JPH09165388A - Carbapenem compound, its production and drug - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new carbapenem compound useful as an antibacterial drug having high antimicrobial activity, safety and oral absorption ability against a variety of pathogenic bacterias such as gram-positive and gram-nega tive bacteria, etc., by reaction of a specific carbapenem compound with a com pound containing a mercapto group. SOLUTION: This compound is a new carbapenem compound of formula I [R<1> is a substituted lower alkyl; R<2> is H or a lower alkyl; Y stands for a linkage or a substituted lower alkylene; W is a moiety or the like of formula II (Ring A is a pyrimidine ring which may be hydrogenated or substituted; X is a substituted hetero atom and may form a ring in combination with a nitrogen atom constituting the ring A)] and useful as an antibacterial drug having excellent antibacterial activity, safety and oral absorption property against a wide rang of pathogenic bacterial such as gram-positive and gram-negative bacteria, etc. This compound is obtained by reacting a carbapenem compound of formula III (L is an eliminating group) with a compound of formula: HS-Y-W containing a mercapto group.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel carbapenem compound which has an excellent antibacterial activity and can be administered not only as an injection but also orally, its production method and an antibacterial agent.

[0002]

2. Description of the Related Art There have been many reports on carbapenem antibiotics represented by thienamycin.
Although thienamycin has excellent antibacterial activity, it is dehydropeptidase-I, a degrading enzyme present in the body.
Due to problems such as instability to (DHP-I), it was not applied clinically. It is known that imipenem, an analog of thienamycin, exhibits a clinical effect when used in combination with cilastatin, an inhibitor of DHP-I. After that, a lot of research was done,
It has been shown that a carbapenem compound having improved antibacterial activity and DHP-I stability can be obtained by introducing a methyl group at the 1β-position and a 3-pyrrolidinylthio group at the 2-position of the carbapenem (Japanese Patent Application Laid-Open No. Sho 60). 233076, JP-A-5-4988, etc.). However, there are very few studies on the carbapenem having a 5-pyrimidylthio group which may be hydrogenated at the 2-position of the carbapenem, and it cannot be said that its characteristics have been sufficiently clarified. For example, JP-A-57-158784 discloses a general formula

Embedded image [Wherein, R ¹ represents a hydrogen atom or a —CR ⁴ R ⁵ R ⁶ group (wherein,
R ⁴ is hydrogen, hydroxyl or protected hydroxyl; R ⁵ and R ⁶ are hydrogen, alkyl, alkenyl, alkynyl, aralkyl or aryl; or R ⁵ and R ⁶ are Indicates that together they form a ring with adjacent carbon atoms. );
R ² represents a hydrogen atom or a carboxyl protecting group; R ³ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, an aryl group or a —SO ₂ R ⁷ group
⁷ represents a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group or an aryl group. )
The; Z is oxygen atom, sulfur atom or -N (R ⁸⁾ - group (wherein, R ⁸ has the same meaning as R ^3.) The; m is 0 or 1; n is 0, 1, 2 Or 3 is indicated. ] A carbapenem compound represented by the following and a salt thereof are disclosed,
In that example 2 (1H) -oxo-3,4,5,6-
A compound having a tetrahydropyrimidin-5-ylthio group at the 2-position of the carbapenem is specifically described.

Further, JP-A-58-198486 discloses a general formula

Embedded image [In the formula, R ¹ is a hydrogen atom, an alkyl group, an alkoxy group or an R ⁵ A-group (in the formula, R ⁵ is a hydroxyl group, an alkoxy group, an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a trialkylsilyloxy group. Group, a mercapto group, an alkylthio group, an amino group or an acylamino group, and A represents an alkylene group which may be substituted with a trifluoromethyl group or a phenyl group.)
R ² represents a hydrogen atom, an alkyl group, a cycloalkyl group or an alkyl group substituted with a lower alkoxy group, a cyano group, an alkoxycarbonyl group or a halogen atom, and R ³ represents a hydrogen atom or an alkyl group, R ⁴ represents a hydrogen atom or a protective group for a carboxyl group, X represents a methylene or a sulfur atom, m represents 0 to 3, and n represents 1 to 3. ] The carbapenem compound represented by these and its pharmacologically acceptable salt are disclosed, and among them, 2-methyl-3,4,5,6-
A compound having a tetrahydropyrimidin-5-ylthio group at the 2-position of the carbapenem is specifically described.

Further, Japanese Patent Laid-Open No. 60-132985 discloses the formula

Embedded image Compounds and pharmaceutically acceptable salts thereof

Embedded image R is hydrogen or alkyl having 1 to 6 carbons. ) Are disclosed in the examples, and 2-amino-3,4,
A compound having a 5,6-tetrahydropyrimidin-5-ylthio group at the 2-position of the carbapenem is specifically described. And, in JP-A-60-202886, the general formula

Embedded image [In the formula, R ¹ and R ² are the same or different hydrogen atoms,
(Provided that R ¹ and R ² are both hydrogen atoms), unsubstituted or substituted alkyl having 1 to 10 carbons, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl or R ¹ and R ² together 3
To a group forming a 6-membered ring, or a halogen atom, R ³ is 1 to 3 ring carbon atoms having the same or different nitrogen, oxygen,
An unsubstituted or substituted 4- to 8-membered ring which may be mediated by a sulfur atom, sulfinyl, sulfonyl or carbonyl group, R ⁴ is a hydrogen atom or a protecting group for a carboxy group, and R ⁵ is a hydrogen atom or a carbon number of 1 ~ 6 represent unsubstituted or substituted alkyl or alkoxy groups. ] And a pharmaceutically acceptable salt thereof are disclosed, the substituent at the 2-position of the pyrimidine ring of the specifically described compound having a pyrimidine ring at the 2-position of the carbapenem is methyl, Only ethyl, methoxymethyl, cyanomethyl, benzyl, isopropyl and fluoromethyl.

[0005]

Conventional carbapenem compounds generally exhibit antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, but their antibacterial activities are not sufficient,
There are problems with physicochemical properties and stability in the body, especially stability against renal dehydropeptidase-1 (DHP-1) and the like. Therefore, the appearance of a highly safe carbapenem compound which has excellent antibacterial activity, shows stable and excellent pharmacokinetics in vivo, and can be used orally in some cases, has been strongly desired.

[0006]

Means for Solving the Problems As a result of intensive investigations, the inventors of the present invention have found that the conventionally known carbapenem 2
Position (1) 2-substituted heteroatom-3,4,5,6-tetrahydropyrimidin-5-ylthio group and (2) optionally substituted 2-oxoperhydropyrimidine-5-
Ilthio, 2-thioxoperhydropyrimidin-5-ylthio, 2-oxoperhydrooxazin-5-ylthio, 2-thioxoperhydrooxazin-5-ylthio, 2-oxoperhydrothiazin-5-ylthio or 2 -A compound with a thioxoperhydrothiazin-5-ylthio group introduced was synthesized for the first time, and this compound unexpectedly changed from a Gram-positive bacterium containing Pseudomonas aeruginosa to a Gram-negative bacterium based on its unique chemical structure. It has been found that it exhibits excellent antibacterial activity against a wide range of pathogenic bacteria, chemical stability and in vivo stability, particularly stability against DHP-I, and in some cases, excellent oral absorption and the like, and based on these findings And completed the present invention.

That is, the present invention is of the formula (I):

Embedded image [Wherein R ¹ is an optionally substituted lower alkyl group, R ² is a hydrogen atom or a lower alkyl group, Y is a bond or an optionally substituted lower alkylene group, and W is
Is the expression

Embedded image (In the formula, ring A is a pyrimidine ring which may be hydrogenated or may be substituted, X represents a substituted hetero atom, and X represents a ring together with a constituent nitrogen atom of ring A. May be formed) or a group or formula represented by

Embedded image (In the formula, Q represents NH, an oxygen atom or a nitrogen atom, X ′ represents an oxo group or a thioxo group, and ring A ′ may be substituted, provided that Q is NH and X is an oxo group. And R ² represents a lower alkyl group.). ] The carbapenem compound represented by these, its ester, or its salt (it may be abbreviated as compound (I) hereafter), (2) Formula (Ia):

Embedded image [The symbols in the formula are as defined above. ] The compound according to (1) above, which is a carbapenem compound represented by:

(3) Formula (Ib):

Embedded image [The symbols in the formula are as defined above. ] The carbapenem compound represented by the following or its ester or its salt, The compound of the said (1) description, (4) Formula (Ia-1):

Embedded image [In the formula, X ¹ represents a substituted hetero atom, and other symbols have the same meanings as described above. ] The compound represented by the above (2) which is a compound represented by the following, or an ester thereof, or a salt thereof, (5) formula (Ia-2):

Embedded image [In the formula, X ² represents a hetero atom, ring B represents an optionally hydrogenated hetero ring, and other symbols have the same meanings as described above. ] The compound represented by the above (2), which is a compound represented by the following formula or an ester thereof, or a salt thereof, (6) Formula (II):

Embedded image [Wherein, L represents a leaving group, and other symbols have the same meanings as described above. ] The compound represented by these, its ester, or its salt, and a formula (III): HS-Y-W [The symbol in a formula shows the same meaning as the above. ] The compound or its salt represented by these is made to react, The manufacturing method of the compound of the said (1) description, (7) The pharmaceutical containing the compound of the said (1), and (8) antibacterial agent The present invention also relates to the drug etc. described in (7) above.

The compound (I) of the present invention has an excellent antibacterial action against a wide range of pathogenic bacteria ranging from Gram-positive bacteria to Gram-negative bacteria, has excellent chemical properties and stability against DHP-1, and can be injected subcutaneously or Shows antibacterial activity by oral administration. In the above formula, the lower alkyl group of the optionally substituted lower alkyl group represented by R ¹ is, for example, a linear or branched C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl). , Butyl, isobutyl, etc.) and the like, and examples of the substituent thereof include cyano group, amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, dimethylamino, etc.), hydroxyl group, C _{1 -4} alkyloxy group (eg, methoxy, ethoxy, etc.), carbamoyloxy group, C _1-4 alkylthio group (eg, methylthio, ethylthio, etc.), C _1-4 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.) , halogen (e.g., fluoro, chloro, bromo, etc.), a sulfamoyl group, C _1-4 alkoxy - carbonyl group (e.g., methoxycarbonyl Ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl), and the like sulfoxy group. The number of such substituents is preferably 1 to 3,
In the case of a plurality of substituents, they may be the same or different. When the lower alkyl group is substituted with an amino group or a hydroxyl group, these may be protected with a protecting group which can be easily removed. As such a protecting group, a silyl group such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl, allyloxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl and p-nitrobenzyloxycarbonyl are preferred.

More preferably, R ¹ is of the formula

Embedded image [Wherein, R ³ represents a hydrogen atom, a halogen, or a hydroxyl group or an amino group which may be substituted, respectively]. As the substituent for the hydroxyl group or amino group represented by R ³ , for example, the above-described removable protecting groups for those groups and the like are used.
R ³ is more preferably a hydroxyl group or the like. Particularly preferred as R ¹ is a (1R) -hydroxyethyl group. When a carboxyl group is present in the carboxyl group at carbapenem 3-position or another substituent, they may be esterified. The esterified carboxyl group is represented by COOR ⁴ . The ester residue of the carboxyl group, that is, R ⁴ is, for example, an ester residue used in the field of β-lactams such as cephalosporin, and other than the ester residue used as a synthetic intermediate, for example, cephalosporin At the 4-position of the skeleton, an ester residue that is commonly used as a group that forms an ester that can be easily eliminated in vivo (ester that can be a so-called prodrug) and a group that is commonly used as an ester residue of a carboxylic acid in the pharmaceutical field, etc. Is mentioned.
Specifically, for example, an optionally substituted C _1-7 alkyl group, C _2-6 alkenyl group, C _6-10 aryl group, C _7-20 aralkyl group or the like is used. Examples of such an optionally substituted C _1-7 alkyl group include methyl, ethyl, propyl, isopropyl, butyl and t-butyl, and examples of the C _2-6 alkenyl group include vinyl, allyl and crotyl. , C _6-10 aryl groups include phenyl and naphthyl, and C _7-20 aralkyl groups include benzyl, phenethyl, benzhydryl,
Trityl or the like is used.

Further, as R ⁴ , the formula:

Embedded image [Wherein R ⁵ is a hydrogen atom or an optionally substituted C _1-6 alkyl group or a C _3-6 cycloalkyl group, and R ⁶ is an optionally substituted C _1-10 alkyl group, C _3-10 cycloalkyl group, C _1-10 alkyloxy group, C _3-10 cycloalkyloxy group, C _3-10 cycloalkyl C _1-6 alkyl group, C _3-10 cycloalkyl C _1-6 alkyloxy group , C _2-6 alkenyl group, C _6-10 aryl group or C _{7- 12} a group represented by the aralkyl group showing a] can also advantageously be employed. In the above formula, as the C _1-6 alkyl group represented by R ⁵ , for example, methyl, ethyl, propyl, isopropyl, butyl, 2,2-dimethylpropyl and the like, and as the C _3-6 cycloalkyl group, for example, cycloalkyl Propyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are used. Examples of the alkyl group of the C _1-10 alkyl group and the C _1-10 alkyloxy group represented by R ⁶ include methyl, ethyl, propyl,
Isopropyl, n-butyl, sec-butyl, tert
-Butyl, pentyl, 2,2-dimethylpropyl, hexyl, peptyl, decyl and the like are a C _3-10 cycloalkyl group, a C _3-10 cycloalkyloxy group, a C _3-10 cycloalkyl C _1-6 alkyl group, And C _3-10 cycloalkyl C
Examples of the cycloalkyl group of the _1-6 alkyloxy group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like, and C _3-10 cycloalkyl C _1-6
As the alkyl group and the C _1-6 alkyl group of the C _3-10 cycloalkyl C _1-6 alkyloxy group, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like are used. Vinyl as the C _2-6 alkenyl group,
Allyl, crotyl and the like are used, as the C _6-10 aryl group, phenyl and naphthyl are used, and as the C _7-12 aralkyl group, benzyl and phenethyl are used. A C _1-7 alkyl group which may be substituted, represented by R ⁴ ,
_2-6 alkenyl group, C _6-10 aryl group, or C _7-20
An aralkyl group, an optionally substituted C _1-6 alkyl group or a C _3-6 cycloalkyl group represented by R ⁵ , and an optionally substituted C ₆ each represented by R ⁶
_1-10 alkyl group, C _3-10 cycloalkyl group, C _1-10 alkyloxy group, C _3-10 cycloalkyloxy group, C _3-10
Cycloalkyl C _1-6 alkyl group, C _3-10 cycloalkyl C _1-6 alkyloxy group, C _2-6 alkenyl group, C _6-10
Examples of the substituent in the aryl group or the C _7-12 aralkyl group include a cyano group, a nitro group, a hydroxyl group, a C _1-4 alkyl-oxy group (eg, methoxy, ethoxy, propoxy, etc.), a carbamoyloxy group,
_1-4 alkyl-thio groups (eg, methylthio etc.), halogens (eg, fluoro, chloro, bromo etc.) and the like can be mentioned. The number of such substituents is preferably 1 to 3, and in the case of a plurality of substituents, they may be the same or different.

The particularly preferred ester residue represented by R ⁴ is a group often used in the manufacturing process of pharmaceuticals (eg, methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tertiary butyl group, 2,2). , 2-
Trichloroethyl group, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, o-nitrobenzyl group,
Phenethyl group, bis (methoxyphenyl) methyl group, p
-Methoxybenzyl group, 3,4-dimethoxybenzyl group, benzhydryl group, trityl group, trimethylsilyl group, 2-trimethylsilylethyl group, or allyl group), or a biologically unstable ester suitable for oral administration Groups that give derivatives (for example, acetoxymethyl group, 1-acetoxyethyl group, 1-acetoxypropyl group, pivaloyloxymethyl group, isopropyloxycarbonyloxymethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, cyclohexyloxy Carbonyloxymethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, ethoxycarbonyloxymethyl group, 1- (ethoxycarbonyloxy) ethyl group, phthalidyl group, (2-oxo-5-methyl-1,3
-Dioxol-4-yl) methyl group and the like).

As a salt of the compound represented by the above formula or an ester thereof, a pharmacologically or synthetically acceptable salt is preferably used. Such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids,
Salts with organic acids, salts with basic or acidic amino acids and the like are used. Inorganic bases capable of forming these salts include alkali metals (eg, sodium, potassium, etc.),
Alkaline earth metals (eg, calcium, magnesium, etc.), and organic bases such as trimethylamine, triethylamine, pyridine, picoline, N, N ′
-Dibenzylethylenediamine, ethanolamine, diethanolamine, tris (hydroxymethylamino)
Methane, dicyclohexylamine, and the like; inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, and maleic acid Acids, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like are used, and examples of basic or acidic amino acids include arginine, lysine, ornithine, aspartic acid, glutamic acid and the like. Of these salts, salts with bases (that is, salts with inorganic bases, salts with organic bases, salts with basic amino acids) are the compounds (I), (Ia), (Ib), (I
a-1) and a carboxyl group represented by COOH of (Ia-2) or compounds (I), (Ia) and (I)
-B) means a salt that can be formed when an acidic group such as a carboxyl group is present in the ester residue or the substituent, and a salt with an acid (that is, a salt with an inorganic acid, a salt with an organic acid, an acidic amino acid) Is a compound (I), (Ia), (Ib),
It means a salt that can be formed when a basic group such as an amino group is present in (Ia-1) and (Ia-2) or an ester thereof.

A hydrogen atom or a lower alkyl group is used as R ^{2 in the} above formula. As the lower alkyl group, a C _1-3 alkyl group or the like is preferably used. As such a C _1-3 alkyl group, methyl, ethyl, propyl or isopropyl can be used, and a methyl group is particularly preferable. As Y in the above formula, a bond or a lower alkylene group which may be substituted is used. As the lower alkylene, a C _1-3 alkylene group or the like is preferably used. Examples of such a C _1-3 alkylene group include methylene, ethylene and propylene. Examples of the substituent of the lower alkylene group include a halogen (eg, fluoro, chloro, bromo), a hydroxy group, a C _1-6 alkyloxy group (eg, methoxy,
Ethoxy), an amino group, a mono- or di-C _1-4 alkylamino group (eg, dimethylamino), and the number is preferably 1 or 2. Y is more preferably a bond.

Ring A in the above formula represents an optionally hydrogenated pyrimidine ring. Examples of ring A include pyrimidine, 1,2-dihydropyrimidine, 1,6-dihydropyrimidine, 4,5-dihydropyrimidine, 2,6-dihydropyrimidine, 1,2,3,4-tetrahydropyrimidine,
1,2,5,6-tetrahydropyrimidine, 1,4,5,6-
Tetrahydropyrimidine or perhydropyrimidine and the like can be used. Ring A is preferably pyrimidine or 1,4,5,6-tetrahydropyrimidine, and more preferably 1,4,5,6-tetrahydropyrimidine. The optionally hydrogenated pyrimidine ring represented by ring A may have a substituent other than X and Y on the ring-constituting carbon atom and / or the ring-constituting nitrogen atom. Examples of such a substituent include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), a C _6-10 aryl group (eg, phenyl, tolyl, naphthyl, etc.) and the like. , The number is 1 or 2
And those substituents are, for example, halogen (eg, fluoro, chloro, bromo, etc.), hydroxy group, C _1-6 alkyloxy group (eg, methoxy, ethoxy, etc.), amino group, mono- or di- It may be further substituted with 1 to 3 substituents such as C _1-4 alkylamino group (eg, methylamino, dimethylamino, etc.). Ring A may be substituted on the ring-constituting nitrogen atom with 1 or 2 C _1-4 alkyl groups (eg, methyl, etc.),
An optionally hydrogenated pyrimidine ring is preferred.

Substituent X represents a substituted heteroatom,
You may form a ring with the nitrogen atom which comprises ring A. X ¹ represents a substituted hetero atom, and X ² represents a hetero atom. Examples of the hetero atom in X, X ¹ and X ² include O, S and N. The substituted heteroatoms of X and X ¹ represent, for example, a substituted hydroxyl group, mercapto group, amino group or imino group. "Substituted heteroatom" represented by X
Is a group which controls the electron density of the pyrimidine ring represented by ring A (that is, an electron-withdrawing group or an electron-donating group), the substituent of the “substituted heteroatom” represented by X is not particularly limited. As such a substituent, for example, an optionally substituted hydrocarbon group, heterocyclic group, acyl group or the like is used. Examples of the hydrocarbon group in the optionally substituted hydrocarbon group include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.), a C _6-10 aryl group (eg, , Phenyl, naphthyl etc.), C _7-12 aralkyl group (eg benzyl, phenethyl etc.), C _3-6 alkenyl group (eg allyl, crotyl etc.), C _3-6 alkynyl group (eg propargyl etc.) etc. Can be raised. Substituents for these hydrocarbon groups include, for example, cyano group, amino group, mono- or di-C _1-4 alkyl (eg, methyl, ethyl, isopropyl, etc.) amino group, hydroxyl group, C _1-4 alkyloxy group ( (Eg, methoxy, ethoxy, etc.), carbamoyloxy group, C _1-4 alkylthio group (eg, methylthio, ethylthio, etc.), C _1-4 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), halogen (eg,
Fluoro, chloro, bromo, etc.), sulfamoyl group,
C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), sulfooxy group or 1 to 4 heteroatoms such as nitrogen atom, oxygen atom, and sulfur atom.
And a 4- to 6-membered heterocyclic group and the like. The number of such substituents is preferably 1 to 3, and in the case of a plurality of substituents, they may be the same or different.

Examples of the heterocyclic group which may be substituted include 4- to 6-membered heterocyclic groups containing 1 to 4 heteroatoms such as nitrogen atom, oxygen atom and sulfur atom. , These may be condensed with 1 or 2 benzene rings or other heterocycles (eg, 4- to 6-membered heterocycles containing 1 to 4 heteroatoms such as nitrogen atom, oxygen atom, sulfur atom) Good. Substituents for these heterocyclic groups include, for example, C _1-6 alkyl groups (eg, methyl, ethyl, etc.), C _6-10 aryl groups (eg, phenyl, etc.),
Cyano group, amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, dimethylamino, etc.), hydroxyl group, C _1-4 alkyl-oxy group (eg, methoxy, ethoxy, etc.), carbamoyloxy group , A C _1-4 alkyl-thio group (eg, methylthio, ethylthio, etc.),
C _1-4 alkyl-sulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), halogen (eg, fluoro, chloro, bromo, etc.), sulfamoyl group, C _1-4
Alkoxy-carbonyl group (eg, methoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), sulfooxy group and the like. The number of such substituents is preferably 1 to 3
In the case of multiple substituents, they may be the same or different. Examples of the acyl group include a C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, etc.), a halogeno C _1-6 alkyl-carbonyl group (eg, trifluoromethylcarbonyl, etc.), a C _1-6 alkoxy-carbonyl group. (Eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), C _6-10 aryl-carbonyl group (eg, benzoyl etc.), C _7-12 aralkyl-carbonyl group (eg, benzylcarbonyl etc.), nitrogen atom , 1 to 4 heteroatoms such as oxygen, sulfur, etc. 4
To 6-membered heterocyclic carbonyl group, carbamoyl group, mono- or di-C _1-4 alkyl (eg, methyl, ethyl, isopropyl, etc.) carbamoyl group, C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propyl) Sulfonyl, butylsulfonyl, etc.), C _6-10 arylsulfonyl group (eg, phenylsulfonyl, etc.),
Examples thereof include a C _7-12 aralkylsulfonyl group (eg, benzylsulfonyl etc.), a 4- to 6-membered heterocyclic sulfonyl group containing 1 to 4 heteroatoms such as nitrogen atom, oxygen atom and sulfur atom.

The above-mentioned "4 containing 1 to 4 heteroatoms"
"6- to 6-membered heterocyclic group", "4- to 6-membered heterocyclic carbonyl group containing 1 to 4 heteroatoms" and "4- to 6-membered heterocyclic sulfonyl group containing 1 to 4 heteroatoms" Examples of the "4- to 6-membered heterocyclic group containing 1 to 4 hetero atoms" include azetidine, furan, pyrrole, thiophene, thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, thiadiazole, triazole,
Examples include groups obtained by removing hydrogen from a heterocycle such as tetrazole, pyridine, pyrimidine, pyridazine, triazine, morpholine, quinuclidine, or a structurally possible hydrogenated product thereof. Further, in the case where X and X ¹ are a substituted amino group or a substituted imino group, in addition to those exemplified as the substituents of X and X ¹ above, a C _1-4 alkyl-sulfonyl group (eg, , Methylsulfonyl, ethylsulfonyl, etc.), mono- or di-C _1-4 alkyl (eg, methyl, ethyl, isopropyl, etc.) sulfamoyl group, C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Butoxycarbonyl), cyano group, nitro group, amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, dimethylamino, etc.), hydroxyl group, C _1-4 alkyl-oxy group (eg, methoxy, Ethoxy, propoxy, etc.) can also be used. The substituted amino group has 1 or 2 substituents, and in the case of 2 substituents, they may be the same or different. Ring B contains 1 to 4 nitrogen atoms,
Other than that, a 5- to 7-membered optionally hydrogenated heterocycle containing 1 to 3 heteroatoms such as oxygen atom or sulfur atom is adopted. Such a heterocycle may have a substituent, and examples of such a substituent include a C _1-6 alkyl group (methyl, ethyl, propyl, isopropyl, butyl, t-butyl etc.), C _{6- 10} Aryl group (phenyl, naphthyl, etc.), cyano group, amino group, mono- or di-C _1-4 alkyl (eg, methyl, ethyl, isopropyl, etc.) amino group, hydroxyl group, C _1-4 alkyloxy group (eg, Methoxy, ethoxy, etc.), carbamoyloxy group, C _1-4 alkylthio group (methylthio,
Ethylthio etc.), C _1-4 alkylsulfonyl group,
(Eg, methylsulfonyl, ethylsulfonyl, etc.) Halogen (eg, fluoro, chloro, bromo, etc.), sulfamoyl group, C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), A sulfooxy group etc. can be mentioned. The number of such substituents is preferably 1 to 3, and in the case of a plurality of substituents, they may be the same or different.

Specific examples of the ring B include thiazole, oxazole, which may be hydrogenated,
Imidazole, 1,3-thiazine, 1,3-oxazine, pyrimidine and the like can be mentioned, and examples of the condensed ring of ring A and ring B include thiazolo [3,2-a] pyrimidine which may each be hydrogenated. , Oxazolo [3,2-a] pyrimidine, imidazo [1,2-a] pyrimidine, pyrimido [2,1-b] [1,3] thiazine, pyrimido [2,1-b] [1,3] oxazine , Pyrimido [1,2-a] pyrimidine and the like. In addition, when X or X ¹ is a substituted imino group, in the above formula,

Embedded image When X or X ¹ is a mono-substituted amino group, the formula is

Embedded image There is an equilibrium relationship with the substituted imino group as shown in.

X and X ¹ are (1) amino or a C _1-4 alkyl group optionally substituted with mono- or di-C _1-4 alkylamino (eg, methylamino, dimethylamino etc.) (eg, A hydroxy group substituted with methyl, ethyl, propyl, butyl, etc.), (2) a 4- to 6-membered heterocyclic group having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom (eg, Thiazolyl, pyridyl, etc.) or C which may be substituted with a hydroxyl group or a C _1-4 alkyloxy group (eg, methyloxy, ethyloxy, propyloxy, butyloxy, etc.)
_1-4 mercapto group substituted with alkyl group (eg, methyl, ethyl, propyl, butyl, etc.), or (3) C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, butyryl etc.), halogeno C _{1- 6} alkyl-carbonyl (eg, trifluoromethylcarbonyl etc.), C _6-10 aryl-carbonyl (eg, benzoyl etc.), carbamoyl, mono- or di-C _1-4 alkyl-carbamoyl (eg, methylcarbamoyl, dimethylcarbamoyl etc.) , C _1-6 alkyloxy-carbamoyl (eg, methyloxycarbamoyl, ethyloxycarbamoyl, etc.), 4- to 6-membered heterocyclic carbonyl having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. Group (eg, thiazolylcarbonyl, pyridylcarbonyl, etc.), C _1-6 alkylsulfo 4 to 6 having 1 to 4 heteroatoms selected from nyl (eg, methylsulfonyl, ethylsulfonyl, etc.), C _6-10 arylsulfonyl (eg, phenylsulfonyl, etc.), nitrogen atom, oxygen atom and sulfur atom. Membered with a membered heterocyclic group (eg, thiazolyl, pyridyl, etc.), C _1-4 alkyl (eg, methyl, ethyl, propyl, butyl, etc.) or hydroxy C _1-4 alkyl (eg, hydroxymethyl, etc.). Preferred are amino or substituted imino groups. Also, the formula

Embedded image [In the formula, D is a C _2-4 alkylene group (eg, ethylene, etc.)
Alternatively, it represents a C _2-4 alkenylene group (eg, ethenylene, etc.). ] It is preferable that it is a group represented by these.

The compound (Ia) has the formula (Ia ')

Embedded image [Wherein Ra is a formula

Embedded image (In the formula, Ra ′ represents a C _1-4 alkyl group (eg, methyl, ethyl, etc.), and Ra ″ represents a carbamoyl group or a mono- or di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, etc.). ] In the above formula, Q represents NH, an oxygen atom or a sulfur atom, the substituent X ′ represents an oxo group or a thioxo group, and Q is NH and When X is an oxo group, R ² represents a lower alkyl group, and the ring A ′ in the above formula may have a substituent on the ring-constituting carbon atom and nitrogen atom in addition to X ′ and Y. Examples of such a substituent include a C _1-6 alkyl group (eg,
Methyl, ethyl, propyl, isopropyl, etc.), C
_6-10 aryl group (eg, phenyl, tolyl, naphthyl, etc.), 4- to 6-membered heterocyclic group having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom (eg, 2-pyridyl) Etc.), a C _7-12 aralkyl group (eg, benzyl, etc.), etc., and the number thereof is preferably 1 to 4. These substituents are, for example, halogen (eg, fluoro, chloro, bromo, etc.) , Hydroxy group, C _1-6 alkyloxy group (eg, methoxy, ethoxy, etc.), amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, dimethylamino, etc.)
May be further substituted with 1 to 3 substituents such as Ring A ′ is a C _1-4 alkyl group (eg, methyl etc.) and a 4- to 6-membered heterocyclic group having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom (eg pyridyl etc.). It is preferable that 1 or 2 substituents selected from () may be present on the ring-constituting nitrogen atom. The compound (Ib) has the formula (Ib ′)

Embedded image [In the formula, Q represents NR ⁰ , O or S, R ⁰ represents a hydrogen atom or a C _1-4 alkyl group (eg, methyl, etc.), and X ′ represents an oxo group or a thioxo group. ] The compound represented by these, its ester, or its salt is preferable.

Production Method 1 The compound (I) of the present invention is, for example, the compound (II)

Embedded image [Wherein, L represents a leaving group, and other symbols have the same meanings as described above. Or an ester or salt thereof [esters and salts similar to those described in (I) can also be used. ] And compound (III) HS-Y-W [The symbol in a formula shows the same meaning as the above. ] It can manufacture by reacting with the compound represented by these, or its salt. As the leaving group represented by L in the compound (II), a leaving group usually used in the field of synthetic organic chemistry can be adopted [for example, Compendium of Organic Synthetic Methods]. , First
Volume-7, John Wely & Sons Inc., New York (19
71-1992), and R.S. C. Laroc
k), Comprehensive Organic Transformatio
n), VCH, New York (1989) and the like]. Specific examples of L include, for example, reactive ester of hydroxyl group [for example, C _1-6 alkane or C
_6-10 arenesulfonyloxy group (eg, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy, etc.) or di C _1-6 alkyl or di C _6-10 arylphosphonooxy group (eg, diphenyl Phosphonooxy etc.)], halogen (eg, chloro, bromo) or C _1-6
Examples thereof include alkane, C _2-6 alkene, C _6-10 arenesulfinyl group and the like. More preferred L
Is a diphenylphosphonooxy group.

As the salt of the compound (III), for example, alkali metal (eg, sodium, calcium, etc.) salt, alkaline earth metal (eg, calcium, magnesium, etc.) salt, ammonium salt, etc. are used. Compound (II) or (III)
When a reactive group such as an amino group, a hydroxyl group, or a carboxyl group is included in the structural formula, these groups may be protected by a protecting group described below according to a conventional method. After the reaction, these protecting groups can be removed according to a conventional method. The reaction between compound (II) and compound (III) usually proceeds advantageously in the presence of a base. Examples of such a base include triethylamine,
Examples thereof include organic amines such as diisopropylethylamine and basic inorganic salts such as sodium hydrogen carbonate and potassium carbonate. Compound (II) and compound (III)
When the mercapto group in the compound (III) is protected during the reaction with and, the protecting group can be removed with a reagent and then reacted with the compound (II). Removal of such protecting groups is described, for example, by T.W. W. Green (Gr
een) and P. G. M. Wuts, Protective
Groups in Organic Synthesis (Protecti
ve Groups in Organic Synthesis), 2nd Edition, John Wel
The deprotection reagents and reaction conditions usually used in the relevant field described in y & Sons Inc., New York (1991) and the like can be adopted. Further, as the protecting group for the mercapto group in the compound (III), a protecting group usually used in the relevant field may be adopted. For example, TW Green and PG
M. Wuts, Protective Groups in Organic Synthesis
Organic Synthesis), 2nd edition, John Wely & Sons In
c. A protecting group for a mercapto group described in New York (1991) and the like can be mentioned. As such a protecting group, silylthioether and the like which are particularly easily removable are more preferable.

The reaction between compound (II) and compound (III) is usually carried out by stirring in an inert solvent. The inert solvent used in the reaction is not particularly limited as long as the reaction is not hindered. , Halogenated hydrocarbons such as chloroform, acetonitrile,
Alkyl nitriles such as propionitrile, nitroalkanes such as nitromethane and nitroethane, and amides such as dimethylformamide and dimethylacetamide are preferable. The reaction temperature varies depending on the starting compounds (II) and (III), the type of base added, the type of solvent and the like, but is usually -40 ° C to 100 ° C, preferably -30 ° C to 50 ° C. The reaction time is generally about 1 minute to 48 hours, preferably about 15 minutes to 24 hours. Compound (I
The production method of I) or its ester or its salt is known in the field of carbapenem (eg, JP-A-57-57).
12318, JP-A 64-25780, etc.). Formula (II
Most of the compounds represented by I) are novel substances, but their production can be carried out according to the methods for producing similar compounds described in the literature. As such documents, for example, JP-A-57-158784, J. Kister
ter) et al., Tetrahedron, 32, 1
395 (1976), H. Rapoport
, Journal of Organic Chemistry (J. Org. Chem.), 36, 46 (1971),
Compendium of Organic Synthetic Method
s), Volumes 1-7, John Wely & Sons Inc., New Y
ork (1971-1992), Comprehensive Organic Synthes
sis), Volumes 1-9, Pergamon Press, Oxford (199)
1 year) and R. C. Larock, Comprehensive Organic Transformation (Co
mprehensive Organic Transformation), VCH, New Yor
k (1989) and so on.

W is an expression

Embedded image [The symbols in the formula are as defined above. ] When it is a group represented by formula (III), the compound represented by formula (III) is represented by formula (IIIa)

Embedded image [The symbols in the formula are as defined above. ] The compound represented by this is shown. Also, W is the formula

Embedded image [The symbols in the formula are as defined above. ] When it is a group represented by formula (III), the compound represented by formula (III) is represented by formula (IIIb)

Embedded image [The symbols in the formula are as defined above. ] The compound represented by this is shown.

The compound represented by the formula (IIIa) is specifically, for example, the compound represented by the formula (IVa)

Embedded image [In the formula, Z represents a hydrogen atom or a protecting group of a mercapto group,
Y has the same meaning as described above. And an optionally substituted diamino compound represented by the formula:

Embedded image [In the formula, X ³ represents a substituted imino group, and L ¹ and L
² represents the same or different removable groups. ] Or a compound of formula (VIa)

Embedded image [Wherein, X ⁴ represents a substituted hydroxyl group, mercapto group or amino group, and L ¹ , L ² and L ³
Are the same or different removable groups. ] The compound represented by the above can be reacted and, if desired, the protecting group represented by Z can be removed. As the substituent of the optionally substituted diamino compound represented by the above formula (IVa), the groups exemplified as the substituent of ring A can be used.

As the salt of compound (IVa), the same salt as the salt of compound (IIIa) can be used. The protecting group for the mercapto group of the compound (IVa) may be the same as the protecting group for the mercapto group of the compound (IIIa), but may be an alkyl type protecting group (eg, benzyl, p-methoxybenzyl, p -Benzyls such as nitrobenzyl, substituted methyls such as diphenylmethyl, triphenylmethyl and methoxymethyl, 2-tetrahydropyranyl, etc., acyl-type protecting groups (eg, alkyloyls such as acetyl, aroyls such as benzoyl, t-butoxycarbonyl etc.)
Alternatively, a silyl type protecting group (eg, t-butyldimethylsilyl, etc.) and the like can also be used. As the substituent of the group represented by X ³ and X ⁴ , the substituent of the group represented by X can be used.

As the removable group represented by L ¹ , L ² and L ³ , a removable group usually used in the field of synthetic organic chemistry can be adopted [eg,
Compendium of Organic Synthetic Meth
ods), Volumes 1-7, John Wely & Sons Inc. NewYo
rk (1971-1992), and R.K. C. Larock, Comprehensive Organic Transform
ation), VCH, New York (1989) and the like. As specific L ¹ , L ² and L ³ ,
For example, a hydroxyl group, a substituted hydroxyl group [eg C _1-6 alkyloxy or C _6-10 aryloxy or C _1-6 alkyloxyyl or C
_6-10 aroyloxy, etc.], mercapto group, substituted mercapto group [eg C _1-6 alkylthio or C
_6-10 arylthio or C _1-6 alkyloylthio or C _6-10 aroylthio, etc.], an amino group or a mono- or di-substituted amino group [eg mono- or di-C
_1-6 alkylamino or mono- or di-C _6-10 arylamino etc.] can be mentioned. In some cases, L ¹ and L ² may combine together to form a double bond with C. Examples of such a group include an oxo group and a thioxo group.

The compound represented by the formula (IIIa) can also be converted into a compound represented by the formula (IIIa) having a different X structure by subjecting to a suitable functional group conversion reaction. For such functional group conversion reaction, R. C. Larock, Comprehensive Organic Transfor
mation), VCH, New York (1989) and the like. The compound represented by the formula (IIIa) has the formula (III-1) or the formula (III-2)

Embedded image [Wherein Y is as defined above, X ⁵ is O, S or N-
Z ¹ and Z ¹ represent a hydrogen atom or a group capable of binding to a nitrogen atom among the substituents of the substituted hetero atom represented by X. And good thiol compound or a reactive derivative thereof optionally substituted represented by], wherein Z ² -L ⁴ [wherein, Z ² is a substituent of the substituted heteroatom represented by X, L ⁴ is Indicates a leaving group. ] It can also manufacture by making the compound represented by these react. The formula (III-1) and the formula (III-2) can be converted into each other or are in an equilibrium state depending on the conditions.

Further, when there is a removable group in Z ² is, Z ² -L ⁴ is wherein L ⁵ -Z ³ -L ⁴ [wherein, Z ³ together with L ⁵ Z ² is shown, L ⁵ is a leaving group, and L ⁴ is as defined above. ] Can be represented. L ⁵ When -Z ³ subjected -L ⁴ a similar reaction, the formula (III
Among the compounds represented by a), a compound having a structure in which X and a nitrogen atom on the ring are combined to form a ring can be produced. As the substituent of the optionally substituted thiol compound represented by the above formula (III-1) or (III-2), the groups exemplified as the substituent of ring A can be used. The reactive derivative of the compound (III-1) or (III-2) is the same as the reactive derivative of the compound (IIIa). The same group as L ¹ is adopted for L ⁴ and L ⁵ . Compound (III-1) or (III-2) and formula Z
The reaction of the compound represented by the ² -L ^4, or L ⁵ -Z ³ -L ^4, for example R. C. Larock, Comprehensive Organic Transformation (Co
mprehensive Organic Transformation), VCH, New
The usual conditions for addition-elimination reaction described in York (1989) and the like can be adopted. The compound (III-1) or (III-2) is the compound represented by the formula (IVa) and the compound represented by the formula (V-
1)

Embedded image [The symbols in the formula are as defined above. ] It can manufacture by making the compound represented by these react. Also in this reaction, for example, R.I. C. Laroc
k), Comprehensive Organic Transformatio
n), VCH, New York (1989), etc., the conditions for usual addition-elimination reaction can be adopted.

The compound represented by the formula (IIIb) is specifically, for example, the compound represented by the formula (IVb)

Embedded image [In the formula, Z represents a hydrogen atom or a protecting group of a mercapto group,
Other symbols have the same meanings as described above. ] 1,3-propanediamine, 3-aminopropan-1-ol or 3-aminopropan-1-ol which may be substituted and which can be synthesized by a reaction known in the literature or similar thereto.
Thiol derivative and formula (Vb)

Embedded image [In the formula, X has the same meaning as described above, and L ¹ and L ² represent the same or different removable groups. ] It can manufacture by making the compound represented by these react and deprotecting Z as needed. Further, the compound represented by the formula (IIIb) can be represented by, for example, the formula (IV′b)

Embedded image [In the formula, Z ′ represents a hydrogen atom or a hydroxyl-protecting group, and other symbols have the same meanings as described above. ] A substituted 1,3-propanediamine, 3-aminopropan-1-ol or 3-aminopropan-1-thiol derivative which is publicly known or can be synthesized by a reaction similar to it, represented by the formula: It can be produced by reacting a compound represented by (Vb), deprotecting Z'if necessary, and converting the resulting hydroxyl group into a mercapto group.
Such conversion of a hydroxyl group to a mercapto group can be performed by, for example, Comprehensive Organic Transformation, VC
The method described in H, New York (1989) and the like can be adopted.

When Z or Z'in the compound (IVb) represents a mercapto group or a hydroxyl group-protecting group, examples of the protecting group include T.I. W. Green and P. G. M. Protective groups commonly used in the field described in Wuts, Protective Groups in Organic Synthesis, Second Edition, John Wely & Sons Inc., New York (1991), etc. Can be adopted. Preferably, for example, an alkyl type protecting group (eg, benzyl such as benzyl, p-methoxybenzyl, p-nitrobenzyl, etc., diphenylmethyl, triphenylmethyl,
Substituted methyls such as methoxymethyl, 2-tetrahydropyranyl, etc., acyl-type protecting groups (eg, alkyloyl such as acetyl, aroyls such as benzoyl, t-butoxycarbonyl, etc.) or silyl-type protecting groups (eg, t
-Butyldimethylsilyl, etc.) and the like, among which p-methoxybenzyl, acetyl, benzoyl, tetrahydropyran-2-yl and the like are more preferable. The reaction conditions of such a reaction, L ¹ used in the reaction
As the removable group represented by L ² and L ² , reaction conditions usually used in the field of synthetic organic chemistry and a removable group can be adopted [similar reactions are described in S. Umezawa et al. Bulletin of the
Chemical Society of Japan (Bull.Ch
em. Soc. Japan), Vol. 44, p. 1411 (1971)
Year) and Y. Abe et al. The Journal of
Antibiotics, 30th
Vol. 1004 (1977), or Compendium of Organic Synthetic Methods, No. 1.
Volume-7, John Wely & Sons Inc. New York (197)
1-1992), and R. C. Larock,
Comprehensive Organic Transformation, VC
H, New York (1989) and the like. ]. Specific examples of L ¹ and L ² include, for example, a hydroxyl group and a substituted hydroxyl group [eg C
_1-6 alkyloxy or C _6-10 aryloxy or C _1-6 alkyloyloxy or C _6-10 aroyloxy, etc.], mercapto group, substituted mercapto group [eg C _1-6 alkylthio or C _6-10 arylthio] Or C _1-6 alkyloylthio or C _6-10 aroylthio etc.], an amino group or a mono- or di-substituted amino group [eg mono- or di-C _1-6 alkylamino or mono- or di-C _6-10 arylamino etc. ] Can be given. In some cases, L ¹ and L ² may combine together to form a double bond with C. Examples of such a group include an oxo group and a thioxo group. Preferable examples of the compound represented by the formula (V) include phosgene, carbonyldiimidazole, thiophosgene, thiocarbonyldiimidazole, carbon disulfide, phenyl chlorocarbonate and p-nitrophenyl chlorocarbonate.

The compound represented by the formula (IIIb) is, for example, a compound represented by the formula (VIb)

Embedded image [In the formula, L ³ represents a removable group, and other symbols have the same meanings as described above. ], Which is publicly known in the literature or which can be synthesized by a reaction similar thereto, which may be substituted 1,
It is also produced by subjecting 3-propanediamine, 3-aminopropan-1-ol or 3-aminopropan-1-thiol derivative to appropriate conditions and cyclizing with elimination of H-L ^3. You can As the reaction conditions of such a reaction and L ³ which can be used, reaction conditions usually used in the field of synthetic organic chemistry and eliminable groups can be adopted [Similar reactions include, for example, compendium of Compendium of Organic Synthetic M
ethods), Volumes 1-7, John Wely & Sons Inc. Ne
w York (1971-1992), and R.W. C. Larock, Comprehensive Organic Transf
ormation), VCH, New York (1989) and the like. ]. Specific examples of L ³ include, for example, a substituted hydroxyl group [eg, C 1-6 alkyloxy or C _6-10 aryloxy or C _1-6 alkyloyloxy or C _6-10 aroyloxy], a substituted mercapto group [Eg C _1-6 alkylthio or C _6-10 arylthio or C _1-6 alkyloylthio or C _6-10 aroylthio etc.], amino group or mono- or di-substituted amino group [eg mono- or di-C _1-6 Alkylamino or mono or di C _6-10
Arylamino and the like].

The compound represented by the formula (IIIb) is, for example, a compound represented by the formula (VI'b)

Embedded image [The symbols in the formula are as defined above. ] An optionally substituted 1,3-propanediamine, 3-aminopropan-1-ol or 3-aminopropan-1-thiol derivative which is publicly known in the literature or can be synthesized by a reaction similar thereto is suitable. It can be produced by subjecting the compound to various conditions, cyclizing with elimination of HL ³ , deprotecting Z ′ if necessary, and converting the resulting hydroxyl group into a mercapto group. The conversion of such a hydroxyl group into a mercapto group is performed by, for example, Comprehensive Organic Transformation.
mation), VCH, New York (1989) and the like. As the reaction conditions for such a reaction and L ³ which can be used, the same ones as described above can be mentioned. The removal of the protecting groups represented by Z and Z ′ described above can be carried out, for example, by T. W.
Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second Edition, John Wely & Sons Inc., New York (1991)
The deprotection reagents and reaction conditions usually used in the relevant field described in the above can be adopted. The substituent of the optionally substituted 1,3-propanediamine, 3-aminopropan-1-ol or 3-aminopropan-1-thiol derivative represented by the above formulas (IVb) and (VIb) is a ring. A '
The groups mentioned above as the substituents can be used.

Production Method 2a Further, the compound (Ia) of the present invention can be prepared, for example, from the compound (VII
a)

Embedded image [In the formula, M and Q are groups that react with each other to form a double bond, in other words, a group in which M and Q react with each other and leave to form a double bond, and other symbols have the same meanings as described above. Show. Or an ester or salt thereof [esters and salts similar to those described in (I) can also be used. ] Can also be manufactured by subjecting the compound to a ring-closing reaction. Specific M and Q include, for example, = O, = S, = Se and the like, and JP-A-4-179.
For example, those described in No. 389 are used. The ring-closing reaction is a reaction known per se [eg, Annual Reports in Organic Synthesis (Annual Reports
in Organic Sythesis) 1975-1993, Academic
Press, Inc, San Diego], Advanced Organic Chemistry 2nd Edition
ry Second Edition), Plenum Press, New York and Lo
ndon (1983), etc.] can be adopted. Specifically, a Wittig type reaction (Wittig, Horner, Emmons reaction), a Peterson type reaction, an aldol type reaction with dehydration, a McMurry type reaction using a low-valence metal, and the like can be used. More preferably, for example

Embedded image [Wherein R ^7, R ⁷ 'represents a lower alkoxy group, a lower alkyl group or an aryl group. ], Etc. as Q, O,
A Wittig type reaction using S, Se or the like can be given.
More specific methods include, for example, the following production methods.

Production Method 2a-1 Compound (Ia) has the formula (VIIa-1):

Embedded image [In the formula, Q ¹ is O or S, and other symbols have the same meanings as described above. ] The compound or its ester represented by these or its salt [Ester or salt can also use the same thing as (I). ] And a compound represented by the formula P (R ⁷ ) ₃ (VIII) or P (R ⁷ ) ₂ R ₇ ′ (VIII ′) (wherein R ⁷ and R ⁷ ′ have the same meanings as described above). It can also be obtained by reacting with and removing the protecting group if necessary. In the structural formula of compound (VIIa-1), when a reactive group such as an amino group, a hydroxyl group or a carboxyl group is contained, these groups may be protected by a protecting group described below according to a conventional method. . After the reaction, these protecting groups can be removed according to a conventional method.

[0037] Examples of the lower alkoxy group represented by R ⁷ or R ⁷ ', for example, methoxy, ethoxy, propoxy,
A C _1-6 alkoxy group such as butoxy, methyl Examples of the lower alkyl groups include ethyl, propyl, butyl, a C _1-6 alkyl group such as pentyl, and the aryl group such as a C _6-10 aryl group such as phenyl Used.
These reactions are usually carried out by heating in a solvent-free or inert solvent. The inert solvent used in the reaction is not particularly limited as long as the reaction is not hindered.For example, benzene, toluene, aromatic hydrocarbons such as xylene, dioxane, diethoxyethane, ethers such as tetrahydrofuran or dichloromethane,
Halogenated hydrocarbons such as chloroform are preferred.
Compound (VIII) or (VIII ') is compound (VIIa-1)
2 molar equivalents or more, preferably 2 to 10 molar equivalents are preferably used. The reaction temperature is the starting compound (VIIa-1),
The temperature is usually about 20 to 160 ° C., preferably about 80 to 140 ° C., though it depends on (VIII), (VIII ′), the type of solvent and the like. The reaction time is usually about 30 minutes to 100 hours, preferably about 1 to 72 hours.

Production Method 2a-2 Compound (I) has the formula (VIIa-2):

Embedded image [The symbols in the formula are as defined above. ] The compound or its ester represented by these or its salt [Ester or salt can also use the same thing as (I). ] Is subjected to a ring-closing reaction, and further, if necessary, the protecting group is removed. Similar to Production Method 2a-1, when a reactive group such as an amino group, a hydroxyl group or a carboxyl group is contained in the structural formula of the compound (VIIa-2), these groups are described below according to a conventional method. It may be protected by a protecting group or may be removed after the reaction by a conventional method. The ring closure reaction is performed in an inert solvent. As a preferable inert solvent, the above-mentioned production method 2a-1 is used.
Aromatic hydrocarbons, ethers and halogenated hydrocarbons as used in. The reaction is about 0 to 1
It is carried out by heating in a temperature range of 60 ° C, preferably about 30 to 140 ° C. The reaction time depends on the compound (VI
Although it depends on the type of Ia-2) and the reaction temperature, it is usually about 30 minutes to 100 hours, preferably about 1 hour to 72 hours.

Production Method 2b In addition, the compound (Ib) of the present invention can be prepared, for example, from the compound (VII
b)

Embedded image [Wherein, M and G are groups that react with each other to form a double bond, in other words, a group in which M and G react and separate to form a double bond, and other symbols have the same meanings as described above. Show. Or an ester or salt thereof [the same ester or salt as in (I)] can be used. ] Can also be produced by subjecting the compound to a ring-closing reaction. Specific M and G include, for example, = O, = S, = Se, etc., and JP-A-4-179.
For example, those described in No. 389 are used. The ring-closing reaction is a reaction known per se [eg, Annual Reports in Organic Synthesis (Annual Reports
in Organic Sythesis) 1975-1993, Academic
Press, Inc, San Diego], Advanced Organic Chemistry 2nd Edition
ry Second Edition) Plenum PressNew York and Londo
n (1983), etc.] can be adopted. Specifically, a Wittig type reaction (Wittig, Horner, Emmons reaction), a Peterson type reaction, an aldol type reaction with dehydration, a McMurry type reaction using a low-valence metal, and the like can be used. More preferably, for example

Embedded image [Wherein, R ⁷ and R ⁷ ′ represent a lower alkoxy group, a lower alkyl group or an aryl group. And the like, and a Wittig reaction. More specific methods include, for example, the following production methods.

Production Method 2b-1 The compound (Ib) has the formula (VIIb-1):

Embedded image [In the formula, G ¹ is O or S, and other symbols have the same meanings as described above. Or an ester or salt thereof [the same ester or salt as in (I) can be used. ] And a compound represented by the formula P (R ⁷ ) ₃ (VIII) or P (R ⁷ ) ₂ R ⁷ ′ (VIII ′) (wherein R ⁷ and R ⁷ ′ have the same meanings as described above). It can also be obtained by reacting with and removing the protecting group if necessary. When a reactive group such as an amino group, a hydroxyl group or a carboxyl group is contained in the structural formula of the compound (VIIb-1), these groups may be protected by a protecting group described below according to a conventional method. . After the reaction, these protecting groups can be removed according to a conventional method.

[0041] Examples of the lower alkoxy group represented by R ⁷ or R ⁷ ', for example, methoxy, ethoxy, propoxy,
A C _1-6 alkoxy group such as butoxy, methyl Examples of the lower alkyl groups include ethyl, propyl, butyl, a C _1-6 alkyl group such as pentyl, and the aryl group such as a C _6-10 aryl group such as phenyl Used.
These reactions are usually carried out by heating without solvent or in an inert solvent. The inert solvent used in the reaction is not particularly limited as long as the reaction is not hindered.For example, benzene, toluene, aromatic hydrocarbons such as xylene, dioxane, diethoxyethane, ethers such as tetrahydrofuran or dichloromethane,
Halogenated hydrocarbons such as chloroform are preferred.
Compound (VIII) or (VIII ') is compound (VIIb-1)
2 molar equivalents or more, preferably 2 to 10 molar equivalents are preferably used. The reaction temperature is the starting compound (VIIb-1),
(VIII), (VIII ') The temperature is usually about 20 to 160 ° C, preferably about 80 to 140 ° C, though it varies depending on the kind of the solvent. The reaction time is usually about 30 minutes to 100 hours, preferably about 1 to 72 hours.

Production Method 2b-2 Compound (Ib) has the formula (VIIb-2):

Embedded image [The symbols in the formula are as defined above. Or an ester or salt thereof [the same ester or salt as in (I) can be used. ] Is subjected to a ring-closing reaction, and further, if necessary, the protecting group is removed. Similar to Production Method 2b-1, in the structural formula of compound (VIIb-2), when a reactive group such as an amino group, a hydroxyl group or a carboxyl group is contained, these groups are described below according to a conventional method. It may be protected by a protecting group or may be removed after the reaction by a conventional method. The ring closure reaction is performed in an inert solvent. As a preferable inert solvent, the above-mentioned production method 2b-1 is used.
Aromatic hydrocarbons, ethers and halogenated hydrocarbons as used in. The reaction is about 0 to 1
It is carried out by heating in a temperature range of 60 ° C, preferably about 30 to 140 ° C. The reaction time depends on the compound (VI
It depends on the kind of Ib-2) and the reaction temperature, but it is usually about 30 minutes to 100 hours, preferably about 1 hour to 72 hours.

Manufacturing methods 2a, 2a-1, 2a-2, 2b,
The raw materials used in 2b-1 and 2b-2, that is, formulas (VIIa), (VIIa-1), (VIIa-2), (VII
As the compounds represented by b), (VIIb-1) and (VIIb-2), compounds represented by the formulas (IIIa) and (IIIb) are used, and known methods [for example, JP-A-59-51.
286, Japanese Patent Laid-Open No. 60-19764, or Comprehensive Organic Synthesis (Comprehensive Orga).
nic Synthesis), Volumes 1-9, PergamonPress, Ox
Ford (1991), etc.] or a method similar or similar thereto. In these manufacturing steps, formulas (IIa), (VIIa), (VIIa-1), (VIIa-2),
(IIb), (VIIb), (VIIb-1) and (VIIb-2)
The compound or its ester represented by or its salt [the same as (I) can be used for the ester or the salt. ] Or in the compound represented by the formula (III), when an amino group is present in the structure, the amino group is preferably protected by a protecting group. Examples of the protecting group for the amino group include Those used in the field of β-lactams and peptides can be appropriately adopted, but among them, for example, formyl, chloroacetyl, phenylacetyl, phenoxyacetyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, P-nitrobenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trityl, allyloxycarbonyl and the like are preferable. When a hydroxyl group is present in the structure of a similar compound, the hydroxyl group may be protected, and examples of the protecting group for the hydroxyl group include those used in the field of β-lactams and peptides. Among them, for example, chloroacetyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, methylthiomethyl, trimethylsilyl, triethylsilyl, t
-Butyldimethylsilyl, t-butyldiphenylsilyl, 2-tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl, p-nitrobenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, allyloxycarbonyl and the like are used, and When a carboxyl group is present in the structure of the same compound, the carboxyl group is preferably protected, and examples of the protective group for the carboxyl group include those used in the field of β-lactams and peptides. , Benzyl, benzhydryl, trityl, p-methoxybenzyl, p-nitrobenzyl, o-
Nitrobenzyl, phenethyl, 2-trimethylsilylethyl, bis (p-methoxyphenyl) methyl, tertiary butyl, allyl and the like are used.

The group represented by X or X'is necessary at the stage of producing the compound represented by the formula (I) or (III), or at the stage of the compound represented by the formula (I) or (III). Depending on the above, it may be converted into a group represented by different X or X ′ by carrying out an appropriate functional group conversion. A known reaction can be used for such a conversion reaction [eg, R. C. Larock, Comprehensive Organic Transformation (Co
mprehensive Organic Transformation), VCH, New Yor
k (1989), etc.]. COOH of target compound (I)
The carboxyl group represented by may be esterified as described above. R ⁴ of the esterified carboxyl group represented by COOR ⁴ is represented by the formula (I) or (II) at the stage leading to the production of the compound represented by the formula (I) or (II). At the compound stage, it may be converted to a different R ⁴ if necessary. For this conversion, β
The reactions usually employed for similar purposes in the field of lactam antibacterial agents can be used. The target compound (I) thus obtained can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, chromatography and the like. When the reaction product contains a protecting group, the compound (I) can be obtained by removing the protecting group by a conventional method, if necessary. Amino, hydroxyl or carboxyl protecting groups have been well studied in the field of β-lactam and peptide synthesis, and methods for protection and deprotection have been established. It can be used in the production of intermediates. For example, methods for removing the protecting group include known methods such as a method using an acid, a method using a base, a method using 0-valent palladium, a method using aluminum chloride, a method using hydrazine, a method using reduction, and a method using sodium N-methyldithiocarbamate. Means can be appropriately selected and used.

Compound (I) exhibits excellent antibacterial activity against Gram-positive and Gram-negative bacteria including clinical isolates, has extremely low toxicity, is well absorbed orally, and is physicochemically and biochemically. Stable (especially stable to DHP-I)
Since it is a valuable antibiotic, it is used as a medicine for humans and livestock, and can be safely used as an antibacterial agent for treating and preventing infectious diseases caused by various bacteria. Further, the compound (I) of the present invention can be added to animal feed as a fungicide, for example, for preserving the feed. It can also be used as a disinfectant to remove harmful bacteria on medical and dental equipment. The compound (I) of the present invention is used alone or in combination with other active ingredients (other antibacterial agents, anti-inflammatory agents, antipyretics, analgesics, etc.), if necessary, in addition to a pharmaceutically acceptable carrier, for example, a stabilizing agent. Agent,
It can be used as a preparation such as an injection, capsule, tablet, liquid (eg, suspension, emulsion, etc.) by a conventional method by appropriately adding an auxiliary agent such as a dispersant. These can be administered parenterally (eg, intravenously or intramuscularly) or orally. Formulations for injection may be presented in ampoules or in use in containers with added preservatives. The preparation may be a suspension, solution or emulsion in an oily or aqueous solvent, and may suitably contain auxiliary agents such as a known suspending agent, stabilizer and / or powder. Good. Compound (I) can also be used as a powder or powder after dissolving in a suitable solvent, for example, sterilized pyrogen-free water immediately before use.

Compound (I) is a binder (for example, syrup, gum arabic, gelatin, sorbitol, gum tragacanth, polyvinylpyrrolidone, methylcellulose, etc.), a filler (for example, lactose, saccharides, corn starch, calcium phosphate, sorbitol, glycine, etc.), Hardeners (eg magnesium stearate, talc, polyethylene glycol, silica, etc.),
Tablets, capsules, powders, and powders for oral administration can be prepared after appropriately mixing with a disintegrating agent (eg, starch and the like) or wetting agent (eg, sodium lauryl sulfate). Tablets, powders and the like can also be film-coated by a method known per se. Oral preparations may be used as liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups and elixirs. Also, these preparations, for example, known antioxidants,
Ingredients such as preservatives, binders, wetting agents, lubricants, thickeners or flavoring agents may be mixed. In addition, other active ingredients (eg, other β-lactam antibiotics) can be mixed into the formulation to provide a formulation with a broader spectrum of antimicrobial activity.

The compounding ratio of the compound (I) to the whole pharmaceutical composition containing the compound (I) varies depending on its form, but may be a ratio which is generally used as an antibacterial agent, for example, capsules, tablets, granules and the like. It is about 30 to 95% by weight in the solid preparation. Compound (I) is useful as a therapeutic agent for bacterial infections, for example, in humans and other mammals (eg, mice, rats, rabbits, dogs, cats, cattle, pigs, etc.), for example, respiratory infections, urinary tract infections, suppuration. It can be used for treatment and prevention of sexual diseases, biliary tract infections, intestinal infections, obstetrics and gynecology infections, otolaryngological infections, surgical infections and the like. For example, in the case of respiratory infection, the daily dose of compound (I) varies depending on the condition and weight of the patient, the method of administration, etc., but in parenteral administration, the active ingredient (ie compound (I) ) Is about 0.5 to 80 mg, preferably about 2 to 40 mg, and is 1 daily.
It is suitable to administer by intravenous or intramuscular injection in 4 to 4 divided doses. The oral dose is divided into 1 to 3 times per day, and the amount of the active ingredient is about 1 per 1 kg of adult body weight.
Approximately 500 mg, preferably about 5 to 100 mg is suitable.

[0048]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in more detail below with reference examples and examples. However, these are merely examples and do not limit the present invention in any way. The following reference examples,
The elution in the column chromatography of the Examples was TL
It was performed under observation by C (thin layer chromatography). In the TLC observation, the 60F ₂₅₄ Merck (Merck) manufactured as a TLC plate, the solvent used as an elution solvent in column chromatography as a developing solvent, employing a UV detector as a detection method. Silica gel for the column is also Kieselgel 60 (70-
230 or 230-400 mesh). CH
The P-20P resin is manufactured by Mitsubishi Kasei. The solvent was purified and dried as needed. The IR spectrum is IR-810 manufactured by JASCO Corporation or FT-200 manufactured by Horiba, Ltd.
It measured using. NMR spectra were obtained using Varian (Va) using tetramethylsilane or sodium 3- (trimethylsilyl) propionate as internal or external reference.
rian) GEMINI 200 (200 MHz) spectrometer and all δ values are given in ppm. In the mixed solvents, the numerical values shown in parentheses are the volume mixing ratios of the respective solvents. % In the mixed solvent indicates percent by volume.
The symbols in Reference Examples and Examples have the following meanings. s: singlet d: doublet t: triplet q: quartet quint: quintet-like dd: double doublet ddd: double doublet m: multiplet dt: double triplet dq: double quartet td: triple doublet tt: triple triplet br: wide J: Coupling constants The abbreviations in Reference Examples and Examples have the following meanings. THF: Tetrahydrofuran DMF: Dimethylformamide DMA: Dimethylacetamide PNB: p-nitrobenzyl (or 4-nitrobenzyl) hexetil: 1- (cyclohexyloxycarbonyloxy) ethyl Py: 2-pyridyl

Reference Example 1a 5- (4-Methoxybenzylthio) -3,4,5,6-tetrahydropyrimidine-2 (1H) -thione 2- (4-produced by the method of JP-A-60-132985.
Methoxybenzylthio) propane-1,3-diamine (0.
Carbon disulfide (0.26 g) in a THF solution (6 ml) of 5 g) at 0 ° C.
g) was added dropwise, and the mixture was stirred at 0 ° C. for 30 minutes and further at room temperature for 1 hour. 6 ml of ether was added to the reaction solution, the insoluble matter was collected by filtration, washed with ether, and then dried under vacuum. The obtained solid was again made into a THF solution (6 ml) and stirred under heating under reflux for 3 hours. The solvent was distilled off under reduced pressure to give the title compound (332 mg)
Was obtained as a white solid. IR (KBr):. 3180, 1605, 1565, 1540, 1510 cm -1 1 H-NMR (CDCl 3) δ: 2.91 (1H, tt, J = 9.4, 4.6Hz),
3.13 (2H, dd, J = 12.6, 9.4Hz), 3.36 (2H, dt, J = 12.6, 4.6
Hz), 3.76 (2H, s), 3.81 (3H, s), 6.56 (2H, brs), 6.86 (2
H, d, J = 8.8Hz), 7.22 (2H, d, J = 8.8Hz).

Reference Example 2a 5- (4-methoxybenzylthio) -2-methylthio-
D of 1,4,5,6-tetrahydropyrimidine 5- (4-methoxybenzylthio) -3,4,5,6-tetrahydropyrimidine-2 (1H) -thione (314 mg)
Sodium hydride (purity 55% in MF solution (3 ml) at 0 ° C
(56 mg) was added, followed by stirring for 30 minutes. 0 in the reaction solution
Methyl iodide (166 mg) was added at 0 ° C, and the mixture was stirred for 1 hour and 30 minutes. After water was added dropwise at 0 ° C. to decompose excess sodium hydride, the reaction solution was extracted with ether and dried over anhydrous sodium sulfate. The solid obtained by evaporating the solvent under reduced pressure was washed with a solvent (ether-hexane, 2: 1) and dried in vacuo to give the title compound (243 mg) as a white solid. IR (KBr):. 1600, 1510 cm -1 1 H-NMR (CDCl 3) δ: 2.32 (3H, s), 2.75-3.00 (1H,
m), 3.10-3.30 (2H, m), 3.40-3.65 (2H, m), 3.75 (2H, s),
3.80 (3H, s), 6.84 (2H, d, J = 8.8Hz), 7.24 (2H, d, J = 8.8H
z).

Reference Example 3a Dimethyl N- (thiazol-2-yl) dithiocarboxylic imidate 2-aminothiazole (1.0 g) in DMF solution (10 ml) at 0 ° C. in 10 N sodium hydroxide solution (1.2 ml), Subsequently, carbon disulfide (1.52 g) was added dropwise. After stirring at 0 ° C. for 30 minutes, 10N sodium hydroxide solution (1.2 ml) was added dropwise. After stirring at 0 ° C. for 30 minutes, methyl iodide (2.98 g) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour. Water (100 ml) was added to the reaction solution, extracted with ether, washed with saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by flash column chromatography (carrier: silica gel, 75 g, developing solvent: ethyl acetate-hexane, 1: 8) to give the title compound (1.
60 g) was obtained as a red oil. IR (neat):. 1540, 1520 cm -1 1 H-NMR (CDCl 3) δ: 2.60 (6H, s), 7.10 (1H, d, J =
3.6Hz), 1.59 (1H, d, J = 3.6Hz).

Reference Example 4a 5- (4-methoxybenzylthio) -2- (thiazole-
2-yl) amino-1,4,5,6-tetrahydropyrimidine dimethyl N- (thiazol-2-yl) dithiocarboxylic imidate (0.39 g) and 2- (4-methoxybenzylthio) propane-1,3 -A solution of diamine (0.43 g) in acetonitrile (10 ml) at room temperature for 2.5 hours, then at 50 ° C.
For 2 hours. The solvent was distilled off under reduced pressure, and the obtained solid was washed with ether and dried in vacuo to give the title compound (3
99 mg) was obtained as a yellow solid. IR (KBr):. 3450, 1640, 1560, 1505 cm -1 1 H-NMR (CDCl 3) δ: 2.96 (1H, tt, J = 9.4, 4.4Hz),
3.23 (2H, dd, J = 12.2, 9.4Hz), 3.52 (2H, dd, J = 12.2, 4.4
Hz), 3.77 (2H, s), 3.80 (3H, s), 6.51 (1H, d, J = 3.6Hz),
6.85 (2H, d, J = 8.6Hz), 7.12 (1H, d, J = 3.6Hz), 7.24 (2H, d,
J = 8.6Hz).

Reference Example 5a 6- (4-Methoxybenzylthio) -5H-2,3,6,7
-Tetrahydrothiazolo [3,2-a] pyrimidine 5- (4-methoxybenzylthio) -3,4,5,6-tetrahydropyrimidine-2 (1H) -thione (805 mg) D
Sodium hydride (purity 55
%, 314 mg) and then stirred for 30 minutes. After adding 1,2-dibromoethane (0.31 ml) to the reaction solution at 0 ° C,
The mixture was stirred at room temperature for 3 hours and at 70 ° C. overnight. After water was added dropwise at room temperature to decompose excess sodium hydride, the reaction solution was extracted with ether and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 40 g, developing solvent:
Purification with methanol-dichloromethane, 1: 9) gave the title compound (370 mg) as a pale yellow solid. IR (KBr): 1630, 1510 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 2.80-3.00 (1H, m), 3.00-3.4
0 (5H, m), 3.40-3.70 (3H, m), 3.76 (2H, s), 3.81 (3H, s),
6.86 (2H, d, J = 8.6Hz), 7.25 (2H, d, J = 8.6Hz).

Reference Example 6a Dimethyl N- (dimethylcarbamoyl) dithiocarboxylic imidate After washing sodium hydride (purity 55% 1.0 g) with hexane, THF (40 ml) was added at 0 ° C., and 1,1- Dimethylurea (1.0 g) was added and the mixture was stirred at room temperature for 30 minutes.
After adding carbon disulfide (2.5 g) dropwise to the reaction solution at 0 ° C,
DMF (10 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, methyl iodide (4.5 g) was added to the reaction solution at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water (100 ml) and extracted with ether. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 50 g, developing solvent: ethyl acetate-
Purification with hexane, 1: 2) gave the title compound (1.18 g) as a brown oil. IR (neat):. 1650, 1565, 1525 cm -1 1 H-NMR (CDCl 3) δ: 2.50 (6 H, s), 3.02 (3 H, s),
3.04 (3 H, s).

Reference Example 7a 2- (Dimethylcarbamoylimino) -5- (4-methoxybenzylthio) perhydropyrimidine Dimethyl N- (dimethylcarbamoyl) dithiocarboxylic imidate (290 mg) and 2- (4-methoxybenzylthio) ) Propane-1,3-diamine (340 mg) in acetonitrile
(10 ml) was stirred at 80 ° C. for 3 hours. The solvent was evaporated under reduced pressure, the obtained solid was washed with ether, and dried in vacuo to give the title compound (318 mg) as a white solid. IR (KBr):. 1615, 1575, 1510 cm -1 1 H-NMR (CDCl 3) δ: 2.80-3.00 (1 H, m), 2.94 (6 H,
s), 3.14 (2 H, dd, J = 11.8, 9.4 Hz), 3.39 (2 H, d
d, J = 11.8, 4.4 Hz), 3.75 (2 H, s), 3.81 (3H, s),
6.85 (2 H, d, J = 8.8 Hz), 7.22 (2 H, d, J = 8.8
Hz). Reference Example 8a The title compound (1.87 g) was obtained as a yellow solid from dimethyl N-benzoyldithiocarboxylic imidate benzamide (1.21 g) in the same manner as in Reference Example 6a. IR (KBr):. 1630, 1440, 1420 cm -1 1 H-NMR (CDCl 3) δ: 2.61 (6 H, s), 7.40-7.60 (3 H,
m), 8.05-8.20 (2 H, m).

Reference Example 9a 2- (benzoylimino) -5- (4-methoxybenzylthio) perhydropyrimidine dimethyl N-benzoyldithiocarboxylic imidate (450
The title compound (566 mg) was obtained as a white solid from (mg) according to the method similar to the reference example 7a. IR (KBr):. 1625, 1600, 1580, 1515 cm -1 1 H-NMR (CDCl 3) δ: 2.85-3.00 (1 H, m), 3.05-3.25
(2 H, m), 3.30-3.50 (2 H, m), 3.74 (2 H, s), 3.81
(3 H, s), 6.86 (2 H, d, J = 8.4 Hz), 7.22 (2H, d,
J = 8.4 Hz), 7.30-7.50 (3 H, m), 8.05-8.15 (2 H,
m). Reference Example 10a The title compound (859 mg) was obtained as a brown oil from dimethyl N-acetyldithiocarboxylic imidate acetamide (1.77 g) and in the same manner as in Reference Example 6a. IR (neat):. 1700, 1570, 1450, 1420 cm -1 1 H-NMR (CDCl 3) δ: 2.26 (3 H, s), 2.50 (6 H, s).

Reference Example 11a 2- (Acetylimino) -5- (4-methoxybenzylthio) perhydropyrimidine dimethyl N-acyldithiocarboxylic imidate (490 mg)
In the same manner as in Reference Example 7a from the title compound (6
26 mg) was obtained as a white solid. IR (KBr):. 1640, 1600, 1510 cm -1 1 H-NMR (CDCl 3) δ: 1.99 (3 H, s), 2.80-3.00 (1 H,
m), 3.16 (2 H, dd, J = 12.0, 9.6 Hz), 3.43 (2 H, d
d, J = 12.0, 4.6 Hz), 3.77 (2 H, s), 3.81 (3H, s),
6.86 (2 H, d, J = 8.6 Hz), 7.23 (2 H, d, J = 8.6
Hz). Reference Example 12a The title compound (590 mg) was obtained as a white solid from dimethyl N- (phenylsulfonyl) dithiocarboxylic imidate benzenesulfonamide (3.14 g) according to the same method as in Reference Example 6a. IR (KBr):. 1470, 1300, 1150 cm -1 1 H-NMR (CDCl 3) δ: 2.54 (6 H, s), 7.45-7.65 (3 H,
m), 7.95-8.05 (2 H, m).

Reference Example 13a 5- (4-methoxybenzylthio) -2- (phenylsulfonylimino) perhydropyrimidine Dimethyl N- (phenylsulfonyl) dithiocarboxylic imidate (734 mg) was prepared in the same manner as in Reference Example 7a. The title compound (578 mg) was obtained as a white solid. IR (KBr): 3350, 1625, 1580, 1510, 1375, 1340, 128
^{. 0, 1250, 1130 cm -1} 1 H-NMR (CDCl 3) δ: 2.70-3.00 (1 H, m), 3.05-3.25
(2 H, m), 3.35-3.60 (2H, m), 3.70 (2 H, s), 3.80
(3 H, s), 6.83 (2 H, d, J = 8.8 Hz), 7.19 (2H, d,
J = 8.8 Hz), 7.30-7.60 (3 H, m), 7.75-7.95 (2 H,
m). Reference Example 14a The title compound (940 mg) was obtained as a brown oil from dimethyl N- (pyrimidin-2-yl) dithiocarbonimidate 2-aminopyrimidine (1.0 g) according to the same method as in Reference Example 6a. It was IR (neat):. 1580, 1550, 1530 cm -1 1 H-NMR (CDCl 3) δ: 2.58 (6 H, s), 7.02 (1 H, t, J
= 4.8 Hz), 8.69 (2 H, d, J = 4.8 Hz).

Reference Example 15a 5- (4-methoxybenzylthio) -2-[(pyrimidin-2-yl)
Imino] perhydropyrimidine dimethyl N- (pyrimidin-2-yl) dithiocarboxylic imidate (400 mg) was prepared according to the same method as in Reference Example 7a.
The title compound (559 mg) was obtained as a white solid. IR (KBr):. 1640, 1580, 1560, 1505 cm -1 1 H-NMR (CDCl 3) δ: 3.00 (1 H, tt, J = 9.6, 4.4 H
z), 3.27 (2 H, dd, J = 12.0, 9.6 Hz), 3.63 (2 H, d
d, J = 12.0, 4.4 Hz), 3.79 (2 H, s), 3.80 (3 H,
s), 6.54 (1 H, t, J = 4.8 Hz), 6.86 (2 H, d, J =
8.8 Hz), 7.26 (2 H, d, J = 8.8 Hz), 8.32 (2 H, d,
J = 4.8 Hz). Reference Example 16a 2-cyanoimino-5- (4-methoxybenzylthio) perhydropyrimidine dimethyl N-cyanodithiocarboxylic imidate (1.48 g)
-DMF (2: 1) mixed solution of and 2- (4-methoxybenzylthio) propane-1,3-diamine (2.29 g)
(75 ml) was stirred at room temperature for 4 hours. The solid obtained by distilling off the solvent under reduced pressure was used as a solvent (ethyl acetate-hexane, 2:
After washing with 1) and vacuum drying, the title compound (2.01 g)
Was obtained as a white solid. IR (KBr): 3250, 3180, 3030, 2170, 1640, 1580, 1510
^{. cm -1 1 H-NMR (} CDCl 3 -DMSO-d 6) δ: 2.83-3.00 (1 H, m), 3.0
0-3.20 (2 H, m), 3.33-3.50 (2 H, m), 3.76 (2 H,
s), 3.79 (3 H, s), 6.84 (2 H, d, J = 8.4 Hz), 7.23
(2 H, d, J = 8.4 Hz), 7.35 (2 H, brs).

Reference Example 17a The title compound (190 mg) was prepared from dimethyl N- (2-thiazolin-2-yl) dithiocarboxylic imidate 2-amino-2-thiazoline (1.02 g) in the same manner as in Reference Example 6a. Obtained as a yellow solid. IR (neat):. 1605, 1550, 1545, 1508 cm -1 1 H-NMR (CDCl 3) δ: 2.52 (6 H, s), 3.46 (2 H, t, J
= 8.0 Hz), 4.26 (2 H, t, J = 8.0 Hz). Reference Example 18a 5- (4-methoxybenzylthio) -2-[(2-thiazolin-2-yl) imino] perhydropyrimidine dimethyl N By a method similar to that in Reference Example 7a from-(2-thiazolin-2-yl) dithiocarboxylic imidate (185 mg), the title compound (172
mg) was obtained as a white solid. IR (KBr):. 1637, 1568, 1510 cm -1 1 H-NMR (CDCl 3) δ: 2.80-3.00 (1 H, m), 3.17 (2 H,
dd, J = 12.2, 10.4 Hz), 3.17 (2 H, t, J = 7.6 Hz),
3.49 (2 H, dd, J = 12.2, 4.8 Hz), 3.75 (2 H, s),
3.81 (3 H, s), 4.06 (2 H, d, J = 7.6 Hz), 6.85 (2
H, d, J = 8.4 Hz), 7.23 (2 H, d, J = 8.4 Hz).

Reference Example 19a The title compound (1.68 g) was obtained as a white solid from dimethyl N- (methylsulfonyl) dithiocarboxylic imidate methanesulfonamide (3.80 g) in the same manner as in Reference Example 6a. Known compound. Reference Example 20a 5- (4-methoxybenzylthio) -2- (methylsulfonylimino) perhydropyrimidine Dimethyl N- (methylsulfonyl) dithiocarboxylic imidate (0.88 g) was prepared according to the same method as in Reference Example 7a.
The title compound (0.8 g) was obtained as a white solid. IR (KBr):. 3350, 1640, 1610, 1580, 1510 cm -1 1 H-NMR (CDCl 3 -CD 3 OD) δ: 2.91 (3 H, s), 2.98 (1 H,
tt, J = 8.4, 4.4 Hz), 3.17 (2 H, dd, J = 12.4, 8.4
Hz), 3.47 (2 H, dd, J = 12.4, 4.4 Hz), 3.80 (2 H,
s), 3.82 (3 H, s), 6.89 (2 H, d, J = 8.6 Hz), 7.2
7 (2 H, d, J = 8.6 Hz).

Reference Example 21a Dimethyl N-[(pyridin-3-yl) carbonyl] dithiocarboxylic imidate 3-pyridinecarboxamide (4.88 g) to Reference Example 6a
Following a method similar to the above, the title compound (4.5 g) was obtained as a yellow solid. Known compound. Reference Example 22a 5- (4-Methoxybenzylthio) -2-[(pyridin-3-yl) carbonylimino] perhydropyrimidine dimethyl N-[(pyridin-3-yl) carbonyl] dithiocarboxylic imidate (1.56 g) From the above, the title compound (1.89 g) was obtained as a white solid according to the same method as in Reference Example 7a. IR (KBr):. 1615, 1600, 1580, 1555, 1515 cm -1 1 H-NMR (CDCl 3) δ: 2.90-3.10 (1
H, m), 3.23 (2 H, dd, J =
12.0, 9.2 Hz), 3.48 (2 H,
dd, J = 12.0, 4.4 Hz),
3.79 (2 H, s), 3.82 (3 H,
s), 6.87 (2H, d, J = 8.8)
Hz), 7.25 (2 H, d, J =
8.8 Hz), 7.30 (1 H, ddd,
J = 7.8, 4.8, 0.8 Hz), 8.3
4 (1 H, dt, J = 7.8, 2.0
Hz), 8.64 (1 H, dd, J =
4.8, 2.0 Hz), 9.30 (1 H,
dd, J = 2.0, 0.8 Hz).

Reference Example 23a The title compound (1.83 g) was obtained as a white solid from dimethyl N- (pyridin-4-yl) dithiocarboxylic imidate 4-aminopyridine (2.82 g) in the same manner as in Reference Example 6a. . IR (KBr):. 1575, 1540 cm -1 1 H-NMR (CDCl 3) δ: 2.52 (6 H, s), 6.79 (2 H, dd, J
= 4.6, 1.6 Hz), 8.49 (1 H, dd, J = 4.6, 1.6 Hz). Reference Example 24a 5- (4-methoxybenzylthio) -2-[(pyridin-4-yl) imino] perhydropyrimidine The title compound (1.41 g) was obtained as a white solid from dimethyl N- (pyridin-4-yl) dithiocarboxylic imidate (1.83 g) according to the same method as in Reference Example 7a. IR (KBr):. 1640, 1605, 1580, 1540, 1510 cm -1 1 H-NMR (CDCl 3) δ: 2.90-3.05 (1 H, m), 3.15 (2 H,
dd, J = 11.8, 8.8 Hz), 3.39 (2 H, dd, J = 11.8, 4.4
Hz), 3.76 (2 H, s), 3.81 (3 H, s), 6.80 (2H, dd,
J = 4.8, 1.6 Hz), 6.86 (2 H, d, J = 8.6 Hz), 7.24
(2 H, d, J = 8.6 Hz), 8.34 (2 H, dd, J = 4.8, 1.6
Hz).

Reference Example 25a 1,3-bis (methylamino) propan-2-ol 1,3-dichloropropan-2-ol (19.3 g) was added to a methanol solution of methylamine (40%, 75 ml), 12 in sealed tube
The mixture was stirred at 0 ° C for 3 hours. The insoluble material was filtered off and the filtrate was concentrated to give the title compound (20.7 g). Reference Example 26a (2-hydroxy-1,3-propanediyl) bis [(methylimino) bisformate t-butyl] 1,3-bis (methylamino) propan-2-ol (17.7 g)
In tetrahydrofuran (100 ml) at 0 ° C, 1N sodium hydroxide solution (195 ml), followed by bis (carbonic acid t-
Butyl) anhydride (72.0 g) in tetrahydrofuran (3
30 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 2 days. Tetrahydrofuran was distilled off under reduced pressure, and the resulting solution was extracted with ether. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by flash column chromatography (carrier: silica gel, 300 g, developing solvent: ethyl acetate-hexane, 1: 4) to give the title compound (26.7 g) as a colorless oil. Got as. IR (neat): 3444, 3976, 1699, 1483, 1392, 1155 cm
^{. -1 1 H-NMR (CDCl} 3) δ: 1.46 (18 H, s), 2.04 (1 H, s),
2.93 (6 H, s), 3.10-3.42 (4 H, m), 3.95-4.02 (1 H,
m).

Reference Example 27a (2-Methylsulfonyloxy-1,3-propanediyl) bis
[(Methylimino) bisformate t-butyl] (2-hydroxy-1,3-propanediyl) bis [(methylimino) bisformate t-butyl] (26.7 g) in tetrahydrofuran (150 ml) under ice-cooling triethylamine ( (14.0 ml)
Subsequently, methanesulfonyl chloride (7.14 ml) was added and the mixture was stirred for 2 hours. Ethyl acetate (300 ml) was added to the reaction solution, and the organic layer was washed successively with water, 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (28.9 g) as a colorless oil. IR (neat):. 1697, 1365, 1174, 1157 cm -1 1 H-NMR (CDCl 3) δ: 1.47 (18 H, s), 2.95 (6 H, s),
2.98 (3 H, s), 3.36-3.57 (4 H, m), 4.98-5.05 (1 H,
m). Reference Example 28a [2- (4-Methoxybenzylthio) -1,3-propanediyl] bis [(methylimino) bis t-butylformate] 4-methoxybenzylmercaptan (15.2 ml) in dimethylformamide solution (240 ml) to sodium hydride (3.
24 g) was added, and the mixture was stirred at room temperature for 10 minutes and at 80 ° C. for 20 minutes.
After cooling the reaction mixture to -10 ° C, (2-methylsulfonyloxy-
1,3-Propanediyl) bis [(methylimino) bisformate t-butyl] solution (28.9 g) in dimethylformamide (45 ml)
After adding, the mixture was stirred at room temperature for 32 hours. The reaction solution was added to ice water and extracted with ether. The combined organic layers were washed with water, then saturated brine, and dried over anhydrous sodium sulfate.
The residue obtained by evaporating the solvent under reduced pressure was purified by flash column chromatography (carrier: silica gel, 280 g, developing solvent: ethyl acetate-hexane, 1: 5) to give the title compound (12.6 g) as a colorless oil. Got as. IR (neat): 2974, 1693, 1512, 1392, 1250, 1174, 11
^{. 53 cm -1 1 H-NMR} (CDCl 3) δ: 1.45 (18 H, s), 2.82 (6 H, s),
3.03-3.24 (3 H, m), 3.39-3.49 (2 H, m), 3.71 (2 H,
s), 3.79 (3 H, s).

Reference Example 29a 2- (4-methoxybenzylthio) -N, N'-dimethyl-1,3-propanediamine [2- (4-methoxybenzylthio) -1,3-propanediyl] bis [( Methylimino) bis-formate t-butyl] (7 g) at 0 ° C with trifluoroacetic acid (15.4 ml) and anisole (15.4 ml)
Was added, and the mixture was stirred at room temperature for 2 hours. Toluene was added to the residue obtained by distilling off the solvent under reduced pressure, and the solvent was again distilled off by azeotropic distillation. Water was added to the obtained residue, and the aqueous layer was washed with hexane. The aqueous layer was adjusted to pH 10.5 with 1N sodium hydroxide and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium carbonate, and the solvent was evaporated under reduced pressure to give the title compound (3.78 g) as a colorless oil. IR (neat): 3388, 2937, 1610, 1512, 1456, 1250 cm
^{. -1 1 H-NMR (CDCl} 3) δ: 1.60 (2 H, brs), 2.36 (6 H, s),
2.59-2.90 (5 H, m), 3.71 (2 H, s), 3.79 (3 H, s),
6.84 (2 H, d, J = 8.8 Hz), 7.25 (2 H, d, J = 8.8 H
z). Reference Example 30a 2- (acetylimino) -1,3-dimethyl-5- (4-methoxybenzylthio) perhydropyrimidine dimethyl N-acetyldithiocarboxylic imidate (404 m
g) and 2- (4-methoxybenzylthio) -N, N'-dimethyl-1,3-
The title compound (798 mg) was obtained as a pale yellow foam by carrying out the same reaction as in Reference Example 7a using propanediamine (629 mg). IR (neat): 3394, 1585, 1520, 1514, 1410, 1244 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 2.09 (3 H, s), 2.96 (6 H, s), 3.0
5-3.34 (5 H, m), 3.77 (2 H, s), 3.81 (3 H, s), 6.86
(2 H, d, J = 8.8 Hz), 7.22 (2 H, d, J = 8.8 Hz).

Reference Example 31a 1,3-Dimethyl-5- (4-methoxybenzylthio) -2- (thiazol-2-ylimino) perhydropyrimidine dimethyl N-acetyldithiocarboxylic imidate (161 m
g) and 2- (4-methoxybenzylthio) -N, N'-dimethyl-1,3-
The title compound (286 mg) was obtained as a pale yellow foam by carrying out the same reaction as in Reference Example 7a using propanediamine (200 mg). IR (neat): 3354, 2931, 1539, 1412, 1304, 1246, 113
^{. 0, 1032, 835 cm -1} 1 H-NMR (CDCl 3) δ: 2.88 (6 H, s), 2.97-3.34 (5 H,
m), 3.77 (2 H, s), 3.81 (3 H, s), 6.49 (1 H, d, J =
4.2 Hz), 6.86 (2 H, d, J = 8.4 Hz), 7.12 (1H, d,
J = 4.2 Hz), 7.24 (2 H, d, J = 8.4 Hz). Reference Example 32a 5- (4-methoxybenzylthio) -1,3-dimethyl-2- (methylsulfonylimino) perhydropyrimidine dimethyl N The title compound (0.98 g) was obtained as a colorless oil from-(methylsulfonyl) dithiocarboxylic imidate (0.79 g) and in the same manner as in Reference Example 30a. IR (neat): 3550, 3500, 1610, 1560, 1530, 1510 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 2.9-3.4 (5 H, m), 3.00 (3 H,
s), 3.12 (6 H, s), 3.77 (2 H, s), 3.82 (3 H, s), 6.
88 (2 H, d, J = 8.6 Hz), 7.24 (2 H, d, J = 8.6 H
z).

Reference Example 33a 2-cyanoimino-5- (4-methoxybenzylthio) -1,3-dimethylperhydropyrimidine dimethyl N-cyanodithiocarboxylic imidate (1.76 g)
To the title compound in the same manner as in Reference Example 30a.
(2.61 g) was obtained as a white solid. IR (KBr):. 2160, 1605, 1560, 1550, 1510 cm -1 1 H-NMR (CDCl 3) δ: 2.85-3.35 (5 H, m), 3.12 (6 H,
s), 3.77 (2 H, s), 3.82 (3 H, s), 6.89 (2 H, d, J
= 8.8 Hz), 7.24 (2 H, d, J = 8.8 Hz). Reference Example 34a 2- [2- (N, N-dimethylamino) ethoxy] -5- (4-methoxybenzylthio) -1,4 2,5,6-Tetrahydropyrimidine 5- (4-methoxybenzylthio) -2-methylthio-1,4,5,6-tetrahydropyrimidine (1.0 g) in 2- (dimethylamino)
Ethanol (3 ml) was added, and the mixture was stirred under heating reflux for 3 hours. The solid obtained by distilling off 2- (dimethylamino) ethanol under reduced pressure was washed with a solvent (ether-hexane, 2: 1) and then dried under vacuum to obtain the title compound (1.02 g) as a white solid. . IR (KBr):. 1640, 1520 cm -1 1 H-NMR (CDCl 3) δ: 2.26 (6 H, s), 2.53 (2 H, t, J
= 5.6 Hz), 2.82 (1 H, tt, J = 9.2, 4.6 Hz), 3.05-3.
70 (4 H, m), 3.75 (2 H, s), 3.81 (3 H, s), 4.09 (2
H, t, J = 5.6 Hz), 6.85 (2 H, d, J = 8.6 Hz), 7.25
(2 H, d, J = 8.6 Hz).

Reference Example 35a 5- (4-methoxybenzylthio) -2- [2- [N-methyl-N- (4-nitrobenzyloxycarbonyl) amino] ethoxy] -1,4,
5,6-Tetrahydropyrimidine 5- (4-methoxybenzylthio) -2-methylthio-1,4,5,6-tetrahydropyrimidine (1.0 g) and 2- [N-methyl-N- (4-nitrobenzyloxy Carbonyl) amino] ethanol (0.
The title compound (464 mg) was obtained as a yellow solid from 9 g) according to the same method as in Reference Example 34a. IR (KBr):. 1700, 1640, 1605, 1520, 1515 cm -1 1 H-NMR (CDCl 3) δ: 2.70-2.90 (1 H, m), 2.99 (3 H,
s), 3.05-3.25 (2 H, m), 3.35-3.55 (2 H, m), 3.55
(2 H, t, J = 5.6 Hz), 3.75 (2 H, s), 3.80 (3H, s),
4.1-4.2 (2 H, m), 5.21 (2 H, s), 6.85 (2 H, d, J
= 8.8 Hz), 7.25 (2 H, d, J = 8.8 Hz), 7.51 (2 H, d,
J = 8.8 Hz), 8.22 (2 H, d, J = 8.8 Hz). Reference Example 36a 5- (benzoylthio) -2-thioxoperhydropyrimidine 5- (4-methoxybenzylthio) -2-thioxo A solution of perhydropyrimidine (1.68 g) in trifluoroacetic acid (65 ml)
After adding anisole (6.5 ml, 65 mmol) to the mixture, the mixture was stirred under heating under reflux for 2.5 hours. Toluene was added to the residue obtained by distilling off the solvent under reduced pressure, and trifluoroacetic acid was further removed by azeotropic distillation under reduced pressure. Pyridine solution of the obtained residue
To (25 ml), benzoyl chloride (0.76 ml) was added at 0 ° C, and the mixture was stirred at 0 ° C for 1 hr. The solvent was distilled off under reduced pressure, ethyl acetate and water were added to the obtained residue, the insoluble matter was collected by filtration, and washed with ethyl acetate to give the title compound (1.
30 g) was obtained as a colorless solid. IR (KBr):. 3174, 1655, 1558, 1209 cm -1 1 H-NMR (DMSO-d 6) δ: 3.10-3.30 (2 H, m), 3.50-3.70
(2 H, m), 4.05-4.20 (1 H, m), 7.50-7.80 (3 H, m),
7.80-8.00 (2 H, m), 8.16 (2 H, brs).

Reference Example 37a 6- (benzoylthio) -3-hydroxy-5H-2,3,6,7-tetrahydrothiazolo [3,2-a] pyrimidine hydrochloride 5- (benzoylthio) -2-thi Oxoperhydropyrimidine
(757 mg) in THF (20 ml) and chloroacetaldehyde
(0.77 ml) was sequentially added, and the mixture was heated under reflux overnight. After cooling the reaction solution, the produced solid substance was collected by filtration and washed with THF to obtain the title compound (935 mg) as a colorless solid substance. IR (KBr):. 3178, 1672, 1637 cm -1 1 H-NMR (DMSO-d 6) δ: 3.20-4.10 (8
H, m), 4.30-4.45 (1 H,
m), 5.60-5.75 (1 H, m),
7.50-7.80 (3 H, m), 7.80-
8.00 (2 H, m). Reference Example 38a 6- (benzoylthio) -5H-6,7-dihydrothiazolo [3,2-
Dichloromethane (40 ml) was added to a] pyrimidine 6- (benzoylthio) -3-hydroxy-5H-2,3,6,7-tetrahydrothiazolo [3,2-a] pyrimidine hydrochloride (1.23 g), After cooling to -78 ° C, diisopropylethylamine (3.24 ml, 18.6 mmol) was added dropwise. The mixture was stirred at 0 ° C for 30 minutes, cooled to -78 ° C again, trifluoromethanesulfonic anhydride (1.24 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour. The reaction solution was washed with pH 7 phosphate buffer and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by flash column chromatography (carrier: silica gel, 50 g, developing solvent: ethyl acetate-hexane, 1: 4) to give the title compound (550 mg) as a colorless oil. I got it as a thing. IR (neat): 3120, 1664, 1635, 1377, 1228, 1200 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 3.30-3.70 (2 H, m), 4.00-4.30
(3 H, m), 6.24 (1 H, d, J = 5.4 Hz), 7.74 (2 H, d,
J = 5.4 Hz), 7.40-7.70 (3 H, m), 7.85-8.05 (2 H,
m).

Reference Example 39a 5- (4-methoxybenzylthio) -2- (2-methoxyethylthio) -1,4,5,6-tetrahydropyrimidine 5- (4-methoxybenzylthio) perhydropyrimidine-2 -
Sodium hydride (purity 60%, 156 mg) was added to a DMF solution (8 ml) of thione (1.0 g) at 0 ° C, and the mixture was stirred for 30 minutes. Add 2-bromoethyl methyl to the reaction solution at 0 ° C.
After adding a solution of ether (518 mg) in DMF (2 ml), 0
The mixture was stirred at ℃ for 1.5 hours and at room temperature overnight. After water was added dropwise at 0 ° C to decompose excess sodium hydride, the reaction solution was extracted with ether. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by flash column chromatography (carrier: silica gel, 50 g, developing solvent: ethanol-ethyl acetate, 1:20 to 1: 4) to give the title compound (797 mg )
Was obtained as a white solid. IR (KBr):. 1600, 1510 cm -1 1 H-NMR (CDCl 3) δ: 2.84 (1 H, tt, J = 9.6, 4.8 H
z), 3.10 (2 H, t, J = 6.0 Hz), 3.18 (2 H, dd, J =
13.2, 9.6 Hz), 3.37 (3 H, s), 3.51 (2 H, dd, J = 1
3.2, 4.8 Hz), 3.58 (2 H, t, J = 6.0 Hz), 3.75 (2
H, s), 3.80 (3 H, s), 6.85 (2 H, d, J = 8.6 Hz),
7.25 (2 H, d, J = 8.6 Hz).

Reference Example 40a 5- (4-methoxybenzylthio) -2- (pyridin-2-yl) -1,
4-5.6-Tetrahydropyrimidine 5- (4-methoxybenzylthio) -2-thioxoperhydropyrimidine (1.34 g) in DMF solution (5 ml), 2-bromopyridine (0.48 ml) was added dropwise at 130 ° C. Stir for hours. Ethyl acetate (20 ml) was added to the reaction solution and extracted with water,
The obtained aqueous layer was made weakly basic with saturated sodium hydrogen carbonate and further extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.43 g) as a yellow oil. IR (neat):. 1614, 1512, 1248 cm -1 1 H-NMR (CDCl 3) δ: 2.86-2.99 (1 H, m), 3.21-3.33
(2 H, m), 3.56-3.65 (2 H, m), 3.76 (2 H, s), 3.80
(3 H, s), 6.85 (2 H, d, J = 8.4 Hz), 6.95 (1H, br
s), 7.09-7.16 (1 H, m), 7.23-7.31 (3 H, m), 7.55-
7.63 (1 H, m), 8.41-8.44 (1 H, m).

Example 1a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-3-[(2-methylthio-1,4,5,5,
6-Tetrahydropyrimidin-5-yl) thio] -7-
Oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl 5- (4-methoxybenzylthio) -2-methylthio-
Anisole (0.75 g) was added to a solution of 1,4,5,6-tetrahydropyrimidine (197 mg) in trifluoroacetic acid (7.5 ml).
After adding, the mixture was stirred with heating under reflux for 2 hours. Toluene was added to the residue obtained by distilling off the solvent under reduced pressure, and trifluoroacetic acid was further removed by azeotropic distillation under reduced pressure. The residue thus obtained was used as an acetonitrile solution (7 ml), and diisopropylethylamine (0.49 g) was added dropwise at 0 ° C. Furthermore, at 0 ° C. (4R, 5R, 6S) -3-[(diphenylphosphono) oxy] -6-[(R) -1-hydroxyethyl]-
4-Methyl-7-oxo-1-azabicyclo [3.2.
0] Hept-2-ene-2-carboxylic acid 4-nitrobenzyl (414 mg) was added, and the mixture was stirred at 0 ° C for 2.5 hr.
A pH 7 phosphate buffer was added to the reaction solution, which was extracted with dichloromethane and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by flash column chromatography (carrier: silica gel, 10 g, developing solvent: methanol-dichloromethane, 1:10) to give the title compound.
(99 mg) was obtained as a yellow solid. IR (KBr):. 3400, 1770, 1710, 1600, 1520 cm -1 1 H-NMR (CDCl 3) δ: 1.27 (3H, d, J = 7.4Hz), 1.34
(3H, d, J = 6.2Hz), 2.34 (3H, s), 3.20-3.80 (6H, m), 3.27
(1H, dd, J = 6.6, 2.6Hz), 4.25 (1H, dd, J = 9.2, 2.6Hz), 4.
25 (1H, quint, J = 6.6Hz), 5.22 (1H, d, J = 13.6Hz), 5.50 (1
H, d, J = 13.6Hz), 7.65 (2H, d, J = 8.8Hz), 8.22 (2H, d, J = 8.8Hz
Hz).

Example 2a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-3-[(2-methylthio-1,4,5,5
6-Tetrahydropyrimidin-5-yl) thio] -7-
Oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate sodium The compound (30 mg) obtained by the method of Example 1a was treated with THF.
(1 ml) and pH 7 phosphate buffer (0.1 M, 1 ml), 10% palladium carbon (30 mg) was added, and the mixture was stirred at room temperature for 1 hr under hydrogen atmosphere. The catalyst was filtered off, washed with water and the filtrate was washed with dichloromethane. The aqueous layer was concentrated under reduced pressure and subjected to column chromatography (carrier: CH
P-20P, 30 ml, developing solvent: water → ethanol-water,
5: 100) and lyophilized to give the title compound (1
1.3 mg) was obtained as a white solid. IR (KBr):. 3400, 1750, 1600 cm -1 1 H-NMR (D 2 O) δ: 1.23 (3H, d, J = 7.2Hz), 1.30 (3H,
d, J = 6.4Hz), 2.59 (3H, s), 3.30-3.90 (6H, m), 3.51 (1H, d
d, J = 6.2, 2.8Hz), 4.26 (1H, quint, J = 6.2Hz), 4.28 (1H, d
d, J = 9.4, 2.8Hz).

Example 3a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-3-[[2- (thiazol-2-yl) amino- 1,4,5,6-Tetrahydropyrimidin-5-yl] thio] -1-azabicyclo [3.
2.0] Hept-2-ene-2-carboxylic acid 4-nitrobenzyl 5- (4-methoxybenzylthio) -2- (thiazole-
After adding anisole (1.2 g) to a trifluoroacetic acid solution (12 ml) of 2-yl) amino-1,4,5,6-tetrahydropyrimidine (393 mg), the mixture was further heated at 50 ° C. for 1 hour under reflux. Stir for 2 hours. Toluene was added to the residue obtained by distilling off the solvent under reduced pressure, and trifluoroacetic acid was further removed by azeotropic distillation under reduced pressure. The residue thus obtained was made into an acetonitrile solution (15 ml), and diisopropylethylamine (0.38 g) was added dropwise at 0 ° C. At 0 ° C (4R,
5R, 6S) -3-[(diphenylphosphono) oxy]-
6-[(R) -1-hydroxyethyl] -4-methyl-7
-Oxo-1-azabicyclo [3.2.0] hept-2-
4-Nitrobenzyl ene-2-carboxylic acid (696 mg)
Was added, and the mixture was stirred at 0 ° C. for 2 hours and at room temperature for 15 minutes. PH7 phosphate buffer was added to the reaction mixture and extracted with ethyl acetate,
Dry over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure is subjected to flash column chromatography.
(Carrier: silica gel, 50 g, developing solvent: methanol-
Purify with dichloromethane, 1:20) to give the title compound (50
3 mg) was obtained as a yellow solid. IR (KBr): 3400, 1770, 1710, 1620, 1560, 1520 cm
^{. -1 1 H-NMR (CDCl} 3) δ: 1.30 (3H, d, J = 7.2Hz), 1.37
(3H, d, J = 6.2Hz), 3.31 (1H, dd, J = 6.6, 2.9Hz), 3.30-3.
85 (6H, m), 4.28 (1H, dd, J = 9.5, 2.9Hz), 4.29 (1H, quint,
J = 6.6Hz), 5.23 (1H, d, J = 13.9Hz), 5.50 (1H, d, J = 13.9H)
z), 6.55 (1H, d, J = 3.7Hz), 7.15 (1H, d, J = 3.7Hz), 7.64 (2
H, d, J = 8.4Hz), 8.21 (2H, d, J = 8.4Hz).

Example 4a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-3-[[2- (thiazol-2-yl) amino- 1,4,5,6-Tetrahydropyrimidin-5-yl] thio] -1-azabicyclo [3.
2.0] Sodium hept-2-ene-2-carboxylate The compound of Example 3a (250 mg) was added with THF (4 ml) and p.
It was dissolved in H7 phosphate buffer (0.1 M, 4 ml), 10% palladium carbon (250 mg) was added, and the mixture was stirred at room temperature for 1 hr under a hydrogen atmosphere. The catalyst was filtered off, washed with water and the filtrate was washed with dichloromethane. The aqueous layer was concentrated under reduced pressure and subjected to column chromatography (carrier: CHP-20P,
70 ml, developing solvent: ethanol-water, 5: 100 → 4
0: 100) and then lyophilized to give the title compound
(140.6 mg) was obtained as a white solid. IR (KBr): 34
^{. 00, 1750, 1610 cm -1} 1 H-NMR (D 2 O) δ: 1.24 (3H, d, J = 7.2Hz), 1.30 (3H,
d, J = 6.6Hz), 3.30-3.85 (6H, m), 3.48 (1H, dd, J = 6.4, 2.8
Hz), 4.26 (1H, dd, J = 9.4, 2.8Hz), 4.27 (1H, quint, J = 6.6
Hz), 6.89 (1H, d, J = 3.8Hz), 7.27 (1H, d, J = 3.8Hz).

Example 5a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-3-[(RS)-(5H
-2,3,6,7-Tetrahydrothiazolo [3,2-a] pyrimidin-6-yl) thio] -1-azabicyclo [3.
2.0] Hept-2-ene-2-carboxylic acid 4-nitrobenzyl 6- (4-methoxybenzylthio) -5H-2,3,6,7
-Tetrahydrothiazolo [3,2-a] pyrimidine (19
0 mg) in trifluoroacetic acid solution (6.6 ml) with anisole
(0.66 ml) was added, and the mixture was stirred with heating under reflux for 3 hr.
Toluene was added to the residue obtained by distilling off the solvent under reduced pressure,
Further, trifluoroacetic acid was removed by azeotropic distillation under reduced pressure.
The residue thus obtained was made into an acetonitrile solution (6 ml), and diisopropylethylamine (0.28 ml) was added dropwise at 0 ° C. Further at 0 ° C. (4R, 5R, 6S) -3-[(diphenylphosphono) oxy] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3. 2.0] Hept-2-ene-2-carboxylic acid
4-Nitrobenzyl (384 mg) was added, and the mixture was stirred at 0 ° C for 1 hr and 30 min. PH7 phosphate buffer was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After adding saturated saline to the extract and shaking,
The precipitate was collected by filtration to give the title compound (220 mg) as a colorless solid. IR (KBr):. 3410, 1770, 1640, 1515 cm -1 1 H-NMR (DMSO-d 6) δ: 1.10-1.30 (6H, m), 3.10-
4.10 (12H, m), 4.25-4.35 (1H, m), 5.15-5.25 (1H, m), 5.3
9 (2H, ABq, J = 14.4Hz), 7.72 (0.5H, d, J = 8.8Hz), 7.73 (0.5
H, d, J = 8.8Hz), 8.26 (1H, d, J = 8.8Hz).

Example 6a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-3-[(RS)-(5H
-2,3,6,7-Tetrahydrothiazolo [3,2-a] pyrimidin-6-yl) thio] -1-azabicyclo [3.
2.0] Hept-2-ene-2-carboxylic acid The compound (180 mg) obtained by the method of Example 5a was treated with THF.
(10 ml) and pH7 phosphate buffer (0.1 M, 10 ml)
It was dissolved in 10% palladium carbon (80 mg), and hydrogenated at room temperature under atmospheric pressure for 1 hour. The catalyst was filtered off and washed with water, and the filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure and subjected to column chromatography (carrier: C
HP-20P, 80 ml, developing solvent: water → ethanol-
Water, 5:95) and lyophilize to give the title compound
(64 mg) was obtained as a white solid. IR (KBr):. 3430, 1755, 1640, 1595 cm -1 1 H-NMR (D 2 O) δ: 1.23 (3H, d, J = 7.2Hz), 1.30 (3H,
d, J = 6.4Hz), 3.30-4.10 (11H, m), 4.20-4.35 (2H, m).

Example 7a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-3-[(RS)-(5H
-2,3,6,7-Tetrahydrothiazolo [3,2-a] pyrimidin-6-yl) thio] -1-azabicyclo [3.
2.0] Hept-2-ene-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) ethyl Example 6a
The compound (20.9 mg) obtained by the method of 1) and sodium hydrogen carbonate (4.6 mg) were dissolved in water (1 ml) and freeze-dried. The obtained solid was dissolved in dry N, N-dimethylacetamide (1 ml) at -15 ° C to give cyclohexyloxycarboxylic acid.
1-Iodoethyl (21 mg) was added, and the mixture was stirred at -15 ° C for 30 minutes,
Stirred at 0 ° C. for 1 hour. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by flash column chromatography (carrier: silica gel, 4 g, developing solvent: ethyl acetate-ethanol, 4: 1 → 1: 1) to give the title compound.
(11 mg) was obtained as a colorless oil. IR (neat):. 3300, 2940, 1760, 1720, 1620 cm -1 1 H-NMR (CDCl 3) δ: 1.10-2.10 (19H, m), 3.00-3.
80 (11H, m), 4.10-4.30 (2H, m), 4.50-4.70 (2H, m), 5.80-
6.00 (1H, m).

Example 8-1a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -3-[(2-methoxy-1,4,5,6-tetrahydropyrimidine-5- Il) Thio] -4-
Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene
2-Carboxyl 4-nitrobenzyl 5- (4-methoxybenzylthio) -3,4,5,6-tetrahydropyrimidin-2 (1H) -one (800 mg) in methyl p-toluenesulfonate (4.9 g ) Was added, and the mixture was stirred at 80 ° C. for 2 hours. The mixture was cooled to room temperature, washed successively with the solvent (ether, ether-acetonitrile 8: 1, ether), and the obtained residue was dried under vacuum. Trifluoroacetic acid solution of this residue
Add anisole (3.0 g) to (30 ml) and then at 50 ° C.
Stir for 1 hour. Toluene was added to the residue obtained by distilling off the solvent under reduced pressure, and trifluoroacetic acid was further removed by azeotropic distillation under reduced pressure. The residue obtained was treated with acetonitrile (20
ml) and diisopropylethylamine at 0 ° C
(1.51 g) was added dropwise. Further at 0 ℃ (4R, 5R, 6S) -3
-[(Diphenylphosphono) oxy] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4 -Nitrobenzyl (1.60 g)
Solution in acetonitrile (30 ml) was added at 0 ° C for 1.5
Stirred for hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, the mixture was washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 30 g, developing solvent: acetonitrile to acetonitrile-ethanol,
2: 1) to obtain the title compound (879 mg) as a white solid. IR (KBr):. 3420, 1770, 1700, 1650, 1610 cm -1 1 H-NMR (CDCl 3) δ: 1.29 (3 H, d, J = 7.4 Hz), 1.36
(3 H, d, J = 6.2 Hz), 3.20-3.70 (6 H, m), 3.29 (1
H, dd, J = 6.6, 2.6 Hz), 3.66 (3 H, s), 4.26 (1 H,
dd, J = 9.8, 2.6 Hz), 4.27 (1 H, quint, J = 6.6 H
z), 5.22 (1 H, d, J = 13.8 Hz), 5.52 (1 H, d, J = 1
3.8 Hz), 7.66 (2 H, d, J = 8.8 Hz), 8.23 (2 H, d, J
= 8.8 Hz).

Example 8-2a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -3-[(2-methoxy-1,4,5,6-tetrahydropyrimidine-5- Il) Thio] -4-
Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene
-2-carboxylic acid According to the method similar to the method of Example 2a from the compound (177 mg) obtained by the method of Example 8-1a, the title compound (93.1 m
g) was obtained as a white solid. IR (KBr):. 3420, 1755, 1660, 1620, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3 H, d, J = 7.2 Hz), 1.30
(3 H, d, J = 6.4 Hz), 3.35-3.60 (3 H, m), 3.51 (1
H, dd, J = 6.0, 2.4 Hz), 3.65-3.90 (3 H, m), 4.00
(3 H, s), 4.27 (1 H, quint, J = 6.0 Hz), 4.28 (1
H, dd, J = 9.8, 2.4 Hz).

Example 9a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -3-[(2-methoxy-1,4,5,6-tetrahydropyrimidin-5-yl) Thio] -4-
Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene
2- (Cyclohexyloxycarbonyloxy) ethyl 2-carboxylate An aqueous solution (2 ml) of the compound (44.4 mg) obtained by the method of Example 8-2a was added to an aqueous solution (17.3 mg) of potassium carbonate (17.3 mg).
ml) and freeze-dried to obtain the solid obtained in Example 10.
Was subjected to the same reaction and purification treatment as for -3a to give the title compound (52
mg) was obtained as a white solid. IR (KBr):. 3400, 1760, 1650, cm -1 1 H-NMR (CDCl 3) δ: 1.20-2.30 (10 H, m), 1.27 (3 H,
d, J = 7.2 Hz), 1.33 (3/2 H, d, J = 6.2 Hz), 1.35
(3/2 H, d, J = 6.2 Hz), 1.59 (3/2 H, d, J = 5.4 H
z), 1.61 (3/2 H, d, J = 5.4 Hz), 3.20-3.70 (6 H,
m), 3.24 (1 H, dd, J = 6.6, 2.4 Hz), 3.70 (3 H,
s), 4.16-4.32 (1 H, m), 4.23 (1 H, dd, J = 9.2, 2.4
Hz), 4.55-4.75 (1 H, m), 6.89 (1 H, q, J = 5.4 H
z).

Example 10-1a (4R, 5S, 6S) -3-[[2- (Dimethylcarbamoylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl] 4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl 2- (dimethylcarbamoylimino) -5- (4-methoxybenzylthio) perhydro Anisole (1.0 g) was added to a solution of pyrimidine (314 mg) in trifluoroacetic acid (10 ml), and the mixture was stirred with heating under reflux for 2 hr. Toluene was added to the residue obtained by distilling off the solvent under reduced pressure, and trifluoroacetic acid was further removed by azeotropic distillation under reduced pressure. The obtained residue was dissolved in acetonitrile (5 ml), and diisopropylethylamine (0.34 g) was added dropwise at 0 ° C. At 0 ° C
(4R, 5R, 6S) -3-[(Diphenylphosphono) oxy] -6-[(R)-
1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hepto-2-ene-2-carboxylate 4-nitrobenzyl (0.58 g) in acetonitrile (10 ml) was added, 0
The mixture was stirred at ℃ for 1.5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, the mixture was washed with water and saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by flash column chromatography (carrier: silica gel, 10 g, developing solvent: ethyl acetate-ethanol, 4: 1) to give the title compound.
(438 mg) was obtained as a white solid. IR (KBr):. 3420, 1770, 1710, 1620, 1580 cm -1 1 H-NMR (CDCl 3 -DMSO-d 6) δ: 1.28 (3 H, d, J = 7.0 H
z), 1.33 (3 H, d, J = 6.2 Hz), 2.96 (6 H, s), 3.28
(1 H, dd, J = 7.0, 2.4 Hz), 3.20-3.80 (6 H, m), 4.1
6 (1 H, quint, J = 7.0 Hz), 4.30 (1 H, dd, J = 9.
2, 2.4 Hz), 5.23 (1 H, d, J = 13.6 Hz), 5.52 (1 H,
d, J = 13.6 Hz), 7.68 (2 H, d, J = 8.8 Hz), 8.23
(2 H, d, J = 8.8 Hz).

Example 10-2a (4R, 5S, 6S) -3-[[2- (Dimethylcarbamoylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl] 4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate sodium Compound (151 mg) obtained by the method of Example 10-1a
THF (5 ml) and phosphate buffer (pH 7, 0.1 M, 5 ml)
10% palladium carbon (151 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hr. The catalyst was filtered off, washed with water, and THF was distilled off from this filtrate under reduced pressure, followed by washing with ethyl acetate. The aqueous layer was concentrated under reduced pressure, purified by column chromatography (carrier: CHP-20P, 50 ml, developing solvent: water to ethanol-water, 1:10), and then lyophilized to give the title compound (92 mg). Was obtained as a white solid. IR (KBr):. 3420, 1750, 1680, 1610, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3 H, d, J = 7.2 Hz), 1.30
(3 H, d, J = 6.4 Hz), 2.95 (6 H, s), 3.30-3.90 (7
H, m), 4.26 (1 H, dd, J = 8.8, 2.0 Hz), 4.27 (1 H,
quint, J = 6.6 Hz).

Example 10-3a (4R, 5S, 6S) -3-[[2- (Dimethylcarbamoylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl] 4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate 1- (cyclohexyloxycarbonyloxy) ethyl Compound obtained by the method of Example 10-2a (46 mg)
1- (Cyclohexyloxycarbonyloxy) ethyl iodide (0.070 mg) was added to the DMA solution (1.5 ml) at -10 ° C, the temperature was raised to 0 ° C over 30 minutes, and then at 0 ° C 2
Stirred for hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 15 g, developing solvent: acetonitrile to acetonitrile-ethanol,
4: 1) and the title compound (15.2 mg) was obtained as a white solid. IR (KBr):. 3420, 1760, 1620, 1580 cm -1 1 H-NMR (CDCl 3) δ: 1.10-2.10 (10 H, m), 1.26 (3 H,
d, J = 7.2 Hz), 1.33 (3/2 H, d, J = 6.2 Hz), 1.35
(3/2 H, d, J = 6.4 Hz), 1.58 (3/2 H, d, J = 5.4 H
z), 1.61 (3/2 H, d, J = 5.4 Hz), 2.97 (6 H, brs),
3.20-3.80 (6 H, m), 3.26 (1 H, dd, J = 7.0, 2.6 H
z), 4.10-4.35 (1 H, m), 4.24 (1 H, quint, J = 6.6
Hz), 4.55-4.75 (1 H, m), 6.88 (1 H, q, J = 5.4 H
z).

Example 11-1a (4R, 5S, 6S) -3-[[2- (Benzoylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl]- Four-
Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene
2-Nitrocarboxylic acid 4-nitrobenzyl 2- (benzoylimino) -5- (4-methoxybenzylthio) perhydropyrimidine (560 mg) following the same method as in Example 10-1a to give the title compound (708 mg) Was obtained as a white solid. IR (KBr):. 3400, 1770, 1715, 1600, 1520 cm -1 1 H-NMR (CDCl 3) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.37
(3 H, d, J = 6.2 Hz), 3.10-3.60 (6 H, m), 3.29 (1
H, dd, J = 6.6, 2.8 Hz), 4.21 (1 H, dd, J = 9.6, 2.
8 Hz), 4.27 (1 H, quint, J = 6.6 Hz), 5.21 (1 H,
d, J = 13.8 Hz), 5.49 (1 H, d, J = 13.8 Hz), 7.30-
7.55 (3 H, m), 7.64 (2 H, d, J = 8.4Hz), 8.08 (2
H, d, J = 7.2 Hz), 8.22 (2 H, d, J = 8.4 Hz).

Example 11-2a (4R, 5S, 6S) -3-[[2- (Benzoylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl]- Four-
Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene
2-sodium carboxylate According to the same method as Example 10-2a from the compound (66 mg) obtained by the method of Example 11-1a, the title compound was obtained.
(23.1 mg) was obtained as a white solid. IR (KBr):. 3430, 1750, 1600 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3 H, d, J = 7.4 Hz), 1.30
(3 H, d, J = 6.2 Hz), 3.35-3.55 (3 H, m), 3.49 (1
H, dd, J = 6.6, 2.6 Hz), 3.65-3.90 (3 H, m), 4.26
(1 H, quint, J = 6.6 Hz), 4.27 (1 H, dd, J = 9.4,
2.6 Hz), 7.45-7.65 (3 H, m), 7.90-8.00 (2 H, m).

Example 11-3a (4R, 5S, 6S) -3-[[2- (Benzoylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl]- Four-
Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene
1- (Cyclohexyloxycarbonyloxy) ethyl-2-carboxylate Compound obtained by the method of Example 11-2a (54.3 mg)
According to the same method as in Example 10-3a, the title compound (54.3 mg) was obtained as a yellow solid. IR (KBr):. 3430, 1760, 1600 cm -1 1 H-NMR (CDCl 3) δ: 1.10-2.10 (10 H, m), 1.24 (3 H,
d, J = 7.2 Hz), 1.34 (3/2 H, d, J = 6.2 Hz), 1.36
(3/2 H, d, J = 6.2 Hz), 1.58 (3/2 H, d, J = 5.4 H
z), 1.60 (3/2 H, d, J = 5.4 Hz), 3.15-3.70 (7 H,
m), 4.15-4.35 (2H, m), 4.55-4.75 (1 H, m), 6.88 (1
H, q, J = 5.4 Hz), 7.30-7.55 (3 H, m), 8.05-8.15
(2 H, m).

Example 12-1a (4R, 5S, 6S) -3-[[2- (Acetylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl]- 4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2
-Carboxylic acid 4-nitrobenzyl 2- (acetylimino) -5- (4-methoxybenzylthio) perhydropyrimidine (560 mg) was treated according to the same method as Example 10-1a to give the title compound (736 mg) as a yellow solid. Got as. IR (KBr):. 3400, 1770, 1715, 1600, 1520 cm -1 1 H-NMR (CDCl 3) δ: 1.24 (3 H, d, J = 7.0 Hz), 1.34
(3 H, d, J = 6.2 Hz), 1.99 (3 H, s), 3.20-3.70 (7
H, m), 4.15-4.35 (2 H, m), 5.21 (1 H, d, J = 13.4 H
z), 5.49 (1 H, d, J = 13.4 Hz), 7.63 (2 H, d, J =
8.8 Hz), 8.22 (2 H, d, J = 8.8 Hz).

Example 12-2a (4R, 5S, 6S) -3-[[2- (Acetylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl]- 4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2
-Carboxylic acid According to the same method as Example 10-2a from the compound (262 mg) obtained by the method of Example 12-1a, the title compound was obtained.
(156 mg) was obtained as a white solid. IR (KBr):. 3400, 1755, 1725, 1695, 1640, 1600 cm -1 1 H-NMR (D 2 O) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.30
(3 H, d, J = 6.2 Hz), 2.16 (3 H, s), 3.30-3.60 (4
H, m), 3.60-4.0 (3 H, m), 4.15-4.35 (2 H, m).

Example 12-3a (4R, 5S, 6S) -3-[[2- (Acetylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl]- 4-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2
-1- (Cyclohexyloxycarbonyloxy) ethyl carboxylate According to the same method as Example 10-3a from the compound (54 mg) obtained by the method of Example 12-2a, the title compound was obtained.
(43.7 mg) was obtained as a white solid. IR (KBr): 3400, 1750, 1600 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.00-2.10 (10 H, m), 1.27 (3 H,
d, J = 7.2 Hz), 1.33 (3/2 H, d, J = 6.2 Hz), 1.35
(3/2 H, d, J = 6.4 Hz), 1.58 (3/2 H, d, J = 5.4 H
z), 1.61 (3/2 H, d, J = 5.4 Hz), 2.05 (3 H, s), 3.
27 (1 H, dd, J = 6.4, 2.6 Hz), 3.20-3.80 (6 H, m),
4.15-4.35 (2 H, m), 4.55-4.75 (1 H, m), 6.88 (1 H,
q, J = 5.4 Hz).

Example 13-1a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-3-[[2- (phenylsulfonylimino) perhydropyrimidin-5-yl] thio] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate 4-nitrobenzyl 5- (4 -Methoxybenzylthio) -2- (phenylsulfonylimino) perhydropyrimidine (525 mg) to Example 10
Following a method similar to that of -1a, the title compound (593 mg) was obtained as a white solid. IR (KBr): 3350, 1770, 1710, 1610, 1570, 1520, 138
. 0, 1345, 1280, 1135 cm -1 1 H-NMR (CDCl 3) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.34
(3 H, d, J = 6.2 Hz), 3.20-3.80 (6 H, m), 3.27 (1
H, dd, J = 7.4, 2.4 Hz), 4.22 (1 H, quint, J = 7.4
Hz), 4.28 (1 H, dd, J = 9.2, 2.4 Hz), 5.20 (1 H,
d, J = 13.6 Hz), 5.48 (1 H, d, J = 13.6 Hz), 7.20-
7.50 (3 H, m), 7.60 (2 H, d, J = 8.8Hz), 7.74 (2
H, d, J = 8.2 Hz), 7.86 (1 H, brs), 7.97 (1 H, br
s), 8.16 (2 H, d, J = 8.8 Hz).

Example 13-2a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-3-[[2- (phenylsulfonylimino) perhydropyrimidin-5-yl] thio] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate sodium Method of Example 13-1a From the compound (300 mg) obtained in Example 10 and following the procedure similar to that of Example 10-2a, the title compound
(192.4 mg) was obtained as a white solid. IR (KBr): 3350, 1750, 1600, 1380, 1340, 1280, 1130
^{. cm -1 1 H-NMR (} D 2 O) δ: 1.14 (3 H, d, J = 7.4 Hz), 1.29
(3 H, d, J = 6.6 Hz), 3.15-3.40 (3 H, m), 3.45 (1
H, dd, J = 6.2, 2.6 Hz), 3.50-3.80 (3 H, m), 4.20
(1 H, dd, J = 8.8, 2.6 Hz), 4.24 (1 H, quint, J =
6.2 Hz), 7.50-7.75 (3 H, m), 7.80-7.95 (2 H, m).

Example 13-3a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-3-[[2- (phenylsulfonylimino) perhydropyrimidin-5-yl] thio] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 1- (cyclohexyloxycarbonyloxy) Ethyl Compound obtained by the method of Example 13-2a (72.3 mg)
According to the same method as in Example 10-3a, the title compound (60 mg) was obtained as a white solid. IR (KBr):. 3340, 1760, 1610, 1570 cm -1 1 H-NMR (CDCl 3) δ: 1.15-2.05 (10 H, m), 1.21 (3 H,
d, J = 7.0 Hz), 1.32 (3/2 H, d, J = 5.8 Hz), 1.33
(3/2 H, d, J = 6.2 Hz), 1.57 (3/2 H, d, J = 5.6 H
z), 1.60 (3/2 H, d, J = 5.6 Hz), 3.20-3.80 (6 H,
m), 3.23 (1 H, dd, J = 7.0, 2.6 Hz), 4.15-4.30 (2
H, m), 4.55-4.75 (1 H, m), 6.87 (1 H, q, J = 5.6 H
z), 7.40-7.60 (4 H, m), 7.60-7.70 (1 H, m), 7.75-
7.90 (2 H, m).

Example 14-1a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-
Oxo-3-[[2-[(pyrimidin-2-yl) imino] perhydropyrimidin-5-yl] thio] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitro Benzyl 5- (4-methoxybenzylthio) -2-[(pyrimidin-2-yl)
Example 1 from imino] perhydropyrimidine (554 mg)
According to the method similar to that for 0-1a, the title compound (527 mg)
Was obtained as a yellow solid. IR (KBr):. 3400, 1770, 1710, 1640, 1580 cm -1 1 H-NMR (CDCl 3) δ: 1.28 (3 H, d, J = 7.2 Hz), 1.36
(3 H, d, J = 6.2 Hz), 3.30 (1 H, dd, J = 7.0, 2.6
Hz), 3.35-3.95 (6 H, m), 4.20-4.40 (2 H, m), 5.22
(1 H, d, J = 13.8 Hz), 5.49 (1 H, d, J = 13.8 Hz),
6.62 (1 H, t, J = 4.8 Hz), 7.64 (2 H, d, J = 8.8 H
z), 8.19 (2 H, d, J = 8.8 Hz), 8.36 (2 H, d, J = 4.
8 Hz).

Example 14-2a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-
Oxo-3-[[2-[(pyrimidin-2-yl) imino] perhydropyrimidin-5-yl] thio] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid Example 14 In the same manner as in Example 10-2a from the compound (256 mg) obtained by the method of 1a, the title compound
(125 mg) was obtained as a white solid. IR (KBr):. 3420, 1755, 1650, 1600, 1580 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 7.0 Hz), 1.30
(3 H, d, J = 6.6 Hz), 3.35-3.70 (4 H, m), 3.70-4.0
0 (3 H, m), 4.27 (1 H, quint, J = 6.2 Hz), 4.28 (1
H, dd, J = 9.6, 2.6 Hz), 7.20 (1 H, t, J = 5.2 H
z), 8.59 (2 H, d, J = 5.2 Hz).

Example 15-1a (4R, 5S, 6S) -3-[[2- (carbamoylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl]- Four
-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl 2-cyanoimino-5- (4-methoxybenzylthio) perhydropyrimidine (500 mg) Trifluoroacetic acid solution (20 m
l) was added anisole (2.0 g), then at room temperature for 2 hours,
Further, the mixture was stirred under heating under reflux for 2 hours. Toluene was added to the residue obtained by distilling off the solvent under reduced pressure, and trifluoroacetic acid was further removed by azeotropic distillation under reduced pressure. The obtained residue was dissolved in acetonitrile (20 ml), and diisopropylethylamine (1.16 g) was added dropwise at 0 ° C. Further 0 ℃
And (4R, 5R, 6S) -3-[(diphenylphosphono) oxy] -6-
[(R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate 4-nitrobenzyl (1.08 mg) in acetonitrile (20 ml) was added and the mixture was stirred at 0 ° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 560 mg of a yellow solid (mixture of the title compound and diphenyl phosphate). This yellow solid was used in the next reaction without purification. IR (KBr):. 3270, 1775, 1720, 1610, 1525 cm -1 1 H-NMR (CDCl 3 -DMSO-d 6) δ: 1.28 (3 H, d, J = 5.8 H
z), 1.31 (3 H, d, J = 6.0 Hz), 3.20-3.90 (7 H, m),
4.15 (1 H, quint, J = 6.0 Hz), 4.31 (1 H, dd, J =
9.6, 2.8 Hz), 5.24 (1 H, d, J = 14.0 Hz), 5.51 (1
H, d, J = 14.0Hz), 7.68 (2 H, d, J = 8.8 Hz), 8.23
(2 H, d, J = 8.8 Hz).

Example 15-2a (4R, 5S, 6S) -3-[[2- (carbamoylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl]- Four
-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid Yellow solid obtained by the method of Example 15-1a (260 mg)
THF (4 ml) and phosphate buffer (pH 7, 0.1 M, 4 m
l), add 10% palladium on carbon (260 mg),
The mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The catalyst was filtered off and washed with water, and the filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure and subjected to column chromatography (carrier: CHP-20P, 80 ml, developing solvent: water to ethanol-water, 5
: 100) and freeze-dried to give the title compound (72.5
mg) was obtained as a white solid. IR (KBr):. 3400, 1750, 1720, 1680, 1615 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3 H, d, J = 7.4 Hz), 1.30
(3 H, d, J = 6.4 Hz), 3.35-3.60 (4 H, m), 3.60-3.9
0 (3 H, m), 4.27 (1 H, dd, J = 9.4, 2.8 Hz), 4.27
(1 H, quint, J = 6.4 Hz).

Example 15-3a (4R, 5S, 6S) -3-[[2- (carbamoylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl]- Four
-Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate 1- (cyclohexyloxycarbonyloxy) ethyl compound obtained by the method of Example 15-2a
(49.4 mg) in an aqueous solution of potassium carbonate (19.6 mg) (4.5 m
l) was added and freeze-dried. DMA solution of the obtained solid
1- (Cyclohexyloxycarbonyloxy) ethyl iodide (0.098 mg) was added to (5 ml) at -10 ° C, and the mixture was stirred for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 5 g, developing solvent:
Acetonitrile-acetonitrile-ethanol, 1: 1)
The title compound (13.8 mg) was obtained as a white solid. IR (KBr):. 3400, 1760, 1615, 1575 cm -1 1 H-NMR (CDCl 3) δ: 1.10-2.10 (10 H, m), 1.25 (3 H,
d, J = 7.0 Hz), 1.33 (3/2 H, d, J = 6.2 Hz), 1.34
(3/2 H, d, J = 6.2 Hz), 1.58 (3/2 H, d, J = 5.4 H
z), 1.61 (3/2 H, d, J = 5.4 Hz), 3.15-3.75 (7 H,
m), 4.15-4.30 (2H, m), 4.50-4.75 (1 H, m), 6.87 (1
(H, q, J = 5.4 Hz).

Example 16-1a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-
Oxo-3-[[2-[(2-thiazolin-2-yl) imino] perhydropyrimidin-5-yl] thio] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4 -Nitrobenzyl 5- (4-methoxybenzylthio) -2-[(2-thiazolin-2-yl) imino] perhydropyrimidine (171 mg) was prepared in the same manner as above to give the title compound (98 mg) as a yellow solid. Obtained. IR (KBr):. 3400, 1770, 1710, 1610, 1570 cm -1 1 H-NMR (CDCl 3) δ: 1.28 (3 H, d, J = 7.4 Hz), 1.36
(3 H, d, J = 6.6 Hz), 3.10-3.80 (9 H, m), 3.90-4.1
5 (2 H, m), 4.15-4.35 (2 H, m), 5.23 (1 H, d, J = 1
3.6 Hz), 5.51 (1 H, d, J = 13.6 Hz), 7.65 (2 H, d,
J = 8.8 Hz), 8.23 (2 H, d, J = 8.8 Hz).

Example 16-2a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-3-[[2-[(2-thiazolin-2-yl) imino] perhydropyrimidin-5-yl] thio] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid Conducted The title compound was prepared in the same manner as in Example 10-2a from the compound (73 mg) obtained by the method of Example 16-1a.
(43 mg) was obtained as a white solid. IR (KBr): 3400, 1750, 1590 cm ^-1 . ¹ H-NMR (D ₂ O) δ: 1.24 (3 H, d, J
= 7.2 Hz), 1.30 (3H, d,
J = 6.4 Hz), 3.30-3.90.
(7 H, m), 3.50 (2 H, t, J
= 7.6 Hz), 3.83 (2 H, t,
J = 7.6 Hz), 4.27 (1 H, q
uint, J = 6.4 Hz), 4.28
(1 H, dd, J = 9.0, 2.2 H
z).

Example 17-1a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-3-[[2- (methylsulfonylimino) perhydropyrimidine-5- Ile] thio] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl 5- (4-methoxybenzylthio) -2- (methylsulfonylimino) perhydro Example 10-from pyrimidine (750 mg)
Following a method similar to that for 1a, the title compound (927 mg) was obtained as a yellow solid. IR (KBr):. 3350, 1770, 1705, 1610, 1570, 1520 cm -1 1 H-NMR (CDCl 3) δ: 1.29 (3 H, d, J = 7.2 Hz), 1.37
(3 H, d, J = 6.4 Hz), 2.89 (3 H, s), 3.25-3.8 (6
H, m), 3.31 (1 H, dd, J = 6.4, 2.2 Hz), 4.2-4.4 (1
H, m), 4.33 (1 H, dd, J = 9.2, 2.2 Hz), 5.24 (1
H, d, J = 14.0 Hz), 5.50 (1 H, d, J = 14.0 Hz), 7.
47 (1 H, brs), 7.57 (1 H, brs), 7.66 (2H, d, J =
8.2 Hz), 8.24 (2 H, d, J = 8.2 Hz).

Example 17-2a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -4-methyl-3-
[[2- (Methylsulfonylimino) perhydropyrimidine-5
-Yl] thio] -7-oxo-1-azabicyclo [3.2.0] hept-2
-Sodium ene-2-carboxylate According to the same method as Example 10-2a from the compound (308 mg) obtained by the method of Example 17-1a, the title compound (204
mg) was obtained as a white solid. IR (KBr):. 3400, 1745, 1600 cm -1 1 H-NMR (D 2 O) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.30
(3 H, d, J = 6.6 Hz), 3.02 (3 H, s), 3.25-3.80 (6
H, m), 3.49 (1 H, dd, J = 6.2, 2.6 Hz), 4.26 (1 H,
dd, J = 9.2, 2.6 Hz), 4.26 (1 H, quint, J = 6.2 H
z).

Example 18-1a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-
Oxo-3-[[2-[(pyridin-3-yl) carbonylimino] perhydropyrimidin-5-yl] thio] -1-azabicyclo [3.
2.0] 4-nitrobenzyl 5- (4-methoxybenzylthio) -2-[(pyridin-3-yl) carbonylimino] perhydropyrimidine (1.0 g) of 4-nitrobenzyl hept-2-ene-2-carboxylate from Example 10 The title compound (1.
08 g) was obtained as a white solid. IR (KBr): 3380, 3250, 1765, 1705, 1600, 1540, 1515
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.24 (3 H, d, J = 7.0 Hz), 1.38
(3 H, d, J = 6.2 Hz), 3.0-3.75 (6 H, m), 3.30 (1
H, dd, J = 7.0, 2.6 Hz), 4.17 (1 H, dd, J = 9.2, 2.
6 Hz), 4.28 (1 H, quint, J = 7.0 Hz), 5.20 (1 H,
d, J = 13.8 Hz), 5.47 (1 H, d, J = 13.8 Hz), 7.36
(1 H, dd, J = 7.8, 4.8 Hz), 7.62 (2 H, d, J = 8.8 H
z), 8.19 (2 H, d, J = 8.8 Hz), 8.35 (1 H, dt, J =
7.8, 1.6Hz), 8.66 (1 H, dd, J = 4.8, 1.6 Hz), 9.27
(1 H, d, J = 1.6 Hz).

Example 18-2a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-3-[[2-[(pyridin-3-yl) carbonylimino] perhydropyrimidin-5-yl] thio] -1-azabicyclo [3.
2.0] Sodium hept-2-ene-2-carboxylate The title compound was prepared in the same manner as in Example 10-2a from the compound (400 mg) obtained by the method in Example 18-1a.
(237 mg) was obtained as a white solid. IR (KBr):. 3430, 1750, 1600 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 7.2 Hz), 1.31
(3 H, d, J = 6.2 Hz), 3.35-3.55 (3 H, m), 3.49 (1
H, dd, J = 6.2, 2.6 Hz), 3.65-3.90 (3 H, m), 4.15-
4.35 (2 H, m), 7.53 (1 H, dd, J = 8.0, 5.2 Hz), 8.
33 (1 H, dt, J = 8.0, 2.0 Hz), 8.63 (1 H, dd, J =
5.2, 2.0 Hz), 9.04 (1 H, d, J = 2.0 Hz).

Example 18-3a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-
Oxo-3-[[2-[(pyridin-3-yl) carbonylimino] perhydropyrimidin-5-yl] thio] -1-azabicyclo [3.
2.0] 1- (Cyclohexyloxycarbonyloxy) ethyl hept-2-ene-2-carboxylate Compound obtained by the method of Example 18-2a (68.5 mg)
According to the same method as in Example 10-3a, the title compound (76.9 mg) was obtained as a white solid. IR (KBr):. 3380, 3250, 1755, 1600, 1540 cm -1 1 H-NMR (CDCl 3) δ: 1.20-2.05 (10 H, m), 1.25 (3 H,
d, J = 7.4 Hz), 1.35 (3/2 H, d, J = 6.2 Hz), 1.37
(3/2 H, d, J = 6.2 Hz), 1.58 (3/2 H, d, J = 5.2 H
z), 1.60 (3/2 H, d, J = 5.2 Hz), 3.00-3.75 (6 H,
m), 3.26 (1 H, dd, J = 7.2, 2.8 Hz), 4.15 (1 H, d
d, J = 9.6, 2.8 Hz), 4.26 (1 H, quint, J = 6.4 Hz),
4.55-4.75 (1 H, m), 6.87 (1 H, q, J = 5.2 Hz), 7.
36 (1 H, dd, J = 8.0, 4.8 Hz), 8.36 (1 H, dt, J =
8.0, 2.0 Hz), 8.67 (1 H, dd, J = 4.8, 2.0 Hz), 9.29
(1 H, d, J = 2.0 Hz).

Example 19a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-3-[[2-[(pyridin-4-yl) imino] perhydropyrimidin-5-yl] thio] -1-azabicyclo [3.2.0] hept-
2-Ene-2-carboxylic acid hydrochloride 5- (4-methoxybenzylthio) -2-[(pyridin-4-yl) imino] perhydropyrimidine (700 mg) in trifluoroacetic acid solution (23 ml) 0 Add anisole (2.3 g) and trifluoromethanesulfonic acid (0.64 g) at 0 ° C and add at 0 ° C.
The mixture was stirred for 0.5 hour. Diisopropylethylamine
(1.1 g) was added, the solvent was evaporated under reduced pressure, toluene was added to the obtained residue, and trifluoroacetic acid was further removed by azeotropic distillation under reduced pressure. The residue obtained is acetonitrile
It was dissolved in (30 ml) and diisopropylethylamine (3.59 g) was added dropwise at 0 ° C. At 0 ℃ (4R, 5R, 6
S) -3-[(Diphenylphosphono) oxy] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.
0] 4-nitrobenzyl hept-2-ene-2-carboxylate (1.27
g) in acetonitrile (30 ml) and add 2 at 0 ° C.
Stirred for hours. Ethyl acetate was added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was washed successively with multi-layered water and water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 15 g, developing solvent: ethanol-acetonitrile,
(4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-3-[[2-[(pyridine- Four
-Yl) imino] perhydropyrimidin-5-yl] thio] -1-
A yellow solid containing 4-nitrobenzyl (238 mg) of azabicyclo [3.2.0] hept-2-ene-2-carboxylate was obtained. This solid was subjected to the same reaction and purification treatment as in Example 10-2a,
The title compound (84 mg) was obtained as a white solid by adjusting the pH to 5.8 with 0.1N hydrochloric acid and freeze-drying. IR (KBr):. 3430, 1750, 1590, 1510 cm -1 1 H-NMR (D 2 O) δ: 1.27 (3 H, d, J = 7.8 Hz), 1.30
(3 H, d, J = 6.6 Hz), 3.4-4.0 (6 H, m), 3.53 (1 H,
dd, J = 5.9, 2.9 Hz), 4.2-4.4 (2 H, m), 7.33 (2 H,
d, J = 7.0 Hz), 8.40 (2 H, d, J = 7.2 Hz).

Example 20-1a (4R, 5S, 6S) -3-[[1,3-Dimethyl-2- (methylsulfonylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo
[3.2.0] 4-Nitrobenzyl 5- (4-methoxybenzylthio) -1,3-dimethyl-2- (methylsulfonylimino) perhydropyrimidine hept-2-ene-2-carboxylate From (974 mg) The title compound was prepared according to the same method as Example 10-1a.
(901 mg) was obtained as a white solid. IR (KBr):. 3430, 1770, 1710, 1600, 1560, 1520 cm -1 1 H-NMR (CDCl 3) δ: 1.30 (3 H, d, J = 6.8 Hz), 1.37
(3 H, d, J = 6.2 Hz), 2.12 (1 H, d, J = 4.8 Hz),
3.02 (3 H, s), 3.20 (3 H, s), 3.22 (3 H, s), 3.25-
3.75 (6 H, m), 3.33 (1 H, dd, J = 6.6, 2.6 Hz), 4.
15-4.35 (1 H, m), 4.32 (1 H, dd, J = 9.2, 2.6 Hz),
5.23 (1 H, d, J = 13.4 Hz), 5.50 (1 H, d, J = 13.
4 Hz), 7.66 (2 H, d, J = 8.8 Hz), 8.24 (2 H, d, J
= 8.8 Hz).

Example 20-2a (4R, 5S, 6S) -3-[[1,3-Dimethyl-2- (methylsulfonylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo
[3.2.0] Sodium hept-2-ene-2-carboxylate The title compound (220
mg) was obtained as a white solid. IR (KBr):. 3430, 1750, 1580, 1530 cm -1 1 H-NMR (D 2 O) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.30
(3 H, d, J = 6.6 Hz), 3.09 (3 H, s), 3.16 (3 H,
s), 3.19 (3 H, s), 3.35-3.55 (3 H, m), 3.50 (1H, d
d, J = 6.2, 2.6 Hz), 3.70-3.95 (3 H, m), 4.20-4.35
(2 H, m).

Example 20-3a (4R, 5S, 6S) -3-[[1,3-Dimethyl-2- (methylsulfonylimino) perhydropyrimidin-5-yl] thio] -6-[(R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo
[3.2.0] 1- (Cyclohexyloxycarbonyloxy) ethyl 1- (cyclohexyloxycarbonyloxy) ethyl hept-2-ene-2-carboxylate The compound (74 mg) obtained by the method of Example 20-2a and a method similar to that of Example 10-3a. According to the title compound
(73.6 mg) was obtained as a white solid. IR (KBr):. 3430, 1760, 1560, 1530 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.1 (10 H, m), 1.28 (3 H,
d, J = 7.4 Hz), 1.34 (3/2 H, d, J = 6.2 Hz), 1.36
(3/2 H, d, J = 6.2 Hz), 1.59 (3/2 H, d, J = 5.4 H
z), 1.62 (3/2 H, d, J = 5.4 Hz), 3.03 (1 H, s), 3.
21 (3/2 H, s), 3.22 (3/2 H, s), 3.23 (3 H, s), 3.2
-3.8 (7 H, m), 4.15-4.4 (2 H, m), 4.55-4.75 (1 H,
m), 6.88 (1 H, q, J = 5.4 Hz).

Example 21-1a (4R, 5S, 6S) -3-[[1,3-Dimethyl-2- (trifluoromethylcarbonylimino) perhydropyrimidin-5-yl] thio]
-6-[(R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl 2-cyanoimino-5- The title compound was prepared from (4-methoxybenzylthio) -1,3-dimethylperhydropyrimidine (1.3 g) in the same manner as in Example 10-1a.
(140 mg) was obtained as a white solid. IR (KBr):. 3400, 1770, 1700, 1640, 1600, 1520 cm -1 1 H-NMR (CDCl 3) δ: 1.29 (3 H, d, J = 7.2 Hz), 1.36
(3 H, d, J = 6.4 Hz), 2.38 (1 H, brs), 3.03 (3 H,
s), 3.08 (3 H, s), 3.25-3.90 (7 H, m), 4.20-4.40
(2 H, m), 5.24 (1 H, d, J = 13.6 Hz), 5.51 (1 H,
d, J = 13.6 Hz), 7.67 (2 H, d, J = 8.8 Hz), 8.24 (2
H, d, J = 8.8 Hz).

Example 21-2a (4R, 5S, 6S) -3-[[1,3-Dimethyl-2- (trifluoromethylcarbonylimino) perhydropyrimidin-5-yl] thio]
-6-[(R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate sodium Obtained by the method of Example 21-1a. Compound (65.1 mg)
According to the same method as in Example 10-2a, the title compound (32 mg) was obtained as a white solid. IR (KBr):. 3420, 1750, 1640, 1595, 1520 cm -1 1 H-NMR (D 2 O) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.30
(3 H, d, J = 6.4 Hz), 3.01 (3 H, s), 3.04 (3 H,
s), 3.35-4.00 (7 H, m), 4.20-4.35 (2 H, m).

Example 21-3a (4R, 5S, 6S) -3-[[1,3-Dimethyl-2- (trifluoromethylcarbonylimino) perhydropyrimidin-5-yl] thio]
-6-[(R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate 1- (cyclohexyloxycarbonyloxy) ethyl Conducted The title compound was obtained from the compound (37 mg) obtained by the method of Example 21-2a according to the same manner as in Example 10-3a.
(33 mg) was obtained as a white solid. IR (KBr):. 3425, 1760, 1635, 1595, 1525 cm -1 1 H-NMR (CDCl 3) δ: 1.2-2.05 (10
H, m), 1.28 (3 H, d, J =
7.0 Hz), 1.31 (3/2 H, d,
J = 6.2 Hz), 1.35 (3/2 H,
d, J = 6.6 Hz), 1.55-1.6
5 (3 H, m), 3.06 (3/2 H,
s), 3.08 (3/2 H, s), 3.10
(3 H, s), 3.30 (1 H, dd,
J = 6.4, 3.2 Hz), 3.35-3.
90 (6 H, m), 4.20-4.35 (1
H, m), 4.28 (1 H, dd, J
= 9.6, 3.2 Hz), 6.87 (1/2)
H, q, J = 5.4 Hz), 6.88
(1/2 H, q, J = 5.4 Hz).

Example 22-1a (4R, 5S, 6S) -3-[[2- [2- (N, N-
Dimethylamino) ethoxy] -1,4,5,6-tetrahydropyrimidin-5-yl] thio] -6-[(R) -1-hydroxyethyl] -4-
Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene
2-Nitrocarboxylic acid 4-nitrobenzyl 2- [2- (N, N-dimethylamino) ethoxy] -5- (4-methoxybenzylthio) -1,4,5,6-tetrahydropyrimidine (500 m
Following a similar method from g), the title compound (370 mg) was obtained as a yellow oil. IR (neat): 3370, 1765, 1705, 1650, 1605, 1520 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.29 (3 H, d, J = 7.0 Hz), 1.34
(3 H, d, J = 6.2 Hz), 2.27 (6 H, s), 2.55 (2 H, d,
J = 5.6 Hz), 3.2-3.8 (7 H, m), 4.10 (2 H, t, J =
5.6 Hz), 4.15-4.35 (2 H, m), 5.22 (1 H, d, J = 13.
8 Hz), 5.50 (1H, d, J = 13.8 Hz), 7.66 (2 H, d, J
= 8.8 Hz), 8.22 (2 H, d, J = 8.8 Hz).

Example 22-2a (4R, 5S, 6S) -3-[[2- [2- (N, N-dimethylamino) ethoxy]-
1,4,5,6-Tetrahydropyrimidin-5-yl] thio] -6-[(R)
-1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid Compound (370 mg) obtained by the method of Example 22-1a
THF (20 ml) and phosphate buffer (pH 7, 0.2 M, 20 m
l), 10% palladium-carbon (700 mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was filtered off, washed with water, THF was distilled off under reduced pressure, and the aqueous solution was washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure, purified by column chromatography (carrier: CHP-20P, 120 ml, developing solvent: water to 20% ethanol-water), and then pH adjusted with hydrochloric acid.
(7.5) Adjusted. This was lyophilized to give the title compound (1
21 mg) was obtained as a white solid. IR (KBr):. 3430, 1750, 1660, 1620, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3 H, d, J = 6.8 Hz), 1.30
(3 H, d, J = 6.6 Hz), 2.80 (6 H, s), 3.35-3.90 (9
H, m), 4.20-4.40 (2 H, m), 4.56 (2 H, t, J = 4.8 H
z).

Example 23-1a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-3-
[[2- [2- [N-Methyl-N- (4-nitrobenzyloxycarbonyl) amino] ethoxy] -1,4,5,6-tetrahydropyrimidine
-5-yl] thio] -7-oxo-1-azabicyclo [3.2.0] hept
2-Nene-2-carboxylic acid 4-nitrobenzyl 5- (4-methoxybenzylthio) -2- [2- [N-methyl-N- (4-nitrobenzyloxycarbonyl) amino] ethoxy] -1, Four,
Following a similar method from 5,6-tetrahydropyrimidine (325 mg), the title compound (315 mg) was obtained as a yellow solid. IR (KBr):. 3400, 1765, 1700, 1655, 1605, 1520 cm -1 1 H-NMR (CDCl 3) δ: 1.29 (3 H, d, J = 7.0 Hz), 1.36
(3 H, d, J = 6.0 Hz), 3.00 (3/2 H, s), 3.01 (3/2
H, s), 3.2-3.75 (6 H, m), 3.29 (1 H, dd, J = 6.8,
2.4 Hz), 3.57 (2 H, t, J = 5.4 Hz), 4.18 (2 H, t,
J = 5.4 Hz), 4.20-4.35 (2 H, m), 5.22 (1 H, d, J =
13.8 Hz), 5.23 (2 H, s), 5.51 (1 H, d, J = 13.8 H
z), 7.52 (2 H, d, J = 8.4 Hz), 7.66 (2 H, d, J =
8.4 Hz), 8.22 (4 H, d, J = 8.4 Hz).

Example 23-2a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-3-
[[2- [2- (N-Methylamino) ethoxy] -1,4,5,6-tetrahydropyrimidin-5-yl] thio] -7-oxo-1-azabicyclo [3.2.0] hept-2- En-2-carboxylic acid Example 23-3a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -3-[[2- [N- (2-
(Hydroxyethyl) -N-methylamino] -1,4,5,6-tetrahydropyrimidin-5-yl] thio] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene- 2-Carboxylic acid According to the same method as Example 10-2a from the compound (314 mg) obtained by the method of Example 23-1a, Example 23 was used.
-2a compound (7.1 mg) was obtained as a white solid. At the same time, the compound of Example 23-3a (29 mg) was obtained as a white solid. Compound IR of Example 23-2a (KBr):. 3420, 1750, 1660, 1620 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 7.4 Hz), 1.30
(3 H, d, J = 6.2 Hz), 2.81 (3 H, s), 3.30-4.00 (7
H, m), 3.51 (2 H, t, J = 5.0 Hz), 4.20-4.35 (2 H,
. m), 4.60 (2 H , t, J = 5.0 Hz) The compound of Example 23-3a IR (KBr):. 3400 , 1750, 1635, 1590 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3 H, d, J = 7.0 Hz), 1.30
(3 H, d, J = 6.2 Hz), 3.03 (3 H, s), 3.30-3.90 (7
H, m), 3.47 (2 H, t, J = 5.2 Hz), 3.76 (2 H, t, J =
5.2 Hz), 4.15-4.35 (2 H, m).

Example 24-1a (4R, 5S, 6S) -3-[(5H-6,7-Dihydrothiazolo [3,2-a] pyrimidin-6-yl) thio] -6-[(R ) -1-Hydroxyethyl] -4-
Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene
2-Carboxylic acid 4-nitrobenzyl 6- (benzoylthio) -5H-6,7-dihydrothiazolo [3,2-a]
Pyrimidine (550 mg) in THF-methanol (1: 1, 20
ml) was added with sodium methoxide (128 mg) at 0 ° C, and the mixture was stirred at 0 ° C for 1 hr. Acetic acid (0.15 ml, 2.57 mm
ol) and acetonitrile (20 ml) were added and the solvent was removed under reduced pressure.
Concentrated to 5 ml. Insoluble matter was removed by filtration, and acetonitrile was used.
It was washed with (20 ml). The filtrate obtained in this way is
And (4R, 5R, 6S) -3-[(diphenylphosphono) oxy] -6-
[(R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hepto-2-ene-2-carboxylate 4-nitrobenzyl (1.17 g) and diisopropylethylamine (0 .
45 ml) was added, and the mixture was stirred at 0 ° C. for 20 minutes and at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, which was washed with pH 7 phosphate buffer and dried over anhydrous magnesium sulfate. The residue produced by distilling off the solvent under reduced pressure was purified by flash column chromatography (carrier: silica gel, 50 g, developing solvent: ethyl acetate-hexane, 1: 1 → 2: 1 → 3: 1) to give the title. Diastereomer 1 (21 mg) and diastereomer 2 (26 mg) of the compound were obtained as colorless oils, respectively. Diastereomer 1 IR (neat): 3440, 3116, 1767, 1709, 1649, 1522 c
^{. m -1 1 H-NMR (} CDCl 3) δ: 1.21 (3 H, d, J = 7.2 Hz), 1.35
(3 H, d, J = 6.4 Hz), 3.15-3.65 (5 H, m), 3.85-4.1
0 (2 H, m), 4.15-4.35 (2 H, m), 5.35 (2 H, ABq, J =
14.0 Hz), 6.24 (1 H, d, J = 5.4 Hz), 6.67 (1 H,
d, J = 5.4 Hz), 7.64 (2 H, d, J = 8.6 Hz), 8.22 (2
H, d, J = 8.6 Hz). Diastereomer 2 IR (KBr): 3448, 3118, 1770, 1649, 1524 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3 H, d, J = 7.4 Hz), 1.36
(3 H, d, J = 6.2 Hz), 3.15-3.75 (5 H, m), 3.90-4.1
0 (2 H, m), 4.15-4.35 (2 H, m), 5.37 (2 H, ABq, J =
14.2 Hz), 6.11 (1 H, d, J = 5.4 Hz), 6.65 (1 H,
d, J = 5.4 Hz), 7.66 (2 H, d, J = 8.0 Hz), 8.24 (2
H, d, J = 8.0 Hz).

Example 24-2a (4R, 5S, 6S) -3-[(5H-6,7-dihydrothiazolo [3,2-a] pyrimidin-6-yl) thio] -6-[(R ) -1-Hydroxyethyl] -4-
Methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene
-2-Sodium Carboxylate Diastereomer 1 Diastereomer 1 obtained by the method of Example 24-1a
(21 mg) in THF (1 ml) and pH 7 phosphate buffer (0.
2 M, 1 ml), 10% palladium on carbon (25 mg)
Was added and hydrogenation was carried out at room temperature for 2 hours at normal pressure. The catalyst was filtered off and washed with water, and the filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, purified by column chromatography (carrier: CHP-20P, 60 ml, developing solvent: water → 5% ethanol), and then lyophilized to give the title compound (6.4
mg) as a colorless solid. IR (KBr):. 3429, 1747, 1649, 1603 cm -1 1 H-NMR (D 2 O) δ: 1.02 (3 H, d, J = 7.0 Hz), 1.29
(3 H, d, J = 6.2 Hz), 3.10-3.25 (1 H, m), 3.25-3.6
0 (3 H, m), 3.85 (1 H, dd, J = 14.8 Hz and 10.4 H
z), 4.10-4.40 (3 H, m), 6.48 (1 H, d, J = 5.2 Hz),
7.02 (1 H, d, J = 5.2 Hz). Diastereomer 2 Diastereomer 2 obtained by the method of Example 24-1a
(32 mg) was reacted in the same manner as diastereomer 1 to obtain the title compound (7.2 mg) as a colorless solid. IR (KBr):. 3431, 1747, 1637, 1606 cm -1 1 H-NMR (D 2 O) δ: 1.15 (3 H, J = 7.0 Hz), 1.29 (3
H, d, J = 6.4 Hz), 3.20-3.50 (4 H, m), 3.50-3.85
(2 H, m), 4.00-4.10 (1 H, m), 4.15-4.35 (2 H, m),
6.33 (1 H, d, J = 5.2 Hz), 6.89 (1 H, d, J = 5.2 H
z).

Example 25-1a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -3-[[2- (2-methoxyethylthio) -1,4,5,6 -Tetrahydropyrimidine-5
-Yl] thio] -4-methyl-7-oxo-1-azabicyclo [3.2.
0] 4-nitrobenzyl 5- (4-methoxybenzylthio) -2- (2-methoxyethylthio) -1,4-hex-2-ene-2-carboxylate-1,4,5,6-tetrahydropyrimidine (390 mg) According to the same method as in Example 10-1a, the title compound (44
6 mg) was obtained as a yellow solid. IR (KBr):. 3400, 1770, 1710, 1605, 1520 cm -1 1 H-NMR (CDCl 3) δ: 1.29 (3 H, d, J = 7.0 Hz), 1.37
(3 H, d, J = 6.2 Hz), 3.12 (2 H, d, J = 5.8 Hz),
3.2-3.8 (6 H, m), 3.29 (1 H, dd, J = 6.8, 2.6 Hz),
3.39 (3 H, s), 3.61 (2 H, t, J = 5.8 Hz), 4.2-4.3
5 (2 H, m), 5.23 (1 H, d, J = 13.6 Hz), 5.52 (1 H,
d, J = 13.6 Hz), 7.66 (2 H, d, J = 8.6 Hz), 8.23
(2 H, d, J = 8.6 Hz).

Example 25-2a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -3-[[2- (2-methoxyethylthio) -1,4,5,6 -Tetrahydropyrimidine-5
-Yl] thio] -4-methyl-7-oxo-1-azabicyclo [3.2.
0] Hept-2-ene-2-carboxylic acid Compound (445 mg) obtained by the method of Example 25-1a
THF (17 ml) and phosphate buffer (pH 7, 0.1 M, 17 m
l), add 10% palladium on carbon (440 mg),
The mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The catalyst was filtered off, washed with water, THF was distilled off under reduced pressure, and the aqueous solution was washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure, purified by column chromatography (carrier: CHP-20P, 70 ml, developing solvent: water to 20% ethanol-water), and then pH adjusted with hydrochloric acid.
(7.5) Adjusted. This was lyophilized to give the title compound (1
90 mg) was obtained as a white solid. IR (KBr):. 3430, 1755, 1595 cm -1 1 H-NMR (D 2 O) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.30
(3 H, d, J = 6.2 Hz), 3.30 (2 H, t, J = 5.4 Hz),
3.35-3.95 (7 H, m), 3.43 (3 H, s), 3.76 (2 H, t, J
= 5.4 Hz), 4.20-4.35 (2 H, m).

Example 26-1a (4R, 5S, 6S) -3-[[2- (Acetylimino) -1,3-dimethylperhydropyrimidin-5-yl] thio] -6-[(R)- 1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl 2- (acetylimino) -1,3-dimethyl-5 The title compound (811 mg) was obtained as a pale yellow foam in the same manner as in Example 10-1a using-(4-methoxybenzylthio) perhydropyrimidine (797 mg). IR (KBr):. 3398, 1770, 1585, 1558, 1520 cm -1 1 H-NMR (CDCl 3) δ: 1.29 (3 H, d, J = 6.8 Hz), 1.32
(3 H, d, J = 6.0 Hz), 1.66 (1H, brs), 2.04 (3 H,
s), 2.93 (3 H, s), 3.05 (3 H, s), 3.12-3.87 (7H,
s), 4.26-4.33 (2 H, m), 5.20 (1 H, d, J = 13.4 H
z), 5.54 (1 H, d, J = 13.4 Hz), 7.70 (2 H, d, J =
8.8 Hz), 8.25 (2 H, d, J = 8.8 Hz).

Example 26-2a (4R, 5S, 6S) -3-[[2- (Acetylimino) -1,3-dimethylperhydropyrimidin-5-yl] thio] -6-[(R)- 1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0]
Sodium hept-2-ene-2-carboxylate The title compound (27) was prepared in the same manner as in Example 10-2a using the compound (442 mg) obtained by the method in Example 26-1a.
8 mg) was obtained as a pale yellow foam. IR (KBr):. 3400, 1751, 1593, 1522, 1410 cm -1 1 H-NMR (D 2 O) δ: 1.23 (3 H, d, J = 7.4 Hz), 1.30 (3
H, d, J = 6.2 Hz), 2.02 (3 H, s), 2.99 (3 H, s), 3.
02 (3 H, s), 3.37-3.52 (4 H, m), 3.70-3.94 (3 H,
m), 4,24-4.30 (2 H, m).

Example 27-1a (4R, 5S, 6S) -3-[[1,3-Dimethyl-2- (thiazol-2-ylimino) perhydropyrimidin-5-yl] thio] -6-[( R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo
[3.2.0] 4-nitrobenzyl 1,3-dimethyl-5- (4-methoxybenzylthio) -2- (thiazol-2-ylimino) perhydropyrimidine hept-2-ene-2-carboxylate (286 mg ) In the same manner as in Example 10-1a.
9 mg) was obtained as a pale yellow foam. IR (KBr): 3390, 1770, 1699, 1523, 1346, 1203, 1138
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.28 (3 H, d, J = 7.2 Hz), 1.29
(3 H, d, J = 5.8 Hz), 2.04 (1 H, brs), 2.83 (3 H,
s), 2.99 (3 H, s), 3.12-3.34 (3 H, m), 3.56-3.64
(2 H, m), 4.23-4.37 (2 H, m), 5.18 (1 H, d, J = 1
4.0 Hz), 5.51 (1 H, d, J = 14.0 Hz), 6.46 (1 H, d,
J = 4.0 Hz), 7.06 (1 H, d, J = 4.0 Hz), 7.65 (2 H,
d, J = 8.4 Hz), 8.19 (2 H, d, J = 8.4 Hz).

Example 27-2a (4R, 5S, 6S) -3-[[1,3-Dimethyl-2- (thiazol-2-ylimino) perhydropyrimidin-5-yl] thio] -6-[( R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo
[3.2.0] Sodium hept-2-ene-2-carboxylate The compound (126 mg) obtained by the method of Example 27-1a was used and the title compound (5
4.2 mg) was obtained as a pale yellow foam. IR (KBr):. 3400, 1755, 1591, 1531, 1412, 1392 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J
= 7.4 Hz), 1.31 (3 H, d,
J = 6.4 Hz), 2.96 (3 H,
s), 3.00 (3 H, s), 3.32-
3.52 (4 H, m), 3.72-3.87
(3 H, m), 4.24-4.30 (2 H, m
m), 6.68 (1 H, d, J = 4.
0 Hz), 7.07 (1 H, d, J =
4.0 Hz).

Example 28-1a (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-3-[[2- (pyridin-2-yl) -
1,4,5,6-Tetrahydropyrimidin-5-yl] thio] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl 5- (4-methoxybenzylthio)- 2- (pyridin-2-yl) -1,
Anisole (0.3 ml) was added to a trifluoroacetic acid solution (3 ml) of 4,5.6-tetrahydropyrimidine (107 mg), and the mixture was stirred with heating under reflux for 3 hr. The solvent was distilled off under reduced pressure, toluene was added to the residue, and trifluoroacetic acid was removed by azeotropic distillation under reduced pressure. An acetonitrile solution (5 ml) of the obtained residue was added to (4R, 5R, 6S) -3-[(diphenylphosphono) oxy] -6-[(R) -1-hydroxyethyl] -4-methyl-7-
Oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate 4-nitrobenzyl (184.3 mg) and diisopropylethylamine (81 μl) in acetonitrile (6 m
l) was added dropwise at 0 ° C over 15 minutes. The reaction solution was further stirred at the same temperature for 1 hour. Phosphate buffer solution in the reaction solution
(pH 7) was added, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 5 g, developing solvent: ethyl acetate → dichloromethane:
Purified with ethanol, 8: 1) to give the title compound (24.9 mg)
Was obtained as a pale yellow foam. IR (KBr):. 3356, 1768, 1520, 1346, 1207, 1136 cm -1 1 H-NMR (CDCl 3) δ: 1.27 (3 H, d, J = 7.4 Hz), 1.34
(3 H, d, J = 6.2 Hz), 2.05 (1 H, brs), 3.28 (1 H,
dd, J = 7.0, 2.2 Hz), 3.36-3.83 (6 H, m), 4.14-4.2
8 (1 H, m), 4.31 (1 H, dd, J = 9.6, 2.2 Hz), 5.27
(1 H, d, J = 12.6 Hz), 5.49 (1 H, d, J = 12.6 Hz),
7.07-7.22 (2 H, m), 7.28-7.33 (1 H, m), 7.60-7.69
(3 H, m), 8.18 (2 H, d, J = 8.8 Hz), 8.43-8.45 (1
H, m).

Example 28-2a (4R, 5S, 6S) -6-[(R) -1-Hydroxyethyl] -4-methyl-7-
Oxo-3-[[2- (pyridin-2-yl) -1,4,5,6-tetrahydropyrimidin-5-yl] thio] -1-azabicyclo [3.2.0] hept-2-ene-2- Sodium carboxylate Compound obtained by the method of Example 28-1a (203.5 mg)
In the same manner as in Example 10-2a using
(22.7 mg) was obtained as a white foam. IR (KBr): 3419, 1755, 1591, 1579 cm ^-1 . ¹ H-NMR (D ₂ O) δ: 1.23 (3 H, d, J = 7.2 Hz), 1.30
(3 H, d, J = 6.2 Hz), 3.37-3.62 (4 H, m), 3.76-3.9
5 (3 H, m), 4.23-4.30 (2 H, m), 7.53-7.60 (1 H, m),
7.79-7.83 (1 H, m), 7.96-8.04 (1 H, m), 8.60-8.63
(1 H, m).

Reference Example 1b 5- (4-methoxybenzylthio) perhydropyrimidine-2-thione 2- (4-produced by the method of JP-A-60-132985.
Methoxybenzylthio) propane-1,3-diamine (0.5
Carbon disulfide (0.26 g) was added dropwise to a THF solution (6 ml) of g) at 0 ° C., and then the mixture was stirred at 0 ° C. for 30 minutes and further at room temperature for 1 hour. Ether (6 ml) was added to the reaction solution, the insoluble material was collected by filtration, washed with ether, and then dried under vacuum. The obtained solid substance was again used as a THF solution (6 ml), and the mixture was stirred with heating under reflux for 3 hours. The solvent was distilled off under reduced pressure to give the title compound (332 mg)
Was obtained as a colorless solid. IR (KBr):. 3180, 1605, 1565, 1540, 1510 cm -1 1 H-NMR (CDCl 3) δ: 2.91 (1H, tt, J = 9.4, 4.6Hz),
3.13 (2H, dd, J = 12.6, 9.4Hz), 3.36 (2H, dt, J = 12.6, 4.6
Hz), 3.76 (2H, s), 3.81 (3H, s), 6.56 (2H, brs), 6.86 (2
H, d, J = 8.8Hz), 7.22 (2H, d, J = 8.8Hz).

Reference Example 2b 1- (t-butoxycarbonyl) -5- (4-methoxybenzylthio) perhydropyrimidin-2-one N, N'-bis (t-butoxycarbonyl) -2- (4-methoxy) Benzylthio) propane-1,3-diamine (3.61
After adding sodium hydride (purity 55%, 0.41 g) to a DMF solution (85 ml) of g) at 0 ° C., the mixture was stirred at room temperature for 3.5 hours. After water was added dropwise at 0 ° C. to decompose excess sodium hydride, the reaction solution was extracted with ether and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel,
100 g, developing solvent: methanol-dichloromethane, 1:
Purification in 20) gave the title compound (2.03 g) as a colorless solid. IR (KBr): 3220, 3120, 1720, 1680, 1610, 1510 cm
^{. -1 1 H-NMR (CDCl} 3) δ: 1.52 (9H, s), 2.86-3.02 (1H,
m), 3.11 (1H, td, J = 9.0,1.4Hz), 3.30-3.52 (1H, m), 3.44
(1H, dd, J = 12.8, 9.2Hz), 3.76 (2H, s), 3.81 (3H, s), 3.9
5 (1H, ddd, J = 12.8, 4.0, 1.4Hz), 5.63 (1H, brs), 6.86 (2
H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.6Hz).

Reference Example 3b 5- (4-methoxybenzylthio) perhydropyrimidin-2-one 1- (t-butoxycarbonyl) -5- (4-methoxybenzylthio) perhydropyrimidin-2-one (705 mg )
Trifluoroacetic acid (2 ml) at 0 ° C followed by anisole (2 m
l) was added and stirred for 1 hour. Ether and hexane were added to the residue obtained by distilling off the solvent under reduced pressure, and the precipitated crystals were collected by filtration. Aqueous sodium hydrogen carbonate solution was added to the obtained crystals.
(5%) was added, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (430 mg) as a colorless solid. IR (neat):. 3250, 1700, 1650, 1510 cm -1 1 H-NMR (CDCl 3) δ: 2.80-3.05 (1H, m), 3.05-6.2
5 (2H, m), 3.25-3.50 (2H, m), 3.74 (2H, s), 3.81 (3H, s),
5.55 (2H, brs), 6.86 (2H, d, J = 8.6Hz), 7.23 (2H, d, J = 8.6H
z).

Reference Example 4b 1- (t-Butoxycarbonyl) -5- (4-methoxybenzylthio) -3-methylperhydropyrimidine-2-
On 1- (t-butoxycarbonyl) -5- (4-methoxybenzylthio) perhydropyrimidin-2-one (500 mg)
Sodium hydride (purity 5
5%, 68 mg) was added, followed by stirring for 30 minutes. Methyl iodide (221 mg) was added to the reaction solution at 0 ° C., and the mixture was stirred for 1 hr. After water was added dropwise at 0 ° C. to decompose excess sodium hydride, the reaction solution was extracted with ether and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel,
40 g, developing solvent: ethyl acetate) and the title compound (1
66 mg) was obtained as a colorless oil. IR (neat):. 1755, 1700, 1605, 1510 cm -1 1 H-NMR (CDCl 3) δ: 1.52 (9H, s), 2.91 (3H, s),
2.90-3.05 (1H, m), 3.09 (1H, dd, J = 11.8, 8.8Hz), 3.32 (1
H, ddd, J = 11.8, 5.6, 1.4Hz), 3.45 (1H, dd, J = 12.8,4.0H
z), 3.77 (2H, s), 3.81 (3H, s), 4.04 (1H, ddd, J = 12.8, 4.
0, 1.4Hz), 6.86 (2H, d, J = 8.8Hz), 7.24 (2H, d, J = 8.8Hz).

Reference Example 5b 1,3-Dimethyl-5- (4-methoxybenzylthio) perhydropyrimidin-2-one 5- (4-methoxybenzylthio) perhydropyrimidin-2-one (126 mg), carbonic acid Dimethyl sulfate (0.17 ml) was added to a solution of potassium (276.4 mg) and benzyltriethylammonium chloride (4.56 mg) in THF (2 ml), and the mixture was stirred at 60 ° C. for 5 minutes.
Stirred for hours. After removing inorganic matter by filtration, ethyl acetate (10 m
l) was added and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the residue obtained by evaporating the solvent under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 5
g, Developing solvent: Ethyl acetate: Hexane, 1: 1 → 5:
Purification in 1) gave the title compound (49 mg) as a colorless solid. IR (KBr):. 1633, 1512, 1277, 1240 cm -1 1 H-NMR (CDCl 3) δ: 2.87 (6H, s), 2.98-3.28 (5H,
m), 3.76 (2H, s), 3.81 (3H, s), 6.86 (2H, d, J = 8.8Hz), 7.
24 (2H, d, J = 8.8Hz).

Reference Example 6b 5- (4-Methoxybenzylthio) -1-methylperhydropyrimidine-2-thione A solution of lithium aluminum hydride (1.2 g) in THF (10 m
l) to N, N'-bis (t-butoxycarbonyl) -2- (4
-Methoxybenzylthio) propane-1,3-diamine
A THF solution (5 ml) of (3.3 g) was gradually added at -78 ° C, and the mixture was heated under reflux for 16 hours. Ether (150 m
After the addition of (l), a saturated aqueous solution of sodium sulfate was added dropwise little by little. The generated precipitate was filtered off, dried over potassium carbonate, and the solvent was evaporated under reduced pressure. THF solution of the residue (40 ml)
Add carbon disulfide (0.55 ml) at −10 ° C. to
The mixture was stirred for 14 minutes while heating under reflux. The solvent was evaporated under reduced pressure, the obtained solid was washed with ethyl acetate, and dried in vacuo to give the title compound (640 mg) as a colorless solid. IR (KBr): 3205, 1608, 1551, 1510, 1304, 1269, 1
^{. 248 cm -1 1 H-NMR} (CDCl 3) δ: 2.90-3.39 (5H, m), 3.32 (3H,
s), 3.76 (2H, s), 3.81 (3H, s), 6.35 (1H, brs), 6.86 (2H,
d, J = 8.8Hz), 7.22 (2H, d, J = 8.8Hz).

Reference Example 7b N, N'-diformyl-2- (4-methoxybenzylthio) propane-1,3-diamine A solution of acetic anhydride (13.9 ml) and formic acid (5.57 ml) stirred at 60 ° C for 2 hours. In addition, while maintaining the internal temperature below 40 ℃ 2-
(4-Methoxybenzylthio) propane-1,3-diamine (7.6 g) was added dropwise, and the mixture was stirred at room temperature for 10 minutes. Ether (80 ml) was added, the mixture was further stirred at room temperature for 30 minutes, and then extracted with water. The aqueous layer was extracted with dichloromethane and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.3
g) was obtained as a colorless oil. IR (neat):. 1651, 1514, 1385, 1242 cm -1 1 H-NMR (CDCl 3) δ: 2.82-3.05 (3H, m), 3.73-3.8
6 (2H, m), 3.73 (2H, s), 3.78 (3H, s), 6,42 (2H, brs), 6.8
6 (2H, d, J = 8.8Hz), 7.26 (2H, d, J = 8.8Hz), 8.18 (2H, s).

Reference Example 8b 1,3-Dimethyl-5- (4-methoxybenzylthio) perhydropyrimidine-2-thione N, N'-diformyl-2- (4-methoxybenzylthio) propane-1,3- Diamine (669 mg) in THF (3
Borane-dimethyl sulfide (0.58 m
(l, 6.15 mmol) was added dropwise over 15 minutes, and the mixture was stirred for 15 minutes while distilling off dimethyl sulfide. The solvent of the reaction solution was evaporated under reduced pressure and the resulting residue was added with a 6N hydrochloric acid solution (1
ml) was added and the mixture was stirred at 100 ° C. for 30 minutes. Reaction solution 2
The mixture was adjusted to pH 10 with an aqueous sodium hydroxide solution, extracted with dichloromethane, washed with saturated brine, and dried over potassium carbonate. Carbon disulfide (0.14 ml) was added dropwise to a THF solution (50 ml) of the residue obtained by distilling off the solvent under reduced pressure, and the mixture was stirred at the same temperature for 30 minutes and heated under reflux for 14 hours. The solvent was evaporated under reduced pressure and the obtained residue was purified by flash column chromatography (carrier: silica gel, 20 g, developing solvent, ethyl acetate: hexane, 1: 4) to give the title compound (117
mg) was obtained as a pale yellow oil. IR (neat):. 1512, 1346, 1271 cm -1 1 H-NMR (CDCl 3) δ: 2.92-3.39 (5H, m), 3.34 (6H,
s), 3.76 (2H, s), 3.81 (3H, s), 6.87 (2H, d, J = 8.8Hz), 7.
22 (2H, d, J = 8.8Hz).

Reference Example 9b 1,3-Bis (pyridin-2-yl) -5- (4-methoxybenzylthio) perhydropyrimidine-2-thione 5- (4-methoxybenzylthio) perhydropyrimidine-2- Thione (537 mg) and 2-chloropyridine (1.88 ml)
Was stirred at 150 ° C. for 5 minutes. The reaction solution was purified by flash column chromatography (carrier: silica gel, 30 g, developing solvent: dichloromethane → dichloromethane: methanol, 10: 1) to obtain the title compound (329 mg) as a yellow solid. IR (KBr): 1738, 1589, 1512, 1464, 1431, 1250 cm
^{. -1 1 H-NMR (CDCl} 3) δ: 3.34-3.47 (1H, m), 3.75 (2H,
dd, J = 12.4, 4.6Hz), 3.77 (3H, s), 3.79 (2H, s), 4.13 (2
H, dd, J = 12.4, 4.6Hz), 6.78 (2H, d, J = 8.8Hz), 7.17-7.26
(4H, m), 7.55-7.75 (4H, m), 8.48-8.51 (2H, m).

Reference Example 10b N- (2,3-dihydroxypropyl) phthalimide After adding potassium phthalimide (97.2 g) to an anhydrous DMF solution (500 ml) of 3-chloro-1,2-propanediol (55.3 g). The mixture was stirred at 130 ° C for 5 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, water (500 ml) was added, and the mixture was extracted with ethyl acetate-THF (1: 1, 1000 ml). The aqueous layer was salted out with sodium chloride, and then ethyl acetate-THF (1:
It was extracted with 1, 400 ml × 3), and the organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from ethanol to give the title compound (92.4 g). IR (KBr):. 3344, 1772, 1710 cm -1 1 H-NMR (CDCl 3) δ: 2.40-2.60 (1H, m), 2.70-2.9
0 (1H, m), 3.50-3.80 (2H, m), 3.80-4.10 (3H, m), 7.70-8.
00 (4H, m).

Reference Example 11b N- [3- (t-butyldimethylsilyloxy) -2-hydroxypropyl] phthalimide N- (2,3-dihydroxypropyl) phthalimide (92.4
Triethylamine (87.3 ml), t-butyldimethylchlorosilane (78.7 g) and 4-dimethylaminopyridine (1.02 g) were sequentially added to an anhydrous dichloromethane solution (500 ml) of g) at 0 ° C, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, extracted with ether, saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution,
The extract was washed successively with saturated saline and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (carrier: silica gel, 900 g, developing solvent:
It was purified by ethyl acetate-hexane, 1:20 → 1: 9 → 1: 3) to obtain the title compound (128.4 g) as a colorless solid. IR (KBr):. 3464, 1707 cm -1 1 H-NMR (CDCl 3) δ: 0.08 (6H, s), 0.91 (9H, s),
2.67 (1H, d, J = 6.4Hz), 3.55-4.05 (5H, m), 7.70-7.90 (4H,
m).

Reference Example 12b N- [3- (t-butyldimethylsilyloxy) -2-
[(Tetrahydropyran-2-yl) oxy] propyl] phthalimide N- [3- (t-butyldimethylsilyloxy) -2-hydroxypropyl] phthalimide (25.2 g) in anhydrous dichloromethane (150 ml) was added to p-toluene. Pyridinium sulfonate (1.88 ml) was added and the mixture was stirred at room temperature for 7 hours. The residue obtained by evaporating the solvent under reduced pressure was subjected to column chromatography (carrier: silica gel, 300 g, developing solvent: ethyl acetate
-Hexane, 1: 9 → 1: 5) and the title compound (31.
5 g) was obtained as a colorless oil. IR (neat):. 2949, 1716 cm -1 1 H-NMR (CDCl 3) δ: 0.05 (6H, s), 0.88 (9H, s),
1.10-1.90 (6H, m), 3.10-3.60 (2H, m), 3.60-4.20 (5H, m),
4.55-4.75 (1H, m), 7.65-7.75 (2H, m), 7.80-7.90 (2H, m
m).

Reference Example 13b N- [3-hydroxy-2-[(tetrahydropyran-2
-Yl) oxy] propyl] phthalimide N- [3- (t-butyldimethylsilyloxy) -2-
[(Tetrahydropyran-2-yl) oxy] propyl] phthalimide (31.5 g) in anhydrous THF (225 ml) was added to acetic acid (1
9.4 ml), tetra-n-butylammonium fluoride TH
F solution (1 M, 112.5 ml) was sequentially added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (carrier: silica gel, 300 g,
Purification with an eluent: ethyl acetate-hexane, 1: 1) gave the title compound (22.9 g) as a colorless solid. IR (KBr):. 3508, 1768, 1709 cm -1 1 H-NMR (CDCl 3) δ: 1.30-1.90 (6H, m), 3.30-4.2
0 (7H, m), 4.60-4.75 (1H, m), 7.65-7.80 (2H, m), 7.80-7.
90 (2H, m).

Reference Example 14b 5-[(Tetrahydropyran-2-yl) oxy] perhydro-1,3-oxazin-2-one N- [3-hydroxy-2-[(tetrahydropyran-2
Dissolve (-yl) oxy] propyl] phthalimide (8.61 g) in ethanol (85 ml) and add hydrazine monohydrate (1.50 ml).
Was added and heated under reflux for 3 hours. After distilling off the solvent under reduced pressure, dichloromethane was added, the precipitate was filtered off and washed with dichloromethane. The filtrate is concentrated and the resulting residue is treated with TH
It was dissolved in F-water (1: 1, 10 ml), sodium carbonate (318 mg) and phenyl chlorocarbonate (0.14 ml) were sequentially added at 0 ° C, and the mixture was stirred at 0 ° C for 30 min and 50 ° C for 6 hr. Saturated saline was added, and the mixture was extracted with ethyl acetate-THF (1: 1),
It was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to column chromatography (carrier: silica gel, 150 g, developing solvent: ethyl acetate-ethanol, 2
(0: 1 → 7: 1) to give the title compound (5.63 g) as a colorless solid. IR (KBr):. 1700 cm -1 1 H-NMR (CDCl 3) δ: 1.40-2.00 (6H, m), 3.30-3.6
5 (3H, m), 3.75-3.95 (1H, m), 4.05-4.40 (3H, m), 4.75-4.
85 (1H, m), 5.40-5.80 (1H, m).

Reference Example 15b 5-hydroxyperhydro-1,3-oxazine-2-
Onto 5-[(tetrahydropyran-2-yl) oxy] perhydro-1,3-oxazin-2-one (0.78 g) in ethanol (31 ml) was added pyridinium p-toluenesulfonate (97 mg). The mixture was stirred at 55 ° C for 3 hours. After evaporating the solvent under reduced pressure, dichloromethane was added to the obtained residue, and the precipitate was collected by filtration to give the title compound (449 mg) as a colorless solid. IR (KBr):. 3265, 3178, 1682 cm -1 1 H-NMR (DMSO-d 6) δ: 2.90-3.10 (1H, m), 3.20
-3.50 (1H, m), 3.85-4.20 (3H, m), 5.20-5.40 (1H, m), 6.9
5-7.10 (1H, m).

Reference Example 16b 5-Benzoylthioperhydro-1,3-oxazine-
2-one triphenylphosphine (921 mg) in anhydrous THF solution,
Diisopropyl azodicarboxylate (0.69 ml) at -20 ℃
Was added and stirred at -20 ° C for 30 minutes. Continue to this 5
A hexamethylphosphoramide solution (5 ml) of -hydroxyperhydro-1,3-oxazin-2-one (274 mg) and thiobenzoic acid (0.41 ml) was added, and the mixture was stirred at room temperature for 2 hours.
Ethyl acetate was added, and the mixture was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (carrier: silica gel, 40 g, developing solvent: ethyl acetate-hexane, 2: 1 →
4: 1 → 1: 0) to give the title compound (535 mg) as a yellow solid. IR (KBr):. 1693, 1662 cm -1 1 H-NMR (CDCl 3) δ: 3.35-3.55 (1H, m), 3.75-3.9
0 (1H, m), 4.15-4.40 (2H, m), 4.50-4.65 (1H, m), 6.10 (1
H, brs), 7.40-7.70 (3H, m), 7.90-8.00 (2H, m).

Reference Example 17b 3-Methyl-2-oxo-5-[(tetrahydropyran-
2-yl) oxy] perhydro-1,3-oxazine Sodium hydride (purity 65%, 345 mg) in anhydrous THF solution (15 ml) was added to 2-oxo-5-[(tetrahydropyran-2- Iyl) oxy] perhydro-1,3-oxazine (1.71 g) was added, and the mixture was stirred at 0 ° C. for 1 hr. Methyl iodide (0.58 ml) was added to the reaction solution at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, salted out with sodium chloride, extracted with ethyl acetate-THF (2: 1), and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (carrier: silica gel, 100 g,
Developing solvent: ethyl acetate-ethanol, 1: 0 → 19: 1)
The title compound (1.35 g) was obtained as a pale yellow oily substance. IR (neat):. 2943, 1693 cm -1 1 H-NMR (CDCl 3) δ: 1.40-1.90 (6H, m), 2.99 (3H,
s), 3.20-3.40 (1H, m), 3.40-3.65 (2H, m), 3.75-3.95 (1
H, m), 4.05-4.20 (1H, m), 4.20-4.35 (2H, m), 4.75-4.85
(1H, m).

Reference Example 18b 5-hydroxy-3-methylperhydro-1,3-oxazin-2-one 3-methyl-2-oxo-5-[(tetrahydropyran-
2-yl) oxy] perhydro-1,3-oxazine (1.35
To an ethanol solution (50 ml) of g) was added pyridinium p-toluenesulfonate (158 mg), and the mixture was stirred at 55 ° C for 3.5 hours. After evaporating the solvent under reduced pressure, dichloromethane was added to the obtained residue, and the precipitate was collected by filtration to give the title compound (378
mg) was obtained as a colorless solid. Furthermore, the residue obtained by concentrating the filtrate under reduced pressure was subjected to flash column chromatography (carrier: silica gel, 15 g, developing solvent: ethyl acetate-
Purification with ethanol, 4: 1) gave the title compound (344 g) as a colorless solid. IR (KBr):. 3402, 1682 cm -1 1 H-NMR (CDCl 3) δ: 2.99 (3H, s), 3.20-3.35 (1H,
m), 3.45-3.65 (2H, m), 4.10-4.35 (3H, m).

Reference Example 19b N- [3-benzoylthio-2-[(tetrahydropyran-2-yl) oxy] -propyl] phthalimide In a solution of triphenylphosphine (3.41 g) in anhydrous THF,
Diisopropyl azodicarboxylate (0.69 ml) at -20 ℃
Was added and stirred at -20 ° C for 30 minutes. Continue to this N
-[3-Hydroxy-2-[(tetrahydropyran-2-
I) oxy] propyl] phthalimide (3.05 g) and thiobenzoic acid (1.53 ml) in anhydrous THF (17 ml) were added-2
The mixture was stirred at 0 ° C for 1 hour and at room temperature for 10 minutes. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography (carrier: silica gel, 200 g, developing solvent: ethyl acetate-hexane, 1: 4). The solvent was distilled off under reduced pressure, and the obtained residue was washed with ether-hexane (1:10) to give the title compound (4.26 g) as a colorless solid. IR (KBr):. 1709, 1664 cm -1 1 H-NMR (CDCl 3) δ: 1.10-1.90 (6
H, m), 3.10-3.60 (4H, m), 3.
75-4.10 (2H, m), 4.10-4.30
(1H, m), 4.60-4.70 (0.6H,
m), 4.85-4.95 (0.4H, m), 7.
35-8.05 (9H, m).

Reference Example 20b 5-[(Tetrahydropyran-2-yl) oxy] perhydro-1,3-thiazin-2-one N- [3-benzoylthio-2-[(tetrahydropyran-2-yl) oxy] ] Propyl] phthalimide (3.48 g) was dissolved in ethanol (40 ml) and hydrazine monohydrate (0.99
ml) was added and the mixture was heated under reflux for 1 hr. After cooling to room temperature, the precipitate was filtered off and washed with ethanol. The filtrate was concentrated, the obtained residue was dissolved in THF-water (1: 1, 40 ml), sodium carbonate (2.60 g) and 4-nitrophenyl chlorocarbonate (2.47 g) were sequentially added at 0 ° C, and the mixture was added at 0 ° C. It was stirred for 1 hour at room temperature and overnight at room temperature. Saturated saline was added, the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure is subjected to flash column chromatography.
(Carrier: silica gel, 40 g, developing solvent: ethyl acetate-hexane, 3: 2 → 2: 1), followed by flash column chromatography (carrier: silica gel, 20 g, developing solvent: ethyl acetate-toluene, 1 : 1) to give the title compound (550 mg) as a colorless oil. IR (neat):. 3277, 1649 cm -1 1 H-NMR (CDCl 3) δ: 1.40-2.00 (6H, m), 3.10-3.3
0 (2H, m), 3.40-3.55 (3H, m), 3.80-4.00 (1H, m), 4.15-4.
40 (1H, m), 4.75-4.85 (1H, m), 5.85-6.15 (1H, m).

Reference Example 21b 5-Hydroxy-2-oxoperhydro-1,3-thiazine 2-oxo-5-[(tetrahydropyran-2-yl) oxy] perhydro-1,3-thiazine (580 mg) Reference example 1
After subjecting to the same reaction and purification treatment as in 5b, the title compound (281 m
g) was obtained as a colorless solid. IR (KBr):. 3194, 1618 cm -1 1 H-NMR (DMSO-d 6) δ: 2.80-3.00 (1H, m), 3.00
-3.50 (4H, m), 3.95-4.10 (1H, m), 7.80-7.95 (1H, m). Reference Example 22b 5-benzoylthio-2-oxoperhydro-1,3-
Thiazine 5-hydroxy-2-oxoperhydro-1,3-thiazine (278 mg) was subjected to the same reaction and purification treatment as in Reference Example 16b to obtain the title compound (219 mg) as a yellow solid. IR (KBr):. 1668, 1641 cm -1 1 H-NMR (CDCl 3) δ: 3.15-3.30 (1H, m), 3.40-3.6
5 (2H, m), 3.70-3.90 (1H, m), 4.30-4.50 (1H, m), 6.05-6.
20 (1H, m), 7.40-7.75 (3H, m), 7.90-8.00 (2H, m).

Reference Example 23b 3-Methyl-5-[(tetrahydropyran-2-yl) oxy] perhydro-1,3-thiazin-2-one Sodium hydride (purity 65%, 228 mg) in anhydrous THF
In solution (22 ml) at 0 ° C 5-[(tetrahydropyran-2-
(Il) oxy] perhydro-1,3-thiazin-2-one (1.22
g) was added and the mixture was stirred at 0 ° C for 20 minutes. Methyl iodide (0.39 ml) was added to the reaction mixture at 0 ° C, and the mixture was stirred at 0 ° C for 1 hr and at room temperature for 30 min. The reaction solution was poured into water, salted out with sodium chloride, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (carrier: silica gel, 50 g, developing solvent: ethyl acetate-hexane, 1: 1) to give the title compound (1.10 g) as a colorless oil. Got as. IR (neat):. 2939, 1633 cm -1 1 H-NMR (CDCl 3) δ: 1.45-1.90 (6 H, m), 3.03 (1.5
H, s), 3.04 (1.5 H, s), 3.10-3.30 (2 H, m), 3.40-3.
65 (3 H, m), 3.80-4.00 (1 H, m), 4.20-4.40 (1 H,
m), 4.75-4.85 (1 H, m).

Reference Example 24b 5-hydroxy-3-methylperhydro-1,3-thiazin-2-one 3-methyl-5-[(tetrahydropyran-2-yl) oxy] perhydro-1,3-thiazine- 2-on (1.10 g) in Reference Example 15b
Subjected to the same reaction and purification treatment as for, to give the title compound (657 mg)
Was obtained as a colorless solid. IR (KBr):. 3392, 1612 cm -1 1 H-NMR (CDCl 3) δ: 1.65-1.75 (1 H, m), 3.05 (3 H,
s), 3.05-3.20 (1 H, m), 3.25-3.60 (3 H, m), 4.25-
4.45 (1 H, m).

Reference Example 25b 5-benzoylthio-3-methylperhydro-1,3-thiazine-2
5-one-3-hydroxy-3-methylperhydro-1,3-thiazin-2-one (644 mg) was subjected to the same reaction and purification treatment as in Reference Example 16b to give the title compound (775 mg) as a yellow solid. Got as. IR (KBr):. 1660, 1622 cm -1 1 H-NMR (CDCl 3) δ: 3.08 (3 H, s), 3.15-3.30 (1 H,
m), 3.40-3.65 (2 H, m), 3.70-3.85 (1 H, m), 4.35-
4.55 (1 H, m), 7.40-7.70 (3 H, m), 7.90-8.00 (2 H,
m).

Reference Example 26b 3-Cyanomethyl-5-[(tetrahydropyran-2-yl) oxy] perhydro-1,3-thiazin-2-one 5-[(Tetrahydropyran-2-yl) oxy] perhydro-1 ,
To 3-thiazin-2-one (1.0 g) was added an anhydrous THF solution (22 ml) of sodium hydride (purity 65%, 187 mg) at 0 ° C, and the mixture was stirred at 0 ° C for 20 minutes. Chloroacetonitrile (0.32 ml) was added to the reaction solution at 0 ° C, and the mixture was stirred at 0 ° C for 10 minutes and at room temperature for 1 hour and a half. The reaction solution was poured into water, salted out with sodium chloride, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (carrier: silica gel,
The product was purified with 50 g, a developing solvent: ethyl acetate-hexane, 2: 3) to obtain the title compound (903 mg) as a colorless oily substance. IR (neat):. 2943, 1626 cm -1 1 H-NMR (CDCl 3) δ: 1.40-2.00 (6 H, m), 3.15-3.40
(2 H, m), 3.50-4.00 (4H, m), 4.25-4.60 (3 H, m),
4.75-4.85 (1 H, m).

Reference Example 27b 3-Cyanomethyl-5-hydroxyperhydro-1,3-thiazine
2-one 3-cyanomethyl-5-[(tetrahydropyran-2-yl) oxy] perhydro-1,3-thiazin-2-one (1.05 g) was subjected to the same reaction and purification treatment as in Reference Example 15b. , Title compound
(570 mg) was obtained as a colorless oil. IR (neat):. 3410, 1616 cm -1 1 H-NMR (CDCl 3) δ: 3.00-3.45 (2 H, m), 3.45-3.75
(2 H, m), 4.30-4.50 (1H, m), 4.42 (2 H, ABq, J = 1
7.4 Hz).

Reference Example 28b 5-benzoylthio-3-cyanomethylperhydro-1,3-thiazin-2-one 3-cyanomethyl-5-hydroxyperhydro-1,3-thiazine
The 2-one (560 mg) was subjected to the same reaction and purification treatment as in Reference Example 16b to give the title compound (859 mg) as a yellow oil. IR (neat):. 1662, 1632, 1209 cm -1 1 H-NMR (CDCl 3) δ: 3.30 (1 H, ddd, J = 12.4, 7.8,
1.0 Hz), 3.56 (1 H, ddd, J = 12.4, 4.0, 1.0 Hz),
3.71 (1 H, ddd, J = 12.6, 7.2, 1.0 Hz), 3.94 (1 H,
ddd, J = 12.6, 3.4, 1.0 Hz), 4.50 (2 H, ABq, 17.4
Hz), 4.40-4.60 (1 H, m), 7.40-7.70 (3 H, m), 7.90-
8.00 (2 H, m).

Example 1b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-3-[(2-thioxoperhydropyrimidin-5-yl) thio] -1-azabicyclo
[3.2.0] 4-Nitrobenzyl hept-2-ene-2-carboxylate Anisole (0.81 g) was added to trifluoroacetic acid solution (7.5 ml) of the compound (200 mg) obtained by the method of Reference Example 1b. After adding, the mixture was stirred with heating under reflux for 3 hours. The solvent was distilled off under reduced pressure, toluene was added to the residue, and trifluoroacetic acid was removed by azeotropic distillation under reduced pressure. Acetonitrile was added to the obtained residue.
(6 ml) was added, and diisopropylethylamine (0.3
2 ml) was added dropwise. Further at 0 ℃ (4R, 5R, 6S) -3
-[(Diphenylphosphono) oxy] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carvone 4-Nitrobenzyl acid salt (443 mg) in acetonitrile (5 m
l) was added and the mixture was stirred at the same temperature for 2 hours. Phosphate buffer (pH 7) was added to the reaction solution, which was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained solid was washed with ethyl acetate and then dried under vacuum to give the title compound.
(296 mg) was obtained as a pale yellow solid. IR (KBr): 1763, 1543, 1520, 1344, 1213 cm ^-1 . ¹ H-NMR (CDCl ₃ , DMSO-d ₆ ) δ: 1.27 (3H, d, J
= 7.0Hz), 1.32 (3H, d, J = 6.2Hz), 3.12-3.65 (7H, m), 4.09
-4.20 (1H, m), 4.28 (1H, dd, J = 2.6, 9.8Hz), 4.53 (1H, d, J
= 5.0Hz), 5.22 (1H, d, J = 13.8Hz), 5.50 (1H, d, J = 13.8Hz),
7.41 (2H, brs), 7.67 (2H, d, J = 8.6Hz), 8.23 (2H, d, J = 8.6
Hz).

Example 2b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-3-[(2-thioxoperhydropyrimidin-5-yl) thio] -1-azabicyclo
[3.2.0] Sodium hept-2-ene-2-carboxylate The compound (170 mg) obtained by the method of Example 1b was treated with THF (7
ml) and a phosphate buffer (pH 7, 0.1 M, 7 ml), 10% palladium carbon (180 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The catalyst was filtered off and washed with water, and the filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure and subjected to column chromatography (carrier: CHP-20P, 60
(ml, developing solvent: water → 5% ethanol-water) and then lyophilized to give the title compound (81.7 mg) as a colorless solid. IR (KBr):. 3394, 1745, 1595, 1545, 1396 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3H, d, J = 7.4Hz), 1.31 (3H,
d, J = 6.4Hz), 3.23-3.78 (7H, m), 4.24-4.31 (2H, m).

Example 3b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-3-[(2-thioxoperhydropyrimidin-5-yl) thio] -1-azabicyclo
[3.2.0] 1- (Cyclohexyloxycarbonyloxy) ethyl 1- (cyclohexyloxycarbonyloxy) ethyl hept-2-ene-2-carboxylate -15 was added to a solution of the compound (49 mg) obtained by the method of Example 2b in DMA (3 ml). 1-Iodoethyl cyclohexyloxycarboxylate (50.1 mg) was added dropwise at ℃, then at the same temperature 3
The mixture was stirred for 0 minutes and further at 0 ° C. for 1 hour. Ethyl acetate was added, and the mixture was washed successively with a phosphate buffer (pH 7) and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by flash column chromatography (carrier: silica gel, 10 g, developing solvent: ethyl acetate: ethanol, 20: 1) to give the title compound (36.5 mg) as a colorless solid. I got it as a thing. IR (neat):. 1759, 1546, 1537, 1277, 1259 cm -1 1 H-NMR (CDCl 3) δ: 1.23-2.05 (19H, m), 2.50-3.
00 (1H, brs), 3.24-3.67 (7H, m), 4.21-4.28 (1H, m), 4.36
(1H, dd, J = 2.2, 9.8Hz), 4.48-4.67 (1H, m), 6.86 (1H, q, J
= 6.4Hz), 7.21 (1H, brs), 7.36 (1H, brs).

Example 4b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-3-[(2-oxoperhydropyrimidin-5-yl) thio] -1-azabicyclo [3.
2.0] 4-Nitrobenzyl hept-2-ene-2-carboxylate Anisole (0.8 g) was added to a trifluoroacetic acid solution (8 ml) of the compound (282 mg) obtained by the method of Reference Example 3b, After stirring at room temperature for 30 minutes, the mixture was further stirred with heating under reflux for 2 hours.
The solvent was distilled off under reduced pressure, toluene was added to the residue, and trifluoroacetic acid was removed by azeotropic distillation under reduced pressure. Acetonitrile (3 ml) was added to the obtained residue, and diisopropylethylamine (0.35 ml) was added dropwise at 0 ° C. At 0 ° C
(4R, 5R, 6S) -3-[(diphenylphosphono) oxy]
-6-[(R) -1-hydroxyethyl] -4-methyl-7
An acetonitrile solution (5 ml) of 4-nitrobenzyl 4-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (476 mg) was added, and the mixture was stirred at the same temperature for 1 hr. Phosphate buffer (pH 7) was added to the reaction solution, which was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the obtained solid was washed with ethyl acetate, and dried in vacuo to give the title compound (196 mg) as a pale yellow solid. IR (KBr):. 1772, 1699, 1680, 1519, 1344 cm -1 1 H-NMR (CDCl 3, DMSO-d 6) δ: 1.26 (3H, d, J
= 6.8Hz), 1.28 (3H, d, J = 6.4Hz), 3.18-3.31 (3H, m), 3.39
-3.61 (4H, m), 4.09 (1H, m), 4.26 (1H, dd, J = 2.4, 9.2Hz),
4.88 (1H, d, J = 4.8Hz), 5.21 (1H, d, J = 13.8Hz), 5.49 (1H,
d, J = 13.8Hz), 5.84 (2H, m), 7.67 (2H, d, J = 8.6Hz), 8.21
(2H, d, J = 8.6Hz).

Example 5b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-3-[(2-oxoperhydropyrimidin-5-yl) thio] -1-azabicyclo [3.
2.0] Sodium hept-2-ene-2-carboxylate The compound (192 mg) obtained by the method of Example 4b was treated with THF (1
It was dissolved in 0 ml) and a phosphate buffer (pH 7, 0.1 M, 10 ml), 10% palladium carbon (210 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hr. The catalyst was filtered off and washed with water, and the filtrate was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure and subjected to column chromatography (carrier: CHP-20P, 10
After purification with 0 ml, a developing solvent: water → 5% ethanol-water), it was freeze-dried to obtain the title compound (122.6 mg) as a colorless solid. IR (KBr):. 3357, 1742, 1653, 1595, 1396 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3H, d, J = 7.2Hz), 1.31 (3H,
d, J = 6.4Hz), 3.22-3.43 (3H, m), 3.49 (1H, dd, J = 2.8, 6.2
Hz), 3.62-3.73 (3H, m), 4.21-4.31 (2H, m).

Example 6b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-3-[(2-oxoperhydropyrimidin-5-yl) thio] -1-azabicyclo [3.
2.0] 1- (Cyclohexyloxycarbonyloxy) ethyl hept-2-ene-2-carboxylate DMA of the compound (48.2 mg) obtained by the method of Example 5b.
1-Iodoethyl cyclohexyloxycarboxylate (63.3 mg) was added dropwise to the solution (2 ml) at -15 ° C, and the mixture was stirred at the same temperature for 3 times.
The mixture was stirred for 0 minutes and further at −0 ° C. for 1 hour. After adding ethyl acetate and washing with phosphate buffer (pH 7) and saturated saline solution successively,
Dry over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure is subjected to flash column chromatography.
The carrier was purified with (carrier: silica gel, 5 g, developing solvent: ethyl acetate: ethanol, 3: 1) to obtain the title compound (19.1 mg) as a colorless foam. IR (neat):. 3300, 1755, 1660, 1274 cm -1 1 H-NMR (CDCl 3) δ: 1.16-2.04 (20H, m), 3.22-3.
55 (7H, m), 4.09-4.27 (2H, m), 4.62-4.65 (1H, m), 5.66 (1
H, brs), 5.82 (1H, brs), 6.86 (1H, q, J = 5.6Hz).

Example 7-1b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-3-[(1-methylperhydropyrimidin-2-thion-5-yl) thio] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic 4-Nitrobenzyl acid compound The compound (300 mg) obtained by the method of Reference Example 6b was used in Example 1
After subjecting to the same reaction and purification treatment as in b, the title compound (499.3 m
g) was obtained as a pale yellow foam. IR (KBr):. 3350, 1770, 1709, 1520 cm -1 1 H-NMR (CDCl 3) δ: 1.29 (3H, d, J = 7.2Hz), 1.37
(3H, d, J = 6.2Hz), 1.63 (1H, brs), 3.21-3.79 (10H, m), 4.
26-4.35 (2H, m), 5.23 (2H, d, J = 13.8Hz), 5.50 (2H, d, J = 1
3.8Hz), 6.65 (2H, d, J = 8.8Hz), 6.24 (2H, d, J = 8.8Hz).

Example 7-2b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-3-[(1-methylperhydropyrimidin-2-thion-5-yl) thio] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic Sodium acid salt The compound (499.3 mg) obtained by the method of Example 7-1b was subjected to the same reaction and purification treatment as in Example 2b to give diastereomer 1 (122.8 mg) and diastereomer 2 of the title compound.
(91.8 mg) was obtained as a colorless solid. Diastereomer 1 IR (KBr):. 3400 , 1751, 1593, 1547 cm -1 1 H-NMR (D 2 O) δ: 1.23 (3H, d, J = 7.0Hz), 1.30 (3H,
d, J = 6.6Hz), 3.22-3.84 (7H, m), 3.27 (3H, s), 4.23-4.30
. (2H, m) diastereomer 2 IR (KBr):. 3369 , 1751, 1593, 1544 cm -1 1 H-NMR (D 2 O) δ: 1.22 (3H, d, J = 7.0Hz), 1.30 (3H,
d, J = 6.6Hz), 3.16-3.60 (7H, m), 3.30 (3H, s), 3.77-3.88
(2H, m).

Example 7-3b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-3-[(1-methylperhydropyrimidin-2-thion-5-yl) thio] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic Acid 1- (cyclohexyloxycarbonyloxy) ethyl diastereomer 1 (49.6 mg) and diastereomer 2 (38.7 mg) of the compound obtained by the method of Example 7-2b were respectively treated in the same manner as in Example 3b. By subjecting to purification treatment, diastereomer 1 (33 mg) and diastereomer 2 (22.2 mg) of the title compound were obtained as colorless solids, respectively. Diastereomer 1 IR (neat):. 3401 , 1765, 1539, 1275, 1074 cm -1 1 H-NMR (CDCl 3) δ: 1.21-1.96 (20H, m), 2.05-3.
73 (10H, m), 4.22-4.31 (2H, m), 4.61-4.68 (1H, m), 6.77
. (1H, brs), 6.87 (1H, q, J = 5.2Hz) diastereomer 2 IR (neat):. 3400 , 1759, 1537, 1277, 1074 cm -1 1 H-NMR (CDCl 3) δ: 1.17-1.95 (20H, m), 3.25-3.
76 (10H, m), 4.18-4.24 (2H, m), 4.61-4.68 (1H, m), 4.55
(1H, brs), 6.87 (1H, q, J = 3.4Hz).

Example 8-1b (4R, 5S, 6S) -3-[(1,3-Dimethyl-2-thioxoperhydropyrimidin-5-yl) thio] -6-
[(R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2
-Nitrobenzyl carboxylate The compound (328.3 mg) obtained by the method of Reference Example 8b was subjected to the same reaction and purification treatment as in Example 1b to give the title compound (410 m
g) was obtained as a colorless solid. IR (KBr):. 3383, 1778, 1759, 1529, 1512 cm -1 1 H-NMR (CDCl 3) δ: 1.30 (3H, d, J = 7.4Hz), 1.38
(3H, d, J = 6.2Hz), 1.57 (1H, brs), 3.30-3.72 (7H, m), 3.4
1 (3H, s), 3.43 (3H, s), 4.24-4.34 (2H, m), 5.24 (1H, d, J =
14.0Hz), 5.51 (1H, d, J = 14.0Hz), 7.66 (2H, d, J = 8.6Hz),
8.24 (2H, d, J = 8.6Hz).

Example 8-2b (4R, 5S, 6S) -3-[(1,3-Dimethyl-2-thioxoperhydropyrimidin-5-yl) thio] -6-
[(R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2
-Sodium carboxylate The compound (410 mg) obtained by the method of Example 8-1b was subjected to the same reaction and purification treatment as in Example 2b to give the title compound (175
mg) was obtained as a colorless foam. IR (KBr): 3427, 1751, 1593, 1529, 1396, 1354 cm
^{. -1 1 H-NMR (D} 2 O) δ: 1.23 (3H, d, J = 7.4Hz), 1.30 (3H,
d, J = 6.2Hz), 3.31-3.51 (4H, m), 3.31 (3H, s), 3.33 (3H,
s), 3.72-3.85 (3H, m), 4.23-4.30 (2H, m).

Example 8-3b (4R, 5S, 6S) -3-[(1,3-Dimethyl-2-thioxoperhydropyrimidin-5-yl) thio] -6-
[(R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2
1- (Cyclohexyloxycarbonyloxy) ethyl carboxylate The compound (51.9 mg) obtained by the method of Example 8-2b was subjected to the same reaction and purification treatment as in Example 3b to give the title compound (2
4.6 mg) was obtained as a colorless foam. IR (neat):. 3401, 1759, 1524, 1350, 1277 cm -1 1 H-NMR (CDCl 3) δ: 1.23-2.05 (2
0H, m), 3.26-3.74 (13H, m),
4.18-4.30 (2H, m), 4.61-4.6
8 (1H, m), 6.88 (1H, q, J = 5.2H
z).

Example 9-1b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-3-[(1-methyl-2-oxoperhydropyrimidine-5- Il) thio] -7-oxo-1-
4-nitrobenzyl azabicyclo [3.2.0] hept-2-ene-2-carboxylate The compound (164 mg) obtained by the method of Example 4b was used in Example 1.
Subjected to the same reaction and purification treatment as for b, and the title compound (140 mg)
Was obtained as a colorless solid which was a mixture of diastereomers (1: 1). IR (KBr):. 3425, 1770, 1645, 1635, 1523 cm -1 1 H-NMR (CDCl 3) δ: 1.31 (3H, d, J = 7.4Hz), 1.38
(3H, d, J = 6.2Hz), 2.93 (3 / 2H, s), 2.96 (3 / 2H, s), 3.20-
3.80 (7H, m), 4.20-4.40 (2H, m), 4.86 (1H, brs), 5.24 (1
H, d, J = 13.6Hz), 5.55 (1H, d, J = 13.6Hz), 7.66 (2H, d, J = 8.
8Hz), 8.24 (2H, d, J = 8.8Hz).

Example 9-2b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-3-[(1-methyl-2-oxoperhydropyrimidin-5-yl) thio] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic Sodium acid The compound (137 mg) obtained by the method of Example 9-1b was subjected to the same reaction and purification treatment as in Example 2b to give diastereomer 1 (33 mg) and diastereomer 2 (of the title compound. twenty four
mg) respectively as a colorless solid. Diastereomer 1 IR (KBr): 3465, 1751, 1638, 1595, 1543, 1535 cm
^{. -1 1 H-NMR (D} 2 O) δ: 1.23 (3H, d, J = 7.2Hz), 1.31 (3H,
d, J = 6.2Hz), 2.86 (3H, s), 3.18-3.80 (7H, m), 4.20-4.32
. (2H, m) diastereomer 2 IR (KBr):. 3390 , 1751, 1637, 1597, 1535 cm -1 1 H-NMR (D 2 O) δ: 1.23 (3H, d, J = 7.2Hz) , 1.30 (3H,
d, J = 6.4Hz), 2.89 (3H, s), 3.16-3.80 (6H, m), 3.48 (1H, d
d, J = 6.4, 2.8Hz), 4.24 (1H, dd, J = 8.8, 2.8Hz), 4.26 (1
H, quint, J = 6.4Hz).

Example 9-3b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-3-[(1-methyl-2-oxoperhydropyrimidin-5-yl) thio] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic 1- (Cyclohexyloxycarbonyloxy) ethyl Acid Acid Diastereomer 1 (68 mg) and diastereomer 2 (71.7 mg) of the compound obtained by the method of Example 9-2b were treated in the same manner as in Example 3b. By subjecting to a purification treatment, diastereomer 1 (63.6 mg) and diastereomer 2 (60 mg) of the title compound were obtained as colorless solids, respectively. Diastereomer 1 IR (KBr): 3400, 1755, 1710, 1640, 1535, 1530 cm
^{. -1 1 H-NMR (CDCl} 3) δ: 1.20-2.05 (10H, m), 1.28 (3
H, d, J = 7.0Hz), 1.34 (3 / 2H, d, J = 6.4Hz), 1.36 (3 / 2H, d, J =
6.2Hz), 1.59 (3 / 2H, d, J = 5.2Hz), 1.61 (3 / 2H, d, J = 5.2H
z), 2.92 (3 / 2H, s), 2.93 (3 / 2H, s), 3.20-3.80 (7H, m),
4.15-4.35 (2H, m), 4.55-4.75 (1H, m), 4.9 (1H, brs), 6.8
8 (1H, q, J = 5.4Hz). Diastereomer 2 IR (KBr): 3400, 1760, 1710, 1640, 1535, 1530 cm
^{. -1 1 H-NMR (CDCl} 3) δ: 1.20-2.05 (10H, m), 1.28 (3
H, d, J = 7.0Hz), 1.34 (3 / 2H, d, J = 6.2Hz), 1.36 (3 / 2H, d, J =
6.4Hz), 1.58 (3 / 2H, d, J = 5.1Hz), 1.61 (3 / 2H, d, J = 5.1H
z), 2.95 (3H, s), 3.15-3.75 (7H, m), 4.15-4.35 (2H, m),
4.55-4.75 (1H, m), 4.8 (1H, brs), 6.88 (1H, q, J = 5.4Hz).

Example 10-1b (4R, 5S, 6S) -3-[(1,3-Dimethyl-2-oxoperhydropyrimidin-5-yl) thio] -6-[(R)
-1-Hydroxyethyl] -4-methyl-7-oxo-
4-Nitrobenzyl 1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate The compound (300 mg) obtained by the method of Reference Example 5b was used in Example 1
Subjected to the same reaction and purification treatment as for b, and the title compound (453 mg)
Was obtained as a colorless solid. IR (KBr):. 3338, 1778, 1709, 1625, 1527 cm -1 1 H-NMR (CDCl 3) δ: 1.31 (3H, d, J = 7.4Hz), 1.73
(3H, d, J = 6.6Hz), 1.62 (1H, brs), 2.92 (3H, s), 2.95 (3H,
s), 2.95-3.78 (7H, m), 4.26-4.34 (2H, m), 5.24 (1H, d, J =
13.8Hz), 5.51 (1H, d, J = 13.8Hz), 7.66 (2H, d, J = 8.4Hz),
8.24 (2H, d, J = 8.4Hz).

Example 10-2b (4R, 5S, 6S) -3-[(1,3-Dimethyl-2-oxoperhydropyrimidin-5-yl) thio] -6-[(R)
-1-Hydroxyethyl] -4-methyl-7-oxo-
Sodium 1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate The compound (453 mg) obtained by the method of Example 10-1b was subjected to the same reaction and purification treatment as in Example 2b. The title compound (2
57 mg) was obtained as a colorless foam. IR (KBr): 3390, 1751, 1601, 1535, 1394, 1275 cm
^{. -1 1 H-NMR (D} 2 O) δ: 1.23 (3H, d, J = 7.4Hz), 1.31 (3H,
d, J = 6.2Hz), 2.87 (3H, s), 2.89 (3H, s), 3.21-3.79 (7H,
m), 4.22-4.29 (2H, m).

Example 10-3b (4R, 5S, 6S) -3-[(1,3-Dimethyl-2-oxoperhydropyrimidin-5-yl) thio] -6-[(R)
-1-Hydroxyethyl] -4-methyl-7-oxo-
1-Azabicyclo [3.2.0] hept-2-ene-2-carboxylate 1- (cyclohexyloxycarbonyloxy) ethyl Compound (51.4 mg) obtained by the method of Example 10-2b was used as Example 3b. Subjected to the same reaction and purification treatment, the title compound
(47.6 mg) was obtained as a colorless solid. IR (KBr): 3302, 1774, 1753, 1618, 1277, 1257, 1
^{. 074 cm -1 1 H-NMR} (CDCl3) δ: 1.21-1.98 (20H, m), 2.91-2.
95 (6H, m), 3.22-3.78 (7H, m), 4.22-4.28 (2H, m), 4.62-
4.68 (1H, m), 6.89 (1H, q, J = 5.6Hz).

Example 11-1b (4R, 5S, 6S) -3-[[1,3-bis (pyridine-2-
Yl) -2-Thioxoperhydropyrimidin-5-yl]
Thio] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-
4-Nitrobenzyl 2-ene-2-carboxylate The compound (156 mg) obtained by the method of Reference Example 9b was used in Example 1.
Subjected to the same reaction and purification treatment as for b, and the title compound (148 mg)
Was obtained as a pale yellow solid. IR (KBr):. 3400, 1772, 1711, 1589, 1520 cm -1 1 H-NMR (CDCl 3) δ: 1.32 (3H, d, J = 7.6Hz), 1.37
(3H, d, J = 6.2Hz), 1.62 (1H, brs), 3.33 (1H, dd, J = 6.4, 2.
8Hz), 3.43-4.48 (8H, m), 5.24 (1H, d, J = 13.8Hz), 5.48 (1
H, d, J = 13.8Hz), 7.18-7.27 (2H, m), 7.59-7.78 (6H, m),
8.21 (2H, d, J = 8.8Hz), 8.45-8.52 (2H, m).

Example 11-2b (4R, 5S, 6S) -3-[[1,3-bis (pyridine-2-
Yl) -2-Thioxoperhydropyrimidin-5-yl]
Thio] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-
Sodium 2-ene-2-carboxylate The compound (148 mg) obtained by the method of Example 11-1b was subjected to the same reaction and purification treatment as in Example 2b to give the title compound (6
6.6 mg) was obtained as a colorless foam. IR (KBr): 3427, 1751, 1592, 1468, 1433, 1319 cm
^{. -1 1 H-NMR (D} 2 O) δ: 1.25 (3H, d, J = 7.2Hz), 1.27 (3H,
d, J = 6.6Hz), 3.35-3.54 (2H, m), 3.75-4.01 (2H, m), 4.12
(1H, dd, J = 9.4, 2.4Hz), 4.19-4.42 (4H, m), 7.45-7.61 (4
H, m), 7.93-8.07 (2H, m), 8.48-8.53 (2H, m).

Example 12-1b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-3-[(2-oxoperhydro-1,3-oxazin-5-yl) thio] -1-azabicyclo [3.2.0] hept-2-ene-2- Carboxylic acid 4
-Nitrobenzyl THF of the compound (416 mg) obtained by the method of Reference Example 16b
-Sodium methoxide (95 mg) was added to a methanol solution (1: 1, 18 ml) at 0 ° C, and the mixture was stirred at 0 ° C for 1 hr. Acetic acid (0.
22 ml) and acetonitrile (40 ml) were added, and the solvent was concentrated under reduced pressure to about 5 ml. The insoluble matter was removed by filtration, and acetonitrile (4
It was washed with 0 ml). The filtrate thus obtained was added to (4
R, 5R, 6S) -3-[(diphenylphosphono) oxy]-
6-[(R) -1-hydroxyethyl] -4-methyl-7-
Oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate 4-nitrobenzyl (1.68 g) and diisopropylethylamine (0.68 ml) were added, and the mixture was stirred at 0 ° C. for 1 hr. Ethyl acetate was added to the reaction solution, which was washed with pH7 phosphate buffer and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting solid was collected by filtration and washed with ethyl acetate to give the diastereomer 1 of the title compound (low polarity) (42
7 mg) was obtained as a colorless solid. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (carrier: silica gel, 50 g, developing solvent: ethyl acetate-ethanol, 1: 0 → 50: 1 → 9: 1) to give the title. Diastereomer 1 of the compound (low polarity) (60 mg) and diastereomer 2 of the title compound (high polarity) (327 mg) were each obtained as colorless solids. Diastereomer 1 IR (KBr):. 3521 , 1761, 1703, 1524 cm -1 1 H-NMR (DMSO-d 6) δ: 1.10-1.25 (6H, m), 3.05
-3.25 (1H, m), 3.25-3.40 (1H, m), 3.50-3.70 (2H, m), 3.7
0-3.90 (1H, m), 3.90-4.20 (2H, m), 4.20-4.35 (1H, m), 4.
35-4.50 (1H, m), 5.08 (1H, d, J = 5.2Hz), 5.39 (2H, ABq, J = 1
4.4Hz), 7.42 (1H, brs), 7.72 (2H, d, J = 8.6Hz), 8.24 (2H,
. d, J = 8.6Hz) diastereomer 2 IR (KBr):. 3402 , 1768, 1703, 1521, 1346 cm -1 1 H-NMR (DMSO-d 6) δ: 1.10-1.25 (6H, m) , 3.05
-3.40 (2H, m), 3.50-3.70 (2H, m), 3.80-3.90 (1H, m), 3.9
0-4.10 (1H, m), 4.15-4.35 (2H, m), 4.45-4.55 (1H, m), 5.
08 (1H, d, J = 5.2Hz), 5.40 (2H, ABq, J = 14.0Hz), 7.35-7.45
(1H, m), 7.72 (2H, d, J = 8.8Hz), 8.25 (2H, d, J = 8.8Hz).

Example 12-2b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-3-[(2-oxoperhydro-1,3-oxazin-5-yl) thio] -1-azabicyclo [3.2.0] hept-2-ene-2- Sodium Carboxylate Diastereomer 1 (140 mg) and diastereomer 2 (175 mg) of the compound obtained by the method of Example 12-1b were subjected to the same reaction and purification treatment as in Example 2b, respectively. Diastereomer 1 (94 mg) and diastereomer 2 (88 mg) of the compound were respectively obtained as colorless solids. Diastereomer 1 IR (KBr):. 3425 , 1749, 1699, 1595, 1394 cm -1 1 H-NMR (D 2 O) δ: 1.23 (3H, d, J = 7.2Hz), 1.30 (3H,
d, J = 6.4Hz), 3.20-3.40 (1H, m), 3.40-3.55 (2H, m), 3.60
-3.85 (2H, m), 4.15-4.30 (3H, m), 4.40-4.55 (1H, m) diastereomer 2 IR (KBr):.. 3417, 1751, 1703, 1597, 1394 cm -1 1 H _{-NMR (D 2 O) δ:} 1.23 (3H, d, J = 7.2Hz), 1.30 (3H,
d, J = 6.4Hz), 3.20-3.50 (2H, m), 3.49 (1H, dd, J = 6.0Hz an
d 2.8Hz), 3.60-3.90 (2H, m), 4.15-4.45 (3H, m), 4.55-4.
70 (1H, m).

Example 12-3b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-3-[(2-oxoperhydro-1,3-oxazin-5-yl) thio] -1-azabicyclo [3.2.0] hept-2-ene-2-- Carboxylic acid 1
-(Cyclohexyloxycarbonyloxy) ethyl Diastereomer 1 (38 mg) and diastereomer 2 (41 mg) of the compound obtained by the method of Example 12-2b were treated and purified in the same manner as in Example 3b. The diastereomer 1 (37 mg) of the title compound was obtained as a colorless solid and the diastereomer 2 (39 mg) was obtained as a pale yellow solid. Diastereomer 1 IR (KBr):. 3427 , 1759, 1705 cm -1 1 H-NMR (CDCl 3) δ: 1.10-2.10 (19H, m), 3.20-3.
50 (3H, m), 3.55-3.80 (2H, m), 4.05-4.40 (4H, m), 4.55-
4.75 (1H, m), 5.35-5.45 (1H, m), 6.80-6.95 (1H, m) diastereomer 2 IR (KBr):.. 3429, 1759, 1705 cm -1 1 H-NMR (CDCl 3 ) δ: 1.10-2.10 (19H, m), 2.20-2.
50 (1H, m), 3.20-3.55 (3H, m), 3.55-3.80 (2H, m), 4.05-
4.40 (3H, m), 4.40-4.75 (2H, m), 5.94 (1H, brs), 6.80-6.
95 (1H, m).

Example 13-1b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-3-[(3-methyl-2-oxoperhydro-1,3-oxazin-5-yl) thio] -7-oxo-1-azabicyclo [3.2.0] hept-2- En-2-
4-Nitrobenzyl Carboxylate The compound (717 mg) obtained by the method of Reference Example 18b was subjected to the same reaction as in Reference Example 16b to give 5-benzoylthio-3-.
Methylperhydro-1,3-oxazin-2-one was obtained as a mixture with triphenylphosphine oxide.
Subsequently, this was subjected to the same reaction and purification treatment as in Example 12-1b to give the diastereomer 1 of the title compound (low polarity).
(782 mg) and diastereomer 2 of the title compound (high polarity) (871 mg) were obtained as colorless solids, respectively. Diastereomer 1 IR (KBr):. 3462 , 1776, 1686, 1523 cm -1 1 H-NMR (DMSO-d 6) δ: 1.10-1.25 (6H, m), 2.86
(3H, s), 3.10-3.40 (2H, m), 3.50-3.80 (2H, m), 3.80-4.2
0 (3H, m), 4.20-4.50 (2H, m), 5.10 (1H, d, J = 5.0Hz), 5.40
(2H, ABq, J = 14.2Hz), 7.72 (2H, d, J = 8.6Hz), 8.25 (2H, d, J
= 8.6 Hz) diastereomer 2 IR (KBr):.. 3332, 1767, 1701, 1676, 1344 cm -1 1 H-NMR (DMSO-d 6) δ: 1.10-1.30 (6H, m), 2.84
(3H, s), 3.20-3.50 (2H, m), 3.50-3.85 (2H, m), 3.85-4.1
0 (2H, m), 4.10-4.35 (2H, m), 4.40-4.60 (1H, m), 5.10 (1
H, d, J = 5.2Hz), 5.40 (2H, ABq, J = 14.0Hz), 7.72 (2H, d, J =
8.6Hz), 8.24 (2H, d, J = 8.6Hz).

Example 13-2b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-3-[(3-methyl-2-oxoperhydro-1,3-oxazin-5-yl) thio] -7-oxo-1-azabicyclo [3.2.0] hept-2- En-2-
Sodium Carboxylate Diastereomer 1 (400 mg) and diastereomer 2 (400 mg) of the compound obtained by the method of Example 13-1b were subjected to the same reaction and purification treatment as in Example 2b, respectively. Diastereomer 1 (262 mg) and diastereomer 2 (264 mg) of the compound were obtained as colorless solids, respectively. Diastereomer 1 IR (KBr): 3415, 1757, 1711, 1686, 1605, 1394 cm
^{. -1 1 H-NMR (D} 2 O) δ: 1.23 (3H, d, J = 7.2Hz), 1.30 (3H,
d, J = 6.2Hz), 2.96 (3H, s), 3.25-3.55 (3H, m), 3.65-3.90
(2H, m), 4.10-4.35 (3H, m), 4.35-4.50 (1H, m). Diastereomer 2 ¹ H-NMR (D ₂ O) δ: 1.22 (3H, d, J = 7.2Hz) , 1.30 (3H,
d, J = 6.4Hz), 2.94 (3H, s), 3.25-3.55 (3H, m), 3.70-3.90
(2H, m), 4.15-4.40 (3H, m), 4.50-4.65 (1H, m).

Example 13-3b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-3-[(3-methyl-2-oxoperhydro-1,3-oxazin-5-yl) thio] -7-oxo-1-azabicyclo [3.2.0] hept-2- En-2-
1- (Cyclohexyloxycarbonyloxy) ethyl Carboxylate Diastereomer 1 (80 mg) and diastereomer 2 (71 mg) of the compound obtained by the method of Example 13-2b were each reacted in the same manner as in Example 3b. And purified to obtain diastereomer 1 (92 mg) and diastereomer 2 (86 mg) of the title compound as colorless solids, respectively. Diastereomer 1 IR (KBr):. 3423 , 1761, 1705 cm -1 1 H-NMR (CDCl 3) δ: 1.10-2.10 (19H, m), 2.20-2.
50 (1H, m), 3.00 (3H, s), 3.10-3.85 (5H, m), 4.00-4.40 (4
. H, m), 4.50-4.75 ( 1H, m), 6.80-7.00 (1H, m) diastereomer 2 IR (KBr):. 3431 , 1759, 1689 cm -1 1 H-NMR (CDCl 3) δ : 1.20-2.10 (19H, m), 2.25-2.
55 (1H, m), 2.98 (1.5H, s), 2.99 (1.5H, s), 3.20-3.65 (4
H, m), 3.70-3.85 (1H, m), 4.10-4.35 (3H, m), 4.35-4.50
(1H, m), 4.55-4.75 (1H, m), 6.88 (1H, q, J = 5.4Hz).

Example 14-1b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-3-[(2-oxoperhydro-1,3-thiazin-5-yl) thio] -1-azabicyclo [3.2.0] hept-2-ene-2- Carboxylic acid 4-
Nitrobenzyl The compound (216 mg) obtained by the method of Reference Example 22b was subjected to the same reaction and purification treatment as in Example 12-1b to give diastereomer 1 (low polarity) (113 mg) of the title compound, and Diastereomer 2 (high polarity) (170 mg) of the title compound was obtained as a colorless solid. Diastereomer 1 IR (KBr): 3425, 1768, 1705, 1641, 1522, 1344 cm
^{. -1 1 H-NMR (DMSO} -d 6) δ: 1.10-1.30 (6H, m), 3.10
-3.70 (6H, m), 3.85-4.10 (2H, m), 4.20-4.35 (1H, m), 5.1
0 (1H, d, J = 5.0Hz), 5.60 (2H, ABq, J = 14.0Hz), 7.74 (2H, d,
J = 8.6Hz), 8.20-8.30 (3H, m). Diastereomer 2 IR (KBr): 3425, 1759, 1707, 1643, 1520, 1342 cm
^{. -1 1 H-NMR (DMSO} -d 6) δ: 1.10-1.25 (6H, m), 3.10
-3.70 (6H, m), 3.80-4.10 (2H, m), 4.20-4.30 (1H, m), 5.1
0 (1H, d, J = 5.2Hz), 5.40 (2H, ABq, J = 14.0Hz), 7.73 (2H, d,
J = 8.6Hz), 8.15-8.30 (3H, m).

Example 14-2b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl]
-4-Methyl-7-oxo-3-[(2-oxoperhydro-1,3-thiazin-5-yl) thio] -1-azabicyclo [3.2.0] hept-2-ene-2- Sodium Carboxylate Diastereomer 1 (110 mg) and diastereomer 2 (167 mg) of the compound obtained by the method of Example 14-1b were subjected to the same reaction and purification treatment as in Example 2b, respectively. Diastereomer 1 (61 mg) and diastereomer 2 (87 mg) of the compound were respectively obtained as colorless solids. Diastereomer 1 IR (KBr):. 3431 , 1749, 1637, 1599 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3H, d, J = 7.4Hz), 1.30 (3H,
d, J = 6.4Hz), 3.15-3.30 (1H, m), 3.30-3.55 (4H, m), 3.65
-3.95 (2H, m), 4.15-4.35 (2H, m) diastereomer 2 IR (KBr):.. 3437, 1749, 1637, 1597 cm -1 1 H-NMR (D 2 O) δ: 1.24 ( 3H, d, J = 7.2Hz), 1.31 (3H,
d, J = 6.4Hz), 3.15-3.30 (1H, m), 3.30-3.75 (5H, m), 3.75
-3.95 (1H, m), 4.20-4.35 (2H, m).

Example 14-3b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-7-
Oxo-3-[(2-oxoperhydro-1,3-thiazin-5-yl)
1- (Cyclohexyloxycarbonyloxy) ethyl Thio] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate Diastereomer 1 obtained by the method of Example 14-2b
(17 mg) and diastereomer 2 (25 mg) were subjected to the same reaction and purification treatment as in Example 3b to give diastereomer 1 (18 mg) and diastereomer 2 (2
5 mg) was obtained as a colorless solid. Diastereomer 1 IR (KBr):. 3421 , 1759, 1639 cm -1 1 H-NMR (CDCl 3) δ: 1.15-2.05 (19 H, m), 2.15-2.35
(1 H, m), 3.00-3.55 (5H, m), 3.55-3.90 (2 H, m),
4.15-4.35 (2 H, m), 4.55-4.75 (1 H, m), 6.35-6.50
. (1 H, m), 6.88 (1 H, q, J = 5.6 Hz) diastereomer 2 IR (KBr):. 3433 , 1759, 1643 cm -1 1 H-NMR (CDCl 3) δ: 1.10- 2.10 (19 H, m), 2.40-2.70
(1 H, m), 3.05-3.80 (7H, m), 4.10-4.35 (2 H, m),
4.55-4.75 (1 H, m), 6.65-6.80 (1 H, m), 6.80-6.95
(1 H, m).

Example 15-1b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-3-
[(3-methyl-2-oxoperhydro-1,3-thiazin-5-yl)
Thio] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-
2-Carboxylic acid 4-nitrobenzyl 5-benzoylthio-3-methylperhydro-1,3-thiazine-2
-One (763 mg) was subjected to the same reaction and purification treatment as in Example 12-1b to give the diastereomer 1 (398 m of the title compound).
g) and diastereomer 2 (325 mg) were obtained as colorless solids, respectively. Diastereomer 1 IR (KBr):. 3471 , 1776, 1709, 1622, 1524, 1338 cm -1 1 H-NMR (DMSO-d 6) δ: 1.10-1.25 (6 H, m), 2.93 (3
H, m), 3.10-3.35 (2 H, m), 3.40-3.85 (4 H, m), 3.85
-4.10 (2 H, m), 4.25-4.40 (1 H, m), 5.10 (1H, d, J
= 5.4 Hz), 5.39 (2 H, ABq, J = 14.0 Hz), 7.73 (2 H,
. d, J = 8.8 Hz) , 8.24 (2 H, d, J = 8.8 Hz) diastereomer 2 IR (KBr):. 3440 , 1770, 1711, 1626, 1340 cm -1 1 H-NMR (DMSO- d ₆ ) δ: 1.10-1.25 (6
H, m), 2.91 (3 H, s), 3.1
0-3.35 (2 H, m), 3.40-3.75
(4 H, m), 3.80-4.10 (2
H, m), 4.25-4.35 (1 H,
m), 5.11 (1H, d, J = 5.2)
Hz), 5.39 (2 H, ABq, J =
14.2 Hz), 7.72 (2 H, d, J
= 8.8 Hz), 8.24 (2 H, d,
J = 8.8 Hz).

Example 15-2b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-3-[(3-methyl-2-oxoperhydro-
1,3-thiazin-5-yl) thio] -7-oxo-1-azabicyclo
[3.2.0] Sodium hept-2-ene-2-carboxylate Diastereomer 1 obtained by the method of Example 15-1b
(393 mg) and diastereomer 2 (319 mg) were subjected to the same reaction and purification treatment as in Example 2b, and diastereomer 1 (259 mg) and diastereomer 2 (201 mg) of the title compound were colorless. Obtained as a solid, respectively. Diastereomer 1 IR (KBr):. 3423 , 1743, 1622, 1601 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3 H, d, J = 7.4 Hz), 1.30
(3 H, d, J = 6.6 Hz), 3.05 (3 H, s), 3.10-3.65 (5
. H, m), 3.70-4.00 ( 2 H, m), 4.20-4.35 (2 H, m) diastereomer 2 IR (KBr):. 3408 , 1745. 1641, 1599 cm -1 1 H-NMR ( D ₂ O) δ: 1.24 (3 H, d, J = 7.2 Hz), 1.31
(3 H, d, J = 6.2 Hz), 3.02 (3 H, s), 3.23 (1 H, d
d, J = 12.2 Hz and 8.2 Hz), 3.40-3.60 (4 H, m), 3.
65-3.80 (1 H, m), 3.80-4.00 (1 H, m), 4.20-4.35 (2
H, m).

Example 15-3b (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl-3-
[(3-methyl-2-oxoperhydro-1,3-thiazin-5-yl)
Thio] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-
1- (Cyclohexyloxycarbonyloxy) ethyl 2-carboxylate Diastereomer 1 obtained by the method of Example 15-2b
(70 mg) and diastereomer 2 (71 mg) were subjected to the same reaction and purification treatment as in Example 3b to give diastereomer 1 (72 mg) and diastereomer 2 (7) of the title compound.
1 mg) was obtained as a colorless solid. Diastereomer 1 IR (KBr):. 3423 , 2937, 1761, 1630, 1276 cm -1 1 H-NMR (CDCl 3) δ: 1.20-2.10 (20 H, m), 2.95-3.10
(1 H, m), 3.07 (3 H, s), 3.25-3.70 (5 H, m), 3.70-
3.95 (1 H, m), 4.15-4.35 (2 H, m), 4.55-4.75 (1 H,
. m), 6.80-6.95 (1 H , m) diastereomer 2 IR (KBr):. 3439 , 2987, 1761, 1628, 1275 cm -1 1 H-NMR (CDCl 3) δ: 1.20-2.10 (19 H, m), 2.52 (1 H,
brs), 3.04 (3 H, s), 3.10-3.65 (6 H, m), 3.65-3.90
(1 H, m), 4.15-4.35 (2 H, m), 4.55-4.75 (1 H, m),
6.88 (1 H, q, J = 5.4 Hz).

Example 16-1b (4R, 5S, 6S) -3-[(3-Cyanomethyl-2-oxoperhydro-
1,3-thiazin-5-yl) thio] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-
2-Ene-2-carboxylic acid 4-nitrobenzyl 5-benzoylthio-3-cyanomethylperhydro-1,3-thiazin-2-one (850 mg) was treated and purified in the same manner as in Example 12-1b. The diastereomer 1 (5
44 mg) and diastereomer 2 (347 mg) were obtained as colorless solids, respectively. Diastereomer 1 IR (KBr):. 3431 , 1770, 1711, 1522, 1344, 1213 cm -1 1 H-NMR (CDCl 3) δ: 1.33 (3 H, d, J = 7.8 Hz), 1.37
(3 H, d, J = 6.6 Hz), 3.10-3.50 (4 H, m), 3.61 (1
H, dd, J = 12.2 Hz and 9.8 Hz), 3.70-4.00 (2 H,
m), 4.20-4.40 (2 H, m), 4.42 (2 H, ABq, J = 17.6 H
z), 5.38 (2 H, ABq, J = 14.0 Hz), 7.66 (2 H, d, J
= 8.4 Hz), 8.24 (2 H, d, J = 8.4 Hz). Diastereomer 2 IR (KBr): 3431, 1770, 1711, 1629, 1522, 1344, 1213
cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.33 (3 H, d, J = 7.2 Hz), 1.36
(3 H, d, J = 6.2 Hz), 3.28 (2 H, d, J = 6.6 Hz),
3.35 (1 H, dd, J = 6.6 Hz and 1.4 Hz), 3.51 (1 H, d
q, J = 9.6 Hz and 7.2 Hz), 3.60-3.70 (2 H, m), 3.7
0-3.90 (1 H, m), 4.29 (1 H, dq, J = 7.2 Hz and 6.2
Hz), 4.38 (1 H, dd, J = 9.6 Hz and 2.8 Hz), 4.45
(2 H, ABq, J = 17.6 Hz), 5.37 (2 H, ABq, J = 13.6
Hz), 7.65 (2 H, d, J = 8.8 Hz), 8.25 (2 H, d, J =
8.8 Hz).

Example 16-2b (4R, 5S, 6S) -3-[(3-Cyanomethyl-2-oxoperhydro-
1,3-thiazin-5-yl) thio] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-
Sodium 2-ene-2-carboxylate Diastereomer 1 obtained by the method of Example 16-1b
(530 mg) and diastereomer 2 (325 mg) were subjected to the same reaction and purification treatment as in Example 2b to give diastereomer 1 (310 mg) and diastereomer 2 (191 mg) of the title compound as colorless. Obtained as a solid, respectively. Diastereomer 1 IR (KBr):. 3429 , 1749, 1605, 1394 cm -1 1 H-NMR (D 2 O) δ: 1.24 (3 H, d, J = 7.2 Hz), 1.30
(3 H, d, J = 6.2 Hz), 3.20-3.55 (4 H, m), 3.71 (1
H, dd, J = 13.4 Hz and 9.0 Hz), 3.90-4.10 (2H, m),
4.20-4.30 (2 H, m), 4.51 (2 H, s) diastereomer 2 IR (KBr):.. 3431, 1751, 1605, 1394 cm -1 1 H-NMR (D 2 O) δ: 1.25 (3 H, d, J = 7.2 Hz), 1.31
(3 H, d, J = 6.4 Hz), 3.30 (1 H, dd, J = 12.4 Hz a
nd 8.0 Hz), 3.40-3.60 (2 H, m), 3.67 (1 H, dd, J =
13.2 Hz and 7.4 Hz), 3.80-4.10 (2 H, m), 4.20-4.3
5 (2 H, m), 4.49 (2 H, ABq, J = 17.6 Hz). The chemical structural formulas of the example compounds are as follows.

Embedded image

TEST EXAMPLE The compound (I) of the present invention and a salt thereof have a broad spectrum of antibacterial activity and can be used for the prevention and treatment of various diseases caused by pathogenic bacteria in humans and animals. [Measurement method] Test example Minimum growth inhibitory concentration (MIC) Minimum growth inhibitory concentration of test compound [MIC: minimal inh
ibitory concentration (unit: μg / ml)] was determined by an agar dilution method. That is,
0.25m aqueous solution of test compound diluted by serial dilution method
Pour l into a petridish, then pour and mix 9.75 ml of Muller-Hinton agar (MH medium). Alternatively, 0.25 ml of an aqueous solution of the test compound diluted by the serial dilution method is used for petridis (petridis).
h), then 9.75 ml of Muller-Hinton agar containing horse serum, hemin and nicotinamide adenine dinucleotide is poured and mixed [S-MH medium. Horse serum (5%), hemin (10 μg / m
l) and nicotinamide adenine dinucleotide (2
0 μg / ml)]. A suspension of the test strain (about 10 ⁶ CFU / ml) is spread on the mixed agar plate. After overnight incubation at 37 ° C., the MIC is the lowest concentration of test compound that completely inhibits the growth of the test organism.

[Table 1] From the above results, it is clear that the carbapenem compound of the present invention has excellent antibacterial activity against strains that are regarded as clinically important.

[0190]

The novel carbapenem compound (I) obtained according to the present invention has excellent properties as an antibacterial agent having, for example, a broad spectrum antibacterial activity. Therefore, the present invention provides a novel clinically useful antibacterial agent. Can be provided.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 519/00 311 C07D 519/00 311 // (C07D 519/00 487: 04 513: 04) ( C07D 519/00 487: 04 498: 04) (C07D 519/00 487: 04)

Claims (18)

[Claims] [Claim 1] The formula: [Wherein R ¹ is an optionally substituted lower alkyl group, R ² is a hydrogen atom or a lower alkyl group, Y is a bond or an optionally substituted lower alkylene group, and W is
Is the formula (In the formula, ring A represents a pyrimidine ring which may be hydrogenated or may be substituted, X represents a substituted hetero atom, and X represents a ring together with a constituent nitrogen atom of ring A. May be formed) or a group represented by the formula: (In the formula, Q represents NH, an oxygen atom or a nitrogen atom, X ′ represents an oxo group or a thioxo group, and ring A ′ may be substituted, provided that Q is NH and X is an oxo group. And R ² represents a lower alkyl group.). A carbapenem compound represented by the formula: or an ester or a salt thereof. 2. The formula: [Wherein R ¹ is an optionally substituted lower alkyl group, R ² is a hydrogen atom or a lower alkyl group, Y is a bond or an optionally substituted lower alkylene group, and ring A is a hydrogen atom. In the pyrimidine ring which may be substituted or substituted, X represents a substituted hetero atom, and X may form a ring together with the constituent nitrogen atom of ring A. ] The compound according to claim 1, which is a carbapenem compound represented by the following formula or an ester or salt thereof. 3. The formula: [Wherein R ¹ is an optionally substituted lower alkyl group, R ² is a hydrogen atom or a lower alkyl group, Y is a bond or an optionally substituted lower alkylene group, and Q is
Represents an NH, an oxygen atom or a nitrogen atom, X ′ represents an oxo group or a thioxo group, and ring A ′ may be substituted. However, when Q is NH and X is an oxo group, R ² represents a lower alkyl group. ] The compound according to claim 1, which is a carbapenem compound represented by the following formula or an ester or salt thereof. 4. The formula: [In the formula, X ¹ represents a substituted hetero atom, and other symbols have the same meanings as in claim 2. ] The compound represented by these, its ester, or its salt, The compound of Claim 2. 5. The formula: [In the formula, X ² represents a hetero atom, ring B represents an optionally hydrogenated hetero ring, and other symbols have the same meanings as in claim 2. ] The compound represented by these, its ester, or its salt, The compound of Claim 2. 6. R ¹ is a cyano group, amino group, mono- or di-C _1-4 alkylamino group, hydroxyl group, C _1-4 alkyloxy group, carbamoyloxy group, C _1-4 alkylthio group, C _{1- 4} alkylsulfonyl group, a halogen, a sulfamoyl group, C _1-4 alkoxy - carbonyl group and to 1 selected from sulfoxy group 3 may be substituted with a substituent C _1-4 alkyl group, R ² is Hydrogen atom or C _1-3 alkyl group, Y is a bond or halogen,
A C _1-3 alkylene group which may be substituted with 1 or 2 substituents selected from a hydroxyl group, a C _1-6 alkyloxy group, an amino group and a mono- or di-C _1-4 alkylamino group; A is halogen, hydroxy group, C _1-6
Alkyloxy group, amino group, mono- or di-C _1-4
C _1-6 alkyl _optionally substituted with 1 to 3 substituents selected from an alkylamino group and a cyano group,
1 or 2 substituents selected from C _6-10 aryl, C _7-12 aralkyl and a 4 to 6 membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. A pyrimidine ring which may be substituted with a group and which may be hydrogenated, wherein X is a substituted hydroxyl, mercapto, amino or imino group, wherein the substituents are (1) a cyano group and an amino group, respectively. Group, mono or di C _1-4 alkylamino group, hydroxyl group, C
_1-4 alkyloxy group, carbamoyloxy group, C _1-4 alkylthio group, C _1-4 alkylsulfonyl group, halogen, sulfamoyl group, C _1-4 alkoxy-carbonyl group, sulfooxy group and nitrogen atom, oxygen source and sulfur C _1-6 alkyl _optionally substituted with 1 to 3 substituents selected from 4- to 6-membered heterocyclic groups containing 1 to 4 heteroatoms selected from atoms, C _6-10 aryl,
C _7-12 aralkyl, C _3-6 alkenyl or C _3-6 alkynyl group, (2) C _1-6 alkyl group, C _6-10 aryl group, cyano group, amino group, mono- or di-C _1-4 alkyl group From amino group, hydroxyl group, C _1-4 alkyloxy group, carbamoyloxy group, C _1-4 alkylthio group, C _1-4 alkylsulfonyl group, halogen, sulfamoyl group, C _1-4 alkoxy-carbonyl group and sulfooxy group A 4- to 6-membered heterocyclic ring which may be substituted with 1 to 3 selected substituents and which contains 1 to 4 hetero atoms selected from a benzene ring and / or a nitrogen atom, an oxygen atom and a sulfur atom, 4- to 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from 1 or 2 optionally condensed nitrogen atom, oxygen atom and sulfur atom, or (3) C
_1-6 alkyl-carbonyl group, halogeno C _1-6 alkyl-
Carbonyl group, C _1-6 alkoxy-carbonyl group, C
_6-10 aryl-carbonyl group, C _7-12 aralkyl-carbonyl group, _4- to 6-membered heterocyclic carbonyl group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, carbamoyl group, mono Or a di C _1-4 alkyl-carbamoyl group, a C _1-6 alkylsulfonyl group, a C _6-10 arylsulfonyl group, a C _7-12 aralkylsulfonyl group or a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. It is a 4- to 6-membered heterocyclic sulfonyl group including 1 to 4, or X is a C _1-6 alkyl group, a C _6-10 aryl group, a cyano group, or an amino group together with a constituent nitrogen atom of ring A. Group, mono or di C _1-4 alkylamino group, hydroxyl group, C _1-4 alkyloxy group, carbamoyloxy group, C _1-4 alkylthio group,
Contains 1 to 4 nitrogen atoms which may be substituted with 1 to 3 substituents selected from C _1-4 alkylsulfonyl group, halogen, sulfamoyl group, C _1-4 alkoxy-carbonyl group and sulfooxy group. Alternatively, a 5 to 7-membered optionally hydrogenated heterocycle containing 1 to 3 heteroatoms selected from oxygen atom and sulfur atom may be formed, and ring A ′ is halogen,
Hydroxy group, C _1-6 alkyloxy group, an amino group and a mono - substituted with or to 1 selected from di -C _1-4 alkylamino group three substituents C _1-6
4 containing 1 to 4 heteroatoms selected from alkyl, C _6-10 aryl, nitrogen atom, oxygen atom and sulfur atom
2. The compound according to claim 1, which is a ring which may be substituted with 1 to 4 substituents selected from a _C.sub.7-12 aralkyl group and a 6-membered heterocycle. 7. The compound according to claim 1, wherein R ¹ is a 1-hydroxyethyl group. 8. The compound according to claim 1, wherein R ² is a methyl group. 9. The compound according to claim 1, wherein Y is a bond. 10. A ring A is an optionally hydrogenated pyrimidine ring optionally substituted with 1 or 2 C _1-4 alkyl groups on the ring-constituting nitrogen atom, and X is (1) amino or A hydroxyl group substituted by a C _1-4 alkyl group which may be substituted by mono- or di-C _1-4 alkylamino, (2) 1 to 4 groups selected from a nitrogen atom, an oxygen atom and a sulfur atom 4 to 6 membered heterocyclic group, or a hydroxyl or C _1-4 alkyloxy mercapto group substituted by optionally C _1-4 alkyl group optionally substituted with a group having a hetero atom or (3) C _1-6 alkyl, -Carbonyl, halogeno C _1-6 alkyl-carbonyl, C _6-10 aryl-carbonyl, carbamoyl, mono- or di-C _1-4 alkyl-carbamoyl, C _1-6 alkyloxy-carbonyl, nitrogen atom, oxygen atom and sulfur atom Chosen from To 4 to 6-membered heterocyclic carbonyl group having 4 heteroatoms, C
_1-6 alkylsulfonyl, C _6-10 arylsulfonyl,
4- to 6-membered heterocyclic group having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, C
An amino or substituted imino group mono- or di-substituted by _1-4 alkyl or hydroxy C _1-4 alkyl, or of the formula: [In the formula, D represents a C _2-4 alkylene group or a C _2-4 alkenylene group. ] The compound of Claim 2 which is a group represented by these. 11. The formula: [Wherein Ra is the formula: (In the formula, Ra ′ represents a C _1-4 alkyl group and Ra ″ represents a carbamoyl group or a mono- or di-C _1-4 alkylcarbamoyl group.). ] The compound represented by these, its ester, or its salt, The compound of Claim 2. 12. The compound according to claim 11, wherein Ra ′ is a methyl group and Ra ″ is a carbamoyl group. 13. A ring A ′ is a 4- to 6-membered heterocyclic group having a C _1-4 alkyl group on the ring-constituting nitrogen atom and 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. The compound according to claim 3, which may have 1 or 2 substituents selected from 14. The formula: Wherein, Q 'is NR ^0, an oxygen atom or a sulfur atom, R ⁰
Represents a hydrogen atom or a C _1-4 alkyl group, and X ′ represents an oxo group or a thioxo group. ] The compound of Claim 3 which is a compound represented by these, its ester, or its salt. 15. The compound according to claim 14, wherein R ⁰ is a hydrogen atom or a methyl group. 16. The formula: [In the formula, L represents a leaving group, and other symbols have the same meanings as in claim 1. ] The compound represented by these, its ester, or its salt, and a formula: HS-Y-W [The symbol in a formula shows the same meaning as claim 1. The method for producing a compound according to claim 1, wherein the compound or a salt thereof is reacted. 17. A pharmaceutical containing the compound according to claim 1. 18. The medicine according to claim 17, which is an antibacterial agent.