WO1985001287A1 - 2-azetidinone derivatives and process for their preparation - Google Patents

Abstract

2-Azetidinone derivatives having a group represented by formula (I), (wherein R1 and R2 may be the same or different and each represents a hydrogen atom, an alkyl group, or an optionally substituted aryl or arylalkyl group) in position 1 and an optionally acylated or protected amino group in position 3, and their salts or esters. They are prepared by: (1) subjecting a 2-azetidinone derivative having formula (II), (wherein R1 and R2 are as defined above) and an amino group, its salt or ester to acylation or to a reaction of introducing a protective group; or (2) reacting a 2-azetidinone derivative having a hydroxy group in position 1 and an optionally acylated or protected amino group in position 3 or its salt with formula (III), (wherein W represents a halogen atom, and other symbols are as defined above), its salt or ester. The end compounds are utilized as excellent antibacterial materials or intermediates for synthesizing antibacterial materials.

Description

 Details

 2-azetidinone derivatives and their production

 Technical field

 The present invention relates to a novel 2-azetidinone derivative which is an excellent antibacterial substance or a useful synthetic intermediate thereof, and a method for producing the same.

 , Background technology

 Conventionally, various 2-azetidinone derivatives have been synthesized and reported (Tetrahedron), Vol. 34 (1978), 1731-1-: 17767, Chemicals. Reviews [Chemical Reviews], Vol. 76 (1976), pp. 113-346, Synthesis, 1973, pp. 327-346, etc .; , Formula in first place

R ¹

 -0-C-COOH

² -azetidinone having a group represented by R ^{2 wherein} R ¹ and R ² are the same or different and each represent a hydrogen atom, an alkyl or an aryl or an arylalkyl group which may have a substituent. Derivatives are not yet known.

 Disclosure of the invention

R ¹

In the present invention, at the 1-position, a formula -ΌC-COOH [wherein the symbols have the same meanings as defined above]

R ² ] is a 2-azetidinone derivative (hereinafter abbreviated as “1 derivative [I]”) having an amino group which may be acylated or substituted at the 3-position, a salt or ester thereof, And its manufacturing method.

O PI R ¹

 The present inventors have found that, for example, the symbol in the formula 1—C—COOH

R ² has the same meaning as that of R ² ), or a 2-azetidinone derivative having an amino group at the 3-position, a salt or ester thereof, is subjected to an acylation reaction or a protective group introduction reaction, or A 2-azetidinone derivative having a hydroxyl group at the 3-position and an amino group optionally acylated or protected at the 3-position, or a salt thereof,

 R

 W-C-COOH C I

R ²

Wherein, ¹ and R ² have the same meanings as described above, and w represents a rho or a logen atom; and a salt or ester thereof, a derivative !: I] is obtained and obtained. It has been found that the derivative [I] obtained is an excellent antibacterial substance or a useful intermediate thereof, and based on these, the present invention is {β}.

In derivative [I], R-, H ² represents the same or are different from each a hydrogen atom, an alkyl, a good § Li Ichiru be substituted or § Li one Ruarukiru group. ^{As the} alkyl group represented by ¹ and ^ ² , for example, a linear or branched alkyl group is used, and among them, a lower alkyl group having 1 to 6 carbon atoms is preferable. Specifically, methyl, ethyl, n-propyl, isopropynole, n-butynole, isobuchinore, n-pentyl, isopentinole, n-hexyl, isohexyl and the like are frequently used. , Is a Ariru group represented by R ^2, they are preferably carbon number 6-1 0, for example phenyl, naphthyl, etc. are used. As the arylalkyl group represented by R ¹ , For example, the alkyl group substituted with the aryl group is used, and one having 7 to 11 carbon atoms is preferable. For example, benzyl, phenethyl, phenylpropyl pill, and naphthylmethyl are commonly used. ^The aryl group and the aryl group of the arylalkyl group represented by ¹ and R ² may have a substituent, and the number of the substituents is preferably 1 to 3. Such substituents include, for example, alkyl, halogen (fluorine, chlorine, bromine or iodine), cyano, hydroxyi, alkoxyi, alkylcarbonyloxy, alkamoyloxy, nitro, amino. , Alkylcarboninorea mino, canoleboxy, alkoxide canoleboninole, carbamoyl, alkylcarbonyl, trifnoreomethyl, etc. (where alkyl is an alkyl group as described above, and alkokizi is an alkyl group as described above. A group in which a group is bonded to an oxygen atom is used. 'Among them, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentoxy, isopentoxy, n-hexyloxy , Isohexyloxy, etc. Lower alkoxy groups are frequently used). Preferred specific examples of the substituted aryl or arylalkyl group represented by β ¹ and β ² include, for example, Ρ-hydroxyphenyl, ρ-methoxyphenyl, 3,4-dihydroxyphenyl, ρ-Chloro-Feninole, ρ-hydroxybenzyl, ρ-methoxybenzyl and the like.

The derivative [ί] has an amino group which may be acylated or protected at the 3-position. Examples of the acyl group of the acylated amino group include, for example, a conventionally known penic acid group. An aryl group substituted on the 6-amino group of the phosphorus derivative, an acyl group substituted on the 7-amino group of the cephalosporin derivative, and the like are used. Hereinafter, in the specification of the present application, in the case of “may have a substituent”, the group is indicated by adding a “肩” to the right shoulder of the group. Was "Alkyl optionally having substituent (s)" is represented by "alkino." In this case, the number of substituents is not limited to 1, and depending on the group to be substituted, 2 to several identical or different substituents According to this notation, the acyl group in the 3-position substituent of the derivative [I] may be, for example, a compound represented by the formula

R ⁵ -CO- '[A] [wherein ΙΓ represents lower alkyl, phenino or complex rf¾. A group represented by the formula:

 R -NH-CH-CO-

R ⁷ [B]

[Wherein β ⁶ is hydrogen, an amino acid residue, a protecting group for an amino group or a compound of the formula B? — (CH ₂ ) _n— CO— {wherein, R ⁸ is a complex; # is a group; Each represents an integer. R ⁷ represents lower alkyl, phenyl heterocarbonylamino or a hetero group, respectively. A group represented by the formula

R ⁹ -R ¹⁰ -CO- 〔C

Where R ⁹ is the formula fl ^u — one {where R ¹¹ is alkyl ΐ complex: is

 N

0-R ¹² phenyl, R ¹² is hydrogen, lower alkyl, lower alkenyl, phenyl * carbonyl or formula β ¹³ —R ^½ (wherein, R ¹³ is lower alkylene or lower

Alkenylene, R represents phenyl, phenylcarbonyl, carbamoyl, carboxyl or its ester or mono- or di-lower alkylamino, respectively. ) Represents each group. R ^1Q is a mere bond or a formula —CO—NH—Cfl— (wherein R ¹⁵ Represents lower alkyl, phenyl or thiazolinole. ) Represents each group. A group represented by the formula (D)

Wherein, JR ¹⁶ may inhibit Dorokishi, hydroxycarboxylic sulfonyl O, carboxy, Urei preparative ^ sulfamoyl Suruhoma is phenoxyethanol carbonyl, a formate Miruokishi, R ¹⁷ is hydrogen, lower alkyl, lower Arukokin, Bruno, androgenic, Nitro and hydroxy represent respectively. ·] Group represented by the formula

R ¹⁸ -R ¹⁹ -CH. -CO-[E]

[Wherein, R ¹⁸ represents cyano, phenyl ^! Phenoxy, lower alkyl, lower alkenyl or a hetero group, and β ¹⁹ represents a mere bond or 1 s—, respectively. A group represented by J or the like is used.

In the symbols β ^{5 to} R ¹⁹ , the alkyl, lower alkyl, and halogen are those described in II ¹ and R ² above, and the lower alkoxy group is the above alkoxy group having 1 to 6 carbon atoms. Used. Examples of the ring group include a 5- to 8-membered ring containing one to several hetero atoms such as a nitrogen atom (which may be oxidized :), an oxygen atom, a sulfur atom, or a fused ring thereof. For example, 1,2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-Chenyl, 1-1, 2- or 3-pyrrolidinyl, 2-, 3- or 4-pyridyl , N-Oxido 2-, 3- or 4-pyridyl, 1, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-viranyl, 2-, 3- or 4-thiopyranyl, pyrazur, 2- , 4 mono- or 5-thiazolyl, 2-, 4-mono or 5-oxazolyl, 3-, 4-mono or 5-isothiazolyl, 3-, 4-mono or 5-isoxazolyl Ryl, 1, 2-, 4- or 5- imidazolyl, 1, 3-, 4-, or 5-birazolyl, 3- or 4-pyridazyl, N-oxoxide 3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl,] -oxido 2-, 4- or 5-pyrimidinyl, 1-1 or 2-pirazurul, 4- or 5--1, 2,3-thiadiazolyl), 3- or 5- (1,2,4-thiadiazolyl :), 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 41- or 5-((1,2,3-oxoxadiazolyl), 3- or 5- ( 1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 1,2,5-okitidiazolyl, 1 or 4— (1,2,3-triazolyl), 1— or 2— ( 1, 2, 4—triazolyl), 1— or 5— (1H-tetrazolyl), 2— or 5— (2H-tetrazolyl), pyrido [2,3-d] pyrimidyl, benzopyranyl, 1,8—, 1,5—, 1,6-, 1,7-, 2,7- or 2,6 —Naphthyridyl, quinolyl, thieno [2,3-b] pyridyl are commonly used. In particular, a 5- or 6-membered heterocyclic group selected from an oxygen atom, a nitrogen atom and a sulfur atom and containing 1 to 4 heteroatoms, such as chenyl, furyl, thiazolyl, imidazolyl, thiadiazolyl, triazolyl, tetrazolyl, Pyridyl, pyrimidinyl and the like are preferred. The amino acid residues, for example glycyl, Araniru, carbonochloridate Li Honoré, Roishinore, Lee Seo port Lee Shinore, Se Li Honoré, threo 'two Honoré, Shisuti two Honoré, Shisuchiru, Mechioniru, alpha-or ^ Asuparuchiru, _alpha one Or; <— Glutamyl, lysinole, arginyl, feniralanil, phenylglycyl, thiclosil, histidyl, tryptophanyl, prolyl, etc. are used. As the amino-protecting group, those similar to the amino-protecting group described below are used. The lower alkylene is preferably a straight-chain or branched one having 1 to 3 carbon atoms, and examples thereof include methylene and ethylene. , Propylene, sodium propylene and the like are used. As the lower alkenyl, one having 2 to 4 carbon atoms is preferable, and for example, a power such as butyl, aryl, isopropenyl or 3-butyr is used.

As the alkenylene, a linear or branched lower alkylene having 2 to 4 carbon atoms is preferable. For example, vinylene, propenylene and the like are used. As the ester in the carboxyl group, for example, a lower alkyl ester having 1 to 6 carbon atoms such as methyl ester, ethyl ester, propyl ester, η-butyl ester, isobutyl ester and tert-butyl ester is used. Heterocyclic group, phenyl, Chiazorinore off Enokin Ruponiru, the Fuenoki i ¾ substituent, those wherein such substituents § Re Ichiru or § reel alkyl mentioned in HR ² is used. Further, as a substituent of thiazolyl *, for example, amino having 2 to 4 carbon atoms (such as acetyl, propionyl, and butyryl) substituted with alkyl, alkyne, halogen, hydroxy, and amino may be used. Complex

As the substituent of the ring group, for example, 7 "-phenyl which may be substituted by alkyl, alkoxy, halogen, nitro, amino or the like as described above may be used. For example, sulfo, sorbamoyl, sulfamoyl, amidino, alkyl having 1 to 3 carbon atoms, etc., which suitably form a salt with sodium, sodium, calcium, etc. Examples of the substituent in the sulfamoyl group include: lower alkyl of from 1 to carbon atoms 3, the substituent of. alkyl ^1! lower alkyl used like an amidino group, a halogen such above, human Dorokishi, Shiano, such as preparative Rifuruo methyl is used, for example. lower alkenyl * As the substituent for ", for example, carboquin, ano and the like are used.

Also, the expression in R ⁹ The anti-isomer represented by

 N

R ¹² - 0,

Represents a mixture thereof.

Said R ⁵ ~! When the substituent represented by I ¹⁹ includes an amino group, a carboxyl group, or a hidden σ-xyl group, it may be protected. As the amino-protecting group, for example, the following amino-protecting groups are used. As the protecting group for the carboxyl group, there can be used any one which can be used as a protecting group for a roupoxyl group in the field of lactams and organic chemistry. For example, methyl, ethyl, n-propyl, isopropyl, tert- Butyl, tert-Amizole, Benzinole, P-2 Trobenzinole, P-Methoxybenzinole, Benghidoriinore, Fenasinore, Pheninole, P-2 Tropheninole, Metoximetinole, ethoxymethyl, ethoxymethyl Benzyloquinmethyl, acetoxymethyl, pinoculoylmethyl, β-tylsulfonylethyl, methylthiomethyl, trityl,?, Β, ^ —tricycloethyl, thioether, 2— Trimethyllinolenoethyl, trimethylsilyl, dimethylsilanol. Acetylmethyl, benzonitrite Ester residues such as benzoylmethyltinole, di-mesinolebenzizolemethyl, phthalimidometyl, propionyloxymethyl, mesylmethyl, benzenesulfoninolemethyl, phenylthiomethyl, dimethylaminoethyl, and silyl groups are used. Above all, β, β,? —Tricyclopentyl, Ρ—dimethylbenzyl, tertiary butyl, 2—trimethylsilylletyl, Ρ—methkinbenzilka, are preferred. As the protecting group for the hydroxyl group, any group that can be used as a protecting group for a hydroxyl group in the field of lactams and organic chemistry can be used. Ester residues such as cetyl and chloroacetyl; carboxyl groups which are esterified such as ^, β, triethoxycarbonyl, 2—trimethylsilylethoxycarbonyl, etc., tert-butynole, benzyl, p-nitro Ether residues such as benzyl, tritel, and methylthiomethyl methine i / ethoxyquinyl; silyl ether residues such as trimethylsilyl and tert-butyldimethylylyl; 2-tetrahydrobilanyl; 4-methyl For example, an acetal residue such as 4-tetrahydrobiranyl is used. In the present invention, the choice of the protecting group is not particularly limited, as is the case with the protecting groups for the amino and carboxyl groups.

 In the above, preferred groups represented by the formula (B) are

R ⁶ -NH-CH- CO- [B]

[In the formula, H ⁶ ′ represents a protecting group for an amino group or a formula R ⁸ — (CH _{2 n-} CO— {wherein, II ⁸ has the same meaning as described above, and represents an integer of 0 to 2, respectively. And represents a phenyl or heterocyclic group, respectively.] And a group represented by the formula [CJ is preferably a group represented by the formula:

 R one c one co-〔c

 II

 N

[In the formula, H ¹¹ is a hetero group or phenyl, is a hydrogen atom, lower alkyl or a formula —R ¹³ —R ¹⁴ ′ wherein R ¹³ is as defined above, and R ¹⁴ is Carboxyl or an ester thereof). A group represented by the formula (E) is preferably used. R ^18, -R ¹⁹ -CH2-CO- (E y

[Wherein, R ¹⁸ ′ represents a hetero group, and β ¹⁹ has the same meaning as described above]. Where H. ^{, R ', R l B 1} R 1 protecting group § Mi amino group represented by R ^1q, phenyl complex ¾, the ester in a lower alkyl, carboxyl group, those such mentioned above is used, in particular, the antibacterial For the action, the equation

 N

 Ό-Ο;

Wherein Q ¹ is an amino or protected amino group, Q ² is lower alkyl, lower alkenyl, formula CH 3

-CH ₂ COOQ ^{3 or} a group represented by the formula C—COOQ ³

A group represented by CH ₃ , COOQ ³ represents carboxyl or an ester thereof] is more useful as an acyl group of an amino group, which is an acylated 3-substituent of the compound [I]. However, lower alkyl, lower alkenyl represented protecting group of the protected Amino groups represented by Q ^1, at Q ^2,

As the ester in the carboxyl group represented by COOQ ³ , those described above are used.

In the above-mentioned acyl group, specific examples of the acyl group represented by the formula H ⁵ —CO— include, for example, 3- (2,6-dichlorophenyl) -15-methyldisoxazole-1-ylcarbonyl, 4-— 2,3-Dioxo1-1piperazinocarbonyl and the like are used. Specific examples of the acyl group represented by the formula R ⁶ — NH— CH-CO-

 7,

WIP a _ For example, D—Aranyl, benzyl N—Carbobensoxy D—Glutamyl! )-Araranil, D-phenyldaricyl-1)-araranil, N-dirubenbenzoyl-D-phenylglycyl, D-araranyl-D-phenylglycyl, r-D-gnoretamyl! ) -Alanil, 2- (4-ethyl-2,3-dioxo-1 1-piperazino carboxamide 2-co-phenyl-2-ethyl, 2- (4-ethyl-2,3-dioxo-1 1-piperazinocarboxamide)- 2- (4-sulfoxyphenyl) acetyl, N— (4-ethyl-2,3-dioxo-1-1-piperazinocarbonyl) -1-D-aralanyl,

N- (4-Ethyl-2,3-dithioxo-—1-piperazinocarbonyl) — ϋ-phenyldaricyl, 2,2-bis- (4-ethyl-1,2,3-dioxo-1-piperazino carboxamide) acetyl , 2— (2—Aminou

4-thiazolyl co2- (4-ethyl 2-, 3-dioxo-1-pipera dinocarboxamido acetyl, 2- (4-hydroxy-6-methyl nicotinamide 2- phenylacetyl, 2- (4- Hydroxy-6—methylnicotinamide) -2- (4-Hydroxyphenylacetyl, 2- (5,8—Dihydroxy 2— (4—Formyl-1-piperazinyl)

5-oxopyrido [2,3-dJ pyrimidine-1 6-carboxamide) -1 2-phenylacetyl, 2— (3,5-dioxo-1,2,4,1-triazine-1-6-force Ruboxamide)-2-(4-hydroxyphenyl acetyl, 2- (3-furfuridenamino 1-2-oxoimidazolidine 11-1 carboxamido) 1-2-phenylacetyl, 2-(kumari 1-3-Carboxamido cou 2-Fenylacetyl, 2— (4-Hydroxy-17-methyl-1,8-Naphthyridine-13-Carboxamide) 1-2-Phenylacetyl, 2— ( 4—Hydroxy 7—Trifluoromethylquinoline 1—3 Carboxamide 1—2-Phenylacetyl, N— [2— (2

14-thiazolyl acetyl] 1-D-phenylglycyl, 2- (6-butane-1-ethyl-1,4-dihydro-14-oxothieno [2,3-b] pyridine-13-carboxamido Doc 2-phenylphenyl, 2- ( Four

1-, 3-Dioxo-1 1-piperazinocarboxamide 1-2-phenylacetyl, 2— (4—n—pentyl-1,2,3-Dioxo-1 1-pi-perazinocarboxamide 1—Che 2-Lacetyl, 2- (4-n-octyl-1,2,3-dioxo-1,1-piperazinocarboxamide) -1-2-Cheninoleacetyl, 2— (4-cyclohexyl-2,3-dioxo-1 1 1

Piperazinocarpoxamide) 1 2—Chenylacetyl, 2— [4-1 (2—1 phenethylethyl 1,2,3-Dioxo 1—piperazinocarboxamide; 1—2—Chenylacetyl, 2 — (3 —Methylsulfonyl- 2-oxoisomidazolidine 1 —carboxamide) 1 —2-Fenylacetyl, 2 1 — (3—Flubridenamino-1 2-oxooxomidazolidin 1 —Carboximid) 1 2— (4 — hydroxyphenyl) acetyl, 2 — (4 — ethic

Nore 1, 2, 3 — Jokiso 1 — Piperazinocarboxami Doc 1 2 — (4 —

Benzyloxyphenyl) acetyl, 2- (4-ethyl-2,3-oxo- 1-piperazinocarboxamide 1-2- (4-methoxyphenyl)

) Acetyl, 2— (8-hydroxy-1,5—naphthyridine-17—carboxamido2—phenylacecetyl, 2— (2—amino-4-thiazolyl) 1-2—formamidoacetyl, 2— (2 —Amino-41-thiazolyl) -12-acetamidoacetyl and the like are used.

Specific examples of the acyl group represented by the formula JR ⁹ — R ^{1 ()} —CO— include, for example, N— [2— (2-amino-4-thiazolinole) -1-2-methoxyminoacetyl J-I! ) 1-alanyl, N— [2 — (2-amino-4 monothiazolyl

1) 2-Methoxyiminoacetyl] 1-D-phenylglycyl, 2- (2d> W1PO -Amino 4-thiazolyl) _ 2-[2-(2-Amino-14-Thiadryl-2-Methoxyiminoacetamide) Acetyl, 2-(2-Chloroacetamide 4- Thiazolyl) 1- 2-methoxyminoacetyl, 2- (2-amino 4- 4-thiazolyl 1-2-methoxyminoacetyl, 2- (2-amino 4- thiazolyl) 2- 2-ethoxy Minoaceter, 2— (2—amino-4thia: / 'ryl) -1—2-propoxyminoacetyl, 2— (2-amino4thiathiazolyl) 1-2—butoxyminoacetyl, 2— -(2-amino-1-4-thiazolinole-2-benzyloxyminoacetyl, 2- (2-amino-4-thiazolyl-2-aryloxyminoacetyl, 2- (2-amino-4-thiazolyl) 1 2— [(1—Methyl 1 1 1 Imino] acetyl, 2- (2-amino-4-thiazolyl) -2-([1-methyl-1-methoxycarbonylcarbonylethyloxymino] acetyl, 2 (2-amino-4-1 Thiazolyl :) 1—2—Carboxymethyloxyminoacetyl, 2— (2—Amino-1-41 thiazolyl) 1—2—Carboxyvinyloxyiminoacetyl, 2— (2—Amino—4 Thiazolyl 1) 2-carboxyethyloxyminoacetyl, 2- (2-amino-4-thiazolyl) -12-methoxycarbonylethyloxyminoacetyl, 2- (2-amino-4-thiazolyl) :) 1 2 1 (3,4-Diacetoxybenzoyl) methoxy xyminoacetyl, 2-(. 2-Amino-5-Chlorol 4-thiazolyl 2- 2-Methoxyxyminoacetyl, 2— [ 2—Amino 5—Bromo-4-thiazolyl) -1-2—Methoxyxyminoacetyl, 2— (2—Amino-1-thiazolylco-2—Oki / Iminoacetyl, 2-Chenyl-2-Methoxyiminoacetyl, Two

—Frill 1 2 —Methoxyxyminoacetyl, 2 — (1, 2,4th Asiazol 3 —Ilk 1—Methoxyxyminoacetyl, 2— (_ 1, 2, 4 1-Methoxyminoacetyl, 2-(: 1,3,4-thiadiazolyl) -12-Methoxyminoacetyl, 2-(_ 4-hydroxyphenyl) — 2-Methoxyxyminoacetyl, 2-Feminium 2-Methoxydiminoacetyl, 2-Feuru-2-oxaminominacetyl, 2--r-D-glutamyloxy) phenyl 1-2-Oxyminozacetinol. , 2-[4-1 (3-amino 1-3-carboki i / aro pokin) Phenyl :! One-two-minoacetyl is used. Equation 17

 R

 ■ Specific examples of the acyl group represented by CH—CO—

16 For example, na-sulfophenylacetyl, na-no-droxyphenylacetone, α-sulpho-clay-dofenylacetinole, α-sulfoclay-dofenylacetinole, a-snolephamoy-norefenylacetinole, a-fu Enoxycanolepo ninolephenylacetyl, a- (ρ-trinoleoxycanoleboninole) pheninoleacetyl, a-formyloxyphenylacetyl are used. Specific examples of the acyl group represented by the formula fi ¹⁸ — R ¹⁹ — CH ₂ — CO— include, for example, cyanoacetyl, phenylacetyl, phenoxyacetyl, trifluoromethylthioacetyl, cyanometylthioacetyl, lH — Tetrazolyl-1-acetyl, chenylacetyl, 2- (2-amino-4-thiazolyl) acetyl, 4-pyridylthioacetyl, 2-phenylphenylthioacetyl, 3,5-dichloro-1,4,4-dioxo 4-oxo For example, pyridin-1-acetyl, ^ -carboxyvinylthioacetyl, 2- (2-aminomethylphenyl) acetyl and the like are used.

The amino group and / or hepoxyl group and Z or hydroxy group in the specific examples of the above-mentioned aryl groups include those having a protecting group. The As the amino-protecting group, those similar to the amino-protecting group can be used. As the protecting groups for the carboxyl group and the hydroxy group, those described above and the like are used.

As the protecting group for the optionally protected amino group as the 3-position substituent of the derivative [I], those used for this purpose in the field of lactam and peptide synthesis are conveniently adopted. For example, aromatics such as phthaloyl, p-nitrobenzoinole, p-tert-butynolebenzoisole, ρ-tert-butynolebenzene snolephoninole, benzenesulfonyl, tonoleensenolephonyl, phenylenoacetyl, and phenoxyacetyl Acyl groups, for example, aliphatic acryl groups such as formyl, acetyl, propionyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfoninole, ethanesnorefonyl, trifluoracetyl, maleyl, and succinyl; For example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, 2-cyanoethoxycarbonyl, β, β, β-trichloro σethoxycarbonyl, monomethylsilyl ethoxycarboxy Nil, Ichi Tylsulfonyl ethoxy carbinole, benzyloxy carbonyl, ρ-Nitro benzodinoleoquin canoleboninole, ρ-methoxy pendinoleoxy carbonyl, diphenyl methyl quinoxy carbonyl, methoxy methoxy carbonyl Esterified carbonyl groups such as carbonyl, acetylmethylinoleoxycarbonyl, isoborninoleoxycarbonyl, phenyloxycarbonyl, etc., and further, for example, trityl, 2-nitrophenylthio, benzylidene, Protecting groups for amino groups other than acyl groups, such as nitrobenzylidene or trialkylsilyl, benzyl, and ρ-nitrobenzoyl, and protons are used. In the present invention, the selection of the protecting group is not particularly limited. Derivative !: I] may have two substituents at the 3-position, for example, an amino group which may be acylated or protected, for example, a lower alkoxy group, for example, It may have a 3-position substituent. Further, the 4-position of the derivative [I] may be unsubstituted or substituted.

 Preferred examples of the derivative [I], its salt or ester include, for example, those represented by the formula

 X

卢⁴

 [1 y

 c ヽ 0-0-COOH

R ²

[Wherein, R ² has the same meaning as described above; R ³ represents an amino group which may be converted to an alkyl group or protected; R ⁴ represents a hydrogen atom, carboquinol, alkoxycarbonyl, a substituent X represents a hydrogen atom or a methoxy group, and X represents a hydrogen atom or a methoxy group, or an aryl group optionally having a substituent or an alkyl group optionally having a substituent. , Its salts or esters. In the formula [I y, the optionally acylated or protected amino group represented by the following meanings is as described above. The alkoxycarbonyl group Ru indicated by R ^4, for example - such as ₆ alkoxycarbonyl alkylsulfonyl group is used, the E ^, and ones mentioned in beta ² used as an 6 alkoxy. Examples of the substituent (1-2) of the optionally substituted carbamoyl group represented by R ⁴ include lower alkyl having 1 to 6 carbon atoms and lower alkoxy having 1 to 6 carbon atoms as described above. In addition to the groups, benzyloxy, phenyl, amino, Ν-methylamino, Ν, Ν-dimethylamino groups and the like are used. As the aryl optionally having a substituent represented by ΙΓ, for example, those described above for R ¹ and R ² can be used. Examples of the alkyl group which may have a substituent represented by R ⁴ include, for example,

R 20

-C- (CH _{2) n} -R 22

 [F]

R ²¹

[In the formula, n is an integer of 0 to 3, R ²⁰ , ¹ and R ²² are the same or different and are a hydrogen atom, a lower alkyl of 1 to 6, a cycloalkyl, an aryl heterocycle * group, (Lower alkyl of 1 to 6) —oxycarbonyl, acyl, halogen, cyano, hydroxy, (lower alkyl of 1 to 6)

 Alkyl), aryloxy, arylalkyloxy, acyloxy, rubamoyloxy, hydroxysulfonyloxy, (carbon number)

1 to 6 lower alkyl monosulfonyloxy, arylsulfonyloxy, nitro, amino, azide, carboxy, (lower alkyl having 1 to 6 carbon atoms) monooxycarbonyl methoxy, carnoxmoyl methoxy, Power mortole, mercapto, (lower alkyl having 1 to 6 carbon atoms): mono, aryl, complex: rf, quaternary ammonium. ] Is used. In the groups represented by R ^{20 to} R ²² , C ^ -s lower alkyl, aryl heterocyclic group, halogen, and the like as described above are used. As the cycloalkyl, those having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl are frequently used. As the substituent in the cycloalkyl, the same substituents as those in aryl described in the above ¹ and ² are used. As the acyl group, in addition to formyl, the acyl group used for the 3-position substituent R ³ of the derivative [I] and the like are used. Quaternary ammonium groups include, for example, pyridine, nicotinic acid amide or isonicotinic acid General formula derived from pyridine derivatives such as pyridine-substituted pyruvamoyl groups such as amides, carboxy-substituted pyridines such as nicotinic acid or isonicotinic acid, and pyridine-substituted pyridines such as pyridinesulfonic acid

[Wherein, "" represents a hydrogen atom, a methyl group, a carbamoylmethyl group, a carboxymethyl group, a carbamoyl group, a carboxy group, a sulfonic acid group or a methkin group.] Or a quaternary ammonium group represented by Quinolinium is used, etc. As the substituent in the quaternary ammonium, the same substituents as those described above for the aryl group represented by R ¹ and R ² are used.

These quaternary ammonium groups can form internal salts with carboxyl groups or sulfo groups in the molecule. When an amino group is present in the substituents represented by Il ^2Q , R ²¹ and R ²² , the amino group may be substituted or protected, and when a carboxyl group or a hydroxyl group is present, May also be protected. Examples of the substituent of the amino group include, but are not limited to, aryl, lower alkyl having 1 to 6 carbon atoms, arylarylmethyl, hydroxysulfonyl, (lower alkyl having 1 to 6 carbon atoms) monosulfonyl, and carboxyl. Bamoyl and the like are used (here, acyl, lower alkyl having 1 to 6 carbon atoms, aryl and the like are used). Further, together with such a substituent, a cyclic amino group such as pyrrolidino, piperidino, morpholino, and piperazino may be formed. As the protecting group for the amino group, the carboxyl group, and the hydroxy group, the same protecting groups as those described above can be used.

 Particularly preferred examples of the group represented by the formula [] include, for example, methyl, ethyl, carbamoyloxymethyl, acetyloxymethyl-aceta

OMP WIP Midmethyl, sorbamoylaminomethyl, methoxymethyl, ethoxy; methyl, methylthiomethyl, ethylthiomethyl, chloromethyl, fluoromethyl, cyanomethyl, azidomethyl, sorbamoylmethyl, methoxycarbonylmethyl, ethoxycarbonyl I Carbonyl methyl, carbamoyl oxethyl, methoxyl, etoxethyl, pyridiniomethyl, pyridinethyl, (4.

 The derivative [ί] of the present invention has various stereoisomers (eg, cis-, trans-, and optically-active isomers) at the 3- and 4-positions of the ^ -lactam ring. Mixtures thereof are also included in the present invention.

 In the above optically active substance, the formula

[I]

COOH

 ? 2

Wherein,, R \ R \ R ⁴ and X are as defined above, the wavy line 4 position: indicating that with respect to R ³ of R ⁴ is 3-position, the cis or trans configuration. :! An optically active compound represented by the formula, that is, a compound in which R ³ has a ^ -coordination (when X is a hydrogen atom, 3

S - coordinating, X turtles 3 JR- coordination compound when butoxy group :) is equivalent ft ³ Gana - high antibacterial activity f raw than the coordination compound, thus derivative [I

Among them, the compounds represented by the formula [H] are particularly preferred for the purpose of the present application.

When R ¹ and R ² are different from each other, or when R ² , R ³ and have an asymmetric carbon atom, an optically active isomer is generated, and when further has an unsaturated bond, a geometric isomer (eg, , A syn-form, an anti-form, a cis-form, a trans-form, a 体 -form, a 体 -form :), and isomers and mixtures thereof are also included in the present invention. The derivative of the present invention [IJ is a carboxyl group at the 1-position substituent and

The ability to use the carboxyl group contained in the 3- and 4-position substituents free of charge; for example, non-toxic cations such as sodium and potassium, arginine, ordinine, phosphorus, histidine, etc. It may be used by forming a salt with a basic amino acid, N-methylglucamine, diethanolamine, triethanolamine, polyhydroxyquinalkylamine such as trishydroxymethylamimethane, or the like. Also derivatives! : I] in the case where a basic group is contained in the 3- or 4-position substituent, for example, a salt with an organic acid such as acetic acid, tartaric acid, methanesulfonic acid, etc., for example, hydrochloric acid, hydrobromic acid, sulfuric acid, A salt with an inorganic acid such as phosphoric acid, for example, a salt with an acidic amino acid such as aspartic acid or glutamic acid may be formed and used. Further, the above-mentioned carboxyl group contained in the derivative [I] can be used after being converted into a biologically active ester derivative having an effect of increasing blood concentration and extending the effective time, for example. Examples of the ester group effective on the in-situ table include methoxymethyl, ethoxymethyl, isoproxymethyl, alkoxymethyl such as methoxyxetinole, α-ethoxyxetinole, and α-alkyloxymethyl such as Alkoxy monoalkylthio groups such as α-substituted methyl group, methylinolethiomethyl, methylthiomethyl, isopropylthiomethyl, etc .; Mono-substituted methyl group, α-alkoxycarbonic acid mono-α-substituted methyl group such as ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyshetinole and the like. When the derivative [I] of the object of the present application is used as an intermediate, these carboxyl groups may be protected by the above-mentioned protecting groups.

Specific examples of such derivatives [I] include, for example, In addition to the compounds, there are the following compounds.

 a) (3 S-3-2-(2 ミ ミ ノ 4 4 4)

 -21-Carboxy methoxy acetamide 1 1 1 (1—Carboquin 1 1-Methyroxy 2—Azetidinone

 ; 3 — [2— (2-aminothiazol-4-yl-1 (Z-12-methyiminoacetamide J—1— (na-carboxy-14-hydroxybenzyloxy-1 2 —Azetidinone

 c) (3S, 4S-1 carboxy methoxy-3 — [(!) ^) — 2— (

 '4-Hydroxy-1,5-naphthyridine, 3-carbonylamino) -2 -phenylacetamido] 1-41-methyl-1-2-azetidinone

 d (3 S, 4 S) — 1 —Carboxymethoxy-3 — ((ϋ) — 2 — (

 4-Hydroxy — 6-Methylpyridine-1-3-carbonylamino1-2- (4-Hydroxyphenylacetamide 1-4-Methyl-2-azetidinone ej (33, 411-3— [2— (2— 1-Carboxydi- 1-methyl-2-acetylaminoacetamide 1-Carboxymethoxy 4- 4-methyl-1 2-azetidinone

 f) (3S-1 carboxymethoxy-3-((1) 1-2 (4-ethyl-2,3-dioxo1-1-piperazino carbonylamino 1-2-phenylacetamido)!-1-2— Azetidinone g) 3, 4 1 trans 1 3 — [2 — (2 — aminothiazo 1-ru 4- 4-yl

—People Z 1 2—Carboxymethoxyiminoacetamide 1 — 4—Carbamoyloxymethyl-1 —Carboxymethoxy 2 —azetidinone 3, 4 Trans 1 3 — [2 — (2 — Notiazo One-Ru 41-Il

-(Z;-2-(1 ノ ノ レ メ チ ル メ チ ル メ チ ル メ チ ル ル 4 4 4 4 4 4 4 4 一 一)

 Ο ΡΙ

> wu ri In

 1 3, 4-1 trans-3-[2-(2-aminothiazo-1-4-yl) 1-(Z) 1-2-(1-carboxy-1-methylethoxyminoacetamide]-1-1-carboxymethoxy I 4-Methoxy methoxylinole 2-azetidinone

 j C 3 S, 4 S j-3-C 2-(5-amino 1, 2, 4-thiadia sol-3-yl-1 (Z-2-ethoxyminoacetamide) 1 1 1 Carboxymethoxy 4 4-Methyl-1-2-azetidinone

 k (3S, 4S; -3-C2- (5-amino-1,2,4-thiadiazol-3-yl) -1 (Z) -2-carboxymethoxyminoacetamide) -1 1-carboxymethoxie 4-metyl 2-azetidine

 1; (3S) —3— [2— (5-amino-1,2,4-thiadiazol-13-yl) 1-1 (Z—2 -— (1-carboxy-1-methylethyoxyminoaceta) Mid) 11-carboxymethoxy 2- 2-azetidinone

In the derivative of the present invention [IJ or a salt or ester thereof, the compound in which the 3-position substituent R ³ is acylated and is an amino group is a valuable antibacterial agent that is active against various Gram-positive and Gram-negative bacteria. Yes, used as medicine for humans and livestock. Further, a compound in which is an amino group which may be protected is useful as a synthetic intermediate of the above antibacterial agent.

 The antimicrobial agents of the present invention can be used alone or in combination with other gf-producing components in any of a variety of pharmaceutical formulations, for example, capsules, tablets, powders or solutions, suspensions or Can be used as elixir. They can be administered orally, intravenously or intramuscularly.

 Tablets for oral administration may contain conventional excipients: for example, binders such as syrup, arabian gum, gelatin, sorbitol, traganth gum or polybutadiene.

OM? X Livinyl pyrrolidone; fillers such as lactose, sugars, corn starch, calcium phosphate, sorbitol or glycine; lubricants such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants such as It may contain an available turbidity agent such as potato starch or sodium radium sulfate. Ιέ¾¾ can be coated by methods well known in the art. Oral liquid formulations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or the like, or can be dry products which are dissolved in water or other suitable solvent before use. . Such liquid preparations may contain suspending agents such as sorbitol syrup, methyl cellulose, glucose sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate, or hydrogenated edible oils such as armored oil. Palm oil, oily esters, propylene glycol or ethyl alcohol, preservatives such as methyl or propyl ρ-hydroquinebenzoate or sorbic acid may also be included. Suppositories may use the usual suppository substrates such as cocoa butter or other glycerides.

Injectables, extincts may be provided in unit use form in containers with added samples or preservatives. The compositions may be in such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and adjuvants such as suspending, stabilizing and / or dispersing agents. May be appropriately contained. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg, sterile, germ-free water, before use. They can also be formulated in suitable forms for absorption by the mucous membranes or bronchial tissues of the nose and throat, for example, powders, liquid sprays or inhalants, rosein, throat paint and the like. For pharmaceutical administration to the eye or ear, capsules in liquid or semi-solid form Or as a dripping agent. In addition, it can be used as an external preparation using hydrophobic or hydrophilic bases such as ointments, creams, lotions, paints, powders and the like.

 In addition to the carrier, it may contain other ingredients such as a binder, an antioxidant, an antiseptic, a lubricant, a suspending agent, a thickening agent or a flavoring agent. Further, the composition may contain other active ingredients to provide a broader spectrum of antibacterial activity. For livestock, it may be prescribed as an intramammary preparation in a long-acting or fast-releasing matrix.

 The antibacterial agent of the present invention may be used as a therapeutic agent for bacterial infections, for example, respiratory tract infections, urinary tract infections, suppurative diseases, biliary tract infections, intestinal infections, obstetrics and gynecology infections, and surgical infections in mammals. Can be used for the treatment of The daily dose will depend on the condition of the patient being treated and the weight of the host, the manner and frequency of administration, and

It depends on the preferred parenteral method for general infection and the oral method for intestinal infection. In general, the daily oral dose should be about 1 to 5 active ingredients per 1 ^ body weight of the patient in one or more applications per day.

 It consists of 600. The optimal daily dose for adult humans is about 10 to about 300 ^ as the active ingredient per 1 K of body weight, divided into 2 to 4 times daily, about 2.5 to about once. It is appropriate to administer a parenteral dose of 150 /.

 Derivatives !: A composition comprising IJ can be administered in a number of unit-use forms such as solid or liquid, which can be taken orally. The compositions in liquid or solid unit form contain 0.5 to 99% of the active substance. The preferred sleep is about 10-60. It is. The composition generally comprises about 15 to about 150% active

It contains. In general, it is preferred to use a dosage in the range of about 250 to 100 »

 OMPI

1PO NATIO The derivative [I] of the object of the present application is a ^2- azetidinone derivative having a group represented by the formula 10-COOH at the 1-position (the symbols in the formula are as defined above) and an amino group at the ^3- position. (Hereinafter abbreviated as "raw material [IV]"), a salt or an ester thereof, and subjected to an allylation reaction or a protecting group introduction reaction.

As the salt or ester of the raw material [IV], for example, a salt of the derivative [I], one described in the ester, or the like is used. A carboxylic acid represented by such a raw material [IV], a salt or ester thereof, and a formula R ⁰ COOH wherein R ⁰ CO represents a 3-position substituent of the derivative [I] and an acyl group as described above; The compound can be converted to a salt by reacting with a salt thereof (for example, an alkali metal salt such as sodium or potassium) or a reactive derivative. When the raw material [IV], its salt or ester has a free amino group, hydroxyl group or hydroxyl group, it may be used as a raw material in this reaction after introducing the above-mentioned protecting group based on a conventional method. . Then, if necessary after the reaction, these protecting groups may be removed by known means. Examples of the reactive derivative of the carboxylic acid represented by the formula R ⁰ COOH include acid halides, acid anhydrides, active amides, active esters, and active thioesters. The following is a general description.

 1) Acid halide:

 Here, as the acid halide, for example, acid chloride, acid bromide and the like are used.

2) Acid anhydride:

Here, the acid anhydride may be, for example, a monoalkyl carbonic acid mixed acid anhydride, an aliphatic carboxylic acid [eg, acetic acid, pivalic acid, valeric acid, isovaleric acid, Mixed acid anhydrides such as trichloroacetic acid, mixed acid anhydrides of aromatic carboxylic acids (for example, benzoic acid, etc.), and symmetrical acid anhydrides are used.

 3) Active amide:

 As the active amide, for example, amides with pyrazole, imidazole, 4-substituted imidazole, dimethylvirazole, benzotriazole and the like are used.

 4) Active ester:

 Here, the raw esters include, for example, methyl ester, ethyl ester, methoxymethyl ester, aronol. Gil ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, and trimethyl phenyl ester. And esters with 1-hydroxyl 1H-2-pyridone, N-hydroxy i-succinimide, N-hydroxyquinphthalimide, etc. Used.

5) Active raw thioester:

Here, as the active raw thioester, for example, a thioester with a heterocyclic thiol such as 2-pyridylthiol and 21-benzthiazolylthiol is used. 1 The various reactive derivatives as described above are appropriately selected depending on the type of carboxylic acid used. In the present acylation method, first, a carboxylic acid, a salt thereof, or a reactive derivative thereof is reacted in an amount of 1 mol or more, preferably 1 to 4 mol, per 1 mol of the raw material [17], a salt or an ester thereof. It is. This reaction is usually performed in a solvent. Solvents include water, aceton, dioxane, acetonitrile, methylene chloride, chloroform, dichloromethane, ethane, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, ,, N —Dimethyl acetate amide, pyridine or In this case, general organic solvents which do not participate in other reactions are used, and among these, the philic solvent can be used by mixing with water. When the carboxylic acid is used in a free state, the reaction is preferably carried out in the presence of a condensing agent. Examples of such a condensing agent include N, J-zinclohexyl carpamide, N-cyclohexyl N-Mori Ho Rinoethyl Carbodi,

 N—Chlohexyl mono-N— (4-Jetylaminino) chlorohexyl carbodiimide, N—ethyl-N— (3-dimethylaminopropyl) carbodiimide, etc. Also, for example, alkali carbonate Metals, trimethylamines, triethynoleamines, tributylamines, trialkylamines such as N-methylmorpholine, N-methylbiperidine, J, N-dialkylanilin, N, N-dialkylbenzylamine Min, pyridine, picolin, lutidine, 1,5-diazavincro [4,3,0J non-one-5-ene, 1,4-diazavinclo [2,2,2] octane, 1,8 —This reaction can be carried out in the presence of a base such as diazavic mouth [5,4,4] indene-17, and the liquid of the base or the above-mentioned condensing agent should also be used as a solvent. The reaction temperature is not particularly limited, but is usually performed under cooling or at room temperature, and the reaction is completed in a few minutes to several tens of hours. Ability to be isolated and purified by concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractionation, chromatography, etc.Use the reaction mixture without isolation as the raw material for the next step Is also good.

 In addition, the reaction for introducing a protecting group into the raw material [IV], a salt or ester thereof may be carried out by a known method [for example, “peptide, alkydids of the liposome” as long as the desired derivative [I] is obtained. Bian Symposium, Oxford, September 1962 'f Peptides, Proceedings of the

OMH Fifth European Symposium, Oxford, Sept. 1962) (the method described in (2), etc.).

The protecting group other than the protecting group for the 3-position amino group of the derivative [I] thus obtained may be removed, if necessary. Such a deprotection method depends on the type of the protecting group. Depending on the method, a method using an acid, a method using a base, a method using hydrazine, a method using reduction, a method using an imino halogenating agent, and then subjecting the agent to an imino agent and then hydrolyzing as necessary are used. Method can be appropriately selected. Here, in the case of the method using an acid, depending on the kind of the protecting group and other conditions, examples of the different acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, brobionic acid, and benzene. In addition to organic acids such as sulfonic acid and p-toluenesulfonic acid, acidic ion exchange resins and the like are used. In the case of the method using a base, the base varies depending on the type of the protecting group and other conditions. For example, a hydroxide of an alkali metal such as sodium or potassium or an alkaline earth metal such as calcium or magnesium is used as the base. In addition to inorganic bases such as carbonates, organic bases such as metal alkoxides, organic amines, and quaternary ammonium salts, basic ion exchange resins and the like are used. When a solvent is used in the above method using an acid or a base, a hydrophilic organic solvent, water or a mixed solvent is often used. In the case of the reduction method, it depends on the kind of the protecting group and other conditions.For example, a metal such as tin or zinc or a metal compound such as chromium dichloride or chromium acetate and an organic or And methods of using an acid such as an inorganic acid, and a method of reducing in the presence of a metal catalyst for catalytic reduction. Examples of the catalyst used in the method of catalytic reduction include platinum wire and platinum sponge. , Platinum black, platinum oxide, platinum catalyst such as colloid platinum, palladium sponge, palladium black, palladium oxide, palladium Palladium catalysts such as barium sulfate, barium palladium carbonate, palladium carbon, palladium silica gel, colloid palladium, reduced nickel, nickel oxide, Raney nickel, and Urushibara nickel. In the case of a reduction method using a metal and an acid, a metal compound such as iron and chromium and an inorganic acid such as hydrochloric acid and an organic acid such as formic acid, acetic acid and propionic acid are used. The reduction method is usually carried out in a solvent. For example, in the method of catalytic reduction, alcohols such as methanol, ethanol, propyl alcohol, and iso-propyl alcohol, and ethyl acetate are frequently used. In the method using a metal and an acid, water, acetone, and the like are frequently used. However, when the acid is a liquid, the acid itself can be used as a solvent. The reaction temperature in the method using an acid, the method using a base, and the method using a reduction is usually performed under cooling or heating. Examples of the imino halogenating agent used in the method of removing a protecting group by reacting with an imino halogenating agent and then an imino etherifying agent and then hydrolyzing as necessary, for example, ³ Phosphorus chloride, phosphorus pentachloride, phosphorus tribromide, oxyphosphorus chloride, zonyl chloride, phosgene and the like are used. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature or under cooling. Alcohols or metal alkoxides are used as the imino etherifying agent to act on the reaction product thus obtained, and alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol and alcohol are used as the alcohol. —Alkanols such as butanol and tert-butanol or compounds in which the alkyl portion thereof is substituted with an alkoxy group such as methoxy, ethoxyquin, propoxy, isopropoxy, butoxy, etc. are used. Alkoxysides include alkali metal alkoxides such as sodium alkoxide, potassium alkoxide, etc. derived from the above-mentioned alcohols, and calcium alkoxides. And alkaline earth metal alkoxides such as barium alkoxide.

 The derivative [I] is abbreviated as a 2-azetidinone derivative [hereinafter referred to as "raw material !: V"] having a hydroxyl group at the 1-position and an amino group which may be converted or protected at the 3-position: ) Or a salt thereof and a conjugated product !; E], or a salt or ester thereof. As the salt and ester of the compound [1] and the salt of the raw material [V], the salts and esters as described in the derivative [I] are used. In addition, when there is a free amino group, carboxyl group, or hydroxyl group in the compound [JI], the raw material [V], or a salt or ester thereof, a protecting group is introduced according to a conventional method, and then used as a raw material for this reaction. You can also. After the reaction, such a protecting group may be removed by a deprotection method as described above, if necessary. Compound [JI], salt or ester 1 to 1 mol of raw material [V] or salt thereof

10 moles, preferably 1 to 5 moles are reacted. This reaction is usually performed in the presence of a base. Examples of the base include inorganic salts such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogencarbonate, and the like, and organic bases such as triethylamine, diisopropylethylamine, pyridine, and the like. Is used. Examples of the reaction solvent include water or ethers such as dioxane and tetrahydrofuran; ketones such as acetone and methylethyl ketone; esters such as ethyl ethyl formate and ethyl ethyl acetate; chloroform; Halogenated carbons such as mouth ethane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and methyl sulfoxide i / do, acetonitride Organic solvents such as lilyl are used alone or as a mixture. Among them, acetonitrile, N, N-dimethylforma Mid is preferred. The reaction is-30-60. The force performed in the temperature range of C 'is usually preferably in the range of 0 to 30. The reaction time varies greatly depending on the type of the compound [Π] and the reaction temperature, but is generally several minutes to several tens of hours. The derivative [I] thus obtained can be isolated and purified by the above-mentioned known means. However, when it is used as a synthetic intermediate, it can be used as a raw material in the next step as a reaction mixture.

 More specifically, the derivative [I] can be produced from a known raw material compound by, for example, a method represented by the following formula.

(1)

[VD απ] R

 (K) XJ l) Deprotection

2) File "(K

 [] [XI]

R 3 '

 Man •,

 Deprotection Deprotection

) Asinore i O o0--cC--COOR ²⁴ o \

 O-C-COOH

 Two

OT) (I) b R ⁴

 (Four)

)

) A

 CX1J [I] c

[Wherein,,,, and X are as defined above, R ²³ is a protecting group for an amino group, R ²⁴ is a protecting group for a carboxyl group, R ²⁵ is a hydroxyl group, halogen J Kyoko, alkyl Sulfonyloxy group or aryl * sulfonyloxy group; Represents an allelic amino group. ]

In the above method (1) to (4), the protecting group of the Amino group represented by R ^23, as a protecting group of the force Rupokinru group represented by R ²⁴ include the same protecting groups as described in said force Used. Alkylsulfonyloxy represented by R ²⁵ As the i group, for example, methanesulfonyloxy, ethanesulfonyloxy and the like are preferable. The arylsulfonyloxy group represented by R ²⁵ is preferably, for example, benzenesulfonyloxy, p-toluenesulfonyloxy, or p-chlorobenzenesulfonyloxy. As the acylated amino group represented by R ³ , the same amino group as the above-mentioned acylated amino group is used. When a free amino group, a carboxyl group or a hydroxyl group is contained, various protecting groups are used. May be included.

 The alkylation reaction in the above reaction formula (1) can be carried out according to, for example, or according to the reaction of the raw material [or its salt with the compound [Π], its salt or ester. In the reaction formulas (1) to (4), the acylation reaction and deprotection are carried out by subjecting the above raw material [IV], a salt or ester thereof to an acylation reaction or a derivative for introducing a protecting group [in the production method of IJ The reaction can be carried out according to or according to the aforementioned acylation reaction and deprotection method.

The ring closure reaction in the reaction formulas (2) and ( ³ ) is a reaction for converting the compound represented by the general formula [KJ or () into a 2-azetidinone derivative. ²⁵ is a halogen atom, alk

 Dispute

When the compound is a rusulfonyloxy group or an arylsulfo-oxy i / group, the ring-closure reaction is carried out with the compound [KJ or [through :! The reaction is carried out by reacting the base with a base. Examples of such bases include inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium phosphate phosphate, sodium phosphate phosphate, and the like, for example, triethylamine. And organic bases such as diisopropylethylamine. Examples of the reaction solvent include water or ethers such as dioxane and tetrahydrofuran; ketones such as acetone and methylethyl ketone; esters such as ethyl formate and ethyl acetate;

OMPI Halogenated hydrocarbons such as loloform, dichloromethane, dichloroethane, etc., for example, amides such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide, and also dimethylsulfoxide, acetonitrile, etc. Organic solvents are used alone or as a mixture. Among them, acetone, dichloromethane, or a combination of water and halogenated hydrocarbons is preferred. The reaction is carried out at a temperature in the range of 0 to: I, 0 ° C, preferably in the range of 20 to 80 ° C.

In the case where R ²⁵ is a hydroxyl group in the starting compound [κ] or [au], the ring-closure reaction is carried out by reacting the compound [K] or [.XE] with a phosphine derivative and an azodicarboxylic acid diester, or triethylamine. The reaction is carried out by reacting a phosphine derivative and carbon tetrachloride in the presence of a base such as As the phosphine derivative, for example, triethylphosphine, tri (n-butyl) phosphine, triphenylphosphine, and the like are used, and among them, triphenylphosphine is preferable. As the azodicarboxylic acid diester, for example, a lower alkyl ester having 1 to 4 carbon atoms can be used. As the solvent, for example, getyl ether, diisopropyl ether, tetrahydrofuran, acetonitril, N, N-dimethylformamide and the like are used. The reaction is carried out in the range of 0 to 80 ° C. I Usually, the range of 20 to 40 ° C is preferable.

 The methoxylation in the above reaction formula (4) is usually easily performed by a method well known in the art. For example, in the presence of methanol, the formula

MO C H g XHJ

In the formula, M represents an alkali metal), and a metal salt of methanol represented by) and a halogenating agent are allowed to act on the compound [XV]. Will be Alkali metal salts of methanol include lithium methoxide, sodium methoxide, potassium methoxide and the like. Examples of the halogenating agent include a halogen compound capable of supplying an H † raw halogen atom, for example, a halogen such as chlorine or bromine, an N-haloimide such as N-chlorosuccinimide or N-bromosuccinimide, or an N-chloroa compound. Noroamides such as cetamide, N-bromoacetamide, etc.] —Chlorobenzenesulfonamide, N-chloro-ρ-trienesulfonamide, etc. N-no, rosulfonamides, 1-no Organic and pochlorides, such as benzobenzotriazoles and t-butyl hibochloride, are used. This reaction is performed in a solvent. Examples of the solvent include tetrahydrofuran, dioxane, dichloromethane, dichloromethane, methanol, acetonitrile, methanol, Ν, ジ メ チ ル -dimethylformamide, Ν, Ν-dimethylacetamide, and the like. Any mixed solvent or any other solvent not involved in this reaction can be used. In the reaction, the raw material compound [XV] is dissolved or suspended in the above-mentioned solvent, and an alkali metal of methanol. Methanol and a halogenating agent are added thereto to cause a reaction. At this time, for 1 mol of the raw material [XV], the methanol is 1 mol or less Ji, the alkanol metal salt of methanol is 1 to 3.5 mol, and the halogenating agent is 1 to 2 mol. It is preferable to react by adding about a mole. The reaction proceeds easily under cooling or at room temperature below about 30. The reaction is stopped by making the reaction system acidic. Suitable acids for terminating the reaction include, for example, formic acid, acetic acid, trichloroacetic acid and the like. After the termination of the reaction, the excess halogenating agent is removed by treating it with a reducing agent such as sodium thiosulfate or a trialkyl ester of phosphorous acid. The reaction is usually stopped for several minutes to several hours, preferably for 0.5 to several hours.

The derivative [I] obtained by the method of the reaction formulas (1) to (4) is, for example, a solvent Any desired purity can be obtained by known separation and purification means such as extraction, recrystallization and chromatography.

 When the derivative [I] thus obtained has a free carboxyl group, it can generally act with a base to form a salt. Therefore, the derivative [I] may be collected as a salt, and the salt obtained may be in a free form or as another salt. Further, the derivative [: I] obtained in free form may be converted into a salt. As a method for converting the derivative [I] obtained as a salt into a free form, for example, a method using an acid or the like is used. The acid used depends on the type of protecting group and other conditions. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, and p-toluenesulfonic acid. Is frequently used. In addition, an acidic ion exchange resin is used. In addition, as the solvent, for example, hydrophilic organic solvents such as acetone, tetrahydrobran, methanol, ethanol, and dioxane, water, or a mixed solvent are often used. This method may be carried out under cooling or heating, if it is usually carried out at room temperature. The reaction time varies depending on the type of the acid and the solvent and the temperature. Generally, it is preferable that the reaction be completed in a single hour. Free-form derivative obtained! : I] can be isolated by known means as described above. Also, derivatives with free carboxyl groups! : When I J is obtained, a carboxyl group can be introduced into an ester by a known method.

The above derivative! : I] The raw material in the starting material [17J used in the method for producing the compound [I] is, for example, a compound [W:!, [XJ, [XI] or [XVI:]) in the method of the above reaction formulas (1) to (4). Can be synthesized by the method of deprotection or a method that is foolproof, and the raw material [V], the compounds [71], [K] and [Ε] can be synthesized, for example, by the following method or a method analogous thereto. Can be manufactured. However, these examples are not intended to limit the starting materials, and any compound that meets the purpose of the present application can be used. Specific examples will be shown later as reference examples. ①:

: L-threonine

CH _a

CXXJ

 (; L-Threo)

B

 CH 3 CH 3,

(L-one thread) (L-one thread;) ②:

 COOH

 (XXI)

 ! ! -Arothreonine-> BocNH --H

 HO H CH 3

CX1J H-OCH ₂ COOPNB

Bo

 CHg CH,

(K) _a (K) b

 (L-Eris mouth) (L-Eris mouth)

OMH ③:

 COOH

 (XXI)

 L-Serine-> BocNH-Il H

 CHoOH

 [XXI J

BocNH

 CKJc

 ④:

L-(+)-tartaric acid

(2 R, 3 R)

Et

 (2 R, 3 R) (L-Eris mouth) H-OCHgPh

Boc

CONH. CONH ₂

CXX1J CXXK3

(L-Eris mouth) (L-Eris mouth)

CONH ₂

 (XXX)

 (L-Ellis mouth)

BocNH CONH 'BocNH CONH,

 H,

 N -N

 Pd-C

 O \ O \

OCH ₂ Ph OH

(XXXI J

 (3 S, 4 S) (3 S, 4 S)

⑤:

 XXMJ (XXXI)

 (2 R, 3 R) (L—Eris mouth)

COOH COOH

 COOCH CONH

C XXXIV 3 [XXVI]

(L-Eli Slot) (L-Eli Slot) ⑤:

COOH

CXXXV3 CONH-OCH ₂ COOPNB

BocNH HH ₂ N-OCH ₂ COOPNB BocNH H

 HO ■ H HO- H

CONH CONH ₂

CXX J 〔K〕 _e

(L-Eris) H-OCH ₂ COOPNB

CONH ₂

 (K) f

 (Eris mouth)

(Wherein Boc is a t-butoxy i carbonyl group, Ph is a phenyl group, P

NB indicates a p-2-nitrobenzyl group, Ms methanesulfonyl group, and Et indicates an ethyl group. ]

 The above method is an example of a method for producing an optically active substance using an amino acid as a raw material, and Method II is an example of a method for producing an optically active substance using a raw material of L − +) -′- lithic acid. The conversion to (2R, 3R) -epethyl succinate getyl ester [XX] can be achieved, for example, by using Tetrahedron 36

Volume, page 87 [1989], and the method described in JP-A-56-110683. The starting material (2R, 3R) -epoxysuccinic acid xxau in Method I is, for example, a journal

• It can be easily obtained by the fermentation method as described in, for example, Journal of Medicinal Chemistry, vol. 6, p. 23 (1963). High compound. Compound [XXM] can be converted to compound [XXIV] by esterification according to a conventional method.

OMPI It is also useful as a raw material for producing optically active 2-azetidinones having various ^4- position substituents.

 The present invention is further described in the following experimental examples, examples, and reference examples. These examples are merely examples, do not limit the present invention, and do not prejudice the scope of the present invention. It may be changed in a range.

Elution by column chromatography in Examples and Reference Examples was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. T in LC observation, the BO F ₂₅ 4 Merck (Merck) manufactured as TLC plates and the solvent used as an elution solvent in column chromatography as a developing solvent, employing a UV detector as a detection method. In addition, spraying 489SHBr onto spots on a TLC plate, heating and hydrolyzing, spraying a ninhydrin reagent, and heating again to change the color from red to reddish purple is also used as a detection method. The eluted fractions containing the target compound were confirmed and collected. When two types of developing solvents are used, by-products are eluted with the solvent used first, and then the target product is eluted with the solvent used unless otherwise specified. In column chromatography purification using “Amberlite” or “Sephadex”, first use water and then ethanol solution unless otherwise specified in the working examples and reference examples as a developing solvent. When drying the target product, anhydrous sodium sulfate was used as a desiccant unless otherwise specified.

 '' Anno Kuichi Light Rohm & Haas

Co. in U.S.A.), "Dowex" is manufactured by Dow Chemical (Dow Chemi ca 1 Co.), and "Sephadex" is manufactured by Pharmacia.

 It is made by Fine Chemicals (Pharmacia Fine Chemicaie).

OMPI The N MR spectrum was measured with an EM390 (90 MHz) or T60 (6 OMHz) Spectral Meter using tetramethylsilane as an internal or external reference, and the total < Five values are shown in ppm. The symbols in the examples and reference examples mean the following.

 a Singlet (singlet)

 d doublet (doublet)

 q quartet

 ABq A B type quartet

 d. d double doublet

 m Manolet Tiblett (multiplet)

 br. Broadband f broad;

 J coupling constant)

 Hz Henolet (_ Herz)

 MilUgram

 g gram

 Milliliter

 Ph phenyl)

 MeOH methanol (methanol)

 CHC13 black mouth Honorem f chloroform)

 DMSO dimethyl snolefoxide (_ aimethylsulf oxide)

Experimental example

 MIC igZ) of the target product obtained in Examples 2.3.4 and 6 was measured by the following method and summarized in the following table.

Measuring method

 The MIC of the test compound is determined by the agar dilution method.

OJ Was decided. That is, an aqueous solution of a test compound, which has been diluted sequentially, is poured into a petri dish, and then 9.0 π of Trypticase soy agar is poured and mixed. Spray the suspension of the test organism (about 10 ⁸ CFUZ ^) on the mixed agar plate. At 37, was cultured overnight (incubation), the lowest concentration of test compound to completely inhibit the growth of the test bacteria, the minimum inhibitory concentration [MIC: the minimal inhibitory concentration) ₀

(1) Escherichia coli N IHJ J C— 2

(2) Serrat la marcescens I F 0

 1 2 6 4 8

 (3) Broteus vulgaris (Proteus vulgaris) IFO 3988

(4) Proteus mirabi 1 (Proteus mirabi 1 is) I F O 3849

(5) Pseudomonas aeruginosa

 I FO 3 4 5 5

Result MIC (^)

Ο: ΜΡΙ "WTPO BEST MODE FOR CARRYING OUT THE INVENTION

 Example 1.

 (3S, 4S) —Synthesis of 3- (t-butoxycarbonylamino) -1-4-methylone-1- (4-nitrobenzyloxycarboninolemethoxy) -2-azetidinone

N- (t-butoxycanolepo ') 2 0-methanthone honinole L-threonine N'-(4-2-butoxybenzyloxymethoxy) amide 2.3 2 g Solvent is added to Ton 400, and 1.66 g of lithium carbonate is added. The temperature of the reaction solution was gradually increased to 60 in 30 minutes. After raising to c, stir at the same temperature for another 30 minutes. The reaction mixture is filtered, and the mixture is concentrated under reduced pressure. Water and ethyl acetate are added to the residue, and the mixture is shaken. The ethyl acetate layer is separated, washed with dilute hydrochloric acid and brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by column chromatography one silica gel 150 g; acid Echiru one ^ ^ hexane, I: 1 to furnish), 1.2 2 g (6 ⁴ title compound as a light colored oil. 8 :) obtained. Leaving in the refrigerator—solidifies, mp 71-75 ° C when washed with petroleum ether.

IR (Ne at) cT ¹ : 3,320, 2,970, 1,770 (br.), 1,700, 1,520,

 1,250

NM (d ₆ -DMSO) δ: 1.31 (3ϋ, d, J = 6Hz, C ₄ -C¾), 1.35 (9¾

S, 3xC¾), 3.75 (lH , d. T, J = 2 & 6Hz, C 4 -H), 3.97 (1

H, d. D, J = 2 & 9 Hz, C ₃ -H), 4.70 (2H, ABq, J = l 5 Hz, OCH ₂ COO), 5.33 (2H, s, COOCH ₂ ), 7.35 (lH, d, J = 9

_{Hz, C 3 -NH), 7.66} (2H, d, J = gHz, aromatic pro tons), 8.22 (2H, d, J = 9Hz, aromatic pro tons). Elementary analysis: as C ₁₈ H ₂₃ N ₃ 0 ₈

 OMPI

"W1PO C (de.) H Ho) N [1o)

 Calculated 52.81 5.66 10.26

 Actual 52.97 5.72 10.34

 —66.5 ° (c = 0.8, MeOH)

 Example 2.

 (3 S, 4 S) — 3— [2— (2-Aminothiazol-1-yl) -1- (Z) — 2-Methoxyoximinoacetamide] — 1—Carboxymethoxy4 —Synthesis of methyl-1-2-azetidinone monosodium salt

a) (3S, 4S) —3— (t-butoxycarbonylamino) -14-methyl-11- (4-nitrobenzoyloxycarbonylmethoxy) 1-2-azetidinone 9 Dissolve 40 in dichloromethane 40 ^, and add anisol 4 and trifluoroacetic acid 20 ^ while stirring under ice-cooling. Stir under ice-cooling for 1.5 hours, add toluene 40 ^ to the reaction mixture, and concentrate under reduced pressure. The residue was suspended in dichloromethane 40 and triethylamine 1.93 and 2- (2-chloroacetamidothiazolu-l 4-inole) 1- (Z) -2-methoxyethoxymino acetylchloro under ice cooling. Add 1.145 g of ride hydrochloride and stir for 1 hour. The solvent is distilled off under reduced pressure, and water 10 and tetrahydrofuran 10 ^ are added to the residue. Adjust the pH to 7 with aqueous sodium bicarbonate solution and stir for 30 minutes under ice-cooling. The reaction mixture is extracted with ethyl acetate, and the extract is washed with an aqueous sodium hydrogen carbonate solution, water, dilute hydrochloric acid, and brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (silica gel 60 g: ethyl acetate-hexane, 2: 1). When solidified from ether, (3S, 4S) -3- (2— (2—chloroacetamidothiazol-14-inole) -1- (Z) —2—methyleneiminoacetamide] — 4-one methyl 1 — 4-nitrobenzyl 7-63 mg (58.3 de.) Of 12-azetidinone was obtained as a colorless powder, with a melting point of 102 to 106 (decomposition).

^{IR (KB r) em _1:} 1,760, 1,670, 1,525, 1,350, 1,040 NMR (d 6 -DMSO) s: iA 0 (3H, d, J-6Hz, C 4 one CH _3), 3.8~4.1 (1H, m, C ₄ one H), 3.8 7 (3H, s, OCH 3),

_{4.25~4.50 (lH, m, C 3} -H), 4.34 (2H, s, C1CH 2), 4.75 (2H, ABq, J = l 5Hz, OCH 2 COO), 5.34 (2H, s, COOCH 2), 7.38 (lH, s, thiazole-5-H), 7.65 (2H, d, J = 9 Hz, aromatic proton), 8.18 (2H, d, J = 9 Hz, aromatic ), 9.26 (1 H, d, J = 8 Hz, C ₃ —

NH), 1 2.8 5 (lH , br s, thiazole one Lou 2-NH) ₀ [-. _{6 0.9.} (c = 0.75, MeOH).

 b) Dissolve the above product a) 6 2 6 «? in a mixture of tetrahydrofuran 10 ^ and water 5 / ^, add sodium N-methyldithiocarbamate 15 6 at room temperature. Stir for 40 minutes. Add N-methyldithiol sodium phosphate 144 w and stir for an additional 50 minutes. Ethyl acetate and brine are added to the reaction mixture, and the mixture is shaken. The organic layer is separated and washed with brine. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was purified by column chromatography (50 g of silica gel: ethyl acetate) to give (3S, 4S) —3— [2— (2— Aminothiazole-1 -inole) 1- (Z) -2 -Methoxyxyminoacetamide] -1 4-Methyl-1 1- (412-Benzyoxycarbonylmethoxy) 1-2-azetidinone is pale yellow 32 6 (60.2 d.) Was obtained as a powder, and the melting point was 90-95 (decomposition).

IR (KBr) em— ¹ : 1,775, 1,670, 1,535, 1,350 _o

NMR (d ₆ -DMSO) δ: 1.37 (3Η, d, J = 6Hz, C4-CH3), 3.82 (3H, s, OC), 3.8 to 4.1 (lH, m, C4—H), 4.32

(1H, d. D, J = 2 & 8Hz, C ₃ -H), 4.73 (2¾ ABq, J =

15Hz, OCH ₂ COO), 5.33 (2H, s, COOCH ₂ ), 6.67 (1

H, s, thiazole one 5- H), 7.13 (2H, br. S, thiazole Ichiru one _{2 -NH 2), 7.6 5 (} 2H, d, J = 9Hz, aromatic pro tons), 8.1 8

(2H, d, J = 9Hz, aromatic proton), 9.10 (1H, d, J = 8

Hz, C ₃ -NH)

^{[Α] ρ 9 - 68.8 °} (c = 0.6 5, MeOH)

 c) The above product b) 300 was dissolved in a mixture of tetrahydrofuran 20 and water 20 td, and the mixture was dissolved in 10 d. Add palladium carbon 30 and stir for 1 hour at room temperature under hydrogen atmosphere. Sodium hydrogencarbonate 50 is added to the reaction mixture, and the mixture is further stirred under a hydrogen atmosphere for 3 hours. The catalyst is removed, the solution is concentrated under reduced pressure, and the residue is purified by column chromatography (Amberlite XAD-2,250 ^; water) and lyophilized to give the title compound as a colorless powder As a result, 1 67 (67, 4 de.) Is obtained.

 IR (KB: 1,770, 1,660, 1,615, 1,530, 1,040.

_{NMR (d 6 -DMSO) 5:} 13.6 (3H, d, J = 6Hz, C 4 -CH 3),

3.77 (3H, s, OCH3) , 3.7~ 4.1 (lH, m, C 4 -H), 3.9 5 (2H, s, C 1 CH 2), 4.23 (lH, d. D, J = 2 & 8 Hz , C ₃ one H), 6.63 (lH, s , thiazole one 5- H), 7.13 (2H, br. s, thiazole one _{2- NH 2), 9.18 (lH} , d, J = 8Hz, C 3 -NH ) ₀ elemental analysis: as _{C 12 H 14 N 5 N a} 0 6 S · ι.5Η 2 0

 C Ho) H (de.) N [io)

 Calculated value 3 5.4 7 4.2 2 1 7.2 4

Actual 3 5.4 2 4.5 2 1 7.0 6 29

 D-1.72.8 ° (c = 0.7, water) Example 3.

 (3 S, 4 S) — 3— [2— (2-aminothiazol-1-yl) 1 (Z)-2— (1 carboxyl 1 —methyl methoxymino) acetamide] — 1 — Synthesis of carboxy, methoxy 4-methyl 2- azetidinone dinadium salt

 a) (3S, 4S) —3— (t-butoxycarbonylamino) 1-41-methyl-1- (4-nitrobenzyloxycarbonylmethoxy) 1-2-azetidinone 1.02 g Dissolve in dichloromethane and add anisol 4 »^ and trifluoroacetic acid 20 while stirring under ice-cooling. Stir under ice cooling for 1.5 hours, add toluene 20 ^ to the reaction mixture, and concentrate under reduced pressure. The residue was suspended in 40 ml of dichloromethane, and triethylamine 2.1 and 2- (2-chloroacetamidothiazol-14-inole) -1- (Z) —2— [1—me Chinole 1- (412-port benzoinoleoxycanoleboninole) ethoxymino] acetylc-mouth ride hydrochloride (prepared by the method described in JP-A-57-131758) 1. 6 Add 2 g and stir for 1.5 hours. Concentrate the reaction mixture under pressure, add ethyl acetate and water to the residue and shake. The ethyl acetate layer is separated and washed successively with an aqueous sodium hydrogen carbonate solution, a saline solution, dilute hydrochloric acid and a saline solution. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by force chromatography (silica gel 80 g; ethyl acetate «xane, 3: 2 :) to give (3S, 4 S)-3-{2-(2-chloroacetamidothiazole 1-4-inole) 1-(Z)-2-[1-methinole 1-(41-2 benzinoleoxy force leboninole) ethoxyminino Acetamid — 4—Methinolay 1— (4—2

r oMPi Carbonyl methoxy) 12-azetidinone is obtained as a colorless foam 918 (47.3 de).

IR (KBr) ¹ : 1,785, 1,765, 1,750, 1,680, 1,525,

 1,35 Oo

_{NMR (d 6 -DMS 0) δ} : 1.41 (3H, d, J = 6Hz, C4-CH3), 1.50 (6H, s, 2xCH 3), 3.8~4.15 (lH, m, C -H), 4.34

(2H, s, C 1 CH ₂ ), 4.44 (lH, d. D, J = 2 is also 8 Hz, C ₃ — H), 4.75 (2H, ABq, J = l 7 Hz, OCH ₂ COO), 5.33 (4H , s, 2 x COOCH ₂ ), 7.37 (lH, s, thiazole-5-H), 7,58 (2

 H, d, J = 9 Hz, aromatic protons), 7.63 (2H, d, J = 9 Hz, aromatic protons), 8.05 (2H, d, J = 9 Hz, aromatic protons), 8.18 (2H, d, J = 9 Hz, aromatic proton), 9.18 (lH, d, J

_{= 8 Hz, C 3 -NH)} , 12.87 (lH, br. S, thiazole one 2-NH). b) Dissolve the product 784 of a) above in a mixture of tetrahydrofuran 15 and water 5 ^, and add sodium N-methyldithiol sodium phosphate 130 while stirring under ice-cooling. . Stir at room temperature for 1 hour, add sodium N-methyl sodium salt, 130 w, and stir for an additional hour.

Ethyl acetate and saline are added to the reaction mixture, and the mixture is shaken. The organic layer is separated and washed with brine. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was purified by column chromatography (silica gel 90 g; ethyl acetate-hexane, 2: 1 then 4: 1) to give (3S, 4S) -3- {2 — (2-aminothiazol-1-yl) 1 (Z) —2— [1-methyl

 1- (4-Nitrobenzenesiloxycarbonyl) ethoxymino] acetamide} — 4-methyl-1- (4-2-nitrobenzyloxycarbonylcarbonyl) 1-2-azetidinonone is pale yellow 5 8 3 as foam (8 3.3 d.) _ _

O PI Obtained o

 I R (KB r: 3,370, 3,120, 1,780, 1,750, 1,680,

1.525, 1,350

NMR (d ₆ -DMS 0) δ: i.40 (3H, d, J = 6 Hz, C ₄ -CH ₃ ), 1.51 (6H, s, 2 CH ₃ ), 3.80 to 10 (lH, m, C ₄ — H), 4.38 (lH, d. D, J = 2 & 8 Hz, C ₃ -H), 4.74 (2 ABq, J = 17 Hz, OCH ₂ COO), 5.34 (4H, s, 2xCOOH ₂ ), 6.71 ( 1H, s, thiazole one 5- H), 7.25 (2H, br. s, Chiazo Honoré one _{2- NH 2), 7.61 (2H} , d, J. = 9Hz, aromatic pro tons),

7.65 (2H, d, J = 9 Hz, aromatic protons), 8.11 (2H, d, J = 9 Hz, aromatic protons), 8.17 (2H, d, J = 9 Hz, aromatic protons) , 9.02 (1H, d, J = 8Hz, C 3 - NH).

 c) Dissolve the product 90 of the above b) in a mixture of 15-hydrohydrofuran 15 and 15 pounds of water, add 10 valadium carbon 490, and stir at room temperature for 1.5 hours under a hydrogen atmosphere. Add sodium hydrogen carbonate (118 w) to the reaction mixture, and stir under a hydrogen atmosphere for another 2 hours. The catalyst is removed and the mixture is washed with a mixture of furan and water (1: 1). ^ Combine the solution and the washing solution and concentrate under reduced pressure to distill off tetrahydrofuran. Wash the remaining aqueous solution with ethyl acetate and concentrate again under reduced pressure to about 5. Purification of the residue by column chromatography (Amberlite XAD-2, 250 m; water) followed by lyophilization yields 238 as a yellow powder. This was dissolved in a small amount of water, purified again by column chromatography (Ampa-One Light XAD-2,200; water), and lyophilized to give the title compound as a pale yellow powder. 8.1 de.) Obtained.

 R (KB, -I

J cm L, 770, 1,660, 1,620 (br.), 1,530, 1,410 _o

_{NMR (d 6 -DMS 0):} 1.25~ 1.50 (9H, m, 3xCH 3), 3.80

~ 4.25 (3H, m, OCH ₂ COO & C ₄ — H), 4.40 (lH, d. D, J = 2 & 8 Hz, C ₃ — H), 6.71 (lH, s, thiazole-5-H),

7.10 (2H, b r. S, thiazole-1 2—NH ₂ ), 11.36 (lH, d,

J = 8Hz, C ₃ -NH) ₀

Elementary analysis: as _{C 15 H 17 N 5 Na 2} O 8 S.2.8H 2 O

 Calculated value 3 4.4 0 4.3 5 1 3.3 7

 Actual 3 4 2 9 4.2 3 1 3.6 5

 [] One 5 0.7. (C = 0.9, water).

 Example 4.

 (3 S, 4 S) — 1—Carboxymethoxy-1 3— [(D) — 2— (4-Ethyl-1,2,3-dioxopiperazine-1 1 —Carbonamino) 1 2 —Fenylacetamide] 1 Synthesis of 4-methyl-2-azetidinone mononadium salt

 a) (3 S, 4 S) — 3— (t-butoxycarbonylamino) 1-41 methyl 1 — (412 trobendinoleoxycanoleboninolemethoxy). 1 2 — Dissolve 1.02 g of azetidinone in dichlormethane 40, and add anisol 4 and trifluoroacetic acid 10 while stirring under ice-cooling. Stir under ice-cooling for 5 minutes, add toluene 20 to the reaction solution and concentrate under reduced pressure. Add ethyl acetate and saline to the residue, neutralize with sodium bicarbonate under ice cooling, and separate the ethyl acetate layer. After washing with brine, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. The residue was dissolved in N, N-dimethylformamide 15 «and dissolved in (D)-2-(4-ethyl 1, 2,3-dioxopi

OMPI Add Razine-111-Rubonylamino) -1-2-Furacetic acid 798 ^ and Dihexyl hexylcarbodiimide 5667, and stir at room temperature for 14 hours. Remove insolubles and concentrate the filtrate under reduced pressure. Dissolve the residue in ethyl acetate, wash with sodium bicarbonate solution and brine, and dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (100 g silica gel; ethyl acetate) to give (3S, 4S) 13-[(D) -2 (4-Ethyl-1,2,3-dioxopiperazine-11-carbonylamino) -12-Phenylacetamide] -14-Methyl-11- (412-Benoxycarbonylmethoxyl) 1-2 — Azetidinone as a colorless foam 164 (10.7 ヂ.) O

I (KB r ^l : 3,300, 2,930, 1,780, 1,715, 1,680,

 1,515, 1,350, 1,185o

NMR (d ₆ -DMSO) δ: i.07 (3H, t, J "= 7.5 Hz, CH. CHa),

1.33 (3H, d, J = 6 Hz, C ₄ — CH ₃ ), 3.2 to 4.1 (7H, m, 3X NCH ₂ & C ₄ —H), 4.22 ClH, d. D, J = 2 & 7 Hz, C ₃ -H),

4.75 C 2H, br. S, OC¾COO), 5.34 (2H, s, COOC¾),

5.43 ClH, d, J = 7.5 Hz, PhCH), 7.2 to 7.5 (5H, m, Ph), 7.66 (2H, d, J = 9 Hz, aromatic proton), 8 · 20 (2Η, d, J = 9 Hz, aromatic pro tons), 9.1 1 (1H, d , J = 7Hz, C 3 -NH),

9.80 (lH, d, J = 7.5 Hz, PhCHNH) _Q

 b) _tf The product 336 from a) is dissolved in a mixture of tetrahydrofuran 20 and water 20 mi, and the mixture is dissolved in 10%. Add palladium carbon 340 and stir at room temperature for 40 minutes in a hydrogen atmosphere. After adding sodium hydrogen carbonate under ice-water cooling, the catalyst is separated, and a mixture of tetrahydrofuran and water (1: 1) is washed with water.合 わ せ Combine the solution and the washing solution and add tetrahydrofuran under reduced pressure.

WTPO Distill off. The residual aqueous solution was washed with ethyl acetate and concentrated again under reduced pressure, and the residue was subjected to force chromatography (Amberlite XAD-2,260 ^; water; 10 d. Ethanol and 20 d. Purification with ethanol and lyophilization gives 240 (80.5 da.) Of the title compound as a colorless powder.

 I R (KB r: 1,770, 1,715, 1,680, 1,610, 1,510,

1,370, 1,185 ₀

NMR (d ₆ -DMS 0) δ: ι.ο 7 (3H, t, J = 7.5 Hz, CH ₂ CH ₃ ),

1.33 (3H, d, J = 6 Hz, C4-CH3), 3.2 to 4.1 (7H, m, 3 x NC¾ & C ₄ — H), 4.23 (1H, d.d, J = i.5 & 7 Hz, C ₃ — H),

5.46 (lH, d, J = 7.5 Hz, PhCH). 7.15-7: 55 (5H, m, Ph), 9.48 (1H, d, J = 7 Hz, C3-NH), 9.77 (1 H, d, J = 7.5Hz, PhCHNH) o

Elementary analysis: as the _{C 21 H 24 N 5 N a} 0 8 · 2.5H 2 0

 c (de.) N (de.)

 4 6.5 0 5.3 9 1 2.9 1

 Actual 4 6.3 9 5.3 4 1 3.0 1

[Α;] ¾ ⁴ one 76.6 ° (c = 0.7, water).

Example 5.

(3 S)-3-[2-(2-aminothiazole-1-4-yl) 1-(Z)-1-2-(1-carboxy-1-methylethoxymino) acetamide]-1- Synthesis of carboxymethoxyl-2-azetidinone sodium salt. a) Dry 1.78 g of N- (t-butoxycarbonyl) -1-L-serine-N- (412-port benzyloxycarbonylmethoxy) amide and 1.57 g of triphenylphosphine Dissolve in tetrahydrofuran 90, add dropwise 0.94 ml of azodicarboxylic acid getyl ester, and stir at room temperature for 5 hours. Zeal. Add 0.393 g of triphenylphosphine and 0.24 of acetyldicarboxylate and stir at room temperature for another 13 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by column chromatography (silica gel 100 g; ethyl acetate-l-xane, 2: 1), and the fraction containing the desired product is collected and concentrated. When a colorless solid formed by adding ether to the residue was taken out, (3S) -3- (t-butoxycarbonylamino) 1-1 (4-212 benzyloxycarbonylmethoxy) was obtained. 1.86 g of a mixture of 2-azetidinone and hydroxycarbonylhydrazine is obtained. The purity of the target product is 63 d. The purity-converted yield is 69.9%.

I (KBr) CT ¹ : 1,780, 1,755, 1,680, 1,520.

NMR (d ₆ — DMSO) s: 1.37 (9H, s, 3 CH ₃ ), 3.43 (iH, d. D, J = 3 & 4.5 Hz, C ₄ —H), 3.78 ClH, t, J = 4.5 Hz, C ₄ — H), 4.3-4.6 (lH, m, C ₃ — H), 4.69 (2H, s, OCH ₂ COO), 5.33 (2H, s, COOCH ₂ ), 7.47 (lH, d, JT _{= 9Hz, C 3 - NB¾ 7.65} (2H, d, J = 9Hz, aromatic pro tons), 8.22 (2H, d, J

= 9Hz, 'aromatic protons).

 b) Dissolve 1.57 g of the product of a) above in dichloromethane 40 ^, and add anisol 4 and trifluoroacetic acid 20 while stirring under ice-cooling.

Stir under ice cooling for 1 hour, add toluene 20 to the reaction solution, and concentrate under reduced pressure. The residue was suspended in dichloromethane (40 ^), and triethylamine 2. and 2- (2-chloroacetamidothiazol-4-ynole) -1- (Z) -2-[1-methyl-1-1 (4-1-2) were added under ice cooling. Tokuguchi benzyloxycarbonyl) ethoxymino] acetylk mouth hydrochloride 1.62 g, and stir for 1.5 hours. Concentrate the reaction mixture under reduced pressure, add ethyl acetate and water to the residue and shake. The ethyl acetate layer is separated, and a sodium hydrogencarbonate aqueous solution, Wash sequentially with saline, diluted hydrochloric acid and saline. The solvent was distilled off under reduced pressure after dried over anhydrous magnesium sulfate, the residue Karamuku port chromatograph I chromatography (Shi Li force Gel 1 0 0 g; acetic Echiru - CHC 1 _3, 1: 1, then 2: 1) Purification yields (3S) —3— {2— (2-chloroacetamidothiazole—4-inole) 1 (Z) —2— [1—methinole 1— (4—nitrobenzinoleoxy) Carbonyl) ethoxymino] acetamide} 11- (4-nitrobenzyloxycarbonylmethoxy) -12-azetidinone As a colorless powder, 511 w (26.8 d.) Is obtained. .

IR (KB r) c *: 3400 (br), 1785, 1750, 1680, 1525, 1350 _o

_{NMR (d 6 - DMSO) 5} : 1.51 (6H, s, 2xCH 3), 3.5~ 3.6 5 (lH, m, C 4 - H), 3.8~4.1 (lH, m, C 4 -H), 4.34 ( 2¾ s, C 1 CH ₂ ), 4.75 (2H, s, OCH ₂ COO), 4.6 to 5.0 (lH, m, C ₃ -H), 5.33 (4H, s, 2xCOOCH ₂ ), 7.37 (1 H, s , Thiazole— 5— H,) 7.59 (2H, d, J "= 9 Hz, aromatic proton),

7.66 (2H, d, J = 9Hz, aromatic protons), 8.06 (2H, d, J = 9Hz, aromatic protons), 8.19 (2H, d, J = 9Hz, aromatic protons) , 9.15 (lH, d, J = 8Hz, C 3 -NH), 12.86 (lH, br.s, Chiazoru 2-NH) o

c) Dissolve 480 w of the product of b) above in a mixture of tetrahydrofuran 12 and water 4 ^, and add sodium N-methyldithiol sodium bamate 81 while stirring under ice-cooling. Stir at room temperature for 1 hour, add sodium N-methyldithiocarbamate 41 and stir for an additional hour. Ethyl acetate and brine are added to the reaction mixture, and the mixture is shaken. The organic layer is separated and washed with brine. After drying over anhydrous magnesium sulfate, concentrate under reduced pressure and remove the residue. Column chromatography (50 g of silica gel; ethyl acetate-hexane,

Purification with 4: 1 and then only ethyl acetate yields (3S) —3— {2— (2-aminothiazol-4-yl) 1- (Z) —2 -— [1-methyl-1-1 (4 12- (Trobenzyloxycarboninole) ethoxymino] acetamide} —11- (412-Methyl benzyloxycarbonyl methoxy) 1-2-zezedinone as yellow foam 8 2.7 de.) Obtained 0

IR (KB r) e ^!: 3370 (br.), 3120, 1780, 1740, 1680, 1525, I 350 _o

_{NMR (d 6 -DMSO) δ:} i.48 (6H, s, 2XCH 3), 3.5~ 3 · 7 (lH, m, C 4 one H), 3.8- 4.1 (lH, m, C 4 -H) , 4.74 (2H, s, 0CH ₂ C00), 4.65 to 95 (lH, m, C ₃ -H), 5.33 (4¾s, 2xCOOCH ₂ ), 6.70 C lH, s, thiazol-1-5-H), 7.25 (2H, br. S, thiazole-1-NH ₂ ), 7.62 (2H, d, J = 9 Hz, aromatic proton), 7.65 (2H, d, J = 9 Hz, aromatic proton), 8.11 (2H, d, J = 9Hz, aromatic pro tons), 8.20 (2H, d, J = 9Hz, aromatic pro tons), 9.02 (lH, d, J = 8Hz, C 3 one NH) ₀

d) The product 310 of the above c) is dissolved in a mixture of petrahydrofuran 15 / ^ and water 15 to give 10 de. Add 310 watts of palladium carbon and stir at room temperature for 1.5 hours in a hydrogen atmosphere. A solution of sodium hydrogen carbonate 76 dissolved in 5 me of water is added to the reaction mixture under ice cooling. The catalyst is separated and washed with a mixture of tetrahydrofuran and water (1: 1 :). The combined solution and washing solution are concentrated under reduced pressure to remove tetrahydrofuran. The remaining aqueous solution is washed with ethyl acetate and concentrated under pressure. The residue was purified by column chromatography (Amber Light XAD-2, 250; water) and freeze-dried. The compound is obtained as a colorless powder, 149 (65.4 de.).

IR (KB r) c ¹ : 1770, 1660, 1605 (br.), 1535, 1410o

_{NMR (d 6 - DMSO):} 1.40 (9H, s, 3 xCH 3), 3.5~3.7 (lH, m, C 4 -H), 3.7~3.9 (lH, m, C 4 - H), 4.03 (2H , B r. S,

OCH ₂ COO), 4.65— 4.95 (lH, m, C ₃ -H), 6.70 (lH, s, thiazole-5-H), 7.02 (2H, thiazole-2-NH ₂ ), 11.49 (lH, d, J = 9Hz, C ₃ — NH) ₀

Elementary analysis: as _{C 14 H 15 N 5 Na 2} 0 8 S · 2.5H 2 O

 C (de.) H N {)

 Calculated value 3 3.3 4 4.0 0 3.8 9

 Actual 3 3.5 4 3.9 4 3.9 0

^{[Α] | 5 - 141.7 °} (c = 0.5, water).

 Example 6.

 (3 S, 4 S) — 3- (t-butoxycarbonylamino) 1-4-force-bamoyl- 1- (41-2-port-benzyloxy- carbonyl-oxy) 1-2-azetidinone synthesis (alkylation) Law)

(3 S, 4 S) — 3— (t-butoxycarbonylamino) — 4 suspension of 1-hydroxyl-2-hydroxyazetidinone 12 3 in acetonitrile 5 ^ Add triethylamine 0.08 ^ while stirring under ice-cooling to obtain a clear solution. Next, add bromoacetic acid 4-benzyl benzyl ester 150 ° and stir at room temperature for 1 hour to precipitate crystals. The solvent is distilled off under pressure, and a mixed solution of ethyl acetate and tetrahydrofuran (2: 1) and water are added to the residue, and the mixture is shaken. The organic layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The remaining crystals were mixed with ethyl acetate and polyester. After addition of the liquid (1: 2), the title compound was obtained as colorless crystals in 144 (65.8 d.), Mp 192-195. Indicates c (decomposition).

IR (KBr); ¹ : 3360, 1790, 1690, 1520, 1350. NMR (d ₆ -DMSO) 5: 1.36 (9H, s, 3xCH ₃ ), 4.60 ClH, d, J = 6 Hz, C ₄ — H), 4.73 (2 s, OCCOO), 495 (1

. H, d d, J = 6 & 9Hz, C 3 -H), 5.28 (2H, ABq, J = 1 5 Hz, COOCH 2), 7.02 (lH, d, J = 9Hz, C 3 - NH), 7.25~ 7.55 (2H, m, CONH 2), 7.66 (2¾ d, J = 9Hz, aromatic pro tons), 8.22 (2H, d, J = 9Hz, aromatic pro tons).

Elementary analysis: as C ₁₈ H ₂₂ N ₄ 0 ₉

 C (de.) H (de.) N [io]

 Calculated value 9.3 2 5.0 6 1 2.7 8

 Actual 9.0 8 5.0 7 12.57

Example 7.

 (3 S, 4 S) — 3 — (t-butoxycarbonylamino) 14-1-1-(12-outlet benzoinoleoxycarbonylmethoxy) 1-2-Synthesis of azetidinone (ring closure) Law)

L-Eris-I-N- (412-Benoxycarbonylmethoxy) 1-N- (t-Butoxycarbonyl) -13-Methanesulfonyloxy-substituted diamide 534 Suspend in 100% acetone and add 415 carbonate. Raise the reaction temperature gradually, raise it to 60 in 20 minutes, then stir for another 25 minutes at the same temperature. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is dissolved in a mixture of ethyl acetate and tetrahydrofuran (4: 1). After washing with brine and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. A mixture of ethyl acetate and ether was added to the residue (1:

When the crystals formed by adding 2) were collected, the title compound was obtained as 2666 ^ (60.7 d), which was identical to that obtained in Example 6.

(Margin below :)

OMM Example 8

 (3 S, 4 S) 1-3-[2-(2-amino thiazole 4-yl) 1-(Z)-2-methoxyimioacetamide 1-1-force rubamoinole 1-force ruboxime toxic Synthesis of 2-azetidinone monosodium salt.

 a) (3 S, 4 S) — 3— (t-Butoxycarbonylamino) 1 4-1 Canoleva'moinole 1 1 1 (412 Trobenzinoleoxycanoleboninolemethoxy) 1 -2-azetidinone 4 Suspend 38 W in dichlormethan 2 and add anisol and trifluoroacetic acid 10 »while stirring under ice-cooling. Stir under ice-cooling for 2 hours, add dioxane 20 to the reaction mixture and concentrate under reduced pressure. Dioxane 20 is again added to the residue, and the mixture is concentrated under reduced pressure. Dichloromethan 2 and tetrahydrofuran 10 W were added to the residue, and while stirring under ice cooling, triethylamine 0.84ι ^ and 2- (2-chloroacetamidothiazol-4-inole) 1 (Z) — 2-Add methoxyminoacetyl chloride hydrochloride 498 W and stir under ice-cooling for 2 hours. The solvent is distilled off under reduced pressure, and the residue is added with tetrahydrofuran 15 and water 15a, and neutralized with sodium hydrogen carbonate. After stirring for 1 hour under ice cooling, tetrahydrofuran is distilled off under reduced pressure, and 20 W of water is added to the residue, and the precipitated crystals are collected. Washing successively with aqueous sodium hydrogen carbonate solution, water, ether, ethyl acetate and ether yields (3S, 4S) -4-butyramoyl-3- (2- (2-chloroacetamidothiazole-4-inole) -1 (Z) — 2-Methoxyminoacetamide) 1-111 (412-nitrobenzyloxycarbonyl methoxy) -12-azetidinone was obtained as colorless crystals 36 3 ^ (60.7), melting point 2 10 0 2 Indicates 13 ° C (decomposition).

I CKB r) ^ ¹ : 3 42 0, 3 2.2 0, 1 7 9 0, 1 7 5 0,

NMR (d ₆ -DMS O) «5: 3.88 (3 H, s, OCH ₃ ),

4.3 5 (2 H, s, C 1 CH ₂ ), 4.6 5 to 4.85 (3 H, m,

0 CH ₂ COO & C ₄ -H), 5.3 2 (2H, s, COOCH ₂ ), 5.33 (lH, d. D, J = 5 & 9 Hz, C ₃ -H), 7.32 (1 H, s, thiazole-5 — H), 7.3 to 7.7 (2H, m, CONH ₂ ), 7.67 (2¾d, J = 9 Hz, aromatic proton), 8.19 (2H, d, J = 9 Hz, aromatic proton) ), 9.35 (lH, d, J = 9Hz, C3-NH), 12.90 (lH, br.s, thiazole

2 -NH) ₀

b) suspending the product 27 a) above the mixed solution of Tetorahi Dorofura emissions and water 3, stir Ν- main Chirujichio force Rubami Nsan'na Application Benefits um ^{7 8} W were added 5 0 minutes at room temperature. Ν—Sodium sodium methyldithiocarbamate

Add 3 9 ^ and stir for another 30 minutes. Ethyl acetate and water are added to the reaction solution, and the mixture is shaken. The organic layer is separated and washed with saline. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, ether was added to the residual solid and the mixture was filtered to give (3S, 4S) — 3— [2- (2-Aminothiazoyl 4-inole) — (Ζ) — 2-methoxyminoacetamide) 1-4-rubamoyl-1-(4-2-benzyloxycarbonyl methoxy)-1-2-azetidinone as yellow crystals 195 m ( 8 3.2%) and shows a melting point of 183-186PC (decomposition).

IR (KBr) ¹ : 1 7 8 5, 1 7 5 0, 1 6 7 5, 1 5 2 0,

 1 3 5 0ο

_{NM (d 6 -DMSO) 5:} 3.80 (3H, s, OCH 3), 4.73 (1 H, d, J = 5Hz, C 4 one H), 4.77 (. 2H, br s, OCH 2 COO), 5.29 (lH, d, J = 5 & 9Hz, C ₃ -H), 5.30 (2H, s, COOCH ₂ ),

6.67 (1 H, s, thiazolo 5-H), 7.10 (2 H, br, s, thiazo Lou 2—NH ₂ ), 7.67 2¾d, J = 9 Hz, aromatic protons), 8.19 (2H, d, J = 9 Hz, aromatic protons), 9.22 (1H, d, J = 9 Hz) , C ₃ -NH) ₀

 c) The product 14 of the above b) is suspended in a mixture of 10 W of tetrahydrofuran and 10 mt of water, 10% palladium carbon 140 ^ is added, and the mixture is stirred under a hydrogen atmosphere at room temperature for 1 hour. Add sodium hydrogen carbonate to the reaction mixture and stir for an additional hour under a hydrogen atmosphere. The catalyst is separated and washed with a mixture of tetrahydrofuran and water (1: 1). The combined solution and washing solution are concentrated under reduced pressure to distill off tetrahydrofuran. The residual aqueous solution was washed with ethyl acetate, concentrated under reduced pressure, and the residue was purified by column chromatography (Amberlite XAD-2,100 »; water) and freeze-dried to give the title compound. 68W (55.1%) as a colorless powder.

IR CKB r) ^ ¹ : 1 780, 1 680, ¹ 620, ¹ 530,

1 0 4 0 _o

NMR (d 6-DMSO) δ: 3.80 (3H, s, OCH ₃ ), 4.16 (2H,

_{ABq, J = 15Hz, OCH 2} COO), 4.66 (lH, d, J = 6Hz, C 4 -. H), 5.20 (lH, d d, J = 6 & 9Hz, C 3 -H), 6.80 (lH , s, Chi Azoru 5- H), 9.18 (lH, d, J = 9Hz, C 3 - NH).

Elemental analysis value: C ₁₂ H ₁₃ N ₆ Na 0 ₇ S · 2.8H ₂₀

 c H N

 Calculated 31.41 4.09 18.32

 Actual 31.31 4.15 18.58

[O D ²⁵ - 3 0.3. (C = 0.5, water).

Example 9

C 3 S, 4 S) — 3— [2— f 2—aminothiazolu-l 4-isole) (Z) — 2-Carboxymethoxyiminoacetamide) 1-4 — Potassium 1-carboxymethoxy 2 — Synthesis of azetidinondinatrium salt <a) (3S, 4S) — 3 — (T—Butoxycarbonylamino) 4 力 イ イ イ モ モ (((4 (4 ((((((4 (((4 — 4 4. Suspend in ice cold 20 and add anisol 2 i and trifluoroacetic acid 10 while stirring under ice-cooling. Stir under ice-cooling for 2 hours, add toluene 20 to the reaction mixture, and concentrate under reduced pressure. Dichloromethane 20 was added to the residue, and then triethylamine 1.06 and 2— (2—chloroacetamidothiazoyl 4-yl) -1- (Z) 1-2— (4-nitrobenzene Ndiloxycarbonyl methoxymino) acetyl chloride hydrochloride (prepared by the method described in JP-A-57-131758), and add 964, followed by stirring under ice-cooling for 2 hours. The solvent is distilled off under reduced pressure, and 15 W of tetrahydrofuran and 15 W of water are added to the residue, and the mixture is adjusted to pH 7 with an aqueous solution of sodium hydrogen carbonate. After stirring under ice-cooling for 1 hour, tetrahydrofuran was distilled off under reduced pressure, and the precipitated crystals were collected and washed sequentially with an aqueous solution of sodium hydrogencarbonate, water, ether, ethyl acetate and ether. (3 S, 4 S) — 4-—Lubamoy Lu 3 — [2 — (2 — Chloroacetamidothiazole 1—4-Nole) 1 (Z) —2 — (4-Nitrobenzyloxyloxycarbonyl methoxycarbonyl) (N) acetamide) 11- (4-nitrobenzenesiloxycarbonyl methoxy) -12-azetidinone force s' Yellow crystals 848 ^ (83.0%) are obtained. Although some impurities were observed by TLC, the crude crystals were used in the next reaction. Melting point 1 4 7 — 1 5 3 ° C ₀ IRC KB r) ^ ¹ : 1 790, 1 7 4 0, 1 6 7 5, 1 5 2 0,

1 3 5 0 ο

NMR (d _fi -DMSO) δ: 4.33 (2H, s, C 1 CH ₂ ), 4.65 to 4.9

OMPI _{(5H, m, 2xOCH 2 COO} & C4- H), 5.2~5.5 (5¾ m, 2xC00 CH 2 & C 3 - H), 7.83 (lH, s, Chiazoru 5H), 7.3~ 7.8 (6H, m, CONH 2 And aromatic protons), 8.15 (2H, d, J = 9Hz, aromatic protons), 8.22 (2H, d, J = 9Hz, aromatic protons), 9.35 (IEd , J = 9Hz, C ₃ - thigh).

Elemental value ': as C ₂₉ H ₂₅ C1N ₈ 0 ₁₄ S .2H ₂₀

 c H (¾) N

 Calculated 42.84 3.59 13.78

 Actual 43.08 3.74. 13.55

b) suspending the product Ί 0 0 ¾f a) above to a mixture of tetra-human Dorofuran 1 5 W and water 5 gas, at room temperature was added the N- methyl-di Chio carba Mi Nsan'na Application Benefits um 1 ² 9 1 hour stir - stir as tetrahydrofuran 4 5 water 5 * you and Ν- methylation di Chio carba Mi Nsan'na door Li Umm 1 2 ⁹ W to add an additional 3 0 minutes. The tetrahydrofuran is distilled off under reduced pressure, water is added to the residue, and the precipitate is taken out of the furnace. Washing sequentially with water, ether, ethyl acetate and ether yields (3S, 4S) -3- (2- (2-aminothiazo-one-4-inole) -1 (Ζ) -2- (4-1) 2-nitrobenzoleoxycanoleboninole methoximino) acetamido] -14-rubamoy-lu-1-1 (4-nitrobenzyloxycarbonylmethoxy) -12-azetidinone as a yellow solid 50 1 (80) obtained, mp 187-19 (C (decomposed).

IRC KB r) ^ ¹ : 3 4 3 0, 3 2 6 0, 1 7 8 5, 1 7 5 0,

 1 6 8 0, 1 5 2 0, 1 3 5 0 ο

_{NMR (d 6 -DMSO) δ:} 4.6~4.85 (5H, m, 2xOCH 2 COO & C 4 -H), 5.15~5.50 (5Η »m, 2 xCOOCH 2 & C 3 - H), 6.76 (lH, s, thiazole —Rou 5— H), 7.17 C 2 H, br.s, thiazole 2 -NH ₂ ), 7.25 to 7.75 (6H, m, CONH ₂ and aromatic protons), 8.18 (2H, d, J = 9 Hz, aromatic protons), 8.22 (2H, d, «Ι -θΗζ »Aromatic proton), 9.15 (1H, d, J = 9 Hz, C ₃ -NH) ₀

Elementary analysis: as _{C 27 H 24 N 8 O 13} S · 1.5H 2 0

 c H (¾) N

 Calculated 44.57 3.74 15.40

 Observed 44.54 3.52 15.1

 c) The product 280 ^ of the above b) is suspended in a mixture of tetrahydrofuran 1 and water 15 and 10% 'radiocarbon 280 W is added thereto. mix. Add 67 W of sodium bicarbonate to the reaction mixture, and stir under a hydrogen atmosphere for another 4 hours. Separate the catalyst and wash with a mixture of tetrahydrofuran and water (1: 1). The combined solution and solution are concentrated to a reduced pressure of “F”, and tetrahydrofuran is distilled off. The remaining aqueous solution is washed with ethyl acetate, concentrated under reduced pressure, and the residue is subjected to column chromatography (Amber Light). Purification with XAD-2,200; water) followed by lyophilization gives 92 ^ (44%) of the title compound as a colorless powder.

IR (KB r) ii ¹ : i 780, 1 680, 166 (br.), 1 410,

1 0 3 0 _o

NMR (D ₂ 0) 5: 4.16 (2Η, s, OCH ₂ COO), 4.68 (2H, s, OCH ₂ COO), 5.18 (lH.d, J = 5 Hz _f C ₄ -H), 5.60 (lH, d, J = 5 Hz, C 3 -H), 7.06 (1 H, s, thiazolone 5—; H).

Elemental analysis: C ₁₃ Hi 2 N ₆ Na ₂ 0 ₉ S · 4H ₂₀

 c H N

 Calculated 28.57 3.69 15.38

28.65 3.41 15.16 ^{«D 2 5 - 2 3.5 °} (c = 0.5 5, water).

Example 10

 (3 S)-3-(t-butoxycarbonylamino)-1-[11-(4-12-trobenzinoleoxycanoleboninole)-1-methylinoethoxy] 1-2 Synthesis.

 (3S) —3— (t-butoxycarbonylamino) 1-1-hydroxy-12-azetidinone 1.019 is dissolved in acetonitrile 50, and the mixture is stirred under ice-cooling while stirring the triethylamine. 0.8 Add 4 W and 2-bromo-2-methylbutanoic acid 4-nitrobenzyl ester 1.8 19 1.5 at room temperature

After stirring for 3 hours at 60 ° C, then concentrate the reaction mixture under reduced pressure. Dissolve the residue in ethyl acetate, wash with water and dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel 1309; ethyl acetate 1 ^ »xane, 1: 1) to give the title compound as a colorless gum. 2 9 (38.8%) are obtained.

IR (KB r) i¾ ¹ : 34 1 0, 1 7 9 0, 1 7 2 0, 1 5 3 0,

1 350, 1 _{170 o}

NMR (d 6-DMSO) δ: 1.37 (9¾ s, ₃ × CH ₃ ), 1.47 (3H, s, CH ₃ ), 1.51 (3H, s, CH ₃ ), 3.36 C lE d. D, J = 3 & 5 Hz ,

C ₄ one _{H), 3.70 (lH r t} , J = 5Hz, C 4 one H), 4.35~4.65 (1

m, C ₃ -H), 5.31 (2E s, COOCH ₂ ), 7.52 (lH, d, J = 9 Hz,

_{C 3 -NH), 7.66 (2¾} d, J = 9Hz, aromatic pro tons), 8.23 (2H, d, J = 9Hz, aromatic pro tons). Example 11

 (3S) —Synthesis of 3- (t-butoxycarbonylamino) -11- (412-benzobenzyloxycarbonylmethoxy) -12-azetidinone.

OMFI N- (t-Butoxycarbonyl) -1 0-Methanesulfonyl-1 L-Serine-1N- (4-Nitrobenzyloxycarbonylmethoxy) amide 3.9 39 Acetone 800 , And add lithium carbonate 3.3 19. Raise the temperature of the reaction solution gradually in a nitrogen atmosphere, raise it to 60 ° C in 20 minutes, and then stir for another 55 minutes at the same temperature. The reaction solution is filtered, the solution is concentrated to a low pressure, and the residue is dissolved in a mixed solution of ethyl acetate 200 and tetrahydrofuran 50 W. Wash sequentially with dilute hydrochloric acid, saline, aqueous sodium bicarbonate and brine, and dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and ether was added to the residue. The resulting solid was collected to give 2.379 (75.0%) of the title compound as colorless crystals, melting point 144-145 ° C Is shown.

IR (KB r) oi ¹ : 3 3 6 0, 1 7 9 0, 1 6 8 0, 1 5 2 0,

 1 3 5 0 ο

NMR (d ₆ -DMSO) <5: l.37 (9H, s, 3xCH ₃ ), 3.43 (l H d .d, J = 3 & 4.5 Hz, C ₄ -H), 3.78 (lH, t, J = 4.5 Hz,

_{C 4 - H), 4.3-4.6 (} lH, m, C 3 -. H), 4.69 (2 H, s, OCH 2 COO), 5.33 (2H s, COOCH 2), 7. 5 (1 H, d _{, J = 9Hz, C 3 -NH} ), 7.65 (2 H, d, J = 9Hz, aromatic protons), 8.22 (2ϋ d, J = 9Hz, aromatic pro tons).

Elementary analysis: ₇ as H ₂₁ N ₃ 0 ₈

 c m H N

 Calculated 51.64 5.35 10.63

 Measured 51.82, 5.18 10.58

 [Na] is 4 1 1 4.0 ° (c = 1, MeOH).

Example 12

 In Example 1, N- (t-butoxycarbonyl) -10-

OMPI Norehonir! (Threonine-1) N— (412 Trobenzinoleoxycanolevonyl methoxy) In place of the amide, N— (t-butoxycarbonyl) -1 0—metanesulfoninole 1—L-arosleonine 1 N— ( (12S) and (3S, 4R) —3-((t-butoxycarbonylamino))-1-methyl-1- (4,2-toro) Benzoxycarbonylmethoxy) -1-azetidinone was obtained in a yield of 75.2%, and showed a melting point of 156 ° -158 ° C.

IR CKB r) ^ ¹ : 3340, 1 785, 1 765, 1 6 90,

 1 5 2 5, 1 3 5 0., 1 2 1 0.

NMR (d ₆ -DMSO) δ: ll 2 (3H, d, J = 6 Hz, C ₄ -CH ₃ ),

1.37 (9H, s, 3 CH ₃ ), 3.95—4.3 (1 H, m, C 4-H),

4.65 (IE d, J = 5 & 9 Hz, C ₃ -H), 4.68 (2 s, OC¾COO), 5.34 (2H, s, COOCH2), 7.54 (lH, d, J = 9 Hz, C ₃ -NH), 7.66 (2H, d, J = 9Hz, aromatic proton), 8.22 (2¾d, J == 9H¾ aromatic proton).

[A] _D 25 +53.3. (c = 0.4, Me0H) _o

Example 13

 (3 S)-3-[2-(2-aminothiazole-4-inole) 1-(Z) 1-2-(1-carboxy 1-1-methyru-toximino) acetamide] 1-1-1-1-carboxy Synthesis of 1-methylethoxy) 1-2-azetidinondinatridium salt.

a) (3S) —3- (t-butoxycarbonylamino) -111 obtained in Example 10 [1-methyl-1— (412-tohopenh benzyloxycarbonyl) ethoxy] By reacting 1,2-azetidinone 1.309 in the same manner as in Example 56), (3S) -3- (2-chloroacetamide) was obtained. Thiazolyl 4-inole) 1 (Z) 2-[1-methyl-1 1- (4-to-2 benzyloxycarbonyl) ethoxymino] acetamido} 1 1-1-methyl-1- 1- (412-nitrobenzyloxycarbonyl) ethoxy] -12-azetidinone is obtained as a colorless foam, 1.45 (59.6%).

IR CKB r) ^ ¹ : 3 3 3 0 (br), 1 7 9 0, 1 7 5 0, 1 6 9 0,

1 5 2 5, 1 3 5 0, 1 1 5 0 _o

 NMR (d6-DMSO): 1.3 to: 1.7 (12H, m, 4XCH3),

3.4~3.6 (lH, n¾ C ₄ one H), 3.75-3.95 (1 H, m, C -H),

4.33 (2K s, C 1 CH 2), 4.75 ~ 5.05 (lH, m, C ₃ — H),

5.30 (4 H, s, 2xCOOCH ₂ ), 7.36 (1 H, s, thiazolo-5-H), 7.58 (2H, d, J = 9 Hz, aromatic proton), 7.63 (2H, d, J = 9 Hz) , Aromatic protons :), 8.05 (2¾d, J = 9Hz, aromatic protons),

 8.20 (2H, d, J = 9 Hz, ¾ ^ proton), 9.80 (lH, d, J = 9Hz, C3-NH), 12.87 (lH, br. S, thiazo-lu2_NH).

 b) The product of a) above 1.2 3? Was reacted in the same manner as in Example 5 c) to give (3S) -3- (2- (2-aminothiazol-4-ynole)-(Z) -2-1-methyl-1- ( 4-nitrobenzoyloxycarbonyl) ethoxymino] acetamide} —1-1-methyl-1- (4-nitrobenzyloxycarbonyl) ethoxy] 1-2—azetidinone or 'yellow' 0.9 1 39 (82.0) is obtained as a colored foam.

IR CKB r) ^ ¹ : 3 3 8 0 (br), 1 7 8 5, 1 7 4 0, 1 6 8 0,

 1 5 3 5, 1 2 5 0ο

NMR (d 6 -DMSO) δ: 1.35 ~ 1.65 (12 H, m, 4xCH 3), 3.3~3.6 (lH, m, C 4 one H), 3.73 C 1 H, t, J = 5Hz, C 4 one H), 4.75 ~ 5.05 (1¾ m, C ₃ —H), 5.32 (4 H, s, 2 xCOOCH ₂ ), 6.70 (1 H, s, thiazole one 5- H), 7.27 (2H, br. S, Chiazoru _{2- NH 2), 7.62 (2H} , d, J = 9 Hz, aromatic pro tons), 7.65 (2 d , J = 9 Hz aromatic proton), 8.12 (2H, d, J = 9 Hz, aromatic proton), 8.22 (2H, d, J = 9 Hz, aromatic proton), 9.06 (lH, d, J = 8Hz, C ₃ -NH) ₀

 c) By reacting the product 460 of b) above in the same manner as in Example 5 d), 244 of the title compound is obtained as a pale yellow powder.

IR (KBr) β * ¹ : 1770, 1660 (sh), l595 (br),

 1530, 1110, 1370.

NMR (d 6-DMSO) 8: 1.25 (3H, s, CH ₃ ), 1.34 (3H, s, CH ₃ ), 1.40 (3H, s, CH ₃ ), 1.45 (3H, s, CH ₃ ), 3.5 ~ 3.7 (lH, m, C ₄ -H), 3.7 ~ 3.95 (1 H, m, C -H), 4.75 ~ 5.0 5 (lH m, C ₃ -H), 6.76 (lH, s, thiazole-5- H), 7.14 (2H, br, s, thiazole-2 — NH ₂ ), 1 1.47 (lE d, J = 9 Hz, C ₃ — NH) ₀

N— (t-butoxycanolebonyl) 1: L-threonine dicyclohexynoleamine salt 4.09 (10 mimol) is suspended in ethyl acetate 100, and 0.2 N sulfuric acid 50 under ice-cooling) ^ Add little by little. Separate the ethyl acetate layer, and extract the aqueous layer four times with ethyl acetate. The ethyl ethyl acetate layers are combined, washed with a small amount (washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and tetrahydrofuran 501-hydroxybenzotriazole is added to the residue. 0— (4-2—Ventinoleoxycanoleboninolemethinole) Hydroxylamine (prepared by the method described in JP-A-57-131758) 3.3 99 Then stir under ice cooling to dicyclo Add xycarbodimid 2.2 79. After stirring the reaction solution at room temperature for 16 hours, the insoluble material is removed, and the solution is concentrated under reduced pressure. The residue Karamukuro chromatograph I - (silica dim 1 80 5>: acetate Echiru one CHC 1 _3, 1: 1, then 3: 2) to furnish, N- (t - butoxycarbonyl) -L - threonine one N- (4 twelve collected by filtration benzyl O alkoxycarbonyl main butoxy) § Mi de colorless foam and L on ³ .7 1 9 (8 ^6.9%) is obtained.

IRC KB r) ^ ¹ : 3380, 1750, 1680, 1525,

1 3 5 0 _o

NMR (d ₆ -SO) 5: 1.01 (3H, d, J = 6Hz, CH ₃ ),

1.37 (9H, s, 3 xCH ₃ ), 3.6 ~ 4.0 (2H, m, 2xCH), 4.56

(2H, s, OCH ₂ COO), 4.76 C 1 H, d, J = 5 Hz, OH), 5.33

C2H, s, COOCH ₂ ), 6,26 (lH, d, J = sHz, BocNH), 7.56 (2H, d, J = 9 Hz, aromatic proton :), 8.22 2H, d, J = 9 Hz, aromatic proton). Reference example 2

Ν-(t-butoxycarbonyl) -l-threonine-1] NT- (4-nitrate benzyloxycarbonylmethoxy) amide 3.409 (7.96 mimol) pyridine 1 Dissolve in 5 ul and add methanesulfonyl chloride 0.80 W at −20 ° C under a nitrogen stream. After stirring for 6 hours under ice-cooling, add ethyl acetate to the reaction mixture and adjust to pH 2 with 3N hydrochloric acid. The ethyl acetate layer is separated, washed successively with a saline solution, an aqueous sodium hydrogen carbonate solution and a saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, ether was added to the residue, and the resulting colorless powder was taken out and washed with ether to give N- (t-butoxycanolefone ') 2-O-metanesulfone. L-threonine-N— (4-2-Trobenziloxycarbonylmethoxy) amide 3.16? C 7 8.5 ¾) obtained. Melting point 5 3— 5 6PC ₀

 I R (KB r) ca: 3360, 2990, 1760, 1700 (br.),

1 6 7 0, 1 5 2 5, 1 3 5 0, 1 1 7 0 _o

NMR (d 6 -DMSO) δ: 1.27 (3H, d, J = 6Hz, CH 3), 1.37 (9H, s, 3XCH 3), 3.08 (3H, s, S0 2 CH 3), 4.0~4.3 (lm , CHNH), 4.58, (2E s, OCH ₂ COO), 4.7-4.9 (lH, m, CHOH), 5.31 (2H, s, COOCH ₂ ), 6.91 (lE d, J = 8Hz, BocNH), 7.65 ( 2H, d, J = 9 Hz, aromatic protons), 8.22 (2H, d, J = 9 Hz, aromatic protons), 1 1.70 ClH, br. S, CONHO) ₀ Reference example 3

Dissolve N- (t-butoxycarbonyl) -1 0-benzyl-L-serine 2.959 (10 mi mori) in MeOH 20 and add 5 palladium carbon 0.69, and add 1.5 p at room temperature under hydrogen atmosphere at room temperature. Stir for hours. The catalyst is removed, the filtrate is concentrated under reduced pressure, and the residue is dissolved in a mixture of 50% tetrahydrofuran and 100 W of water. 0— (412 trobenzyloxycarbonyl methinolate) Hydroxylamin 2.7 Add 19 and adjust to PH4, then 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride Add an aqueous solution of salt 2.30 and stir at room temperature for 2 hours while adjusting the pH to 4-4.5. The reaction solution is extracted with ethyl acetate, and the extract is washed with 1N citric acid, water, an aqueous solution of sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and a mixed solution of ethyl acetate and hexane (2: 1 :) is added to the residue to obtain a colorless powder. The concentrate is concentrated under reduced pressure, and the residue is purified by column chromatography (silica gel 200: ethyl acetate-CHC 1a, 2: 1), and the resulting powder is combined with the powder obtained earlier. And washed with ether, N- (t-butoxycarbonyl) -l-cell -J (412 benzyloxycarbonyl methoxy) amidoka 1.

 78 5 (4 3.2%) obtained.

Melting point 1 2 1— 1 2 fC ₀

IR (KB r) cw ¹ : 3 3 1 0, 1 75 0, 1 6 7 0, 1 5 3 0,

 1 3 5 0 o

NMR (d 6 -DMSO) δ: 1.37 (9H, s, 3 CH ₃ ), 3.35 to 3.61 (2H, m, CH ₂ OH), 3.7 to 4.05 (lH, m, CH), 4.54 (2¾ s,

OCH ₂ COO), 4.82 (lH, t, J = 6 Hz, OH), 5.32 (2H, s,

 COOCH2), 6.58 (iH, d, J = 8Hz, BocNH), 7.64 (2H, d, J = 9Hz, aromatic proton), 8.22 (2E d, J = 9Hz, good | ¾ proton),

 1 1.29 (IEbr.s, CONHO).

Elementary analysis: as ₇ N ₂₃ N ₃ 0 ₉

 c H (¾) N m

 Calculated 49.39 5.61 10.16

 Actual 49.22 5.54 10.10

Reference example 4

 Dissolve N- (t-butoxycanoleboninole) -L-serine-N- (4-nitrobenzoyloxycarbonylmethoxy) amide 5.9 999 (14.5 mimol) in pyridine 4, Under a nitrogen stream at a temperature of 20 to 130 ° C

Hoyrk mouth ride 1.6 8 W is dripped. The temperature of the reaction solution gradually rises, reaches 0 ° C after 30 minutes, and is stirred for 1 hour under ice cooling. Add 300 mL of phosphoric acid and adjust the pH to 2 to 2.5 with 3 N hydrochloric acid. The ethyl acetate layer was separated, washed with saline, aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate.

Dry with a steam. The solvent is distilled off under reduced pressure, and the residue is allowed to stand at room temperature.ェ Add acetic acid 2 and ether 25 dew and remove

O PI And N- (t-butoxycarbonyl) -1-0-methansulfonyl L-serine-1- (4-2-benzyloxycarbonyloxycarbonyl) amide was obtained as colorless crystals in 2.059 (28.9%) as colorless crystals. . The mother liquor is concentrated under reduced pressure, and the residue is purified by force chromatography (silica gel 100: 9: ethyl acetate, monochloroform, 3: 2, then 2: 1 :) to obtain a solid. The product was washed with a mixture of ethyl acetate and hexane (1: 1) to give 2.29 to the above crystals. Total yield 4.9 79 (6 9.8%).

Melting point 10 2-1 0 4 ° C ₀

IR (KBr) i ¹ : 3 3 5 0, 3 2 8 0-, 1 7 7 0, 1 6 8 0,

1 5 1 5, 1 3 6 0, 1 1 8 5 ₀

_{NMR (d 6 -DMSO): 1.39} (9H, s, 3XCH3), 3.13 (3E s, CH 3 S0 2), 4.1- 4.4 (3H, m, CHCH 2 S0 2), 4.56 (2H, s, OCH 2 COO), 5.32 (2H, s , COOCH 2), 7.0~7.25 (1 H, m, CHNH), 7.64 (2H, d, J = 9Hz, aromatic protons), 8.21 (2H 'd,

JT = 9Hz, aromatic proton), 11.64 (lH, br CONHO),

 Elemental analysis: S 18 ίί25 3 On S

 c H (¾) N

 Calculated 3.99 5.13 8.55

 Measured 44.11 5.19 8.51

_D 24-i 5.f (c = o.9, Me0H) _o

Reference example 5

Dissolve (2R, 3R) -epoxyconodic acid getyl ester 1 3.19 (69.7 mimol) in ethanol 5 and stir the mixture under ice-cooling to give a hydroxylation power of 3.94 in ethanol. The solution dissolved in 120 * is dropped. After stirring for 3 hours under ice cooling, ethanol is distilled off under reduced pressure. Add 50 W »and ether 100 W to dissolve and separate the aqueous layer. The ether layer is extracted three times with diluted saline, and the combined aqueous layers are acidified with 3N hydrochloric acid. After the salt is saturated, the mixture is extracted four times with ethyl acetate. The extract is washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure. As a result, (23R) -epoxysuccinic acid monoethyl ester was found to have a boiling point.

 4.7 69 (42.7) as a colorless oil at 1 2 1-1 2 2 ° C (0.85 »* Hg)

 )can get. The product crystallizes on standing and recrystallizes from isopropyl ether monolithic oil ether (1: 2) to give colorless crystals.

Melting point 5 5— 5 6 ° C ₀

 -1

R rKB r) ca ¹ : 3420 (br.) 74 0 (br.),

1 3 8 0, 1 3 1 0, 1 2 1 0 _o

NMR (CDC 13) 5: 1.33 (3H, t, J = 7 Hz; CH ₃ ), 3.72

(2H, s, 2 x CH), 4.28 (2H, q, J = 7 Hz, CH ₂ ), 1 0.63

 (lH, s, COOH).

As Elemental analysis C ₆ H ₈ 0 ₅

 c (¾) H

 Calculated value 45.01 5.04

 Found 44.81 5.12

[N] _D 23-l 19.0. (C = 0.985, ethanol).

Reference example 6

 Dissolve (2R, 3R) monoethyl succinate monoethyl ester 3.29 (20 millimoles) in concentrated ammonia water 60W to give 45—50. Stir with C for 2-3 hours. The reaction mixture is concentrated under reduced pressure, and the remaining solid is recrystallized from water to give 2.129 colorless crystals. 2.0 9 of these are water ethanol

Recrystallized to form L-Eli Slow ³ —Hydroxysparagine colorless

W1PO 1.99 (68%) are obtained as crystals. This product does not show a definite melting point IR (KB r) oi ¹ : 3 86 0, 3 18 0, 16 9 0, 1 6 7 0,

1 5 1 0, 1 4 0 5, 2 9 0, 1 1 7 0 Elemental analysis value C ₄ H ₈ N ₂ O ₄

 c N

 Calculated 32.44 5.44 18.91

 Actual 32.39 5.50 19.11

 a i) 23+ 6.f (c = 0.54, water).

Reference Example 7-L-erythro-slow 3—Hydroxyasno ヽ⁰ Lagin 7 40 W (5 mmol) was suspended in a mixture of dioxane and water (1: 1) 15 ^, and triethylamine 1.4! ^ And bicarbonate were suspended. Add di-t-butyl 1.749 and stir at room temperature for 3 hours. Add 25 W of ethyl acetate and 12 W of water to the reaction mixture and shake. Separate the aqueous layer and extract the organic layer with saline. The aqueous layers are combined, adjusted to ρΗ1.5-2.0 with an aqueous solution of potassium hydrogen sulfate under ice-cooling, and dissolved until the salt is saturated. Then, the mixture is mixed with ethyl acetate and tetrahydrofuran (2: 1) four times with vinegar. Extract twice with acid ethyl only. The extract is washed with saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, ether 3 was added to the residue, the mixture was allowed to cool overnight, and then passed through the furnace, whereupon L-erythritol—N— (t-butoxycarbonyl) -13-hydroxysparagine was formed. 1.049 (84¾) obtained.

 Melting point 1 2 1-1 2 4 ° C (decomposition).

IR (KB r) ii ¹ : 3400, 3300 (br.), 1 720,

 1 6 7 5, 1 6 0 0, 1 5 2 0 ο

NMR (d ₆ -DMSO) δ: 1.39 (9¾ s, 3 x CH ₃ ), 4.07 (lH, d, J = 3Hz, CHOH) , 4.42 (lH, d. d, J = 3 & 9Hz, CHNH), 6.23 (1 H. J = 9Hz, OHNH), 6.95~7.45 (2H, CONH 2). Elemental value: as C ₉ Hi 6 N ₂ 0 ₆ · ½Η ₂ Ο

 c H N Calculated 42.77 6.53 1 1.09

 Measured 42.82 6.63 10.85

[A] _D 24 + 27.5. (C = 0.9, water).

 Reference Example 8

 Dissolve L-erythro N- (t-butoxycarbonyl) -13-hydroxyhydroxysparagine 1.24 (5 mimol) and sodium bicarbonate 63 W in water 50 W. Next, after adding 0-benzylhydroxylamin hydrochloride 1.2 ^, the reaction solution is adjusted to pH4. To this is added an aqueous solution of 1.059- 3- (3-dimethylaminopropyl) carbodiimide hydrochloride 1.059 dissolved in 5 nt of water, and the mixture is stirred at room temperature for 3 hours while maintaining the pH at 4-5. The reaction solution is saturated with sodium chloride, and extracted with a mixture of ethyl acetate and tetrahydrofuran (4: 1). Wash the extract sequentially with 1N citrate, 3% aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, the residue crystallizes. When this was recrystallized from ethyl acetate, L-erythro-benzyloxy-N- (t-butoxycarbonyl) -13-hydroxyspartate diamide was converted into colorless crystals as 888.8 m (50.3%). can get.

 Melting point 1 4 6—1 4 8 ° C.

IR (KBr) ca ¹ : 3 3 1 0, 3 2 2 0, 1 6 9 0, 1 6 7 0,

1 5 3 0 _o

NMR (d 6-DMSO) 5: 1.37 (9H, s, 3xCH ₃ ), 3.85-4.25 (2H, 2XCH), 4.77 ( 2H, s, OCH 2), 5.4-5.7 (lH, OH), 6.2- 6.55 (1¾ CONH), 7.05~7.30 (2ϋ CONH 2), 7.39 C 5E s, Ph), 10.8-11.3 (IE C0NH) _o

Reference Example 9

 L-eryth-one i-benzyloxy N- (t-butoxycarbonyl)

-. 3 arsenide Dorokishia Nono ⁰ dissolved Ragin acid Jiami de 2.1 2 9 (6 Mi Rimoru) to pin lysine 3 0 is added dropwise under one 2 (f C outcome data Nsuruhoniru Kurorai de 0.6 W argon atmosphere one Stir at 20 ° C for 30 minutes, then at 3 ° C for 20 hours, add a mixture of ethyl acetate and tetrahydrofuran (1: 1) under ice-cooling, and adjust the aqueous layer to pH 2 with 6N hydrochloric acid. After shaking well, the organics are separated off, the aqueous layer is re-extracted with ethyl acetate, the combined organic layers are washed with brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. When ether was added to the mixture and the mixture was filtered, L-erythro-N-benzyloxy-N- (t-butoxycarbonyl) -13-methanesulfoninoleoxyxaspartate diamide was converted to colorless crystals as 1.84 9 (7 1.2%) obtained et al l Ru _σ

 Melting point 1 38—140 ° C (decomposition).

IR (KB r) <¾ ¹ : 3 3 1 0, 3 2 3 0 (sh), 1 6 9 0, 1 6 7 0,

1 5 3 0, 1 3 7 0, 1 1 8 0 _o

_{NMR (d 6 -DMSO) δ:} 1.40 (9H, s, 3 xCH 3), 3.13 (3H, s, S0 2 CH 3), 4.2-4.5 (lH, CHNH), 4.80 (2ϋ s, OCH 2), 4.98 (lH, d, J = 7.5Hz, CHOS0 2), 6.45~6.75 (1 H.CONH), 7.2-7.7 (7H, Ph & CONH 2), 11.58 (lH, b r. s, CONH). Elemental analysis value C ₁₇ H ₂₅ N ₃ 0 ₈ S

ca N Calculated 47.32 5.84 9.74

 Obtained 47.59 5.97 9.75

a ^ _{D25 + 1 3 (c = 0985)} DMSO).

 Reference Example 10

The L- Ellis port one Benjiruokishi N-(t-butoxycarbonyl) Single 3-methane-sulfonyl O carboxymethyl § scan Nono ⁰ sweat Ragin acid di § Mi de 3.2 4 (7.5 millimeter mol) tons 7 5 0 W Dissolve and add carbon dioxide rim 3.1 19 under argon atmosphere. Stir for 20 minutes while gradually increasing the temperature, 5

 When the temperature reaches 0 ° C, stir for another 35 minutes at the same temperature. After cooling, the reaction solution is filtered and washed with heated tetrahydrofuran 400. Combine the solution and washing solution and concentrate under reduced pressure. Add a mixture of tetrahydrofuran and ethyl acetate (1: 1) and water to the residue, dissolve and shake well. The organic layer is separated and the aqueous layer is extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic layers are combined, washed sequentially with brine, aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. When ether was added to the residue and the mixture was filtered, (3 S, 4 S) — 1—benzyloxy 3 —

 (t-butoxy canole; i <ninole amino) 2.39 (91.5%) of colorless crystals are obtained as colorless crystals.

 Melting point 2 32-2 35 ° C (decomposition)

IR (KB r) ^ ¹ : 3 3 3 0, 3 1 7 0, 1 7 9 5, 1 7 0 0,

 1 6 6 5, 1 5 3 0 ο

NMR (d 6 -DMSO) δ: 1.37 (9H, s, 3 x CH ₃ , 4.47 (lH, d, J = 5 Hz, C ₄ — H), 4.92 (lH, d. D, J = 5 & 9 Hz, C ₃ -H), 4.99 (2H, s, OCH ₂ ), 6.95 (1 H, d, J = 9 Hz, C ₃ — NH),

7.40 (5H, s, aromatic protons), 7.46 (2H, b r . S, CONH 2)

f O PI Elemental analysis value C ₁₆ H _{21 3} 0 ₅

 c H (¾) N m

 Calculated 57.30 6.31 12.53

 Observed 57.40 6.42 12.51

_{[A] D} 23 + 31.3. (c = 0.45, DMS0) _o

Reference Example 11

 (3S, 4S) -Benzyloxy 3- (t-butoxycarboxamide) -14-Lubamoy sole 2-azetidinone 67 1 ^ (2 millimoles) was suspended in MeOH 40; Add 0% paradium carbon 140 W and stir at room temperature for 25 minutes in a hydrogen atmosphere. The catalyst is removed, the filtrate is concentrated under reduced pressure and ether is added to the residue. The resulting precipitate is collected to give (3S, 4S) -3- (t-butoxycarbonylamino) -14-carbamoinole-1-hydroxy-12-azetidinone (435f, 85.6%). The product does not show a clear melting point, changes color at around 130 ° C, and decomposes at around 156 ° C.

IR CKB r) ^ ¹ : 3 3 3 0, 3 1 9 0, 1 7 8 0, 1 6 9 0,

 1 6 6 5, 1 5 2 5, 1 1 6 5.

NMR (d ₆ -DMSO) 5: 1.37 OH s, 3xCH ₃ ), 4.32 (1¾ d, J = 5 Hz, C ₄ -H), 4.88 (lH, d.d, J-5 & 9 Hz, C ₃ — H ), 6.90 (lH, d, J = 9Hz, C 3 -NH) 0

As elemental圻値 _{C 9 His N 3 0 5 ·} ½Η 2 0

 c HC¾) N>

 Calculated 42.52 6.34 16.53

 Found 42.79 6.46 16.34

α Ίτ) 25 + 18.5 ° C (c

Reference Example 12

 L-Erythro N- (t-butoxycarbonyl) -1 3-hydroxyhydroxy. Lagin 1.999 (8 mimol), 0— (412-Trobenzyloxycarbonylmethyl) hydroxylamin 2.359 and 1-Hydroxybenzotriazole 1.359 to tetrahydrofuran 4 8 and add dicyclohexylcarbodiimide 1.8 29 while stirring under ice-cooling. After stirring at room temperature for 19 hours, insoluble materials are separated and washed with ethyl acetate. The furnace and washing liquids are concentrated under reduced pressure, and the residue is dissolved in a mixture of ethyl acetate and tetrahydrofuran (4: 1), and washed successively with aqueous sodium hydrogen carbonate, saline, dilute hydrochloric acid and saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and ethyl acetate 40 and hexane 20 W are added to the residue to obtain a powder. After washing with a mixture of ethyl acetate and hexane (2: 1) and ether, L-erythritol Γ ^ — (4-nitrobenzyloxycarbonyl methoxy) mono- (t-butoxy) There are obtained 2.1 49 (58.6%) of carbonyl) 1-hydroxyhydroxyparagine.

 Melting point 140-142 ° C.

IR (KBr) cai ¹ : 3 3 6 0, 1 7 5 0, 1 6 7 0, 1 5 2 5,

1 3 5 0 _o

NMR (d 6-DMSO) δ: 1.37 (9¾ s, 3 x CH ₃ ), 3.9—4.25 (2H, m, C ₂ — H & C ₃ — H), 4.53 (2 H, s, OCH ₂ COO), 5.33 (2H, s, COOCH ₂ ), 6.45 (lH, d, J-9Hz, C ₂ NH), 7.0 to 7.35 (2H, m, CONH ₂ ), 7.66 (2H, d, J = 9 Hz, Homura Proto ^ , 8.22 (2H, d, J = 9 Hz, H «proton), 1 1.12 (lH, br.,

CONHO).

Reference Example 13

ΟΜΡΙ What

 L-erythro N- (4-nitrobenzyloxycarbonyl methoxy) 1-N- (t-butoxycarbonyl) 1-3-hydroxyl. Dissolve largine 1.1 49 (2.5 mimol) in pyridine 10 W and add methanesulfonyl chloride 0.25 »at 120 ° C. Stir under ice-cooling for 14 hours, add a mixture of ethyl acetate and tetrahydrofuran (3: 1), and adjust to pH 2-2.5 with 3N hydrochloric acid. Separate the organic layer. Eat i ^, wash with aqueous sodium bicarbonate and brine, and dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with cooled ethyl acetate and ether to give L-erythro- (4-nitrobenzyloxycarbonylcarbonyl) -1-N- (t-butoxycarbonyl) 13-Methanesulfonyloxyaspartic acid diamide is obtained as colorless crystals (965) (72.2%).

 Melting point 1 56-1 57 ° C (decomposition)

IR (KBr) oi ¹ : 3 4 4 0 _J 3 3 2 0, 1 7 5 0, 1 6 9 5,

1 6 70, 1 5 2 5, 1 3 70, 1 3 5 5 ₀

NMR (d 6- DMSO) 3: 1.37 (9H, s, 3xCH 3), 3.13 (3H, s, CH 3 S0 2), 4.2- 4.6 (lR m, C 2 -H), 4.56 (2H, s, _{OCH 2 COO), 4.92 (lH} , d, J two _{7Hz, C 3 -H), 5.32} (2H, s, COOCH 2), 6.66 (lH, d, J -8Hz, C 2 -NH), 7.35-7.65 _{(2 H 5 m, CONH 2} ), 7.65 (2H, d, J - 9 H z, aromatic protons),

 8.22 (2H, d, J2 9Hz, proton H 碰), 11.78 (1br · s, CONHO).

Reference Example 14

(2R, 3R) monoepoxysuccinic acid 7 B.29 Add concentrated ammonia water 1.2 little by little under ice-cooling. Reduce after stirring at 45-47 ° C for 48 hours Concentrate under reduced pressure, add water 200 to the residue and concentrate again under reduced pressure. Dissolve the residue in water 120) ^, add activated carbon 1.29 and filter. Add 50 W of concentrated hydrochloric acid to the furnace liquid under cooling with ice water, and leave to cool overnight. The precipitated crystals are collected and washed with cold water 6 to obtain L-erythro- 3 -hydroxyspartic acid as colorless crystals.

IR (Nu jol) cj » ¹ : 3460, 3210, 1690.

Elemental analysis: as C ₄ Η _τ N0 ₅

 c <H N

 Calculated value 32.22 4.73 9.40

 Actual 32.02 4.84 9.54

 [Na] is 4.5 + 55.6 ° (c = 0.9, lN).

Reference Example 15

Email the L- collar Ro one 3- arsenide Dorokishiasunoヽ⁰ Ragin acid 2 9.8 Tano Ichiru

Suspend the suspension in 300 W, add 20 W of concentrated hydrochloric acid, and heat to reflux for 8 hours. The solvent is distilled off under reduced pressure, methanol is added to the residue, and the solvent is distilled off again. Dissolve the solidified residue in a mixture of water 60 »and ethanol 60 W, add pyridine 1 5.89 under ice-water cooling, shake well, and leave to cool overnight. Precipitated crystals

The precipitate was washed with 50% ethanol and then with ethanol to give 23.85> (73%) of L-erythro ₃ -hydroxyaspartic acid -methyl ester as colorless crystals. Can be The product contains some unreacted raw materials according to the bed layer chromatography. When recrystallized from 50% ethanol, a pure product is obtained as colorless crystals having a melting point of 2226-229 * C (decomposition).

IR (Nu jol) m: 3 17 5, 17 70, 17 55, 16 20 _o Elemental analysis: as C ₅ H ₉ N 0 ₅

 nm N

OMPI Calculated value 3 6.81 5.56 8.59

 Measured 36.57 5.65 8.54

[ _D 25 + 64.4. (c = l, IN fiber) ₀

Reference Example 16

 L—Eris mouth 1 3—Hydroxyasno ヽ. Laginic acid-Metilester 6.

Add 52 9 (40 millimo) to concentrated aqueous ammonia 20 », stir at room temperature for 8 hours, and concentrate under reduced pressure. Water is added to the residue, and the mixture is concentrated again. Water 80 * and ethanol 80 are added to the residue, and the mixture is heated, shaken well, and left to cool. The crystals were collected and washed with cooled 5.0 ethanol 80 to give L-erythro-3-hydroxyhydroxyparagine 4.79 (79%), which was obtained in Reference Example 5. The IR spectrum matches what is obtained.

 [Is 4 +46.3. (C-0.5, TR).

Reference Example 17

Suspend 3.579 (30 mimol) of L-alanothreonin in a mixture of dioxane 1 &) ^ and water 18 and add triethylamine 5.04β under ice-water cooling. Then adding bicarbonate di t one-butyl 7.8 5 ⁹ Ru stirred at room temperature for 3 hours. Add bicarbonate g-tert-butyl 1.9 69 and stir for an additional 14 hours. Add 80 W of ethyl acetate and 4 O aZ of water to the reaction mixture, shake well, and separate the aqueous layer. The organic layer is extracted with saline (20) ^. Combine the aqueous layers, wash with 40 W of ethyl acetate, and adjust the pH to 2.0 to 2.5 by adding a 10% aqueous solution of potassium hydrogen sulfate under ice-cooling. After salting out with sodium chloride, extract four times with 80 * each of ethyl acetate. The extracts are combined, washed twice with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in 150 nl of tetrahydrofuran, and 1-hydroxybenzotriazole 5.059 and 0- (4-to-open-hole benzyloxycarbonyl) were dissolved. Methyl) Hydroxinoreamin 8 4 And then add 6.8 1 of dicyclohexylcarbodimid while stirring under ice-cooling. After stirring the reaction solution at room temperature for 22 hours, the insoluble material is removed from the furnace, and the concentrated solution is concentrated under reduced pressure. The residue is dissolved in a mixture of ethyl acetate and tetrahydrofuran (4: 1), washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate 80 under heating, hexane 80 is added, and the precipitated powder is collected to obtain a mixed solution of ethyl ethyl hexane and hexane (1: 1). After washing with 200 W, N- (t-butoxycarbonyl) -1-L-aros-leonine-1-N- (412-trobenzylyloxycarbonylmethoxy) amide is obtained at 10.99 (85.1¾). .

 Melting point 1 4 1 — 1 4 3 ° C

IR (KB r) ¹ : 3 3 3 0, 1 7 5 5, 1 6 7 0, 1 5 3 0,

 1 3 5 0.

NMR (d 6-DMSO) δ: 1.04 (3H, d, J = 6 Hz, CH ₃ ),

1.35 (9H, s, 3X CH 3), 3.5~3.9 (2H, m, 2X CH), 4.54 (2H, s, OCH 2 COO), 4.82 (1 H, d, J = 5Hz, OH), 5.32 ( 2¾ s., COOCH ₂ ), 6.5-6.85 (lH, m, C ₃ — NH), 7.63

(2H. D, J = 9 Hz, aromatic proton), 8.19 (2H, d, J = 9 Hz, group proton), 1 1.15 (lH, br. S, C0NH0) _o

[A] _{D 24- 25. ^ (c = 1} , MeOH).

 When this product was reacted with methanesulfonyl chloride in pyridine in the same manner as in Reference Example 2, N- (t-butoxycarbonyl) -1 0-methansulfonyl-1 L-alothreonine-1 N— (4— (2) Benzinoleoxycanolephonyl methoxy) amide is obtained in a yield of 83.0.

Melting point 15 3—15 5 ° C (decomposition). IR (KB r) os: 3 3 3 0, 1 7 5 0, 1 6 9 0, 1 6 7 5,

1 5 3 0, 1 3 5 0 _o

_{NMR (d 6 -DMSO): 1.29} (3H, d, J = 6Hz, CH 3), 1.37 (9H s, 3 xCH 3), 3.95-4.3 (1 H, m, CH), 4.55 (2H, s, OCH ₂ COO), 4.65 to 4.95 (lH, m, CH), 5.31 (2H, s,

COOCH ₂ ), 7.13 (lH, d, J = 9 Hz, Bo cNH), 7.63 (2K d, J-9 Hz, aromatic proton), 8.20 (2H, d, J = 9 Hz, aromatic proton), 1 1.73 (lHbr.s, CONHO).

[ _D 25-12.0 ° (c = 0.5, MeOH).

 Industrial applicability

2-azetidinone derivatives (I) have excellent antibacterial activity and are caused by gram-positive or negative bacteria in humans and mammals, including dogs, cats, cattle, cows, horses, mice, guinea pigs, etc. It is used as a therapeutic agent for infectious diseases, as a preservative for animal feed and industrial water, or as a disinfectant for sanitary appliances, and as a degradant for 3-lactam antibiotics when used in combination with antibiotics. You. Further, the compound in which R ³ is a protected amino group in the derivative (I) can be used as a useful synthetic intermediate of a 2-azetidinone derivative having excellent antibacterial activity.

OMPI

Claims

The scope of the claims

1. In the first position, the formula — 0— C— COOH (where, and and ^ are the same or different

R ^{2 represents} a hydrogen atom, an alkyl, an aryl or an arylalkyl group which may have a substituent] or a group which is acylated or protected at the 3-position. 2-azetidinone derivatives having a good amino group, salts or esters thereof.

 2. Claim 4 having a carboxyl, alkoxycarbonyl, optionally substituted rubamoyl, an optionally substituted aryl or an optionally substituted alkyl group at the 4-position. Compound described in item 1 ¾

R ¹

 3. In the first position, the formula — 0— C— COOH (where R and are the same or different

R ^{2 represents} a hydrogen atom, an alkyl, or an aryl or arylalkyl group which may have a substituent], and a 2-azetidinone derivative having an amino group at the 3-position The salt or ester is subjected to an acylation reaction or

Is characterized by being subjected to a protecting group introduction reaction.

 Λ

 A method for producing a 2-azetidinone derivative, a salt or ester thereof, having a group represented by the formula (wherein the symbols have the same meanings as described above) having an amino group protected or protected at position 3 by acylation.

4. A 2-azetidinone derivative or a salt thereof having a hydroxyl group at the 1-position and an optionally amino-protected or protected amino group at the 3-position R ¹

W-C-COOH

 R2

[Wherein, R ¹ and R are the same or different and each represents a hydrogen atom, an alkyl, an aryl or an arylalkyl group which may have a substituent, and W is a halogen atom. Reacts with compounds, their salts or esters

R ¹

In the first place, the formula 1—C—COOH [symbol in the formula

R ² has the same meaning as described above: a method for producing a 2-azetidinone derivative having a group represented by! And an amino group which may be acylated or protected at the 3-position, a salt or an ester thereof.

'' O PI