4-diisopropyl-
[2- (p-nitrobenzyloxyamino) -ethyl]-
Carbamoyl {-1,3-thiazol-2-yl) azetidine 1- (4- {isopropyl- [2- (p-nitrobenzyloxyamino) -ethyl] obtained in Reference Example 60 (4).
-Carbamoyl {-1,3-thiazol-2-yl)-
776 mg of 3-methanesulfonyloxyazetidine (1.43
was dissolved in 23 ml of dimethylformamide, and 982 mg (8.60 mmol) of potassium thioacetate was added at room temperature.
The mixture was stirred in a 90 ° C oil bath for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 3-acetylthio-1- (4-diisopropyl- [2- (p-nitro) as a light brown solid. Benzyloxyamino) -ethyl] -carbamoyl {-1,3-thiazol-2-yl) azetidine
46 mg, yield 46%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H,
d, J = 8.4 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.15 (
0.4H, br s), 7.04 (0.6H, br s), 5.19 (2H, s),
4.66-4.20 (4H, m), 4.08-3.88 (2H, m), 3.66
-3.26 (4H, m), 2.96 (3H, s), 2.36 (3H, br s
), 1.63 (3H, br s) Reference Example 61 3-acetylthio-1- (4-{(1S) -2-methyl-
[1- (p-nitrobenzyloxycarbonylamino)
Methyl] -propylcarbamoyl] -1,3-thiazol-2-yl) azetidine

[0748]

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(1) ((1S) -1-hydroxymethyl-
2-methyl-propyl) -carbamic acid t-butyl ester L-valinol (2.00 g, 19.4 mmol) in methylene chloride (50 ml),
It was dissolved in 50 ml of methanol, and 5.08 g (23.3 mmol) of di-t-butoxycarbonyl anhydride was added under ice cooling, followed by stirring at room temperature for 3 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous solution was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1).
Purified in 1), colorless oily ((1S) -1-hydroxymethyl-2-methyl-propyl) -carbamic acid t-
4.19 mg of butyl ester was obtained in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 4.70-4.59
(1H, br s), 3.74-3.66 (1H, m), 3.65-3.57 (1H,
m), 3.48-3.39 (1H, m), 2.38-2.30 (1H, br s),
1.89-1.78 (1H, m), 1.45 (9H, s), 0.96 (3H, d, J =
(6.6 Hz), 0.94 (3H, d, J = 6.6 Hz) (2) ((1S) -1-azidomethyl-2-methyl-propyl) -carbamic acid t-butyl ester Obtained in Reference Example 61 (1). ((1S) -1-hydroxymethyl-2-methyl-propyl) -carbamic acid t-
3.00 g (14.8 mmol) of butyl ester was dissolved in 150 ml of tetrahydrofuran, and under ice cooling, 4.78 ml (22.2 mmol) of diphenylphosphoryl azide and 5.
82 g (22.2 mmol), diethyl azodicarboxylate-
9.67 g (22.2 mmol) of a 40% toluene solution was added under a nitrogen atmosphere, and the mixture was stirred for 2 hours. After confirming the completion of the reaction,
Ethyl acetate and saturated saline were separated and extracted into the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 9:
Purification was performed in 1) to obtain 3.26 g of colorless oily ((1S) -1-azidomethyl-2-methyl-propyl) -carbamic acid t-butyl ester in a yield of 90%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 4.59-4.45
(1H, m), 3.56-3.47 (1H, m), 3.42 (2H, d, J = 4.4H
z), 1.86-1.74 (1H, m), 1.45 (9H, s), 0.95 (3H, d,
J = 6.6 Hz), 0.93 (3H, d, J = 7.3 Hz) (3) ((2S) -2-t-butoxycarbonylamino-3-methyl-butyl) -carbamic acid p-nitrobenzyl ester Reference Example 61 3.26 g (13.3 mmol) of ((1S) -1-azidomethyl-2-methyl-propyl) -carbamic acid t-butyl ester obtained in (2) was dissolved in 160 ml of methanol, and was dissolved in 3.26 g of 10% palladium carbon. For 1 hour at room temperature
Catalytic hydrogen reduction was performed. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in methylene chloride (160 ml), and under ice cooling, 4.31 g (20.0 mmol) of p-nitrobenzyl chloroformate and 2.80 ml (20.0 ml) of triethylamine were added.
0.0 mmol) and stirred overnight at room temperature. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous solution was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 8: 1 to 1: 1) to give pale yellow crystals of ((2S) -2-t-butoxycarbonylamino-). 3-
Methyl-butyl) -carbamic acid p-nitrobenzyl ester was obtained in 3.13 mg, 62% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H,
d, J = 8.8Hz), 7.50 (2H, d, J = 8.8Hz), 5.43-5.31 (1
H, br s), 5.19 (2H, s), 4.57-4.49 (1H, br d, J =
8.8Hz), 3.60-3.49 (1H, m), 3.40-3.29 (1H, m),
3.26-3.13 (1H, m), 1.82-1.71 (1H, m), 1.43 (9
H, s), 0.96 (3H, d, J = 7.3Hz), 0.93 (3H, d, J = 6.6H
z) (4) 3-tert-butyldiphenylsilyloxy-1-
(4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl] -1,3-thiazol-2-yl) azetidine Obtained in Reference Example 61 (3). 3.13 g (8.21 mmol) of ((2S) -2-t-butoxycarbonylamino-3-methyl-butyl) -carbamic acid p-nitrobenzyl ester
Was dissolved in 31 ml of 1,4-dioxane, and 4N-
Hydrochloric acid gas-1,4-dioxane solution (31 ml) was added, and the mixture was stirred at room temperature for 4 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue, followed by filtration. The filtrate was washed with ethyl acetate to give pale yellow crystalline ((2S) -2).
-Amino-3-methyl-butyl) -carbamic acid p-
1.82 g of nitrobenzyl ester hydrochloride was obtained at a yield of 70%. Subsequently, 1.29 g (4.05 mmol) of the obtained ((2S) -2-amino-3-methyl-butyl) -carbamic acid p-nitrobenzyl ester hydrochloride and 3- (3) obtained in Reference Example 2 (4). t-butyldiphenylsilyloxy-1- (4
-Carboxyl-1,3-thiazol-2-yl) azetidine (1.48 g, 3.37 mmol) in dimethylformamide (74 ml)
615 μl (4.05 mmol) of diethyl phosphoryl cyanide under ice-cooling under a nitrogen atmosphere, and triethylamine 1.14.
ml (8.10 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1), and 3-t-butyldiphenylsilyloxy-1- (4-{(1S 1.55 g of) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl] -1,3-thiazol-2-yl) azetidine was obtained in a yield of 74%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.11 (2H,
d, J = 8.8Hz), 7.64-7.60 (4H, m), 7.49-7.39 (8H,
m), 7.35 (1H, s), 7.20-7.18 (1H, br d, J = 9.8H
z), 5.56-5.48 (1H, br s), 5.20 (1H, d, J = 13.7H
z), 5.08 (1H, d, J = 13.7Hz), 4.78-4.72 (1H, m),
4.14-4.06 (2H, m), 4.04-3.94 (3H, m), 3.46 (1
H, dt, J = 13.7, 3.9Hz), 3.31 (1H, ddd, J = 13.7, 10.
7, 5.9Hz), 1.95 -1.86 (1H, m), 1.07 (9H, s), 1.01
(3H, d, J = 6.8 Hz), 0.99 (3H, d, J = 6.8 Hz) (5) 3-hydroxy-1- (4-{(1S) -2-methyl- [1- (p-nitro Benzyloxycarbonylamino) methyl] -propylcarbamoyl] -1,3-thiazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-{(1S ) -2-Methyl- [1
-(P-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl] -1,3-thiazole-2
-Yl) azetidine (1.54 g, 2.20 mmol) was dissolved in anhydrous tetrahydrofuran (78 ml).
(2.64 mmol) and 2.64 ml (2.64 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution were sequentially added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction,
Ethyl acetate and water were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-hydroxy-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) amino]. ) Methyl) -propylcarbamoyl] -1,3-thiazol-2-yl) azetidine as a white solid, 927 mg,
Obtained in 91% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.09 (2H,
d, J = 8.8Hz), 7.41 (2H, d, J = 8.8Hz), 7.39 (1H, s),
7.19-7.14 (1H, br d, J = 9.5Hz), 5.54-5.46 (1H,
m), 5.22 (1H, d, J = 13.6Hz), 5.06 (1H, d, J = 13.6H
z), 4.87-4.78 (1H, m), 4.37-4.26 (2H, m), 4.04
-3.90 (3H, m), 3.47-3.40 (1H, m), 3.38-3.30
(1H, m), 2.38 (1H, d, J = 7.3Hz), 1.94-1.83 (1H,
m), 1.00 (3H, d, J = 7.3 Hz), 0.99 (3H, d, J = 7.3 Hz) (6) 3-methanesulfonyloxy-1- (4-{(1
S) -2-Methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl]-
1,3-thiazol-2-yl) azetidine 3-hydroxy-1- (4) obtained in Reference Example 61 (5)
-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl] -1,3-thiazol-2-yl) azetidine 920
mg (1.98 mmol) was dissolved in methylene chloride (46 ml), and methanesulfonyl chloride (461 μl (5.95 mmol) and triethylamine (834 μl (5.95 mmol)) were added under ice cooling.
The reaction system was returned to room temperature and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction system,
The aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane:
Purified with ethyl acetate = 1: 4), 3-methanesulfonyloxy-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl] methyl pale yellow solid] -Propylcarbamoyl] -1,3-thiazol-2-yl) azetidine was obtained in a yield of 1.06 g at a yield of 99%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.10 (2H,
d, J = 8.8Hz), 7.45 (1H, s), 7.41 (2H, d, J = 8.8Hz),
7.18-7.12 (1H, br d, J = 8.8Hz), 5.50-5.45 (1H, b
rs), 5.42 (1H, tt, J = 6.6, 4.4Hz), 5.22 (1H, d, J =
13.2Hz), 5.08 (1H, d, J = 13.2Hz), 4.49-4.40 (2H,
m), 4.29-4.20 (2H, m), 4.04-3.95 (1H, m), 3.44
(1H, dt, J = 13.9, 4.4Hz), 3.38-3.24 (1H, m), 3.1
2 (3H, s), 1.94-1.85 (1H, m), 1.01 (3H, d, J = 6.6H
z), 0.99 (3H, d, J = 6.6 Hz) (7) 3-acetylthio-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl]- Propylcarbamoyl] -1,3-thiazol-2-yl) azetidine 3-methanesulfonyloxy-1- (4-{(1S) -2-methyl- [1- (p) obtained in Reference Example 61 (6). -Nitrobenzyloxycarbonylamino) methyl] -propylcarbamoyl] -1,3-thiazol-2-yl) azetidine (1.06 g, 1.96 mmol) in dimethylformamide 53
of potassium thioacetate at room temperature (1.34 mg).
7 mmol), and the mixture was stirred in an 80 ° C. oil bath for 8.5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system.
The aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n
-Hexane: ethyl acetate = 2: 3) to give 3-acetylthio-1- (4-{(1S) -2-methyl- [1- (p-nitrobenzyloxycarbonylamino) methyl) as a light brown solid. ] -Propylcarbamoyl] -1,3-thiazol-2-yl) azetidine was obtained in 785 mg, 77% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.12 (2H,
d, J = 8.8Hz), 7.42 (2H, d, J = 8.8Hz), 7.41 (1H, s),
7.20-7.16 (1H, br d, J = 9.5Hz), 5.54-5.45 (1H, b
rs), 5.21 (1H, d, J = 13.2Hz), 5.09 (1H, d, J = 13.2H
z), 4.51 (2H, dt, J = 11.0, 8.4Hz), 4.47-4.39 (1H,
m), 4.03-3.93 (3H, m), 3.45 (1H, dt, J = 13.2, 4.0H
z), 3.37-3.68 (1H, m), 2.37 (3H, s), 1.95-1.84
(1H, m), 1.00 (3H, d, J = 7.3Hz), 0.99 (3H, d, J = 7.3
Hz) <Reference Example 62> 3-acetylthio-1- [4- (p-nitrobenzyloxycarbonylamino) methyl-1,3-thiazole-2
-Yl] azetidine

[0750]

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(1) 1- (4-azidomethyl-1,3-
Thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-thiazole- obtained in Reference Example 2 (2). 2-yl) azetidine 1.02 g (2.3
9 mmol) was dissolved in 50 ml of tetrahydrofuran, and 0.8 ml of diphenylphosphoryl azide (3.
71 mmol), 950 mg of triphenylphosphine
(3.62 mmol), diethyl azodicarboxylate-
1.32 g (3.59 mmol) of a 40% toluene solution was added under a nitrogen atmosphere, followed by stirring for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated saline were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 8: 1) to give a colorless transparent syrup of 1- (4-
Azidomethyl-1,3-thiazol-2-yl) -3-
t-Butyldiphenylsilyloxyazetidine was added to 1.0
6 g, 99% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.66-7.36 (1
0H, m), 6.45 (1H, s), 4.78-4.71 (1H, m), 4.24 (2H,
s), 4.12 (2H, dd, J = 8.6, 6.2Hz), 4.02 (2H, dd, J = 8.
6, 5.7Hz), 1.06 (9H, s) IR (liquid film) 2858, 2170, 2100, 1527, 1313, 118
2, 1143, 1114 cm ^-1 Mass spectrum (FAB ⁺ ): 450 [M + H] ⁺ high-resolution mass spectrum (FAB ⁺ ): Actual value: 450.1793
[M + H] ⁺ , Calculated: 450.1784 (C ₂₃ H ₂₈ ON ₅ SSi) (2) 3-t-butyldiphenylsilyloxy-1- [4
-(P-Nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine 1- (4-azidomethyl- obtained in Reference Example 62 (1)
1.06 g (2.37 m) of 1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine
was dissolved in 53 ml of methanol and subjected to catalytic hydrogen reduction at room temperature in the presence of 1.05 g of 20% palladium hydroxide-carbon. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product is treated with methylene chloride 5
The solution was dissolved in 3.2 ml, and under ice cooling, 0.76 g (3.52 mmol) of p-nitrobenzyl chloroformate and 0.5 ml (3.59 mmol) of triethylamine were added, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the obtained residue to carry out a liquid separation operation. After the aqueous layer was separated and extracted with ethyl acetate, the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: ethyl acetate = 3: 2) to give 3-yellow solid.
t-butyldiphenylsilyloxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,
3-thiazol-2-yl] azetidine in 867.2 m
g, yield 61%. ¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H, d,
J = 8.3Hz), 7.62 (4H, d, J = 8.3Hz), 7.50 (2H, d, J =
8.3Hz), 7.50-7.34 (6H, m), 6.37 (1H, s), 5.38 (1H,
br t, J = 5.4Hz), 5.20 (2H, s), 4.78-4.71 (1H, m),
4.26 (2H, d, J = 5.4Hz), 4.10 (2H, dd, J = 8.3, 6.8H
z), 4.00 (2H, dd, J = 8.3, 4.7 Hz), 1.06 (9H, s) (3) 3-hydroxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3 -Thiazol-2-yl] azetidine 3-t-butyldiphenylsilyloxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3-thiazole- obtained in Reference Example 62 (2). 2-
867.2 mg (1.44 mmol) of yl] azetidine was dissolved in 45 ml of anhydrous tetrahydrofuran, and 0.1 ml (1.75 mmol) of acetic acid, 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added under ice-cooling.
1.72 ml (1.72 mmol) were sequentially added, and the mixture was stirred for 4.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 15: 1) to give 3-hydroxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1, 3-thiazol-2-yl] azetidine as a yellow solid, 45
7 mg yield 87%. ¹ H-NMR (500 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H, d,
J = 8.6Hz), 7.51 (2H, d, J = 8.6Hz), 6.40 (1H, s), 5.
38 (1H, br s), 5.21 (2H, s), 4.88-4.80 (1H, m), 4.3
2 (2H, dd, J = 9.1, 6.8Hz), 4.27 (2H, d, J = 5.7Hz),
3.95 (2H, dd, J = 9.1, 4.5 Hz), 2.23 (1H, d, J = 7.9 Hz) (4) 3-methanesulfonyloxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,
3-thiazol-2-yl] azetidine 3-hydroxy-1- [4 obtained in Reference Example 62 (3).
-(P-Nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine 45
7 mg (1.25 mmol) was dissolved in 25 ml of methylene chloride, and 0.29 ml of methanesulfonyl chloride was added under ice cooling.
(3.75 mmol), triethylamine 0.53 ml
(3.80 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: toluene: acetonitrile = 1:
Purified in 1) to obtain 499.4 mg of 3-methanesulfonyloxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine as a yellow solid. Obtained at a rate of 90%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H, d,
J = 7.8Hz), 7.51 (2H, d, J = 7.8Hz), 6.46 (1H, s), 5.
44-5.38 (2H, m), 5.26 (2H, s), 4.43 (2H, dd, J = 9.8,
6.8Hz), 4.28 (2H, d, J = 5.9Hz), 4.24 (2H, dd, J = 9.
8, 4.4 Hz), 3.10 (3H, s) (5) 3-acetylthio-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine Reference Example 62 499.4 mg (1.13 mmol) of 3-methanesulfonyloxy-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in (4). Was dissolved in 25 ml of dimethylformamide, 1.0 g (6.93 mmol) of potassium thioacetate was added at room temperature, and the mixture was heated in an oil bath at 80 ° C.
Stir for 6.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with 0.5M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 2: 1), and 3-acetylthio-1- [4- (p-nitrobenzyloxycarbonylamino-methyl) as a light brown solid was obtained. 265.2 mg of [-1,3-thiazol-2-yl] azetidine, yield 56
%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.21 (2H, d,
J = 8.42Hz), 7.51 (2H, d, J = 8.4Hz), 6.42 (1H, s), 5.
39 (1H, br t, J = 7.5Hz), 5.21 (2H, s), 4.51 (2H, t,
J = 8.1Hz), 4..50-4.38 (1H, m), 4.27 (2H, d, J = 7.5H
z), 3.96 (2H, dd, J = 8.1, 5.1 Hz), 2.36 (3H, s) Reference Example 63 3-acetylthio-1- [4- (methoxycarbonylamino) methyl-1,3-thiazole-2- Il] azetidine

[0752]

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(1) 3-t-butyldiphenylsilyloxy-1- [4- (methoxycarbonylamino-methyl)
[1,3-thiazol-2-yl] azetidine 1- (4-azidomethyl- obtained in Reference Example 62 (1)
2.12 g (4.71 mmol) of 1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine
Is dissolved in 106 ml of methanol, and 20% palladium hydroxide is dissolved.
Catalytic hydrogen reduction was performed at room temperature in the presence of 2.12 g. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in 100 ml of methylene chloride, and 0.43 ml (5.65 mmol) of methyl chloroformate and 0.79 ml (5.65 mmol) of triethylamine were added under ice-cooling, and the mixture was added at room temperature.
Stir for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the obtained residue to carry out a liquid separation operation. After the aqueous layer was separated and extracted with ethyl acetate, the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
The residue was purified with ethyl acetate) to give 1.88 g of 3-t-butyldiphenylsilyloxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine as a pale yellow oil. Obtained at a rate of 45%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.60 (4H,
d, J = 1.5 Hz), 7.48 -7.31 (6H, m), 7.19 (1H, t,
J = 8.1 Hz), 7.00 (1H, s), 4.78-4.68 (1H, m
), 4.24 (2H, d, J = 5.8 Hz), 4.09 (2H, t, J = 9.
0, 6.6 Hz), 3.99 (2H, t, J = 9.0, 5.0 Hz), 3.67
(3H, s), 1.06 (9H, s) (2) 3-hydroxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl]
Azetidine 3-t-butyldiphenylsilyloxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine obtained in Reference Example 63 (1) 1.88 g (3.90 mmol) To anhydrous tetrahydrofuran 94
acetic acid 0.27 ml (4.68 mmo) under ice-cooling.
l), 4.68 ml (4.68 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution were sequentially added, and the mixture was stirred as it was for 30 minutes. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-
Hydroxy-1- [4- (methoxycarbonylamino-
Methyl) -1,3-thiazol-2-yl] azetidine was obtained as a white solid in 426 mg, in a yield of 45%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.39 (1H, s
), 4.79-4.39 (1H, m), 4.31 (2H, dd, J = 9.1,
6.7 Hz), 4.25 (2H, d, J = 5.8 Hz), 3.94 (2H, dd,
J = 9.1, 4.3 Hz), 3.68 (3H, s) (3) 3-Methanesulfonyloxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine Reference Example 63 3-hydroxy-1- [4 obtained in (2)
426 mg (1.75 mmol) of-(methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine was dissolved in 20 ml of methylene chloride, and 0.16 ml (2.10 mmol) of methanesulfonyl chloride was added under ice cooling. 0.29 ml (2.10 mmol) of triethylamine was added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
Ethyl acetate), 448 mg of 3-methanesulfonyloxy-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine as a pale yellow solid, yield 80%. I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.45 (1H, s
), 5,45-5.36 (1H, m), 4.43 (2H, dd, J = 9.6,
6.7 Hz), 4.25 (2H, s), 4.25 (1H, t.J = 5.8 Hz
), 4.23 (1H, t.J = 5.8 Hz), 3.69 (3H, s), 3.
10 (3H, s) (4) 3-acetylthio-1- [4- (methoxycarbonylamino-methyl) -1,3-thiazol-2-yl] azetidine 3-methane obtained in Reference Example 63 (3) Sulfonyloxy-1- [4- (methoxycarbonylamino-methyl)
-1,3-thiazol-2-yl] azetidine 448 mg
(1.39 mmol) was dissolved in 13 ml of dimethylformamide, and 952 mg (8.34 mmol) of potassium thioacetate was added at room temperature.
And stirred in a 90 ° C. oil bath for 6 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2) to give 3-acetylthio-1- [4- (methoxycarbonylamino-methyl) -1 as a light brown solid. 3-thiazol-2-yl] azetidine was obtained in 441 mg in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.41 (1H, s
), 4.50 (2H, t, J = 8.5 Hz), 4.49-4.45 (1H, m
), 4.25 (2H, d, J = 5.7 Hz) 3.56 (2H, dd, J = 8.5,
5.3 Hz), 3.68 (3H, s), 2.05 (3H, s) Reference Example 64 3-Acetylthio-1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidine

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(1) 1- [4- (Benzoylamino-methyl) -1,3-thiazol-2-yl] -3-t-butyldiphenylsilyloxyazetidine 1 obtained in Reference Example 62 (1) -(4-azidomethyl-
1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine 2.53 g (5.60 mmol)
Was dissolved in 120 ml of methanol and subjected to catalytic hydrogen reduction at room temperature in the presence of 2.53 g of 20% palladium hydroxide. After confirming the completion of the reaction, the reaction solution was filtered. To the filtrate, 1.90 ml (8.40 mmol) of benzoic anhydride was added under ice-cooling, and the mixture was stirred as it was for 2.5 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the obtained residue to carry out a liquid separation operation. After the aqueous layer was separated and extracted with ethyl acetate, the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1 to ethyl acetate) to give 1- [4- (benzoylamino-methyl) -1,3- (3-chlorobenzene) as a pale yellow oil. Thiazol-2-yl]
-3-t-butyldiphenylsilyloxyazetidine
1.49 g, yield 50%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.79 (2H,
d, J = 7.3 Hz), 7.63 -7.55 (4H, m), 7.55-7.31
(9H, m), 6.79 (1H, br s), 6.44 (1H, s), 4.79-
4.68 (1H, m), 4.51 (2H, d, J = 5.4 Hz), 4.11
(2H, dd, J = 8.4, 7.3 Hz), 4.01 (2H, dd, J = 8.4,
5.0 Hz), 1.06 (9H, s) (2) 1- [4- (benzoylamino-methyl) -1,
3-thiazol-2-yl] -3-hydroxyazetidine 1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] -3 obtained in Reference Example 64 (1).
-T-butyldiphenylsilyloxyazetidine 1.49 g
(2.82 mmol) was dissolved in 75 ml of anhydrous tetrahydrofuran, and under ice cooling, 3.39 ml of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution (3.39 mmo
l) was added in sequence, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 2 to ethyl acetate: methanol = 9: 1).
And purified by 1- [4- (benzoylamino-methyl)
[1,3-thiazol-2-yl] -3-hydroxyazetidine was obtained as a white solid in 582 mg in a yield of 71%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.79 (2H, d
d, J = 7.4 Hz), 7.60- 7.36 (3H, m), 6.82 (1H, b
rs), 6.46 (1H, s), 4.85-4.77 (1H, m), 4.51
(2H, d, J = 5.6 Hz), 4.31 (2H, dd, J = 8.9, 6.6 H
z), 3.95 (2H, dd, J = 8.5, 4.4 Hz) (3) 1- [4- (benzoylamino-methyl) -1,
3-thiazol-2-yl] -3-methanesulfonyloxyazetidine 1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] -3 obtained in Reference Example 64 (2).
-Hydroxyazetidine (582 mg, 2.01 mmol) was dissolved in methylene chloride (30 ml), and methanesulfonyl chloride 0.19 ml (2.41 mmol), triethylamine 0.34
ml (2.41 mmol) and 5.8 ml of pyridine.
Stir for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give a light yellow solid 1-
739 mg of [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine was obtained at a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.80 (2H,
d, J = 6.9 Hz), 7.57 -7.41 (3H, m), 6.71 (1H, b
s), 6.53 (1H, s), 5.46-5.38 (1H, m), 4.54 (
2H, d, J = 5.2 Hz), 4.44 (2H, ddd, J = 9.6, 6.6, 0.
9 Hz), 4.25 (2H, ddd, J = 9.6, 9.3, 0.9 Hz), 3.1
0 (3H, s) (4) 3-acetylthio-1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidine 1- [4 obtained in Reference Example 64 (3). -(Benzoylamino-methyl) -1,3-thiazol-2-yl] -3
-Methanesulfonyloxyazetidine 739 mg (2.01 m
mol) was dissolved in 20 ml of dimethylformamide, and 1.38 g (12.1 mmol) of potassium thioacetate was added at room temperature.
The mixture was stirred in a 0 ° C. oil bath for 3.5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1-ethyl acetate) to give 3-acetylthio-1- [4- (benzoylamino-methyl)-as a light brown solid. [1,3-Thiazol-2-yl] azetidine was obtained in 698 mg in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.08 (2H,
d, J = 7.8 Hz), 7.55 -7.46 (3H, m), 6.77 (1H, br
s), 6.49 (1H, s), 4.47-4.38 (4H, m), 4.47-
4.38 (1H, m), 3.97 (2H, dd, J = 8.6, 5.2 Hz),
2.37 (3H, s) Reference Example 65 3-Acetylthio-1- [4- (benzenesulfonyl-
Amino) methyl-1,3-thiazol-2-yl] azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] azetidine 1 obtained in Reference Example 62 (1) -(4-azidomethyl-
2.12 g (4.71 mmol) of 1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine
Is dissolved in 106 ml of methanol, and 20% palladium hydroxide is dissolved.
Catalytic hydrogen reduction was performed at room temperature in the presence of 2.12 g. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product is dissolved in methylene chloride (100 ml), and benzenesulfonyl chloride (0.90 ml (7.07 mmo
l), 0.98 ml (7.07 mmol) of triethylamine were added,
The mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the obtained residue to carry out a liquid separation operation. After the aqueous layer was separated and extracted with ethyl acetate, the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-t as a pale yellow oil.
-Butyldiphenylsilyloxy-1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazole-
755 mg of 2-yl] azetidine was obtained in a yield of 28%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.80 (2H,
d, J = 7.5 Hz), 7.61 (4H, d, J = 6.3 Hz), 7.54-
7.30 (9H, m), 6.21 (1H, s), 5.07 (1H, t, J = 6.0
Hz), 4.74-4.66 (1H, m), 4.05 (2H, d, J = 6.3
Hz), 3.99 (2H, dd, J = 7.6 Hz), 3.89 (2H, dd,
J = 8.8, 4.8 Hz), 1.07 (9H, s) (2) 1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] -3-hydroxyazetidine Reference Example 65 ( 2.79 g (4.95 mmol) of 3-t-butyldiphenylsilyloxy-1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] azetidine obtained in 1) was added to anhydrous tetrahydrofuran 14
Dissolve in 0 ml, and add 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution under ice-cooling to 5.94 ml
(5.94 mmol) was added sequentially, and the mixture was stirred for 2 hours.
After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 1- [4- (benzenesulfonyl-
Amino) methyl-1,3-thiazol-2-yl] -3
1.06 g of hydroxyazetidine as a white solid,
Obtained in 66% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.79 (2H,
d, J = 7.5 Hz), 7.50 -7.41 (3H, m), 6.25 (1H, s
), 5.51 (1H, br s), 4.80-4.70 (1H, m), 4.19
(2H, t, J = 9.1 Hz), 4.03 (2H, t, J = 3.5 Hz),
3.83 (2H, dd, J = 9.1, 4. Hz) (3) 1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] -33-methanesulfonyloxyazetidine Reference Example Dissolve 1.06 g (3.26 mmol) of 1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] -3-hydroxyazetidine obtained in 65 (2) in 50 ml of methylene chloride. Then, 0.38 ml (4.89 mmol) of methanesulfonyl chloride and 0.68 ml (4.89 mmol) of triethylamine were added under ice cooling, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent:
Ethyl acetate) to give 1.16 mg of 1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine as a pale yellow solid, yield 91. %. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.82 (2H,
d, J = 7.3 Hz), 7.61 -7.46 (3H, m), 6.33 (1H, s
), 5.42-5.33 (1H, m), 5.15 (1H, t, J = 5.9 Hz
), 4.34 (2H, dd, J = 9.8, 6.7 Hz), 4.14 (2H, dd,
J = 9.8, 4.1 Hz), 4.08 (2H, d, J = 6.3 Hz), 3.10
(3H, s) (4) 3-acetylthio-1- [4- (benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] azetidine 1- [4 obtained in Reference Example 65 (3). -(Benzenesulfonyl-amino) methyl-1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine 1.16 g
(2.98 mmol) was dissolved in 35 ml of dimethylformamide, and at room temperature potassium thioacetate 2.04 g (17.9 mmol)
Was added and stirred in a 90 ° C. oil bath for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: ethyl acetate = 5: 1) to give 3-acetylthio-1- [4- (benzenesulfonyl-amino) methyl-1 as a light brown solid. , 3-thiazol-2-yl]
Azetidine was obtained in 1.00 g, 91% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.82 (2H,
d, J = 7.4Hz), 7.58-7.42 (3H, m), 6.23 (1H, s
), 5.40-5.50 (1H, m), 4.48-4.30 (3H, m),
4.09 (2H, d, J = 5.8 Hz), 3.90 (2H, dd, J = 8.3,
4.5 Hz), 2.37 (3H, s) Reference Example 66 3-Acetylthio-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine Obtained in Reference Example 62 (1). 1- (4-azidomethyl-
2.47 g (5.50 mmol) of 1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine
Was dissolved in 120 ml of methanol and subjected to catalytic hydrogen reduction at room temperature in the presence of 2.47 g of 20% palladium hydroxide. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
This residue was dissolved in methylene chloride (115 ml), thienyl chloride (0.71 ml, 6.60 mmol) and triethylamine (0.92 ml, 6.60 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the obtained residue to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t- as a pale yellow oil.
1.88 g of butyldiphenylsilyloxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine was obtained in a yield of 64%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.75-7.32
(13H, m), 7.11-7.03 (1H, m), 6.65 (1H, br s
), 4.80-4.70 (1H, m), 4.47 (2H, d, J = 5.0 Hz
), 4.11 (2H, t, J = 8.5 Hz), 4.01 (2H, dd, J =
8.5, 5.0 Hz), 1.06 (9H, s) (2) 3-hydroxy-1- [4- (thiophen-2-
Carbonyl-amino) methyl-1,3-thiazole-2
-Yl] azetidine 3-t-butyldiphenylsilyloxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] obtained in Reference Example 66 (1).
Dissolve 2.18 g (4.08 mmol) of azetidine in 110 ml of anhydrous tetrahydrofuran, and add 1.0M tetra-n-
Butyl ammonium fluoride-tetrahydrofuran solution
4.90 ml (4.90 mmol) were sequentially added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1),
3-Hydroxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine was obtained as a white solid in 571 mg, 47% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.53 (1H,
d, J = 3.5 Hz), 7.46 (1H, d, J = 5.4 Hz), 7.60 (1
H, dd, J = 4.9, 3.8 Hz), 6.87 (1H, br s), 6.46 (
1H, s), 4.87-4.78 (1H, m), 4.48 (2H, d, J =
5.6 Hz), 4.33 (2H, dd, J = 8.7, 4.6 Hz), 3.98 (2
H, dd, J = 8.7, 4.6 Hz) (3) 3-Methanesulfonyloxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine Reference Example 66 3-hydroxy-1- [4 obtained in (2)
-(Thiophen-2-carbonyl-amino) methyl-
1,3-thiazol-2-yl] azetidine 571 mg (1.
(93 mmol) in 28 ml of methylene chloride, and 0.18 ml (2.32 mmol) of methanesulfonyl chloride and 0.33 ml (2.32 mmol) of triethylamine were added under ice cooling.
Stir for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 1: 1) to give 3-methanesulfonyloxy-1 as a pale yellow solid.
-[4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine
mg, 91% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.56 (1H,
d, J = 5.4 Hz), 7.47 (1H, d, J = 5.4 Hz), 7.07 (1
H, dd, J = 5.1, 3.7 Hz), 6.87 (1H, br s), 6.50 (
1H, s), 4.57 (2H, t, J = 8.6 Hz), 4.50 (2H, t,
J = 5.4 Hz), 4.50 (2H, d, J = 5.4 Hz), 4.48-4.3
7 (1H, m), 4.36 (2H, dd, J = 8.6, 5.5 Hz), 2.36
(3H, s) (4) 3-acetylthio-1- [4- (thiophene-2
-Carbonyl-amino) methyl-1,3-thiazole-
2-yl] azetidine 3-methanesulfonyloxy-1- [4- (thiophen-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine obtained in Reference Example 66 (3) 623 mg (1.67 mmol) in dimethylformamide 18 m
l, and potassium thioacetate 1.14 g (1
0.0 mmol) and stirred in a 90 ° C. oil bath for 4 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1 to ethyl acetate) to give a light brown solid, 3-acetylthio-1- [4-.
(Thiophen-2-carbonyl-amino) methyl-1,
[3-Thiazol-2-yl] azetidine in 490 mg, yield
91%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.56 (1H,
d, J = 5.4 Hz), 7.47 (1H, d, J = 5.4 Hz), 7.07 (1
H, dd, J = 5.1, 3.7 Hz), 6.87 (1H, br s), 6.50 (
1H, s), 4.57 (2H, t, J = 8.6 Hz), 4.50 (2H, t,
J = 5.4 Hz), 4.50 (2H, d, J = 5.4 Hz), 4.48-4.3
7 (1H, m), 4.36 (2H, dd, J = 8.6, 5.5 Hz), 2.36
(3H, s) Reference Example 67 3-Acetylthio-1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazol-2-yl]
Azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine Obtained in Reference Example 62 (1). 1- (4-azidomethyl-
2.47 g (5.50 mmol) of 1,3-thiazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine
Was dissolved in 120 ml of methanol and subjected to catalytic hydrogen reduction at room temperature in the presence of 2.47 g of 20% palladium hydroxide. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
The residue was dissolved in 115 ml of methylene chloride, and 0.65 ml (6.60 mmol) of 2-furoyl chloride and 0.92 ml (6.60 mmol) of triethylamine were added thereto under ice cooling, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the obtained residue to carry out a liquid separation operation. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- [4- (furan-2-furan) as a pale yellow oil. 1.60 g (carbonyl-amino) methyl-1,3-thiazol-2-yl] azetidine was obtained in a yield of 60%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.75-7.58
(4H, m), 7.50-7.09 (9H, m), 6.68 (1H, br s
), 4.82-4.70 (1H, m), 4.47 (2H, d, J = 5.5 Hz
), 4.11 (2H, t, J = 8.3 Hz), 4.02 (2H, dd, J =
8.3, 5.0 Hz), 1.06 (9H, s) (2) 1- [4- (furan-2-carbonyl-amino)
Methyl-1,3-thiazol-2-yl] -3-hydroxyazetidine 3-t-butyldiphenylsilyloxy-1- [4- (furan-2-carbonyl-) obtained in Reference Example 67 (1)
Amino) methyl-1,3-thiazol-2-yl] azetidine (1.90 g, 3.68 mmol) was dissolved in anhydrous tetrahydrofuran (95 ml), and the mixture was cooled under ice-cooling with a 1.0M tetra-n-butylammonium fluoride-tetrahydrofuran solution 4.41.
ml (4.41 mmol) were sequentially added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 10: 1) to give 1-
[4- (furan-2-carbonyl-amino) methyl-
[1,3-thiazol-2-yl] -3-hydroxyazetidine was obtained as a white solid in 426 mg in a yield of 47%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.44 (1H, s
), 7.12 (1H, d, J = 3.5 Hz), 7.04 (1H, br s),
6.49 (1H, dd, J = 3.4, 1.7 Hz), 6.45 (1H, s), 4.
86-4.78 (1H, m), 4.48 (2H, d, J = 5.7 Hz), 4.
33 (2H, t, J = 8.8 Hz), 3.98 (2H, dd, J = 8.8, 4.4
Hz) (3) 1- [4- (furan-2-carbonyl-amino)
Methyl-1,3-thiazol-2-yl] -3-methanesulfonyloxyazetidine 1- [4- (furan-2-) obtained in Reference Example 67 (2).
Carbonyl-amino) methyl-1,3-thiazole-2
-Yl] -3-hydroxyazetidine 426 mg (1.72 mm
ol) was dissolved in 20 ml of methylene chloride, and 0.16 ml (2.07 mmol) of methanesulfonyl chloride and 0.29 ml (2.07 mmol) of triethylamine were added under ice-cooling.
Stirred for hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 20: 1) to give 1- [4- (furan-2-carbonyl-amino) methyl-1,3 as a pale yellow solid. -Thiazol-2-yl]-
481 mg of 3-methanesulfonyloxyazetidine were obtained in a yield of 78%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.45 (1H,
d, J = 0.9 Hz), 7.13 (1H, d, J = 3.5 H), 7.00 (1
H, s), 6.53 (1H, s), 6.50 (1H, dd, J = 3.5, 1.8
Hz), 5.49-5.38 (1H, m), 4.51 (2H, d, J = 5.8
Hz), 4.48 (2H, dd, J = 3.1, 1.0 Hz), 4.29 (2H,
dd, J = 5.8, 4.9 Hz), 3.10 (3H, s) (4) 3-acetylthio-1- [4- (furan-2-carbonyl-amino) methyl-1,3-thiazole-2-
[Il] azetidine 1- [4- (furan-2-) obtained in Reference Example 67 (3).
Carbonyl-amino) methyl-1,3-thiazole-2
-Yl] -3-methanesulfonyloxyazetidine 481
was dissolved in 14 ml of dimethylformamide, and 921 mg (8.07 mmo) of potassium thioacetate was added at room temperature.
l) was added and the mixture was stirred in a 90 ° C. oil bath for 6 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-acetylthio-1- [4- (furan-2-carbonyl-amino) methyl as a light brown solid. -1,3-thiazol-2-yl]
Azetidine was obtained in 341 mg in a yield of 83%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.45 (1H, s
), 7.12 (1H, d, J = 3.5 Hz), 7.09-6.94 (2H, m
), 6.49 (2H, t, J = 2.5 Hz), 4.56 (2H, t, J = 8.5
Hz), 4.50 (2H, d, J = 5.7 Hz), 4.48-4.38 (1H,
m), 4.02 (2H, dd, J = 8.5, 6.1 Hz), 2.36 (3H,
s) Reference Example 68 3-acetylthio-1- (4-phthalimidomethyl-
1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-phthalimidomethyl-1,3-thiazol-2-yl) azetidine 3-t-butyldiphenyl obtained in Reference Example 2 (2) 1.50 g (3.53 mmol) of silyloxy-1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidine
Was dissolved in 75 ml of tetrahydrofuran, and under ice-cooling, 519 mg (5.30 mmol) of phthalimide, 1.39 g (5.30 mmol) of triphenylphosphine, 2.03 ml (5.30 mmol) of a 40% solution of diethyl azodicarboxylate in toluene.
Was added under a nitrogen atmosphere, and the mixture was stirred as it was for 2 hours.
After confirming the completion of the reaction, ethyl acetate and saturated saline were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 5) to give 3-t-butyldiphenylsilyloxy-1- (4-phthalimidomethyl-1, pale yellow oil). 3-thiazol-2-yl) azetidine
1.52 mg, 78% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.88 (2H, d
d, J = 5.5, 3.1 Hz), 7.33 (2H, dd, J = 5.5, 3.1 Hz)
), 7.60 (4H, dd, J = 7.9, 1.4 Hz), 7.47 -7.34 (
6H, m), 6.26 (1H, s), 4.83 (2H, s), 4.76-4.
68 (1H, m), 4.26-4.08 (2H, m), 4.08-3.92
(2H, m), 1.05 (9H, s) (2) 1- (4-phthalimidomethyl-1,3-thiazol-2-yl) -3-hydroxyazetidine 3 obtained in Reference Example 68 (1) -T-butyldiphenylsilyloxy-1- (4-phthalimidomethyl-1,3
-Thiazol-2-yl) azetidine 1.52 g (2.57 mm
ol) was dissolved in 76 ml of anhydrous tetrahydrofuran, and cooled to 1.0 M tetra-n-butylammonium fluoride- under ice-cooling.
3.29 ml (3.29 mmol) of a tetrahydrofuran solution was sequentially added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate),
1- (4-phthalimidomethyl-1,3-thiazole-
2-yl) -3-hydroxyazetidine was obtained as a white solid in 864 mg, 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.87 (2H, d
d, J = 5.4, 3.1 Hz), 7.73 (2H, dd, J = 5.4, 3.1 Hz)
), 6.32 (1H, s), 4.79 (2H, s), 4.78 -4.70 (1
H, m), 4.27 (2H, dd, J = 9.2, 6.9 Hz), 3.91 (2H,
dd, J = 9.2, 4.6 Hz) (3) 1- (4-phthalimidomethyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine 1- obtained in Reference Example 68 (2) 864 mg (2.74 mmol) of (4-phthalimidomethyl-1,3-thiazol-2-yl) -3-hydroxyazetidine was treated with methylene chloride 35
methanesulfonyl chloride 0.2 under ice-cooling.
5 ml (3.29 mmol), triethylamine 0.46 ml (3.29
mmol) and stirred for 1 hour. After confirming the completion of the reaction, diethyl ether was added to the reaction system and stirred for 30 minutes. The reaction system was filtered, the residue was washed with diethyl ether, and white solid 1- (4-phthalimidomethyl-1,
726 mg of 3-thiazol-2-yl) -3-methanesulfonyloxyazetidine was obtained in a yield of 67%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.91 (2H, d
d, J = 5.5, 2.8 Hz), 7.86 (2H, dd, J = 5.5, 3.5 Hz
), 6.70 (1H, s), 5.46-5.39 (1H, m), 4.63 (
2H, s), 4.36 (2H, dd, J = 10.0, 6.6 Hz), 4.09 (
2H, dd, J = 10.0, 3.4 Hz), 3.27 (3H, s) (4) 3-acetylthio-1- (4-phthalimidomethyl-1,3-thiazol-2-yl) azetidine Reference Example 68 (3) 726 mg (1.85 mmol) of 1- (4-phthalimidomethyl-1,3-thiazol-2-yl) -3-methanesulfonyloxyazetidine obtained in the above was dissolved in 22 ml of dimethylformamide, and the thiol was added at room temperature. 1.26 g (11.1 mmol) of potassium acetate was added, and the mixture was stirred in a 90 ° C oil bath for 6.5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1).
: 1) to give a light brown solid 3-acetylthio-
1- (4-phthalimidomethyl-1,3-thiazole-
599 mg of 2-yl) azetidine were obtained in a yield of 87%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.88 (2H, d
d, J = 5.4, 2.9 Hz), 7.73 (2H, dd, J = 5.4, 3.1 Hz
), 6.35 (1H, s), 4.82 (2H, s), 4.52 (2H, t,
J = 8.4 Hz), 4.45-4.35 (1H, m), 3.98 (2H, dd,
J = 8.4, 5.7 Hz), 2.34 (3H, s) Reference Example 69 3-acetylthio-1- (4-succinimidomethyl-
1,3-thiazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-succinimidomethyl-1,3-thiazol-2-yl) azetidine 3-t-butyl obtained in Reference Example 2 (2) 1.50 g (3.53 mmol) of diphenylsilyloxy-1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidine
Was dissolved in 75 ml of tetrahydrofuran, and under ice cooling, 525 mg (5.30 mmol) of succinimide, 1.39 g (5.30 mmol) of triphenylphosphine, 2.03 ml (5.30 mmol) of a 40% solution of diethyl azodicarboxylate in toluene.
Was added under a nitrogen atmosphere, and the mixture was stirred as it was for 4 hours.
After confirming the completion of the reaction, ethyl acetate and saturated saline were separated and extracted in the reaction system, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-succinimidomethyl-1) as a pale yellow oil. , 3-thiazol-2-yl) azetidine
1.79 g, 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.65-7.57
(4H, m), 7.49-7.36 (6H, m), 6.30 (1H, s),
4.75-4.66 (1H, m), 4.60 (2H, s), 4.21 (4H, d
d, J = 14.2, 7.1 Hz), 4.12 (4H, dd, J = 14.2, 7.1
Hz), 4.09 (2H, t, J = 8.5 Hz), 3.99 (2H, dd, J =
8.5, 4.9 Hz), 1.05 (9H, s) (2) 3-hydroxy-1- (4-succinimidomethyl-1,3-thiazol-2-yl) azetidine 3 obtained in Reference Example 69 (1) -T-butyldiphenylsilyloxy-1- (4-succinimidomethyl-1,3
-Thiazol-2-yl) azetidine 1.79 g (3.53 m
mol) was dissolved in 141 ml of anhydrous tetrahydrofuran, and 1.0M tetra-n-butylammonium fluoride-
4.24 ml (4.24 mmol) of a tetrahydrofuran solution were sequentially added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate:
Purified by methanol = 20: 1), 3-hydroxy-
1- (4-succinimidomethyl-1,3-thiazole-
2-yl) azetidine as a white solid, 456 mg, yield
49%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.34 (1H, s
), 4.84-4.74 (1H, m), 4.62 (2H, s), 4.31 (2
H, dd, J = 9.9, 6.6 Hz), 3.94 (2H, dd, J = 9.9, 4.4
Hz), 2.76 (4H, m) (3) 3-Methanesulfonyloxy-1- (4-succinimidomethyl-1,3-thiazol-2-yl) azetidine 3-Methane obtained in Reference Example 69 (2). Hydroxy-1- (4
Succinimidomethyl-1,3-thiazol-2-yl) azetidine (459 mg, 1.72 mmol) in methylene chloride 5
Dissolve in 0 ml and add methanesulfonyl chloride under ice-cooling.
0.16 ml (2.06 mmol), triethylamine 0.29 ml (
2.06 mmol) and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction system,
The aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-methanesulfonyloxy- as a pale yellow solid.
1- (4-succinimidomethyl-1,3-thiazole-
515 mg of 2-yl) azetidine were obtained in a yield of 87%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.43 (1H, s
), 5.44-5.34 (1H, m), 4.62 (2H, s), 4.44 (2
H, dd, J = 10.3, 6.6 Hz), 4.24 (2H, dd, J = 10.3,
4.2 Hz), 3.09 (3H, s), 2.76 (4H, s) (4) 3-acetylthio-1- (4-succinimidomethyl-1,3-thiazol-2-yl) azetidine Reference Example 69 (3) 515 mg (1.49 mmol) of 3-methanesulfonyloxy-1- (4-succinimidomethyl-1,3-thiazol-2-yl) azetidine obtained in the above was dissolved in 15 ml of dimethylformamide, and the thiol was added at room temperature. 1.02 g (8.95 mmol) of potassium acetate was added, and the mixture was stirred in a 90 ° C. oil bath for 8 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 3-acetylthio-1- (4-succinimidomethyl-1,3-thiazol-2-yl) azetidine as a light brown solid.
238 mg, obtained in a yield of 49%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.37 (1H, s
), 4.62 (2H, s), 4.51 (2H, t, J = 8.5 Hz), 4.4
5-4.35 (1H, m), 3.97 (2H, dd, J = 8.4, 5.4 Hz
), 2.76 (4H, s), 2.35 (3H, m) Reference Example 70 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-oxazol-2-yl) azetidine

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(1) (2S) -3- (t-butyldiphenylsilyloxy) -2-isothiocyanato-propionic acid methyl ester t-butyldiphenylsilyloxy-N- obtained in Reference Example 39 (1) 32.0 g (65.1 mmol) of carbobenzyloxy-L-serine methyl ester was dissolved in 960 ml of methanol, and subjected to catalytic hydrogen reduction in the presence of 32.0 g of 10% palladium carbon at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 95: 5) to give colorless oily t-butyldiphenylsilyl Oxy-L-serine methyl ester
19.7 g was obtained in a yield of 85%. Subsequently, the obtained t-butyldiphenylsilyloxy-L-serine methyl ester
19.7 g (55.0 mmol) was dissolved in 590 ml of methylene chloride, and at room temperature, 6.62 ml (110 mmol) of dicarbonated carbon and triethylamine 1
9.3 ml (138 mmol) was added and stirred overnight. Then 13.2 ml (138 mmol) of ethyl chloroformate and 19.3 ml of triethylamine
(138 mmol), and the mixture was further stirred for 1 hour. After confirming the completion of the reaction, methanol was added to the system and stirred for 30 minutes. Ethyl acetate and saturated saline were added to the reaction solution, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene), and yellow crystals of (2S) -3- (t-butyldiphenylsilyloxy) -2-isothiocyanate-
14.8 g of methyl propionate was obtained in a yield of 67%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.70-7.62
(4H, m), 7.48-7.38 (6H, m), 4.28 (1H, dd, J = 3.7,
5.1Hz), 4.05 (1H, dd, J = 5.1, 10.3Hz), 3.95 (1H, d
d, J = 3.7, 10.3 Hz), 3.80 (3H, s), 1.06 (9H, s) (2) (2S) -3- (t-butyldiphenylsilyloxy) -2-[(3-hydroxyazetidine -1-carbothioyl) -amino] -propionic acid methyl ester (2S) -3- (t-butyldiphenylsilyloxy) -2-isothiocyanate obtained in Reference Example 70 (1)
13.4 g (33.5 mmol) of propionic acid methyl ester was dissolved in 245 ml of tetrahydrofuran, and 4.90 g of the 3-hydroxyazetidine obtained in Reference Example 31 (1) was added to the system at room temperature.
(67.1 mmol) of a 50 ml aqueous solution was added, and the mixture was stirred as it was overnight. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene to toluene: acetonitrile = 3: 1) to obtain a yellow solid (2S)-
3- (t-butyldiphenylsilyloxy) -2-[(3
-Hydroxyazetidine-1-carbothioyl) -amino] -propionic acid methyl ester was obtained in 9.60 g at a yield of 61%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.61-7.55
(4H, m), 7.47-7.36 (6H, m), 5.94 (1H, br d, J = 8.
1Hz), 5.19 (1H, dt, J = 2.9, 8.1Hz), 4.71-4.64 (1
H, m), 4.40-4.33 (1H, m), 4.31-4.23 (1H, m),
4.18 (1H, dd, J = 2.2, 10.3Hz), 4.04 (1H, dd, J = 2.9,
10.3Hz), 4.02-3.96 (1H, m), 3.94-3.88 (1H,
m), 3.76 (3H, s), 2.24 (1H, br d, J = 5.9Hz), 1.04 (9
H, s) (3) (2S) -2-{[3- (benzoyloxy) -azetidine-1-carbothioyl] -amino] -3- (t-
Butyldiphenylsilyloxy) -propionic acid methyl ester (2S) -3- (t-butyldiphenylsilyloxy) -2-[(3-hydroxyazetidine-1-carbothioyl)-obtained in Reference Example 70 (2). Amino] -propionic acid methyl ester (21.1 g, 44.6 mmol) was added to pyridine 630.
The reaction mixture was dissolved in 3 ml, and 30.0 g (133 mmol) of benzoic anhydride and 545 mg (4.46 mmol) of 4-dimethylaminopyridine were added to the reaction system under ice-cooling, followed by stirring at room temperature for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed sequentially with 0.5N aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
4: 1) to give (2S) -2-（[3
-(Benzoyloxy) -azetidine-1-carbothioyl] -amino] -3- (t-butyldiphenylsilyloxy) -propionic acid methyl ester (23.3 g, yield 9)
Obtained at 1%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.10-8.05
(2H m), 7.65-7.54 (4H, m), 7.52-7.45 (3H, m),
7.44-7.35 (6H, m), 5.96 (1H, br d, J = 8.1Hz), 5.
47-5.40 (1H, m), 5.20 (1H, dt, J = 8.1, 2.9Hz), 4.
57-4.51 (1H, m), 4.49-4.40 (1H, m), 4.27-4.2
0 (1H, m), 4.20 (1H, dd, J = 2.2, 10.3Hz), 4.06 (1H,
dd, J = 2.9, 10.3Hz), 3.77 (3H, s), 1.04 (9H, s) (4) (2S) -2-｛[3- (benzoyloxy)-
Azetidine-1-carbothioyl] -amino} -3-hydroxy-propionic acid methyl ester (2S) -2-{[3- (benzoyloxy) -azetidine-1-carbothioyl] obtained in Reference Example 70 (3).
-Amino] -3- (t-butyldiphenylsilyloxy)
-Dissolve 23.3 g (40.0 mmol) of methyl propionate in 700 ml of tetrahydrofuran, and add 1.0 M
48.4 ml (48.4 mmol) of a tetra-n-butylammonium fluoride-tetrahydrofuran solution was added, and the mixture was stirred overnight. After confirming the completion of the reaction, ethyl acetate and saturated saline were added to the reaction system to carry out a liquid separation operation, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 3: 1) to give (2S) -2-｛[3- (benzoyloxy) -azetidine-1-carbotic oil] as a white solid. 12.6 g of -amino} -3-hydroxy-propionic acid methyl ester in a yield of 92%
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.08-8.04
(2H, m), 7.64-7.59 (1H, m), 7.51-7.45 (2H, m),
6.00 (1H, d, J = 7.3Hz), 5.49-5.43 (1H, m), 5.25
(1H, dt, J = 7.3, 3.7Hz), 4.63-4.56 (2H, m), 4.32
-4.24 (2H, m), 4.12-4.02 (2H, m), 3.82 (3H, s) (5) 3-benzoyloxy-1-[(4S) -4-methoxycarbonyl-1,3-oxazoline-2 -Yl] azetidine 2-chloro-3-ethylbenzoxazol tetrafluoroborate 15.1 g (55.9 mmol) of acetonitrile 380
(2S) -2- ｛obtained in Reference Example 70 (4) in a ml solution.
12.6 g (37.2 mmol) of [3- (benzoyloxy) -azetidine-1-carbothioyl] -amino} -3-hydroxy-propionic acid methyl ester was treated with acetonitrile 5
A 00 ml solution was added dropwise under ice cooling under a nitrogen atmosphere, and after completion of the addition, the mixture was stirred for 1 hour. Next, 10.4 ml (74.4 mmol) of triethylamine was added to the system, and the mixture was further stirred for 1.5 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, liquid separation was performed, and then the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with a saturated saline solution,
The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give 3-benzoyloxy-1-[(4S) -4-methoxycarbonyl as a light brown solid. -1,
9.12 g of 3-oxazolin-2-yl] azetidine, yield
81% obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.08-8.04
(2H, m), 7.63-7.58 (1H, m), 7.49-7.44 (2H, m),
5.50-5.44 (1H, m), 4.69 (1H, dd, J = 6.6,9.5Hz),
4.55 (1H, dd, J = 6.6, 8.1Hz), 4.51-4.44 (3H, m),
4.20-4.14 (2H, m), 3.78 (3H, s) (6) 3-benzoyloxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine Reference Example 70 (5) 3-benzoyloxy-1 obtained in
-(4-methoxycarbonyl-1,3-oxazoline-
9.12 g (30.0 mmol) of 2-yl) azetidine was added to toluene 450
was dissolved in 180 ml of methylene chloride, 63.8 g of manganese dioxide was added to the system, and the mixture was heated under reflux for 5 hours. After confirming the completion of the reaction,
The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: toluene: acetonitrile = 1: 1) to give 3-benzoyloxy-1- (4-methoxycarbonyl-1,3-oxazole) as pale yellow crystals. -2-yl) azetidine in 5.
24 g, 58% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.08-8.04
(2H, m), 7.84 (1H, s), 7.63-7.58 (1H, m), 7.50
-7.44 (2H, m), 5.60-5.53 (1H, m), 4.61 (1H, dd,
J = 5.9, 9.5Hz), 4.31 (1H, dd, J = 3.4, 9.5Hz), 3.89
(3H, s) (7) 3-Hydroxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine 3-benzoyloxy-1 obtained in Reference Example 70 (6)
-(4-methoxycarbonyl-1,3-oxazole-
5.24 g (17.3 mmol) of 2-yl) azetidine was dissolved in methanol 2
The resultant was dissolved in 60 ml of methylene chloride and 80 ml of methylene chloride, and a catalytic amount of sodium methoxide was added at room temperature, followed by stirring for 1 hour.
After confirming the completion of the reaction, a 4N-hydrochloric acid gas-dioxane solution was added for neutralization under ice cooling, and the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 95: 5), and 3-hydroxy-1- (4-methoxycarbonyl-1,3-oxazole) as pale brown crystals was obtained. 2.65 g of -2-yl) azetidine was obtained in a yield of 77%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.81 (1H,
s), 4.83-4.76 (1H, brs), 4.41 (2H, dd, J = 6.6, 9.
5Hz), 4.06 (2H, dd, J = 4.4, 9.5Hz), 3.88 (3H, s), 2.
39-2.30 (1H, brs) (8) 3-t-butyldiphenylsilyloxy-1- (4
-Methoxycarbonyl-1,3-oxazol-2-yl) azetidine 3-hydroxy-1- (4) obtained in Reference Example 70 (7)
-Methoxycarbonyl-1,3-oxazol-2-yl) azetidine (2.64 g, 13.4 mmol) was dissolved in dimethylformamide (80 ml), and ice-cooled t-butyldiphenylsilane (6.97 ml, 26.8 mmol), imidazole 1.82g
(26.8 mmol), and the mixture was stirred overnight under ice-cooling.
After confirming the completion of the reaction, methanol was added to the system and stirred for 30 minutes. Next, ethyl acetate and 10% saline were added to the system, and a liquid separation operation was performed. The aqueous layer was separated and extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 4: 1 to 3: 1).
To give 4.95 g of 3-t-butyldiphenylsilyloxy-1- (4-methoxycarbonyl-1,3-oxazol-2-yl) azetidine as a pale yellow solid, yield 85%
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.78 (1H,
s), 7.62-7.58 (4H, m), 7.48-7.36 (6H, m), 4.74
-4.67 (1H, m), 4.15 (1H, dd, J = 6.6, 9.5Hz), 4.08
(1H, dd, J = 5.1, 9.5 Hz), 3.87 (3H, s), 1.06 (9H, s) (9) 3-t-butyldiphenylsilyloxy-1-
(4-Hydroxymethyl-1,3-oxazole-2-
Yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-methoxycarbonyl-1,3) obtained in Reference Example 70 (8)
-Oxazol-2-yl) azetidine 4.95 g (11.3 mm
ol) in 100 ml of anhydrous tetrahydrofuran, and 1.29 g (33.9 mmol) of lithium aluminum hydride prepared in advance.
Was added dropwise to a suspension of 250 ml of anhydrous tetrahydrofuran under ice-cooling under a nitrogen atmosphere, and after completion of the dropwise addition, the mixture was stirred for 5 minutes under the same conditions. After confirming the completion of the reaction, magnesium sulfate decahydrate was gradually added to the system under the same conditions, and when the foaming from the system had subsided, the mixture was stirred at room temperature for 1 hour. Thereafter, ethyl acetate was gradually added to the system, and then saturated saline was added. After separating and extracting the aqueous layer with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: toluene: acetonitrile = 3:
Purified in 1) to give a white solid 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-
Oxazol-2-yl) azetidine 3.88 g, 84% yield
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.63-7.59
(4H, m), 7.47-7.36 (6H, m), 7.13 (1H, s), 4.73-
4.66 (1H, m), 4.45 (2H, s), 4.11 (2H, dd, J = 6.6,
8.8Hz), 4.04 (2H, dd, J = 5.1, 8.8Hz), 2.21-2.15
(1H, br s), 1.06 (9H, s) (10) 3-t-butyldiphenylsilyloxy-1-
(4-Formyl-1,3-oxazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1- (4-hydroxymethyl-1,3-
Oxazol-2-yl) azetidine 3.88 g (9.50 mmol)
Was dissolved in 190 ml of anhydrous methylene chloride, 19.4 g of activated manganese dioxide was added to the solution, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 3: 1) to give 3-t-butyldiphenylsilyloxy-1- (4-formyl-1) as pale yellow crystals. , 3-oxazol-2-yl) azetidine 3.09 g, · to give in 80% yield ^{1 H-NMR (400MHz, CDCl} 3): δ (ppm) 9.75 (1H,
s), 7.80 (1H, s), 7.63 -7.58 (4H, m), 7.48-7.37
(6H, m), 4.75-4.68 (1H, s), 4.16 (2H, dd, J = 6.6,
9.5 Hz), 4.10 (2H, dd, J = 5.1, 9.5 Hz), 1.06 (9H, s) (11) 3-t-butyldiphenylsilyloxy-1-
(4-Carboxy-2-yl) azetidine 3.09 g of 3-t-butyldiphenylsilyloxy-1- (4-formyl-1,3-oxazol-2-yl) azetidine obtained in Reference Example 70 (10) ( 7.60 mmol) was dissolved in anhydrous methylene chloride (18 ml), and t-butanol (93 ml,
2M 2-methyl-2-butene tetrahydrofuran solution
5.70 ml (11.4 mmol) were added. Subsequently, sodium chlorite 1.72 g (15.2 mmol), sodium dihydrogen phosphate 1.82 g
(15.2 mmol) of an 18 ml aqueous solution was dropped into the system under ice cooling, and 1
Stirred for hours. After confirming the completion of the reaction, ethyl acetate and 1M
-Hydrochloric acid solution (pH: 2 to 3) was added. After separating and extracting the aqueous layer with ethyl acetate, the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride to methylene chloride: methanol = 9: 1) to obtain a brown solid 3
1.90 g of -t-butyldiphenylsilyloxy-1- (4-carboxyl-1,3-thiazol-2-yl) azetidine was obtained at a yield of 59%. Mass spectrum (FAB ⁺ ): m / z: 423 [M + H] ⁺ Reference Example 71 3-acetylthio-1- (4-azetidinocarbonyl-)
1,3-oxazol-2-yl) azetidine

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(1) 1- (4-azetidinocarbonyl-
1,3-oxazol-2-yl) -3-t-butyldiphenylsilyloxyazetidine 3-t-butyldiphenylsilyloxy-1- (4-methoxycarbonyl-1, obtained in Reference Example 70 (8) 3
-Oxazol-2-yl) azetidine 2.00g (4.58mmo
l) was dissolved in 100 ml of toluene, 13.7 ml of a 0.67 M azetidine-trimethylaluminum-benzene solution was added at room temperature under a nitrogen atmosphere, and the mixture was stirred in a 100 ° C. oil bath for 5.5 hours. After confirming the completion of the reaction, 100 ml of 10% aqueous acetic acid and 200 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 1 to ethyl acetate) to obtain 1- (4-azetidinocarbonyl-1,3-oxazole) as a light brown solid. -2-yl) -3-t
-875 mg of butyldiphenylsilyloxyazetidine,
Obtained in 41% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.67 (1H,
s), 7.65-7.57 (4H, m), 7.48-7.37 (6H, m), 4.72
-4.66 (1H, m), 4.54-4.47 (2H, m), 4.18-4.11
(2H, m), 4.10 (2H, dd, J = 6.6, 8.8Hz), 4.04 (2H, d
d, J = 5.1, 8.8Hz), 2.30 (2H, quintet, J = 7.7Hz), 1.0
6 (9H, s) (2) 1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) -3-hydroxyazetidine 1- (4-azetidin obtained in Reference Example 71 (1) Dinocarbonyl-1,3-oxazol-2-yl) -3-t-
870 mg of butyldiphenylsilyloxyazetidine (1.88 m
mol) was dissolved in 44 ml of anhydrous tetrahydrofuran, and under ice cooling, 2.26 ml (2.26 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was added thereto, followed by stirring for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 9: 1) to obtain 1- (4-azetidinocarbonyl-1,3- Oxazol-2-yl) -3-hydroxyazetidine was obtained as white crystals in a quantity of 396 mg in a yield of 94%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.70 (1H,
s), 4.81-4.74 (1H, m), 4.53 (2H, dd, J = 6.8, 7.8H
z), 4.34 (2H, dd, J = 6.8, 9.8Hz), 4.16 (2H, dd, J =
6.8, 7.8Hz), 3.99 (2H, dd, J = 4.9, 8.8Hz), 2.34 (1
H, d, J = 7.8 Hz), 2.31 (2H, quintet, J = 7.8 Hz) (3) 1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) -3-methanesulfonylazetidine 390 mg (1.75 mmol) of 1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) -3-hydroxyazetidine obtained in Reference Example 71 (2) was treated with 20 ml of methylene chloride.
Methanesulfonyl chloride under ice-cooling 406 μl
(5.24 mmol) and 734 μl (5.24 mmol) of triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, and the mixture was filtered. The residue was washed with diisopropyl ether and dried under reduced pressure to give a light yellow solid, 1- (4-azetidinocarbonyl-).
1,449-mg of 1,3-oxazol-2-yl) -3-methanesulfonylazetidine was obtained at a yield of 85%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.74 (1H,
m), 5.40-5.34 (1H, m), 4.55-4.49 (2H, br t, J =
7.3Hz), 4.47 (2H, ddd, J = 11.0, 6.6, 0.7Hz), 4.29
(2H, dd, J = 11.0, 4.4Hz), 4.19-4.12 (2H, br t, J =
7.3 Hz), 3.09 (3H, s), 2.32 (2H, quintet, J = 7.3 Hz) (4) 3-acetylthio-1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidine Reference 470 mg (1.56 mmol) of 1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) -3-methanesulfonylazetidine obtained in Example 71 (3) was dissolved in 25 ml of dimethylformamide, and the solution was dissolved at room temperature. 1.07 g (9.36 mmol) of potassium thioacetate was added thereto, and the mixture was stirred in an oil bath at 80 ° C for 8.5 hours. After confirming the completion of the reaction, add 10%
A saline solution was added, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol =
95: 5) to obtain 330 mg of a light brown solid of 3-acetylthio-1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidine in a yield of 75%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.71 (1H,
s), 4.54 (2H, t, J = 8.8Hz), 4.55-4.49 (2H, br t,
J = 8.1Hz), 4.43-4.35 (1H, m), 4.18-4.12 (2H, br
t, J = 8.1Hz), 4.00 (2H, dd, J = 8.8, 5.9Hz), 2.35 (3
H, s), 2.36-2.26 (2H, m) Reference Example 72 3-acetylthio-1- (4-morpholinocarbonyl-
1,3-oxazol-2-yl) azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine 3-t-butyldiphenyl obtained in Reference Example 70 (8) Silyloxy-1- (4-methoxycarbonyl-1,3
-Oxazol-2-yl) azetidine 1.00 g (2.29mmo
l) was dissolved in 50 ml of toluene, and 6.87 ml of a 0.67 M morpholine-trimethylaluminum-toluene solution was added at room temperature under a nitrogen atmosphere, followed by stirring in an 80 ° C. oil bath for 4 hours. After confirming the completion of the reaction, 50 ml of 10% aqueous acetic acid and 100 ml of ethyl acetate were added to the system under ice cooling, followed by stirring at room temperature for 1 hour. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2),
3-t-butyldiphenylsilyloxy- as a light brown solid
400 mg of 1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine was obtained at a yield of 36%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.68 (1H,
s), 7.62-7.59 (4H, m), 7.48-7.37 (6H, m), 4.73
-4.67 (1H, m), 4.15-4.09 (2H, m), 4.05 (2H, d
d, J = 8.8, 5.1Hz), 3.75-3.65 (8H, br s), 1.06 (9
H, s) (2) 3-Hydroxy-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine 3-t-butyldiphenylsilyloxy-1 obtained in Reference Example 72 (1) -(4-morpholinocarbonyl-1,
730 mg (1.48 m) of 3-oxazol-2-yl) azetidine
was dissolved in 37 ml of anhydrous tetrahydrofuran, and under ice cooling, 1.78 ml (1.78 mmol) of a 1.0 M solution of tetra-n-butylammonium fluoride-tetrahydrofuran was added, followed by stirring for 1.5 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate: methanol = 95: 5-9:
Purification was performed in 1) to give 377 mg of 3-hydroxy-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine as white crystals in a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.71 (1H,
s), 4.82-4.74 (1H, m), 4.35 (2H, dd, J = 9.5, 6.6H
z), 4.00 (2H, dd, J = 9.5, 4.4 Hz), 3.76-3.65 (8H,
m), 2.42-2.30 (1H, brs) (3) 3-methanesulfonyloxy-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine Obtained in Reference Example 72 (2). 3-hydroxy-1- (4
-Morpholinocarbonyl-1,3-oxazole-2-
Il) azetidine 370mg (1.48mmol) in methylene chloride 19ml
344 μl of methanesulfonyl chloride under ice-cooling
(4.44 mmol) and 622 μl (4.44 mmol) of triethylamine were added, and after 10 minutes, the reaction system was returned to room temperature and stirred for 1 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: methanol = 93: 7),
Light yellow crystals of 3-methanesulfonyloxy-1- (4-
404 mg of morpholinocarbonyl-1,3-oxazol-2-yl) azetidine was obtained at a yield of 100%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.75 (1H,
s), 5.41-5.34 (1H, m), 4.48 (2H, ddd, J = 9.5, 6.
6, 1.5Hz), 4.30 (2H, ddd, J = 9.5, 4.0, 1.5Hz), 3.78
-3.65 (8H, m), 3.10 (3H, s) (4) 3-acetylthio-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine Obtained in Reference Example 72 (3). 400 mg (1.21 mmol) of 3-methanesulfonyloxy-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine was dissolved in 20 ml of dimethylformamide, and 827 mg (7.24 mmol) of potassium thioacetate was added at room temperature. ) Was added and the mixture was stirred in an 80 ° C. oil bath for 6 hours. After confirming the completion of the reaction, ethyl acetate and 10
% Saline was added, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol =
95: 5) to give 266 mg of 3-acetylthio-1- (4-morpholinocarbonyl-1,3-oxazol-2-yl) azetidine as a light brown solid in a yield of 71%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.72 (1H,
s), 4.55 (2H, t, J = 8.4Hz), 4.43-4.36 (1H, m), 4.
02 (2H, dd, J = 9.5, 5.9Hz), 3.76-3.66 (8H, br s),
2.36 (3H, s) <Reference Example 73> 3-acetylthio-1- [4- (3-methoxy-azetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine

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(1) 3-tert-butyldiphenylsilylthio
Xy-1- [4- (3-methoxy-azetidine-1-cal
Bonyl) -1,3-oxazol-2-yl] azetidine 3-t-butyldiphenyl obtained in Reference Example 70 (8)
Silyloxy-1- (4-methoxycarbonyl-1,3
-Oxazol-2-yl) azetidine 1.57g (3.60mmo
l) was dissolved in 80 ml of toluene, and 0.67M 3-methoxyaze
Thidine (obtained in Reference Example 31 (2))-trimethyla
Luminium-toluene solution (10.8 ml) under nitrogen atmosphere at room temperature
And stirred in a 60 ° C. oil bath for 30 minutes. After confirming the completion of the reaction,
Under ice cooling, 100 ml of 10% aqueous acetic acid and 200 ml of ethyl acetate
Was added and stirred at room temperature for 1 hour. Then in the reaction system
Ethyl acetate was further added, liquid separation was performed, and the aqueous layer was treated with acetic acid.
Separation extraction was performed with ethyl. The obtained organic layer is saturated
After washing with sodium bicarbonate and saturated saline, it was dried over anhydrous sodium sulfate.
After drying, filtration, and the filtrate were concentrated under reduced pressure. The resulting residue is
Ricagel column chromatography (elution solvent: acetic acid
)) To give 3-t-butyldiffee as a light brown solid.
Nylsilyloxy-1- [4- (3-methoxy-azetidi
1-carbonyl) -1,3-oxazole-2-i
[Azetidine] was obtained at a yield of 1.50 g and a yield of 90%. ¹ H-NMR (400MHz, CDCl _Three ): δ (ppm) 7.69 (1H,
s), 7.63-7.59 (4H, m), 7.48-7.37 (6H, m), 4.73
-4.76 (2H, m), 4.37-4.19 (3H, m), 4.10 (2H, d
d, J = 8.8, 6.6Hz), 4.03 (2H, dd, J = 8.8, 5.1Hz), 4.0
2-3.98 (1H, m), 3.32 (3H, s), 1.06 (9H, s) (2) 3-hydroxy-1- [4- (3-methoxy-aze
(Thidine-1-carbonyl) -1,3-oxazole-2
-Yl] azetidine 3-t-butyldiphenyl obtained in Reference Example 72 (1)
Silyloxy-1- [4- (3-methoxy-azetidine-
1-carbonyl) -1,3-oxazol-2-yl] a
1.49 g (3.23 mmol) of zetidine in anhydrous tetrahydrofuran 7
Dissolve in 5 ml and add 1.0 M tetra-n-butylamine under ice-cooling.
3.88 ml of monium fluoride-tetrahydrofuran solution (3.8
8 mmol), and the mixture was stirred for 1 hour. Confirmation of reaction completion
Then, the reaction solution is concentrated under reduced pressure, and the residue is
Chromatography (elution solvent: ethyl acetate: methanol
= 95: 5 to 9: 1) to give 3-hydroxy-1
-[4- (3-methoxy-azetidine-1-carbonyl)
[1,3-oxazol-2-yl] azetidine in white
486 mg was obtained as a solid in a yield of 60%. ¹ H-NMR (400MHz, CDCl _Three ): δ (ppm) 7.71 (1H,
s), 4.81-4.66 (2H, m), 4.34 (2H, dd, J = 9.5, 6.6H
z), 4.39-4.20 (3H, m), 4.04-3.98 (1H, m), 3.99
(2H, dd, J = 9.6, 4.4Hz), 3.32 (3H, s), 2.45 (1H, d,
J = 6.6Hz) (3) 3-Methanesulfonyloxy-1- [4- (3-me
Toxi-azetidine-1-carbonyl) -1,3-oxo
Sazol-2-yl] azetidine 3-hydroxy-1- [4 obtained in Reference Example 73 (2)
-(3-methoxy-azetidine-1-carbonyl) -1,
3-Oxazol-2-yl] azetidine 480mg (1.89mm
ol) in 24 ml of methylene chloride and methane
439 μl (5.67 mmol) of rufonyl chloride, triethylamido
795 ml (5.67 mmol) was added and 10 minutes later, the reaction system was cooled to room temperature.
And stirred for 30 minutes. After confirming the completion of the reaction,
Ethyl acetate and saturated aqueous sodium bicarbonate were added to the system, and the aqueous layer was washed with ethyl acetate.
And extracted. Wash the obtained organic layer with saturated saline.
After purification, dry over anhydrous sodium sulfate, filter, and filtrate
It was concentrated below. Ethyl acetate and diisopropyl
And the filtrate is filtered.
3-methanesulfonyloxy as a pale yellow solid
-1- [4- (3-methoxy-azetidine-1-carboni
Ru) -1,3-oxazol-2-yl] azetidine
6 mg was obtained with a yield of 94%. ¹ H-NMR (400MHz, CDCl _Three ): δ (ppm) 7.76 (1H,
s), 5.41-5.34 (1H, m), 4.72-4.63 (1H, m), 4.29
(2H, dd, J = 11.0, 4.4Hz), 4.38-4.20 (5H, m), 4.0
3-3.97 (1H, m), 3.32 (3H, s), 3.10 (3H, s) (4) 3-acetylthio-1- [4- (3-methoxy-a
(Zetidine-1-carbonyl) -1,3-oxazole-
2-yl] azetidine 3-methanesulfonyloxy obtained in Reference Example 73 (3)
Ci-1- [4- (3-methoxy-azetidine-1-carbo
Nyl) -1,3-oxazol-2-yl] azetidine 58
Dissolve 0mg (1.75mmol) in 30ml of dimethylformamide
Then, at room temperature, potassium thioacetate (1.20 g, 10.5 mmol) was added.
Then, the mixture was stirred in an 80 ° C. oil bath for 6 hours. After confirming the completion of the reaction,
Ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was extracted with ethyl acetate.
Separated extraction with chill. The obtained organic layer was saturated with aqueous sodium bicarbonate,
After washing with a saline solution, the extract was dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure. Silica gel obtained residue
Column chromatography (elution solvent: ethyl acetate-vinegar
Purified with ethyl acetate: methanol = 97: 3), pale brown
Solid 3-acetylthio-1- [4- (3-methoxy-a
(Zetidine-1-carbonyl) -1,3-oxazole-
336 mg of 2-yl] azetidine were obtained in a yield of 62%. ¹ H-NMR (400MHz, CDCl _Three ): δ (ppm) 7.73 (1H,
s), 4.72-4.65 (1H, m), 4.54 (2H, t, J = 8.8Hz), 4.
43-4.19 (4H, m), 4.03-3.97 (1H, m), 4.01 (2H, d
d, J = 8.8, 5.1 Hz), 3.31 (3H, s), 2.35 (3H, s) Reference Example 74 3-acetylthio-1- [4- (3-t-butyldiphenyl
Lucylyloxyazetidine-1-carbonyl) -1,3
-Oxazol-2-yl] azetidine

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(1) 1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) -1,3
-Oxazol-2-yl] -3-hydroxyazetidine 3-hydroxy-1- (4) obtained in Reference Example 70 (7).
500 mg (2.52 mmol) of -methoxycarbonyl-1,3-oxazol-2-yl) azetidine was dissolved in 25 ml of toluene, and 0.67M 3-t-butyldiphenylsilyloxyazetidine (obtained in Reference Example 42 (2)). -Trimethylaluminum-toluene solution (11.3 ml) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred in an 80 ° C oil bath for 15 minutes. After confirming the completion of the reaction,
Under ice cooling, 20 ml of 10% aqueous acetic acid and 50 ml of ethyl acetate were added to the system, followed by stirring at room temperature for 0.5 hour. Subsequently, ethyl acetate was further added to the reaction system, liquid separation was performed, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: methanol = 95: 5 to 9: 1),
1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] -3-hydroxyazetidine as a light brown solid
4 g, 100% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.68 (1H,
s), 7.61 (4H, dd, J = 8.1,1.5Hz), 7.47-7.36 (6H,
m), 4.81-4.74 (1H, m), 4.65-4.52 (2H, m), 4.40
-4.36 (1H, m), 4.33 (2H, dd, J = 9.5, 6.6Hz), 4.18
-4.11 (1H, m), 4.06-3.97 (1H, m), 3.98 (2H, dd,
J = 9.5, 5.1 Hz), 1.06 (9H, s) (2) 1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) -1,3-oxazol-2-yl]- 3-methanesulfonyloxyazetidine 1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) obtained in Reference Example 74 (1)
1,3-Oxazol-2-yl] -3-hydroxyazetidine (1.68 g, 3.53 mmol) was dissolved in methylene chloride (84 ml), and 820 μl of methanesulfonyl chloride (10.6 g) was added under ice cooling.
mmol), 1.49 ml (10.6 mmol) of triethylamine.
After 10 minutes, the reaction system was returned to room temperature and stirred for 0.5 hour. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride: ethyl acetate = 1: 1) to give 1- [4- (3-t-butyldiphenylsilyloxyazetidine-1) as a pale yellow solid. -Carbonyl) -1,3-oxazol-2-yl] -3-methanesulfonyloxyazetidine was obtained in 1.56 g in a yield of 80%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.72 (1H,
s), 7.61 (4H, d, J = 6.8Hz), 7.45 (2H, t, J = 6.8Hz),
7.39 (4H, t, J = 6.8Hz), 5.40-5.34 (1H, m), 4.64-
4.59 (1H, m), 4.59-4.52 (1H, m), 4.45 (2H, dd,
J = 10.7, 5.9Hz), 4.39-4.32 (1H, m), 4.28 (2H, dd,
J = 10.7, 4.9Hz), 4.18-4.12 (1H, m), 4.05-4.00
(1H, m), 3.10 (3H, s), 1.07 (9H, s) (3) 3-acetylthio-1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-
1,3-Oxazol-2-yl] azetidine 1- [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) obtained in Reference Example 74 (2)
1,6-Oxazol-2-yl] -3-methanesulfonyloxyazetidine (1.56 g, 2.81 mmol) was dissolved in dimethylformamide (80 ml), and at room temperature, potassium thioacetate (1.92 g, 16.8 mmol) was added. The mixture was stirred in an oil bath for 7.5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1 to 1:
Purified in 1) to give a light brown solid 3-acetylthio-1-
863 mg of [4- (3-t-butyldiphenylsilyloxyazetidine-1-carbonyl) -1,3-oxazol-2-yl] azetidine was obtained in a yield of 57%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.69 (1H,
s), 7.63-7.60 (4H, m), 7.47-7.36 (6H, m), 4.64
-4.54 (2H, m), 4.53 (2H, t, J = 8.8Hz), 4.43- 4.32
(2H, m), 4.18-4.13 (1H, m), 4.06-4.00 (1H, m),
4.00 (2H, dd, J = 8.8, 5.9Hz) 2.36 (3H, s), 1.06
(9H, s) Reference Example 75 3-acetylthio-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-oxazol-2-yl] azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,
3-thiazol-2-yl] azetidine 1.39 g (4.83 m) of 3- (p-nitrobenzyloxycarbonylamino) azetidine hydrochloride obtained in Reference Example 57 (4).
mol) and the 3-t-butyldiphenylsilyloxy-1- (4-carboxyl-) obtained in Reference Example 70 (11).
1.70 g of 1,3-oxazol-2-yl) azetidine
(4.02 mmol) dissolved in 85 ml of dimethylformamide,
Under a nitrogen atmosphere, ice-cooled diethyl phosphoryl cyanide 80
1 μl (4.83 mmol), triethylamine 1.70 ml (12.1 mmo
l) was added and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction,
Ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was saturated with aqueous sodium bicarbonate,
After washing successively with a saturated saline solution, the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 1: 2-ethyl acetate),
3-t-butyldiphenylsilyloxy- as a pale yellow solid
There was obtained 596 mg of 1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl] azetidine in a yield of 23%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 7.71 (1H, s), 7.61 (4H, d, J = 8.8Hz),
7.53-7.49 (2H, m), 7.47-7.38 (6H, m), 5.30-
5.26 (1H, m), 5.21 (2H, s), 4.89-4.80 (1H, m),
4.72-4.66 (1H, m), 4.59-4.51 (1H, m), 4.51-
4.42 (1H, m), 4.37-4.30 (1H, m), 4.12 -4.06 (2H,
m), 4.02 (2H, dd, J = 8.8, 4.9Hz), 3.97-3.90 (1H,
m), 1.06 (9H, s) (2) 3-hydroxy-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl ] Azetidine 3-t-butyldiphenylsilyloxy-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3- obtained in Reference Example 75 (1). Thiazol-2-yl] azetidine 640 mg
(0.976 mmol) was dissolved in 32 ml of anhydrous tetrahydrofuran, and under ice-cooling, 67 μl of acetic acid, (1.17 mmol), and 1.17 ml (1.17 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution were sequentially added thereto. Stir for 1.5 hours. After confirming the completion of the reaction, add 10%
A saline solution was added, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: methylene chloride: methanol = 95: 5-
9: 1) to give 3-hydroxy-1- [4- [3-
(P-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazole-2-
[Il] azetidine as a white solid, 360mg, 88% yield
I got it. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H, d,
J = 8.8Hz), 7.73 (1H, s), 7.51 (2H, d, J = 8.8Hz), 5.
46-5.40 (1H, m), 5.21 (2H, s), 4.89-4.74 (2H,
m), 4.60-4.40 (2H, m), 4.39-4.31 (1H, m), 4.33
(2H, dd, J = 9.5,6.6Hz), 3.98 (2H, dd, J = 9.5, 5.1H
z), 3.96-3.90 (1H, m) (3) 3-methanesulfonyloxy-1- [4- [3-
(P-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazole-2-
[Il] azetidine 3-hydroxy-1- [4] obtained in Reference Example 75 (2)
360 mg (0.863 mmol) of-[3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl] azetidine is dissolved in 18 ml of methylene chloride and cooled with ice. Methanesulfonyl chloride 200μl (2.59mmol), triethylamine 363μl
(2.59 mmol) was added, and after 10 minutes, the reaction system was returned to room temperature.
The mixture was stirred for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. After washing the obtained organic layer with saturated saline,
The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride to methylene chloride: methanol = 95: 5), and 3-methanesulfonyloxy-1- [4- [3- (p -Nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] -1,3-thiazol-2-yl] azetidine to 39
0 mg was obtained in a yield of 91%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.23 (2H,
d, J = 8.8Hz), 7.77 (1H, s), 7.51 (2H, d, J = 8.8Hz),
5.40-5.34 (1H, m), 5.11-5.27 (1H, m), 5.21 (2H,
s), 4.90-4.81 (1H, m), 4.60-4.53 (1H, m), 4.4
5 (2H, dd, J = 10.3, 6.6Hz), 4.39-4.30 (1H, m), 4.
27 (2H, dd, J = 10.3, 4.4Hz), 3.99-3.92 (1H, m), 3.
10 (3H, s) (4) 3-acetylthio-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-
Carbonyl] -1,3-thiazol-2-yl] azetidine 3-methanesulfonyloxy-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine- obtained in Reference Example 75 (3). 1-carbonyl] -1, 3
-Thiazol-2-yl] azetidine 390 mg (0.787 mmol)
Was dissolved in 20 ml of dimethylformamide, 539 mg (4.72 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in an oil bath at 80 ° C. for 10.5 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
1: 3-ethyl acetate) to give 3-acetylthio-1- [4- [3- (p-nitrobenzyloxycarbonylamino) -azetidine-1-carbonyl] as a light brown solid.
195 mg of [1,3-thiazol-2-yl] azetidine,
Obtained in a yield of 52%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.24 (2H,
d, J = 8.8Hz), 7.75 (1H, s), 7.51 (2H, d, J = 8.8Hz),
5.16-5.10 (1H, br d, J = 5.9Hz), 5.21 (2H, s), 4.8
9-4.80 (1H, m), 4.60-4.10 (4H, m), 4.53 (2H,
t, J = 8.8Hz), 3.99 (2H, dd, J = 9.5, 5.9Hz), 3.98-3.
91 (1H, m), 2.36 (3H, s) Reference Example 76 3-Acetylthio-1- [4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1 , 3-oxazol-2-yl}
Azetidine

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(1) 3-t-butyldiphenylsilyloxy-1- [4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole- 2-yl @ azetidine (3S) -3-amino-1 obtained in Reference Example 52 (4)
-P-Nitrobenzyloxycarbonylpyrrolidine 905m
g (3.41 mmol) and 3-t obtained in Reference Example 70 (11)
-Butyldiphenylsilyloxy-1- (4-carboxyl-1,3-oxazol-2-yl) azetidine 1.
20 g (2.84 mmol) were suspended in 36 ml of dimethylformamide, and 556 μl (3.41 mmol) of diethylphosphoryl cyanide and 478 μl of triethylamine (3.41 mmol) were cooled under ice-cooling under a nitrogen atmosphere.
mmol) and stirred overnight at room temperature. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-
Hexane: ethyl acetate = 1: 2 to 1: 3)
3-t-butyldiphenylsilyloxy-1- [4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] as a pale yellow solid
-1,3-Oxazol-2-yl} azetidine was converted to 936
mg in a yield of 49%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
m), 7.72 (1H, s), 7.63- 7.58 (4H, m), 7.53 (2H,
m), 7.48-7.37 (6H, m), 6.85-6.80 (1H, br t, J =
8.1Hz), 5.24 (2H, d, J = 8.1Hz), 4.75-4.67 (1H,
m), 4.65-4.58 (1H, m), 4.16-4.09 (2H, m), 4.06
(2H, dd, J = 8.8, 5.1Hz), 3.83-3.75 (1H, m), 3.64-
3.46 (2H, m), 3.38 (1H, dd, J = 11.0, 4.4Hz), 2.30
-2.20 (1H, m), 2.04-1.90 (1H, m), 1.06 (9H, s) (2) 3-hydroxy-1- [4-[(3S) -1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine-3
-Ylcarbamoyl] -1,3-oxazol-2-yl} azetidine 3-t-butyldiphenylsilyloxy-1- [4-[(3S) -1- (p-) obtained in Reference Example 76 (1). Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yldazetidine (1.10 g, 1.64 mmol) in anhydrous tetrahydrofuran (55 m).
acetic acid under ice-cooling, 113 μl of acetic acid, (1.97 mmol),
1.97 ml (1.97 mmol) of a 1.0 M solution of tetra-n-butylammonium fluoride-tetrahydrofuran were sequentially added, and the mixture was stirred overnight as it was. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 95: 5) to give 3-hydroxy-1- [4-
[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-
Oxazol-2-yl diazetidine was obtained as a white solid in 687 mg in a yield of 97%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
m), 7.75 (1H, s), 7.52 (2H, m), 6.89-6.82 (1H,
m), 5.27-5.20 (2H, m), 4.84-4.77 (1H, m), 4.66
-4.59 (1H, m), 4.36 (2H, dd, J = 8.8, 7.3Hz), 4.01
(2H, dd, J = 8.8, 5.2Hz), 3.82-3.74 (1H, m), 3.67
-3.52 (3H, m), 3.45-3.39 (1H, m), 2.30-2.20
(1H, m), 2.03-1.93 (1H, m) (3) 3-methanesulfonyloxy-1- [4-[(3
S) -1- (p-Nitrobenzyloxycarbonyl)-
Pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl {azetidine 3-hydroxy-1- [4 obtained in Reference Example 76 (2)
-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3
-Oxazol-2-yl diazetidine 680mg (1.58mm
ol) was dissolved in 34 ml of methylene chloride, and 366 μl (4.73 mmol) of methanesulfonyl chloride and 663 μl (4.73 mmol) of triethylamine were added under ice-cooling. After 10 minutes, the reaction system was returned to room temperature and stirred for 2 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 96: 4) to give 3-methanesulfonyloxy-1- [4-[(3S)-) as a pale yellow solid. 1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine-3
-Ylcarbamoyl] -1,3-oxazol-2-yl} azetidine was obtained in a yield of 760 mg and a yield of 95%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
m), 7.78 (1H, s), 7.52 (2H, m), 6.85-6.80 (1H,
m), 5.42-5.37 (1H, m), 5.24 (2H, d, J = 8.1Hz), 4.
66-4.58 (1H, m), 4.49 (2H, dd, J = 10.3, 6.6Hz),
4.31 (2H, dd, J = 10.3, 4.4Hz), 3.82-3.74 (1H, m),
3.64-3.75 (2H, m), 3.44-3.38 (1H, m), 3.11 (3
H, s), 2.30-2.20 (1H, m), 2.04-1.96 (1H, m) (4) 3-acetylthio-1- [4-[(3S) -1-
(P-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole-2
-Ill @ azetidine 3-methanesulfonyloxy-1- [4-[(3S) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1 obtained in Reference Example 76 (3). , 3-Oxazol-2-yl} azetidine 760
mg (1.49 mmol) was dissolved in 38 ml of dimethylformamide, 1.02 g (8.95 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in an oil bath at 80 ° C for 10.5 hours. After confirming the completion of the reaction,
Ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was saturated with aqueous sodium bicarbonate,
After washing with saturated saline, drying over anhydrous sodium sulfate,
After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 6-ethyl acetate) to give 3-acetylthio-1- [4-[(3S)-as a light brown solid. 1
-(P-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole-
533 mg of 2-yl diazetidine was obtained at a yield of 73%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
m), 7.76 (1H, s), 7.52 (2H, m), 6.87-6.80 (1H, br
s), 5.24 (2H, d, J = 7.3Hz), 4.66-4.58 (1H, m), 4.
56 (2H, t, J = 8.8Hz), 4.44-4.36 (1H, m), 4.03 (2
H, dd, J = 8.8, 5.9Hz), 3.79 (1H, dt, J = 11.0, 6.6H
z), 3.65-3.51 (2H, m), 3.40 (1H, dd, J = 11.0, 4.4
Hz) 2.36 (3H, s), 2.32-2.20 (1H, m), 2.23-1.9
1 (1H, m) Reference Example 77 3-acetylthio-1- [4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole-2- Il
Azetidine

[0780]

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(1) 3-t-butyldiphenylsilyloxy-1- [4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole- 2- (yl) azetidine (3R) -3-amino-1 obtained in Reference Example 53 (5)
-P-Nitrobenzyloxycarbonylpyrrolidine 798m
g (3.01 mmol) and 3-t obtained in Reference Example 70 (11)
-Butyldiphenylsilyloxy-1- (4-carboxyl-1,3-oxazol-2-yl) azetidine 1.
06 g (2.51 mmol) was dissolved in 50 ml of dimethylformamide, and under ice-cooling under a nitrogen atmosphere, 464 μl (3.01 mmol) of diethylphosphoryl cyanide and 422 μl of triethylamine (3.01 mmol)
mmol) and stirred overnight at room temperature. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-
Hexane: ethyl acetate = 1: 2 to 1: 3)
3-t-butyldiphenylsilyloxy as light brown solid
1- [4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl]-
1,3-Oxazol-2-yl diazetidine in 813m
g, 48% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
m), 7.72 (1H, s) 7.63- 7.59 (4H, m), 7.53 (2H, m),
7.48-7.38 (6H, m), 6.86-6.60 (1H, m), 5.24 (2
(H, d, J = 8.1Hz), 4.77-4.68 (1H, m), 4.64-4.58
(1H, m), 4.15-4.09 (2H, m), 4.05 (2H, dd, J = 8.8,
5.1Hz), 3.82-3.75 (1H, m), 3.64-3.49 (2H, m),
3.38 (1H, dd, J = 11.0, 5.1Hz), 2.30-2.20 (1H,
m), 2.06-1.90 (1H, m), 1.06 (9H, s) (2) 3-hydroxy-1- [4-[(3R) -1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine-3
-Ylcarbamoyl] -1,3-oxazol-2-yl} azetidine 3-t-butyldiphenylsilyloxy-1- [4-[(3R) -1- (p-) obtained in Reference Example 77 (1). Nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl {azetidine (810 mg, 1.21 mmol) was added to anhydrous tetrahydrofuran 40
of acetic acid under ice-cooling, 83 μl of acetic acid, (1.45 mmol),
1.45 ml (1.45 mmol) of a 1.0 M tetra-n-butylammonium fluoride-tetrahydrofuran solution was sequentially added, and the mixture was stirred overnight as it was. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate to ethyl acetate: methanol 95: 5) to give 3-hydroxy- as a pale yellow oil.
1- [4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl]-
507 m of 1,3-oxazol-2-yl} azetidine
g, 97% yield. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
m), 7.75 (1H, s), 7.52 (2H, m), 6.89-6.83 (1H, br
s), 5.28-5.20 (2H, m), 4.84-4.76 (1H, m), 4.6
6-4.58 (1H, m), 4.36 (2H, dd, J = 8.8, 6.6Hz), 4.0
1 (2H, dd, J = 8.8, 4.4Hz), 3.82-3.74 (1H, m), 3.6
4-3.51 (2H, m), 3.44-3.37 (1H, m), 2.32-2.20
(1H, m), 2.08-1.92 (1H, m) (3) 3-methanesulfonyloxy-1- [4-[(3
R) -1- (p-Nitrobenzyloxycarbonyl)-
Pyrrolidin-3-ylcarbamoyl] -1,3-oxazol-2-yl {azetidine 3-hydroxy-1- [4 obtained in Reference Example 77 (2)
-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3
-Oxazol-2-yl diazetidine 500mg (1.16mm
ol) was dissolved in 25 ml of methylene chloride, 269 μl (3.48 mmol) of methanesulfonyl chloride and 488 μl (3.48 mmol) of triethylamine were added under ice cooling, and after 10 minutes, the reaction system was returned to room temperature and stirred for 3 hours. After confirming the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate to ethyl acetate: methanol = 96: 4) to give 3-methanesulfonyloxy-1- [4-[(3R)-) as a pale yellow solid. 1- (p
-Nitrobenzyloxycarbonyl) -pyrrolidine-3
-Ylcarbamoyl] -1,3-oxazol-2-yl} azetidine was obtained in a yield of 546 mg and a yield of 92%. Mass spectrum (FAB ⁺ ): m / z: 510 [M + H] ⁺ (4) 3-acetylthio-1- [4-[(3R) -1-
(P-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole-2
-Ill @ azetidine 3-methanesulfonyloxy-1- [4-[(3R) -1- (p-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1 obtained in Reference Example 77 (3). , 3-Oxazol-2-yl} azetidine 540
mg (1.06 mmol) was dissolved in 27 ml of dimethylformamide, 726 mg (6.36 mmol) of potassium thioacetate was added at room temperature, and the mixture was stirred in an oil bath at 80 ° C. for 9 hours. After confirming the completion of the reaction, ethyl acetate and 10% saline were added to the reaction system, and the aqueous layer was separated and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: n-hexane:
(Ethyl acetate = 1: 6 to ethyl acetate) to give 3-acetylthio-1- [4-[(3R) -1-] as a light brown solid.
(P-nitrobenzyloxycarbonyl) -pyrrolidin-3-ylcarbamoyl] -1,3-oxazole-2
-Ildazetidine was obtained in 281 mg in a yield of 54%. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.22 (2H,
m), 7.76 (1H, s), 7.52 (2H, m), 6.86-6.80 (1H,
m), 5.23 (2H, d, J = 7.3Hz), 4.64-4.58 (1H, m), 4.
56 (2H, t, J = 8.8Hz), 4.44-3.86 (1H, m), 4.03 (2
H, dd, J = 8.8, 5.9Hz), 3.79 (1H, dd, J = 11.0, 6.6H
z), 3.65-3.52 (2H, m), 3.40 (1H, dd, J = 11.0, 4.4
Hz), 2.12 (3H, s), 2.32-2.20 (1H, m), 2.23-1.9
2 (1H, m) Test Example 1 In Vitro Antibacterial Activity The antibacterial activity was measured by an agar plate dilution method, and the minimum inhibitory concentration (μg / ml) against various pathogenic bacteria was determined. Table 6 shows the results. In the table, specific bacteria A, B and C are as follows. A: Staphylococcus aureus 209P strain B: Pneumococcus 10664 strain (penicillin resistant strain) C: Haemophilus influenza 9787 strain (β
-Lactamase-producing strain) [Table 6] ------------------------------- μg / ml) Compound Specific test bacteria A B C ----------------- Compound 0.05 0.20 0.10 Compound of Example 4 0.05 0.20 0.20 Compound of Example 5 0.05 0.20 0.20 Compound of Example 6 0.05 0.20 0.20 Compound of Example 19 0.05 0.20 0.10 Compound of Example 22 0.05 0.20 0.10 Compound of Example 24 ≦ 0.012 0.025 0.05 Compound of Example 25 0.025 0.10 0.39 Compound of Example 56 0.05 0.20 0.20 Compound of Example 57 0.025 0.20 0.20 Compound of Example 58 ≦ 0.012 0.20 0.20 Compound of Example 59 ≦ 0.012 0.20 0.20 Compound of Example 60 0.025 0.39 0.39 Compound of Example 61 0.025 0.20 0.39 Compound of Example 67 ≦ 0.012 0.39 0.20 Example Compound of No. 9 ≦ 0.012 ≦ 0.012 0.78 Compound of Example 70 ≦ 0.012 ≦ 0.012 0.78 Compound of Example 71 ≦ 0.012 ≦ 0.012 0.39 Compound of Example 72 ≦ 0.012 0.025 0.20 Compound of Example 76 0.05 0.20 0.39 Compound of Example 80 0.025 0.20 0.39 Compound of Example 81 ≦ 0.012 0.20 0.39 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− The above results Indicates that the compounds of the present invention have strong antibacterial activity. Test Example 2 Pharmacokinetic compound (20 mg / kg) was subcutaneously administered to mice (n = 3, ddy male, SLC) and 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours after administration
Plasma drug concentration at time was measured by bioassay. Table 7 shows the obtained pharmacokinetic parameters.
In the table, Cmax represents the maximum plasma concentration, T1 / 2 represents the plasma half-life, and AUCall represents the area under the plasma concentration curve (versus time). [Table 7] ---------------------------------------------- ------------------- Compound Cmax T1 / 2 AUCall (μg / ml) (hr) (μg · hr / ml) ---------- -------------------------------------------------- ----- Compound of Example 3 127.17 0.25 83.90 Compound of Example 4 157.38 1.02 165.19 Compound of Example 11 56.56 0.33 40.38 Compound of Example 57 48.15 0.38 45.31 Compound of Example 58 63.88 0.41 47.38 Compound of Example 60 46.14 0.30 27.88 Compound of Example 67 40.20 0.45 34.13 Compound of Example 76 52.80 0.19 27.88 ------------------------------- ---------------------------------- Test Example 3 In vivo antibacterial activity (mouse infection treatment experiment) 4 weeks old DdY male mouse (Japan SLC)
0.2 ml of S. pneumoniae 9605 (PRSP) was intraperitoneally inoculated (containing 5% mucin, 1-5 × 10 ³ cfu / mouse), and immediately after infection, the test compound was subcutaneously administered 0.1 ml once. Mouse is 1
Using a group of 7 animals, the test compound was serially diluted 2-fold, and the ED ₅₀ was calculated from the survival rate 7 days later by the probit method.
Table 8 shows the test results. Formulation Example 1 (Injection) 500 mg of the compound of Example 3 is dissolved in 5 ml of distilled water for injection, passed through a filter for sterilization, and then lyophilized to give a lyophilized preparation for injection. Formulation Example 2 (capsule) Compound of Example 24 50 mg Lactose 128 mg Corn starch 70 mg Magnesium stearate 2 mg 250 mg After mixing the powder of the above formulation and passing through a 60-mesh sieve, the powder is placed in a 250 mg No. 3 gelatin capsule. Put into capsules. Formulation Example 3 (tablet) Compound of Example 24 50 mg Lactose 126 mg Corn starch 23 mg Magnesium stearate 1 mg 200 mg The powder of the above formulation was mixed, wet-granulated using corn starch paste, dried, and then compressed using a tablet machine. Then, a tablet of 200 mg per tablet is obtained. The tablets can be sugar-coated if necessary.

[0782]

According to the present invention, 1- having the general formula (I) of the present invention.
Methylcarbapenem compounds or pharmacologically acceptable salts thereof have excellent antibacterial activity and can be used as dehydropeptidase I
And β-lactamase, and high urinary recovery. Furthermore, since it has low renal toxicity, it is useful as a medicine, especially as an antibacterial agent.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/5377 A61K 31/541 31/541 A61P 11/00 A61P 11/00 31/04 31/04 C07D 487 / 04 134 (72) Inventor Osamu Kanno 1-58, Hiromachi, Shinagawa-ku, Tokyo F-term in Sankyo Co., Ltd. 4C050 KA17 KA18 KB05 KB13 KB13 KB16 KC04 KC05 KC07 4C086 AA01 AA02 AA03 CC08 MA01 MA04 NA14 ZA59 ZB35

Claims (31)

[Claims] 1. A compound of the general formula [Wherein R ¹ is a group represented by the formula (1) COOR ³ wherein R ³ is a hydrogen atom, a C1-C6 alkyl group or a C3
—C6 cycloalkyl group], (2) Formula CONR ⁴
A group represented by R ^{5 wherein} R ⁴ and R ⁵ are the same or different and are each a hydrogen atom, a C1-C6 alkyl group (the same or different one or two groups selected from the following substituent group A) ), A C3-C6 cycloalkyl group,
A 3- to 6-membered heterocyclic group or a C6-C10 aryl group (which may be substituted with one or two same or different groups selected from the following substituent group B), or
A group forming a 3- to 6-membered nitrogen-containing heterocycle together with the nitrogen atom to which they are bonded (optionally substituted by one or two same or different groups selected from the following substituent group B) )], (3) a cyano group, (4) a formula CH ₂ O
Group [wherein, R ⁶ is a hydrogen atom, C1-C6 alkyl or C3-C6 cycloalkyl group] represented by R ⁶ or,
(5) a group represented by the formula CH ₂ NR ⁷ R ⁸ wherein R ⁷ represents a hydrogen atom, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group, and R ⁸ represents a hydrogen atom, C1-C6 alkyl Group,
A C3-C6 cycloalkyl group, a C1-C6 alkanoyl group, a C6-C10 arylcarbonyl group (which may be substituted with one or two same or different groups selected from the following substituent group B), C1- C6 alkoxycarbonyl group, 5- or 6-membered aromatic heterocyclic carbonyl group, C1-
Or showing a C6 alkylsulfonyl group or a C6-C10 arylsulfonyl group, or shows a succinimide group (which may be condensed with a phenyl group) R ⁷ and R ⁸ together with the nitrogen atom to which they are attached R ² represents a hydrogen atom or a C1-C6 alkyl group; n represents 1, 2 or 3; and X represents a sulfur atom or an oxygen atom. Substituent group A is
Hydroxyl group, amino group (optionally substituted with one or two C1-C6 alkyl groups), carbamoyl group (amino part may be substituted with one or two C1-C6 alkyl groups), carboxyl Group, cyano group, C1-C
Substituent group B includes a hydroxy C1-C4 alkyl group and an amino C1-C4 alkyl group (the amino portion may be substituted with one or two C1-C6 alkyl groups) A carbamoyl group (an amino moiety may be substituted with one or two C1-C6 alkyl groups), a carboxyl group,
A group consisting of a hydroxyl group, an amino group (which may be substituted with one or two C1-C6 alkyl groups), a C1-C6 alkoxy group, and a C1-C6 alkyl group. Or a pharmacologically acceptable salt or ester derivative thereof. 2. The method of claim 1, wherein R ¹ is of the formula CONR ⁴ R
^A 1-methylcarbapenem compound which is a group represented by ⁵ , a cyano group or a group represented by the formula CH ₂ NR ⁷ R ⁸ , or a pharmaceutically acceptable salt or ester derivative thereof. 3. The method of claim 1, wherein R ¹ is of the formula CONR ⁴ R
^A 1-methylcarbapenem compound which is a group represented by ⁵ or a group represented by the formula CH ₂ NR ⁷ R ⁸ , or a pharmaceutically acceptable salt or ester derivative thereof. 4. The method of claim 1, wherein R ¹ is of the formula CONR ⁴ R
1-methylcarbapenem compound, which is a group represented by ⁵ , or a pharmaceutically acceptable salt or ester derivative thereof. 5. One of the first to fourth aspects
In the above item, 1-methylcarbapenem compound wherein R ² is a hydrogen atom or a C1-C3 alkyl group, or a pharmaceutically acceptable salt or ester derivative thereof. 6. One of the first to fourth aspects
In the above item, 1-methylcarbapenem compound wherein R ² is a hydrogen atom, or a pharmaceutically acceptable salt or ester derivative thereof. 7. One of the first to sixth aspects selected from the above.
In the above item, 1-methylcarbapenem compound wherein R ³ is a hydrogen atom or a C1-C3 alkyl group, or a pharmaceutically acceptable salt or ester derivative thereof. 8. Any one selected from claims 1 to 6
In the above item, 1-methylcarbapenem compound wherein R ³ is a hydrogen atom, a methyl group or an ethyl group, or a pharmaceutically acceptable salt or ester derivative thereof. 9. Any one selected from claims 1 to 8
In the above item, 1-methylcarbapenem compound wherein R ⁴ is a hydrogen atom or a C1-C3 alkyl group, or a pharmaceutically acceptable salt or ester derivative thereof. 10. A 1-methylcarbapenem compound according to claim 1, wherein R ⁴ is a hydrogen atom, methyl or isopropyl group, or a pharmaceutically acceptable salt or ester derivative thereof. 11. The method according to claim 1, wherein R ⁵ is a hydrogen atom, a C1-C6 alkyl group (one or two same or different groups selected from substituent group A). Or a 4- to 6-membered nitrogen-containing heterocyclic group-containing 1-methylcarbapenem compound or a pharmaceutically acceptable salt or ester derivative thereof. 12. The method according to claim 1, wherein R ⁵ is a hydrogen atom, a C1-C6 alkyl group (one or two identical or different groups selected from substituent group A). May be substituted with), azetidinyl,
A 1-methylcarbapenem compound which is a pyrrolidinyl or piperidinyl group, or a pharmaceutically acceptable salt or ester derivative thereof. 13. The compound according to claim 1, wherein R ⁴ and R ⁵ are a group forming a 4- to 6-membered nitrogen-containing heterocyclic ring together with a nitrogen atom to which they are bonded. (The same or different 1 or 2 selected from substituent group B
1-methylcarbapenem compound or a pharmaceutically acceptable salt or ester derivative thereof. 14. The method according to claim 1, wherein R ⁴ and R ⁵ are taken together with the nitrogen atom to which they are attached to form an azetidino, piperazino, morpholino or thiomorpholino group (these being the same). Wherein the group may be substituted with one or two same or different groups selected from substituent group B), or a pharmacologically acceptable salt or ester derivative thereof. 15. The 1-methylcarbapenem compound according to any one of claims 1 to 14, wherein R ⁶ is a hydrogen atom or a C1-C3 alkyl group, or a pharmaceutically acceptable salt or ester derivative thereof. . 16. A 1-methylcarbapenem compound according to any one of claims 1 to 14, wherein R ⁶ is a hydrogen atom, or a pharmaceutically acceptable salt or ester derivative thereof. 17. A 1-methylcarbapenem compound according to any one of claims 1 to 16, wherein R ⁷ is a hydrogen atom or a C1-C3 alkyl group, or a pharmaceutically acceptable salt or ester derivative thereof. . 18. The 1-methylcarbapenem compound according to claim 1, wherein R ⁷ is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt or ester derivative thereof. 19. The 1-methylcarbapenem compound according to any one of claims 1 to 16, wherein R ⁷ is a hydrogen atom, or a pharmacologically acceptable salt or ester derivative thereof. 20. The method according to any one of claims 1 to 19, wherein R ⁸ is a hydrogen atom, a C1-C3 alkyl group, a C1-3 alkanoyl group, a benzoyl group (selected from substituent group B). A 1-methylcarbapenem compound which is a C1-C3 alkoxycarbonyl group, a thiophenecarbonyl group, a furancarbonyl group or a pyridinecarbonyl group, or a pharmacologically acceptable thereof. Salt or ester derivatives. 21. The method according to any one of claims 1 to 19, wherein R ⁸ is a hydrogen atom, a benzoyl group (substituted by one or two same or different groups selected from substituent group B). Thiophene-2-carbonyl group, furan-2-carbonyl group or pyridine-3
-A 1-methylcarbapenem compound which is a carbonyl group or a pharmacologically acceptable salt or ester derivative thereof. 22. A 1-methylcarbapenem compound wherein n is 1 or a pharmacologically acceptable salt or ester derivative thereof according to any one of claims 1 to 21. 23. The 1-methylcarbapenem compound according to any one of claims 1 to 22, wherein X is an oxygen atom, or a pharmaceutically acceptable salt or ester derivative thereof. 24. The method of claim 1, wherein R ¹ is of the formula CONR ⁴ R
A group represented by ⁵ wherein R ⁴ is a hydrogen atom or C1-C3
An alkyl group, wherein R ⁵ is a hydrogen atom, a C1-C6 alkyl group (which may be substituted with one or two same or different groups selected from substituent group A), or a 4- to 6-membered nitrogen-containing heterocyclic group; A 1-methylcarbapenem compound or a pharmaceutically acceptable salt or ester derivative thereof, wherein R ² is a hydrogen atom, n is 1, and X is an oxygen atom or a sulfur atom. 25. The method of claim 1, wherein R ¹ is of the formula CONR ⁴ R
Group (wherein, represented by ^5, R ⁴ is a hydrogen atom, a methyl or isopropyl group, R ⁵ is a hydrogen atom, the same or different 1 or 2 are selected from C1-C6 alkyl group (substituent group A ), Azetidinyl,
A pyrrolidinyl or piperidinyl group), and n
Is 1 and X is an oxygen atom or a sulfur atom, or a pharmacologically acceptable salt or ester derivative thereof. 26. The method of claim 1, wherein R ¹ is of the formula CONR ⁴ R
A group represented by ⁵ (wherein R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen-containing heterocycle (the same or selected from substituent group B) Or a 1-methylcarbapenem compound wherein R ² is a hydrogen atom, n is 1, and X is an oxygen atom or a sulfur atom, or A pharmacologically acceptable salt or ester derivative thereof. 27. The method of claim 1, wherein R ¹ is of the formula CONR ⁴ R
A group represented by ^{5 wherein} R ⁴ and R ⁵ are taken together with the nitrogen atom to which they are attached to an azetidino, piperazino, morpholino or thiomorpholino group (these groups being identical groups selected from substituent group B) Or 1-methylcarbapenem compound wherein R ² is a hydrogen atom, n is 1 and X is an oxygen atom or a sulfur atom. Or a pharmacologically acceptable salt or ester derivative thereof. 28. The 1-methylcarbapenem compound according to claim 1, wherein R ¹ is a cyano group, R ² is a hydrogen atom, n is 1, and X is an oxygen atom or a sulfur atom, or a pharmacologically active compound thereof. Acceptable salt or ester derivatives. 29. The method of claim 1, wherein R ¹ is of the formula CH ₂ NR ⁷
A group represented by R ⁸ , wherein R ⁷ is a hydrogen atom or C1-3
An alkyl group, wherein R ⁸ is a hydrogen atom, a C1-C3 alkyl group, a C1-3 alkanoyl group, a benzoyl group (even when substituted with one or two same or different groups selected from substituent group B) good), C1-C3 alkoxycarbonyl group, a thiophene group, a furan group or pyridine carbonyl group), R ² is a hydrogen atom, n is 1, X is an oxygen atom or a sulfur atom 1-methylcarbapenem compound or a pharmaceutically acceptable salt or ester derivative thereof. 30. The method of claim 1, wherein R ¹ is of the formula CH ₂ NR ⁷
A group represented by R ⁸ (wherein R ⁷ is a hydrogen atom or a methyl group, and R ⁸ is a hydrogen atom, a benzoyl group (substituent group B
Thiophene-2-carbonyl group, which may be substituted with one or two same or different groups selected from
A furan-2-carbonyl group or a pyridine-3-carbonyl group), R ² is a hydrogen atom, and n is 1
A 1-methylcarbapenem compound wherein X is an oxygen atom or a sulfur atom, or a pharmaceutically acceptable salt or ester derivative thereof. 31. A 1-methylcarbapenem compound selected from the following compounds, or a pharmaceutically acceptable salt or ester derivative thereof. (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl]-
1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-carbamoyl-1,3-oxazol-2-yl) azetidine-3-
Yl] thio-6-[(1R) -1-hydroxyethyl]
-1-Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-hydroxymethyl-1,3-thiazol-2-yl) azetidine-3
-Yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-hydroxymethyl -1,3-oxazol-2-yl) azetidine-
3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-cyano -1,
3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-cyano-1,
3-oxazol-2-yl) azetidin-3-yl]
Thio-6-[(1R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6 -[(1R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-morpholinocarbonyl-1,3-oxazole -2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em -3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-azetidinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- [4- (4-aminoazetidino) carbonyl-1,3-thiazol-2-yl]
Azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- [4 -(4-Aminoazetidino) carbonyl-1,3-oxazol-2-yl] azetidin-3-yl] thio-6-[(1R) -1-
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- [4- (4-hydroxyazetidino) carbonyl-1,3-thiazole-2 −
Yl] azetidin-3-yl] thio-6-[(1R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
M-3-carboxylic acid (1R, 5S, 6S) -2- [1- [4- (4-hydroxyazetidino) carbonyl-1,3-oxazole-2
-Yl] azetidin-3-yl] thio-6-[(1R)-
1-hydroxyethyl] -1-methyl-carbapene-2
-M-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-thiazol-2-yl) azetidin-3-yl] thio-6-[(1R ) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-
carboxylic acid. (1R, 5S, 6S) -2- [1- (4-thiomorpholinocarbonyl-1,3-oxazol-2-yl) azetidin-3-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3
-Carboxylic acid (1R, 5S, 6S) -2- {1- [4- (piperidin-4-ylcarbamoyl) -1,3-thiazole-2-
Yl] azetidin-3-yl {thio-6-[(R) -1-]
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (piperidin-4-ylcarbamoyl) -1,3-oxazole-2
-Yl] azetidin-3-yl {thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
M-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (azetidin-3-ylcarbamoyl) -1,3-thiazole-2-
Yl] azetidin-3-yl {thio-6-[(R) -1-]
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (azetidin-3-ylcarbamoyl) -1,3-oxazole-2
-Yl] azetidin-3-yl {thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
M-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((3S)-
Pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((3S)-
Pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((3R)-
Pyrrolidin-3-ylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((3R)-
Pyrrolidin-3-ylcarbamoyl) -1,3-oxazol-2-yl] azetidin-3-yl {thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (piperazine-1-carbonyl) -1 , 3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3
-Carboxylic acid (1R, 5S, 6S) -2- {1- [4- (piperazine-1-carbonyl) -1,3-oxazol-2-yl]
Azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-m-
3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1,3-thiazol-2-yl] azetidin-3-yl} thio-6- [ (R) -1-Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (2-amino-ethylcarbamoyl) -1 , 3-oxazole-2-
Yl] azetidin-3-yl {thio-6-[(R) -1-]
Hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((1S)-
1-aminomethyl-2-methyl-propylcarbamoyl) -1,3-thiazol-2-yl] azetidine-3
-Ill @ thio-6-[(R) -1-hydroxyethyl]-
1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4-((1S)-
1-aminomethyl-2-methyl-propylcarbamoyl) -1,3-oxazol-2-yl] azetidine-
3-yl @ thio-6-[(R) -1-hydroxyethyl]
-1-Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- [4-[(2-amino-ethyl) -isopropyl-carbamoyl) -1,3-
Thiazol-2-yl] azetidin-3-yl {thio-
6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- [4-[(2-amino-ethyl ) -Isopropyl-carbamoyl) -1,3-
Oxazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-
Carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- [4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl) -1,
3-thiazol-2-yl] azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- [4-[(2-hydroxy-ethyl) -isopropyl-carbamoyl) -1,
3-Oxazol-2-yl] azetidin-3-yl}
Thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-aminomethyl-1, 3-thiazol-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-
Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- [1- (4-aminomethyl-1,3-oxazol-2-yl) azetidine-3-
Yl] thio-6-[(R) -1-hydroxyethyl] -1
-Methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-thiazol-2-yl] azetidine-3- Yl @ thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3
-Carboxylic acid (1R, 5S, 6S) -2- {1- [4- (benzoylamino-methyl) -1,3-oxazol-2-yl]
Azetidin-3-yl {thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-m-
3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-thiazole-2-
Yl] azetidin-3-yl] thio-6-[(R) -1-
Hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid (1R, 5S, 6S) -2- {1- [4- (benzenesulfonylamino-methyl) -1,3-oxazole-2
-Yl] azetidin-3-yl] thio-6-[(R) -1
-Hydroxyethyl] -1-methyl-carbapene-2-
Em-3-carboxylic acid (1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) methyl] -1,3-thiazol-2-yl} azetidin-3-yl ) Thio-6
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- {4-[(thiophen-2-carbonyl-amino) ) Methyl] -1,3-oxazol-2-yl {azetidin-3-yl) thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (1R, 5S, 6S) -2- (1- {4-[(furan-2
-Carbonyl-amino) methyl] -1,3-thiazole-
2-yl {azetidin-3-yl) thio-6-[(R)
-1-hydroxyethyl] -1-methyl-carbapene-
2-M-3-carboxylic acid (1R, 5S, 6S) -2- (1- {4-[(furan-2
-Carbonyl-amino) methyl] -1,3-oxazol-2-yl {azetidin-3-yl) thio-6-
[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid