JPH0425264B2 - - Google Patents

Description

[Detailed description of the invention]

Technical Field The present invention provides novel 4-cyano-4-substituted-2-azetidinone derivatives, which are useful intermediates for the synthesis of optically active derivatives, and some of which have antibacterial activity and β-lactamase inhibitory activity. The present invention relates to a method for producing a 2-azetidinone derivative. Background technology Recently, a new type of β with a sulfo group at the 1st position has been developed.
-Lactam antibiotics have been discovered and reported from nature (Nature, vol. 289, p. 590 (1981), vol. 291, p. 489 (1981)). In addition, the synthesis of analogues has also been reported (for example,
No. 164672, JP-A-56-125362, etc.). In the latter report, 2-azetidinone-1 with a substituent at the 4-position
- Although a method for synthesizing sulfonic acids has been described, the number of reaction steps is long and complicated, and a simple production method is not yet known. DISCLOSURE OF THE INVENTION The present invention provides a novel formula 4-cyano-2-azetidinone derivatives represented by [wherein R ¹ represents an optionally acylated or protected amino group, X represents hydrogen or a methoxy group, and W represents hydrogen or a sulfo group]; and Regarding its manufacturing method. As a result of various studies, the present inventors found that the formula [wherein R ² is an acylated or protected amino group, Y is halogen or the formula -OCOR ³ , -
SCOR ³ or

[Formula] (R ³ is a hydrocarbon group, n is 1 or 2), X and W have the same meanings as above] and a cyano compound in the presence of a phase transfer catalyst 4-cyano-2-azetidinone derivative [] can be obtained by reacting the above and removing the protecting group as necessary, and that the obtained compound [] is suitable for the synthesis of 4-substituted-2-azetidinone derivatives, especially for optical activity. For example, when compound [ ] is subjected to a hydration reaction and protective groups are removed as necessary, the formula 4-carbamoyl-2- [wherein R ⁴ is an optionally acylated or protected amino group, and X and W have the same meanings as above]
It was discovered that azetidinone derivatives could be obtained, and the present invention was completed based on these findings. That is, the present invention provides the production of a 4-cyano-2-azetidinone derivative [], which is characterized by reacting the compound [] with a cyano compound in the presence of a phase transfer catalyst, and removing the protecting group as necessary. It is about law. In the above formula, the acyl group in the acylated amino group represented by R ¹ , R ² and R ⁴ is,
For example, the previously known penicillin derivative 6
An acyl group substituted at the amino group at position, an acyl group substituted at the amino group at position 7 of a cephalosporin derivative, etc. are used. Examples of such acyl groups include formula (1) R ⁵ -CO- [A] [wherein R ⁵ is lower alkyl, phenyl which may have a substituent or unsubstituted]. [indicates an optional heterocyclic group], formula (2) {In the formula, R ⁶ is hydrogen, an amino acid residue that may have a substituent, a protecting group for the amino group, the formula R ⁸ −(CH ₂ ) _n −CO− [In the formula, R ⁸ is an amino group, a heterocyclic group which may have a substituent, a phenyl group which may have a substituent, a lower alkyl group which may have a substituent, m is an integer from 0 to 3, respectively] R ⁷ is hydrogen, lower alkyl which may have a substituent, phenyl which may have a substituent, heterocyclic group which may have a substituent or a substituent. a group represented by the formula (3) R ⁹ −R ¹⁰ −CO− [C] [wherein R ⁹ is the formula

[Formula] {In the formula, R ¹¹ is a heterocyclic group that may have a substituent or a phenyl group that may have a substituent, and R ¹² is hydrogen or a phenyl group that may have a substituent. phenyl, lower acyl, lower alkyl, or a group represented by the formula -R ¹³ -R ¹⁴ (in the formula, R ¹³ represents lower alkylene or lower alkenylene, and R ¹⁴ represents a carboxyl group or an ester thereof), respectively. }, R ¹⁰ is a simple bond or a formula

[Formula] (In the formula, R ¹⁵ represents lower alkyl or a heterocyclic group that may have a substituent.)
A group represented by the formula (4) [In the formula, R ¹⁶ is hydroxyl, carboxyl,
sulfo, formyloxy, halogen or azide group, and R ¹⁷ represents hydrogen, lower alkyl, lower alkoxy, halogen or hydroxyl group, respectively], a group represented by the formula (5) R ¹⁸ −R ¹⁹ −CH ₂ −CO - [E] [In the formula, R ¹⁸ is cyano, phenyl which may have a substituent, phenoxy which may have a substituent, lower alkyl which may have a substituent,
An alkenyl group which may have a substituent or a heterocyclic group which may have a substituent, R ¹⁹ is a simple bond or -S-, respectively] is used. In R ⁵ to ^{R 19} in the above formulas [A] to [E],
Examples of lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl,
Alkyl having 1 to 6 carbon atoms such as isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl is used. Examples of lower alkoxy include methoxy,
Ethoxy, n-propoxy, isopropoxy, n
-butoxy, isobutoxy, sec-butoxy,
tert-butoxy, pentoxy, isopentoxy,
Alkoxy having 1 to 6 carbon atoms such as hexyloxy and isohexyloxy is used. Examples of alkenyl include vinyl, allyl, isopropenyl, 2-methallyl, 2-butenyl, and 3-butenyl. The cycloalkenyl preferably has a 5- to 6-membered ring, such as cyclohexenyl, cyclohexadienyl, and the like. The lower alkylene preferably has 1 to 3 carbon atoms, and examples thereof include methylene, dimethylmethylene, ethylene, methylethylene, and trimethylene. The lower alkenylene preferably has 1 to 3 carbon atoms,
Examples include vinylene and propenylene. Specific examples of halogens include:
Chlorine, bromine, iodine, and fluorine are used. Examples of the heterocyclic group include a 5- to 8-membered ring containing one to several heteroatoms such as a nitrogen atom (which may be oxidized), an oxygen atom, a sulfur atom, or a fused ring thereof, which has a bond to a carbon atom. For example, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thienyl, 2-
or 3-pyrrolidinyl, 2-, 3- or 4-
Pyridyl, N-oxide-2-, 3- or 4-
pyridyl, 2-, 3- or 4-piperidinyl,
2-, 3- or 4-pyranyl, 2-, 3- or 4-thiopyranyl, pyrazinyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5- Isothiazolyl, 3-, 4- or 5-isoxazolyl, 2
-,4- or 5-imidazolyl, imidazolidinyl, 3-,4- or 5-pyrazolyl, pyrazolidinyl, 3- or 4-pyridazinyl, N-oxide-3- or 4-pyridazinyl, 2-,4
- or 5-pyrimidinyl, N-oxide-2
-,4- or 5-pyrimidinyl, piperazinyl, 4- or 5-(1,2,3-thiadiazolyl), 3- or 5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 1 ,2,5
-thiadiazolyl, 4- or 5-(1,2,3
-oxadiazolyl), 3- or 5-(1,2,
4-oxadiazolyl), 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,
2,3- or 1,2,4-triazolyl, 1H
or 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 etc. are frequently used. Examples of amino acid residues include glycyl, alanyl, valyl,
leucyl, isoleucyl, seryl, threonyl,
Cysteinyl, cystyl, methionyl, α- or β-aspartyl, α- or γ-glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, histidyl, tryptopyl, prolyl, etc. are used. As the protecting group for the amino group, those similar to the protecting groups for the amino group described below are used. As a lower acyl group,
Those having 2 to 4 carbon atoms are preferred, such as acetyl, propionyl, butyryl, isobutyryl, and the like. Examples of substituents for lower alkyl which may have a substituent and alkenyl which may have a substituent include phenyl, carbamoyl, methylcarbamoyl, carboxyl,
Cyano, halogen, hydroxyl, etc. are used. Substituents for phenyl which may have a substituent, phenoxy which may have a substituent, and cycloalkenyl which may have a substituent include:
For example, lower alkyl having 1 to 3 carbon atoms, 1 carbon number
-3 lower alkoxy, halogen, amino, benzyloxy, hydroxyl, acyloxy having 2 to 10 carbon atoms, aminomethyl, carbamoylamino methyl, 3-amino-3-carboxypropoxy, etc. are used. Examples of the substituent of the heterocyclic group which may have a substituent include alkyl having 1 to 8 carbon atoms, which may have a substituent, and 1 to 8 carbon atoms, which may have a substituent.
~3 lower alkoxy, hydroxyl, carboxyl, oxo, monochloroacetamide, aldehyde, trifluoromethyl, amino, halogen,
Phenyl which may have the above substituents (e.g. 2,6-dichlorophenyl), coumarin-3-carbonyl, 4-formyl-1-piperazinyl, pyrrolealdoimino, furanaldimino, thiophenaldo Imino, mesyl, mesylamino, a protecting group for amino group, acylamino having 2 to 4 carbon atoms which may be substituted with halogen, etc. are used. As the protecting group for the amino group, those similar to the protecting groups for the amino group described below are used.
Examples of substituents for amino acid residues that may have substituents include amino, protecting groups for amino groups,
Carbamoyl, methylcarbamoyl, benzyl, etc. are used. As the protecting group for the amino group,
The same protecting groups for amino groups as described below are used. Examples of the carboxy ester represented by R ¹⁴ include methyl ester, ethyl ester, propyl ester, t-butyl ester, paranitrobenzyl ester, and 2-trimethylsilylethyl ester. Among the substituents represented by R ⁵ to R ¹⁹ above, an amino group,
If carboxyl or hydroxyl groups are present, they may be protected. As the protecting group for the amino group, for example, the "protecting group for the amino group" mentioned in R ¹ below can be used. As the protecting group for the carboxyl group, all those that can be used as the protecting group for the carboxyl group in the field of β-lactam and organic chemistry can be used, such as methyl, ethyl,
n-propyl, isopropyl, tert-butyl,
tert-amyl, benzyl, P-nitrobenzyl,
P-methoxybenzyl, benzhydryl, phenacyl, phenyl, P-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, pivaloyloxymethyl, β-methylsulfonylethyl, methylthiomethyl, trityl, β, β , β-trichloroethyl, β-iodoethyl, 2-trimethylsilylethyl, trimethylsilyl, dimethylsilyl, acetylmethyl, P-nitrobenzoylmethyl, P-
Mesylbenzoylmethyl, phthalimidomethyl,
Ester residues such as propionyloxymethyl, mesylmethyl, benzenesulfonylmethyl, phenylthiomethyl, dimethylaminoethyl, and silyl groups are used. Among these, β, β, β-trichloroethyl, P-nitrobenzyl, tertiary butyl, 2-trimethylsilylethyl, and P-methoxybenzyl are preferred. As protecting groups for hydroxyl groups, all those that can be used as protecting groups for hydroxyl groups in the field of β-lactams and organic chemistry can be used, such as ester residues such as acetyl, chloroacetyl, β, β, β- Esterified carboxyl groups such as trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, tert-butyl, benzyl, P-nitrobenzyl, trityl, methylthiomethyl, β-
Ether residues such as methoxyethoxymethyl, silyl ether residues such as trimethylsilyl and tert-butyldimethylsilyl, and acetal residues such as 2-tetrahydropyranyl and 4-methoxy-4-tetrahydropyranyl are used. In the present invention, the selection of the protecting group is not particularly limited, as is the case with the protecting groups for amino groups and carboxyl groups. In the above acyl group, the formula R ⁵ -CO-[A]
Specific examples of the acyl group represented by include 3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl-carbonyl. formula

Specific examples of the acyl group represented by [Formula] [B] include, for example, D
-alanyl, D-phenylalanyl, α-benzyl-N-carbobenzoxy-γ-D-glutamyl-D-alanyl, D-phenylglycyl-D-alanyl, N-carbobenzoxy-D-phenylglycyl, D-alanyl-D - phenylglycyl,
γ-D-glutamyl-D-alanyl, N-carbobenzoxy-D-alanyl-D-phenylglycyl, D-carbamoyltryptophyl-D-phenylglycyl, N-[2-amino-3-(N-methylcarbamoyl) propionyl]-D-phenylglycyl, N-carbobenzoxy-D-phenylglycyl-D-phenylglycyl, D-alanyl-D-alanyl, 2-[2-amino-3-(N-methylcarbamoyl)propionamide]acetyl, D -2-(4-ethyl-2,3-dioxo-
1-piperazinocarboxamide)-2-(4-methoxyphenyl)acetyl, D-2-[2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)acetamide]-2-phenyl Enylacetyl, 2-(2-aminothiazol-4-yl)-2
-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)acetyl, D-2-(4-
Ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-thienylacetyl, D-2-
(4-n-dodecyl-2,3-dioxo-1-piperazinocarboxamide)-2-phenylacetyl, D-2-(4,6-dienyl-2,3-dioxo-1-piperazinocarboxamide) )-2-phenylacetyl, D-2-(4-cyclohexyl-2,3-dioxo-1-piperazinocarboxamide)-2-thienylacetyl, D-2-(4-n
-amyl-6(S)-methyl-2,D-3-dioxo-1-piperazinocarboxamide)-2-thienylacetyl, D-2-(4-ethyl-5-methyl-2,3-dioxo- 1-piperazinocarboxamide)-2-thienylacetyl, D-2-(8-
Hydroxy-1,5-naphthyridine-7-carboxamide)-2-phenylacetyl, D-2-(4
-n-octyl-2,3-dioxo-1-piperazinocarboxamide)-2-phenylacetyl,
2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-(4-chlorophenyl)acetyl, α-N-(4-ethyl-2,3-
dioxo-1-piperazinocarbonyl)glutaminyl, D-N-(4-ethyl-2,3-dioxo-1-piperazinocarbonyl)phenylalanyl, D-2-(4-ethyl-2,3-dioxo-
1-piperazinocarboxamide)-2-(4-hydroxyphenyl)acetyl, 2-(4-ethyl-
2,3-Dioxo-1-piperazinocarboxamide)-2-(1-cyclohexen-1-yl)acetyl, D-2-(4-n-octyl-2,3-dioxo-1-piperazinocarboxamide) )-2-
Thienylacetyl, 2-(4-ethyl-2,3-
dioxo-1-piperazinocarboxamide)-2
-(2-methylthiazol-4-yl)acetyl,
2-(4-n-octyl-2,3-dioxo-1
-piperazinocarboxamide)-2-(2-aminothiazol-4-yl)acetyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-furylacetyl, D-2 -(4-
Ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-(2-pyrrolyl)acetyl, D
-2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide)-3-chloropropionyl, D-2-[4-(2-hydroxyethyl)-
2,3-dioxo-1-piperazinocarboxamide]-2-phenylacetyl, D-2-[4-(2
-chloroethyl)-2,3-dioxo-1-piperazinocarboxamide]-2-phenylacetyl,
D-2-[(3-furfurylideneamino-2-oxoimidazolidin-1-yl)carboxamide]
-2-phenylacetyl, D-2-[(3-furfurylideneamino-2-oximidazolidine-1
-yl)carboxamide]-2-(4-hydroxyphenyl)acetyl, D-2-[[2-oxo-3
-(thiophene-2-aldoimino)imidazolidin-1-yl]carboxamide]-2-phenylacetyl, D-2-[(3-furfurylideneamino-2-oxoimidazolidin-1-yl)carboxamide]-2 -Thienylacetyl, D-2-
[(3-Methylsulfonyl-2-oxoimidazolidin-1-yl)carboxamide]-2-phenylacetyl, 2-[(3-furfurylideneamino-
2-oxoimidazolidin-1-yl)carboxamide]-2-(2-aminothiazol-4-yl)acetyl, D-2-[[2-oxo-3-(thiophene-2-aldimino)imidazolidine-
1-yl]carboxamide]-2-thienylacetyl, D-2-(4-hydroxy-6-methylnicotinamide)-2-(4-hydroxyphenyl)
Acetyl, D-2-[5,8-dihydro-2-(4
-formyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxamide]-2-phenylacetyl, D-2-(3,5
-dioxo-1,2,4-triazine-6-carboxamide)-2-(4-hydroxyphenyl)acetyl, D-2-(coumarin-3-carboxamide)-2-phenylacetyl, 2-(4- Ethyl
2,3-dioxo-1-piperazinocarboxamide)-2-(2-chloro-1-cyclohexene-1
-yl)acetyl, 2-(4-hydroxy-7-
Trifluoromethylquinoline-3-carboxamide)-2-phenylacetyl, N-[2-(2-aminothiazol-4-yl)acetyl]-D-phenylglycyl, D-2-[[3-(2,6 -dichlorophenyl)-5-methylisoxazole-4
-yl]carboxamide]-2-thienylacetyl, D-2-(carbamoyl)amino-2-thienylacetyl, N-carbamoyl-D-phenylglycyl, and the like are used. Formula R ⁹ −R ¹⁰ −CO−
Specific examples of the acyl group represented by [C] are:
For example, N[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl]-D-alanyl, 2-(2-chloroacetamidothiazole-
4-yl)-2-methoxyiminoacetyl, 2-
(2-aminothiazol-4-yl)-2-isopropoxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl, 2-(2-aminothiazol-4-yl)- 2
-oxyiminoacetyl, 2-thienyl-2-methoxyiminoacetyl, 2-furyl-2-methoxyiminoacetyl, 2-(4-hydroxyphenyl)-2-methoxyiminoacetyl, 2-phenyl-2-methoxyiminoacetyl ,2-thienyl-2-oxyiminoacetyl,2-thienyl-2
-dichloroacetyloxyiminoacetyl, 2-
[4-(3-amino-3-carboxypropoxy)
Phenyl]-2-oxyiminoacetyl, 2-(5
-chloro-2-aminothiazol-4-yl)-
2-methoxyiminoacetyl, 2-(2-aminothiazol-4-yl)-2-(1-carboxymethoxyimino)acetyl, 2-(2-aminothiazol-4-yl)-2-(1-carboxyethoxy imino)acetyl, 2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetyl, 2-(2-aminothiazol-4-yl)-2-(1- methoxycarbonyl-1-methylethoxyimino)acetyl,
2-(2-aminothiazol-4-yl)-2-
(1-carboxy-1-cyclopropylmethoxyimino)acetyl, 2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-cyclobutylmethoxyimino)acetyl, 2-(2-aminothiazole) -4-yl)-2-(1-carbamoyl-1-methylethoxyimino)acetyl, etc. are used. formula

Specific examples of the acyl group represented by [Formula] [D] include α-sulfophenylacetyl, α-hydroxyphenylacetyl, α-formyloxyphenylacetyl, α-
Carboxyphenylacetyl, 2-bromo-2-
Phenylacetyl, 2-azido-2-phenylacetyl, etc. are used. Formula R ¹⁸ −R ¹⁹ −CH ₂ −
Specific examples of the acyl group represented by CO-[E] include cyanoacetyl, phenylacetyl, phenoxyacetyl, trifluoromethylthioacetyl, cyanomethylthioacetyl, 1H-
Tetrazoyl-1-acetyl, 2-thienylacetyl, 2-(2-aminothiazol-4-yl)
Acetyl, 2-(2-chloroacetamidothiazol-4-yl)acetyl, 4-pyridylthioacetyl, 3,5-dichloro-1,4-dihydro-
4-Oxopyridine-1-acetyl, β-carboxyvinylthioacetyl, 2-(2-N-carbobenzoxyaminomethylphenyl)acetyl, 2
-(2-ureidomethylphenyl)acetyl, etc. are used. As protecting groups for the protected amino groups represented by R ¹ , R ² and R ⁴ , those used for this purpose in the field of β-lactam and peptide synthesis are conveniently employed. For example, phthaloyl, P-nitrobenzoyl, P-tert-butylbenzoyl, P
Aromatic acyl groups such as -tert-butylbenzenesulfonyl, benzenesulfonyl, toluenesulfonyl, etc., such as formyl, acetyl, propionyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, trifluoroacetyl, phenylacetyl, maloyl , aliphatic acyl groups such as succinyl, esterified carboxyl groups such as benzyloxycarbonyl, P-nitrobenzyloxycarbonyl, P-methoxybenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, methoxycarbonyl groups, as well as e.g. trityl , 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene, di- or trialkylsilyl, t-butyldimethylsilyl, t
Protecting groups for amino groups other than acyl groups, such as -butyldiphenylsilyl, benzyl, and P-nitrobenzyl, are used. In the present invention, the selection of the protecting group is not particularly limited as with the carboxy protecting group, but in particular monochloroacetyl, trityl, benzyloxycarbonyl, P-methoxybenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, P -nitrobenzyloxycarbonyl is preferred. Y is halogen or formula -OCOR ³ , -SCOR ³
or

[Formula] (R ³ is a hydrocarbon group, n is 1 or 2). Here, chlorine, fluorine, iodine, and bromine are used as the halogen. Examples of hydrocarbon groups include
In addition to lower alkyl, alkenyl, cycloalkenyl, etc. which may have substituents as mentioned in R ⁵ to ^{R 19} , carbon atoms having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, etc. cycloalkyl groups such as phenyl, tolyl, xylyl, biphenyl, naphthyl, anthryl, phenanthryl, etc., aralkyl groups such as benzyl, phenethyl, phenylpropyl, naphthylmethyl, etc. are used. These cycloalkyl, aryl, and aralkyl groups may have a substituent, and examples of such substituents include the same substituents as the phenyl or phenoxy substituents described for R ⁵ to ^{R 19} . In particular, Y is, for example, lower acyloxy (e.g. acetoxy, propionyloxy, etc.), lower alkylsulfonyl (e.g. methylsulfonyl,
Good results can be obtained when showing ethylsulfonyl, etc.). X represents hydrogen or a methoxy group. W
represents hydrogen or a sulfo group. In the present invention, the compound [] is obtained by reacting the compound [] with a cyano compound in the presence of a phase transfer catalyst, and removing the protecting group as necessary. The compound [] can be used as a free substance or as a salt with various acids or bases, an ester, a silyl derivative (W
=H) can be used as the principle of this reaction. In addition, since the compound [] has substituents at the 3- and 4-positions, cis-trans isomers exist, and since the carbons at the 3- and 4-positions are asymmetric carbons, there are theoretically at least 4 types in total. Stereoisomers exist, and these stereoisomers can be used alone or in mixtures.
The same applies to the case where the group represented by R ² has an asymmetric carbon, and the resulting stereoisomer can be used either singly or as a mixture. The salt of the compound [] has a sulfo group at the 1-position,
When a carboxyl group is present in R ² , non-toxic cations such as sodium and potassium,
Salts with basic amino acids such as arginine, ornithine, lysine, and histidine, and polyhydroxyalkylamines such as N-methylglutamine, diethanolamine, triethanolamine, and trishydroxymethylaminomethane are used. In addition, when R ² contains a basic group, salts with organic acids such as acetic acid, tartaric acid, methanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
Salts with inorganic acids such as phosphoric acid, such as arginine,
Salts with acidic amino acids such as aspartic acid and glutamic acid are used. Furthermore, when R ² contains a carboxyl group, it can be converted into an ester derivative and used. Examples of the ester group in this case include methoxymethyl, ethoxymethyl, isopropoxymethyl, α-methoxyethyl, α- Alkoxymethyl such as ethoxyethyl,
α-alkoxy-α- such as α-alkoxyethyl
Substituted methyl group, alkylthiomethyl group such as methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, acyloxymethyl group such as pivaloyloxymethyl, α-acetoxybutyl, or α-acyloxy-α-substituted methyl group, ethoxycarbonyloxy α-alkoxycarbonate-α-substituted methyl groups such as methyl and α-ethoxycarbonyloxyethyl are used. Compound [] that has been silylated with a silylating agent can also be used as a raw material. Examples of the silylating agent include those of the formula P ¹ , P ² , P ³ , Si, Hal [where P ¹ , P ² , and P ³ are each, for example, lower alkyl having 1 to 4 carbon atoms (for example, methyl, ethyl, n -propyl, i
-propyl, n-butyl, etc.), aryl (e.g. phenyl, tolyl, etc.), Hal represents halogen, preferably chloro, bromo, and one or two of P ¹ , P ² , P ³ One is halogen, preferably chloro, bromine, P ¹ ,
One of P ² and P ³ may be a hydrogen atom]
Compounds represented by the following are used. moreover,
For example, hexaalkyl (C _1-4 ) cyclotrisilazane, octaalkyl (C _1-4 ) cyclotetrasilazane, trialkyl (C _1-4 ) silylacetamide,
Bis-trialkyl (C _1-4 ) silylacetamide and the like are also used as silylating agents. Preferred silylating agents include, for example, the formula [In the formula, Y ¹ and Y ² are lower alkyl,
phenyl, benzyl or lower alkoxy group,
There is a silyl compound represented by the following formula: Y ³ means a t-butyl or isopropyl group, and Y ⁴ means a reactive group that leaves the silylating agent. Examples of lower alkyl groups represented by Y ¹ and Y ² in the silylating agent represented by the above general formula include methyl, chloromethyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc. Examples of alkoxy groups used include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy. In addition, as the reactive group ^Y4 that leaves the silylating agent, in addition to halogen (e.g. chloro, bromine, etc.), examples include N-(trialkylsilyl)trifluoroacetimidoyloxy group; N-(trialkylsilyl)
Acetimidoyloxy group; Acylamino group such as formylamino, acetylamino, propionylamino, butyrylamino, trifluoroacetylamino; (tri-t-butyldimethylsilyl)amino, isopropyldimethylsilylamino, chloromethyldimethylsilyl)amino, etc. (trialkylsilyl)amino group; amino; methylamino,
Alkylamino groups such as ethylamino and propylamino; N,N-dimethylamino, N-chloromethyl-N-methylamino, N,N-diethylamino, N,N-dipropylamino, N-methyl-N
N,N such as -ethylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, etc.
-Dialkylamino group; a heterocyclic group such as imidazoyl is used. The alkyl group in these reactive groups represented by Y ⁴ preferably has 1 to 4 carbon atoms, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl. Specific examples of such silyl compounds include N,O-bis(t-butyldimethylsilyl)
Trifluoroacetamide, N,O-bis(isopropyldimethylsilyl)acetamide, bis(dimethylisopropylsilyl)acetamide,
Isopropyldimethylsilylacetamide, bis(dimethyl tert-butylsilyl)acetamide,
N-methyl-N-t-butyldimethylsilylacetamide, N-methyl-N-isopropyldimethylsilyltrifluoroacetamide, N-t-butyldimethylsilyldiethylamine, 1,3-bis(chloromethyl)-1,1,3 ,3-tetra-
t-Butyldimethyldisilazane, N-isopropyldimethylsilylimidazole, t-butyldiphenylchlorosilane, isopropyldiethyldichlorosilane, isopropylmethyldichlorosilane, tert-butyldimethylchlorosilane, isopropyldimethylchlorosilane, t-butyldiethylchlorosilane, etc. are used. Among these, when tert-butyldimethylchlorosilane, isopropyldimethylchlorosilane, etc. are used, the silyl derivative can be stably isolated. The temperature of the silylation reaction is 0~
It is carried out at a temperature of 50°C, preferably up to 38°C, usually at room temperature (approximately 20°C), and the reaction time is several minutes (approximately 10
minutes) or 24 hours. The reaction can be carried out using, for example, ethyl acetate, dioxane, tetrahydrofuran, N,N
It is convenient to carry out the reaction in a solvent such as -dimethylacetamide, N,N-dimethylformamide, dichloromethane, chloroform, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, a mixed solvent thereof, or any other solvent that does not participate in the reaction. This reaction can also be carried out using inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, trialkylamines such as triethylamine, tributylamine, trialkylamines such as tribenzylamine, N -Methylmorpholine, N-methylpiperidine, N,N-
Organic tertiary amines such as dialkylaniline, N,N-dialkylbenzylamine, pyridine, picoline, lutidine, or 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2, It can be carried out in the presence of an organic base such as 2,2]octane, 1,8-diazabicyclo[5,4,4]undecene-7, and a liquid base can also be used as a solvent. The silyl derivative of the compound [] thus obtained is
The reaction mixture is used as it is or after isolation and purification by known means as described below, as a raw material for the reaction with a cyano compound. In the 1-silyl derivative of the compound [] thus obtained, if the above R ² is a protected amino group, the protecting group is removed and then subjected to an acylation reaction to obtain the desired compound [] 1-
Silyl derivatives can also be produced. This acyl conversion reaction at the 3-position proceeds with good yield and is easy to operate, making it extremely useful for the synthesis of various 2-oxoazetidine derivatives substituted with desired acyl groups. The reaction with the cyano compound can also be carried out continuously. Further, as the cyano compound, for example, a compound represented by the formula Z-CN [wherein Z represents an alkali metal or an alkaline earth metal] can be used. Specifically, for example, potassium cyanide, sodium cyanide, calcium cyanide, etc. can be used. In this reaction, about 1 to 3 mol, preferably 1 to 1.1 mol, of the cyano compound is reacted per 1 mol of the compound []. Usually carried out in a solvent. Solvents used include water or ethers such as dioxane, tetrahydrofuran, and diethyl ether, esters such as ethyl acetate and ethyl formate,
Carbon tetrachloride, chloroform, halogenated hydrocarbons such as dichloromethane, benzene, toluene,
Hydrocarbons such as n-hexane, amides such as dimethylformamide and dimethylacetamide,
methanol, ethanol, isopropanol, t
Alcohols such as -butanol, and common organic solvents such as dimethyl sulfoxide, sulfolane, and hexamethylphosphoramide are used alone or in combination. Among them, for example, water, dioxane, tetrahydrofuran, carbon tetrachloride, dichloromethane, chloroform, benzene, dimethylformamide, dimethylacetamide, methanol,
Solvents such as isopropanol and dimethyl sulfoxide are preferred. Furthermore, when this reaction is carried out in the presence of a phase transfer catalyst, R ¹
This facilitates the production of compounds in which a CN group is introduced into the cis-coordination, and more favorable results can be obtained. The phase transfer catalyst referred to here promotes the reaction by solubilizing one of the reaction substrates, which exist separately in two phases (liquid and liquid), into the other liquid phase in the form of an ion pair. means substance. Such phase transfer catalysts include, for example, a cation (ammonium ion or phosphonium ion) in which four identical or different groups selected from an alkyl group, an aryl group, and an aralkyl group are bonded to a nitrogen atom or a phosphorus atom, and an acid. groups (anions, e.g. Cl ^- , Br ^- ,
I ^- , F ^- , ClO ^- ₄ , BF ^- ₄ , BH ^- ₄ , HSO ^- ₄ , OH ^- ,
H ₂ PO ^- ₄ , etc.), which achieves the purpose of this reaction. Specifically, for example, tetramethylammonium chloride, tetraethylammonium chloride, tetra-n-butylammonium chloride, tri-n-chloride
Tetraalkyl ammonium halides (4 to 50 carbon atoms in total) such as octylmethylammonium, trimethylstearyl ammonium chloride, tetra-n-amylammonium bromide, n-hexyltrimethylammonium bromide, phenyltrimethylammonium bromide, etc. Aryltrialkyl halide (9 to 50 carbon atoms in total) ammonium, benzyldimethyldecylammonium chloride,
Aralkyltrialkyl halides (total carbon number 13-50) such as benzyltriethylammonium chloride and ceylbenzyldimethylammonium chloride
An ammonium ion and a halogen ion substituted with four identical or different groups selected from alkyl groups such as ammonium, aryl groups, and aralkyl groups, such as hydrogen sulfate tetra-n
- Alkyl groups such as tetraalkyl hydrogen sulfate (total carbon number 4 to 50) ammonium such as butylammonium and tetramethylammonium hydrogen sulfate,
Those consisting of ammonium ion and HSO ^- ₄ (hydrogen sulfate ion) substituted with four same or different groups selected from aryl group and aralkyl group, tetraalkyl hydroxide (such as tetra-n-butylammonium hydroxide) 16 to 50 carbon atoms in total) consisting of an ammonium ion substituted with four identical or different groups selected from alkyl groups such as ammonium, aryl groups, and aralkyl groups, and OH ^- (hydroxyl ion), such as tetrabromide. - Tetraalkyl halide (total carbon number 4 to 50) phosphonium such as n-butylphosphonium, aralkyl triaryl halide (total carbon number 9 to 50) phosphonium such as benzyl triphenyl chloride phosphonium, n-butyl triphenyl bromide Alkyltriaryl halide such as phosphonium (total carbon number 19-50) Phosphonium ion and halogen ion substituted with four identical or different groups selected from alkyl groups, aryl groups, and aralkyl groups such as phosphonium etc. are used. Among others, for example tri-n-octylmethylammonium chloride, tetra-n-hydrogensulfate
-butylammonium, tetra-n-amylammonium bromide, benzyltriethylammonium chloride, tetra-n-butylphosphonium bromide, etc. are used. These phase transfer catalysts are used in the reaction in an amount of about 0.01 to 1 mol, preferably 0.05 to 0.2 mol, per 1 mol of the compound []. The solvent when using a phase transfer catalyst is preferably a mixture of water and an organic solvent such as those mentioned above, and the mixing ratio is 0.5 to 5 parts of organic solvent to 1 part of water, preferably 0.5 to 5 parts.
A mixture of 1 part is used. The reaction temperature is usually in the range of 0 to 20°C, but the conditions are not particularly limited, and heating and cooling may be performed as necessary. Further, the reaction time is appropriately determined depending on the solvent used, temperature, etc., but the reaction usually ends in a short time. After the completion of the reaction, the produced compound [) can be obtained with any purity by means of separation and purification known per se, such as solvent extraction, recrystallization, chromatography, etc., but the reaction mixture can be used as a raw material for the next reaction. It may also be used as When the thus obtained compound [] has a protecting group, the protecting group can be removed if necessary. Depending on the type of protecting group, methods for removing the protecting group include methods using acids,
The reaction can be carried out by appropriately selecting a commonly used method such as a method using a base, a method using reduction, a method using thiourea or sodium N-methyldithiocarbamate. In the case of a method using an acid, examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, and benzenesulfonic acid, although it depends on the type of protecting group and other conditions. In addition to organic acids such as acid and P-toluenesulfonic acid, acidic ion exchange resins and the like are used. In the case of a method using a base, the base may be, for example, a hydroxide or carbonate of an alkali metal such as sodium or potassium or an alkaline earth metal such as calcium or magnesium, although it depends on the type of protecting group and other conditions. In addition to organic bases such as inorganic bases, 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 acid or base method, a hydrophilic organic solvent, water or a mixed solvent is often used. In the case of the reduction method, it depends on the type of protecting group and other conditions, but for example, metals such as tin and zinc, or metal compounds such as chromium dichloride and chromium acetate, and organic and inorganic compounds such as acetic acid, propionic acid, and hydrochloric acid are used. A method using an acid such as an acid, a method of reduction in the presence of a metal catalyst for catalytic reduction, etc. are used, and examples of catalysts used in the catalytic reduction method include platinum wire, platinum sponge, platinum black, Platinum catalysts such as platinum oxide and colloidal platinum, palladium sponge, palladium black, palladium oxide, palladium barium sulfate, palladium barium carbonate, palladium carbon,
Palladium silica gel, palladium catalysts such as colloidal palladium, reduced nickel, nickel oxide,
Raney nickel, Urushibara nickel, etc. are used.
In the case of a reduction method using a metal and an acid, metal compounds such as iron and chromium, organic acids such as hydrochloric acid, and organic acids such as formic acid, acetic acid, and propionic acid are used. Reduction methods are usually carried out in a solvent; for example, in catalytic reduction methods, methanol,
Alcohols such as ethanol, propyl alcohol, isopropyl alcohol, and ethyl acetate are frequently used. Furthermore, in the method using a metal and an acid, water, acetone, etc. are often used, but when the acid is liquid, the acid itself can also be used as a solvent. The reaction temperature is usually cooled or heated. The obtained compound [] can be isolated and purified by the above-mentioned known means, but the reaction mixture can also be used as a raw material for the next reaction. In addition, in the obtained compound [], when R ² is an amino group, the formula R ⁰ COOH [] [wherein R ⁰ CO represents an acyl group as described for R ¹ , R ² and R ⁴ Acylation can also be carried out as appropriate by reacting with a carboxylic acid represented by the following formula or a reactive derivative thereof. The compound [] in which R ² is an amino group can be used as a free form or as a salt as mentioned in the compound [].
It may also be used in the form of an ester or silyl derivative. As reactive derivatives of carboxylic acid [],
For example, acid halides, acid anhydrides, activated amides,
Active esters and the like are used, and specific examples of such reactive derivatives of organic acids are as follows. (1) Acid anhydride: Examples of acid anhydrides include mixed acid anhydrides of hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, etc.), monoalkyl carbonic acid mixed acid anhydrides, aliphatic carboxylic acids (e.g., acetic acid, etc.). , pivalic acid, valeric acid, isopentanoic acid, trichloroacetic acid, etc.), mixed acid anhydrides of aromatic carboxylic acids (such as benzoic acid, etc.), symmetrical acid anhydrides, etc. are used. (2) Active amide: As the active amide, for example, an amide with imidazole, 4-substituted imidazole, dimethylpyrazole, benzotriazole, etc. is used. (3) Active ester: Examples of the active ester include methyl ester, ethyl ester, methoxymethyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester,
In addition to esters such as trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, 1-hydroxy-1H-2-pyridone,
Esters of N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide, N-hydroxyphthalimide, etc. and acids such as the above-mentioned carboxylic acids are used. Such reactive derivatives of organic acids are appropriately selected depending on the type of acid used. Furthermore, when using a free acid as an acylating agent, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of such condensing agents include N,N'-dicyclohexylcarbodiimide, N-cyclohexyl N'-morpholinoethylcarbodiimide, and N-cyclohexyl-N'-(4-diethylaminocyclohexyl).
Carbodiimide, N-ethyl N'-(3-dimethylaminopropyl)carbodiimide, etc. are used. The acylation reaction is usually carried out in a solvent.
The solvent used is water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine, or other general organic solvents that do not participate in the reaction. It can also be used in combination with In addition, the acylation reaction can be carried out using, for example, inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, trialkylamines such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine, and N,N -Dialkylaniline, N,
N-dialkylbenzylamine, pyridine, picoline, lutidine, organic tertiary amine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,
4-diazabicyclo[2,2,2]octane,
This can be carried out in the presence of an organic base such as 1,8-diazabicyclo[5,4,4]undecene-7, and a liquid base or the above-mentioned condensing agent can also be used as a solvent. Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature. Furthermore, in the acylation reaction, when the compound [] and the acylating agent [] have an asymmetric carbon, the stereoisomers can be used either singly or as a mixture. Furthermore, if a mixture of these isomers is produced in this reaction, each can be isolated by conventional methods such as column chromatography and recrystallization, if necessary. If the compound thus obtained (R ² ≠NH ₂ ) has a protecting group, it can be removed in the same manner as described above, if necessary. Furthermore, in the compound [] obtained by the above method, when W represents hydrogen, it is also possible to perform sulfonation. The sulfonation in this reaction refers to the compound [] (W=
This refers to the introduction of a sulfo group into the 1-position of H), and is carried out by reacting the compound [] (W=H) with, for example, sulfuric anhydride or a reactive derivative of sulfuric anhydride. The compound [] (W=H) is
It can be used as a free substance or in the form of a salt, ester, or silyl derivative as mentioned in connection with the compound [], and can also be subjected to the reaction in the form of a stereoisomer that can theoretically exist alone or in the form of a mixture.
Reactive derivatives of sulfuric anhydride include, for example, sulfuric anhydride-base complexes (e.g. sulfuric anhydride-base complexes).
Pyridine, sulfuric anhydride - trimethylamine, sulfuric anhydride - picoline, sulfuric anhydride - lutidine, sulfuric anhydride -
(N,N-dimethylformamide, etc.), adducts of sulfuric anhydride-dioxane, sulfuric anhydride-chlorosulfonic acid, etc. are used. The above sulfonation reaction is performed on the compound [] (W=H)
About 1 to 10 mol, preferably about 1 to 5 mol of sulfuric anhydride or its reactive derivative is used per mol. The reaction temperature is about -78 to about 80°C, preferably about -20 to about 60°C. In the above reaction, a solvent may be used, such as water, ethers such as dioxane, tetrahydrofuran, and diethyl ether, esters such as ethyl acetate and ethyl formate, chloroform, dichloromethane, etc. Halogenated hydrocarbons, hydrocarbons such as benzene, toluene, n-hexane, N, N
-Common organic solvents such as amides such as dimethylformamide and N,N-dimethylacetamide can be used alone or in combination. Although it varies depending on the raw material [ ] (W=H) used, the sulfonating agent, the reaction temperature, and the type of solvent, the reaction usually completes in several tens of minutes to several tens of hours, but sometimes it may take several tens of days. . After the reaction is complete, the reaction mixture is extracted with a solvent,
The compound [] (W
=SO ₃ H) can be obtained in any purity. Furthermore, if a protecting group is present, it can also be removed by the method described above. When the compound [] thus obtained is in a free form, it may be converted into a salt or ester as described for the compound [] by a conventional method, or conversely, it may be converted into a salt or ester as described for the compound [].
When obtained in the form of an ester, it may be converted into the free form by conventional methods. The 4-cyano-2-azetidinone derivative [] thus obtained is a novel compound,
In addition to its wide range of uses as an advantageous synthetic intermediate for various 4-substituted-2-azetidinone derivatives, W
= SO ₃ H has antibacterial activity and β-lactamase inhibitory activity. For example, compound [] is produced by subjecting compound [] to a hydration reaction and removing a protecting group as necessary. In this reaction, the cyano group of the compound [] is converted to a carbamoyl group.
The compound [] used as a raw material may be in a free form, or may be a salt, an ester, or a silyl derivative as described in the compound []. In addition, since the compound [] has substituents at the 3- and 4-positions, cis-trans isomers exist, and since the carbons at the 3- and 4-positions are asymmetric carbons, there are theoretically at least 4 types in total. Stereoisomers exist, and these stereoisomers can be used alone or in mixtures. The same applies to the case where the group represented by R ¹ has an asymmetric carbon, and the resulting stereoisomer can be used either singly or as a mixture. This hydration reaction may be carried out by any method as long as it can convert the 4-position cyano group of the compound [] into a carbamoyl group.
A method of reacting an acid or base with a compound []
A method of reacting hydrogen peroxide with hydrogen peroxide in the presence of a base is used. Examples of such bases include hydroxides of alkali metals such as lithium, potassium, and sodium, or alkaline earth metals such as calcium and magnesium (e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide). inorganic bases such as magnesium hydroxide, etc.) or carbonates (e.g., sodium carbonate, potassium carbonate, calcium carbonate, etc.), metal alkoxides (e.g., sodium methylate, sodium ethylate, etc.), organic amines (e.g., triethylamine, N-dimethyl aniline, diisopropylamine, etc.), quaternary ammonium salts (e.g., tetra-n-butylammonium hydroxide, etc.)
Organic bases such as, basic ion exchange resins, etc. are used. Among these, preferred bases are, for example, alkali metal hydroxides (eg, sodium hydroxide, etc.). Examples of acids include hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid,
Inorganic acids or their salts such as ferric chloride, zinc chloride, manganese dioxide, boron trifluoride, palladium chloride, titanium tetrachloride, organic acids such as formic acid, acetic acid, p-toluenesulfonic acid, trifluoroacetic acid, silica gel, Acidic ion exchange resin etc. are used. Particularly preferred are acids such as hydrochloric acid, sulfuric acid, manganese dioxide, palladium chloride, and titanium tetrachloride. The amount of such base or acid used is usually 0.1 to 4.0 mol, preferably 0.1 to 1.0 mol, per 1 mol of the compound. In addition, when using hydrogen peroxide, add a base to 1 mole of compound [].
The amount used is 0.05 to 4.0 mol, preferably 0.05 to 1.0 mol.
The amount of hydrogen peroxide used is usually 1.0 to 10 mol, preferably 1.0 to 4 mol, per 1 mol of the compound []. This reaction is usually carried out in a solvent, such as water, ether (e.g. tetrahydrofuran, dioxane, etc.), acid amide (e.g. N,N-dimethylformamide,
(N,N-dimethylacetamide, etc.), hydrocarbons (such as benzene), ketones (such as acetone), alcohols (such as methanol,
(ethanol, propanol, butanol, etc.),
halogenated hydrocarbons (e.g. chloroform, dichloromethane, etc.), fatty acids (e.g. formic acid, acetic acid, etc.), esters (e.g. ethyl acetate, etc.),
Dimethyl sulfoxide, sulfolane, hexamethylphosphoramide, or mixtures thereof are used, among which water, isopropanol, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, etc. are frequently used. Furthermore, when a mixture of water and an organic solvent is used as a solvent, the reaction can also be carried out in the presence of a phase transfer catalyst. As the phase transfer catalyst, the same one as used in the reaction of the compound [] and the cyano compound described above is used. These phase transfer catalysts are about 0.1 to 2 mol, preferably 0.5 to 1 mol, per 1 mol of compound [].
Used in molar reactions. The reaction temperature is usually 0 to 80
The temperature range is 0.degree. C., but the conditions are not particularly limited, and heating and cooling may be performed as necessary. The reaction time is usually completed within a short time. After the reaction is complete, the reaction mixture is subjected to, for example, solvent extraction,
The compound [] can be made to any purity by subjecting it to purification and separation means known per se, such as recrystallization and chromatography, but the reaction mixture can also be used as a raw material for the next reaction. In addition, if a mixture of isomers is produced in this reaction, they may be isolated by known means if necessary, and if a protecting group exists in the substituent of the compound [], if necessary, the above-mentioned It can also be removed in the same way. When W in the compound [] obtained in this way is hydrogen, W is sulfonated in the same manner as the sulfonation of the compound [] (W=H).
It is obvious that this can lead to a compound [ ] in which is a sulfo group. If the compound [] thus obtained is in free form, it may be converted into the above-mentioned salt or ester by a conventional method, or if the compound [] is obtained as a salt or ester, it may be converted into a free form by a conventional method. good. Among the obtained compounds [ ], W=SO ₃ H is a new compound and has excellent antibacterial activity and β-lactamase inhibitory activity (German application).
P3148021.7). Also, when the compound [] is reacted with hydrogen sulfide, -
A compound with CSNH ₂ is produced. In this reaction, it is preferable to react about 1.0 to 3 moles of hydrogen sulfide with respect to 1 mole of the compound [ ] or its salt, ester, or silyl derivative. Advantageously, the reaction proceeds at room temperature or below. The reaction is preferably carried out in a solvent such as chloroform, dichloromethane, benzene, ethyl acetate, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, acetic acid, water, or the like. The reaction is usually completed in a short time. Furthermore, when the compound [] is reacted with an alcohol such as methanol or ethanol, a compound having an alkoxycarbonyl group in place of the cyano group at the 4-position of the compound [] is produced. The reaction is carried out by reacting the compound [] with an equimolar amount or more of an alcohol, but the alcohol itself is often used as a solvent. When using a solvent, for example, chloroform, dichloromethane, benzene, tetrahydrofuran, dioxane, N,N-
Preferably, the reaction is carried out in a solvent such as dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or the like. The reaction temperature is usually in the range of 0 to 80°C, but the conditions are not particularly limited, and heating and cooling may be performed as appropriate. The reaction time and other conditions are appropriately determined depending on the solvent used, temperature, etc.; The reaction time can be shortened by coexisting a Lewis acid such as , zinc chloride, or boron trifluoride. Note that the raw material compound [] of the present invention can be produced, for example, by the method shown below.
When Y is an acyloxy group, the starting compound [] (W=H) of the present invention can be used, for example, as described in Tetrahedron Letters, 4059 (1978),
Or the method described in JP-A-54-76570,
or by a similar method, or for example by Annalen der Hemie.
Chemie) 1974 , 539, the following 1),
It can be synthesized by route 2). In each of the above steps, R ² , Y, and X have the same meanings as defined above, R ²⁰ represents a protected amino group, and R ²¹ represents an acylated amino group. In addition, the raw material compound [] where W=SO ₃ H is,
Compound of W=H obtained as above []
It can be synthesized by sulfonating. This sulfonation can be carried out in the same manner as the sulfonation of the compound [] (W=H). Next, the present invention will be specifically explained with reference to Examples and Reference Examples. Note that the NMR spectrum was measured using a Varian HA100 model (100MHz), using tetramethylsilane as a reference, and the δ value is expressed in ppm. Also s
is singlet, br, s is wide singlet,
d is doublet, dd is double doublet, t is triplet, q is quartet, m is multiplet, ABq is AB type quartet, J is binding constant, THF is tetrahydrofuran, DMF is dimethylformamide, DMSO is dimethyl sulfoxide, br .or broad means broad and arom means aromatic. In the following reference examples and examples, unless otherwise specified, silica gel column chromatography is
Art.9385, 230-400 mesh, TLC analysis of the crude product before chromatographic purification using Kiesel Gel 60 (manufactured by Merck & Co., Ltd.) revealed that Rf of the main spot newly appeared on the TLC plate.
- Collect fractions that have the same value.
TLC is Art.5642 unless otherwise specified, HPTLC Kiesel Gel 60F ₂₅₄ (manufactured by Merck & Co.)
Detect with a UV detector using the same plate and developing solvent as used in chromatography. In addition, for XAD-(100 to 200 mesh) column chromatography, water to 20
Absorption at 254 nm (LKB
Collect each fraction using UVI CORD2 (made in Sweden). The collected fractions are freeze-dried to produce purified products. Best Mode for Carrying Out the Invention Reference Example 1 (3S,4S)-4-cyano-3-[D-2-(4-
0.488 g of ethyl-2,3-dioxo-1-piperazinocarboxamide)-2-(thiophen-2-yl)acetamido-2-azetidinone was dissolved in 2 ml of dimethylformamide, and sulfuric anhydride-2-acetidinone was dissolved in 2 ml of dimethylformamide.
Add 3.5 ml of dimethylformamide containing 0.536 g of dimethylformamide complex at -70°C,
The reaction was carried out at 0°C for 2 days. Add 0.5 pyridine to the reaction solution
ml and then concentrated under reduced pressure. Water was added to the residue to remove insoluble materials, and the liquid was passed through a sodium type column of Dowex 50W resin (manufactured by Dow Chemical Company), and then purified with an Amberlite XAD-resin (manufactured by Rohm and Haas Company) column. 3S,4S)-4-cyano-3-[D-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-2-(thiophen-2-yl)]-acetamido-2-azetidinone- 0.350 g of sodium 1-sulfonate was obtained. IRν ^KBr _nax cm ^-1 : 1780, 1710, 1675, 1510, 1280,
1260, 1050 NMR (DMSO-d ₆ , ppm): 1.10 (t, J = 5Hz,
CH ₃ ), 3.41 (q, J = 5Hz, -CH ₂ -), 3.60
(m, -CH ₂ -), 3.93 (m, -CH ₂ -), 4.90 (d,
J=4Hz, _C4 -H), 5.30(dd, J=4.8Hz,
C ₃ −H), 5.83 (d, J=4Hz,

[Formula] ), 6.90-7.60 (m, arom H), 9.76 (d, J=
4Hz, NH), 9.83 (d, J = 8Hz, NH) Reference example 2 (1) (3S, 4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyimino]acetamide - Dissolve 0.220 g of 4-cyano-2-azetidinone in 2 ml of DMF, which contains 0.275 g of sulfuric anhydride-DMF complex.
A 1.8 ml solution of DMF was added at -70°C, and the mixture was reacted at 0°C for 3 days. Add 0.5ml of pyridine to the reaction solution,
When processed in the same manner as Reference Example 1, (3S, 4S) −3
-[2-(2-chloroacetamidothiazole-
0.170 g of sodium 4-yl)-2-methoxyiminoacetamido-4-cyano-2-azetidinone-1-sulfonate was obtained. IR ν ^KBr _nax cm ^-1 : 1780, 1670, 1540, 1260, 1055 NMR (D ₂ O, external reference, ppm): 4.04 (s,
OCH ₃ ), 4.44 (s, −CH ₂ −), 5.26 (d, J=
5Hz, _C4 -H), 5.46(d, J=5Hz, _C3-
H), 7.50(s,

[Formula]) (2) Chloroacetamide derivative obtained in (1) above
0.150g was dissolved in 6ml of water, 0.050g of sodium monomethyldithiocarbamate was added under ice cooling, and the mixture was stirred at room temperature (approximately 25°C) for 3 hours. When the reaction solution is purified with an XAD-column, (3S, 4S)
-3-[2-(2-aminothiazol-4-yl]-2-methoxyimino]acetamide-4
0.067 g of sodium -cyano-2-azetidinone-1-sulfonate was obtained. IR ν ^KBr _nax cm ^-1 : 1780, 1665, 1610, 1520, 1260,
1050 NMR (D ₂ O, external reference, ppm): 4.00 (s,
OCH ₃ ), 5.24 ((d, J=5Hz, C ₄ −H),
5.45 (d, J = 5 Hz, C ₃ - H), 7.06 (s,

[Formula]) Reference Example 3 (1) 0.482 g of (3S,4R)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyimino]acetamido-4-cyano-2-azetidinone Dissolved in 2ml of DMF, containing 0.597g of sulfuric anhydride-DMF complex.
A 3.9 ml solution of DMF was added at -70°C, and the mixture was allowed to react at 0°C for 2 days. Add 0.5ml of pyridine to the reaction solution,
When processed in the same manner as Reference Example 1, (3S, 4R) −3
-[2-(2-chloroacetamidothiazole-
0.390 g of sodium 4-yl)-2-methoxyiminoacetamido-4-cyano-2-azetidinone-1-sulfonate was obtained. IR ν ^KBr _nax cm ^-1 : 1785, 1670, 1550, 1260, 1055 NMR (D ₂ O, external reference, ppm): 4.06 (s,
OCH ₃ ), 4.44 (s, −CH ₂ −), 5.14 (d, J=
2Hz, _C4 -H), 5.40(d, J=2Hz, _C3-
H), 7.43(s,

[Formula]) (2) Chloroacetamide derivative obtained in (1) above
0.190g was dissolved in 6ml of water and treated in the same manner as in Reference Example 2 (2) using 0.052g of sodium monomethyldithiocarbamate to obtain (3S,4R)-
3-[2-(2-aminothiazol-4-yl)
-2-methoxyimino]acetamido-2-azetidinone-1-sulfonate sodium 0.074
g was obtained. IR ν ^KBr _nax cm ^-1 : 1780, 1660, 1615, 1520, 1280,
1250, 1050 NMR (D ₂ O, external reference, ppm): 4.02 (s,
OCH ₃ ), 5.12 (d, J = 3Hz, C ₄ −H), 5.37
(d, J=3Hz, C ₃ −H), 6.96(s,

[Formula]) Reference example 4 D-2-(4-ethyl-2,3-dioxo-1
-piperazinocarboxamide)-2-(thiophen-2-yl)acetic acid 1.196 g, methylene chloride 20 ml,
While stirring a mixture of 0.530 g of triethylamine under ice cooling, 0.775 g of powdered phosphorus pentachloride was added. After stirring for 1 hour under ice cooling, the mixture was concentrated under reduced pressure, n-hexane was added to the residue, and the mixture was washed by decantation several times. Dry tetrahydrofuran was added to the residue to remove insoluble matter. On the other hand, (3S,4S)-3-amino-4-cyano-
2-Azetidinone p-toluenesulfonate
Dissolve 0.992g in 15ml of dry tetrahydrofuran,
To this was added 1.060 g of triethylamine under ice cooling, and then the tetrahydrofuran solution of acid chloride prepared above was added. After stirring at room temperature (approximately 25°C) for 40 minutes, it was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [developed with ethyl acetate:chloroform:methanol (3:3:1)].
When attached to (3S, 4S)-4-cyano-3-[D-2
-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-2-(thiophenone-2-
yl)]0.560 of acetamido-2-azetidinone
g was obtained. IR ν ^KBr _nax cm ^-1 : 1785, 1710, 1670, 1500 NMR (DMSO-d ₆ , ppm): 1.09 (t, J=5Hz,
CH ₃ ), 3.40 (q, J=5Hz, -CH ₂ -), 3.56
(m, -CH ₂ -), 3.90 (m, -CH ₂ -), 4.76 (d,
J=4Hz, _C4 -H), 5.30(dd, J=8,4Hz,
C ₃ −H), 5.83 (d, J=4Hz,

[Formula] ), 6.90-7.60 (m, aromH), 9.03 (br.s,
NH), 9.70 (d, J=4Hz, NH), 9.80 (d,
J=8Hz, NH) Reference example 5 0.960 of p-toluenesulfonate of (3S,4S)-3-amino-4-cyano-2-azetidinone
g was suspended in 15 ml of dry tetrahydrofuran, 1.400 g of triethylamine was added under ice-cooling, and then 2-(2-
Chloroacetamidothiazol-4-yl)-2
- A solution of 1.040 g of methoxyiminoacetic chloride hydrochloride dissolved in 10 ml of dry tetrahydrofuran was added. After stirring for 30 minutes at room temperature (approximately 25℃),
After concentration under reduced pressure, the residue was subjected to silica gel column chromatography [developed with ethyl acetate:chloroform:methanol (3:3:1)] to obtain (3S,
4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyimino]acetamido-4-cyano-2-azetidinone, 0.910
g was obtained. IR ν ^KBr _nax cm ^-1 : 1790, 1675, 1540, 1050 NMR (DMSO + D ₂ O, ppm): 3.93 (s, OCH ₃ ),
4.33 (s, −CH ₂ −), 4.83 (d, J=4Hz, C ₄ −
H), 5.40 (d, J=4Hz, C ₃ −H), 7.46 (s,

[Formula]) Reference example 6 (3S,4S)-3-amino-4-cyano-2-azetidinone p-toluenesulfonate 0.540g
was suspended in 10 ml of dry tetrahydrofuran, 0.787 g of triethylamine was added under ice cooling, and then 2-(2
-chloroacetamidothiazol-4-yl)-
2-methoxyiminoacetic acid chloride hydrochloride 0.600
A solution of 50 g dissolved in 5 ml of dry tetrahydrofuran was added. After stirring at room temperature (approximately 25°C) for 30 minutes, the reaction solution was filtered and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography [ethyl acetate:chloroform:methanol (3:
3:1), it becomes (3S, 4R)-3-[2
-(2-chloroacetamidothiazol-4-yl)-2-methoxyimino]acetamido-2-
0.525 g of azetidinone was obtained. IR ν ^KBr _nax cm ^-1 : 1780, 1670, 1540, 1040 NMR (DMSO-d ₆ , ppm): 3.92 (s, OCH ₃ ),
4.36 (s, −CH ₂ −), 4.53 (d, J=2Hz, C ₄ −
H), 5.23 (dd, J=2,5Hz, _C3 -H), 7.50
(s,

[Formula] ), 9.10 (s, NH), 9.56 (d, J=5Hz, NH) Reference example 7 (3S, 4RS)-3-amino-4-cyano-2-
Azetidinone P-toluenesulfonate 5g,
To an ice-cold, stirred solution of 4.2 g of pyridine and 100 ml of methylene chloride was added 3 g of phenylacetic acid chloride. After stirring at room temperature (25°C) for 10 minutes, the mixture was shaken with water, and the organic layer was separated and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and purify the residue using a silica gel column [ethyl acetate:n-hexane (2:
1)] Then, 1.16 g of (3S,4S)-4-cyano-3-phenylacetamido-2-azetidinone (A),
Then, 0.84 g of the corresponding (3S,4R)-derivative (B) was obtained. (A) IR ν ^KBr _nax cm ^-1 : 2250, 1770, 1665, 1530, 1350 NMR (DMSO-d ₆ , ppm): 3.60 (s, -CH ₂ -),
4.20 (d, J = 4Hz, C ₄ −H), 4.86 (dd, J =
4.8Hz, _C3 -H), 6.56(d, J=8Hz,
NH), 7.26 (s, aroma H) (B) IR ν ^KBr _nax cm ^-1 : 2250, 1780, 1660, 1520, 1350 NMR (DMSO-d ₆ , ppm): 3.60 (s, -CH ₂ -),
4.10 (d, J = 2Hz, C ₄ −H), 4.80 (dd, J =
2.8Hz, _C3 -H), 6.60(d, J=8Hz,
NH), 7.20 (s, arom H) Reference example 8 (3S,4R)-3-amino-4-cyano-2-azetidinone P-toluenesulfonate 1.66 g,
A mixture of 0.5 g of pyridine and 5 ml of methylene chloride was stirred at room temperature (approximately 25°C) for 15 minutes. While stirring this under ice-cooling, add 10 ml of propylene oxide,
Then 1.1 g of 2-trimethylsilyl-ethoxycarbonyl chloride was added. After stirring at room temperature for 30 minutes, it was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography [developed with ethyl acetate:n-hexane (1:1)] to give (3S, 4R).
-4-cyano-3-(2-trimethylsilyl)ethoxycarboxamide-2-azetidinone 1.0
g was obtained. IR ν ^film _nax cm ^-1 : 2950, 1885, 1710, 1510, 1250,
860, 840 NMR (CDCl ₃ , ppm): 0.03 (s, CH ₃ ), 1.00 (t,
J = 8 Hz, -CH ₂ -), 4.20 (t, J = 8 Hz, -
CH ₂ −), 4.60 (d, J=2Hz, C ₄ −H), 5.33
(dd, J=2.8Hz, C ₃ −H), 5.70(d, J=
8Hz, NH), 6.80 (br.s, NH) Reference example 9 (3S, 4RS)-3-amino-4-cyano-2-
Azetidinone P-toluenesulfonate 11.2g
was suspended in 50 ml of tetrahydrofuran, 5 g of triethylamine was added under ice cooling, stirred for 30 minutes, and then concentrated under reduced pressure. methylene chloride in the residue
20ml, add 80ml of propylene oxide and dissolve.
6.8 g of carbobenzoxy chloride was added to this solution under ice cooling. After stirring at 25℃ for 30 minutes,
Concentrated under reduced pressure. Ethyl acetate and water were added to the residue and mixed, and the organic layer was taken, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. residue
Purification with a column using 150 g of silica gel [developed with ethyl acetate:n-hexane (1:1)] yields 2.1 g of (3S,4R)-3-benzyloxycarboxamide-4-cyano-2-azetidinone as an oily substance. Furthermore, (3S,4S)-4-cyano-3-
3.21 g of benzyloxycarboxamide-2-azetidinone was obtained as crystals. (3S, 4S) Integrated mp 167-170℃ (dec.) IR ν ^KBr _nax cm ^-1 : 3380, 3260, 2245, 1805, 1765,
1675, 1525 NMR (DMSO-d ₆ , ppm): 4.50 (d, J = 5Hz,
C ₄ −H), 5.10 (s, −CH ₂ −), 5.16 (dd, J=
5.8Hz, _C3 -H), 7.26(s, aroma H),
8.16 (d, J=8Hz, NH), 8.56 (broad s,
NH) Reference Example 10 (1) Dissolve 0.298 g of (3R,4R)-3-benzyloxycarboxamide-4-methylsulfonyl-2-azetidinone in 15 ml of THF, add 0.25 g of palladium black, and stir in a hydrogen stream for 2 hours. Ta. The catalyst was removed and the solution was concentrated under reduced pressure to about 3 ml. Separately, 0.555 g of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) was added to 10 ml of methylene chloride, and 0.25 g of triethylamine was added to this under ice cooling.
Next, 0.42 g of phosphorus pentachloride was added and stirred for 5 minutes. After stirring at room temperature for 30 minutes, it was concentrated under reduced pressure, and the residue was washed with n-hexane.
5 ml of THF was added to remove insoluble materials. This solution was added to a mixed solution of the previously prepared solution and 1 ml of propylene oxide under ice cooling. After evaporating the solvent under reduced pressure, the residual ethyl acetate solution was washed with water and concentrated under reduced pressure. Purify the residue with a silica gel column [n-hexane-ethyl acetate (1:1)]
Then, 0.13 g of (3R,4R)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamide]-4-methylsulfonyl-2-azetidinone was obtained. IR ν ^KBr _nax cm ^-1 : 3370, 3270, 1790, 1680, 1540 NMR (DMSO-d ₆ , ppm): 3.00 (s, CH ₃ ),
3.93 (s, CH ₃ ), 4.33 (s, -CH ₂ -), 4.93
(d, J=5Hz, C ₄ −H), 5.57(dd, J=5,
9Hz, _C3 -H), 7.53(s,

[Formula] ), 8.30 (d, J=9Hz, NH), 9.40 (s,
NH), 12.73 (s, NH) (2) (3R, 4R)-3-[2-
(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamide]-4-
0.46g of methylsulfonyl-2-azetidinone
It was dissolved in 3 ml of DMF, and 0.36 g of anhydrous sulfuric acid-pyridine complex was added thereto and reacted for 12 days. Ether was added and the oil that separated was washed with ether. Dissolve the oil in water,
10 ml of Dowex 50W resin (manufactured by Dow Chemical Company) sodium form was added and stirred for 30 minutes. The resin was removed and the solution was purified using a column filled with XAD-resin (manufactured by Rohm and Haas) to obtain (3R,4R)-3-[2-(2-chloroacetamidothiazol-4-yl)-2 -methoxyiminoacetamide] 0.023 g of sodium-4-methylsulfonyl-2-azetidinone-1-sulfonate was obtained. IR ν ^KBr _nax cm ^-1 : 3450~3400, 1785, 1685, 1672,
1280, 1260, 1052 NMR (DMSO-d ₆ , ppm): 3.84 (s, CH ₃ ),
4.33 (s, −CH ₂ −), 5.15 (d, J=5Hz, C ₄
-H), 5.71 (dd, J=5.9Hz, C ₃ -H),
7.53(s,

[Formula] ), 9.45 (d, J=9Hz, NH), 12.88 (s,
NH) Reference example 11 (3R,4R)-3-amino-4-cyano-2-
Azetidinone P-toluenesulfonate 0.30g
was dissolved in 12 ml of tetrahydrofuran, 0.12 g of triethylamine was added to the solution under ice cooling, and then 2-(2-
Chloroacetamidothiazol-4-yl)-2
-(1-p-nitrobenzyloxycarbonyl-
0.60 g of 1-methylethoxyimino)acetic chloride hydrochloride was added. Stir at room temperature for 40 minutes, concentrate under reduced pressure, and purify the residue with a silica gel column [ethyl acetate-chloroform-methanol (3:3:
1)] Then, (3S,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-
0.27 g of p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-4-cyano-2-azetidinone was obtained. IR ν ^KBr _nax cm ^-1 : 1785, 1740, 1675, 1530 Reference example 12 100 g of P-toluenesulfonate of (3S, 4S)-3-amino-4-cyano-2-azetidinone,
The mixture was dissolved in 850 ml of a tetrahydrofuran-water (1:1) solution, and 74.1 g of sodium hydrogen carbonate was gradually added thereto while stirring at a temperature below 10°C. Then 3-5
℃, carbobenzoxy chloride was added over 40 minutes, and the mixture was further stirred at the same temperature for 30 minutes. 300 ml of ethyl acetate was added to the reaction solution and the mixture was shaken, and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure and collecting the precipitated crystals, 34 g of (3S,4S)-4-cyano-3-benzyloxycarboxamide-2-azetidinone was obtained. The IR and NMR spectra of this compound matched those of the compound obtained in Reference Example 9. Reference example 13 (1) (3R,4R)-4-methylsulfonyl-3-
12.3g of tritylamino-2-azetidinone
A solution of 1.6 g of potassium cyanide dissolved in 24 ml of water was added to the solution in 150 ml of DMF under ice cooling, and the mixture was stirred at room temperature (approximately 25° C.) for 30 minutes. Ice water and ethyl acetate were added to the reaction solution, and the ethyl acetate layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a silica gel column [developed with ethyl acetate:n-hexane (1:1)] to give (3S,4RS)-
6.7 g of 4-cyano-3-tritylamino-2-azetidinone (4R:4S=1:1) was obtained. IR ν ^KBr _nax cm ^-1 : 2230, 1770 (2) (3S,4RS)-4-cyano-3 obtained in (1) above
- To a solution of 10.6 g of tritylamino-2-azetidinone dissolved in 20 ml of acetone, 6.3 g of p-toluenesulfonic acid monohydrate was added to make a homogeneous solution, and the precipitated crystals were collected and washed with a small amount of acetone and then ether. did. The liquid was concentrated under reduced pressure, and acetone was added to the residue to collect precipitated crystals. Concentrate the liquid and perform the same operation as above to obtain a total of 3.4 g of (3S,
4R)-3-amino-4-cyano-2-azetidinone/p-toluenesulfonate (A) was obtained.
After concentrating the liquid under reduced pressure, ether was added to the residue.
The resulting insoluble matter is removed and washed with ether to yield (3S,4S)-3-amino-4-cyano-2-azetidinone p-toluenesulfonate (B)4.1
g was obtained. This product contained approximately 10% of (3S, 4R). (A) IR ν ^KBr _nax cm ^-1 : 1770, 1200 NMR (DMSO-d ₆ , ppm): 2.30 (s, CH ₃ ),
4.55 (d, J = 2Hz, C ₄ −H), 4.95 (d, J =
2Hz, _C3 -H), 7.03(d, J=8Hz, arom
H), 7.46 (d, J=8Hz, aromaH), 8.30~
9.00 (broad, NH ₂ ), 9.46 (broad s, NH) IR ν ^KBr _nax cm ^-1 : 1800, 1180 Reference example 14 (1) (3S, 4RS)-4-cyano-3-tritylamino-2- To a mixture of 1.10 g of azetidinone, 0.50 g of triethylamine, and 20 ml of methylene chloride, 0.56 g of tert-butyldimethylsilyl chloride was added while stirring under ice cooling. Room temperature (about 25℃)
After stirring for 30 minutes, the reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography [developed with ethyl acetate:n-hexane (1:3)] to give (3S,4RS)-1-tert. 0.64 g of -butyldimethylsilyl-4-cyano-3-tritylamino-2-azetidinone was obtained. IR ν ^KBr _nax cm ^-1 : 2950, 2240, 1760, 1260 NMR (CDCl ₃ , ppm): 0.13 (s, CH ₃ ), 0.80
(s, t-Bu), 3.03 (d, J=2Hz, C ₄ −
H), 3.10 (d, J=8Hz, NH), 3.43 (d,
J=5Hz, _C4 -H), 4.46(dd, J=2,8
Hz, _C3 -H), 4.50 (dd, J=5,8Hz, _C3-
H), 7.00-7.50 (m, aromaH) (2) 0.469 g of the 4-cyano compound obtained in (1) above,
A mixture of 5 ml of methanol, 0.33 ml of 30% hydrogen peroxide solution and 1 ml of 1N sodium hydroxide solution was stirred at room temperature (approximately 25° C.) for 4 hours. After concentrating the reaction solution under reduced pressure, ethyl acetate and saturated brine were added to the residue, and the organic layer was separated and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (developed with ethyl acetate) to obtain (3S,4RS)-4-carbamoyl-3-tritylamino-2-azetidinone (4R:4S=1:1). 0.557 g of mixture) was obtained. IR ν ^KBr _nax cm ^-1 : 1750, 1670 NMR (DMSO−d ₆ + D ₂ O, ppm): 3.46 (d, J
= 4 Hz, C ₄ - H), 3.56 (d, J = 2 Hz, C ₄ -
H), 4.03 (d, J=2Hz, C ₃ −H), 4.26
(d, J=4Hz, C3 _- H), 7.2~7.7(m,
aromH) Reference example 15 (1) (3S,4S)-4-acetoxy-3-benzyloxycarboxamide-2-azetidinone 6g
A solution of 1.5 g of potassium cyanide dissolved in 5 ml of water was added to a solution of 1.5 g of potassium cyanide dissolved in 30 ml of dimethylformamide under ice cooling, and the mixture was stirred at room temperature (approximately 25° C.) for 30 minutes. Pour into ice water and extract with ethyl acetate.
The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Dissolve the residue in 30 ml of methylene chloride and add triethylamine
2.2 g was added thereto, and 3.2 g of tert-butylsilyl chloride was added under ice cooling. After stirring at room temperature for 30 minutes, it was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography [developed with ethyl acetate:n-hexane (1:1)] to give (3S, 4R).
-3-benzyloxycarboxamide-1-
tert-butyldimethylsilyl-4-cyano-2
-Azetidinone, 0.300 g was obtained. IR ν ^film _nax cm ^-1 : 2950, 2920, 2140, 1745, 1720,
1250 NMR (CDCl ₃ , ppm): 0.06 (s, CH ₃ ), 0.90
(s, t-Bu), 4.36 (d, J=2Hz, C ₄ −
H), 4.70 (dd, J=2.8Hz, _C3 -H),
5.02 (s, −CH ₂ −), 5.46 (d, J=8Hz,
NH), 7.23 (s, arom H) (2) 0.300 g of the 4-cyano compound obtained in (1) above
Dissolve in 5 ml of ethanol, add 0.3 ml of 30% hydrogen peroxide solution and 1N aqueous sodium hydroxide solution under ice cooling.
0.15 ml was added and stirred at room temperature (approximately 25°C) for 1 hour. After concentrating under reduced pressure, ethyl acetate and water were added to the residue and shaken, and the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. When concentrated under reduced pressure and subjected to silica gel column chromatography (developed with ethyl acetate), (3S,4R)-3-benzyloxycarboxamide-4-carbamoyl-
0.04 g of 2-azetidinone was obtained. mp 153-155℃ (dec.) IR ν ^KBr _nax cm ^-1 : 1770, 1705, 1690, 1665, 1520,
1250 NMR (DMSO- _d6 , ppm): 3.91 (d, J=2
Hz, C ₄ −H), 4.42 (dd, J=2.8Hz, C ₃ −
H), 5.06 (s, -CH ₂ -), 7.18, 7.60 (respectively br
s, CONH ₂ ), 7.36 (s, arom H), 8.04
(d. While stirring, 0.1 ml of 30% hydrogen peroxide solution and then 0.1 ml of 1N sodium hydroxide solution were added. After 10 minutes, the precipitated crystals were collected and washed with a small amount of 99% ethanol.
Dry to give (3S,4S)-3-benzyloxycarboxamide-4-carbamoyl-2-azetidinone
Obtained 42 mg. The solution was subjected to XAD-column chromatography (developed with 30% ethanol water), and 37 mg of (3S,4S)-3-benzyloxycarboxamide-4-carbamoyl-2-azetidinone was added.
I got it. mp 236-240℃ (dec.) [α] ²⁰ _D +10.43 (DMSO, e=1) IR ν ^KBr _nax cm ^-1 :3400, 3310, 1775, 1740, 1675,
1545 NMR (DMSO, ppm): 4.14 (d, J=5Hz, _C4
-H), 5.06 (s, -CH ₂ -), 5.08 (dd, J=5,
8Hz, _C3 -H), 7.30 (broad S, _NH2 ), 7.35
(s, arom H), 7.52 (d, J=8Hz, NH),
8.33 (broad s, NH) Example 1 1.06 g of (3S-4R, S)-4-cyano-3-triphenylmethylamino-2-azetidinone was dissolved in 12 ml of dichloromethane, and hydrogen sulfate tetra-n-
1.02 g of buterammonium was added, and while stirring on ice, 0.68 ml of 30% hydrogen peroxide solution and 4.5 ml of 1N aqueous sodium hydroxide solution were added, followed by vigorous stirring for 50 minutes. The reaction solution was poured into ice water containing 1.3 ml of 1N hydrochloric acid, and after separation, the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with an aqueous solution of sodium thiosulfate and common salt, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography [eluted with chloroform:ethyl acetate:methanol (50:50:5)] and (3S,4S)-4-carbamoyl-3-triphenylmethyl. Amino-2-azetidinone
0.223g was obtained. IR ν ^KBr _nax cm ^-1 : 3370, 1750, 1675, 705 NMR (DMSO-d ₆ , ppm): 3.44 (d, J=5Hz,
C ₄ −H), 3.55 (d, J=10Hz, NH), 4.10 (dd,
J=5, 10Hz, C3 _- H), 6.90(broad s,
NH ₂ ), 7.0−7.6 (m, arom H), 7.89 (s,
NH) Reference example 17 (3S,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamide]-4 - Dissolve 0.38 g of cyano-2-azetidinone in 2 ml of dimethyl sulfoxide, add 0.1 ml of 30% hydrogen peroxide solution and 0.1 ml of 1N aqueous sodium hydroxide solution, and stir at about 25°C for 30 minutes. The reaction solution was added to an XAD-column and purified [eluted with 30% ethanol] to obtain (3S,
4S)-4-carbamoyl-3[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p
0.12 g of -nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamide]-2-azetidinone is obtained. IR ν ^KBr _nax cm ^-1 : 1760, 1750, 1680, 1520, 1350 NMR (DMSO-d ₆ , ppm): 1.52 (s, CH ₃ ),
4.27 (d, J = 6 Hz, C ₄ −H), 4.34 (s,
ClCH ₂ −), 5.32 (s, −CH ₂ −), 5.46 (dd, J
=6.9Hz, _C3 -H), 7.41(s,

[Formula] ), 7.60, 8.08 (respectively d, J=9Hz, arom H),
8.47 (s, NH), 8.86 (d, J = 9 Hz, NH) Example 2 Dissolve 160 mg of (3S, 4S)-4-cyano-3-triphenylmethylamino-2-azetidinone in 2 ml of dichloromethane and add hydrogen sulfate tetra 154 mg of -n-butylammonium was added, and while stirring under ice cooling, 0.103 ml of 30% hydrogen peroxide solution and 0.68 ml of 1N aqueous sodium hydroxide solution were added, followed by vigorous stirring for 30 minutes. The reaction solution was poured into ice water containing 0.22 ml of 1N hydrochloric acid, and after separation, the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography [chloroform: ethyl acetate: methanol (50:
50:5)] and 75 mg of (3S,4S)-4-carbamoyl-3-triphenylmethylamino-2-azetidinone were obtained. IR, NMR of this compound
The spectra were consistent with those of the compound obtained in Example 1. Example 3 12.2 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone and 2.44 g of tri-n-octylmethylammonium chloride were dissolved in 120 ml of carbon tetrachloride, and while stirring, 2.15 g of potassium cyanide was added. A solution dissolved in 30 ml of water was added under ice cooling. After stirring vigorously for 15 minutes at the same temperature, the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with water, and then treated in the same manner as in Reference Example 13, 1) to obtain (3S,4RS)-4-cyano-3.
7.66 g of -tritylamino-2-azetidinone was obtained. This compound was a mixture of (3S,4R):(3S,4S)=1:5. Γ (3S, 4R) body NMR (CDCl ₃ , ppm): 2.94 (d, J = 11Hz, Tr
(trityl) NH- ), 3.00 (d, J=2Hz,
C ₄ −H), 4.64 (dd, J=2, 11Hz, C ₃ −H),
6.40 (s, NH), 7.1-7.7 (m, aroma H) Γ (3S, 4S) body NMR (CDCl ₃ , ppm): 3.17 (d, J = 11Hz,
TrN H −), 3.56 (d, J=5Hz, C ₄ −H),
4.64 (dd, J=5, 11Hz, C3 _- H), 6.30 (s,
NH), 7.1-7.7 (m, arom H) Reference example 18 (3R,4RS)-4-cyano-3-tritylamino-2-azetidinone obtained in Example 3 3.54
g was dissolved in 40 ml of chloroform, 3.4 g of tetra-n-butylammonium hydrogen sulfate was added, and while stirring under ice-cooling, 2.3 g of 30% hydrogen peroxide and 15 ml of 1N aqueous sodium hydroxide were added, followed by vigorous stirring for 30 minutes. The organic layer was separated, and the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with water, and treated in the same manner as in Example 2 to obtain 0.76 g of (3S,4S)-4-carbamoyl-3-tritylamino-2-azetidinone. The IR and NMR spectra of this compound matched those of the compound obtained in Example 1. Example 4 0.5 mmol of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone and 0.1 mmol of tetra-n-amylammonium bromide were dissolved in 2 ml of benzene, and potassium cyanide was added to the solution.
A solution of 0.55 mmol in 0.55 ml of water was added at 15°C. After stirring vigorously for 15 minutes, the same treatment as in Example 3 resulted in (3S,4RS)-4-cyano-3
-tritylamino-2-azetidinone (3S,
4R):(3S,4S)=1:4 mixture was obtained. Example 5 In Example 4, when the reaction was carried out using benzyltriethylammonium chloride instead of tetra-n-amylammonium bromide, (3S,4RS)-
4-cyano-3-tritylamino-2-azetidinone (4R:4S=1:3.5) was obtained. Example 6 In Example 4, when the reaction was carried out using tetra-n-butylphosphonium bromide instead of tetra-n-amylammonium bromide, (3S,4RS)-
4-cyano-3-tritylamino-2-azetidinone (4R:3S=1:3.5) was obtained. Industrial applicability 4-cyano-2-azetidinone derivative []
is used as an advantageous synthetic intermediate in the synthesis of optically active 4-substituted-2-azetidinone derivatives having excellent antibacterial activity and β-lactamase inhibitory activity, and W is a sulfo group. [ ] itself has antibacterial activity and β-lactamase inhibitory activity, and is effective against humans, dogs, cats,
As a therapeutic agent for infectious diseases caused by Gram-positive or negative bacteria in mammals including cattle, horses, mice, guinea pigs, etc., as a preservative for animal feed and industrial water, or as a disinfectant for sanitary tools.
Furthermore, when used in combination with a β-lactam antibiotic, it can be used as an agent for preventing the degradation of the antibiotic.

Claims (1)

[Claims] 1 formula [Wherein, R ² is an acylated or protected amino group, X is hydrogen or a methoxy group, W is hydrogen or a sulfo group, Y is a halogen or the formula -OCOR ³ , -SCOR ³ or [Formula] (R ³ represents a hydrocarbon group, n represents a group represented by 1 or 2)] and a cyano compound are reacted in the presence of a phase transfer catalyst, and the protective group is removed as necessary. The formula is characterized by A method for producing a 4-cyano-2-azetidinone derivative represented by the formula [wherein R ¹ is an optionally acylated or protected amino group, and X and W have the same meanings as above].