KR840001054B1 - Process for preparing novel 3-thiovinyl cepholosporin derivatives - Google Patents

Abstract

H2, CH2CN; R=alkyl, L-H2NCH(CO2H)CH2, Ph, pyridazinyl, tetrazolo≮4,5-b≉pyridazinyl, dioxotetrahydrotriazinyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, oxadiazolyl; R1=H, CHR3O2CR4 (R3=H, alkyl; R4=alkyl, cyclo- hexyl)≉were prepd. an are useful as bactericides (no data, a formulation is given). Thus , 2-benzolyl)acetamido≉-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo≮4.2.0≉oct-2-ene was treated with 2-mercaptopyrimidine and the product was deprotected (aq. HCO2H) to give I (R0=Me; R=2-pyrimidinyl; R1=H).

Description

Method for preparing novel 3-thiovinyl-sephalosporin derivatives

The present invention relates to a 3-thiovinyl-sephalosporin-based novel substance having the following general chemical formula and a method for preparing a salt thereof.

In the above formula (I), R is selected from the following list.

1) Alkyl, L-2-amino-2-carboxy-ethyl and phenyl

2) pyrid-2-yl, pyrid-yl or pyrid-4-yl and copper N-oxides,

3) pyrimidin-2-yl, pyridazin-3-yl (substituted with alkyl, methoxy, amino or acylamino groups in the 6-position), and the like N-oxides and tetrazolo [4,5-b Pyridazine-6-day,

4) 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl is in the 4-position, 1,3,4-triazol-5-yl or 2-alkoxy-carbonyl-1,3,4-triazol-5-yl are each substituted at the 1-position with the following groups,

a) an alkyl group unsubstituted or substituted with an alkoxy, alkylthio, phenyl, formyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl, or thiazoridin-2-yl group,

b) allyl, 2,3-dihydroxyfurophyll, 1,3-dihydroxyfurop-2-yl or 2-formyl-2-hydroxy-ethyl, 3-formyloxy-2-hydroxyfuro Phil, 2,3-bisporyloxyfurophil, or 1,3-bisporyloxy-2-furophil group,

c) an alkyl group containing 2-4 carbon atoms, and substituted with the following groups, ie hydroxyl, carbamoyloxy, asyloxy, wherein the acyl moiety may be substituted with amino, alkylamino, or dialkyl amino groups , Alkylsulfonyl, alkylsulfonyl, amino, dialkylamino, sulfoamino, alkylsulfonylamino, alkylamino, stoolamoylamino, asylamino (the acyl moiety is preferably hydroxyl, amino, alkylamino or dialkylamino groups May be substituted), alkoxycarbonyl amino, ureido, alkylureido or dialkylureido group.

d) a group corresponding to one of the following structural formulas:

Where alk denotes a chelylene group containing 1-4 carbon atoms, X ^α and Y ^α correspond to or represent oxygen or sulfur atoms, R ^α represents an alkyl group, or X ^α and Y ^α represent It may be the same as the oxygen and sulfur elements may be different and represents ^α and R groups together form an alkylene group containing 2-3 carbon atoms and R is an alkyl group ^γ represents a hydrogen atom or having from 1 to 3 carbon atoms Indicates.

e) an alkyl group having 2-5 carbon atoms substituted with an alkoxyamino or hydroxy amino group.

5) 1,4-Dialkyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 1-alkyl-5,6-dioxo -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl or 2-alkyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2 4-triazin-3-yl,

6) 1,3,4-triazol-5-yl, 1,2,3-triazol-5-yl or 1-alkyl-1,2,4-triazol-5-yl (alkoxycarbo at 3 position May or may not be substituted with a nil group)

7) a) 1,3,4-thiadiazol-5-yl is an alkyl group, trifluoromethyl, alkoxy, alkylthio, hydroxyalkylthio (alkyl moiety having 2-4 carbon atoms), alkylsulfonyl, Or unsubstituted or substituted with a hydroxyl, hydroxyalkyl, carboxyl, carboxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, asylamino or asylaminoalkyl group.

b) 1,2,4-thiadiazol-5-yl substituted with an alkyl or alkoxy group.

8) a) 1,3,4-oxadiazol-5-yl is unsubstituted or substituted with the following groups: alkyl, trifluoromethyl, phenyl, aminoalkyl, alkylaminoalkyl, dialkyl Aminoalkyl or asylamino alkyl groups.

b) oxazol-2-yl or 4-alkyl-oxazol-2-yl.

9) Tetrazol-5-yl, optionally substituted at the 1-position with the groups listed below.

a) an alkyl group substituted or unsubstituted with an alkoxy, scallop, carboxyl, formyl or stoolamoyl group,

b) an alkyl group having 2-4 carbon atoms, such as hydroxyl, amino, alkylamino, dialkylamino, asylamino, carboxyalkylamino, stoolamoylamino, sulfonylamino, ureido, alkylureido or dialkyl ureido An alkyl group substituted with

c) an alkyl group having 2-5 carbon atoms and substituted with a hydroxyimino or alkoxyimino group,

d) phenyl, 2,3-dihydroxyfurophyll, 1,3-dihydroxyfurope-2yl or 2-formyl-2-hydroxy-ethyl, 3-formyloxy-2-hydroxyfurofill, 2,3-bispotyloxyfurophyll or 1,3-bisformyloxy-2-propyl group,

e) a group having the general formula (II) wherein R ^β represents a hydrogen atom, or a group of the above formula (III), R ⁰ represents a hydrogen atom or an alkyl, vinyl, cyanomethyl group; R 'is hydrogen or a group having the structure

In the above structural formula, R 'is a hydrogen atom or an alkyl group and R' 'is an alkyl group or a cyclohexyl group.

The alkyl or asher moiety or group described above is considered straight or branched chain having from 1 to 4 carbon atoms (unless otherwise noted).

Substituents at the 3-position of the general formula (I) are cis or trans, or cis, trans complex.

In the text, the trans-stereoisomer is called E and the cis-stereoisomer is called Z for convenience.

OR ⁰ may be one of the neo- or anti-geoisomeric positions and such isomers and complexes fall within the scope of the invention. Syn-type is represented by the following structural formula.

Anti type is represented by the following structural formula.

Equivalently, if the R group bears a hydroxyaminoalkyl or alkoxyaminoalkyl substituent, they represent the neo-anti-isomers and the isomers and their complexes are also within the scope of the present invention.

If the R group is a 1,4,5,6-tetrahydrotriazinyl group substituted at the 1 or 4 position or a 1,2,5,6-tetrahydro-triazinyl group is substituted at the 2-position, the following tautomerism Appeared.

When the R group has a formylalkyl substituent, it may be present in free aldehyde form or in aldehyde hydrate form. In particular, this form applies only to the cases described below.

As indicated by nuclear magnetic resonance studies, when R is 5,6-dioxo-4-formylmethyl-1,4,5,6-tetrahydro-1,2,4-triazine-3- In solvents such as formic or trifluoroacetic acid, etc., in the presence or absence of (heavy) water, the product is mostly freealdehyde type, and in (solvent) water and basic solvents added with sodium bicarbonate, most are aldehyde hydrate form. In neutral solvents such as dimethyl sulfoxide (d ₆ ), free aldehyde and aldehyde hydrate forms, and water is gradually converted from free aldehyde to aldehyde hydrate. In general, structural (Ia) products are preferred.

Among the above Rs, the following groups are meant. Ie methyl, ethyl furophyl, isofurofil, butyl, isobutyl, second grade, third grade, 1,3,4-thiadiazol-5-yl, 2-methyl-1,3,4-thiadia Sol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 2-ethyl-1,3,4-thiadiazol-5-yl, 2-furophyl-1,3 , 4-thiadiazol-5-yl, 2-isofurofil-1,3,4-thiadiazol-5-yl, 2-butyl-1,3,4-thiadiazol-5-yl, 2 -Isobutyl-1,3,4-thiadiazol-5-yl, 2-2 grade, butyl-1,3,4-thiadiazol-5-yl-2,3-gradebutyl-1,3, 4-thiadiazol-5-yl, 2-hydroxymethyl-1,3,4-thiadiazol-5-yl, 2- (2-hydroxyethyl-1,3,4-thiadiazole- 5-yl, 2-aminoethyl, 1,3,4-thiadiazol-5-yl, 2-methylamino-methyl-1,3,4-thiadiazol-5-yl, 2- (2- Aminoethyl) -1,3,4-thiadiazol-5-yl, 2- (2-methylaminoethyl) -1,3,4-thiadiazol-5-yl, 2-carboxy-methyl- 1,3,4-thiadiazol-5-yl, 2- (2-carboxyl) -1,3,4-thiadiazol-5-yl, 2-methoxy-1,3,4-teeth Diazol-5-yl, 2-Methylthio-1,3,4-thiadiazol-5-yl , 2-methylsulfonyl-1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl, 2-methylamino-1,3,4- Chiadizol-5-yl, 2-dimethylamino-1,3,4-thiadiazol-5-yl, 2-acetylamino-1,3,4--thiadiazol-5-yl, 2- Methylsulfonyl-1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl, 2-methylamino-1,3,4-thiadiazole -5-yl, 2-dimethylamino-1,3,4-thiadiazol-5-yl, 2-acetylamino-1,3,4-thiadiazol-5-yl, 2-hydroxy- 1,3,4-thiadiazol-5-yl, 2-acetamidomethyl-1,3,4-thiadiazol-5-yl, 2- (2-acetamidoethyl) -1,3 , 4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 3-ethyl-1,2,4-thiadiazol-5-yl, 3-ethyl- 1,2,, 4-thiadiazol-5-yl, 3-methoxy-1,2,4-thiadiazol-5-yl, 1,2,3-triazol-5-yl, 1,3 , 4-triazol-5-yl, 1-methyl-1-methoxycarbonyl- 1,2,4-triazol-5-yl, 3-methoxycarbonyl-1-ethyl-1,2,4 -Triazol-5-yl, 1-methyl-3-ethoxycarbonyl-1,2,4- Riazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-tetrazol-5-yl, 1-ethyl-tetrazol-5-yl, 1-furophyl-tetrazol-5-yl, 1- (2-hydroxy-ethyl) -tetrazol-5-yl, 1- (3-hydroxyfurophyll) -tetrazol-5yl, 1-methoxymethyl-tetrazol-5-yl, 1- Carboxymethyl-tetrazol-5-yl, 1-sulfonyl-tetrazol-5yl, 1- (2-methylamino-ethyl) -tetrazol-5-yl, 1- (2-dimethylaminoethyl) Tetrazol-5-yl, 1- (2-dimethylaminoethyl) tetrazol-5-yl, 1- (3-dimethylaminofurophyll) -tetrazol-5-yl, 1- (2-sulfa Moylamino-ethyl) -tetrazol-5-yl, 1- (2-acetamidoethyl) -tetrazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4 -Yl, pyrid-2-yl-1-oxide, 6-methyl-pyridazin-3-yl, 6-methyl-pyridazin-3-yl-1-oxide, 6-methoxypyridazin-3-yl , 6-amino-pyridazin-3-yl, 6-acetamido-pyridazin-3-yl, tetrazolo [4,5-b] pyridazin-6-yl, 5,6-dioxo-4- Methyl-1,4,5,6-tetraha Dro-1,2,4-triazin-3-yl, 5,6-dioxo-4-ethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4-furophyll-1,4, 5,6-tetrahydro-1,2,4-triazin-3-yl,

4-allyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-hydroxy- Ethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (3-hydroxyfurophyll) -1,4,5 , 6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4-methoxymethyl-1,4,5,6-tetrahydro-1,2,4-tree Azin-3-yl, 5,6-dioxo-4- (2-methoxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5, 6-dioxo-4-methoxymethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-ethoxye 7) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- (2-acetamidoethyl) -5,6-dioxo-1,4, 5,6-tetrahydro-1,2,4-triazin-3-yl, 4-benzyl-5,6-dioxo-1,4, 5, 6-tetrahydro-1,2,4-triazine -3-yl, 5,6-dioxo-4-phenethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl,

5,6-dioxo-4- (2-glycylooxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazine- 3-yl, 5,6-dioxo- 4- (3-Glycosyloxy-furophyll) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-furo Panyloxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- (2,2-dimethoxyethyl) -5,6dioxo-1 , 4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- (3,3-dimethoxyfurophyll) -5,6-dioxo-1,4,5,6 -Tetrahydro-1,2,4-triazin-3-yl, 4- (2,2-diethoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1, 2,4-triazin-3-yl, 4- (3,3-diethoxyfurophyll) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine 3-yl, 4- (2,2-bis-methyl-thio-ethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-3- 1, 4- (3,3-bis-methylthiopropyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4triazin-3-yl, 4- (2 , 2-bis-ethylchioethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-tree Jean-3-yl,

4- (3,3-bis-ethylchiopurophyll) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6- Dioxo-4- [2- (1,3-dioxolin-2-yl) -methyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5, 6-dioxo-4- (1,3-dioxolin-2-yl) -methyl-1,4,5,6-terahydro-1,2,4-triazin-3-yl, 5,6- Dioxo-4- [2- (1,3-dichiolin-2-yl) -ethyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5, 6Dioxo-4- (1,3-dithiolan-2-yl) -methyl-1,4,5, 6-tetrahydro-1,2,4-triazin-3-yl, 5,6-di Oxo-4- [2- (1,3-oxaxolan-2-yl) -methyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl-5,6 -Dioxo-4-(1,3-dioxan-2-yl) -methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-di Oxo-4- [2- (1,3-dithia-2--2-, -ethyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl,

5,6-dioxo-4- (1,3-dioxian-2-yl) -methyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5 , 6-dioxo-4- [2- (1,3-dioxian-2-yl, -ethyl] -1,4,5,6-tetrahydro-1, 2,4-triazin-3-yl , Pyrimidin-2-yl, 5,6-dioxo-4- [methylcarbamoylmethyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5, 6-dioxo-4- (2-methylcarbamoylethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- Ethylcarbamoylmethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4-dimethylcarbamoylmethyl-5,6-dioxo-1,4,5, 6-tetrahydro-1,2,4-triazin-3-yl, 4- (2-dimethylmethylbamoylethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1 , 2,4-triazine-3-yl, 4-diechcarbamoylethyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-3- 1,4-Dimethylcarbamoylmethyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4-dimethylcarbamoylmethyl-5 , 6-dioxo-1,4,5,6-tetrahydrate -1,2,4-triazin-3-yl, 4- (2-dimethylcarbamoylethyl) -5,6-dioxo-1,4, 5,6-tetrahydro-1,2,4 Triazine-3-yl,

4-Diethylcarbamoylethyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-3-yl, 4-acetonyl-5,6-di Oxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-oxo-butyl) -1,4,5,6 Tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (3-oxobutzyl) -1,4,5,6-tetrahydro-1,2,4- Triazine-3-yl, 5,6-dioxo-4- (methoxycarbonylmethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5, 6-dioxo-4- (2-methoxy-carbonylethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo- 4- (ethoxycarbonylmethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-1,4, 5,6-tetra Hydro-1,2,4-triazin-3-yl, 5,6-dioxo-1,4,5,6-tetrahydro-4- (thiazolidin-2-yl) -methyl-1,2 , 4-triazin-3-yl, 4- (2,3-dihydroxyfurophyll) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine -3-yl, 4- (1,3-dihydroxyfurov-2-yl) -5,6-di Oxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl,

5,6-dioxo-4- (2-formyl-2-hydroxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- (2 -Aminoethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- (3-aminofurophyll) -5,6 -Dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-3-yl, 5,6-dioxo-4- (2-methyl-aminoethyl) -1,4 , 5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (3-methylaminofurophyll) -1,4,5,6-tetrahydro- 1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-ethylaminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazine 3-yl, 4- (2-dimethylaminoethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- (3-Dimethylaminofurophyll) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- (2-dimethylamino Chill) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- (3-dimethylaminofurophyll) -5,6- Dioxo-1,4,5,6-tetrahydro-1,2,4-triazine -3 days,

5, -dioxo-4- (2-sulfoaminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-Methylsulfonylaminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (3-methylsulfonyl Aminofurophyll) -1,4,5,6-tetrahydro- 1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-sulfamoylaminoethyl) -1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (3-sulfamoylaminofurophyll) -1,4,5,6-tetra Hydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-glycolylaminoethyl) -1,4,5,6-tetrahydro-1,2,4 -Triazin-2-yl, 5,6-dioxo-4- [2- (2-hydroxypropionamido) -ethyl] -1,4,5,6-tetrahydro-1,2,4 -Triazin-3-yl, 5,6-dioxo-4- (2-glycylaminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl ,

4-([2- (L) -alanylaminoethyl] -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5, 6-dioxo-4- (3-glycosylaminofurophyll) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-Methyl-aminoacetamidoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- (2-dimethylaminoacetamidoethyl ) -5,6-dioxo-1,, 4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- (2-dimethylaminoacetamidoethyl) -5 , 6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-methoxycarbonylaminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4-(2-ethoxycarbonylaminoethyl) -1,4, 5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-methoxycarbonylaminoethyl) 1,4,5,6-tetrahydro -1,2,4-triazin-3-yl, 5,6-dioxo-4- (2-ethoxy-carbonylaminoethyl) 11,4,5,6-tetrahydro-1,2, 4-tree Zin-3-yl, 5,6-dioxo-4- (2-ethoxy-carbonylaminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazine-3- 1,5,6-dioxo-1,4,5,6-tetrahydro-4- (2-ureidoethyl) -1, 2,4-triazin-3-yl,

5,6-dioxo-1,4,5,6-tetrahydro-4- (3-ureido-furophyll) -1,2,4-triazine- 3-yl, 5,6-dioxo- 4- [2- (3-methyl-ureido) ethyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- [ 3- (3-methylureido) -furophyll] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- [2 -(3-Ethyleuido) -ethyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- [2- (3,3-dimethyl- Ureido-ethyl] -5,6-dioxo-1,4,5, 6-tetrahydro-1,2,4-triazin-3-yl, 4- [3- (3,3-dimethylurey Fig.-Furophil] -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4- [2- (3,3-dimethylyl Rado) -Ethyl] -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 4-(2,2-dimethoxyfurophyll) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,40triazin-3-yl, 4- (3,3-dimethoxy-2-hydroxyfurophyll) -5 , 6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- [3- ( Octanoic gasoline-2-yl) -2-hydroxy-furo Peel] -1,4,5- tetrahydro-1,2, 4-triazine-3-yl,

5,6-dioxo-4- (2-hydroxy-2-methoxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6 -Dioxo-4- (3-hydroxy-3-methoxyfurophyll) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl ,, 5,6-di Oxo-4- (2-ethoxy-2-hydroxyoxy) -1,4,5, 6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4 -(3-ethoxy-3-hydroxyfurophyll) -1,4,5,6-tetrahydro-1,2,4-triazine-1,2,4-triazin-3-yl, 5, 6-dioxo-4- (2-hydroxy-2-puroxyoxyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-di Oxo-4- (2-hydroxyaminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (2- Hydroxyimino-furophyll) -1,4,5,6-tetrahydro-1,2,4-triazine, 5,6-dioxo-4- (2-methoxyiminoethyl) -1,4 , 5,6-tetrahydro-1,2,4-triazin-3-yl, 5,6-dioxo-4- (3-methoxyiminofurophyll) -1,4,5,6-tetrahydro -1,2,4-triazine-3 -Work,

5,6-dioxo-4- (2-ethoxyiminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 1- (formylmethyl)- 1,2,4-triazol-5-yl, 1- (2-formylethyl) -1,3,4-triazol-5-yl, 1-carbamoylmethyl-1,3,4-triazole -5-yl, 1- (2-hydroxyethyl) -1,3,4-triazol-5-yl, 1- (2-carbamoyloxyethyl) -1,3,4-triazole- 5-day, 1- (2-glycylooxyethyl) -1,2,4-triazol-5-yl, 1- (2-acetamidoethyl) -1,3,4-triazole- 5-day, 1- (2-glycilooxyethyl) -1, 2,4-triazol-5-yl, 1- (2-acetamidoethyl-1,3,4-triazole-5 -Yl, l-dimethylcarbamoylmethyl-1,3,4-triazol-5-yl, l- (2-dimethylcarbamoylethyl) -l, 3,4-triazol-5-yl- 1-acetonyl, 1,3,4-triazol-5-yl, 1- (thiazolidin-2-yl-methyl) -1,3,4-triazol-5-yl,

1- (2,3-dihydroxypropyl) -1,3,4-triazol-5-yl, 1- (1,3-yldihydroxy-2-propyl (-1,3,4-triazole -5-yl, 1- (2-formyl-2-hydroxyethyl) -1,3,4-triazol-5-yl, 1- (2-ylminoethyl) -1,3,4 -Triazol-5-yl, 1- (2-methylaminoethyl) -1,3,4-triazol-5-yl, 1- (2-dimethylaminoethyl) -1,3,4- Triazol-5-yl, 1- (2-methylsulfonylaminoalkyl) -1,3,4-triazol-5-yl, 1- (2-sulfamoylaminoethyl) -1,3,4- Triazol-5-yl, 1- (2-glycosylaminoethyl) -1,3,4-triazol-5-yl, 1- (2-glycosylaminoethyl) -1,3,4- Triazol-5-yl, 1- (2-methoxycarbonylaminoethyl) -1,3,4-triazol-5-yl, 1- (2-ureidoethyl) -1,3,4 -Triazol-5-yl, 1- [2- (3,3-dimethylureido) -ethyl] -1,3,4-triazol-5-yl, 1- (3,3-dimethoxy- 2-hydroxyfurophyll) -1,3,4-triazol-5-yl, 1- (2-hydroxy-2-methoxyethyl) -1,3,4-triazol-5-yl- 1- (2-hydroxyiminomethyl) -1,3,4-triazol-5-yl, 1- (2-methoxy Iminoethyl) -1,3,4-triazol-5-yl,

1-formylmethyl-2-methoxycarbonyl-1,3,4-triazol-5-yl, 2-ethoxycarbonyl-1-formylmethyl-1,3,4-triazol-5-yl, 1- (2-formylethyl) -2-methoxycarbonyl-1,3,4-triazol-5-yl, 1- (2-hydroxyethyl) -2-methoxycarbonyl-1,3 , 4-triazol-5-yl, 1-carbamoylmethyl-2-methoxycarbonyl-1,3,4-triazol-5-yl, 1-2- (carbamoylethyl) -2-meth Oxycarbonyl-1,3,4-triazol-5-yl, 1- (2-acetamidoethyl) -2-methoxycarbonyl-1,3,4-triazol-5-yl, 1 -(2,2-dimethoxyethyl) -2-methoxycarbonyl-1,3,4-triazol-5-yl, 1- (dimethylcarbonylmethyl) -2-methoxycarbonyl-1 , 3,4-triazol-5-yl, 1-acetonyl-2-methoxycarbonyl-1,3,4-triazol-5-yl, 1-(2,3-dihydroxyfurophyll) 2-methoxycarbonyl-1,3,4-triazol-5-yl, 1- (1,3-dihydroxyfurop-2-yl) -2-methoxycarbonyl-1,3,4 -Triazol-5-yl, 1- (3-formyl-2-hydroxyethyl) -2-methoxycarbonyl-1,3,4-triazol-5-yl, 1- (2-dimethyl -Aminoethyl) -2-methok Carbonyl-1,3,4-triazol-5-yl,

2-methoxycarbonyl-1- (2-methylsulfonylaminoethyl) -1,3,4-triazol-5-yl, 2-methoxycarbonyl-1- (2-sulfamoylamino-ethyl ) -1,3,4-triazol-5-yl, 2-methoxycarbonyl-1- (2-methoxycarbonylaminoethyl) -1,3,4-triazol-5-yl, 2 -Methoxycarbonyl-1- (2-ureidoethyl) -1,3,4-triazol-5-yl, 2-methoxycarbonyl-1- [2- (3-methylureido)- Ethyl] -1,3,4-triazol-5-yl, 1- [2- (3,3-dimethylureido) ethyl] -2-methoxycarbonyl-1,3,4-triazole- 5-yl, 1- (3-3-dimethoxy-2-hydroxyfurophyll) -2-methoxycarbonyl-1,3,4-triazol-5-yl, 1- (2-hydroxy- 2-methoxyethyl) -2-methoxycarbonyl-1,3,4-triazol-5-yl, 1,4-dimethyl-5,6-dioxo-1,4,5,6- Tetrahydro-1,2,4-triazol-yl, 1,4-dimethyl-5,6-dioxo-1,4,5, 6-tetrahydro-1,2,4-triazine-3- 1-ethyl-4-methyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 1-ethyl-4-methyl-5 , 6-dioxo-1,4,5, 6-tetrahydro -1,2,4-triazin-3-yl,

4-Methyl-1-methyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 1-methyl-5,6-dioxo- 1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 1-ethyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2, 4-triazin-3-yl, 2-methyl-5,6-dioxo-1,4,5, 6-tetrahydro-1,2,4-triazin-3-yl, 2-ethyl-5, 6-dioxo-1,4,5,6-tetrahydro-1,2,4-trijin-3-yl, 1-ethyl-1,2,4-triazol-5-yl, 2- (2 -Hydroxy-ethylchio) -1,3,4-thiadiazol-5-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-oxadiazol-5-yl, 2- Phenyl-1,3,4-oxadiazol-5-yl, 2-aminomethyl-1,3,4-oxadiazol-5-yl, 2-acetamidoethyl-1,3,4-oxa Diazol-5-yl, 2-dimethylaminomethyl-1,3,4-oxadiazol-5-yl, oxazol-2-yl,

4-Methyloxazol-2-yl, 1-formyl-methyl-tetrazol-5-yl, 1- (2-formylethyl) -tetrazol-5-yl, 1-sulfamoylmethyl-tetrazol-5 -Yl, 1- (2-carboxymethylaminoethyl) -tetrazol-5-yl, 1- (2-sulfoaminoethyl) -tetrazol-5-yl, 1- (2-ureidoethyl) Tetrazol-5-yl, 1-2- (3-methylureido) -ethyl-tetrazol-5-yl, 1-2- (3,3-dimethylureido) -ethyl-tetrazol-5 -Yl, 1- (2-hydroxyiminoethyl) -tetrazol-5-yl, 1- (3- (hydroxyiminofurophyll) -tetrazol-5-yl, 1- (2-methoxyimino Methyl) -tetrazol-5-yl, 1- (3-methoxyiminofurophyl (-tetrazol-5-yl, 1- (2,3-dihydroxyfurophyll) -tetrazol-5-yl, 1- (1,3-dihydroxyfurop-2-yl) -tetrazol-5-yl, 1- (2-formyl-2-hydroxyethyl) -tetrazol-5-yl, 1- ( 2,2-dimethoxyethyl) -tetrazol-5-yl, 1- (3,3-dimethoxyfurophyll) -tetrazol-5-yl, 1- (2-hydroxy-2-methoxy Chill) -tetrazol-5-yl, 1- (2-ethoxy-2-hydroxy ) -Tetrazol-5-yl, 2-hydroxy-1- (2-furooxyl) -tetrazol-5-yl, 1- (3-hydroxy-3-methoxy-furophyll) -tetra Zol-5-yl, 1- (3-ethoxy-3-hydroxy-furophyl) -tetrazol-5-yl, and 1- (dioxolan-2-yl-ethyl) -tetrazol-5-yl .

Among the meanings of R ⁰ are hydrogen, methyl, ethyl, furophyll, isofurophyll, butyl, isobutyl, secondary butter, vinyl and cyanome lacquer. In the meaning of said R ', they are especially hydrogen, a pivalyloxymethyl, and a cyanomethyl group.

According to the present invention, a substance having the general formula (I) (R represents a group other than triazinyl or triazolyl group substituted with a group having the general formula (IV)) It is prepared by reacting one of the alkaline earth metals with a cephalosporin derivative of the following structural formula (or, if appropriate, an isomer mixture of this derivative).

R-SH (Ⅶ)

R is as described above and, if necessary, protected with acetal form (as defined in General Formulas (II) and (III)) to obtain cephalosporin of General Formula (I) wherein R is a formyl or acylalkyl group,

[Wherein R ⁰ is as described above and R ₁ is hydrogen or a group having the formula (V) or a group that can be easily eliminated, such as methoxymethyl, tertiary-butyl, benzhydryl, p-nitrobenzyl or p-methoxy Benzyl and n is 0 or 1. If n = 0, the obtained material is of the bicyclooct-2-ene or bicyclooct-3-ene type, and if n = 1, the bicyclooct-2-ene type (according to the CA nomenclature) is obtained. Substituents substituted at the 3-position carbon atom of the crooctene have a stereoisomer configuration of E or Z.

R ₂ represents a protecting group for a hydrogen atom or an amino group, and R ₃ represents a group having the following structural formula (a) or (b).

-O-SO ₂ -R ₃ '(Ⅸ) a

Or -O-CO-R ₃ b (Ⅸ) b

R ₃ ′ is an alkyl, trifluoromethyl or trichromomethyl group or an optionally substituted phenyl group such as a halogen atom, an alkyl or a nitro group, and R '' ₃ is the same as R ' ₃ or isylmethyl, 2-asylethyl , 2-asylfurophyl alkoxycarbonylmethyl, 2-alkoxycarbonyl ethyl or 2-alkoxycarbonyl-furophil group]. The obtained oxide is reduced and appropriately removed by protecting groups.

It is understood that it is desirable to provide protection if the R groups of the general formula are susceptible to reaction (particularly if R is an amino, alkylamino, hydroxyl or carboxyl group). If R ⁰ is hydrogen, the oxime is protected in a known way without affecting the rest of the molecule.

It is understood that the R group may interfere with the reduction reaction and it is preferable to use a substance having a general structural formula of n = 0. (Particularly R is hydroxyl, scallop, sulfignyl, or sulfonyl group). The reaction is generally carried out in the presence of organic base, i.e., pyridine, tertiary organic base, etc. in the following structural formula.

The X ₁ , Y ₁ , Z ₁ is an alkyl or phenyl group or two of them form a ring with the nitrogen atom to which they are attached. For example, diisofurophylethylamine or diethylamine is used.

If the thiol alkali metal salt or alkaline earth metal salt of the general structural formula is used, it is not necessary to react in the presence of the organic base mentioned above. The reaction takes place advantageously in an organic solvent such as dimethylformamide, tetrahydrofuran or acetonitrile or a mixture of such solvents. The reaction may be carried out in the solvent described above in the presence of an alkali metal sodium bicarbonate, optionally in the presence of water.

The reaction is carried out at -20 ° C and the reflux temperature of the reaction mixture, and the temperature is appropriately selected depending on the used bias. The reaction time can be varied from 5 minutes to 48 hours depending on the same used tooth. The reaction may also be carried out arbitrarily in nitrogen. In the case where biocta-3-ene of the general structural formula is to be used, it is preferable to use a substance in which R ₁ is other than hydrogen. Reducing the oxide and removing the protecting group can be carried out by the above-described method.

-alk' OH 기이다) 다음 구조식(Ⅰ')을 갖는 물질로 부터 알려진 방법으로 분자의 나머지 부위에 영향을 미치지 않고 알콜에서 에스텔이나 카바메이트를 얻어 적절하면 이렇게 해서 생성된 썰폭사이드를 환원시키고보호기를 탈락시켜 제조할 수 있다.According to the present invention, R ⁰ and R 'of the general formula (I) are as described above, and R is 5,6-dioxo-1,4,5,6-tetrahydro 1,2,4-triazine-3- The 1,3,4-triazol-5- or 2-alkoxycarbonyl-1,3,4-triazol-5-yl group at the 4-position is carbamoyl oxy or asyloxy group at 1 position, respectively. Substances representing those substituted at the acyl moiety with 2-4 alkyl groups, optionally substituted with amino, alkylamino, or dialkylamino groups, are functional derivatives of the corresponding substances of general formula (I) (R ^0). And R 'are as described above and R is 5,6-dioxo-4-hydroxyalkyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl or 1-hydroxy Hydroxyalkyl-1,3,4-triazol-5-yl or 2-alkoxycarbonyl-1-hydroxyalkyl-1,3,4-triazol-5- selected from

-alk 'OH group) A method known from a substance having the following formula (I') is used to obtain esters or carbamates from alcohols without affecting the rest of the molecule and, where appropriate, reduce the sulfoxides produced and It can be prepared by dropping.

-alk'-OH 및 n은 상술한 바와 같고 R₂'는 수소만 제외한 R₂와 같게 정의된다. 에스텔화 작용은 온도 -50℃와 반응물질의 환류온도에서 실시하며 특히 산무수화물(혹은 할라이드와 같은 기타반응성 유도체)로 불활성 유기용매 예컨데 에텔(테트라하이드로푸란), 염화용매(예 : 메칠렌크로라이드) 혹은 동 혼합용매에서 축합시키고 이때 축합은 질소함유 염기 예를 들면 피리딘, 4-디메칠아미노-피리딘 혹은 트리알킬아민(트리에칠렌아민)의 존재하에서 알카리성 축합제(예 : 중조)로 축합시켜적절할때 얻어진 S-옥사이드를 환원시키고 보호군을 탈락시켜 제조한다.In the structural formula R ⁰ , R ₁ ,

-alk'-OH and n are as described above and R ₂ 'is defined as R ₂ except hydrogen. The esterification is carried out at a temperature of -50 ° C and the reflux temperature of the reactants, especially as acid anhydrides (or other reactive derivatives such as halides), inert organic solvents such as ether (tetrahydrofuran) and chloride solvents (e.g. Ride) or in a copper mixed solvent, which is condensed with an alkaline condensing agent (e.g. sodium bicarbonate) in the presence of a nitrogen-containing base such as pyridine, 4-dimethylamino-pyridine or trialkylamine (triethyleneamine). Prepared by reducing the S-oxide obtained when appropriate and dropping the protective group.

Carbamate is obtained by known methods without affecting the rest of the molecule. In particular, the reaction of chlorosulfonyl isocyanate or trichloro acyl isocyanate is obtained by reacting an inert organic solvent such as tetrahydrofuran or acetonitrile at a temperature of -80 -20 ° C and removing a protective group.

The material of general formula (I) can also be obtained in the same manner as in any of the above processes.

According to the present invention, in general formula (I), R ⁰ and R 'are as described above and R is 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-3 -The group is 1,2-4-triazol-5-yl or 2-alkoxycarbonyl-1,3,4-triazol-5-yl in the 4-position is sulfoamino, alkylsulfonylamino, Alkyl group having carbon number that can be substituted with sulfamoylamino, asylamino (optionally substituted with hydroxyl, amino, alkylamino, dialkylamino in the acyl region), alkoxycarbonylamino, ureido, alkylureido, and dialkylureido 1,3,4-oxadiazole-, which is substituted with < RTI ID = 0.0 > or 1,3,4-thiadiazol-5-yl < / RTI > Displayed as 5-yl or asylamino, schamomoamino, sulfoamino, eureido. Alkyl ureido and dialkyl ureido also represent a tetrazol-5-yl group which may be substituted in the 1-position with a C2-C4 alkyl group substituted by the group. These are all obtained by known methods for the formation of amides, sulfamides, carbamate or urea groups, which are functional derivatives of the corresponding amines, which do not affect other parts of the molecule, from the mutants having the following structural formula (II '). It is prepared by reducing a small poxade and removing a protecting group.

-NH₂는 5,6-디옥소-1,4,5,6-테트라하이드로-1,2,4-트리아진-3-일기는 4위치에, 1,3,4-트리아졸-5-일 혹은 2-알콕시카보닐-1,3,4-트리아졸-5-일기는 1-위치에(알킬부위는 탄소 2-4개인) 아미노 알킬기로 각각 치환된 것을 나타내며 또한 1,3,4-치아디아졸-5-일기로 아미노 혹은 아미노알킬기로 치환된 것을 나타내며 1,3,4-옥사디아졸-5-일에는 아미노알킬기로 치환되거나 테트라졸-5-일기는 1위치에 탄소수 2-4개의 알킬부위를 갖는 아미노알킬로 치환된 것을 나타낸다.R ⁰ , R ₁ , R ₂ ′ and n in the structural formula are as described above.

-NH ₂ is a 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-3-yl group at the 4 position, and 1,3,4-triazole-5- The mono or 2-alkoxycarbonyl-1,3,4-triazol-5-yl group represents a 1-position (substituted 2-4 carbon atoms) amino amino group respectively and also 1,3,4- It is substituted with an amino or aminoalkyl group by a cationadiazole-5-yl group and substituted by an aminoalkyl group by 1,3,4-oxadiazol-5-yl or a tetrazol-5-yl group by 2-4 carbon atoms in 1 position. Substituted with aminoalkyl having three alkyl sites.

It is also understood that a material having a scallop, sulfonyl, or stoolamoyl group is made of a material having the general structure (I ') of n = 0.

According to the present invention, the general structural formula (I) and R ⁰ and R 'are as described above and R is 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-3 -1 is substituted with 1,3,4-triazol-5-yl or 2-alkoxycarbonyl-1,3,4-triazol-5-yl at 1 position is substituted with a zizoridin-2-yl-alkyl group at 1 position Or substituted by a group of the general formula (IV) or a hydroxyaminoalkyl or iminoalkyl moiety having 1-5 carbon atoms and substituted by an alkoxyiminoalkyl group, and R is a tetrazol-5-yl group Substances represented by substitution of a hydroxyiminoalkyl or alkoxyiminoalkyl group having 1-5 carbons in the noalkyl moiety are addition reaction derivatives of the substance of general formula (I), wherein R ⁰ and R 'in the formula (I) As described above and R is substituted with formyl alkyl group (or its hydrate) as one of the heterocyclic structures described above. Through the stacking amine, alcohol, hydroxylamine or an alkoxy carbonyl group and an amine such as an addition reaction of the addition reaction, each corresponding to a known method, such as in derivative form sikimeuro elimination of the protecting group can be obtained.

-alk'CHO는 5,6-디옥소-4-포밀알킬-1,4,5,6-테트라하이드로-1,2,4-트리아진-3-일이나 1-포밀알킬 -1,3,4-트리아졸-5-일기를 표시한다.(Wherein R ⁰ , R ₁ , and R ₂ are as described above and −

-alk'CHO is 5,6-dioxo-4-formylalkyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl or 1-formylalkyl-1, The 3,4-triazol-5-yl group is represented.

The reaction is usually carried out in an organic solvent at 20 ° C. and the reflux temperature of the reaction mixture. The organic solvent is selected according to the solubility of the product. In the general formula (I) '경우 it is advantageous to use pyridine, dimethyl sulfoxide, dimethylformamide as a solvent when R ₁ and R ₂ are represented by hydrogen atoms.

In the general formula (I), if R represents a substance representing a substituent of the general formula (IV) and lowers, the reaction is carried out in an acidic solvent.

According to the present invention, in general formula (I), R 'denotes a group of general formula (V), and R' and R 'are materials as described above in which R' is a hydrogen atom in general formula (I). It can be obtained by protecting the amine group by esterifying it in a known manner that does not affect other parts of the molecule when preparing esters in the acid. In general, alkali metal salts or tertiary amine salts of substances of formula (I) (preliminarily protecting the amine groups and appropriately protecting the R groups and oximes) are then treated with substances of formula (XI) and inert organic compounds such as dimethylformamide. It is obtained by reacting a solvent at 0-30 degreeC temperature.

Z ₂ -CH-OCO-R '＂(Ⅸ)

Wherein R 'and R''are as described above and Z ₂ is a halogen element.

The material of general formula (XI) may be prepared by the method described in German patent application 2,350,230. The thiols of the formula (can be used for tautomerisation) are prepared by applying one of the following methods, depending on the R group. If R is a pyrid-3-yl group: H. M. Hoechst and Lee. Hitch. J. Am. Chem. Soc. 73, 1210 (1951), wherein R is a pyrid-3-yl-1-oxide group, J. Med. Chem., 17, 1065 (1974) The method described by J. Chem. Soc 2937 (1960) if R is a pyrid-4-yl-1-oxide group.

If R is a pyridazin-3-yl group substituted with an alkyl or methoxy group or an N-oxide derivative of this group, the method described in Belgian patent 787,635, pyridazin-3-yl substituted with an amino group or such The process described in Belgian patent 579,291 in the case of an N-oxide derivative of a group. If R is an alkyl, methoxy substituted pyridazin-3-yl group or an N-oxide derivative of such a group, the method described in Belgian patent 787,635, wherein R is a pyridazin-3-yl group substituted with an amino group or In the case of N-oxide derivatives, the method described in Belgianium Patent 579,291, in which R is a pyridazin-3-yl group substituted with an acylamino group or an N-oxide derivative of such groups, M, Fumagai and M peninsula Zasshi 84, 995 (1963) and by T. Hori and T. Ureda (Chem. Pharm Bull 11,11 4 (1963)), wherein R is a tetrazolo [4,5-b] pyridazine-6-yl group Method of Belgian Patent 804,251.

R is 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group at position 4 or 2-alkoxycarbonyl-1,3,4- If the triazole-5-yl group is substituted in the 1-position with an R ^r group selected from a) an allyl group, an alkyl group (2-4 carbons and optionally alkoxy, alkylthio, phenyl, carbamoyl, alkylcarbamoyl, di Alkylcarbamoyl, acylalkoxycarbonyl, or chiarizin-2-yl group)

b) 2,3-dihydroxy furophil group or 1,3-dihydroxy furof-2-yl group (optionally protected in cyclic acetal form).

c) alkyl groups [2-4 carbons, hydroxyl, carbamoyloxy, dialkylamino, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, stoolamoylamino, asylamino (optionally substituted), alkoxycarbonylamino To be substituted with ureido, alkyl ureido or dialkyl ureido

d) groups of general formula (II) or (III)

e) hydroxyiminoalkyl or alkoxyiminoalkyl groups:

Substituted with R ^r selected from the above materials, the thiosemicarbazide and alkyl oxalate of the formula (VIIa) are alkali metal alcoholates such as sodium methacrylate or sodium methacrylate or potassium tertiary butylate. Peson and M. The reaction described is applied by the method described by Antoin (Bull. Soc. Chim. France (1970) 1950).

R ^r NH CS NH-NH ₂ (VIIa)

(R ^r is as described above).

It is not necessary to purify the material obtained in order to prepare the material of structural formula (I) (do not need to liberate the protecting group).

Chiosemikabaji of structural formula (Ka) is K. a. Janssen (Acta. Chim Scand, 22,1 (1968) described the method, which was prepared according to the method described by Waikazarov and J. W. Poyowsky (Tokreddy Academy Nauk, SSSR, 134 824 (1966)). When R ^r is an amino group, the protective sieve is reacted The protection of the amino group and the removal of the protecting group are carried out according to a conventional method which does not affect the rest of the molecule.

R is substituted with an alkyl, allyl or alkoxy alkyl group at 1 position with a 1,3,4-triazol-5-yl group or with an alkyl group (with 1-4 carbon atoms) substituted vice versa in a) If substituted with a group described in c) or with an alkoxyimino alkyl group (excluding the chiazoridin-2-yl group). It is obtained by applying one of the methods of Peson and M Antonin (Bull. Soc. Chim. France 1950 (197 0)).

If R is substituted with 1,3,4-triazol-5-yl at 1 position with thiazoridin-2-yl alkyl or hydroxy-iminoalkyl, then cysteamine or hydroxyl amine is substituted with 1-dialkoxy. Alkyl-5-mercapto-1,3,4-triazole (from Methanocarga (J: Pharm. Soc. Japan 75, 1149 (1955) by 4-dialkoxyalkyl-thiosemicacarbide) Obtained).

R is 1,3,4-triazol-5-yl at 1,2,2-dihydroxyfurophyll or 1,3-dihydroxyfurop-2-yl (optionally protected in a cyclic acetal form) If substituted or if R is represented by a group of the general formula (II) or (III). Obtained by applying the method described by Kanao (J. pharm. Soc. Papan 75, 1149 (1955)).

R is a 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group at the 4-position or 2-alkoxycarbonyl-1,3,4 The -triazol-5-yl or -1,3,4-triazol-5-yl groups are each substituted with acyloxy alkyl by mouth in position 1-5,6-dioxo-4-hydroxyalkyl-3 -Mecapto-1,4,5,6-tetrahydro-1,2,4-triazine or 2-alkoxycarbonyl-1-hydroxyalkyl-5-merselto-1,3,4-triazole or 1-hydroxy-alkyl-5-mercapto-1,3,4-triazole (mercapto groups are previously protected (e.g., by C. G. Cruze. Tet. Lett. 1725 (1976), according to the method) Acylation liberates the mercapto group in an acidic solvent (acylation method is a known method that acylates alcohol without affecting the rest of the molecule).

R is a 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group at the 4-position 2-alkoxycarbonyl 1,3,4-triazole- If the 5-yl or 1,3,4-triazol-5-yl group is substituted with aminoalkyl or alkylamino alkyl at the 1 position, for example obtained by releasing the amine group to the corresponding material protected by tert-butoxy carbonyl groups.

R is a 2-alkoxycarbonyl-1,3,4triazole in which the 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group is 4-position- If 5- or 1,3,4-triazol-5-yl is substituted with sulfoamino alkyl at position 1, it is substituted with tert-butoxa carbonyl aminoalkyl group similarly to the method described in Belgian patent 847-237. Obtained from commercially available materials.

R is a 1,4-dialkyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group or 1-alkyl-5,6-dioxo-1,4,5 , 6-tetrahydro-1,2,4-triazin-3-yl is obtained by the method described in Belgium patent 830,455,

R is 2-alkyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl or 1-alkyl-3-alkoxycarbonyl-1,2 M, if it is a, 4-triazol-5-yl group. Peson and M. Obtained according to the method described by Antonin (C. R. Acad. Sci., SerC, 267,25, 1726 (1968)).

If R is a 1,2,3-triazole-5-yl group, it is obtained by the method described in French patent application 2,215,942.

If R is a 1,3,4-triazole-yl group, then M. Obtained by J. Pharm. Soc. Jap. 75,1149 (1955).

If R is a 1,3,4-thiadiazole-5-yl group substituted with an alkyl, alkoxy, alkylthio, alkylsulfonyl, anino, alkylamino, dialkylamino or asylamino group, it is described in Belgian patent 830,821. According to the method.

If R is substituted with hydroxyalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl in the 1,3,4-thiadiazole-5-yl group, the method of German patent application 2,446,254 is used.

If R is substituted with a carboxyalkyl group on 1,3,4-thiadiazol-5-yl, the method applies to German Patent Application No. 1,953,861.

If R is a 1,3,4-thiadiazole-group substituted with a trifluoromethyl group, the method described in German Patent Application No. 2,162,575 is followed.

According to the method described in Japanese Patent Application No. 77 / 48.666, when R is substituted with a carboxyl group on the 1,3,4-thiadiazole-5-yl group.

When R substitutes an acylamino alkyl group for the 1,3,4-thiadiazole-5-yl group, it follows the method as described in Japanese patent application 76 / 80,857.

If R is a 1,3,4-thiadiazole-5-yl group substituted with a hydroxy alkylthio group. Nanini, Arz. Forsch. Application of the method described in 27 (2), 343 (1977).

If R is substituted with an alkyl or alkoxy group on 1,2,4-thiadiazole-5-yl group, German patent application 2,806,226 or Chem. Ber. According to the method described in 90 184 (1957).

If R is a 1,3,4-oxadiazol-5-yl group as defined in 8a. Hogart J. Chem. Application of the method described by Soc.4811 (1952).

If R is an oxazol-2-yl or 4-alkyl-oxazol-2-yl group; Breads, J. Org. Chem. 32 The method described in 2079 (1967) is applied.

If R is tetrazol-5-yl substituted in the 1-position of alkyl, hydroxyalkyl or phenylrofoil according to the method described in Belgian patent 830,821.

If R is a tetrazol-5-yl group substituted with an alkoxyalkyl at position 1, it is further reacted with isothiocanatoalkoxyalkyl derivative at the reflux temperature of the reaction mixture in a solvent such as sodium azide ethanol.

Isothio cyanatoalkoxy alkyl derivatives are Schmidt Chem. It can be obtained by applying the method described in Ber 73 286 (1940).

If R is a tetrazol-5-yl group substituted with a carboxyalkyl group at position 1 according to the method described in Belgian patent 858,112.

If R is a tetrazol-5-yl group substituted with a sulfoalkyl group at the 1 position, the method described in Belgian patent 856,498 or J. Het. Chem 15,981 (1078) d. a. Obtained according to the method described by the burger.

If R is a tetrazol-5-yl group substituted at the position with an aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl group, obtained by subjecting the method described in German patent application 2738711.

R is schopamoylalkyl at 1 position. Tetrazol-5-yl groups substituted with a schopamoylaminoalkyl, or a sulfoaminoalkyl group, according to the method described in Belgian patent 856,636.

If R is a tetrazol-5-yl substituted with an acylaminoalkyl group or a 1,3,4-thiadiazol-5-yl group substituted with a hydroxyl group, according to the method described in US Pat. No. 4,117,123.

If R is a tetrazol-5-yl group substituted with an eureidoalkyl, an alkylureidoalkyl or a dialkylureido alkyl group in the 1 position, the alkali metal iso isopropyl from the counterpart substituted with an aminoalkyl group (the mercapto group is previously protected) Treatment with thiocyanate, alkyl isocyanate or dialkylcarbamoyl halide liberates the mercapto group under conditions recited in Belgian patent 847,237.

If R is a tetri-5-yl group substituted with a carboxyalkylaminoalkyl group at position 1, follow the method described in German patent application 2715597.

If R is a tetrazol-5-yl group substituted at the 1 position with a 2,3-dihydrooxy purophil group, according to the method described in US Pat.

When R is a tetrazol-5-yl group substituted with a 1,3-dihydroxy-furofer-2-yl group at 1 position, sodium azide is substituted with 2,2-dimethyl-1,3-dioxolane-5- Addition reaction with monoisothiocyanate (suitably releases hydroxyl groups).

If R is a tetrazol-5-yl group substituted at the position of 9e with a group of the above-mentioned structural formula (II) or (III), or a group described with 9c, sodium azide is represented by J. Pharm. Sci., 52 (9), 909 (1963), al. this. Similar to the method described by ortho, it is reacted to the corresponding isothiocyanate. When R had a hydroxyl or hydroxyaminoalkyl substituent, it was understood that the alcohol or oxime function was adequately protected with, for example, a tetrahydro pyranyl group.

Substances of structural formula (I) include acid derivatives of R ' ₃ SO ₃ H or R'' ₃ COOH (see Structural Formulas (IXa) and (IXb))

(R ₃ SO ₂ ) ₂ O (a) R ' ₃ SO ₂ Hal (b) (R'' ₃ CO) ₂ O (c) R'' ₃ CO Hal (d) (XII)

(Wherein R ′ ₃ and R ″ ₃ are as described above and Hal is a halogen element).

It can be prepared by acting on a material having the following formula (XIII) (a mixture of isomers).

In the structural formula n is as described above, R ' ₁ is the same as R ₁ but not hydrogen. Substances are microoct-2-ene or bicyclooct-3-ene or 3-oxo ethylidene-bicyclooctane if n = 0 and bicyclooct-2-ene or 3-oxo if n = 1 -Ethylidene-bicyclooctane type and R ' ₄ is represented by a group having the general formula (XVI).

(Wherein R ⁰ is as described above and R ′ ₂ is defined as R ₂ excluding only hydrogen atoms) (R ₄ represents a group that can be easily removed). When R ₁ and R ₂ are hydrogen, the protective group is removed from the amine group or the acid group.

It has been found that oxime needs to be protected if R ₄ is a group of the general formula (XIV) wherein R ⁰ is hydrogen.

The reaction is generally carried out in the presence of tertiary bases as defined in the general formula (e.g., triethylamine or N, N-dimethylaniline) and in organic chlorides (e.g. Directly in a solvent such as ether, dioxane or tetrahydrofuran, an amide such as dimethylacetamide or dimethylformamide, acetonitrile or N-methylpyrrolidone, or a basic solvent such as pyridine. It is carried out at temperatures between -78 ° C and the reflux temperature of the reaction mixture in the presence of alkaline condensing agents (eg alkali metal bicarbonate, caustic soda or caustic). When appropriate the reaction is carried out in nitrogen. It is not necessary to purify the intermediate of general formula (XIII) before carrying out this reaction. The dropping of the protecting group of the amine group or the acid group can be carried out in the same manner as in the case of obtaining the substance of Structural Formula (I).

The substance of the formula (VII) is a substance having the general formula (XVI) and one of the acids or copper active derivatives of the following formula (XV) in which the amine group has been previously protected (wherein R ₁ , R ₃ and n Is as described above and if n =-the substance is bicyclooct-2-ene or bicyclooct-3-ene type and n = 1 bicyclooct-2-ene type of carbon atom at 3 position of bicyclooctene. Substituents represent the E or Z stereoisomers) and act on a mixture of animal matter and the resulting oxide is reduced appropriately and the protecting groups are obtained appropriately.

Provided that R ⁰ is as described above.

R ₁ , R ₃ and n are as described above. Reduction of oxides or removal of protecting groups can be carried out under the conditions described in patent application 83-1132 when preparing the material of formula (I).

The substance of formula (XIII) (when n is 0) can be obtained by hydrolyzing enamine (or mixture of isomer enamines) having formula (XVII).

R ′ ₁ and R ′ ₄ are the same as described above.

The substance is in the form of bicyclooct-2-ene or bicyclooct-3-ene, and the substituents on the carbon atom at the 3-position of bicyclooctene represent the formation of the E and Z solids and R ₇ and R ₈ are the same or different ( Optionally substituted with hydroxyl, alkoxy, amino, alkylamino, or dialkylamino groups) and form a 5-6 ring saturated heterocyclic ring with an attached nitrogen atom, indicated by an alkyl or phenyl group, selected from nitrogen, oxygen, sulfur, etc. It optionally contains a bicyclic element and is substituted with an alkyl group.

Enamines of the general formula (XVII) (R ₇ and R ₈ each represent a methyl group) are preferably hydrolyzed.

The reaction is carried out at temperatures between 20 ° C. and the reflux temperature of the reaction mixture in an aqueous or organic solvent in an organic acid (eg formic acid or acetic acid) or in an inorganic acid (eg hydrochloric acid or sulfuric acid) and in the presence or absence of a solvent.

When the reaction is carried out in an organic solvent, it is hydrolyzed by adding water to the reaction mixture, and hydrolyzed by appropriate treatment with an inorganic base (for example, alkali metal bicarbonate) or an organic base (tertiary amine or pyridine).

The reaction is carried out in the presence of a solvent and the solvent need not be mixed with the acidic aqueous layer. If it is not mixed, it may be stirred vigorously and contacted.

Solvents used are chlorinated solvents acetylacetate, tetrahydrofuran, acetonitrile, dimethylformamide and alcohols, and it is not necessary to purify intermediates of formula (XVII).

The material of the general formula (XIII) can be obtained by oxidizing the general formula (XIII) (where n is 0) by applying the method described in German Patent Application No. 2637176 when n is 1. Likewise, a substance having the general formula (XVI) and (XVI) in which n is 1 is oxidized by applying the method described in German Patent Application No. 2,637,176 to the substance of the general structural formula (XVI) in which n is 0. Get A substance of the general formula (XVII) wherein R ₇ and R ₈ are as described above, except for alkyl groups substituted with hydroxyl, amino or alkyl amino, is a substance of the formula

Wherein R ₇ and R ₈ are defined as being the same or different as R ₉ and R ₁₀ and each represents the following general structural formula.

-X ₂ R ₁₁ (XIX) a

X ₂ is an oxygen atom and R ₁₁ is an alkyl or phenyl group

One of R ₉ and R ₁₀ represents the structural formula (XIX) a (wherein X ₂ is oxygen, sulfur element and R ₁₁ is alkyl or phenyl group) and the other represents an amino group having the following structural formula.

R ₁₂ and R ₁₃ are defined as R ₇ and R ₈ , and R ₉ and R ₁₀ each represent a group of the structural formula (XIX) b. The substance of the above formula (XVII) can be obtained by acting on a cephalosporin derivative of the following formula:

R ' ₁ and R' ₄ are as described above, and the resultant material is 3-methyl-bicyclooct-2-ene or 3-methyl-bicyclooct-3-ene or 3-methylene-bicyclooctane type. to be. If a material different from the (XIX) group-NR ₇ R ₈ is selected in the material of the formula (XVIII), it is preferable to select a material in which the amine HNR ₁₂ R ₁₃ is more volatile than the HNR ₇ R ₈ .

The reaction is generally carried out in an organic solvent such as dimethyl sulfoamide or hexamethyl phosphorotriamide or in a solvent mixture (e.g., dimethylformamide / tetrohydrofuran, dimethylformamide / dimethylacetamide, dimethylformamide). Amide / etheryl or diethylformamide / dioxane) and at 20 ° C. and the reflux temperature of the reaction mixture. When R ₄ is a group having the general structure (XIV) (which is an R ⁰ hydrogen atom), the oxime is preferably protected under the above conditions. Substances of the formula (XVII), wherein R ₁ ′ and R ₄ ′ are as described above and R ₇ and R ₈ are represented by hydroxyl, amino or alkylamino substituted alkyl groups, wherein the general formula (XVII), wherein R ₇ And R ₈ can be obtained by the transition reaction of an amine from a substance of an alkyl group, in particular a methyl group).

The amine of the following structural formula and the substance of the structural formula (XVII) are reacted under the above-mentioned conditions in which the raw material of the general formula (XVIII) is acted on the derivative of the structural formula (XX).

R ₇ ′ and R ₈ ′ represent the same or different alkyl groups substituted with hydroxyl, amino or alkylamino groups.

Materials having the structural formula (XIX) are described in Chem. Ber. 101 41 (1968). Chem. Ber. 101,3058 (1968) and Chem. Ber. 106 3725 (1973), prepared by the method described by H. Bradrack.

Separosporin derivatives of general formula (XX), wherein R ₄ 'represents a group of general formula (XIV)

(Wherein R ₁ 'is as described above) can be prepared by reacting the acid of the formula (XV) or a derivative thereof with the conditions described in obtaining the substance of the formula (I). Structure (representing a group wherein R ₁ 'has the following structural formula (Ⅴ)) (XX) and cephalosporin derivatives to Sefar of (XXⅡ) is R ₁ is R ₁ is formula (Ⅴ) attributed the following structural formula in the material of formula (Ⅰ) a hydrogen atom ( A process for preparing the material of I) can be obtained by esterifying the corresponding acid.

Structural Formula (XX) of the material (or R ₁ 'is the case of (XXⅡ) Im) protecting group R _1' and the R ₄ 'is a 7-amino cephalosporin of Sepharose following structural formula (XXⅢ) according to the methods described in each reference Can be taken down.

The site of the double bond is as described above.

If R ₄ 'is a formaldehyde: J. Amer. Chem. Soc. 80.J. 1156 (1958). city. Following the method described by Shhhan.

R ₄ 'if it is a acetyl, chloroaceyl, trichloroaceyl, phenyl acetyl, phenoxy acetyl or benzoyl group. H. According to the method described by Hulin Low Separosporin and Penicillin Acadcmic Press (1972).

If R ₄ ′ is a tertiary butoxycarbonyl group, Z Physiol. Chem. 357,1651 (1976), according to the method by El Morrower and Hoffsail.

If R ₄ ′ is 2,2,2-trichloro-1,1-dimethyl-enoxycarbonyl, Jay, wet season Angew. Chem. Int-Ed. According to 17 (5), 361 (1978).

R ₄ ′ is 2,2,2-trichloro-ethoxycarbonyl, 2-chloro-1,1-dimethyl-ethoxycarbonyl, 2-cyano-1,1-dimethylethoxycarbon Neyl, 20trimethylsilyl-ethoxycarbonyl, benzyl-oxycarbonyl, P-methoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, P-nitrobenzyloxycarbonyl, or vinyloxycarbon Indicated by Neil: Chloroformate is operated in the presence of an aqueous organic solvent and an alkali metal bicarbonate or obtained according to Belgian Patent No. 788,885.

If R ₄ is a diphenylmethoxycarbonyl group, the corresponding azide formate is acted in the presence of an aqueous organic solvent and a carbonate in the alkali metal.

If R ₄ is 2- (biphenyl-4-yl) -isopropoxycarbonyl, then Helv. Chem. Acta. Similar to the method described in 51 924 (1968).

If R ₄ is quinol-8-yl oxycarbonyl or allyloxycarbonyl, act on the corresponding carbonate in the basic aqueous organic solvent.

If R ₄ is 0-nitrophenylthio or P-nitrophenylthio. Jervas. J. Amer. Chem. Soc. 85, 3660 (1963).

J when R ₄ 'NH- is substituted with dimethylaminomethyleneamino. F. feet. J. Org. Chem. 42 (15) 2639 (1977), similar to the method described.

R ₄ 'NH- is substituted with 4-nitro-benzylideneimino or 3,4-dimethoxy-benzylideneimino, R. a. Shirestone. According to the method described in Tetrahedron Lett, 33, 2915 (1977).

If R ₁ ′ is a methoxymethyl group, S. Three meals. By Tetrahedron Lett, 33, 2915 (1977).

If R ₁ 'is a third-level assistant, al. second. Thread only J. Med. Chem. 9,444, (1966).

If R ₁ ′ is P-nitrobenzyl or P-methoxybenzyl, then R, R, Schubert, J. Org. Chem. By 38 (17) 2994.

If R ₁ is benzhydryl, it is according to Flan Patent Application 73 / 03,263.

The substance of formula (VII) is from the substance of formula (XXIV).

In the above, R ', R ₁ ', R ₃ and n are as described above and Hal is chlorine, bromine atom.

Isomers of the substances of structures (I), (XIII), (XIII), (XVII), and (XX) can be separated by chromatography or crystallization.

The novel materials according to the invention can be converted to acids and added salts.

Substances by the process of the invention can be obtained in the form of trifluoro acetates, tabric acids or water and in the form of a dissolved product with paratoluenesulfonate.

The substance in which R in the formula (I) is defined by the present invention may be converted or liberated into salts with other acids by conventional means, obtained in the form of salts.

The material according to the invention can be converted to metal salts or to addition salts with nitrogen-containing bases. These salts can be obtained by reacting metal bases (e.g., alkali or earth metal bases), ammonia, or amines with the material according to the invention, wherein the solvent is exchanged with the salt of an organic acid using alcohol, ether or water. Happens as. The precipitated salt is concentrated by filtration, then separated by filtration, decantation or freeze vacuum drying.

Examples of pharmaceutically acceptable salts include addition salts with hydrochloric acid (hydrochloric acid, bromic acid, sulfates, nitrates, phosphates) or organic acid salts (amber salts, humarates, maleates, P-toluenesulfone salts) and alkali metal salts (sodium, Carry, lazium) or methylamine, triethylamine, methylamine, furophilamine, diisofurophylamine, N, N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-β -Phenethylamine, N, N'-dibenzylethylenediamine, diphenyleneamine, benzhydrylamine, quinine, corinine, arginine, lysine, leucine, or dibenzylamine).

The novel materials according to the invention are optionally purified by physical methods such as crystallization or chromatography.

The novel cephalosporin derivatives and their pharmaceutically acceptable salts according to the invention exhibit particularly useful antimicrobial activity.

VITRO and VIVO show significant effects on gram negative and positive bacteria. In VITRO, the substance of formula (I) has antibacterial activity against Staphylococcus aureus Siimth, which is susceptible to penicillin G at concentrations of 0.5 and 15 µg / cc, and 1-30 for strains of Staphylococcus aureus resistant to penicillin G. Antimicrobial activity was observed at the concentration of μg / cc.

(Staphylococcus aureus MB9),

In Escherichia coli Monod, sensitivity was shown at 0.001-1 µg / cc at 0.06-30 µg / cc. Proteus marganii was sensitive at 0.01-30µg / cc and Enter obacter aerogenes at 0.1-30µg / cc.

In the VIVO experiment, the substance of Structural Formula (I) was (Staphylococcus aureus Smith susceptible to penicillin G) and was administered at a dose of 0.2-15 mg / kg per day for subcutaneous injection to mice infected. Subcutaneous injection is charged at 0.001 and 10mg.kg daily.

Substance LD ₅₀ of Structural Formula (I) is 15 g / kg and 2.5 g / kg or more in a subcutaneous injection in mice.

Of particular interest are products in which R represents the meaning listed below in formula (I) a.

1) methyl, L-2-amino-2-carboxyl or phenyl,

2) pyrid-2-yl or pyrid-2-yl-N-oxide

3) N-oxides of pyridazin-3-yl or those substituted with methyl or acetoamido groups at the pyrimidin-2-yl or 6 position;

4) 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl having the following groups substituted at the 4 position,

a) 1-2 carbon atoms substituted with one to three carbon atoms of alkyl, alkoxy, alkylthio, phenyl, formyl, carbamoyl, alkyl carbamoyl, dialkylcarbamoyl, alkoxycarbonyl or thiazoridin-2-yl An alkyl group having,

b) allyl or 2,3-dihydroxyfurophil group,

c) hydroxyl, carbamoyloxy, asyloxy (substituted or unsubstituted with an amino group), amino, alkylsulfonylamino, asylamino (substituted or unsubstituted with an amino group), alkoxycarbonylarmoni, eureido or alkylureido Substituted 2-3 alkyl groups.

d) in the formula (II), alk has 1-2 alkylenes of carbon, X ^α and Y ^α are oxygen atoms, R ^α is an alkyl group and R ^β represents a hydrogen atom,

e) an alkyl group having 1-3 carbon atoms substituted with an alkoxyimino or hydroxyimino group.

4) 1,3,4-triazol-5-yl or 2-alkoxycarbonyl-1,3,4-triazol-5-yl substituted with a group of formula (II) or formyl alkyl or 2 A group substituted with a 3-dihydroxy purophil group,

5) 1,4-Dialkyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 1-alkyl-5,6-dioxo -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl or 2-alkyl-5,6-dioxo-1,2,5,6-tetrahydro 1,2, 4-triazin-3-yl,

6) 1-alkyl-3-alkoxycarbonyl-1,2,4-triazol-5-yl,

7) a) 1,3,4-thiadiazol-5-yl (substituted or unsubstituted with alkyl, amino, aminoalkyl, alkyl amino alkyl, dialkylaminoalkyl, or acylaminoalkyl groups)

b) 1,2,4-thiadiazol-5-yl substituted with an alkyl group,

8) a) 1,3,4-oxadiazol-5-yl substituted with alkyl or phenyl group,

b) 4-alkyl-oxazol-2-yl,

9) tetrazol-5-yl substituted at the 1 position with the following groups,

a) an alkyl group unsubstituted or substituted with formyl group,

b) an alkyl group having 2-3 carbons substituted with hydroxyl, amino, alkylamino, dialkylamino, or acylamino,

c) R ⁰ of the above formula (II) is a hydrogen atom, methyl, vinyl, cyanomethyl group and R 'is a hydrogen atom and the alkyl or acyl group mentioned above has 1-2 carbon atoms, unless aliased. It is understood to have.

Of these products, substances of formula (Ia) are particularly active.

R ⁰ in structural formula (Ia) is methyl, vinyl or cyanomethyl,

R 'is hydrogen

R is selected from the following.

1) Pyrid-2-yl and its N-oxide

2) 6-methyl-pyridazin-3-yl N-oxide

3) 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl substituted with the following at the 4 position;

Alkyl group having 1-2 carbon atoms substituted with alkoxy, alkylthio, phenyl or formyl group, allyl or 2,3-dihydroxyfurophyll group, hydroxyl, carbamoyloxy, asyloxy (substituted with amino group, unsubstituted), 2-3 carbon atoms substituted with alkylsulfonylamino, asylamino (substituted or unsubstituted with an amino group), alkoxycarbonylamino or alkylureide, 1-3 alkyl groups substituted with alkoxyimino, hydroxyamino group,

4) substituted with dimethoxyalkyl group at the 1-position of 2-alkoxycarbonyl-1,3,4-triazol-5-yl,

5) 1,4-dialkyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl,

6) 1-alkyl-3-alkoxycarbonyl-1,2,4-triazol-5-yl,

7) 1,3,4-thiadiazol-5-yl substituted with alkyl, dialkylaminoalkyl, or acylaminoalkyl groups, 1,2,4-thiadiazol-5-yl substituted with alkyl groups,

8) phenyl-1,3,4-oxadiazol-5-yl and 4-alkyl-oxazol-2-yl,

9) alkyl group, hydroxyl, dialkylamino, acylamino group substituted with 2-3 alkyl, dimethoxyalkyl, alkyl, acyl groups in the 1 position of tetrazol-5-yl (without separate indicator) It is understood to have one to two carbon atoms.

Preferred among these products are materials having the structure (la).

Where R ⁰ is methyl

R 'is hydrogen

R is selected from the following materials.

1) pyrid-2-yl-N-oxide,

2) 6-methyl-pyridazin-3-yl-1-oxide,

3) 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl having the following groups substituted at the 4 position,

a) an alkyl group of 1-2 carbons substituted with alkoxy, alkylthio or formyl,

b) allyl or 2,3-dihydroxy purophil group,

c) an alkyl group having 2-3 carbons substituted with a hydroxyl, carbamoyloxy, asyloxy or asylamino group (with or without an acyl moiety substituted by an amino group), alklonylamino, alkylureid,

4) 1-alkyl-3-alkoxycarbonyl-1,2,4-triazol-5-yl,

5) 1,3,4-thiadiazol-5-yl substituted with dialkylaminoalkyl or acylaminoalkyl,

6) Tetrazol-5-yl substituted with the following group at 1-position,

a) alkyl group

b) an alkyl group having 2-3 carbons substituted with a hydroxyl or acylamino group. It is understood that an alkyl or an acyl group or the aforementioned site (unless specifically stated) has 1-2 carbon atoms.

The following materials are of particular interest.

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido-2-carboxy-3- {2- [4- (2,3-dihydroxyfurophyll ) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3 yl) -thiovinyl} -8-oxo-5-thia-1-aza- Bicyclo [4,2,0] oct-2-ene, S yn-isomer, E-type)

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2- [5,6-dioxo-4- (2 -Formyloxy-ethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thio-vinyl} -8-oxo-5-thia-1-aza-r Cyclo [4,2,0] oct-2-ene, Syn-isomer, E-type.

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2- [5,6-dioxo-4- (formyl Methyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3 yl] -thiovinyl} -8-oxo-5-thia-1-aza-bicyclo [4,2 , 0] oct-2-ene, syn-isomer, E-type, 3- {2- [4- (2-acetamido-ethyl) -5,6-dioxo-1,4,5,6- Tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -7-2-[(2-amino-thiazol-4-yl) -2-methoxyimino-acetamido]- 2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene; syn-isomer, E-type and

7- [2- (2-Amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2- [4- (2-methoxyethyl)- 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn-isomer, E-form,

The following example does not have a limiting meaning but only shows how the present invention can be realized.

In this example, the product is described by Chemical Abstract Nomenclature. All the cephasophorin eurotes mentioned represent stereochemistry represented by the following partial structural formula.

Example 1

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-Togyloxyvinyl) -5-thia-1-aza-bicyclo- [4.2.0] -oct-2-ene (Syn-isomer, mixture of E- and Z-form) (8.03 g), di A mixture of methylformamide (8 0 cc), methylmercaptan (1.59 g) and N-ethyl-N, N-diisofurophylamine (1.53 cc) is heated to 40 ° C. in an autoclave for 5 hours. The mixture was washed with ethyl acetate (500 cc), diluted with solids (3 x 250 cc), 0.1 N hydrochloric acid (100 cc), 1% sodium bicarbonate (100 cc) and half saturated saline (2 x 200 cc), dried over sodium sulfate, 20 Dry and concentrate under reduced pressure (20 mmHg) at < RTI ID = 0.0 > The residue is dissolved (by volume) in a mixture of 50:50 cyclohexane and ethyl acetate (100 cc) and chromatographed on Melksilica gel (0.04-0.06 mm) (300 g) (column diameter 6 cm height: 36 cm).

Elution is carried out in a 05:50 (volume) mixture of cyclohexane and ethyl acetate (8 liters) at 40 kPa pressure to collect 125 cc fractions. Fractions 25 to 57 are mixed and evaporated to dryness under 20 ° C. (20 mmHg). 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -3- (2-methylisovinyl) Collect (8 g) -8-oxo-5-oxide-5-chia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer E and Z-form mixture) in the form of a creamy foam stabilizer do.

Infrared spectrum (CHBr ₃ ): characteristic bands (cm ⁻¹ ) are 3380, 1800, 1720, 1080, 1515, 1370, 1205, 1045, 835, 750 and 740.

Proton nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.17 (s, 3H, -CH ₃ E-gud): 2.35 (s, 3H, -CH ₃ Z type): 3.25 3.93 (AB, J = 18.2H, -SCH ₂ -Z-type): 3.44 and 4.3 (AB, J = 18.2H, -SCH ₂ -Z type): 4.09 (s, 3H, -OCH ₃ ): 4.58 ( d, J = 9,1H, H at 6 position): 6.12 (dd, J = 4 and 9,1H, H at 7 position): 6.17 (d, J = 10,1H, -CH = CH-S-CH ₃ , Z type) 6.65 (d, J = 15,1H, -CH = CH-S-CH ₃ , E type): 6.88 (d, J = 10,1H, = CH = S = CH ₃ , Z type) : 7.15 (d, J = 15,1H, = CH-S-CH ₃ , E type): 6.72 (s, 1H, Chiazole (H in position): 0.98 (s, 1H, -COOCH): 7.07 (s , Broad, 1H, (C ₆ H ₅ ) ₃ CNH-).

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -3- (2-methylthiovinyl)- 8-oxo5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (a mixture of Syn-isomers E and Z form (2.30)) with methylene chromide (25 cc) and dimethyl In acetamido (1.04 cc) solution, incubate for 30 minutes with phosphorus trichloride (0.46 cc) at -10 ° C. Dilute the mixture with erythroate (500 cc) and saturate with 2% thickener (2 × 100 cc). Washed with brine (2 × 100 cc), dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure of 20 ° C. (20 mm Hg).

The residue is dissolved in methylene chromide and the solution is chromatographed on Melksilica gel (0.04-0.06) (15 0 g) (column diameter: 4 cm, height 20 cm). A 60:40 mixture of (by volume) of cyclohexane and ethyl acetate (2 liters) is eluted at 40 kPa pressure. Collect 215 cc of sort. Fraction 4-3 was concentrated at 20 ° C. under reduced pressure (20 mmHg). 2-benzhydryloxycarbonyl-7 [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -3- (2-methylthiovinyl) -8 -Oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (mixture of Xyn isomers E and Z form) (1.32 g) is obtained as a cream foam.

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3390, 1780, 1715, 1680, 1515, 1370, 1200, 1050, 1035, 750 and 740.

Proton nuclear magnetic resonance spectrum (350MH ₂ , CDCL ₃ δ = ppm, J = HZ): 2.18 (s, 3H, CH ₃ , E-type): 2.31 (s, 3H, -CH ₃ , Z-type): 3.44 ( AB, J = 18,2H, -SCH ₂ , E-type): 3.80 (AB, J = 18, 2H, -SCH ₂ -Z-type): 4.08 (s, 3H, -OCH ₃ ): 5.06 (d, J = 4,1H, H in 6 position): 5.80 (dd, J = 4 and 9,1H, H, E in 7 position): 5.90 (dd, 4, 9,1H, H, Z in 7 position ): 6.14 (d, J = 11,1H, -CH = CHS-Z-type (6.64 (d, J = 16,1H, -CH = CHS, E-type): 6.70 (d, J = 11,1H , = CHS-Z type: 6.79 (s, 1hH, H at 5th position of toothbrush): 6.93 (s, 1H, -COOCH-): 6.98 (d, J = 16,1H, = CHS-, E type) .

2-benzhydryloxycarbonyl-7- [2-methoxyimino- (2-trimethylamino-thiazol-4-yl) -acetamido] -3- (2-methylthiovinyl) -8- Dissolve oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (a mixture of Syn isomers E and Z (1.26 g) in formic acid (35 cc), add water and mix the mixture to 50 Heat for 15 minutes at C. Let stand, cool, filter (20 mmHg, 20 ° C.), dry under reduced pressure and concentrate.

The residue is triturated in diethyl ether (20 cc), filtered, washed with ether (20 cc) and dried. 7-[(2-2-aminothiazol-4-yl) -2-methoxyimino-acetamido-2-carboxy-3- (2-methylthiovinyl) -8-oxo-5-thia-1 -Aza-Beccyclo [4.2.0] oct-2-ene (Syn isomer, mixture of Form E and Z) (0.63 g) is obtained as a lysate with creamy powdered formic acid.

Rf = 0.34 and 0.48 [silica gel chromatography plate, solvent: ethylacetate / acetone / formic acid / water 60: 20: 1: 1 (volume ratio).

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3320, 1770, 1675, 1530, 1035 proton nuclear magnetic resonance spectrum (350MHZ, DMSO d ₆ , ppm at δ, HZ, J) E-type: 2.34 (s , 1H, -SCH ₃ ): 3.61 and 3.77 (AB, J = 18,2H, -SCH _2- ): 3.86 (s, 3H, -OCH ₃ ): 5.14 (d, J = 4,1H H at 6 position ): 5.62 (dd, J = 4 and 9,1H, H at 7 position): 6.77 (s, 1H, Hazole at position 5): 6,85 (d, J = 16, 1H, -CH-S -): 7.04 (d, J = 16,1H, = CH-S): 9.57 (d, J = 9,1H, -CONH-): Z type: Observe the following signals: 2.35 (s, 3H,- SCH ₃ ): 6.74 (d, J = 13,1H, = CH = CH-S-CH ₃ ) and 6.83 (d, J = 13,1H, = CHS-).

2-benzhydryl oxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-Tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, a mixture of Form E and Z) can be prepared as follows.

Bis- (dimethylamino) -ethoxymethane (0.91 g) to 2-benzhydryloxy-carbonyl-7- [2-methoxyimino-2-2-trimethylamino-thiazol-4-yl) Acetamido] -3-methyl-8-oxo-5-chia-1-bicyclo [4.2.0] oct-2-ene (Syn isomer) (2.5 g) and dimethylformamide (50 cc) And heated at 80 ° C. The solution turns greenish brown.

Leave at 80 ° C for 20 minutes, cool down immediately, place in ethyl acetate (200cc) and wash the mixture with water (3x80cc) and saturated saline (50cc). Ethyl acetate is stirred at 20 ° C. for 1 hour in the presence of 1N hydrochloric acid (37.5 cc). The aqueous phase is removed and the organic phase is washed with saturated tritium (20cc) and again with saturated brine (20cc).

The organic phase is dried over magnesium sulfate, filtered in the presence of decolorized carbon and concentrated at 40 ° C. under reduced pressure (20 mmHg).

The residue was dissolved in anhydrous pyridine (10 cc), cooled the solution to 5 ° C. in an ice bath, tosyl chloride (0,87 g) was added and the reaction mixture was returned to 20 ° C. After an hour and a half, the mixture is poured into ice water (200 cc), and when a precipitate is formed, it is filtered, washed with water (2 x 20 cc) and dissolved in ethyl acetate (50 cc).

The solution was washed with saturated sodium bicarbonate solution (20cc) and saturated brine (20cc) and concentrated to dryness at 40 ° C. under reduced pressure (20cc) under decolorized coal drying over magnesium carbonate. The solution obtained by dissolving the residue in chromide (13 cc) is cooled to -10 ° C in a freeze / methanol bath. 85% pure m-crorofer benzoic acid (0.226 g) is added to methylene chloride (10 cc) for 15 minutes. The reaction mixture was left for 20 minutes between −10 ° C. and + 5 ° C., washed twice with saturated saturated solution (20 cc), dried over magnesium sulfate, filtered in the presence of decolorized coal, and concentrated to dryness at 40 ° C. under reduced pressure (20 mmHg). The residue is chromatographed on a column of silica gel (26 g) (diameter 1.7 cm high 20 cm). Eluate with ethyl acetate / cyclohexane mixture (120,240,200 and 120cc, respectively 70:80, 30:70, 40:60, 60:40 (volume ratio)) to obtain an elution fraction 20cc.

Sort 17-34 was evaporated and 2-benz-hydryloxycarbonyl-7- [2-methoxyimino- (2-trichil-aminothiazol-4-yl) -acetamido] -8-pretend -5-side-3- (2-tosyloxyvinyl)-5-thia-1-aza-bicyclo [4.2.0] -oct-2-ene (Syn-type, E-Z type mixture (0.88g) Advantageous.

2-benzhydryloxcarbonyl-3-methyl-8-oxo-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -5- Chia-1-aza-bicyclo [4.2.0] oct-2-ene, Syn isomer can be prepared as follows.

7-amino-2- was dissolved in an aqueous solution of 2- (2trimethylaminothiazol-4-yl) -2-methoxyimino-acetic acid (Syn isomer) (7.2 g) in methylene chloride (22.5 cc). Benzhydryloxycarbonyl-3-methyl-8-oxo-5-thia-1-azabicyclo- [4.2.0] oct-2-ene (3.15 g) dissolved in (31.5 g) methylene chloride At once. The temperature rises from 8 ° C. to 14 ° C. The mixture is stirred for 1 hour and 15 minutes and the temperature is lowered to 20 ° C. while stirring. Wash with 0.5-hydrochloric acid (10c c) and wash with distilled water (10cc) and saturated sodium bicarbonate solution (20cc). Insoluble matters are removed by filtration, the organic phase is washed again with distilled water (2 x 200 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mmHg).

The residue is chromatographed on a silica gel (125 g) column (3 cm in diameter and 33 cm in height). Elution is carried out in an ethyl acetate / cyclohexine mixture (a composition ratio of 1.2 and 1 liter for each volume ratio of 20:80, 40:60) and 50cc of the elution milk powder is collected. Milk powder 31 to 44 were evaporated and 2benzhydryloxycarbonyl-3-methyl-8-oxo-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) acet Amido] -5-chia-1-aza-bicyclo [4.2.0] oct-2-ene, Syn isomer (2.8 g) is obtained as pale yellow solid. 7-amino-2-benzhydryloxycarbonyl-3-methyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene is described in the patent application No. 73 / 03,263. It can be prepared by one method.

Example 2

Thiophenol (0.90 cc) and N-ethyl-N, N-diisofurophylamine (1.53 cc) were added to 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trichil). -Amino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct 2-ene (syn isomer, a mixture of E and Z forms) (8.03 g) was added to a solution dissolved in dimethylformamide (80 cc) and cooled to + 2 ° C. in nitrogen.

The cerium compound was stirred at 20 ° C. for 2 hours, diluted with ethyl acetate (320cc), washed with water (3 × 150cc), 0.1N hydrochloric acid (100cc), 5% deionized solution (150cc) and saturated brine, and dried over sodium sulfate. And concentrated to dryness under reduced pressure (20 mmHg) at 20 ° C. It is dissolved in methylene chloride (35 cc) and chromatographed on a column (melon silica gel (0.04-0.06 mm) (2.50 g) 6 cm in diameter and 30 cm in height). Collect 100 cc milk powder. The milk powder 12-32 was evaporated at 20 ° C. and reduced pressure (20 mm Hg) to yield 2-benzhydryl oxycarbonyl-7- [2-methoxyamino-2-2- (2-triethylamino-teeth) on yellow poppal. Zol-4-yl (acetamide) -8-oxo-5-oxide-3- (2-phenylthiovinyl) -5-thia-1-azi-1 ㅣ cyclo [4.2.0] oct-2- En (a mixture of Syn isomers E and Z (4.8 g) is obtained).

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ^-1 ) are 3380, 2820, 1975, 1720, 1680, 1580, 14 75, 1445 and 1440.

Proton nuclear magnetic resonance spectrum (350MHZ, CDCl ₃ , ppm to δ, HZ in J): 3.93-3113 (AB, J = 19,2H, -SCH ₂ -E type): 4.32 and 5.0 AB, J = 19,2H , -SCH _2- , E type: 4.05 (s, 3H, -OCH ₃ , Z type): 4.51 (d, 1H, J = H, E type at 4,6 position): 4.56 (d, 1H, J = H, Z type at 4, 6 position): 6.10 (dd, J = 4 and 9.1H, H, E type at 7 position) 6.14dd, J = H, Z type at 4, 9, 1H, 7 position) : 6.41 (d, J = 11, 1H, -CH = CH-S, Z type), 6.6 (d, J = 16, 1H, CH = CH = S, E type): 6.71 (s, 1H, thiazole H, Z form 5): 6.72 (s, 1H, thiazol) H, Z form 5: 5,933 (s, CO ₂ CH): 7.09 (s,-NH-, thiazole).

2-benzhydryloxycarbonyl-7- [2-methoxyamino 2- (2-trimethylamino-thiazol-4-yl) acetamido] -8-oxo-5-oxide-3- (2 -Phenylthiovinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (syn, a mixture of isomers E and Z) (4.8 g) was mixed with methylene chloride (51 cc) Phosphorus trichloride (0.98 cc) was added to the solution dissolved in methylacetamide (2.02 cc), stirred at −10 ° C. for 1 hour, and placed in ethyl acetate (300 cc). The solution is washed with 5% thick solution (2 x 150 cc) and saturated brine (150 cc), dried over sodium sulfate and concentrated to dryness under reduced pressure (20H g at 20 ° C).

It is dissolved in methylene chloride (30 cc), and the solution is chromatographed on a column of Melx silica gel (250 g) (0.02-0.06 mm) (diameter 5 cm, height 30 cm).

Elute to 65:35 (by volume) mixture of cyclohexane and ethyl acetate (2 L) at 0.4 bar pressure. Collect 100 cc milk powder. Evaporation of powdered milk 10-16 gave creamy foamed 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) acetamido [- 8-oxo-3- (2-phenylthiovinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (mixture with Syn isomer E) (2.6 g) is obtained.

Proton nuclear self-resonance spectrum (350MHZ, CDCl ₃ , ppm to δ, HZ to J): 3.42 and 3.52 (AB, J = 19,2H, -SCH ₂ -E type): 3.50 and 3.88 (AB, J = 19, 2H, -SCH ₂ -Z type: 4.07 (s, 3H, -OCH ₃ E type): 4.09 (s, 3H, -OCH ₃ , Z type): 5.07 (d, J = 4,1H, 6 position H, E type): 5.10 (d, J = 4,1H, H, Z type at 6 position): 5.87 (dd, J = 4 H, E type at 4H, 9H, 7 position): 5.93 (dd J = 4 and 9, 1H, H, Z type at 7 position): 5.93 (dd, J = 4, 9, 1H, H, Z type at 7 position): 6.41 (d, J = 4, 1H,- CH = CH-S-, Z type: 6.70 (d, J = 16,1H, -CH-CH-S-, E type6.76 (s, H at position 5): 6.95 (s, -CO ₂ CH): 6.95 (d, J = 11, 1H, -CH = CH-S-, Z type): 7.22 (d, J = 16,1H, -CH = -CH-S, E type): 7.01 (s , Wide area, -NH-thiazol).

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-3- (2-phenyl Thiovinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene] (mixture of Syn isomers E and Z) (2.6 g) is dissolved in formic acid (40 cc) and the solution is water. Dilute to (12.5cc) and heat at 50 ° C for 20 minutes. Cool and filter off the insoluble material and evaporate to dry the filtrate under reduced pressure (20 mmHg). The residue was triturated in ethyl ether (50cc), filtered, washed with ether (50cc), and dried. A yellow powder was dissolved in formic acid to give 7- [2- (2-aminothiazol-4-yl) -2-methoxy. Mino-acetamido] -2-carboxy-3- (2-phenylthiovinyl) -8-oxo-5-chia = 1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, E And a mixture of Z) (1.3 g).

Infrared spectra (kBr), characteristic bands (cm ^-1 ) are 3320, 1775, 1680, 1530, 1380, 1045, 945, 745 and 690.

Proton nuclear magnetic resonance spectra (DMSO d ₆ , 350MHZ, ppm at δ Hz J): 3.65 and 3.94 (AB, J = 18, 2H, -SCH ₂ , E-type): 3.84 (s, 3H, -OCH ₃ ): 7.17 (H, E at d, J = 4,1H, 6 position): 5.22 (H, Z at d, J = 4,1H, 6 position): 5.73 (dd, J = 4 and 9 , H, E type at 1H, 7 position): 6.61 (d, J = 11,1H, -CH = CH-S-, Z type): 6.80 (d, J = 11,1H, -CH = CH-SS (Z type): 6.98 (d, J = 15, 1 H, -CH = CH-S-, E type): 7.06 (d, J = 15, 1H, -CH-CH-S-, E type): 6.74 (s, H at tooth position 5): 7.18 (wide signal, -NH ₃ ⁺ and -CO ₂ H): 8.11 (s, HCO _2- ): 9.58 (d, J = 9, 1H, -CON H -).

Example 3

7- [2- (2-aminothiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxo-3- (2-tosyloxyvinyl) -5-thia- Dissolved in 1-aza-bicyclo- [4.2.0] oct-2-ene (Syn isomer, Form E) and formic acid (0.1 g) and anhydrous N, N-dimethylmethylamide (1 cc) Dissolve the lysate with thiophenol (0.02 g) and cool to 0 ° C.

A solution in which N, N-diisoprophyl-N-ethylamine (0.069 g) was dissolved in N, N-dimethylmethylamide (3 cc) was added dropwise. The reaction mixture is again warmed and incubated at 25 ° C. for 1 hour. Evaporation of the melt at 30 ° C. and reduced pressure (10 mmHg) gave a residue (0.19 g). Chromatography experiment of the residue [silica gel chromatography: field solution: ethyl acetate / acetone / water / acetic acid mixture (volume) ratio of 50: 20: 10: 10] to 7- [2- (2-amino- thiazole -4-yl) -methoxyimino-acetamido] -2-carboxy-8-oxo-3- (2-phenylthiovinyl) -5-thia-1-aza-bicyclo [4.2.0] oct- 2-ene (Syn isomer Form E Rf = 0.62 is shown. 7- [2- (2-Amino-thiazol-4-yl) -methoxyimino-acetamido] -2-carboxy-8- A solution of oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza = bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) and formic acid is obtained as follows. Can be.

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-3- (2-tosyl Vinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer E type) (1.5 g) was dissolved in a mixture of formic acid (30 cc) and distilled water (10 cc), followed by solution. Heated at 50 ° C. for 30 min.

After cooling, the precipitate was filtered off and the filtrate was concentrated to dryness at 30 ° C. and reduced pressure (10 mmHg). The residue was triturated in ethyl ether (50 cc), the insoluble solids were filtered off, washed with dieth ether (2 × 25 cc) and dried under reduced pressure (25 mmHg) at 7 ° C. to 7- [2- (2-amino-thiazol- 4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxo-3- (2-mosyloxyvinyl) -thia-1-aza-bicyclo [4.2.0] oct-2 -N (Syn isomer, Form E) (075 g) is obtained as a melt of formic acid value.

Rf = 0.57: silica gel chromatography:

Eluate: Ethyl acetate / acetone / water / acetic acid mixture (volume) 50: 20: 10: 10. 1 R Spectrum (kBr): Characteristic band (cm ^-1 ) is 3400, 3340, 3000, 2820, 2200, 1775, 1720, 1670, 1630, 1370, 1190, 1165, 1070. Proton nuclear magnetic resonance spectrum (350MHz, DMSO d ₆ = ppm, Hz = J) 2.42 (s, 3H, -CH ₃ , tosyl): 3.55 And 3.78 (AB, J = 19, 2H, -SCH _2- ): 3.83 (s, 3H, -OCH ₃ ): 5.14 (d, J = 4, 1H, H at 6 position), 5.75 (dd, J = 4 and 9,1H, H at 7 position: 6.65 (d, J = 12,1H), -CH = C H-OSO ₂ ): 6.73 (s, 1H, H at tooth position 5): 7.18 (s , a wide ^{_{area, -NH 3 +): 9.58 (}} d, J = 9,1H, -CONH-).

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido-3- (2-tosyloxyvinyl) -3 -Oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2 (-Syn isomer, Form E) is prepared as follows.

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -3- (2-tooxyoxyvinyl)- 8-oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (3 g) was dissolved in methylene chloride (30 cc), N, N-dimethylacetamide (1.2 cc) is added. The solution is placed in a dry nitrogen atmosphere, stirred for 90 minutes between -10 ° C and 1 ° C, diluted with ethyl acetate (250cc) and washed with an aqueous saturated sodium bicarbonate solution (15cc) and saturated brine (2x100cc).

After drying over magnesium sulfate and filtration, the organic solution is concentrated to dryness at 30 DEG C and low pressure (20 mmHg). The organic solution is concentrated to dryness under reduced pressure (20 mmHg) at 30 ° C. The residue was taken in methylene chloride (20 cc) and the solution was chromatographed on a column of silica gel (0.04-0.063 mm) (240 g) (height 25 cm, diameter 5 cm). Eluate the mixture with cyclohexane and ethylacetate (2L) at 60:40 (volume ratio), and collect 100cc of milk powder. Concentrate the milk powder 8-13 under reduced pressure of 30 ℃ (20mmHg). 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -4- (2-tosyloxyvinyl)- Obtain 3-oxo-5-thia-1-aza-1 | cyclo [4.2.0] ox-2-ene (Syn isomer E form) (1.7 g).

Rf = 0.52: silica gel chromatograph plate: eluate: cyclohexane / ethyl acetate (volume) 50: 50.

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3400, 1790, 1725, 1685, 1520, 1375, 1190, 1180, 1075, 1050, 755, 740.

Proton nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , ppm N, Hz J): 2442 (s, 3H, -CH ₃ , tosyl), 3.33 and P.42 (AB, J = 19,2H, -SCH ₂ ): 4.07 (s, 3H, -OCH ₃ ): 5.03 (d, J = 4, 1H, H at 6 position): 5.87 (dd, J = 4 and 9, 1H, H at 7 position), 6.71 ( s, 1H, Chiazole, H at 5 position: 6.87 (s, 1H, -CO ₂ CH-): 6.87 (d, J = 10, 1H, -CH = CH-SOS _2- ): 7.0 (s, Wide area, 1 H, -NH thiazole). 7.78 (d, J = 9, 1H, -CONH-).

2-benzashidrilloxycarbonyl-7- [2-methoxysimino-2- (2-trimethylamino-4-thiazol-4 -yl) -acetamido-8-oxo-5-oxide- 3- (2-Tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomers Form E and Form Z) is prepared as follows.

Dicyclohexylcarbodiamide (1.85 g) to Syn-2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetic acid (7.97 g) to methylene chloride (100 cc) It is added to the dissolved solution with stirring and cooled to + 4 ° C. The solution is stirred at + 4 ° C for 40 minutes at 20 ° C for 30 minutes and then filtered.

The filtrate was cooled to -30 < 0 > C and 7-amino-2-benzhydryloxycarbonyl-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [ 4.2.0] Quickly add a solution of oct-2-ene (a mixture of Form E and Z (3.47 g) dissolved in methylene chloride (30 cc) containing triethylamine (0.84 cc). Remove the bath and stir the reaction mixture for 1 h 50 min at 20 ° C. Concentrate to dryness under reduced pressure (20 mmHg) at 20 ° C., add residue to ethyl acetate (250 cc) and wash organic phase with water (3 × 100 cc) and 0.05 N After washing with hydrochloric acid (100cc), 1% sodium bicarbonate solution (100 cc) and semi-saturated aqueous saline (2 × 100cc), dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure (20 ° C., 20 mmHg).

The residue is taken up in ethyl acetate (20 cc) and cyclohexane is added. The solution is filtered and chromatographed on a column (6 cm in diameter, 30 cm in height) of Melxilica gel (0.04-0.06 mm) (300 g).

Elution is carried out under a 40:60 (volume) mixture of cyclohexane and ethyl acetate (4 liters) under 40 K pa pressure to collect 125 cc milk powder. Concentrate the 6-25 milk powder at 20 ° C. low pressure (20 mmHg) to yield 2-benzhydryl oxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl)- Acetamido-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, E and Z (4.8 g) is obtained in a cream foam form.

Perform chromatographic separation twice as described above to separate from z-type (1.21g) 읠 12-16 milk powder, form E (1.49g) from 22-40 milk powder and 17-21 milk powder from E and It contains Z-type complex (0.8 g).

Infrared Spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3380, 1800, 1720, 1680, 1510, 1375, 1175, 1045, 1000 and 735.

Proton nuclear magnetic resonance spectrum (350MHz, CDCl ₃ , ppm = δ, Hz = J): 2.03 (s, 3H, -C ₆ H ₄ -CH ₃ ): 3.36 and 4.07 (2d, J = 19,2H,- SCH _2- ): 4.09 (s, 3H, -OCH ₃ ): 4.52 (d, J = 4,1H, H at 6 position): 6.16 (dd, J = 4 and 9,1H, 7 position H), 6.43 (AB, J = 8,2H, -CH = CH): 6.86 (s, 1H, -CH-OCO): 6.71 (s, 1H, H at diasol 5 position): 7.75 (d, J = 9 Sat Pachi, H), E type:

Infrared Spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3380, 1800, 1725, 1685, 1515, 1380, 1190, 1180, 1070, 1050, 755 and 753.

Proton nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , δ in ppm, J at Hz): 2.45 (s, 3 H, -C ₆ H ₄ -CH ₃ ): 3.19 and 3.77 (2d, J = 18, 2H, -SCH _2- ): 4.08 (s, 3H, -OCH ₃ ): 4.6 (d, J = 4, H at 6 position): 6.18 (dd, J = 4 and H at 9, 7 position), 6.72 (s , 1H, H azole at position 5): 6.93 (d, J = 12, 1H, -CH = CH-OSO _2- ): 7.11 (d, J = 12, 1H, -CH = CH-OSO _2- ) : 6.90 (s, 1H, -COOCH-): 7.73 (d, J = 9,2H, H on tosyl groups).

7-amino-2-benzhydryloxycarbonyl-3-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-chia-1-aza-bicyclo [4.2.0] oct-2- En (E-Z mixture) is prepared as follows.

2-benzoacetoxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza in acetonitrile (150 cc) -A solution of bicyclo [4.2.0] oct-2-ene (a mixture of Form E and Z) (4.06 g) is stirred with p-toluenesulfonic carbohydrate (2.28 g) at 20 ° C. for 16 hours.

The mixture was concentrated to 10 cc under reduced pressure (20 mmHg) at 20 ° C., diluted with ethyl acetate (150 cc), washed with 2% sodium bicarbonate (100 cc), washed with saturated aqueous saline solution (2 × 150 cc), and dried over sodium sulfate. Concentrate to dryness under reduced pressure (20 mmHg) at 20 ° C. Thus 7-amino-2-benzhydryloxycarbonyl-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct- 2-ene (a mixture of form E and Z) (3.5 g) is obtained as a brown solid.

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3430, 3360, 1780, 1725, 1970, 1170, 1180, 1070, 745 and 700.

Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , ppm J in Hz): 2.43 (s, 3H, -CH ₃ ): 3.12 and 3.75 (2d, J = 18, 2H, -SCH _2- ): 4.36 ( d, J = 4, 1H, H at 6 position: 4.75 (d, J = 4, 1H, H at 7 position): 6.87 (d, J = 12, 1H, -CH = OSO _2- ): 6.90 ( S, 1H, COOCH-): 6.99 (d, J = 12, 1H, CHOSO _2- ): 7.40 and 7.71 (2d, J = 9, -C ₆ H _4- ).

2-benzhydrooxycarbon-7-t-butoxycarbonyl-amino-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0 Oct-2-ene (E and Z mixed) is obtained by the method described in Example 14 of the divided application 83-1132.

Example 4

2-benzohydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido-8-oxo-5-oxide-3- ( 2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer E type) (5.02 g) with dimethylformamide (75 cc), Nt-butoxy Carbonyl-L-cysteine (2.21 g) and N, N-diisofurophylethylamine (2.61 cc) are stirred in nitrogen at 60 ° C. for 2 hours 30 minutes.

After angulation, the mixture is diluted with ethyl acetate (500 cc) and the organic phase is washed with water (2 x 400 cc), washed with 0.1 N hydrochloric acid (250 cc) and saturated with half-saturated aqueous saline solution (2 50 cc) in sodium sulfate. Dried, filtered and concentrated to dryness under reduced pressure (20 mmHg) at 20 ° C. The residue is dissolved in acetonitrile (50 cc).

Diphenyldiazomethane (0.97 g) was added to acetonitrile (25 cc) at 20 ° C. with stirring and the mixture was stirred at 20 ° C. for 2 hours and diluted with ethyl acetate (500 cc). In a separatory funnel, wash with 0.05 N hydrochloric acid (100 cc) in 1% sodium bicarbonate solution (100 cc) and half saturated salt solution (2 x 100 cc), dry over sodium sulfate, and filter.

Concentrate to dryness under reduced pressure (20 mmHg) at 20 ° C.

The residue is taken up in a mixture of cyclohexane and ethyl acetate (50 cc), 60:40 (volume), and the solution is chromatographed on a melk silica gel (0.04-0.06 mm) (200 g) column (diameter 6 cm, height 30 cm). Elution is carried out with an electric mixture (4 L) under 40 kPa pressure. Collect 115 cc milk powder. Combine milk powder 11-23 and concentrate under reduced pressure (20 mmHg) at 20 ° C. to yield 2-benzhydryloxycarbonyl-3- [2- (2-L-benzhydryloxy-carbonyl-2-t-butoxycarbon Nylamino-Ethyl) -thiominyl] -7- [2-methoxyimino-2-2 (trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- Tooth -1-aryl-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (3.57 g) is obtained.

Infrared spectra (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3380, 1796, 1710, 1690, 1510, 1 445, 11365, 1045, 940, 750 and 740.

) : 6.10 (dd, J=4와 9, 1H, 7위치에 H) : 6.39(d, J=7, 1H, -NHCOO-) : 6.41(d, J=16, 1H,=C HS-) : 6.71(s,1H, 치아졸 H) : 6.85(s, 1H,

) : 6.93(s, 1H,

) : 7.10(S, 1H, -NH-C(C₆H₅)₃).Furotone Hex Resonance Spectrum (350MHz, CDCl ₃ , ppm, δ, Hz J): 1.48 (s, 9H, -C (CH ₃ ) ₃ ): 2.95 and 3.75 (2d, J = 18,2H, -SCH _2- ): 3.20 (d, J = 7, 2H, -SCH _2- ): 4.08 (s, 3H, OCH ₃ ): 4.48 (d, J = 4, 1H, H in 6 position): 4.67 (mt, 1H,

): 6.10 (dd, J = 4 and 9, 1H, H in 7 positions): 6.39 (d, J = 7, 1H, -NHCOO-): 6.41 (d, J = 16, 1H, = C HS-) : 6.71 (s, 1H, Chiazole H): 6.85 (s, 1H,

): 6.93 (s, 1H,

): 7.10 (S, 1H, -NH-C (C ₆ H ₅ ) ₃ ).

Dimethylacetamide (1.35cc) was added with stirring with phosphorus trichloride (0.50cc) to 2-benzhydryloxycarbonyl-3-2- (2-L-benzhydryloxycarbonyl-2-t-part Methoxycarbonyl-amino-ethyl) -thiovinyl-7- [2-methoxy-imino-2- (2-trimethylamido-thiazol-4-yl) -acetamido] -8-oxo- A solution obtained by dissolving 5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (4.14 g) in methylene chloride (45 cc), Cool to 10 ° C. and add. The mixture was stirred at −10 ° C. for 1 hour, diluted with ethyl acetate (600c c), washed with 2% sodium bicarbonate (2 × 100 cc) and half-saturated saline solution (2 × 100 cc), prepared in sodium sulfate, filtered, and then -2. Concentrate to dryness under reduced pressure (20 mmHg).

The residue was dissolved in a mixture of cyclohexane and ethyl acetate (60 cc) and 65:35 (volume) and chromatographed on a Velk silica gel (0.04-0.06 mm) (250 g) column (5 cm in diameter). Elution is carried out under a 40 kpa pressure mixture of 65:35 (volume) of cyclohexane and ethyl acetate (2 L) to obtain 130 cc of milk powder.

Combine milk powders 5 to 8, concentrate at reduced pressure (20 mmHg), 20 ° C, and dry to yield 2-benzhydryloxycarbonyl-3- [2- (2-L-benzhydryloxycarbonyl-2- on yellow foam). t-butoxycarbonylamino-ethyl) -thiovinyl] -7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo- 5-Aza-1-bicyclo [4.2.0] octo-2-ene (Syn isomer, Form E) (2.78 g) is obtained.

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3400, 1780, 1710, 1690, 1515, 1495, 1450, 1390, 1370, 1050, 945, 755 and 745.

Furotone Hex Resonance Spectrum (350MHz, CDCl ₃ , δ = ppm, J = Hz): 1.43 (s, 9H, (CH ₃ ) ₃ -C-): 3.22 (2AB, limit, 4H, -SCH _2- ) : 4.10 (S, 3H, -OCH ₃ ): 4.70 (m, 1H, CHNH-): 5.36 (s, Wide area, 1H, -NHCOO-): 5.04 (d, J = 4, 1H, H at 6 positions) : 5.85 (dd, J = 4 and H at positions 9 and 7): 6.41 (d, H = 16, 1H, = CHS-): 6.8 (s, 1H, H of toothbrush): 6.88 (s, 1H, -CH-COO-CH-): 6.93 (S, 1H, -COOCH-): 7.03 (s, 1H, -NH-C (C ₆ H ₅ ) ₃ ): 7.08 (d, J = 16, 1H,- CH = CHS-).

2-benzhydryloxycarbonyl-3- [2- (2-L-benzhydryloxycarbonyl-2-t-butoxycarbonylamino-ethyl) -thiovinyl] -7- [2-methoxy Mino-2- (2-trimethylamino-1,3-thiazol-4-yl) -acetamido] -3-oxo-5-thia-1-aza-bicyclo [4.2.0] -oct- 2-ene (Xyn isomer, Form E) (2.71 g) is dissolved in formic acid (40 cc), diluted with water (40 cc) and stirred at 50 ° C. for 30 minutes. The mixture is cooled at 20 ° C., filtered and concentrated to dryness under 30 ° C. reduced pressure (0.05 mmHg).

The residue is continued to be absorbed in ethanol for 3 hours (75 cc per hour) and the solution is evaporated to dryness at 20 ° C. under reduced pressure (20 mmHg). The solid residue is treated with ethanol (200 cc) while refluxing and the cooling suspension is filtered. Wash with dry ethyl ether (3 × 25 cc) and dry to afford 3- [2- (2-L-amino-2-carboxyl) -thiovinyl] -7- [2- (2-amino1, 3-teeth Zol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, E) (1.34 g).

Infrared spectrum (KBr), characteristic band (cm ⁻¹ ) is 3500, 2000, 1750, 1660, 1530, 103 5, 940.

CHCOOH) : 6.77(s, 1H, 치아졸 H) : 6.92(AB, 2H, -CH=CH-) : 7.20(s, 3H, -⁺NH₃-) : 9.58(d, J=9, 1H,-CONH-).Proton nuclear magnetic resonance spectra (350MHZ, DMSO d ₆ , ppm = δ, Hz = J): 3 to 3.7 0 (hump, 4H, -SCH ₃ -Sephalosporin and side chains): 3.87 (s, 3H, -OCH ₃ ): 5.15 (d, J = 4, 1H, H at 6 position): 5.65 to 5.72 (H and 2 at H, 7H)

CHCOOH): 6.77 (s, 1H, Chiazole H): 6.92 (AB, 2H, -CH = CH-): 7.20 (s, 3H,- ⁺ NH _3- ): 9.58 (d, J = 9, 1H, -CONH-).

Example 5

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (6.0 g) and dimethylformamide (60 cc) and N, (2.1 cc) 2-mercaptopyridine (1.33 g) is reacted with N-diisopurophylethylamine in nitrogen at 20 DEG C for 2 hours. The mixture is diluted with ethyl acetate (400 cc), the organic phase is washed with distilled water (2 × 500 cc), washed with half saturated sodium bicarbonate (300 cc) and then with half saturated saline (300 cc). Dry over magnesium sulfate, filter, and concentrate under filtration under 70 deg. The residue was dissolved in methylene chloride (25 cc) and chromatographed on a column (5 cm in diameter) of Melk silica gel (0.04-0.06 mm) (300 g). Elution is carried out with an 80:20 (volume) mixture of methylene chloride and ethyl acetate (4 L). Collect 100 cc milk powder. Combine milk powder from 17 to 34 and concentrate to dryness under reduced pressure (20 mmHg) at 35 ° C. The residue was dried under reduced pressure (0.2 mmHg) at 20 DEG C for 15 minutes to give 2-benzhydryloxycarbonyl-7- [2-methoxyimino 2- (triethylamino-thiazol-4-yl) -acetic acid on a yellow foam. Amido] -8-oxo-5-oxide-3- [2- (pyrid-2-yl) -thiovinyl [-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (3.9 g) is obtained.

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl-acetamido] -8-oxo-5-oxide-3- [ 2- (pyrid-2-yl) -thiovinyl] -5-thia-1-azi-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (3.9 g), Dimethylforma Mide (1.6 cc) methyl chromide (40 cc) and phosphorus trichloride (0.7 cc) are stirred at −15 ° C. for 1 hour.

The resulting solution is poured into ethyl acetate (600 cc) and the organic phase is washed with half saturated sodium bicarbonate (2 x 200 cc). Dry over sodium sulfate and filter. The filter cake is washed with ethyl acetate (100 cc) and the filtrates are combined and concentrated under reduced pressure (20 mmHg) at 35 ° C. The residue was taken up in methylene chloride (30 cc) and chromatographed on a column (4 cm in diameter) of melk silica (0.04-0.06 mm) (150 g). Elution is carried out with a 95: 5 (volume) mixture of methylene chloride and ethyl acetate (4.5 L).

Collect 100 cc milk powder. The milk powders 10 to 40 are combined and concentrated to dryness at 35 ° C. (20 mmHg) and the residue is dried for 15 minutes at 20 ° C. (0,2 mmHg) to give 2-benzhydryloxycarbonyl-7- [2-methoxyimino- 2- (2-trimethyl-amino-thiazol-4-yl) -acetamido] -8-oxo-3-2- (pyrid-2-yl) -thiovinyl-5-thia-1-aza Obtain bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (2.4 g).

2-benzhydryloxycarbonyl-7- [2-methoxyamino-2- (2-trimethyl amino-thiazol-4-yl) -acetamido] -8-oxo-3- [2- ( Pyrid-2-yl) -thiovinyl] -5-thia-1-aza-bicyclo [4. 2. 0] Octoc-2-ene (Syn isomer, Form E) (2.40 g) is added to a formic acid (21 cc) and distilled water (20 cc) and stirred at 50 ° C for 1 hour. After cooling the suspension is filtered and the filter cake is washed with distilled water (20 cc). The combined filtrates are washed with distilled water at 35 ° C. under reduced pressure (0.2 mmHg). Concentrate under 35 ° C. reduced pressure (0.2 mmHg) and the residue is taken up in ethanol (100 cc) and concentrated under reduced pressure (20 mmHg). The solid obtained is decomposed with distilled water (20 cc) at 20 ° C., the mixture is filtered and the filter cake is washed with distilled water (15 cc), ethanol (1 2 cc) and ether (20 cc). Dry at 25 ° C. under reduced pressure (0.2 mmHg) for 15 minutes to afford 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxo-3 -[2- (pyrid-2-yl) -thiovinyl] -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Sy n isomer, Form E) (1.05 g) Get

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3500, 2820, 2600, 1775, 1670, 165 0, 1630, 1575, 1450, 1415, 1380, 1040, 940 and 765.

Proton nuclear magnetic resonance spectra (350MHz, DMSO d ₆ , ppm = δ, Hz = J): 3.72 and 3. 95 (2d, J = 18, 2H, H in 4 positions): 3.85 (s, 3H, -OCH ₃ ): 5.20 (d, J = 4, 1H, H at 6 position): 5.57 (dd, J = 4 and 9, H at position 7): 6.76 (s, 1H, H of toothbrush): 7.15 (d , J = 17, 1H, -CH-CHS-): 7.18 (s, 2H, amino): 7.44 (d, J = 16, 17, -CH = CHS-): 7.75 and 8.2 (d, t, 1H, J = 8, H at pyridine 4 position: 8.50 (t, 1H, J = 4. H2 of pyridine): 9.50 (d, J = 19, 1H, -CONH-).

Example 6

2-benz in which 2-mercapto-pyridine-N-oxide (0.43 g) and N, N-diisofurophylethylamine (0,6 cc) were dissolved in anhydrous N, N-dimethylmethylamide (85 cc) Hydryloxycarbonyl-7- [2-methoxyimino-2 (2-trichiminomino-thia-4--4-)-acetamido] -8-oxo-3- (2-tosyloxyvinyl) To a -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (3,4 g) solution was added and the mixture was stirred at 25 ° C. for 30 minutes. 2-mercaptopyridine-N-oxide (0.43 g) and N, N-diisofurophyletchamine (0.6 cc) are further added, and the mixture is stirred at 25 ° C. for 10 minutes and then diluted with ethyl acetate.

The mixture is washed with water (2 × 200 cc), washed with 0.1 N hydrochloric acid (200 cc) and saturated brine (200 cc), dried over magnesium sulfate and the solution is evaporated under 40 ° C. reduced pressure (30 mmHg). The residue (3.5 g) is added to the material obtained in the same way (0.5 g) and the mixture is chromatographed on Melk silica gel (0.04-0.06 mm) (30 g) (column diameter 5 cm). Elution is carried out at 50 kpa pressure to 10 liters of the mixture of acetylacetate and ethanol 98: 2 (volume).

Collect 120 cc lactation. Unchanged starting material (1.1 g) is recovered from milk powders 2 to 4. Concentrate and dry the powder at 45 to 75 at 40 ° C. and reduced pressure (30 mmHg) to form 2-benzohydryloxycarbonyl 7- [2-methoxyimino-2- (2-trimethylamino-thiazole-) as a gray foam. 4-yl) -acet-amido-8-oxo-3- [2- (pyrid-2-yl-1-oxide) -thiovinyl] -5-thia-1-aza-bicyclo [4.2.0 ] Oct-2ene (Syn isomer, Form E) (1.6 g) is obtained.

Infrared spectrum (CHBr ₃ ): characteristic bands (cm ⁻¹ ) are 3390, 1780, 1720, 1680, 1585, 1510, 1465, 1420, 1040, 945 and 450.

Proton nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , ppm = δ, Hz = J): 2.60 and 3.69 (AB, J = 18, 2H, -SCH _2- ): 4.80 (s, 3H, NOCH ₃ ): 5.12 (d, J = 4, 1H, H at 6 position): 5 .97 (dd, J = 4 and 9, 1H, H at 7 position): 6.57 (d, J = 16, 1H, -CH = CHS- ): 6.76 (s, 1H, H of toothbrush): 7.0 (s, 2H, CH (C ₆ H ₅ ) ₂ and (C ₆ H ₅ ) ₃ CNH-): 7.1 to 7.5 hemp, directional): 8.25 ( d, J = 9, 1H, -CONH-).

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl-acetamide-8-oxo-3- [2- (pyrid- 2-yl-1-oxide) -thiovinyl] -5-thia- 1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E ((2,3g)) formic acid (54cc ), Dilute with distilled water (21 cc) and stir for 20 minutes at 50 ° C. Heat filtration and evaporate the solvent under reduced pressure (10 mmHg) at 40 ° C. The residue is dissolved in 50 cc of ethanol and the mixture is decompressed at 40 ° C. (30 mmHg). Evaporation to dryness Repeat this operation once more The residue is taken up in ethanol (50cc), the solids are filtered off, washed with ethanol (15cc) and ethylethyl (2x2 5cc) and decompressed at 25 ° C (10mmHg). Dry under gray powder 7- [2-amino-thiazol-4-yl) -acetamido] -2-carboxy-8-oxo-3- [2- (pyrid-2-yl-1-oxide ) -Thiovinyl] -5-thia-1-azi-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (0.98 g) Get

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3300, 1770, 1670, 1540, 1470, 142 0, 1040, 950 and 760.

Nuclear Magnetic Resonance Spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 3.75 and 4.16 (AB, J = 18, 2H, -SCH _2- ): 3.88 (S, 3H, = NOCH ₃ ): 5.24 (d, J = 4, 1H, H at 6 position): 5.73 (dd, J = 4 and 9, 1H, H at 7 position): 6.78 (S, 1H, H of toothbrush): 7.05 and 7.32 (AB , J = 16, 2H, -CH = CH-S: 7.63 (d, J = 7, 1H, H at 3 position of pyrimine group): 7.1 to 7.5 (Hump and pyridine in 4H, 4- ⁺ 5 position of NH ₂ ): 7.63 (d, J = 7, 1H, H at 3 position of pyridine): 8.22 (d, J = 6, H at 6 position of pyridine): 9.64 (d, J = 9, 1H, -C ONH-).

Example 7

2-benzhydryloxycarbonyl obtained by dissolving 2-mercapto-pyrimidine (1.12 g) and N, N-diisopurophyl-ethylamine (1.75 cc) in N, N-dimethylmethylamide (50 cc). -7- [2-methoxyimino-2-(2-trimethylaminochizol-4-yl) acetamido] -8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza Add to bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (5.0 g) solution and stir the reaction mixture in nitrogen at 20 ° C. for 15 min and dilute with ethyl acetate (250 cc). The organic solution was continuously washed with distilled water (250cc), semi-saturated sodium bicarbonate solution (250cc) and finally with saturated brine (250cc). The organic solution was dried over magnesium sulfate, filtered and the solvent was dried under reduced pressure (40 占 폚). Evaporated under 25 mmHg, 33 kpa). The resulting (5 g) material is chromatographed on Melk Sealica gel (0.04-0.06 mm), column (4 cm height 30 cm). Elution is carried out at a 95: 5 (volume) mixture of methylene chloride and ethyl acetate (25 L) at 60.3 kpa to collect 100 cc milk powder. Milk powder 15 to 24 were combined and concentrated under reduced pressure at 40 ° C. (25m mHg, 3.3 kpa) to yield 2-benzhydryloxycarbonyl-7- (2-methoxyimino-2- (2-triethylamino-thiazole- 4-yl) -acetamido-3-oxo-3- [2- (pyrimidin-2-yl) -thiovinyl] -5-thia-1-aza-bicyclo [4.2.0] oct-2- N (Syn isomer, E flavor) (3.0 g) is obtained.

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3100, 2820, 1785, 1730, 1685, 159 5, 1585, 1575, 1550, 1495, 1450, 1420, 1190, 1045, 945, 770, and 750.

) : 6.98과 7.63(2d, J=6, 2H, 트란스비닐부위) : 7.0 (t, J=5, 1H, 피리미딘환 5위치에 H), 7.0에서 7.4(Mt, 25H, 방향성) : 8.52(d, 2H, 피리미딘환의 4와 6위치에 -H) 9.0(d, J=9, 1H, -CONH -).Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , ppm δ, Hz = J): 3.65 and 3.7 7 (2d, J = 18, 2H, -SCH _{2 in} 4): 4.06 (s, 3H, = NOCH ₃ ): 5.08 (d, J = 4, 1H, H at 6 position): 5.90 (d, J = 4, 1H, H at 7 position): 6.75 (S, 1H, H at toothbrush ring): 6.94 ( S, 1H, -CH of benzhydryl

): 6.98 and 7.63 (2d, J = 6, 2H, transvinyl site): 7.0 (t, J = 5, 1H, pyrimidine ring at 5 position), 7.0 to 7.4 (Mt, 25H, aromatic): 8.52 (d, 2H, -H at positions 4 and 6 of the pyrimidine ring) 9.0 (d, J = 9, 1H, -CONH-).

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-3-[2- (Pyrimidin-2-yl) -thiovinyl] -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (2.9 g) formic acid (30 cc) Dissolve in. Distilled water (13 cc) is added and the mixture is heated at 50 ° C. for 30 minutes. After cooling, it is filtered and the filtrate is washed with distilled water (5 cc). The solution is concentrated under reduced pressure at 30 ° C. (1 mmHg, 0.13 kpa) and the residue is continued to be absorbed four times for ethanol anhydrous (30 cc) each and the suspension is evaporated each time as described above. The dry residue is dissolved in distilled water (30 cc) and the mixture is filtered and the filter cake is subsequently washed with water (15 cc), ethanol (30 cc) and finally with ether (30 cc). Drying under reduced pressure at 20 ° C. (0.2 mm Hg, 0.027 kpa) gave 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2- as a beige powder. Carboxy-3-oxo- [2- (pyrimidin-2-yl) thiovinyl] -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (1.4 g) is obtained.

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3320, 3200, 3100, 2100, 1770, 166 5, 1560, 1550, 1040, 945, 770 and 750.

Proton nuclear magnetic resonance spectrum (350 MHz, DMSOd ₆ , ppm δ, Hz J): 3.72 and 3.90 (2d, J = 18, 2H, -SCH in 4 position): 3.86 (S, 3H, = NOCH ₃ ) : 5.20 (d, J = 4, 1H, H in 6 position): 5.77 (dd, J = 4 and 9, 1H, H in position 7): 6.74 (S, 1H, H in toothbrush ring): 7.1 2 and 7.46 (2d, J = 6, 2H, -transvinyl site): 7.14 (S, 2H, -NH ₂ to thiazole ring): 7.27 (wide, 1H, H to 5 position of pyrimidine ring): 8.66 (d, J = 5, 2H, H) at the 4 and 6 positions of the pyrimidine ring: 9.00 (d, J = 9, 1H, -CONH-).

Example 8

2-benzhydryloxabolic with 8-mercapto-3-methyl-pyridazine-1-oxide (0.738 g) and N, N-diisopropylethylamine (0.89 cc) at 22 ° C. with stirring in nitrogen Nyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -2-oxo-3- (2-tosyloxyvinyl) -5-thia A solution obtained by dissolving -1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (4.0 g) in dimethylformamide (40 cc) is added.

The mixture was stirred at 25 ° C. for 15 minutes, diluted with ethyl acetate (600 cc), washed with water (2 × 120 cc), 0.1N hydrochloric acid (120 cc), 2% sodium bicarbonate solution (2 × 120 cc) and half saturated saline (2 × 12). 0 cc), dried over sodium sulfate, filtered and concentrated under reduced pressure (20 mmHg) at 20 ° C. The residue is dissolved in ethyl acetate (10 cc) and the solution is filtered through a Melksilica gel (0.05-0.2 mm) (50 g) column (2.4 cm in diameter). Elution is carried out with ethyl acetate (500 cc) and the colorless milk powder (100 cc), pale yellow milk powder 2 (20 cc) and milk powder 3 (360 cc) are continuously collected. Concentrate to dryness under reduced pressure (20 mmHg) at 20 ° C.

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylaminothiazol-4-yl) -acetamido] -3- [2- (6-methylpyridazine 3-yl-1-oxide) -thiovinyl] -8-oxo-5-chia-1-aza-bicyclo [4.2.0] -oct-2-ene (Syn isomer, Form E) (4 g) Obtained in dark blue, orange foam.

Infrared spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3400, 1780, 1720, 1680, 1530, 149 5, 1450, 1330, 1210, 1050, 1040, 1000, 945, 810, 755 and 700.

Proton nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.45 (S, 3 H, -CH ₃ ): 3.62 and 3.77 (2d. J = 18, 2H, -SCH _2- ) : 4.09 (S, 3H, -OCH ₃ ): 5.98 (d, J = 4, 1H, H at 6 position): 5.93 (dd, J = 4 and 9, 1H, H at 7 position): 6.03 (S, 1H, 6H): 6.7 6 (S, 1H, H of toothbrush): 6.95 (S, 1H, -COOCH-).

2-benzhydryloxycarbonyl-7- [2-methoxyamino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -3-2- (6-methyl-pyri Diazin-3-yl-1-oxide) -thiovinyl] -8-oxo-5-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E ) (3.9 g) and formic acid (60 cc) distilled water (25 cc) were stirred at 50 ° C. for 30 minutes, the mixture was cooled at 20 ° C., filtered, and the filtrate was concentrated to dryness under 30 ° C. reduced pressure (0.05 mmHg).

The residue is dissolved in ethanol (50 cc) and the mixture is concentrated to dryness at 20 ° C. under reduced pressure (20 mmHg). Repeat this operation twice. The solids are treated with ethanol (40 cc) while refluxing for 5 minutes. Cool the suspension to 20 ° C. and filter, dry to yellow powder 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3-2- (6-Methylpyridazine-3-yl-1-oxide) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E (1.96 g).

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3420, 3320, 3230, 1765, 1655, 162 0, 1535, 1325, 1210, 1040, 1000 and 810.

Proton nuclear magnetic resonance spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 2.33 (S, 3H, -CH ₃ ): 3.70 and 3.97 (2d, J = 18, 2H, -SCH _2- ) , 3.86 (S, 3H, -OCH ₃ ), 5.23 (d, J = 4, 1H, H at 6 position), 5.81 (dd, J = 4 and 9, 1H, H at 7 position): 6.76 (S, 1H, the tooth sol H): 7 .18 and 7.20 (hump, 5H, -CH = CH- , and -NH ₃ ^+): 7.31 and 7.86 (2d, J = 7, H) of the already minced: 9.62 (d, J = 9, 1H, -CONH-).

3-mercapto-6-methyl-pyridazine-1-oxide is prepared according to Belgium Patent 787,635.

Example 9

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido-8-oxo-5-oxide-3- ( 2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (5 g) and 6-acetamido-3-mercapto-pyri A solution of chopped (1.05 g) and dry N, N-dimethylmethylamide (50 cc) was treated with N, N-diisoprophylethylamine (1.1 cc) and the reaction mixture was heated at 60 ° C. for 1 hour 40 minutes. do. Dilute ethyl acetate (300cc), wash with midstream (3x200cc) and wash with saturated brine (250cc). After drying over magnesium sulfate, the organic phase was concentrated to dryness under reduced pressure (30 mmHg) at 40 ° C., and the residue was chromatographed on a seala gel (0.06-0.04 mm column) diameter 5 cm). Elution is carried out under 50 kpa pressure with a mixture of cyclohexane and ethyl acetate 25:75 (volume).

Collect 100cc of milk powder, and powder 10 ~ 22 contains pure substance, and concentrate under 40 ℃ reduced pressure (30mmHg) to give 3- [2- (6-acetamido-pyridazin-3-yl)-of brown foam. Thiovinyl] -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-4-yl) -acetamido] -8-oxo-5-oxide-5 -Toa-1-aza-bicyclo [4.2. 0] oct-2-ene (Syn isomer, Form E (2.2 g)).

Rf = 0.48 silica gel chromatography: eluent cyclohexane / ethyl acetate 20: 80 (volume).

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3380, 3220, 1785, 1715, 1700, 1 680, 1450, 1370, 1040, 935 and 750.

Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.05 (S, 3H, CH ₃ CONH-): 3.26 and 4.8 (2d, J = 18, 2H, -S (O ) CH _2- ): 4.08 (S, 3H, -NOCH ₃ ): 4 .62 (d, J = 4, 1H, H at 6 position): 6.12 (dd, J = 4 and 9, 1H, 7 position H): 6.75 (S, 1H, H of toothbrush): 7.0 (S, 1H, -CH (C ₆ H ₅ ) ₂ ): 7.09 (S, 1H, (C ₆ H ₅ ) ₃ CNH-): 7.18 (d, J = 4, 1H, H at 5 positions of pyridazine): 7.12 (d, J = 16, 1H, -CH = CH-S-): 7.25 to 7.5 (mt, aromatic + -CH = CHS flute + H) at minced 4 position: 8.30 (d, J = 9, 1H, CONH-): 6.50 (S, 1H, CH ₃ CONH-).

3- [2- (6-acetamido-pyridazin-3-yl) -thiovinyl-2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino- Chiazol-4-yl) -acetamido-8-oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (2.2 g ) Was dissolved in methylenechromite (12cc) containing N, N-dimethylacetamide (0.47cc), cooled at -10 ° C, treated with phosphorus trichloride (0.23cc) and the reaction mixture was -10 ° C. Stir for 2 hours. N, N-dimethylacetamide (0.47cc) and phosphorus chloride (0.23cc) are further added and the mixture is stirred at −10 ° C. for 1 hour and then diluted with saturated aqueous sodium bicarbonate (150cc). The aqueous phase is extracted with ethyl acetate (100 cc) and the organic extract is washed with brine (2 x 50 cc), dried over magnesium sulfate and evaporated to dryness at 40 ° C under reduced pressure (30 mmHg). The residue is chromatographed on a column (Seal 4 cm) of Silaca gel (0.04-0.06 mm). The eluate is used as a mixed solution of cyclohexane and ethyl acetate (1.51) 40: 60 (volume) at 40 decompression pressure and about 100 cc of milk powder is collected. 3 to 10 milk powder contains pure material and concentrated to dryness under reduced pressure (30 mmHg) at 40 ° C. to 3- [2- (6-acetamido-pyridazin-3-yl) -thiovinyl] -2- on yellow foam. Benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza Obtain bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (1 g).

Rf = 0.58 silica gel chromatography: eluent: cyclohexane: ethyl acetate 30: 70 (volume).

Infrared spectra (CHBr ₃ ): Characteristic bands (cm ^-1 ) are 3400, 3360, 2820, 1780, 1715, 1 705, 1680, 1580, 1510, 1490, 1445, 1400, 1040, 940, 840 and 755.

3- [2- (6-acetamido-pyridazin-3-yl) -thiovinyl] -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2-2- (2-tri Cyl-amino-1,3-thiazol-4-yl) acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn Isomer, Form E) (1 g) is dissolved in formic acid (23.5 cc), distilled water (9 cc) is added, and the mixture is heated at 50 ° C. for 25 minutes. The precipitate is filtered off and the solution is concentrated under reduced pressure (10 mmHg) at 40 ° C. The residue is dissolved in ethanol (50 cc) and evaporated under 40 ° C. reduced pressure (30 mmHg). This operation is repeated and the residue is dissolved in ethanol (50 cc) and the insoluble material is filtered off and washed with ethylethyl (30 cc).

3-2- (6-acetamido-pyridazin-3-yl) -thiovinyl-7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] 2-Carbox-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (Syn isomer, Form E) (0.51 g) is obtained as a cream solid.

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3300, 1760, 1660, 1550, 1510, 10 35 and 940.

Proton nuclear magnetic resonance spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 2.10 (S, 3H, CH ₃ CONH-), 3.72 and 3.98 (AB, J = 17, 2H, -SCH _2- ) : 3.86 (S, 3H, = NOCH ₃ ): 5.2 (d, J = 4, 1H, H at 6 position): 5.78 (dd, J = 4 and 9, 1H, H at 7 position): 6.76 ( S, 1H, H of tooth sol: 7.20 (S, 2H, CH ₂ ): 7.19 (d, J = 10, 1H, -CH-CH-S-): 7.33 (d, J = 9, 1H,- CO NH-): 8.27 (d, J = 9, 1H, H in pyridazine 4), (s, broad, 1H, -CO ₂ H). 3-acet amido-6-mercapto-pyridazine is M, Kumagai and M. Prepared by the method described in Peninsula, Nippon Kagaku Zasshi 84,995 (1 963).

Example 10

5,6-dioxo-4-methyl-3-thioxo-perhydro-1,2,4-triazine (0.7 g) and N, N-diisopuroethyl ethylamine (0.77 cc) 2-benzhydryloxycarbonyl-7- [2- (methoxyimino-2- (2-trimethylamino-thiazol-4-yl) acetamido] dissolved in dimethylformamide (40 cc) -8-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] -oct-2ene (syn isomer, Form E) (4 g) solution The mixture was heated at 60 ° C. for 90 minutes, diluted with ethyl acetate (200 cc), washed with distilled water (4 × 100 cc), dried over magnesium sulfate, filtered and dried under reduced pressure at 40 ° C. The residue was melted silica gel (0.05). Chromatograph at -0.06 mm) (column diameter 4 cm), eluting at 50 kPa with ethyl acetate 31. Collect 100 cc milk powder. Concentrate to dryness under.

2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -Thiovinyl] -7- [2-methoxyamino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1- Aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2.8 g) is obtained.

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3360, 3200, 2829, 1795, 1710, 1 680, 1590, 1515, 1490, 1450, 1040 and 760.

Proton nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 3.30 (S, 3H, -CH ₃ -of triazine): 3.30 and 4.0 (AB. J = 18, -S (O) CH _2- ): 3.88 (S, 3H, = NOCH ₃ ): 4.65 (d, J = 4, 1H, H at 6 position): 6.02 (dd, J = 4 and 0, 1H, H at 7 position ): 6.32 (d, J = 16, 1H, -CH = CH-S-): 6.68 (S, 1H, toothbrushed): 6.92 (S, 1H, -CH (C ₆ H ₅ ) ₂ ): from 7.15 7. 5 (hump, aromatic + (C ₆ H ₅ ) CNH-+-CH = CHS).

Phosphorous trichloride (0.53 cc) to 2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-4-methyl-1, 4,5,6-tetrahydro-1,2,4 -Triazin-3-yl) -thiovinyl] -7- [2-methoxyimino-2- (2-triethylaminothiazol-4-yl) -acetamido] -8-oxo-5-oxide -5-Cia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (28 g) was converted to methylene chromide (30 cc) and N, N-dimethylacetamide ( 1.1 cc) was added to the solution, cooled at -30 ° C, the reaction mixture was stirred for 2 hours between -15 ° and -10 ° C, diluted with ethyl acetate (250cc) and saturated saturated solution (2x100cc) and Wash with saturated saline solution (250cc), dry over magnesium sulfate and filter. The filtrate was evaporated under reduced pressure (30 mmHg) at 40 ° C. and the residue was chromatographed with silica gel (0.04-0.06 mm) (120 mm) (column diameter 4 cm, height 20 cm). Elution is carried out under a 50 kPa pressure in a 20:80 (volume) mixture of cyclohexane and ethyl acetate (21). Collect 100 cc milk powder. Milk powders 4 and 16 are concentrated to dryness at 40 ° C. under reduced pressure (30 mmHg).

2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -Ciovinyl] -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) acetamido-8-oxo-5-thia-1-aza-bicyclo [4 , 2,0] oct-2-ene (syn isomer, Form E) (1.75 g) is obtained as a cream solid.

Infrared spectrum (CHBr ₃ ): characteristic bands (cm ⁻¹ ) are 3380, 1785, 1710, 1680, 1515, 1 490, 1445, 1040, 940, 755 and 740.

Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 3.41 (S, 3H, -CH _{3 of} triazine), 3.58 and 3.68 (AB, I = 18, 2H, -SCH _2- ): 4.04 (S, 3H, = NOC H ₃ ): 5.10 (d, J = 4, 1H, H in 6 position): 5.95 (dd, J = 4 and 9, 1H, H in 7 position): 6.74 (S, 1H, H of chiazole): 6.84 (d, J = 17, 1H, -CH = CH-S-): 6.96 (S, 1H, -CH (C ₆ H ₅ ) ₂ ): 7.03 ( d, J = 9, 1H, -CONH-): 7.15 to 7.55 (hump, aromatic + (C ⁹ H ₅ ) ₃ CNH + -CH = CHS-): 10.8 (s, 1H, -NH- of triazine).

2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -Thiovinyl] -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo Dissolve [4,2,-]-oct-2-ene (syn isomer, Form E) (1.7 g) in formic acid (24 cc), add distilled water (16 cc) and heat the reaction mixture at 50 ° C. for 25 minutes And concentrated to dryness under reduced pressure (10 mmHg) at 40 ° C. Solids are dissolved in ethanol (40 cc) and the mixture is evaporated to dryness at 40 ° C. under reduced pressure (30 mmHg). This operation is repeated once, and the obtained residue is dissolved in ethanol (30 cc). Insoluble matters were filtered off, washed with ethanol (10 cc) and ether (2 x 50 cc) and dried under reduced pressure (10 mmHg) at 25 ° C to give 7- [2- (2-aminothiazol-4-yl) -2 as a cream solid. -Methoxyimino-acetamido] -2-carboxy-3- [2- (5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazine 3-yl) -thiovinyl'-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.85 g) is obtained.

Rf = 0.37 silica gel chromatography plate: eluent: ethyl acetate / water / acetic acid (volume ratio) 3: 2: 2

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3300, 3260, 2600, 1770, 1705, 168 0, 1630, 1585, 1530, 1375, 1040 and 950.

Proton nuclear magnetic resonance spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 3.35 (s, 3H, CH _{3 of} triazine): 3.65 and 2.88 (AB, J = 18, 2H, -SCH ₂ -), 3.78 (s, 3H, = NOCH ₃ ), 5.22 (d, J = 4, 1H, H at 6 position): 5.80 (dd, J = 4 and 9, 1H, H at 7 position): 6.75 ( s, 1H, H of azole: 6.83 (d, J = 16, CH = CH-S-): 7.11 (d, J = 16, 1H, -CH = CH-S-): 7.20 (s, wide area , 3H, -NH ₃ ⁺ ): 9.58 (d, 9, 1H, -CONH-): 5,6-dioxo-4-methyl-3-thioxo-perhydro-1,2,4-triazine M. With peson. Antoine. Bull. Soc. Chim. Prepared according to the method described in Fr., 1590 (1970).

Example 11

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E ((7.02 g), dimethylformamide (50 cc), Diisopuroethylethylamine (1.34cc) and 5,6-dioxo-4-ethyl-3-thioxo-perhydro-1,2,4-triazine (1.3 3 g) in nitrogen at 60 ° C Stir for 2 hours.

The cooled mixture was diluted with ethyl acetate (600 cc) and the organic phase washed with water (2 x 125 cc), washed with 0.5-hydrochloric acid (150 cc), semisaturated sodium bicarbonate (2 x 125 cc) and saturated brine (2 x 125 cc). Then dried over magnesium sulfate and concentrated to dryness under reduced pressure (20mmHg) at 30 ℃. The residue is dissolved in ethyl acetate (150 cc) and the solution is concentrated to dryness under melksilica gel (20 mmHg). The residue is dissolved in ethyl acetate (150 cc) and the solution is chromatographed on a Melx silica gel (0.04-0 .06 mm) column (7 cm in diameter). Elution is carried out with ethyl acetate 2 ₁ at 40 kPa pressure. Collect 100 cc of milk powder. Milk powders 10 to 23 were concentrated to dryness under reduced pressure (20 mmHg) at 20 ° C. (2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-4-ethyl-1,4,2) 5,6-tetrahydro-1,2,4-triazin-3-yl) thiovinyl] -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl)- Acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (5.3 g) is obtained.

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3500, 2000, 1785, 1710, 1685, 152 0, 1495, 1450, 1040, 945, 755 and 700.

) : 4.0( s, 3H, -COH) : 4 .68(d, J=4, 1H, 6위치에 H) : 6.04(dd, J=4와 9, 1H, 7위치에 H) : 6.70(s, 1H, 치아졸의 H) : 6.85(d, J=16, -CH=CHS-) : 6.97(s, 1H, -COOCH-).Proton nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , ppm 8, Hz H): 1.27 (t, J = 7, 3H, -CH ₃ ): 3.40, 4.12 (2d, J = 18, 2H, -SCH _2- ): 3.86 (q, J = 7, 2H,

): 4.0 (s, 3H, -COH): 4.68 (d, J = 4, 1H, H at 6 position): 6.04 (dd, J = 4 and 9, 1H, H at 7 position): 6.70 ( s, 1H, H of chiazole: 6.85 (d, J = 16, -CH = CHS-): 6.97 (s, 1H, -COOCH-).

2-benzhydryloxycarbonyl-2- [2- (5,6-dioxo-4-ethyl) in which dimethylacetamide (1.95 cc) and phosphorus trichloride (1 cc) were dissolved in methylene chloride (100 cc) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl) -7- [2-methoxyamino-2- (2-triethylamino-thiazole -4-yl) -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (5.2 g) solution continued The mixture was stirred for 1 hour and 20 minutes at -12 ° C, further added phosphorus trichloride (0.5 cc) and stirring was continued at -12 ° C for 15 minutes. The mixture was diluted with ethyl acetate (600 cc), washed with 2% sodium bicarbonate (2 x 250 cc) and half saturated saline (2 x 250 cc), the organic phase was dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mmHg) at 20 ° C. Let's do it. Residual oil is purified by chromatography on a melt silica gel (0.05-0.2 mm) (100 g) column (4.5 cm in diameter). The product is fixed in advance in silica gel (25 g). Elution is carried out with ethyl acetate (500 cc) and 50 cc of milk powder is collected. The milk powders 5 to 9 are concentrated to dryness at 20 ° C. under reduced pressure (20m mHg).

2-benzhydryloxycarbonyl-3- [20 (%, 6-dioxo-4 [ethyl-1,4,5,6-tetra-hydro-1,2,4-triazin-3-yl) -Ciovinyl] -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (5.3 g) is obtained as an orange foam.

Infrared spectrum (CHBr ₃ ): characteristic bands (cm ⁻¹ ) are 3385, 1785, 1710, 1680, 1515, 1 490, 1445, 1040, 940, 755 and 740.

)‥4.05 (s, 3H, -OCH₃) : 5.12(d, J=4, 1H, 6위치에 H) : 5.94(dd, J-4와 9, 1H, 7위치에 H) : 6.77(s, 1H, 치아졸의 H) : 6.87(d, J=16, 1H, -CH=CHS-) : 6.97(d, J=9, 1H, -CON H-) : 6.96(s, 1H, -COOCH-) : 8.20(s, 1H, =NNHCO- 또는

).Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , ppm, δ, Hz, J): 1.34 (t, J = 7, 3H, -CH ₃ ): 3.60 and 3.70 (2d, J = 18, 2H,- SCH _2- ): 3.95 (q, J = 7, 2H,

) ‥ 4.05 (s, 3H, -OCH ₃ ): 5.12 (d, J = 4, 1H, H at 6 position): 5.94 (dd, J-4 and H at 9, 1H, 7 position): 6.77 (s , 1H, H azole: 6.87 (d, J = 16, 1H, -CH = CHS-): 6.97 (d, J = 9, 1H, -CON H-): 6.96 (s, 1H, -COOCH -): 8.20 (s, 1H, = NNHCO- or

).

2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-4-ethyl-1,4,5,6-tedhydro-1,2,4-triazin-3-yl) -Thiovinyl] -7- [2-methoxyimino-thiazol-4-yl) -acetamino] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2 -N (syn isomer, Form E) (3 g) is dissolved in formic acid (30 cc) and the solution is diluted with water (14 cc) and heated at 50 ° C. for 30 min with stirring. The mixture is cooled to 20 ° C. and filtered. The filtrate is concentrated to dryness under reduced pressure (0.05 mmHg) at 30 ° C. The solid is dissolved in ethanol (100 cc) and the mixture is concentrated to dryness under 20 ° C. reduced pressure (20 mm Hg). Repeat this operation three times. Solids are treated with ethanol (500 cc) at 60 ° C. Some insoluble material is removed and the solution is concentrated to 40 cc (30 ° C. 20 mm Hg) and cooled to 4 ° C. After filtration, the insoluble matter was dried and 7- [2- (2-aminothiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-2- [2- (5,6-di Oxo-4-ethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl-8-oxo-5-thia-1-aza-bicyclo [4 , 2,0] oct-2-ene (syn isomer, Form E) (1.49 g).

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3500, 2200, 1770, 1700, 1680, 153 0, 1040 and 940.

) : 3.86(s, 3H, OCH₃) : 5.20(d, J=4, 1H, 6위치에 H) : 5.78(dd, J=4와 9, 1H, 7위치에 H) : 6.75(s, 1H, 치아졸의 H) : 6.95d(, J=16, 1H, -CH=CHS-) : 7.13(d. J=16, 1H, = CHS-) : 7.18(s, 3H, NH₃ ⁺) : 9.63(d, J=9, 1H, -CONH-).Proton nuclear magnetic resonance spectra (350 MHz, DMSO d ₆ , δ in ppmm, J in J): 1.22 (t, J = 7, 3H, -CH ₃ ): 3.65 and 3.79 (2d, J = 18, 2H,- SCH _2- ): 3.80 (pm J = 7, 2H,

): 3.86 (s, 3H, OCH ₃ ): 5.20 (d, J = 4, 1H, H at 6 position): 5.78 (dd, J = 4 and 9, 1H, H at 7 position): 6.75 (s, 1H, the tooth sol H): 6.95d (, J = 16, 1H, -CH = CHS-): 7.13 (d J = 16, 1H, = CHS-):. 7.18 (s, 3H, NH 3 +) : 9.63 (d, J = 9, 1H, -CONH-).

5,6-Dioxo-4-ethyl-3-thioxo-perhydro-1,2,4-triazine was prepared according to the method of Belgium patent 83 0,455.

Example 12

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide (2- Tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] -oct-2-ene (syn isomer, Form E) (9.79 g), dimethylformamide (50 cc), 5, A mixture of 6-dioxo-4-isopurophyl-3-thioxo-perhydro-1,2,4-pitazine (2.28 g) and N, N-diisofurophylethylami (2.12 cc) Stir at 60 ° C. for 1 hour and 40 minutes in nitrogen. The mixture was diluted with ethyl acetate (600 cc), washed sequentially with water (2 x 150 cc), 1-N hydrochloric acid (100 cc), 2% sodium bicarbonate (2 x 150 cc) and half saturated saline solution (2 x 150 cc), and sodium sulfate Dry, and concentrated to dryness at 20 mmHg, 20 ° C. Purify by chromatography on a column of Velx silica gel (0.05-0.2 mm) (300 g) (column diameter 5 cm). Elution is carried out with a 40:60 (volume) mixture of cyclohexane and ethylate (1 5 ₁ ) to collect the milk powder 1 ₁ . Dry milk 9 to 14 are concentrated to dryness at 20 ° C. under 29 mmHg.

2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-4-isopurophyll-1,4,5,6-tetrahydro-1,2,4-triazine-3- Yl) -thiovinyl] -7- [2-methoxy-amino-2- (2-tricinamino-thiazol-4-yl) -acetamido] -3-oxo-5-thia-1-aza Bicyclo [4,2,0] oct-2-ene (sy n isomer, Form E) (7.4 g) is obtained as a yellow orange foam.

).Proton nuclear magnetic resonance spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 1.45 (d, J = 7, 6H, -CH (CH ₃ ) ₂ : 3.68 and 4.29 (2d, J = 19, 2H, -SCH _2- ): 3.84 (s, 3H, -OCH ₃ ): 4.35 (mt, 1H, -CH- (OH ₃ ) ₂ ): 5.05 (d, J = 4, 1H, 6 position H): 5.86 (dd, J = 4 and H at positions 9, 1H, 7): 6.78 (s, 1H, H of toothbrush): 6.97 (s, 1H, -COOCH-): 6.96 (d, J = 16, 1H, -CH-CHS0): 7.11 (d, J = 16, 1H, = CHS-): 8.74 (s, 1H, -NH-C (C ₆ H ₅ ) ₃ : 9.05 (d, J = 9 , 1H, -CONH-): 12.53 (s, 1H, = NNH-CO- or

).

2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-4-isopurophyll-1,4,5,6-tetrahydro-1,2,4-triazine-3- Yl) -thiovinyl] -7- [2-methoxyimino-2- (1-tritylamino-thiazol-4-yl) -acetamido] -3-oxo-5-oxide-5-thia- 1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (7.3 g) and dimethylacetamide (2.73 cc) dissolved in methylene chloride (100c c) Mix and treat with phosphorus trichloride (1.25cc) for 1 hour and 30 minutes with stirring at -10 ° C. The mixture is diluted with ethyl acetate (600 cc), washed with 2% sodium bicarbonate (2 x 150 cc), dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C. under reduced pressure (20 mmHg). The residue was fixed on Melk silica gel (0.05-0.2 mm) (50 g), the powder was fixed on a column of silica gel (200 g) (4 cm in diameter) and eluted with an ethyl acetate and cyclohexane (80: 20) (volume) mixture. Collect 200 cc milk powder. Dry milk powders 3 and 4 were concentrated to dryness at 20 mmHg pressure and 20 ° C. to give 2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-4-isofurophyl-1,4) as a yellow orange foam. , 5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl ) -Acetamino] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (5.3 g) is obtained.

Infrared spectra (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3400, 1790, 1720, 1685, 1520, 1 495, 1450, 1045, 945, 760 and 740.

) : 7.0(d, J=16, 1H, =CHS-) : 8.78(s, 1H, -NHC(C₆H₅)₃) : 9.58(d, J=9, 1 H, -CONE-) : 12.52(s, 1H, =NNHCO- 혹은

).Proton nuclear magnetic resonance spectra (350 MHz, DMSO d ₆ , ppm δ, Hz J): 1.46 (d, J = 7, 6H, -CH (CH ₃ ) ₂ ): 3.64 and 3.84 (2d, J = 18 _{, 2H, -SCH 2 -):} 3.82 (s, 3H, -OCH 3): 4 .36 (mt, 1H, -CH (CH 3) 2): 5.24 (d, J = 4, in the 1H, 6 position H): 5.76 (dd, J = 4 and 9, 1H, H at 7 position): 6.72 (s, 1H, H of toothbrush): 6.94 (d, J = 16, 1H, -CH = CHS-): 6.94 (s, 1 H,

): 7.0 (d, J = 16, 1H, = CHS-): 8.78 (s, 1H, -NHC (C ₆ H ₅ ) ₃ ): 9.58 (d, J = 9, 1H, -CONE-): 12.52 (s, 1H, = NNHCO- or

).

2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-4-iso-furophyll-1,4,5,6-tetrahydro-1,2,4-triazine-3 -Yl) -thiovinyl] -7- [2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thio-1-aza -Bicyclo [4,2,0] oct-2-ene (syn isomer, E-form) (5.25 g) is dissolved in formic acid (50 cc) and the solution is diluted with water (20 cc) and stirred at 50 ° C. for 30 minutes. After heating it is cooled to 20 ° C. The mixture is filtered and the solution is concentrated to dryness under reduced pressure (0.05 mmHg) at 30 ° C. The residue is dissolved in ethanol (25 cc) and removed at 20 ° C. 20 mm Hg pressure. Repeat this operation three times. The solids are treated with ethanol (600 cc) at reflux and the mixture is filtered and concentrated at 20 ° C., 20 mm Hg.

Filtration and drying of insoluble matter resulted in yellow powder, 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2- (5 , 6-dioxo-3-isopurophyll-1,4,5, 6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-thia-1-aza Obtain bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2 g).

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3500, 2200, 1775, 1705, 1680, 1 520, 1050 and 950.

Proton nuclear magnetic resonance spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 1.48 (d, J = 7, 6H, -CH (CH ₃ ) ₂ )): 3.64 and 3.82 (2d, J = 18, 2H, -SCH _2- ): 3.85 (s, 3H, -OCH ₃ ): 4.42 (mt, 1H, CH (CH ₃ ) ₂ ): 5.22 (d, J = 4, 1H, 6 position H): 5.78 (dd, J = 4 and 9, 1H, H in position 7): 6.74 (s, 1H, H of toothbrush): 6.93 (d, J = 16, 1H, -CH = CHS-): 7.07 (d, J = 16, 1H, = CHS-): 7.18 (s, 3H, -NH3 ⁺ ): 9.62 (d, J = 9, 1H, -CONH-): 12.55 (s, 1H, = NNHCC- Or NN = C = C-OH), 5,6-dioxo-4-isopurophyll-3-thioxo-perhydro-1,2,4-triazine is prepared according to Belgian patent 830,455.

Example 13

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -3-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (5.8 g), dimethylformamide (58 cc), 4- (2-methoxyethyl) -5,6-dioxo-8-thioxo-perha-dro-1,2,4-triazine (1.3 g) with diisopurophylethylamine (0.819 mg) The mixture was stirred at 60 ° C. for 80 minutes under nitrogen. The mixture is cooled to 20 ° C. and diluted with ethyl acetate (300 cc), the organic phase is washed 4 with water (total 100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under 20 ° C. reduced pressure (20 mmHg). The residue dissolved in ethyl acetate (250cc) was filtered over a column of silica gel (32g) and eluted with ethylacetate (500cc). The eluate was evaporated to dryness under reduced pressure (20 mmHg) at 20 ° C. to yield 2-benzhydryloxycarbonyl-2- {2- [5,6-dioxo-4- (2-methoxyethyl) as a beige solid. -1,4,5,6-tetrahydro-1,2,4-tria-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethylamino-thiazol 4-yl) -acetamido] -8-oxo-3-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (5.4 g) is obtained. .

Infrared spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3400, 2830, 1800, 1700, 1690, 152 5, 1495, 1450, 1370, 1210, 1110, 1040, 945, 755 and 700.

Proton nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 3.32 (s, 3H, -CH ₂ OC ₃ ): 3.60 (t, J = 5, 2H, -CH ₂ O- ): 4.05 (t, J = 5, 2H, -CH ₂ N)): 3.34 and 4.1 (dd, J = 18, 2H, -S (O) CH _2- ): 4.00 (s, 3H, = NOCH ₃ ): 4.66 (d, J = 4, 1H, H at 6 position): 6.08 (dd, J = 4 and 9, 1H, H at position 7): 6.71 (s, 1H, H of toothbrush): 6.85 ( d, J = 16, 1H, -CH = CHS-): 6.97 (s, 1H, -COOCH-).

Dimethylacetamide (2.06 cc) and phosphorus trichloride (0.91 cc) were converted to 2-benzhydrooxycarbonyl-3- {2- [5,6-dioxo-4- (2-methoxyethyl) -1. , 4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4- Yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (5.3 g) It is added to a solution dissolved in methylene chloride (53 cc) and cooled to -10 ° C.

The solution is stirred at -10 [deg.] C. for 2 hours and diluted with ethyl acetate (750 cc). Wash with saturated sodium bicarbonate solution (2x100cc) and saturated brine (2x100cc), dry over magnesium sulfate, and concentrate to 50cc under 20 ℃ reduced pressure (20mmHg). Add isoprofil ether (200cc). The solid formed is separated by filtration, washed with isoprofil ether (20 cc) and dried to give a cream solid (4.2 g). This solid is dissolved in a mixture of ethyl acetate and cyclohexane 70:30 (volume) and chromatographed on a column (6 cm in diameter, 20 cm in height) of Melk Sealica gel (0.04-0.06 mm). Elution is carried out at 40 kPa pressure with a mixture of ethyl acetate and cyclohexane (15 00 cc) 70:30 (volume), to collect 75 cc milk powder. Concentrate and dry the milk powder 9 to 10 under reduced pressure (20 mmHg) at 20 ° C. to give 2-benzhydryloxycarbonyl-3- {2- [5,6-dioxo-4 (2-methoxyethyl) as a cream solid. -1,4,5,6-tetrahydro- 1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethylamino-thiazole 4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2.9 g) is obtained. .

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3400, 2820, 1785, 1720, 1690, 159 0, 1525, 1495, 1450, 1370, 1210, 1110, 1040, 945, 755 and 705.

).Proton nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 3.34 (s, 3H, -CH ₂ OCH ₃ ): 3.65 (t, J = 5, 2H, -CH ₂ O- ): 4.11 (t, J = 5, 2H, -CH ₂ N): 3.60 and 3.6 8 (2d, J = 18, 2H, -SCH _2- ): 4.06 (s, 3H, = NOCH ₃ ): 5.11 ( d, J = 4, 1H, H in 6 position: 5.95 (dd, J = 4 and H in 9, 7 position): 6.76 (s, 1H, H of toothbrush): 6.86 (d, J = 16, -CH = CHS-): 6.93 (d, J = 9, 1H, -CONH-): 6.97 (s, 1H,

).

2-benzhydryloxycarbonyl-3- {2- [5,6-dioxo-4- {2-methoxy ethyl-) 1,4,5,6-tetrahydro-1,2,4-tri Azin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia- Dissolve 1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2,8 g) in formic acid (50 cc), add water (25 cc) and stir the mixture while stirring. Heat 15 ° C. The blend is diluted with water, cooled, filtered and concentrated to dryness at 40 ° C., 0.05 mm Hg.

The residue is dissolved in ethanol three times and each time the mixture is evaporated to dryness under reduced pressure (0.05 mmHg). The residue is dissolved in ethanol (200 cc) under reflux, the mixture is filtered warm and the residue is dissolved in ethanol (100 cc) with reflux. The blend is filtered off and the combined filtrate twice is concentrated to 20 cc and cooled to 0 ° C. The obtained solid is filtered off and dried. Yellow solid 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2- [5,6-dioxo-4- (2-methoxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl} -8-oxo-5-thia-1-aza- Bicyclo [4,2,0] oct-2-ene (syn isomer, Form F) (1.45 g) is obtained.

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3480, 2830, 1775, 1710, 1680, 163 5, 1590, 1535, 1380, 1110, 1040 and 940.

) : 3.62과 3.7 3(2d, J-18, 2H, -SCH₂-) : 3.96(s, 3H, =NOCH₃) : 5.18(d, J=4, 1H, 6위치에 H) : 5.81(dd, J=4와 9, 1H, 7위치에 H) : 6.78(s, 1H, 치아졸의 H) : 6.87(d, J=15, 1H, -CH=CH-S-) : 7.29(d, J=15, 1H, -CH=CH-S) : 6.70(s, 광역, 3H, -NH₃ ⁺) : 9.55(d, J=9, 1H, -CONH-): 12.64(s, 1H, =NNHCC- 혹은 =NN

).Proton nuclear magnetic resonance spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 3.36 (s, 3H, -CH ₂ OCH ₃ ): 3.56 (t, J = 5, 2H, -CH ₂ O) 4.10 (t, J = 5, 2H,

): 3.62 and 3.7 3 (2d, J-18, 2H, -SCH _2- ): 3.96 (s, 3H, = NOCH ₃ ): 5.18 (d, J = 4, 1H, H in 6 position): 5.81 ( dd, J = 4 and H at positions 9, 1H, and 7): 6.78 (s, 1H, H of toothbrush): 6.87 (d, J = 15, 1H, -CH = CH-S-): 7.29 (d , J = 15, 1H, -CH = CH-s): 6.70 (s, ^{_{wide, 3H, -NH 3 +):}} 9.55 (d, J = 9, 1H, -CONH-): 12.64 (s, 1H, = NNHCC- or = NN

).

4- (2-methoxyethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine is made by the method of Belgian patent 830,455.

Example 14

2-benzhydryloxycarbonyl-7- [2-methoxy-imino-2- (2-trimethyl amino-thiazol-4 -yl) -acetamido] -8-oxo-5-oxide- 3- (2-Tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (8.03 g) with dimethylformamide (150 cc) and 5,6-dioxo-4- (2-methylthioethyl) -3-thioxo-perhydro-1,2,4-triazine (2.19 g) and diisopurophyl ethylamine (1.7 cc) is stirred at 60 ° C. for 4 hours.

The mixture was poured into ethyl acetate (300cc), washed with water (3 × 200cc) and saturated brine (200cc), dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C and 20mmHg (2.7kPa). The product is first settled on melxica gel (0.05-0.2 mm) (20 g) and chromatographed on silica gel (200 g) (column diameter 3.4 cm, height 40 cm). Elution is carried out by the following mixing ratio of cyclohexane and ethyl acetate. Volume 40: 60 (500 cc), volume 30: 70 (500 cc), volume 20: 80 (500 cc), volume 10: 90 (500 cc), and finally eluted with ethyl acetate (2 L) to obtain 120 cc milk powder. Milk powder 22 to 32 are concentrated to dry creamy cream 2-benzhydryl-oxycarbonyl-3- {2- [5,6-dioxo-4- (2-methylthioethyl) -1,4,5 , 6-tetrahydro-1,2,4-triazin-2-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl)- Acet-amido-8-oxo-5-oxide-5-thia-1-azabicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (5,66 g) is obtained.

The obtained product is fixed on Melk Sealica gel (0.05-0.2 mm) (15 g) and the powder is placed on a column of silica gel (100 g) (diameter 3 cm, height 30 cm). Elution is carried out with a mixture of cyclohexane and ethyl acetate (1.5 L) 20:80 (volume) to give 60 cc of milk powder. Concentrate 3-19 at 20 ° C. (20 mHg) (2.7 kPa) to yield 2-benzhydryloxycarbonyl-3- {2- [5,6-dioxo-4- (2-methylchio) as a yellow foam. Ethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl} -7- [2-methoxyimino-2- (2-triethylamino -Thiazol-4-yl) -acetamido-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (4.16 g) Get

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 1785, 1715, 1680, 1525, 1490, 144 5, 1040, 940, 750 and 700.

).Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.18 (s, 3H, -SCH ₃ ): 2.78 (s, J = 6, 2H, H ₂ S): 3.58 and 3.67 (d, J = 18, J = 18, 2H, -SCH _2- ): 3.95 and 4.05 (m, 5H, -OCH ₃ and NCH _2- ): 5.08 (d, J = 4, 1H, 6 position H): 5.93 (dd, J = 4 and 9, 1H, H at 7 position): 6.74 (s, 1H, H of toothbrush): 6.82 (d, J = 16, 1H, -CH = CHS-) : 6.95 (s, 1H, -COOCH-): 11.55 (s, Wide 1H, = NNHCO- or = NN

).

2-benzhydryloxycarbonyl-3- {2- [5,6-dioxo-4- {2-methylthioethyl) -1,4,5, 6-tetrahydro-1,2,4- Triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trityl-amino-thiazol-4-yl) -acetamido] -8-oxo-5- Chia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (4.16 g) is concentrated to dryness in formic acid (40 cc, 20 mmHg: 2.7 kPa). The residue is dissolved in ethanol and the mixture is concentrated to dryness at 20 ° C. (20 mmHg) (2.7 kPa). (20 ° C, 20mmHg, 2.7kPa) The precipitate was filtered off and dried to afford 7- [2-amino-thiazol-4yl-2-methoxyimino-acetamido] -2-carboxy-3-2- [5 , 6-dioxo-4- (2-methylthioethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl-8-oxo-5 -Cia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1.95 g).

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3600, 2200, 1770, 1710, 1680, 158 5, 1535, 1040 and 945.

) : 5.2,(d, J=4, 1H, 6위치에 H) : 5.78(d d, J=4와 9, 1H, 7위치에서 H) : 6.73(s, 1H, 치아졸의 H) : 6.92(d, J=16, 1H, -CH=C HS-) : 7.12(d, J=16, 1H, =CHS-) : 7.15(s, 3H, -NH₃ ⁺) : 9.66(d, J=9, 1H, -CONH -) : 12.61(s, 1H, =NNHCO- 혹은 =N-N

).Proton nuclear magnetic resonance spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 2.12 (s, 3H, -SCH ₃ ): 2.73 (t, J = 7, 2H, -CH ₂ S-CH ₃ ): 3.64 and 3.82 (2d, J = 18, 2H, -SCH _2- ): 3.85 (s, 3H, -OCH ₃ ): 4.0 (t, J = 7, 2H,

): 5.2, (d, J = 4, 1H, H at 6 position): 5.78 (dd, J = 4 and 9, 1H, H at 7 position): 6.73 (s, 1H, H of toothbrush): 6.92 (d, J = 16, 1H , -CH = C HS-): 7.12 (d, J = 16, 1H, = CHS-): 7.15 (s, 3H, -NH 3 +): 9.66 (d, J = 9, 1H, -CONH-): 12.61 (s, 1H, = NNHCO- or = NN

).

5,6-Dioxo-4- (2-methylthioethyl) -3-thiooxo-perhydro-1,2,4-triazine can be prepared as follows. 4- (2-Methylthioethyl) -thiosemicarbazide (13,6 g) was added to a solution of sodium (1,83 g) in methanol (80 cc) and dimethyl hydroxide (10.8 c4) was added dropwise for 15 minutes. . The mixture is heated at reflux for 3 hours, cooled and then added to ethyl ether (1 L) with stirring.

The precipitate is filtered off and the resulting yellow solid is dissolved in water (100 cc). The pH of the solution is cooled to 2 in 1N hydrochloric acid while cooling on an ice bath. After filtration and drying, a white solid (3 g) is obtained. This was crystallized and purified twice from boiling water (50cc) to give 5,6-dioxo-4- (2-methylthioethyl) -3-thioxo-perhydro-1,2,4-triazine. (2. 4 g) is obtained.

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3550, 3490, 3280, 3220 and 1690.

2- (2-Methylthioethyl) -Ciocemic Carbazide was prepared by adding hydrazine hydrate (6.8cl) to an ethanol (500 cc) solution of methyl-N- (2-methylthioethyl) -dithiocarbamate (26 g). It is prepared by heating under reflux for 3 hours. After concentration, the resultant was dried at 20 ° C. and 20 mm Hg (2.7 kPa), and the oil phase obtained was dissolved in diethyl ether (100 cc). The resulting precipitate is filtered off and dried. Thiosemicarbazide (18.16 g), m.p. Obtain 70 ° C.

Infrared spectrum (KBr): Characteristic bands (cm ^-1 ) are 3320, 3200, 3160, 1635, 1550 and 12 60.

Example 15

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (10.04 g), dimethylformamide (200 cc), A mixture of 4-benzyl-5, 6-dioxo-3-thioxo-perhydro-1,2,4-triazine (2,82 g) and diisopropyl ethylamine (2.1 cc) was stirred at 60 ° C. for 3 hours. do. It is then added to ethyl acetate (500 cc) and the mixture is washed with water (2 x 250 cc) and saturated sodium chloride solution (2 x 200 cc), dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C and 20 mmHg (2.7 kPa). . The residue is dissolved in a cyclohexane and ethyl acetate mixture 20:80, and the solution is subjected to chromatography using a column of Melk silica gel (0.04-0.06 mm) (200 g) (column diameter 8 cm, height 30 cm). Elution is carried out with cyclohexane and ethyl acetate (2 L) at a pressure of 40 kPa to obtain 100 cc of milk powder. Milk powder 45-60 evaporated at 20 ° C., 20 mmHg (2.7 kPa), and 2-benzhydryloxocarbonyl-3- [2-methoxyimino-2- (2-tritylamino-thiazol-4- Yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2.68 g) Obtained in cream form.

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3380, 1800, 1720, 1670, 1520, 14 95, 1450, 1045, 940, 755.

) : 6.02(dd, J=4와 9, 1H, 7위치에서 H) : 6.70(s, 1H, 치아졸의 H) : 6.80(d, J=16, 1H, -CH=CHS-) : (6.94(s, 1H, -COOCH-) : 11.87(s, 1H, =NHCO- 또는

).Proton nuclear magnetic resonance spectrum (350MHz, CDCl ₃ , δ in ppm, Hz J): 3.32 and 4 (3d, J = 1.8, 2H, -SCH _2- ): 3.97 (s, 3H, -OCH ₃ ): 4.60 (d, J = 4, 1H, H in 6 position): 5.0 (s, 2H,

): 6.02 (dd, J = 4 and 9, 1H, H at 7 positions): 6.70 (s, 1H, H of toothbrush): 6.80 (d, J = 16, 1H, -CH = CHS-): ( 6.94 (s, 1H, -COOCH-): 11.87 (s, 1H, = NHCO- or

).

2-benzhydryloxycarbonyl-3- [2- (4-benzyl-5,6-dioxo-1,4,5,6- in a mixture of methylene chloride (25 cc) and dimethyl acetate (0.95) Tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -7- [2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -aceamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (s yn isomer, Form E) (2.68 g) was added at -10 ° C for 30 minutes. The reaction is stirred with phosphorous chloride (0.44 cc). The mixture was diluted in ethyl acetate (200 cc), the mixture was washed with 50% bath solution (50 cc), water (2 x 50 cc) and saturated saline solution, dried over sodium sulfate, and concentrated to 20 ° C and 20 mmHg (2.7 kPa). To dry. This product is first fixed on Melk silica gel (0.05-0.2 mm) (20 g) and then placed on a column of silica gel (40 g) (column diameter: 1.4 cm, height: 15 cm). Elution is carried out in a mixture 20:40 of cyclohexane and ethyl acetate (1 L) to obtain a 60 cc milk powder. Milk powder 2-13 is distilled off at 20 DEG C under 20 mmHg (2.7 kPa). 2-benzhydroxycarbonyl-3- [2- (4-benzyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-thiazol-4- Il) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1.78 g) in creamy form Obtained.

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3390, 1785, 1720, 1680, 1520, 14 95, 1450, 1045, 940.

).Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , δ in ppm, Hz J): 3.54 and 3.6 4 (2d, J = 18, 2H, -SCH _2- ): 4.02 (s, 3H, -OCH ₃ ): 5.06 (d, J = 4, 1H, H in 6 position): 5.1 0 (s, 2H, NCH _2- ): 5.92 (dd, J = 4 and 9, 1H, H in 7 position): 6.74 (s, 1H, H) in tooth sol: 6.82 (d, J = 16, 1H, -CH = CHS-): .95 (s, 1H, -COOCH-): 7.03 (d, J = 9, 1H, -CONH- ): 11.60 (S, 1H, = NNH-CO- or

).

2-benzhydryloxycarbonyl-3- [2- (4-benzyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -Thiovinyl] -7- [2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -aceamido] -8-oxo-5-oxide-5-thia-1-aza Add bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) to a mixture of formic acid and water (16 cc) and stir at 50 ° C for 30 minutes. The cooling solution is filtered and concentrated to dryness at 50 ° C. under 20 mm Hg (2.7 kPa). The residue is taken up in ethanol (20 cc) and the mixture is evaporated to dryness at 20 ° C. under 20 mm Hg (2.7 kPa). Repeat this twice.

The resulting yellow solid is treated with ethanol (100 cc) under reflux. A small amount of insoluble material was filtered off and the solution was concentrated (20 ° C., 20 mm Hg, 2.7 kPa). The residue was cooled at 4 ° C. for 3 hours, filtered and the precipitate was dried to give 7- [2- (2-amino-thiazol-4-yl) -2-methoxy-imino-acetamido] -3 -[2- (4-Benzyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -2-carboxy-8 A yellow powder of -oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.69 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3500, 2300, 1770, 1710, 1680, 15 85, 1530, 1045, 945.

) : 5.18(d, J=4, 1H, 6위치에 H) : 5.78(dd, J=4와 9, 1H, 7위치에서 H) : 6.75(s, 1H, 치아졸의 H) : 6. 86(d, J=16, 1H, -CH=CHS-) : 7.05(d, J=16, 1H, CHS) : 7.20(s, 3H, -NH₃ ⁺) : 9.6 0(d, J=9, 1H, -CONH-) : 12.69(s, 1H, =NNHCC- 혹은

).Proton nuclear magnetic resonance spectra (350 MHz, DMSO d ₆ , ppm at δ, Hz J): 3.58 and 3.78 (2d, J = 18, 2H, -SCH _2- ): 3.88 (s, 3H, -OCH ₃ ) : 5.10 (s, 2H,

): 5.18 (d, J = 4, 1H, H at 6 position): 5.78 (dd, J = 4 and 9, 1H, H at 7 position): 6.75 (s, 1H, H of toothbrush): 6. 86 (d, J = 16, 1H, -CH = CHS-): 7.05 (d, J = 16, 1H, CHS): 7.20 (s, 3H, -NH ₃ ⁺ ): 9.6 0 (d, J = 9 , 1H, -CONH-): 12.69 (s, 1H, = NNHCC- or

).

Triazine starting materials are prepared as follows.

4-benzyl-thiocemiccarbazide was prepared according to the method of J. Chem. Soc. 2527 (1927), and then dimethyloxalate (6.76 cc) was added to methanol (50 cc) at 20 ° C. ) Is added to a solution of sodium (1.15 g)). The mixture is heated under reflux for 2 hours and then cooled at 4 ° C. for 3 hours before the precipitate is removed by filtration. The sodium salt thus obtained is dissolved in water (50cc) again, and 1N hydrochloric acid is added while cooling to 4 ° C. to make the acidity of pH 2 into a liquid. After 1 hour the product was filtered and dried to afford 4-benzyl-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine.

Infrared spectrum (KBr): characteristic band (cm ^-1 ): 3440, 3320, 1680, 1625, 1495, 145 0, 1350, 730, 695.

Example 16

2-benzhydryloxycarbonyl-7- [2-methoxy imino-2- (2-tritylamino-triazol-4-yl) -acetamido] -8-oxo-5-oxide-3 -(2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) 10 g, dimethylformamide (50 cc), 4- (2,2-dimethoxyethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-lysine (2,56 g) and N-ene-diisopropylethylamine (1.9 cc) The mixture is stirred at 60 ° C. under nitrogen for 2 hours 30 minutes. After diluting it with ethyl acetate (600 cc), the mixture was washed with water (2 x 125 cc), 1N hydrochloric acid (150 cc), half saturated sodium bicarbonate (2 x 150 cc) and half saturated saline (2 x 150 cc), and After drying, filtered and concentrated to dryness under reduced pressure (20 ℃, 20mmHg, 2.7kPa). The residue was again dissolved in methylene chloride (30 cc) and chromatographed on a column of Melksilica gel (0.02-0.06 mm) (column diameter 7 cm, height 35 cm).

The elution is carried out at 40:60 of cyclohexane and ethyl acetate mixture under a pressure of 40 kPa to give 100 cc milk powder. Powdered milk 27-46 is concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 20 ° C. 2-benzhydryloxocarbonyl-3- {2- [4- (2,2-dimethoxyethyl) -5, 6-dioxo-1,4,5,6-tetrahydro-1,2, 4-triazin-3-yl] -thiovinyl} -7- [2-methoxy-imino-2- (2-tritylamino-thiazol-4-yl) -acetamido] -8-oxo The 5-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E (8.5 g) is obtained in beige.

Infrared spectrum (KBr): Characteristic band: cm ^-1 or less at 3380, 3250, 1795, 1720, 1685, 1520, 149 0, 1445, 1040, 940, 760, 700.

) : 4.60-4.68(m, 2H, 6위치에 H H, -CH(OCH₃)₂) : 6.07(dd, J=4와 9, 1H, 7위치에서 H) : 6.70(s, 1H, 치아졸의 H)‥6.82(d, J=16, 1H, -CH=CHS-) : 6.96(s, 1H ,

).Proton nuclear magnetic resonance spectrum (δ, Hz at 350 MHz, CDCl ₂ , ppm J): 3.34 and 4.1 2 (2d, J = 18, 2H, SCH _2- ): 3.40S, 6H, -CH (OCH ₃ ) ₂ ): 9.94-4.06m, (5H, -OCH ₃ ),

): 4.60-4.68 (m, 2H, HH at 6 position, -CH (OCH ₃ ) ₂ ): 6.07 (dd, J = 4 and 9, 1H, H position at 7): 6.70 (s, 1H, toothbrush H) ‥ 6.82 (d, J = 16, 1H, -CH = CHS-): 6.96 (s, 1H,

).

2-benzhydryloxycarbonyl-3- {2- [4- (2,2-dimethoxyethyl) -5,6-dioxo-1,4,5,6 in methylene chloride (100 cc) -Tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trityl-amino-thiazol-4-yl) -acet Yamido] -8-oxo-5-oxide-5-chia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (8.5 g) and dimethylacetamide ( 3 cc) is added to phosphorus trichloride with stirring at -10 < 0 > C. Phosphorous trichloride (0.7cc) is added after 1 hour 30 minutes and the same amount is added again 2 hours later. The mixture is diluted in ethyl acetate (600 cc), and the mixture is washed with 2% sodium bicarbonate solution and half saturated saline solution (2 x 150 cc), dried over sodium sulfate, and concentrated to dryness at 20 DEG C under 20 mmHg (2.7 kPa) pressure. The residue is taken up in ethyl acetate (50 cc) and the solution is subjected to chromatography on a column of Melksilica gel (0.05-0.2 mm) (100 g) (column diameter 3 cm, height 25 cm). Elution is carried out in ethyl acetate (1 ₁ ) to obtain a 200 cc milk powder. Powdered milk 3, 4, 5 is concentrated to dryness at 20 mm Hg, 2.7 kPa, 20 ℃. 2-benzhydroxycarbonyl-3- {2- [4- (2,2-dimethoxyethyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4- Triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-tritylamino-chiazol-4-yl) acetamido] -8-oxo-5-thia- 1-Aza-bicyclo [4,2,0] oct-2-ene (syn isomer. Form E) (7.5 g) is obtained in orange.

Infrared spectrum (CHBr): Characteristic band: cm ^-1 or less at 3380, 1780, 1720, 1680, 1515, 1490, 14 45, 755, 740.

) : 4.02(s, 3H, =NOCH₃) : 4.65(t, J=5, 1H, -CH(OCH₃)₂) : 5.08(d, J=4, 1H, 6위치에 H) " 5.92(dd, J=4와 9, 1H, 7위치에 H) : 6.73(s, 1H, 치아졸의 H) : 6.83(d, J=16, -CH=CHS-) : 6.95(s, 1H , -COOCH-).Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₂ , δ, Hz at ppm J): 3.40 (s, 6 H, -CH (OCH ₃ ) ₂ ): 3.54 and 3.66 (2d, J = 18, 2H,- SCH _2- ): 3.98 (d, J = 5, 2H,

): 4.02 (s, 3H, = NOCH ₃ ): 4.65 (t, J = 5, 1H, -CH (OCH ₃ ) ₂ ): 5.08 (d, J = 4, 1H, H in 6 position) 5.92 ( dd, J = 4 and 9, 1H, H position 7): 6.73 (s, 1H, H of toothbrush): 6.83 (d, J = 16, -CH = CHS-): 6.95 (s, 1H,- COOCH-).

1.a) 2-benzhydryloxycarbonyl-3- {2- [4- (2,2-dimethoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro- 1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxy imino-2- (2-trityl amino-thiazol-4-yl) -acetamido]- 8-oxo-5-oxide-5-chia-1 -aza-bicyclo [4,2,0] oct-2-ene (new isomer, Form E) was added to 98% formic acid (20cc) at 50 ° C for 30 minutes React. The residue is dissolved in acetone (50 cc) and the mixture is concentrated to dryness under reduced pressure (20 mM mHg, 2,7 kPa) at 30 ° C. Repeat this operation twice. The resulting solid was stirred for 10 minutes at 60 ° C., the cooled suspension was filtered and the residue was dried to give 7- {2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido]. 2-carboxy-3- [2-5,6-dioxo-4-formylmethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] Obtain -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer. Form E) (0.51 g).

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3500, 2300, 1770, 1715, 1680, 154 0, 1050 and 950.

) : 5.38(d, J=4, 1H, 6위치에 H) : 6.03(d, J=4, 1H, 7위치에 H) : 7.22(d, J=16, 1H, -CH=CHS- ) : 7.50(s.1H, 치아졸의 H) : 7.72(d, J =16,1H,=CH-) 9.74(s 광역, 1H,-CHO).Proton nuclear magnetic resonance spectrum (350 MHz, CF ₃ COOD, ppm δ, Hz J): 3.87 (AB limit, 2H, -SCH _2- ): 4.30 (s, 3H, -OCH ₃ ): 5.20 (s, Wide area, 2H,

): 5.38 (d, J = 4, 1H, H in 6 position): 6.03 (d, J = 4, 1H, H in 7 position): 7.22 (d, J = 16, 1H, -CH = CHS-) : 7.50 (s.1H, H of chiazole): 7.72 (d, J = 16,1H, = CH-) 9.74 (s wide area, 1H, -CHO).

) : 5.31(d, J=4, 1H, 6위치에 H) : 5.96(d, J=4, 1H, 7위치에 H) : 7.06(d, J=16, 1H, -CH=CHS- ) : 7.43(s, 1H , 치아졸의 H) : 7.56(d, J=16, 1H, =CHS-) : 9.67(s, 광역, 1H, -CH).Proton nuclear magnetic resonance spectra (350 MHz, CF ₃ COOD + D ₂ O, ppm δ, Hz J): 3.82 (AB limit, 2H, -SCH _2- ): 4.26 (s, 3H, -OCH ₃ ): 5.10 (s, wide area, 2H,

): 5.31 (d, J = 4, 1H, H in 6 position): 5.96 (d, J = 4, 1H, H in 7 position): 7.06 (d, J = 16, 1H, -CH = CHS-) : 7.43 (s, 1H, H of chiazole): 7.56 (d, J = 16, 1H, = CHS-): 9.67 (s, broad, 1H, -CH).

b) The following processes are also possible.

2-benzhydryloxycarbonyl-3- {2- [4- (2,2-dimethoxyethyl) -5,6-dioxo-1,4, 5,6-tetrahydro-1,2, 4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -acetamido] -8-oxo-5 -Cia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1 g), pure formic acid (40 cc), water (1.27 cc) and melk silica gel (0.05-0.2 mm) (6 g) is heated at 50 ° C. for 30 minutes with stirring. The reaction mixture was concentrated to dryness at 20 mmHg (2.7 kPa) at 30 ° C, and the obtained powder was adjusted to a column of Melk silica gel (0.05-0.2 mm) (20 g) (diameter 2 cm, height 17 cm), and ethyl acetate / formic acid / water 3: 1: Elution with 1 (volume ratio) mixture. Collect 10 cc milk powder. In milk powder 3, 26 is concentrated to dryness at 27 ° C., 0.05 mmHg (0.007 kPa). The resulting yellow solid is dissolved in ether (60 cc) and the mixture is filtered. The residue was dried and 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2- (5,6-dioxo- 4-formylmethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4 , 2,0] oct-2-ene (syn isomer. Form E) (0.4 g) is obtained. The nuclear branch resonance and infrared characteristic of this product are the same as described in (a).

2. 7- [2- (2-Amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2- (5,6-dioxo-4- Formylmethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2 , 0] Oct-2-ene (syn isomer, Form E) (0.297 g), a mixture of water (100 cc) and sodium bicarbonate (0.042 g) is stirred until dissolved under nitrogen, filtered and lipophilic. 7- [2- (5,6-dioxo-4-formylmethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo Soda salt of -5-chiya-1-pala-cyclo [4,2,0] oct-2-ene (syn isomer, Form E) is obtained as aldehyde hydrate (0.28 g).

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3420, 3200, 1760, 1710, 1670, 160 0, 1530, 1040 and 945.

Proton nuclear magnetic resonance spectrum (350 MHz, DMSO a6 + D20, ppm to δ, Hz J): 3.54 (AB, limiting, 2H, -SCH _2- ): 5.06 (d, J = 4, 1H, 6 position H): 5.08 (s, 1H, -CH (OH) ₂ ): 5.63 (d, J = 4, 1H, H in 7 position): 6.44 (d, J = 16, 1H, -CH = CHS-) : 6.76 (s, 1H, H of chiazole): 7.24 (d, J = 16, 1H, = CHS-): 9.60 (s, 0.05H, -CHO).

The NM R spectrum of the soda salt as an aldehyde hydrate of this product, recorded in CF ₃ COOD, was the aldehyde type in this solvent, solution. [One. Same spectrum as described in (a).

3. Saturate with carbon dioxide while bubbling through a solution of L-lysine (0.233 g) dissolved in distilled water (2.8 cc). The resulting solution was prepared with 7- [2- (2-amino-thiazol-4-yl) -methoxy-imino-acetamido] -2-carboxy-3- [2- (5,6-dioxo- 4-formylmethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4 , 2,0] Oct--2-ene (syn isomer, Form E) (1 g) was added to a suspension dissolved in distilled water (2.8 cc), stirred at 20 ° C. for 2 minutes, filtered, and the filtrate was lipophilic and 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2- (5,6-dioxo-4-formylmethyl-1,4, 5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2- Syn (isomer. Form E) aldehyde hydrate, lysine salt (1.23 g) is obtained in the form of a creamy lipophilic.

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3420, 3200, 1765, 1710, 1660, 160 0, 1530, 1040 and 945.

4- (2,2-Dimethoxyethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine is prepared as follows. Methyl soda solution was prepared in methanol (140 cc) with soda (4.15 g), 4- (2,2-dimethoxyethyl) -thiocemiccarbazide (32.3 g) and ethyl oxalate (26.3 g) were added and the mixture was Was refluxed for 4 hours with stirring and left to cool. Leave overnight and filter the resulting suspension and wash the precipitate with ether (3 × 25 cc). The solid is dissolved in water (40 cc), cooled to about 4 ° C., the solution is acidified to pH 3 with 4N hydrochloric acid, and left at 4 ° C. for 30 minutes. After filtration, 4- (2,2-dimethoxyethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (12 g) as a white solid is obtained. Immediately mp (kofler) = 170 ° C. (decomposition).

Infrared spectrum (KBr): Characteristic bands (cm ^-1 ) are 3280, 3250, 1695, 1380, 1130 and 10 50.

) : 4.94(t, J=5.5, 1H, -CH(OCH₃)₂. 4-(2,2-디메톡시에칠)-치오세미카바자이드은 다음과 같이 제조될 수 있다.Proton nuclear magnetic resonance spectrum (80 MHz, DMSOd ₆ , ppm is δ, Hz is J): 3.30 (s, 6H, -CH (OCH ₃ ) ₂ : 4.38 (d, J = 5.5,

): 4.94 (t, J = 5.5, 1H, -CH (OCH ₃ ) _2. 4- (2,2-dimethoxyethyl) -thiocemiccarbazide can be prepared as follows.

2,2-Dimethoxyethylisothiocyanate (37.7 g) was added to a solution of hydrazine hydrate (14.35 g) and ethanol (40 cc) at 5-9 ° C. for 1 hour with stirring. The mixture is left at 4 ° C. for 12 hours and the mixture is concentrated to dryness at 20 ° C. under reduced pressure (20 mmHg, 27 kPa). Crystallize the yellow syrup. Solids are dissolved in hot methanol (50 cc) and the solution is filtered. Dilute to diethyl ether (200 cc). After 10 hours at 4 [deg.] C. it is filtered and 4- (2,2-dimethoxyethyl) -thiosemicarbazide (32.3 g) is obtained as a white solid. Immediate mp (kofler) = 69 ° C.

Example 17

2-benzhydryloxycarbonyl-3- [2-4- (2,2-diethoxyethyl) -5,6-dioxo-1,4,5, 6-tetrahydro-1,2,4 -Triazin-3-yl-thiovinyl] -7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -8-acetamido] -8-oxo-5 -Oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) was treated with tosylate (1 5.06 g) and 4- ( 2,2-diethoxyethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (8 g) was added to N, N-diisofurophylethylamine (2.85 cc) was prepared in the presence of dimethylformamide (75 cc) in the presence of a solution. Chromatography is performed on a column (5 cm in diameter and 40 cm in height) of Melx silica gel (0.05-0.2 mm) (250 g). At this time, the elution is carried out with a 30:70 (volume) mixture of cyclohexane and ethyl acetate (51). The expected substance (8.35 g) obtained a reddish red foam.

, -OCH₃와 -SCH-) : 4.65(d, J=4, 1H, 6위치에 H) : 4.72(6, J=5, 1H, -CH(OEt₂) : 6.04(dd, J=4와 9. 1H, 7위치에 H) : 6.70(s, 1H, 치아졸의 H) : 6.85(d, J=16, 1H, -CH=CHS-) : 6.97(s, 1H,

) : 11.94(s, 광역, 1H, =NNH CO- 혹은=NN

).Furon NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Mz is J): 1.15 (t, J-7, 6H, -CH 3): 3.38 (d, J = 18, 1H, -SCH-): 3.50 3.72 (2q, AB, J = 9 and 7.4H, -OCH _2- ): 3.90 and 4.20 (hump, 6H,

, -OCH ₃ and -SCH-): 4.65 (d, J = 4, 1H, H in 6 position): 4.72 (6, J = 5, 1H, -CH (OEt ₂ ): 6.04 (dd, J = 4 And 9.H at 1H, 7 position: 6.70 (s, 1H, H of toothbrush): 6.85 (d, J = 16, 1H, -CH = CHS-): 6.97 (s, 1H,

): 11.94 (s, wide area, 1H, = NNH CO- or = NN

).

2-benzhydryloxycarbonyl-2-2- [4-2,2-diethoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4- Triazin-3-yl] -thiovinyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide- 5-Cia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) ((8.30 g), methylene chloride (100 cc) and dimethylacetamide (2.88 cc) solution was treated with phosphorus trichloride (1.33 cc) for 2 hours at -10 ° C. The product was chromatographed on a column of Melksilica gel (0.05-0.2 mm) (200 g) (4 cm in diameter, 44 cm in height). Treat as in Example 16. Develop with a mixture of cyclohexane and ethyl acetate (21) 30:70 (volume).

2-benzhydryloxycarbonyl-3-2- [4-2,2-diethoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-tri Azin-3-yl] -thiovinyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia-1 A yellow orange foam form of aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (5.3 g) is obtained.

The product is dissolved in ethyl acetate (20 cc) and purified by addition of isofurophyll ether (100 cc) to give a cream solid (45 g).

Infrared Spectrum (CHBr ₃ ): Characteristic bands (cm-3) are 3390, 1785, 1720, 1685, 1515, 1495, 1050, 940, 750 and 740.

-SCH=) : 4.76(t, J=5, 1H, -CH(OEt)₂) : 5.09(d, J=4, 1H, 6위치에 H) : 5.92(dd, J=4와 9, 1H, 7위치에 H) : 6.75(s, 1H, 의치아졸 H) : 6.85(d, J=16, 1H, -CH=CHS-) : 6.92(d, J=9, 1H, -CONH-) : 6.92(s, 1H,

) : 11.30(s, 광역, 1H, NNHCO- 혹은=NN

).Furon NMR spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 1.18 (t, J = 7, 6H, -CH ₃ ): 3.52 and 3.75 (2q, AB, J = 7 and 10, 4H, -OCH _2- ): 3.60 (d, J = 18, 1H, -SCH =): 3.97 to 4.06 (hump, 6H, -OCH ₂ ,

-SCH =): 4.76 (t, J = 5, 1H, -CH (OEt) ₂ ): 5.09 (d, J = 4, 1H, H in 6 position): 5.92 (dd, J = 4 and 9, 1H , H at position 7: 6.75 (s, 1H, dentureazole H): 6.85 (d, J = 16, 1H, -CH = CHS-): 6.92 (d, J = 9, 1H, -CONH-): 6.92 (s, 1 H,

): 11.30 (s, wide area, 1H, NNHCO- or = NN

).

2-benzhydryloxycarbonyl-3-2- [4- (2,2-diethoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4 -Triazin-3-yl] -thiovinyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -2-oxo-5-thia 1-Aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1 g) was dissolved in pure formic acid (25 cc), heated at 50 ° C. for 20 minutes, and then 40 ° C., 20 mm Hg. Concentrate to dryness (2.7 kPa). The residue is dissolved in acetone (20 cc) and the mixture is concentrated to dryness at 20 ° C., 20 mm Hg (2.7 kPa). This operation is repeated twice and the residue is dissolved in acetone (40 cc) and the mixture is heated to reflux for 10 minutes with stirring. Cool the suspension and filter. Obtain yellow powder (0.6 g) and purify as follows.

The former product (50 mg) was dissolved in pure formic acid (5 cc), and melkyl cargel (0.05-0.2 mm) (2,5 g) was added and the mixture concentrated to dryness at 20 ° C., 0.05 mm Hg (0.007 kPa). The powder is settled in a column of Sealica gel (5 g) (diameter 2.5 cm, height 3 cm) and developed into a 3: 2: 2 (volume) mixture of ethyl acetate / acetic acid / water (100 cc). Collect 10 cc milk powder. Condensate 2 to 7 is concentrated to dryness (30 ° C., 0.05 mmHg, 0.007 kPa).

7- (2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2- (5,6-dioxo-4-formylmethyl -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0 ] Oct-2-ene (syn isomer, Form E) (30 mg) was obtained in the form of a cream powder, and the infrared characteristic value and the characteristic value were the same as those shown in Example 16.1 (a).

4- (2,2-diethoxyethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine can be prepared as follows.

4- (2,2-diethoxyethyl) -thiosemicarbazide (18.6 g) and dimethyl oxalate (13.15 g) were slowly added to the sodium solution in anhydrous ethanol (70 cc) and the mixture was added under nitrogen for 4 hours. Reflux. The cooling mixture is washed with water (300cc) and ethyl acetate (15cc) and acidified to pH = 2 with concentrated hydrochloric acid while cooling to 4 ° C. The mixture is settled and the aqueous phase is extracted with ethyl acetate (3 x 100 cc), the organic phase is washed with saturated salt (3 x 100 cc) and dried over sodium sulfate. It is filtered and concentrated to dryness at 20 ° C., 20 mmHg (2.7 kPa). A crude yellow emulsion (22.6 g) 4- (2,2-diethoxyethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine is obtained.

4- (2,4-diethoxyethyl) -thiosemicarbazide can be prepared as follows.

Hydrazine hydrate (27.3 cc) was added to a solution of 2,2-diethoxyethyl isothiocyanate (94 g) dissolved in ethanol (150 cc) at 4 ° C. for 1 hour. The mixture is stirred at 4 ° C. for 20 minutes and filtered. The desired product (86 g) is obtained at a white solid m.p. = 96 占 폚.

Example 18

2-benzhydryloxycarbonyl-7- [2-methoxy imino-2- (2-trimethyl amino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3 2-) tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (7.33 g) and dimethylformamide (37 cc) , 4- (2,2-dimethoxyethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (2.04 g) and N, N-diisopurophyll Ethylamine (1.39 cc) is stirred in nitrogen at 50 ° C. for 3 hours 30 minutes. The mixture is poured into water (250cc) and the extract is dissolved in water (2x200cc), 0.1N hydrochloric acid (100cc), water (100cc) and saturated saline solution (100cc) and insoluble material is filtered off. After drying, 2-benzhydryloxycarbonyl-3-2- [4- (2,2-dimethoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1, 2,4-triazin-3-yl] -thiovinyl-7- [2-methoxy imino-2- (2-triethyl amino-thiazol-4-yl) -acetamido] -8-oxo -5-Oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (4.7 g) is obtained as a cream powder.

Infrared spectrum (KBr): Characteristic bands (cm ^-1 ) are 3400, 3250, 1800, 1725, 1695, 1590, 1555, 1520, 1495, 1450, 1210, 1080, 1060, 1035, 1025, 940, 755, 745 and 700.

: 3.76과 4.23(2d, J=18, 2H,

) : 4.58(J=6, 1H,

) : 5.14(d, J=4, 1H, 6위치에 H) : 6.08(dd, J=4와 9, 1H, 7위치에 H) : 6.98(s, 1H, -CO₂CH(C₆H₅)₂) : 7.03과 7.7(2d, J=16, 2H, -CH=CH-) : 8.62(s, 1H, 치아졸의 -NH-) : 9.57(d, J=9, 1H, 7위치에 -CINH-) : 12.72(s, 1H,

혹은

).Furon NMR spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 3.25 (s, 6H, -OCH ₃ ): 3.98 (hump, 5H, = NOCH ₃

3.76 and 4.23 (2d, J = 18, 2H,

): 4.58 (J = 6, 1H,

): 5.14 (d, J = 4, 1H, H in 6 position): 6.08 (dd, J = 4 and 9, 1H, H in 7 position): 6.98 (s, 1H, -CO ₂ CH (C ₆ H ₅ ) ₂ ): 7.03 and 7.7 (2d, J = 16, 2H, -CH = CH-): 8.62 (s, 1H, -NH- of toothbrush): 9.57 (d, J = 9, 1H, 7 position -CINH-): 12.72 (s, 1H,

or

).

2-benzhydryloxycarbonyl-3-2- [4- (2,2-dimethoxyethyl) -5,6-dioxo-1,4,5-tetrahydro-1,2,2,4 -Triazin-3-yl] -thiovinyl-7- [2-ethoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide -5-Cia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (6.7 g) was added to methylene chloride (70 cc) and dimethylacetamide (2.3 cc). Dissolve and treat with phosphorus trichloride (1.1 cc) at -8 ° C for 35 minutes. The mixture was diluted with ethyl acetate (200 cc) and the mixture was washed with saturated sodium bicarbonate solution (200 cc) and water (2 × 10 cc), dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C. and 20 mm Hg (2,7 kPa). . The residue is settled in melksilica gel (0.06-0.2 mm) (20 g) and chromatographed on a column (3.5 cm in diameter, 60 cm in height) of copper silica gel (0.06-0.2 mm) (140 g). The developing solution is a 20:80 (volume) mixture of cyclohexane and ethyl acetate (1 L). Powder 5 to 12 (120 cc milk powder) are concentrated to dryness at 30 ° C. at 20 mmHg (2,7 kPa). The residue was dissolved in ethyl acetate (50 cc) and added while stirring diisopurophyl ether (200 cc). Filtration and drying resulted in white solid 2-benzhydryloxycarbonyl-3- [22- [4- (2,2-dimethoxyethyl) -5,6-dioxo-1,4,5,6- Tetrahydro-1,2,4-triazin-3-yl] -thiovinyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] Obtain 8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (anti isomer, Form E) (3.8 g).

) : 4.10(s, 3H, NCCH₃) : 4.66(t, J=6, 1H,

) : 5.08(d, J=4, 1H, 6위치에 H) : 6.02(dd, J=4와 9, 1H, 7위치에 H) : 6.77(d, J=16, 1H, -CH=CH-S-) : 6.96(s, 1H,

) : 9.55(d, J=9, 1H,-CONH-) : 10.90(s, 1H,

).Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3400, 1785, 1720, 1695, 1585, 1510, 1490, 1205, 1075, 1020, 940, 700. Furon NMR spectrum (350MHz, CDCl ₃ , ppm is δ, Hz is J): 3.41 (s, 6H, -OCH ₃ ): 3.50 and 3.57 (2d, J = 18, 2H, -SCH ₂ ): 4.00 (d, J = 6, 2H,

): 4.10 (s, 3H, NCCH ₃ ): 4.66 (t, J = 6, 1H,

): 5.08 (d, J = 4, 1H, H in 6 position): 6.02 (dd, J = 4 and 9, 1H, H in 7 position): 6.77 (d, J = 16, 1H, -CH = CH -S-): 6.96 (s, 1H,

): 9.55 (d, J = 9, 1H, -CONH-): 10.90 (s, 1H,

).

2-benzhydryloxycarbonyl-3-2- [4- (2,2-dimethoxyethyl) -5,6-dioxo-1,4,5, 6-tetrahydro-1,2,4 -Triazin-2-yl] -thiovinyl-7- [2-methoxyimino-2- (2-trimethyl-amino-thiazol-4-yl) -acetamido] -8-oxo-5- Chia-1-aza-bicyclo [4.2. 0] Oct-2-ene (anti isomer, Form E) (3.5 g) is dissolved in formic acid (300 cc) and stirred at 50 ° C. for 30 minutes. Concentrate to dryness at 30 ° C., 0.05 mmHg (0.007 kPa). The residue is taken up in acetone (250 cc) and the mixture is concentrated to dryness at 20 ° C., 20 mm Hg (2.7 kPa). Repeat this operation twice. The solids obtained are refluxed with acetone (100 cc), the mixture is left to cool, filtered off and washed with die ethyl ethyl (50 cc). Obtain the expected product (2.1 g). Purification is carried out as follows. The former product (2 g), suspended in water (62 cc) and dissolved in water (16.5 cc), sodium bicarbonate (3.3 g) is added with vigorous stirring in nitrogen. The mixture is warmed to 30 ° C. and treated with animal charcoal and filtered. The pH of the filtrate is 5.4 and vinegar is added to make it 3.2. Heated to 80 ° C, treated with activated charcoal, filtered and left to stand at 4 ° C for 1 hour. After filtration and drying, 7-p2- (2-amino-thiazol-4-yl) -2-methoxy imino-acetamido] -2-carboxy-3- [2- (5,6- Dioxo-4-formylmethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-8-oxo-5-thia-1-aza Obtain bicyclo [4,2,0] oct-2-ene (anti isomer, Form E) (1.2 g).

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3700-2300, 1770, 1715, 1685, 1630, 1590, 1525, 1060, 1030 and 940.

) : 5.35(d, J=4, 1H, 6위치에 H) : 5.58(d, J=4, 1H, 7위치에 H) : 7.24와 7.74(2d, J=16, 2H, -CH=CHS-) : 8.14(s, 1H, 치아졸의 H) : 5.88(d, J=4, 1H, 7위치에 H) : 7.24와 7.74(2d, J=16, 2H, -CH=CHS-) : 8.14(s, 1H, 치아졸의 H) : 9.77(s, 1H, -COCH).Proton NMR spectrum (350 MHz, CF ₃ COOD, ppm δ, Hz J): 3.86 (s, wide 2H, -SCH _3- ): 4.43 (s, 3H, = NOCH ₃ ): 5.18 (s, wide, 2H,

): 5.35 (d, J = 4, 1H, H at 6 position): 5.58 (d, J = 4, 1H, H at 7 position): 7.24 and 7.74 (2d, J = 16, 2H, -CH = CHS 8.14 (s, 1H, H of toothbrush): 5.88 (d, J = 4, 1H, H at position 7): 7.24 and 7.74 (2d, J = 16, 2H, -CH = CHS-): 8.14 (s, 1 H, H of chiasole): 9.77 (s, 1 H, -COCH).

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-tosyloxy vinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (anti isomer, Form E) It is prepared as follows.

7-amino-2-benzhydryloxycarbonyl-3- (2-tosyloxyvinyl) -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct- 2-ene (E isomer) (8.5 g) was mixed with methylene chloride (100 cc). Bucourt. 2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetyl acid (anti isomer) (7.1 g) and 4-di prepared according to Tetrahedron 34,2233-2243 (1978) Methyl aminopyridine (0.1 g) is added and the mixture is cooled to 5 ° C. and a 25 minute drop of a methylene fluoride (50 cc) solution of N, N′-dicyclohexylcarbodiimide is added dropwise. The mixture was stirred at 20 ° C. for 2 hours, the residue was dissolved in ethyl acetate (300 cc), the solution was filtered, washed with water (100 cc) and saturated brine (100 cc), dried over sodium sulfate and filtered again, 20 ° C., 20 mm Hg (2.7 kPa). Concentrated to dryness). It is fixed on Melk Sealica gel (0.06-0.2mm) (50g) and chromatographed on column (4cm, 60cm in height) of Sealica gel (200-g) (0.06-0.2mm). Hexane and ethyl acetate 70: 30 (volume) mixture (0.5 L), 60: 40 (volume) mixture (0.5 L) and 50: 50 (volume) mixture (4 L) and 120 cc milk powder are collected. Concentration drying of 17 to 32 at 20 ° C. and 20 mmHg (2,7 kPa) afforded the desired material (7.33 g).

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3400, 3280, 1805, 1730, 1680, 1555, 1520, 1495, 1450, 1375, 1190, 1180, 1070, 1035, 1025, 935.

) : 4.14(s, 3H, NOCH₃) : 4.59(d, J=4, 1H, 6위치에서 H) : 6.34(dd, J=4와 9, 1H, 7위치에 H) : 6.90(s, 1H, COOC

) : 6.92와 7.15(2d, J=12, 2H, -CH=CH-) : 7.47(s, 1H, 치아졸의 5위치에 H) : 7.43(d, J=8, 4H, -OSO₂C₆H₄CH₂).Proton NMR spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.44 (s, 3H, C ₆ H ₄ CH ₃ ): 3.16 and 3.84 (2d, J = 18, 2H,

): 4.14 (s, 3H, NOCH ₃ ): 4.59 (d, J = 4, 1H, H at 6 position): 6.34 (dd, J = 4 and 9, 1H, H at 7 position): 6.90 (s, 1H, COOC

): 6.92 and 7.15 (2d, J = 12, 2H, -CH = CH-): 7.47 (s, 1H, H at 5 positions of the toothbrush): 7.43 (d, J = 8, 4H, -OSO ₂ C ₆ H ₄ CH ₂ ).

Example 19

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-Tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form Z) (22.59 g), dimethylformamide (112 cc) 4 -(2,2-dimethoxyethyl) -5,6-dioxo-3-thioxo-drot-1,2,4-lysine (6.29 g) and N, N-diisopurophyl ethylamine 50 degreeC (4,27 cc). Stir for 5 hours in nitrogen.

Place in water (500cc) in the presence of ethyl acetate (500cc), decanted the organic phase, wash with water (2 × 250cc), wash with 01N hydrochloric acid and saturated aqueous saline (200cc), dry in sodium sulfate, and filter 20 ℃, 20mmHg Concentrated to dryness (2.7kPa). The product is fixed on melt silica gel (0.0 6-0.2 mm) (75 g) and chromatographed on a column (4 cm in diameter, 80 cm in height) of pafzm Celica gel (0.06-0.2 mm) (500 g). Expand with ethyl acetate 41. Collect 300 cc milk powder.

Concentrate to dry powder 5 to 12 at 20 ° C and 30 mmHg (4 kPa) to give 2-benzhydryloxycarbonyl-3-2- [4- (2,2-dimethoxyethyl) -5,6 as a creamy powder -Dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-2-yl] -thiovinyl-7- [2-methoxyimino-2- (2-trimethylamino- Chiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2- (syn isomer, type ZE) ( 18.5 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3380, 3200, 1800, 1725, 1685, 1585, 1515, 1495, 1445, 1080, 1040, 750, 740.

The cream colored powder (18.5 g) (syn isomer Z form) is treated with phosphorus trichloride (3.03 cc) for 45 minutes at -8 ° C. with stirring of methylene chloride (137 cc) and dimethylacetamide (6.43 cc). . The mixture was poured into ethyl acetate and the mixture was washed with saturated sodium bicarbonate (150 cc) and water (2 × 10 0 cc), dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C., 20 mmHg, (2.7 kPa). The product thus obtained is fixed in Melk Sealica gel (0.06-0.2 mm) (40 g) and chromatographed on a column (4.5 cm in diameter, 80 cm in height) of the same Sealica gel (400 g). It expands with the ethyl acetate 21. Collect 360 cc of milk powder. Dry milk 2 to 5 was evaporated to dryness at 30 ° C., 20 mmHg (2.7 kPa), the residue was dissolved in ethyl acetate (100 cc) and stirred with diisopurofylether (1 L). Filtered and dried to give 2-benzhydryloxycarbonyl-3-2- [4- (2,2-dimethoxyethyl) -5,6-dioxo-1,4,5,6-tetra as a cream powder Hydro-1,2,4-triazin-3-yl] -thiovinyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido]- Obtain 8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (s yn isomer, Form E) (6.8 g).

Infrared Spectrum (CHBr ₃ ): Oily zones (cm ⁻¹ ) are 3400, 1790, 1720, 1685, 1585, 1515, 1495, 1450, 1220, 1080, 1505, 1040, 750 and 740.

).Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 2.30 (s, 6H, C (OCH ₃ ) ₂ ): 3.22 and 3.78 (2d, J = 18, 2H, -SCH _2- ) : 3.85 (s, 3H, NOCH ₃ ): 3.88 (d, J = 5, 2H, NCH _2- ): 4.50 (t, J = 5, 1H, -CH (OCH ₃ ) ₂ ): 5.23 (d, J = 4, 1H, H at 6 position: 5.78 (d, J = 4 and 9, 1H, H at 7 position): 6.58-6.70 (2d, J = 10, 2H, -CH = CHS): 6.72 (s , 1H, H azole: 6.88 (s, 1H, -COOCH): 8.75 (s, wide area, 1H, -NHC (C ₆ H ₅ ) ₃ ): 9.58 (d, J = 9, 1H, -CONH -): 12.63 (s, wide area, 1H,

).

The cream powder product (syn isomer, Z type) (5 g) was heated in formic acid (200 cc) at 50 ° C. for 30 minutes, concentrated at 30 ° C., 0.05 mm Hg (0.007 kPa), and the residue was dissolved in acetone (200 cc), and the mixture was 20 Concentrate to dryness at 20 mmHg (2.7 kPa), repeat this procedure twice: Residual solids are refluxed in acetone (200 cc), heated, cooled, filtered and washed with ethyl ether 100 cc. (2.8 g) is obtained. Purification is carried out as follows.

Suspension of the above material (1 g) in water (31 cc) and the sodium bicarbonate (0.15 g) dissolved in water (9 cc) is added with vigorous stirring slightly warmed to 30 ℃. The pH is brought to 6.2 with excess sodium bicarbonate and the mixture is treated with decolorized charcoal, filtered and added with vinegar acid to pH = 3.2. The suspension is treated at 80 ° C. and treated with carbon black and left at 4 ° C. for 3 hours. Filter and dry to 7- [2-amino-thiazol-4-yl)-(2-methoxyimino-acetamido] -2-carboxy-2-3 [2- (5,6-dioxo-4 -Formylmethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4, 2,0] oct-2-ene (syn isomer Z form) (0.4 g) is obtained as a white powder.

Proton's NMR spectrum (350 MHz, CH ₃ COOD, ppm δ, Hz J): 3.77 and 3.84 (2c, J = 18, 2H, -SCH _2- ): 5.18 (s, 2H,> N-CH _2- ): 5.28 (d, J = 4, 1H, H at 6 position): 6.02 (d, J = 4, 1H, H at 7 position): 6.84 and 7.05 (2d, J = 10, 2H, -CH = CHS -): 7.48 (s, 1H, H of chiasol): 9.72 (s, 1H, CHO) /

Example 20

7- [2- (2-Amino-thiazol-4-yl) -2-methoxyimino-acetamido-2-carboxy-8-oxo-3- (2-tosyloxyvinyl) -5-thia- 1-aza-bicyclo [4,2,2,0] oct-2-ene (syn isomer, Form E) (1 g), dimethylamide (20 cc) and 5,6-dioxo-4- (2, 2-Dimethoxyethyl) -3-thioo-pyhydro-1, 2,4-triazine- (0.44) is stirred at 60 ° C for 5 hours. Concentrate to dryness at 30 ° C., 0.05 mm Hg (0.007 kPa), and dissolve the residue in water (30 cc), filter off, and dry to obtain a crude product (0.9 g).

Purification is carried out as follows. The above preparation (0.5 g) is treated with boiling isoprotropin (2 × 10 cc) and the mixture is filtered and cooled. Filtration and drying resulted in yellow powdery 7- [2- (2-aminothiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2- (4- (2, 2-dimethoxyethyl) -5,6 dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -8-oxo-5-thia Obtain 1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.215 g).

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3500, 3300, 1780, 1715, 1680, 159 0, 1535, 1050, 950.

).Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 3.62 and 3.81 (2d, J = 18, -SCH _2- ): 3.84 (s, 2H, -OCH ₃ ): 3.97 ( d, J = 3, 2H,> NCH _2- ): 4.58 (t, J = 3, 1H, -CH (OCH ₃ ) ₂ ): 5.20 (d, J = 4, 1H, H in 6 position): 5.77 (dd, J = 4 and H at positions 9, 1H, 7): 6.74 (s, 1H, H of toothbrush): 6.91 (d, J = 16, 1H, -CH = CHS-): 7.09 (d, J = 16, 1H, = CHS- ): 7.17 (s, 3H, -NH 3 +): 9.60 (d, J = 9, 1H, -CONH-): 12,64 (s, 1H, = NNHC O- or

).

7- [2- (2-Amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxo-3- (2-tosyloxyvinyl) -5-thia- 1-Aza-bicyclo [4,2,0] octo-2-ene (syn isomer, Form E) is prepared as follows.

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-benzhydryloxy carbonyl-8-oxo-3- (2-tosyloxyvinyl ) -5-Cia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.25 g), formic acid (10 cc) and water (3 cc) were added at 50 ° C. Stir for 30 minutes. Water (8 cc) is added and the mixture is filtered and concentrated to dryness at 30 ° C., 0.05 mm Hg (0.007 kPa). The residue is taken up in ethanol (2 × 20 cc) and the mixture is concentrated to dryness at 20 ° C., 20 mm Hg (2.7 kPa) each time. The obtained solid was dissolved in diethyl ether (20 cc), filtered and dried to give 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] on a yellow powder. Carboxy-3-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.12 g) Get

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3360, 3200, 3100, 2000, 1770, 167 0, 1630, 1530, 1370, 1190, 1175, 1070, 1045, 925, 810.

Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 2.45 (s, 3H, -CH ₃ ): 3.58 and 3.80 (2d, J = 18, 2H, -SCH _2- ): 3.88 (s, 3H, -OCH ₃ ): 5.18 (d, J = 4, 1H, H at 6 position): 5.78 (dd, J = 4 and 9, 1H, H at 7 position): 6.68 and 7.20 (2d , J = 12, 1H, -CH = CH-): 6.74 (s, 1H, H of the toothbrush): 7.20 (s, 2H, -NH ₂ ): 7.51 and 7.88 (2d, J = 8, 4H, Sat Pragmatic): 9.58 (d, J = 9, 1H, -CONH-).

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl ) -5-Cia-1-aza-bicyclo [4,2,0] octo-2-ene (syn isomer, Form E) can be prepared as follows.

In acetone (10 cc) solution of 4-bromo-2-methoxyamino-3-oxo-butyryl chloride (syn isomer) (2 g), acetone (50 cc), water (5 g), cooled to -10 ° C for 7 minutes. And 7-amino-2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2] blended with sodium bicarbonate (2.8 g) To a solution of oct-2-ene (E-type) (4.7 g) and the mixture was stirred at −10 ° C. for 1 hour and then concentrated to dryness at 20 ° C. and 20 mmHg (2.7 kPa) to obtain a brown solid A (11 g). . A portion of (6 g) of A is chromatographed on a column (5 cm in diameter and 25 cm in height) of Melk Sealica gel (0.04-0.06 mm). Run at 40 kPa with a mixture of cyclohexane and ethylacet (2.51) 65:35 (volume) and collect 125 cc milk powder. Dry milk 10 to 14 was concentrated to dryness at 20 ° C., 20 mmHg (2.7 kPa), and 2-benzhydryloxycarbonyl-7- (4-bromo-2-methoxyimino-3-oxo-butyrylamino)- 3-oxo-3- (2-tosyvinylvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1 g) in yellow foam form Get

Infrared spectrum (CHBr ₃ ): characteristic band (cm ⁻¹ ) is 3390, 1785, 1720, 1685, 1515, 1 495, 1455, 1375, 1190, 1180, 1075, 1045, 950, 810, 760, 740.

Proton NMR spectrum (CDCl ₃ , 350 MHz, ppm δ, Hz J): 2.43 (2s, 3H, -C ₆ H ₄ CH ₃ ): 3.53 (AB, J = 17, 2H, -SCH _2- ) : 4.14 (s, 3H, = NOCH ₃ ): 4.35 (s, 2H, -CH (C ₆ H ₅ ) ₂ ): 6.85 and 6.92 (2d, J = 12, 2H, -CH = CH-): 7.17 ( d, J = 9, 1H, CONH-): Hump, 1, 2H, -CH (C ₆ H ₅ ) ₂ ) at 7. 2 and 2H at the meta position of the tosyl group: 7.74 (d, J = 8, 2H, 2H in the all-to position of the bobbin machine. Add tetrahydrofuran (25cc) of crude A (5 g) obtained above to chiourea (0.5 g), water (50 cc) and ethanol (25 cc) for 5 minutes at 20 ° C, and stir the mixture at 20 ° C for 30 minutes. . Concentrate dry at 20 ° C., 20 mmHg (2.7 kPa). The residue was dissolved in ethyl acetate (150cc) and brine (50cc) and dispersed. The residue was washed with organic phase (2 × 100 cc) and saturated brine (100cc), dried over sodium sulfate and filtered, and then heated to 20 ° C. and 20m mHg ( Concentrated to 2.7 kPa).

The material thus obtained is chromatographed on a column of Melk Sealica gel (0.04-0.06 mm) (120 g) (diameter: 4 cm, height 20 cm). A 30:70 (volume) mixture of cyclohexane and ethyl acetate (21) was developed under 40 kPa pressure. Collect 50 cc of fraction. Concentration and drying of fractions 16-38 at 20 ° C., 20 mmHg (2.7 kPa) yielded 7 [-2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido]-7 as a cream solid. 2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E Type) (0,75 g).

7 amino-2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] octo-2-ene (syn Isomers, Form E) can be prepared as follows.

2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3 in which acetonitrile (25 cc) solution of p-toluenesulfonic acid hydrate (3.49 g) was dissolved in acetonitrile (75 cc) at 35 ° C. 25 minutes dropwise into a solution of oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (type E) (6.1 g) Add. The mixture was stirred at 35 ° C. for 45 minutes, poured into saturated sodium bicarbonate solution (500 cc), contacted with stirring for 30 minutes, and the mixture was extracted with ethyl acetate (500 cc). The organic phase is washed with water (100 cc), dried over sodium sulfate, filtered and concentrated to dryness at 25 ° C., 20 mmHg (2.7 kPa) to give 4.7 g) of brown foam.

Rf = 0.18 Sealica gel chromatography plate, dihexane and ethyl acetate 50:50 (volume) mixture, 2-benzhydryloxycarbonyl-7-tert-butoxycarbonyl-amino-8-oxo-3- Methyl chloride (75 cc) and dimethylacetamide of (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] octo-2-ene (type E) (7.1 g) (4.62 cc) solution is reduced to phosphorus trichloride (2.03 cc) as described in Example 19.

Chromatography with silica gel yields the desired product (6.1 g): developing solution: cyclohexane and ethyl acetate 50: 50 (volume).

Infrared spectrum (CHBr ₃ ): Characteristic band (cm ⁻¹ ) is 3425, 1780, 1720, 1505, 1370, 1190, 1180, 1075, 760.

Proton NMR spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 1.50 (s, 9H, -C (CH ₂ ) ₃ ): 2.42 (s, 3H, -CH ₃ ): 3.35 and 3.42 ( 2d, J = 18, 2H, -SCH _2- ): 4.92 (d, J = 4, 1H, H at 6 position): 5.59 (dd, J = 5 and 9, 1H, H at 7 position): 6.84 ( d, J = 12, 1H, -CH = CHS-): 6.88 (s, J = 12, 1H, = CHS-).

4-Bromo-2-methoxyimino-3-oxo-butyryl chloride (syn isomer) is prepared as follows. Two drops of dimethylformamide were added to a solution of 2-ketimino-3-oxo-butylic acid (syn isomer) (4.08 g) at dimethyl ether (50 cc) at 20 ° C. and dissolved in ethyl ether (5 cc). Add chromide (2cc) dropwise for 15 minutes. The mixture is stirred at 20 ° C. for 1 hour, a further drop of dimethylformamide is added and the reaction is continued for 15 minutes. The mixture is concentrated to dryness at 20 ° C., 20 mmHg (2.7 kPa), the residue is taken up in petroleum ether (2 × 30 cc) and the solvent is evaporated off at 20 ° C., 20 mmHg (2.7 kPa). The 2-methoxyimino-3-oxo-butanoyl chloride (syn isomer) thus obtained was dissolved in methylene chloride (50 cc), and 5.4 N ether hydrochloride (0.2 cc) and bromine (1.14 cc) were added to this solution at 20 ° C. Add from The mixture was stirred at 20 ° C. for 20 hours and concentrated to dryness at 20 ° C., 20 mmHg (2.7 kPa), to give 4-bromo-2-methoxyimino-3-oxo-butyryl-chloride (syn isomer) (5.42 g) in brown emulsion. Get)

Proton NMR spectrum (60 MHz, CDCl ₃ , ppm δ, Hz J): 4.25 (s, 3H, —OCH ₃ ): 4.23 (s. 2H, —CH ₂ —).

2-methoxyimino-3-oxo-butylic acid (syn isomer) is prepared as follows.

Ethanol (300cc) and 1N caustic soda solution (330cc) are heated to reflux for 15 hours in ethyl 2-methoxyimino-3-oxo-butylate (syn isomer) (52 g). Aethanol is evaporated under 20 mmH g (2.7 kPa) pressure and the residue is extracted with methylene chloride (150 cc). The aqueous phase is treated with animal charcoal (1 g), filtered, saturated with salt, cooled to 4 ° C and acidified to pH 2 in the presence of methylene chloride (200 cc) with 2N hydrochloric acid. The aqueous phase is reextracted (2 × 10 cc) with the same solvent and ethyl acetate (6 × 200 cc) is extracted. The organic phase is dried over sodium sulfate and concentrated to dryness at 20 ° C., 20 mmHg (2.7 kPa) separately. The residue is combined and treated with diisopropyl ether (80 cc) for 4 hours with vigorous stirring.

The obtained crystals were filtered and dried to afford 2-methoxyimino-3-oxo-butylic acid- (syn isomer (8.9 g).

Infrared spectrum (CHBr ₃ ) characteristic bands (cm ⁻¹ ) are 3400, 2830, 2300, 1730, 1695, 1370, 1035.

Proton NMR spectrum (60 MHz, CDCl ₃ , ppm δ, Hz J): 2.48 (s, 3H, -CH ₃ C O-): 4.18 (s, 2H, -OCH ₃ ): 11.2 (s, 1H , -COOH).

Ethyl 2-methoxyimino-3-oxo-butylate (syn isomer) is known as Al. Bucourt. Manufactured according to Terahed edron 34, 2233 (1978).

Example 21

7- [2- (2-Amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2- [4- (2,2-dimethoxy-ethyl) ) -5,6, -dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl] -8-oxo-5-thia-1-aza A pure formic acid (100cc) solution of bicyclo [4,2,0] oct-2--ene (syn isomer, Form E) (0.1 g) was stirred at 50 ° C. for 30 minutes, and then again at 50 ° C. and 30 mm Hg (4 kPa). The mixture was concentrated to dryness, and the residue was placed in acetone (10 cc), and the mixture was concentrated at 20 mm Hg (2.7 kP a) at 20 ° C. The residue was treated by refluxing with acetone (20 cc), and the mixture was cooled and filtered.

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3-(5,6-dioxo-4-formylmethyl-1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct- 2-ene (syn isomer, Form E) (0.088 g) is obtained as a yellow powder. All properties are consistent with those of the product obtained in Example 16 (1-a).

Example 22

4-carbamoylmethyl-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (1.5 g) and N, N-diisoprophylethylamine (0.65 cc) 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-3- (2-tosyl To N, N-dimethylformamide (70 cc) solution of oxyvinyl) -5-thia-1-azabicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (3.7 g) The reaction mixture is heated for 3 hours at 60-65 ° C. in nitrogen, diluted with ethyl acetate (300 cc) and washed with distilled water (3 × 100 cc). Dry over magnesium sulfate and filter.

The solvent was evaporated under reduced pressure (40 mmHg, 4.4 kPa) at 40 ° C. to obtain the expected crude product (3.1 g). The obtained crude product (3.7 g) is chromatographed by a column of Melk silica gel (0.04-0.06 mm) (4 cm in diameter and 30 cm in height) by the above-described operation.

It is developed under 40 kPa pressure with ethyl acetate. Collect 200 cc milk powder. Evaporation of milk powders 11 to 32 under 40 ° C. reduced pressure (35 mmHg, 4.4 kPa) was carried out under 2-benzhydryloxycarbonyl-3- [2- (2-carbamoylmethyl-5,6-dioxo-1,4, 5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) Acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer) (2.7 g) is obtained.

Infrared spectrum (CHBr ₃ ) characteristic bands (cm ⁻¹ ) are 3450, 3390, 3190, 2820, 1780, 1720, 1685, 1590, 1475, 1450, 1050, 945, 755, 700.

).Proton NMR spectrum (60 MHz, CDCl ₃ , ppm δ, Hz J): 3.62 and 3.88 (AB, J = 16, 2H, -SCH _2- ): 3.83 (s, 3H, -NOCH ₃ ): 4.41 (s-wide, 2H, -CH ₂ CONH ₂ ): 5.22 (d, J = 5, 1H, H at 6 positions) -5.75 (dd, J = 5 and H at 9, 1H, 7 positions): 6.71 (s , 1H, H) of toothazole: 6.85 and 6.95 (AB, J = 16, -CH = CH-S-): 6.94 (s, 1H, -CH (C ₆ H ₅ ) ₂ ): 7.15 to 7.5 0 ( Mt, 25H, Directional): 7.71 and 8.80 (2s, 2 × 1H, -CONH): 9.58 (d, J = 9, 1H, -CONH- C ₇ ): 12.65 (s, 1H, = NH = C-CH Or-N

).

The product (syn isomer, Form E) (2.7 g) is dissolved in formic acid (47 cc), distilled water (30 cc) is added and the reaction mixture is heated at 50 ° C. for 30 minutes. Dilute with distilled water (17cc) and filter. The filtrate is concentrated under reduced pressure at 40 ° C. (5 mmHg, 0.67 kPa). The residue is dissolved in anhydrous ethanol (50 cc) and evaporated under 40 ° C. reduced pressure (30 mmHg, 4 kPa). Repeat this operation two more times. The residue was poured into ethanol (50cc), the insoluble matters were filtered off, washed with anhydrous ethanol (2 5cc) and ether (2 × 52cc), and dried under reduced pressure (5mmHg, 0.67kPa) at 20 ° C. 2- (2-amino-thiazol-4-yl) 2-methoxyimino-acetamido] -3- [2- (4-carbamoylmethyl-5,6-dioxo-1,4,5, 6-tetrahydro-1,2,4-triazine-3-yl) -thiovinyl] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct- 2-ene (sy n isomer, Form E) (1,3 g) is obtained.

Infrared spectrum (KBr) bands (cm ⁻¹ ) are 3410, 3200, 3100, 2000, 1770, 1710, 1680. 1630, 1590, 1380, 1040 and 945.

혹은

, δ>12ppm).Prototok NMR spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 3.63 and 3.83 (AB, J = 18, 2H, -SCH ₂ ): 3.87 (s, 2H, = NOCH ₃ ): 4.45 ( s, Wide, 2H, -CH ₂ -CONH ₂ ): 5.20 (d, J = 4, 1H, H at 6 position): 5.78 (dd, J = 4 and 9, 1H, H at 7 position): 6.75 ( s, 1H, H of toothbrush: 6.90 and 7.08 (2d, J = 16, s × 1H, -CH = CH-S-): 7.32 (s.wide, 2H, -NH ₂ of toothazole): 7.71 (s, wide area, 2H, -CONH ₂ ): 9.60 (d, J = 9, 1H, -CONH-C ₇ ): (NH =

or

, δ> 12 ppm).

4-Carbamoylmethyl-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine can be prepared by the following method.

4-ethoxycarbonylmethyl-thiosemicarbazide (8.33 g) (GANTE NANTSCH, Chem. Ber., 97, 989 (1964)) was suspended in ethanol in a saturated solution of ammonia (250 cc) and the reaction mixture at 25 ° C. Stir for 22 hours, filter off the insolubles, wash with alcohol (2X 25cc) and dry to afford 4-carbamoylmethyl-thiocemiccarbazide (6.1 g).

m.p. = 188 ° C

4-carbamoylmethyl-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (3.8 g) is a combination of 4-carbamoyl methyl-thiosemica carbazide (6.8 g) Oxalate (6.7 g) in M. Peson and M. Antoine, Bull. Soc. Chim. Obtained by condensation according to the method of France 1590 (1970).

Infrared spectrum (KBr) characteristic bands (cm ⁻¹ ) are 3350, 3480, 3430, 3270, 3100, 2000, 1710, 1690, 1670, 1365, 1200.

Example 23

N, N-Dimethyl Formamide (240 cc) of 4-N, N-Dimethylcarbamoylmethyl-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (4 g) The solution is treated with formic acid (0,60 cc) and heated to 60 ° C. in nitrogen.

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-Tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (8 g) was added and N, N-diisopurophyll was added. Ethylamine (2.8 cc) is added and N, N-dimethylmethamide (20 cc) is added dropwise for 10 minutes. The mixture is stirred at 60 ° C. for 2 hours 20 minutes, diluted with distilled water (600 cc) and extracted with ethyl acetate (2 × 250 cc). The organic extract was dissolved in 0.1 N hydrochloric acid solution (200 cc). Continue washing with half saturated sodium bicarbonate (200 cc) and dry over magnesium sulfate. The residue obtained by concentration under reduced pressure (30 mm Hg, 4 kPa) at 30 ° C. is chromatographed on a column of silica gel (0.04-0.06 mm) (height 30 cm, diameter 5 cm). It was developed with ethyl acetate (2.5 L) and then with 95: 5 (volume) mixture of ethyl acetate and methanol (1.5 L). Milk powders (100cc each) 32 to 37 were combined and concentrated to dryness. Salmon-colored solid 2-benzhydryloxy-carbonyl-3- {2- [4- (N, N-dimethylcarbamoylmethyl) -5 , 6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-tri Cylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E) (2.5 g).

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3380, 3200, 1800, 1725, 1685, 1590, 1520, 1495, 1450, 1040, 945, 755, 740.

The salmon colored solid product (syn isomer, Form E) (2.4 g) was treated with N, N-dimethylacetamide (1.47 cc) and phosphorus trichloride (0.44 cc) in a methylene chloride (48 cc) solution. Stir at 10 ° C. for 3 hours. The reaction mixture is diluted with methylene chloride (100 cc) and placed in a half saturated sodium bicarbonate solution (100 cc). The organic phase is washed with half saturated saline (100 cc) and dried over magnesium sulfate. Concentrated to dryness under reduced pressure (30 mmHg, 4 kPa) at 30 ° C. and the residue was silica gel 0.04-0. Chromatograph is carried out on a column of diameter of 2.2 mm and a height of 30 cm. At this time, it is developed with ethyl acetate (600cc). Collect 25 cc milk powder, combine milk powders 10 to 21 and concentrate to dryness, and 2-benzhydryloxycarbonyl-3- {2- [4- (N, N-dimethylcarbamoylmethyl-5,6-dioxo -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethylamino-thiazol 4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0 [oct-2-ene (syn isomer, Form E) (1.3 g) is obtained. .

Infrared spectrum (CHBr ₃ ) characteristic bands (cm ⁻¹ ) are 3400, 1790, 1730, 1690, 1670, 1590, 1520, 1500, 1460, 1050, 760, 740.

).Proton NMR spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.97 and 3.40 (S, 2X, 3H, -CON (CH ₃₂ ): 3.60 and 3.75 (2d, J = 18, 2H -SCH ₂ -): 4.08 (s, 3H, = NOCH ₃ ): 4.73 (s, Wide, 2H, CHCON): 5.08 (d, J = 4, H at 6 position), 6.77 (s, 1H, 5 position of toothbrush H): 6.88 (d, J = 16, 1H, -CH = CH-S-): 6.92 (s, 1H, -CO ₂ CH (C ₆ H ₅ )): 7.0 to 7.6 (hump, 27H, directional -CONH and -CH = CHS-): 7.81 (s, wide, 1H, -NH- of Trichil): 11.25 (s, wide, 1H, -N = C-OH of triazine or

).

Distilled water (9 cc) to 2-benzhydryloxycarbonyl-3-2- [4- (N, N-dimethylcarbamoyl-methyl) -5,6-dioxo-1,4,5,6-tetra Hydro-1,2,4-triazin-3-yl] -thiovinyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido]- 8-oxo-5-thia-1-aza-bicyclo was added to a 98% formic acid solution of [4,2,0] oct-2-ene (syn isomer, E-form) (1.3 g) and the reaction mixture was heated to 50 ° C. Heat 45 minutes at. The insoluble material is filtered off and the solution is concentrated to dryness under 40 ° C. (10 mmHg, 1.33 kPa). The residue is taken up, dissolved in ethanol (20 cc) and concentrated under reduced pressure (30 mmHg: 4 kPa) at 30 ° C. The solids were taken up in ethanol (25 cc), filtered and washed continuously with methanol (3 x 5 cc) and ethyl ether (3 x 10 cc) and dried to afford 7- [2- (2-amino-thiazol-4-yl) -2-. Methoxy-imino-acetamido] -2-carboxy-3- {2- [4- (N, N-dimethylcarbamoyl-methyl-5,6-dioxo-1,4,5,6- Tetrahydro-1,2,4-triazin-5-yl] -thiovinyl} -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.62 g) is obtained.

Whole ultraviolet spectrum (KBr): Characteristic bands (cm ^-1 ) are 3420, 3320, 3210, 1780, 1720, 1690, 0660, 1530, 1040 and 945.

) : 5.21(d, J=4, 1H, 6위치에 H) : 5.79(dd, J=4와 9, 1H, 7위치에 H) : 6.75(s, 1H, 치아졸의 H) : 6.88과 7.10(2d, =16, 2H, -CH=CH -S-) : 7.19(s, 광역, 1H, -NH₂) : 9.60(d, J=9, 1H, -CONH-C₇) : 12.73(s, 1H, 트리아진의 -N

또는

).Proton NMR Spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 2.88 and 3.08 (2s, 2 × 3H, -CON (CH ₃ ) ₂ ): 3.61 and 3.82 (2d, J = 18, 2H , -SCH _2- ): 3.85 (s, 3H, = NOC H ₃ ): 4.80 (s, wide area, 2H,

): 5.21 (d, J = 4, 1H, H at 6 position): 5.79 (dd, J = 4 and 9, 1H, H at position 7): 6.75 (s, 1H, H of toothbrush): 6.88 and 7.10 (2d, = 16, 2H, -CH = CH -S-): 7.19 (s, wide area, 1H, -NH ₂ ): 9.60 (d, J = 9, 1H, -CONH-C ₇ ): 12.73 ( s, 1H, -N of triazine

or

).

Soda salt of 4- (N, N-dimethylcarbamoyl-methyl) -5,6-dioxo-4-thioxo-perhydro-1,2,4-triazine is M. Antoine, Bull, Soc. Chim.F. (1970) (1590) is prepared by reacting ethyloxalate with 4- (N, N-dimethylcarbamoylmethyl) thiosecarbazide in methanol in the presence of methylsoda.

Infrared spectrum (KBr) bands (cm ⁻¹ ) are 3200, 1696, 1640, 1580 and 1530.

Example 24

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3 -(2-Tosyloxyvinyl) -5-thia-1-aza-bicyclo- [4,2,0] oct-2-ene (syn isomer, E-type) (18.2 g) and 5,6-di Diisopurophylethylamine dissolved in oxo-4-ethoxycarbonyl-methyl-3-thioxo-perhydro-1,2,4-triazine (4.8 g) and dimethylformamide (182 cc) ( 3.11 cc) solution is heated at 80 ° C. for 1 hour 20 minutes. The mixture was cooled, diluted with ethyl acetate (2000 cc), washed with saturated sodium bicarbonate (3 x 100 cc) and brine (2 x 100 cc), dried over magnesium sulfate, filtered and reduced pressure (20 mmHg: 2,7 kPa). Concentrated to dryness. The residue is chromatographed on a column of Melksilica gel (0.06-0.2 mm) (313 g) (diameter 4.9 cm, height 31 cm). At this time, it is developed with a mixture of cyclohexane and ethyl acetate (20 00cc) and 20:80 (volume) and ethyl acetate (2200cc). Collect 100 cc milk powder and concentrate dry milk powder 10-40 under reduced pressure (20 mmHg: 2.7 kPa) to give a yellow foamed 2-benz-hydryloxycarbonyl-3- [2- (5,6-dioxo). 4-ethoxycarbonylmethyl-1,4, 5,6-tetrahydro-1,2,4-triazin-3-yl) thiovinyl] -7- [2-methoxyimino-2-(2 -Triethyl amino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn Isomer, E-form) (6.15 g).

Infrared spectrum (KBr) bands (cm ⁻¹ ) are 3400, 1795, 1720, 1685, 1590, 1515, 1490, 1445, 1210, 1040, 935, 750 and 700.

COO-) : 4.63(d, J=4, 1H, 6위치에 H) : 6.05(dd, J=4와 9, 1H, 7위치에 H) : 6.70(s, 1H, 치아졸의 H) : 6.76(d, J=16, 1H-CH=CHS-) : 6.95(s, 1H,

) : 11.54(s, 1H, N-NHCO- 또 는

).Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 1.28 (t, J = 7, 3H, -CH ₂ CH ₃ ): 3.32 and 4.50 (2d, J = 18, 2H-SCH ₂ -): 4.02 (s, 3H, -OCH ₃ ): 4.23 (q, J = 7, 2H, -O-CH ₂ CH ₃ ): 4.60 (s, 2H,

COO-): 4.63 (d, J = 4, 1H, H in 6 position): 6.05 (dd, J = 4 and 9, 1H, H in position 7): 6.70 (s, 1H, H of toothbrush): 6.76 (d, J = 16, 1H-CH = CHS-): 6.95 (s, 1H,

): 11.54 (s, 1H, N-NHCO- or

).

To a solution of yellow foam-type product (syn isomer E type) (6 g) and dimethylacetamide (2.27 cc) dissolved in methylene chloride (60 cc), cooled to -10 ° C and phosphorus trichloride (1 cc) was added. do . The mixture was kept at −10 ° C. for 1 hour 20 minutes, diluted with methyl acetate (750 cc), and the mixture was washed with saturated aqueous sodium bicarbonate solution (3 × 100 cc) and brine (2 × 100 cc), and then decompressed (20 mm Hg: 2.7). evaporated to dryness under kPa). The residue was chromatographed on a column (2.1 cm in diameter and 18 cm in height) of Melk Sealica gel (0.06-0.2 mm) (35 g). Develop with ethyl acetate (0.5 L) and collect 30 cc milk powder. Concentrate to dry powder 2-7 at 20 mmHg (2.7 kPa) 2-benz-hydryloxycarbonyl-3- [2- (5,6-dioxo-4-ethoxycarbonyl-methyl-1,4 , 5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -7- [2-methoxyimino-2- (2-trimethylamine-thiazol-4-yl ) -Acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] -oct-2-ene (syn isomer, E-type) (5.2 g) in yellow foam form Get

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3400, 1780, 1720, 1685, 1590, 1525, 1490, 1445, 1210, 1035, 940, 750, 700.

) : 5.09(d, J=4, 1H, 6위치에 H) : 5.94 (dd, J=4와 9, 1H, 7위치에 H) : 6.72(s, 1H, 치아졸의 H) : 6.75(d, J=16, 1H-CH= CHS-) : 6.94(s, 1H,

) : 11.05(s, 1H, N-NHCC- 또 는

*).Proton NMR spectrum (350MHz, CDCl ₃ , ppm δ, Hz J): 1.28 (t, J = 7, 3H, -CH ₂ CH ₃ ): 3.55 and 3.64 (2d, J = 18, 2H -SCH ₂ -): 4.06 (s, 3H, -OCH _3- ): 4.26 (q, J = 7, 2H, -O-CH ₂ CH ₃ ): 4.63 (s, 2H,

): 5.09 (d, J = 4, 1H, H at 6 position): 5.94 (dd, J = 4 and 9, 1H, H at position 7): 6.72 (s, 1H, H of toothbrush): 6.75 ( d, J = 16, 1H-CH = CHS-): 6.94 (s, 1H,

): 11.05 (s, 1H, N-NHCC- or

*).

The solution dissolved in 98% formic acid (100 cc) of the yellow foam material (syn isomer, E-type) (5 g) and distilled water (30 cc) were heated at 50 ° C. for 15 minutes, and the mixture was cooled and diluted with water (70 cc). The filtrate was concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa). The residue was taken up in ethanol (3 x 50 cc) and concentrated each time under reduced pressure (20 mmHg: 2.7 kPa). After cooling, filtered off and dried in vacuo (20 mmHg, 2.7 kPa) 7- [2- (amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2 -(5,6-Dioxo-4-ethoxy carbonylmethyl-1,4,5,6-tetrahydro-1,2,4-triazin-yl) -thiovinyl] -8-oxo-5- Tooth-1-aza-bicyclo [4,2,0] -oct-2-ene (syn isomer, E-type) (1.9 g) is obtained as a yellow solid.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3340, 3320, 3130, 1780, 1725, 1690, 1590, 1040, 945.

) : 5.18(d, J=4, 1H, 6위치에 H) : 5.77(dd, J=4와 9, 1H, 7위치에 H) : 6.72(s, 1H, 치아졸의 H) : 6.87(d, J=16, 1H, -CH=CHS-) : 7.08(d, J=16, 1H, -CH=CHS-) : 7.15(s, 광역, 12H, -NH₂) : 9.58 (d, J=9, 1H, -CONH-) : 12.80(s, 1H, NNHCO- 또는

). 5,6-디옥소-4-에톡시카보닐메칠-3-치옥소-퍼하이드로-1,2,4-트리아진은 다음과 같이 얻을 수 있다.Proton NMR spectra (350 MHz, DMSO d ₆ , ppm δ, Hz J): 1.22 (t, J = 7, 3H, -CH-CH _2- ): 3.60 and 3.85 (2d, J = 18, 2H- SCH _2- ): 3.85 (s, 3H, -OCH _3- ): 4.15 (q, J = 7, 2H, -OCH ₂ -CH ₃ ): 4.66 (s, 2H,

): 5.18 (d, J = 4, 1H, H at 6 position): 5.77 (dd, J = 4 and 9, 1H, H at position 7): 6.72 (s, 1H, H of toothbrush): 6.87 ( d, J = 16, 1H, -CH = CHS-): 7.08 (d, J = 16, 1H, -CH = CHS-): 7.15 (s, wide area, 12H, -NH ₂ ): 9.58 (d, J = 9, 1H, -CONH-): 12.80 (s, 1H, NNHCO- or

). 5,6-Dioxo-4-ethoxycarbonylmethyl-3-thioxo-perhydro-1,2,4-triazine can be obtained as follows.

A solution of ethylisochio cyanoacetate dissolved in anhydrous ethanol (185 cc) is added to a suspension of ethylhydrazino-oxalate (24.4 g) dissolved in anhydrous ethanol (185 cc) at 25 ° C for 5 minutes. After the mixed solution is dissolved, white precipitates are produced. After stirring for 20 hours in nitrogen, a solution prepared from sodium (8.5 g) in ethanol (! 85cc) was added for 15 minutes, and the mixture was heated for 4 hours in a Korean wave. The reddish brown suspension is concentrated to dryness under reduced pressure (20mmHg: 2.7kPa), and the residue is dissolved by adding 4N hydrochloric acid (100cc) and ethyl acetate (2,000cc), the insoluble substance is filtered off and the organic phase is washed with saturated brine (4 × 250cc). Dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa) to give a reddish brown rubber (43 g). This was dissolved in saturated sodium bicarbonate solution (300cc), the brown solution was washed with isofurophyll ether (3 × 10 0cc), added with 1N hydrochloric acid to pH = 1 and extracted with ethyl acetate (500cc). The organic phase was washed with saturated brine (2 × 50 cc), dried over magnesium sulfate, filtered over charcoal charcoal and concentrated to dryness under reduced pressure (20 mmHg: 2.7 kPa) to give a brown solid 5,6-dioxo-4-ethoxycarbonyl-methyl. Obtain 3-3-oxo-perhydro-1,2,4-triazine (9.5 g).

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3500, 2800, 1740, 1700, 1645, 1380, 1235, 1200.

) : 12.50 (s, 1H, -NHCO-). 에칠이소치오씨아노 아세테이트는 D. 호프와 R풀만, Chem. Ber. 109, 3047(1976)에 의거하여 제조될 수 있다.Proton NMR spectrum (80 MHz, DMSO d ₆ , ppm δ, Hz J): 1.38 (t, J = 7, 3H, -CH ₂ CH ₃ ): 4.30 (q, J = 7, 2H, -CH ₂ CH ₃ ): 5.03 (s, 2H,

): 12.50 (s, 1H, -NHCO-). Ethylisociocyanoacetate is D. Hof and R Pullman, Chem. Ber. 109, 3047 (1976).

Example 25

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-Tosyloxyvinyl) -5-thia-1-aza-bicyclo- [4,2,0] oct-2-ene (syn isomer, Form E) (10.04 g) and dimethylformamide (200 cc) , A mixture of 4-allyl-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (2.22 g) and N, N-diisopropyl-ethylamine (2.1 cc) Stir at 60 ° C. nitrogen for 3 hours. The mixture was diluted with ethyl acetate (600 cc), washed with water (2 × 200 cc) and half saturated saline (2 × 100 cc), dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C. and 20 mm Hg. The residue is taken up in methylene chloride (50 cc) and melksilica gel (0.05-0. Mm) (20 g) is added and the mixture is concentrated to dryness at 20 ° C., 20 mm Hg. The powder was fixed in a column of Melksilica gel (0.05-0.2 mm) (200 g) (diameter 6 cm), developed into a mixture of cyclohexane and ethyl acetate (1 l of 10: 90 (volume)) and again with ethyl acetate (2 l). Collect 120 cc milk powder and concentrate the dry milk powder 8-28 at 20 ° C. and 20 mm Hg to dry the product with 3- [2- (4-allyl-5,6-dioxo-1,4, 5,6-tetrahydro. -1,2,4-triazin-3-yl) thio-vinyl] -2benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylaminothiazol-4-yl ) -Acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E-type) (3.7 g) Obtained as an orange foam.

Infrared spectrum (CHBr ₃ ): Characteristic band (cm ^-1 ) is 3380, 1800, 1720, 1670, 1515, 1045, 940.

) : 7.09(d, J=16, 1H, CHS-) : 8.78(s, 1H, -NH(C₆H₅)₃) :9.04(d, J=9, 1H, -CONH-) : 12.62(s, 1H, =N-NH-CO- 또는 N-N

).Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 3.60 and 4.29 (2d, J = 18, 2H, -SCH _2- : 3.85 (s, 3H, -OCH ₃ ): 4.45 ( d, J = 5, 2H, -SCH _2- ): 5.05 (d, J = 4, 1H 6-position H): 5.17-5.27 (Mt, 2H, = CH ₂ ): 5.78-5.92 (Mt, 2H, H at position 7 and -CH = CH _2- : 6.97 (s, 1H,

): 7.09 (d, J = 16, 1H, CHS-): 8.78 (s, 1H, -NH (C ₆ H ₅ ) ₃ ): 9.04 (d, J = 9, 1H, -CONH-): 12.62 ( s, 1H, = N-NH-CO- or NN

).

Trichloride (0.40 cc) 3- {2- [4- (al-3-yl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine- 3-yl] -thiovinyl} -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethyl-amino-thiazol-4-yl) -acetamido]- Soluble in 8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2.34 g) and methylene chloride (23 cc) The mixture of dimethylacetamide (0.85cc) was cooled to -10 ° C, and the mixture was stirred at -10 ° C for 30 minutes. It is injected into ethyl acetate (250cc), and the mixture is washed with water (50cc), saturated aqueous sodium bicarbonate (50cc) and saturated brine (2x50cc), dried over sodium sulfate, filtered and concentrated to dryness at 30 ° C and 20mmHg. The residue was dissolved in methylene chloride (10 cc) and chromatographed on a column of Melksilica gel (0.05-0.2 mm) (10 g) (1.4 cm in diameter).

The developing solution uses a 20:80 (volume) mixture of cyclohexane and ethyl acetate (500 cc). Collect 60 cc fractions. Evaporation of fractions 2 through 4 under reduced pressure (20 mmHg) at 20 ° C. resulted in yellow foamed 3- [2- (4-al-3-yl) -5,6-dioxo-1,4,5,6- Tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2-(2-trimethylamine-thiazol -4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] -oct-2-ene (syn isomer, E-type) (1.34 g) Get

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3380, 1780, 1720, 1680, 1515, 1490, 1040, 940, 750, 735.

-) : 5.09(d, J= 4, 1H, 6위치에 H), 5.26-5.28(2d, 2H, =CH₂) : 5.78-5.88(mt, 1H, -CH=CH₂) : 5.92(d d, J=4와 9, 1H, 7위치에 H) : 6.74(s, 1H, 치아졸의 H) : 6.86(s, J=16, -CH=CHS- ) : 6.96(s, 1H,

) : 7.05(d, J=9, 1H, -CONH-) : 11.68(s, 1H, =NMHCO-혹은

).Proton NMR spectrum (350MHz, CDCl ₃ , ppm δ, Hz J): 3.57 and 3.66 (2d, J = 18, 2H-SCH _2- ): 4.03 (s, 3H, -OCH _3- ): 4.52 ( d, J = 4, 2H,

-): 5.09 (d, J = 4, 1H, H in 6 position), 5.26-5.28 (2d, 2H, = CH ₂ ): 5.78-5.88 (mt, 1H, -CH = CH ₂ ): 5.92 (dd , J = 4 and 9, 1H, 7 at position H): 6.74 (s, 1H, H of toothbrush): 6.86 (s, J = 16, -CH = CHS-): 6.96 (s, 1H,

): 7.05 (d, J = 9, 1H, -CONH-): 11.68 (s, 1H, = NMHCO-or

).

The product (syn isomer, Form E) (1.34 g) obtained in the form of the above yellow foam was dissolved in formic acid (13 cc), water (6.5 cc) was added, and the mixture was heated with stirring at 50 ° C. for 30 minutes. After cooling the mixture is filtered and the solution is concentrated to dryness under 30 ° C. reduction (0.05 mmHg).

The residue is taken up in enolnol (50 cc) and the solvent is removed at reduced pressure (20 mmHg: 20 ° C. and the procedure is repeated three times. The residue is treated with ethanol (100 cc) under reflux and some insoluble material is filtered off and the residue is dried. Yellow powdery 3- {2- [4- (al-3-yl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-yl] -Thiovinyl} -7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxo-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3600, 2300, 1775, 1710, 1680, 1535, 1040, 934.

).Proton NMR spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 3.63 and 3.80 (2d, J = 18, 2H-SCH _2- ): 3.88 (s, 3H, -OCH ₃ ): 4.48 ( d, J = 4, 2H, -NCH _2- ): 5.19-5.27 (mt, 3H, H at CH ₂ and 6 position): 5.74-5.92 (mt, 2H, -CH = CH ₂ and H at position 7) : 6.74 (s, 1H, H of toothbrush): 6.91 (d, J = 16, 1H, -CH = CHS-): 7.09 (d, J = 16, 1H, = CHS-): 7.18 (s,- NH ⁺ ₃ ): 9.60 (d, J = 9, 1H, -CONH-): 12.61 (s, 1H, = N-NHCC- or

).

4-allyl-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine can be prepared according to the method described in Belgium patent 83 0,445.

Example 26

2-benzhydrooxycarbonyl-7- [2-ethoxyimino-2- (2-trichilimino-thiazol-4-yl) acetamido-8-oxo-3-oxide-3- (2 -Tosyloxyvinyl) -5-thia-1-aza-bicyclo-[4,2,0] oct-2-ene (syn isomer, Form E) (5.02 g) with dimethyl pomide (93 cc), 4 -(2,2-Dimethyl-dioxoran-4-yl-methyl) 5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (1.5 g) and N, N -A mixture of diisopuroethylethylamine (1.05 cc) is stirred for 3 hours (60 ° C.) under nitrogen. Dilute with ethyl acetate (200 cc) and wash the mixture with water (4 x 200 cc), dry over sodium sulfate, filter, and longitudinally tune at 20 ° C, 20 mmHg (2.7 kPa)-residue silica gel (0.06-0.2 mm) (10 g) is fixed, and the powder is integrated into a column of 2.5 mm (40 cm in diameter) of melt silica gel (0.06-0.2 mm) (40 g in height) and developed into ethyl acetate (1,31). Load 60 cc milk powder. Dry milk powder 6-20 was concentrated to dryness at 20 ° C. and 20 mmHg (2.7 kPa) to give a yellow coma, 2-benzhydryloxycarbonyl-3-2- [4- (2,2-dimethyl-dioxolane-). 4-yl-methyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl-7- [2-methoxyimino -2- (2-tritylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct- 2-ene (syn isomer, Form E) (2.48 g) is obtained.

Proton NMR Spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 1.32-1.43 (2S, 6H, -C (CH ₃ ) ₂ ): 3.34-4.05 (2d, J = 18, 2H, -SCH _2- ): 3.74 (t, J = 6 2H, -CH ₂ C-): 3.84 (s, 3H, = NOCH ₃ ): 3.95 (t, J = 6,2H,> N-CH _2- ): 4.38 (Quintuplet J = 6, 1H,> CH-O-): 4.65 (d, J = 4 1H, H at 6 position): 6.06 (dd, J = 4-9, H at 7 position): 6.71 (s, 1H, H) of toothazole: 6.84 (d, J = 16, 1H, -CH = CHS): 6.96 (s, 1H, -COOCH <): 11.60 (s, 1H, = N-NHCC-).

2-benzhydryloxycarbonyl-3-2- [4- (2,2-dimethyl-dioxoran-4-yl-methyl) -5,6-dioxo-1,4,5,6- Tetrahydro-1,2,4-triazin-3-yl] -thiovinyl-7- [2-methoxy-imino-2 (2- (2-tritylamino-thiazol-4-yl) -acetami 8] oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2.48 g) .9 g) solution and deketyl acetamide (0.85 cc) are added to phosphorus trichloride (0.4 cc) at -10 ° C for 40 minutes.

The mixture was poured into ethyl acetate (2500 cc) and the mixture was washed successively with saturated sodium bicarbonate solution (200 cc), water (2 x 100 cc) and saturated brine (100 cc), dried over sodium sulfate, and filtered to 20 ° C. Concentrate to dryness at 20 mmHg (2.7 kPa). The residue was taken up in methylene chloride (20 cc), and melk silica gel (0.06-0.2 mm) (10 g) was added and the mixture was concentrated to dryness at 20 ° C. and 20 m mHg, and the powder obtained was melted silica gel (0.06-0.2 mm) (40 g) column. (1.5cm in diameter, 1.5cm in height).

Run on ethylene chloride (500 cc) to collect 60 cc milk powder. Milk powder 2-7 is combined and concentrated to dryness at 20 ° C. and 20 mmHg to give 2-benzhydryloxycarbonyl-3- {2- [4- (2,2-dimethyl-dioxolane-4- Yl-methyl) -5,6-dioxo-1,4,5,, 6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino -2- (trityl-amino-thiazol-4-yl) -acetamido) -8-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E type) (1,4 g).

2-benzhydryloxycarbonyl-3- {2- [4- (2,2-dimethyl-dioxolan-4-yl) -methyl-5,6-dioxo-1,4,5,6 -Tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -acetami Fig. 8) -8-chia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1,4 g), formic acid (13 cc), water (6.5 cc) The mixture is heated to 50 ° C. for 30 minutes. After cooling to 20 ° C, filtered and concentrated to dryness at 30 ° C, 0.05mmHg (0.007kPa). The residue is taken up in ethanol (100 cc) and the solvent is removed at 20 ° C. and 20 mmHg (2.7 kPa). The same procedure is repeated twice. The yellow solid is taken up in boiling ethanol (100 cc) and the mixture is filtered and the filtrate is 20. Concentrate and filter to 50 cc at (20 mmHg, 2.7 kPa). Solids are washed with dimethyl ether (20 cc) and dried to 7- [2- (2-amino-thiazol-4-yl) -2. -Methoxyimino-acetamido] -2-carboxy-3-yl] -thiovinyl} -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct 2-ene (syn Isomer, Form E) (0.49 g) is obtained. NMR of this product shows that it contains about 25% of formic acid esters or other alcohol groups. Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3650, 2200, 1770, 1710, 1680, 1590, 1530, 1045, 945.

Proton to NMR spectrum (350MHz, DMSOd ₆ + D ₂ O, ppm is δ, Hz is H): Diol: 3.87 (S, 3H, = NOCH ₃ ): 5.20 (d, J = 4, 1H, 6-position H ): 575 (d, J = 4, H at position 7): 6.74 (s, 1H, H of toothbrush): 6.96-7.10 (2d, J = 16, 2H, = CH = CH-S-): formic acid Ester: 3.87 (s, 2H, = NOCH ₃ ): 5.18 (d, J = 4, 1H, H in 6 positions): 5.75 d, J = 4, 1H, H in 7 positions: 6.74 (s, 1H, Tooth) H): 6.93-7.08 (2d, J = 16, 2H, -CH = CHS-): 8.22 (s, 1H, HCOO-).

4- (2,2-Dimethyl-dioxoran-4-yl-methyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine is It can be removed. A solution of methanol (50 cc) in anhydrous methanol (1.12 g) was prepared, and 4- (2,2-dimethyl-dioxolan-4-yl-methyl-thiocemiccarbazide (10 g) was added under stirring at 25 ° C. under nitrogen. Diethyl oxalate (6.6 cc) was added dropwise for 10 minutes and the mixture was heated to reflux for 2 hours, cooled to 20 ° C., diluted with dieth ether (1 ₁ ), filtered and dried to give a white solid (3.7). The product is taken up in methylene chloride (200 cc) and the mixture is stirred in the presence of N-hydrochloric acid (10 cc) The organic phase is decanted and washed with saturated brine (2 x 20 cc) and dried under vorticed soda. And concentrated to dryness at 20 mmHg (2.7 kPa) at 20 ° C. The remaining emulsion is dissolved in methylene chloride (50 cc) and scraped to crystallize The mixture is left for 3 hours at 4 ° C. Filter dried to 4- (2 , 2-Dimethyl-dioxoran-4-yl-methyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-tri A white crystalline form of azine (1.5 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3600, 3100, 1680, 1575, 1535, 1210, 1060.

) : 3.95(m, 2H, -CH₂O-) : 4.50(m, 3H,

).Proton's NMR spectrum (350 MHz, DMSOd ₆ , ppm is δ, Hz is H): 1.30-1.42 (2S, 6H,

): 3.95 (m, 2H, -CH ₂ O-): 4.50 (m, 3H,

).

4- (2,2-Dimethyl-dioxoran-4-yl-methyl (-thiosemicabazide can be prepared by the following method. N- (2,2-, prepared according to US Pat. No. 4,064,242). Dimethyl-dioxolan-4-yl-methyl) -diiocarbamate (23.6 g), methyl mixture of anhydrous ethanol (500 cc) and hydrazine hydrate (5.6 g) were heated to reflux for 2 hours and 30 minutes at 20 ° C. , Concentrated to dryness under 20 mmHg (2.7 kPa), and the residue was taken up in ethyl ether (100 cc), filtered, and dried to give a cream solid (4-, 2,2-dimethyl-dioxolane-4) having a melting point of 145 ° C. -Yl-methyl) -chiosemicacarbazide (15.2 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3340, 3200, 1630, 1555, 1380, 1370, 1240, 1210, 1060.

) : 3.90(s, 2H, -NH₂) : 4.10(dd, J=6-7, 2H, -CH₂O) : 4.38(m, 1H,

) : 7.78(t, J=5, 1H, -CH₂NH-) : 7.98(s, 1H ,

).Proton NMR spectrum (80 MHz, CDCl ₃ , ppm δ, Hz H): 1.38-1.48 (s, 6H, C (CHδ) ₂ ): 3.72 (dd, J 6, 2H,

): 3.90 (s, 2H, -NH ₂ ): 4.10 (dd, J = 6-7, 2H, -CH ₂ O): 4.38 (m, 1H,

): 7.78 (t, J = 5, 1H, -CH ₂ NH-): 7.98 (s, 1H,

).

Example 27

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxo-3- (2-tosyloxyvinyl) -5-thia -1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.58 g) solution with -5,6-dioxo-4- (2-hydroxyethyl) A N, N-dimethylmethamide (10 cc) solution of 3-thioxo-perhydro-1,2,4-triazine (0.31 g) is heated at 30-60 ° C. for 4 hours. The reaction mixture is cooled and diluted with ethyl ether (150 cc), the precipitate is washed with filtration ether (2 x 25 cc) and dried. Prepared amorphous beige powder 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2- [5,6 -Dioxo-4- (2-hydroxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -8-oxo-5- Chia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, form E (0.58 g is obtained. Rf = 0.42: silica gel chromatography phase: developing solution: 60: 20 ( Volume) of ethyl acetate, a mixture of acetic acid, water, and purification of the product can be carried out as follows.

The product was diluted and dissolved in caustic soda solution (50cc) and filtered through a small amount of insoluble matter in a mixed solution of pH 5 with dilute hydrochloric acid.The solution was first added to distilled water (1 L) in a column of XAD-2 resin (2.4 cm in diameter). And then to water and ethanol (1 L): 95: 6 (volume). Concentrated under reduced pressure (5 mmHg) at 30 ° C. and dried to give 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3 in light yellow crystalline form. -{2- [5,6-dioxo-4- (2-hydroxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl [-thiovinyl } -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.2 g) is obtained.

) : 5.10(d, J=4, 1H, 6위치의 H) : 5.65(dd, J=4, 9, 1H, 7위치의 H) : 9.39(d, J=16, 1H, -CH=CH-S-) : 6.73(s, 1H, 치아졸 5위치의 H) : 7.17(s, broad, 2H, -NH₂) : 7.37(d, J=16, 1H, -CH=CH-S-) : 9.54(d, J=9, 1H, -CONH-C₇).Proton NMR spectrum (350 MHz, DMSOd ₆ , ppm d, Hz J): 3.60 (t, J = 5, 2H, N-CH ₂ -CH ₂ OH): 3.84 (s, 3H, = NOCH ₃ ): 3.92 (t, J = 5, 2H,

): 5.10 (d, J = 4, 1H, 6 position H): 5.65 (dd, J = 4, 9, 1H, 7 position H): 9.39 (d, J = 16, 1H, -CH = CH -S-): 6.73 (s, 1H, H at position 5): 7.17 (s, broad, 2H, -NH ₂ ): 7.37 (d, J = 16, 1H, -CH = CH-S-) : 9.54 (d, J = 9, 1H, -CONH-C ₇ ).

The pale yellow crystalline substance (syn isomer, Form E) (0.13 g) is dissolved in a 1 / 100-N sodium bicarbonate solution (21 cc). Let the solution be lyophilized by freezing at -80 ° C. The light yellow crystalline form of the sodium salt (syn isomer, Form E) (0.145 g) is obtained in a white lyophilic form.

Rf = 0.28 silica gel chromatography phase:

) : 3.91(t, J : 6, 2H,

) : 3.87(s, 3H, : NOCH₃) : 5.07(d, J : 4, 1H, 6위치의 H) : 5.60(dd, J : 4-9, 1H, 7위치의 H) : 6.31(d, J : 16, 1H, -CH=CH-S-) : 6.71(s, 1H, 치아졸의 5위치의 H) : (7.17(s, broad 2H, -NH₂) : 7.36(d, J=16, 1H, -CH=CHS-) : 9.54(d, J=9, 1H, -CONH-).Developing solution: 60: 20: 20) by volume of ethyl acetate, acetic acid, water mixture Fufonton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 3.50 (AB, not resolved 2H, -SCH _2- ): 3.60 (t, J: 6, 2H,

): 3.91 (t, J: 6, 2H,

): 3.87 (s, 3H,: NOCH ₃ ): 5.07 (d, J: 4, 1H, 6 positions H): 5.60 (dd, J: 4-9, 1H, 7 positions H): 6.31 (d , J: 16, 1H, -CH = CH-S-): 6.71 (s, 1H, H at 5 positions of the toothazole): (7.17 (s, broad 2H, -NH ₂ ): 7.36 (d, J = 16, 1H, -CH = CHS-): 9.54 (d, J = 9, 1H, -CONH-).

5,6-dioxo-4- (2-hydroxyethyl) -3-thioxo-perhydro-1,2,4-triazine is M. Peron and M. It can be prepared by the method described by Anthony (Bull. Soc. Chim. France 1590 (1970)).

To a 4- (hydroxyethyl) -thiosemicarbazide (5 g) and ethyloxalate (5.5 cc), a solution of methylsoda made of soda (0.85 g) and methanol (37 cc) was added to reflux the mixture for 3 hours. The resulting precipitate was filtered, washed with methanol and washed with methanol (2 x 5 cc) to give a sodium salt. The resulting sodium salt was taken up in distilled water (25 cc). The solution was filtered and acidified with 1N hydrochloric acid (pH 2). Washed and dried in air to afford 5,6-dioxo-4- (2-hydroxyethyl) -3-thioxo-perhydro-1,2,4-triazine (2.4 g) (mp = 230 &lt; 0 &gt; C). Obtained: The sodium salt was dissolved in anhydrous methanol solution of dioxo5,6-4- (2-hydroxyethyl) -3-thioxo-perhydro-1,2,4-triazine (4.73 g). Treated with hexahexanoate, you get 4.7 g of sodium salt.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3420, 3200, 3070, 1655, 1575, 1560, 1395, 1205, 1080, 1045, 835.

4- (2-hydroxyethyl) thiosemicarbazide is Y. Kazakov and Lee. Why. Obtainable according to the method described by Pokowski (Doklady Acad. Nauk. SSSR 134, 824 (1960)).

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxo-3- (2-tosyloxyvinyl) -5-teeth The -1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) may be prepared by the following method.

2-benzhydroxycarbonyl-7- [2-methoxyimino-2- (2-tritylamino-thiazol-4 -yl) -acetamido] -8-oxo-3- (2-tosyloxy A mixture of pure formic acid (80 cc) and water (25 cc) in vinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (5.93 g) The resulting solution was heated at 50 ° C. for 30 minutes, cooled at 20 ° C., filtered and concentrated to dryness under 30 ° C. 20 mm Hg (2.7 kPa). The residue is taken up in acetone (150 cc) and concentrated to dryness at 20 ° C., 20 mmHg (2.7 kPa). This tissue is repeated two more times and the residue is dissolved in ether (75 cc) and filtered.

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxo-3- (2-tosyloxyvinyl) -5-teeth 1-Aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (3.4 g) is obtained as a yellow powder.

Example 28

2-benzhydroxycarbonyl-7- [2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -acetamido] -8-oxo-3- (2-tosyloxy Vinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (10.04 g) with dimethylformamide (200 cc) and 4- (2- Tetra-butoxycarbonyl-amino-ethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine- (3.46 g) and N, N-diisopropylethyl The mixture of amines (2.1 cc) was stirred at 60 to 3 hours 30 minutes, diluted with ethyl acetate (800 cc), the mixture was washed with half brine (400 cc), dried over sodium sulfate and filtered, and the temperature was 30 ° C, 20 mmHg (2, The product obtained by drying and concentrated at 7 kPa) is dissolved in methylene chloride (50 cc) and chromatographed on a column (3 cm in diameter and 30 cm in height) of Melx silica gel (0.06-0.2 mm) (100 g). Development is a mixture of 50:50 (volume) of cyclohexane and ethyl acetate (500cc) 25:75 (volume) of cyclohexane and ethylacetate (500cc), and the mixture of ethylacetate (500cc), 25: Collect 125 cc of fractions by developing 75 (volumes) of cyclohexane and ethyl acetate (500 cc) and a mixture of ethyl acetate alone (1.5 ₁ ). The fractions 9-21 were concentrated to dryness at 20 mmHg, 2.7 kPa, 20 ° C. to give brown foamy-2-benzhydroxycarbonyl-3- {2- [4- (2-tetra-butoxycarbonyl-amino- Ethyl) -5,6-dioxo-1,4,5,6-tetra hydro-1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxy imino-2 -(2-tritylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2- Syn (syn isomer, Form E) (7.69 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3380, 1795, 1715, 1690, 1590, 1520, 1495, 1445, 1205, 1160, 1040, 940, 750, 700.

Proton NMR Spectrum (350MHz, CDCl ₃ , ppm δ, Hz J): 1.36 (s, 9H, C (CH ₃ ) ₂ ): 3.30-4.65 (2d, J = 8, 2H, -SCH _2- ) : 3.30 (m, 2H, -CH ₂ NHCO-): 3.95 (m, 2H, -CH ₂ -CH ₂ NH-): 4.0 (s, 3H, CH ₃ ON =): 5.20 (d, J = 4, H ₆ ): 6.03 (dd, J = 4-9, H ₇ ): 6.70 (s, H of toothbrush): 6.86 (d, J = 16, -CH = CHS-): 6.94 (s, -COOCH) : 11.7 (s, board, -NH-, triazine -NH-).

2-benzhydroxy carbonyl-3- {2- [4- (2-tetra-butoxycarbonylamino-ethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1, 2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxy-imino-2- (2-tritylamino-thiazol-4-yl) -acetamido] -8 Oxo-5-oxide-5-chia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (3.36 g) Treated with amide (1.2cc) solution with phosphorus trichloride (1.04cc), stirred for 1 hour and 30 minutes at -10 ° C, diluted with ethyl acetate (250cc) and diluted with 2% crude steel solution (150cc) and half saturated saline (2x). 100 cc), dried over sodium sulfate, filtered, and concentrated to dryness at 20 ° C and 20 mmHg (2.7 kPa). The product thus obtained is fixed to melk silica gel (0.06-0.2 mm) (5 g) and chromatographed on a column (3 cm in diameter and 15 cm in height) of the melk silica gel (0.06 0.2 mm) (50 g). The development develops in ethyl acetate 6 ₁ to collect 600c c fractions. The fraction 2-2 was concentrated to dryness at 20 ° C. and 20 mm HG (2.7 kPa) in brown foam to form 2-benzhydroxy carbonyl-3- {2- [4- (2-tetra-butoxycarbonylamino-ethyl ) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl)]-thiovinyl} -7- [2-2-methoxyimino- (2-trityl amino-thiazol-4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E) (1.97 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3400, 3280, 1790, 1695, 1590, 1520, 1495, 1450, 1040, 945, 755, 700.

Proton NMR spectrum (350MHz, CDCl ₅ , ppm δ, Hz J): 1.33 (s, 9H, -C (CH ₃ ) ₂ ): 3.20 (m, 2H, -CH ₂ CH ₂ N): 3.64- 3.86 (2d, J = 18, 2H, -SCH ₂ ): 3.83 (2d, J = 6, 2H, -CH ₂ -CH ₂ N): 3.84 (s, 3H, = NOCH ₃ ): 5.25 (d, J = 4, 1H, H ₆ ): 5.77 (dd, J = 4 and 9, 1H, H ₇ ): 6.72 (s, 1H, H of chiazole): 6.92 (s, 1H, -COOCH <): 9.93 and 7.02 (d, J = 9, 1H, -NHCO-), 12.55 (s, 1H, -NH- of triazine).

2-benzhydroxy carbonyl-3- {2- [4- (2-tert-butoxycarbonyl amido-ethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1 , 2,4-triazin-3-yl] -thiovinyl} -7- (2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -acetamido] -8- A mixture of oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1.88 g), formic acid (35 cc) water (15 cc) Heat 30 minutes at, add water (20 cc) and cool the mixture at 20 ° C., filter and dry under 50 ° C., 0.05 mm Hg (0.007 kPa) Concentrate to dryness in ethanol (2 ± 100 cc) and mix the mixture Concentrate to dryness at 20 ° C. and 20 mm Hg (2.7 kPa), respectively.The residue was treated with ethanol (50 cc) for 15 minutes at 45 ° C. and the mixture was filtered, washed with ether (2 × 20 cc) and dried to obtain 7- [2- (2-amino-thiazol-4-yl) -2-methoxy imino-acetamido] -3- {2- [4- (2-amino ethyl) -5,6-dioxo-1,4 , 5,6-tetrahydro-1,2,4-tria 3-yl] -thiovinyl-2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1.08 g) The yellow powder is obtained by formate.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3500, 2200, 1770, 1710, 1680, 1630, 1530, 1380, 1040, 930.

Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 3.12 (m, 2H, -CH-CH ₂ -NH ₂ ): 3.51 and 3.60 (2d, J = 18, 2H, -SCH _2- ): 3.85 (s, 3H, CH ₃ ON): 4.2 (t, J = 6, 2H,> NCH ₂ -CH ₂ -NH ₂ ): 5.12 (d, J = 4, 1H, H ₆ ): 5.67 (dd, J = 4 and 9, 1H, H ₇ O): 6.44 (d, J = 8, 1H, -CH-CHS-): 6.73 (s, 1H, H of azole): 7.2 (s, Wide area, 2H, -NH ₂ ): 8.18 (s, 1H, H of formate): 9.55 (d, J = 9, 1H, -NHCO-).

4- (2-tert-butoxycarbonylamino-ethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine can be prepared as follows.

4- (2-tert-butoxycarbonylamino-ethyl) -thiosemicarbazide (9.37 g) was added to a solution of sodium (0.92 g) in methanol (40 g) at 20 ° C. and dimethyl oxalate (5.4 g). Is introduced dropwise for 10 minutes. The mixture was heated to reflux for 3 hours, cooled, water (100 cc) was added, concentrated hydrochloric acid (3 cc) was introduced dropwise, and the mixture was extracted with ethyl acetate (2 x 100 cc). The extract is washed with saturated brine (2 x 50 cc) and dried over sodium sulfate. Concentrate to dryness at 20 ° C., 20 mmHg (2.7 kPa), and remove the residue in methylene chloride (65 cc) and crystallize. When left at 20 ° C. for 2 hours and filtered, 4- (2-tert-butoxycarbonylamino-ethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4- Triazine (Focus 160 ° C) is obtained.

Infrared Spectrum (KBr): Characteristic band (cm ^-1 ) is 3380, 3150, 1685, 1640, 1545 and 1370.

Proton NMR spectrum (80 MHz, DMSO d ₆ , ppm δ, Hz J): 1.45 (s, 9H, -C (CH ₃ ) ₃ ): 3.32) q, J = 5, 2H, -CH ₂ CH- NH-): 4.38 (t, J = 5, 2H, -CH ₂ -CH ₂ -MH-): 6.72 (d, J = 5, 1H, CH ₂ CH ₂ NH-): 12.3 (s, wide area, 1H , -NH-) of triazine.

4- (2-tert-butoxycarbonylamino-ethyl) -thiosemicarbazide can be prepared as follows.

A mixture of N- (2-3-tert-butoxycarbonyl-amino-ethyl) -dithiocarbamate (22.53 g) ethanol (90 cc) and hydrazine hydrate (4.4 cc) is heated under reflux for 1 hour 30 minutes. The solution is concentrated to dryness at 30 ° C. 20 mm HG (2.7 kPa). The residue is dissolved in the presence of diethyl ether (100 cc) and crystallized within 5 minutes. The mixture is left at 20 ° C. for 1 hour, filtered and dried. Obtained 4- (2-tert-butoxycarbonylamino-ethyl) -thiosecarbazide (melting point: 85 degreeC) of pinkish white crystals (11.3g).

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3450, 3350, 1700, 1620, 1545, 1510, 1390, 1370, 1250, 1225, 1160.

Proton NMR spectrum (80 MHz, CDCl ₃ , ppm δ, Hz J): 1.48 (s, 9H, -C (CH ₃ ) ₃ ): 3.45 and 3.80 (2t, J = 5, 4H, -CH ₂ CH _2- ). Triethylamine (15.5 cc) was added to a solution of 2-3-butoxycarbonylamino-ethylamine (17.62 g) 95% ethanol (110 cc) and carbon dioxide (6.65 cc) was between 20 ° C and 25 ° C. Instill 10 minutes while maintaining the temperature of. The mixture is stirred at 22 ° C. for 1 hour 30 minutes. Methylamiodide (6.85cc) is added and the mixture is stirred for 1 hour 30 minutes. Concentrated to dryness at 20 ° C., 20 mmHG (2.7 kPa), the residue was taken up in ethyl acetate (200 cc), the organic phase was washed with water (3 × 100 cc), dried over sodium sulfate, filtered and concentrated at 20 ° C., 20 mmHg (2.7 kPa) To dry. Methyl N- (2-tert-butoxycarbonylamino-ethyl) -dithio carbamate (23.2 g) is obtained as a yellow emulsion.

Infrared spectrum (CHBr ₃ ): Characteristic band (cm ^-1 ) is 3440, 3370, 1700, 1505, 1430, 1380, 1370, 945.

Proton NMR spectra (80 MHz, CDCl ₃ , ppm δ, Hz J): 1.50 (s, 9H, -C (CH ₃ ) ₃ ): 2.65 (s, 3H, -CH ₃ ): 3.50 and 3.80 (2t , J-5, 4H, -CH ₂ -CH _2- ).

2-3-butoxycarbonylamino-ethylamine is prepared by hydrazine decomposition of N-tert-butoxycarbonyl phthalamido ethylamine. Hydrazine hydrate (10.8 cc) is added to a ethanol (540 cc) suspension of 2-3-butoxycarbonyl-phthalamido ethylamine (53.7 g) and the mixture is heated at reflux for 25 minutes. After cooling to 0 ° C. and filtration, the filtrate is concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa). Obtain 2-N-tert-butoxycarbonyl amino-ethylamine (19.6 g) yellow emulsion.

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3460, 3380, 3320, 1700, 1585, 1500, 1390, 1370, 1160, 490.

Proton NMR spectrum (60MHz, CDCl ₃ , ppm δ, Hz J): 1.48 (s, 9H, -C (CH ₃ ) ₃ ): 2.20 (s, wide area, 2H, -NH ₂ ) -2.80 (t , J = 5, 2H, H ₂ N-CH ₂ -CH ₂ ) -3.18 (t, J = 5, 2H, H ₂ NCH ₂ CH ₂ ) -5.50 (s, broad, 1H, -MHCO-).

Example 29

2-benzhydroxycarbonyl-7- [2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- ( 2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (10.04 g), dimethylformamide (200 cc), 4 -(2-acetamidoethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (2.76 g) with diisopurophylethylamine (2.1 cc) It is stirred for 3 hours at 60 ℃ in nitrogen. The cooled mixture was diluted with ethyl acetate (800 cc) and the organic phase was washed with water (1.2 L) and dried over sodium sulfate. It is filtered and concentrated to dryness under reduced pressure (20 mmHg) at 20 ° C.

The residue was triturated with ether (150 cc) and the insoluble matter was filtered and dried to obtain 3- {2- [4- (2-acetamidoethyl) -5,6-dioxo-1,4, as a light brown solid. 5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trichil Amino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E Type)

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3370, 1795, 1710, 1680, 1520, 1495, 1445, 750, 735.

).Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 1.75 (s, 3H, -COCH ₃ ): 3.65 and 3.90 (2d, J = 18, 2H, -SCH ₂ ): 3.86 ( s, 3H, -OCH ₃ ): 3.88 (t, 2H, NCH _3- ): 5.26 (d, J = 4, 1H, -CH = CHS-): 6.95 (s, 1H, -COOCH-): 7.0 ( d, J = 16, 1H, = CHS-): 7.78 (t, J = 6, -NHCOOCH ₃ ): 8.81 (s, 1H, -NHC (C ₆ H ₅ ) ₃ ): 9.60 (d, J = 9 , 1H, CONH): 12.60 (s, 1H, = -N-NHCO- or

).

Dimethylacetamide (3.4 cc) treated with phosphorus trichloride was treated with 2- {2- [4- (2-acetamidoethyl) -5,6-dioxo-1,4,5,6-tetrahydro -1,2,4-triazin-3-yl] -thiovinyl} -2-benzhydryloxycarbonyl-7-2-methoxyimino-2- (2-trimethylamino-thiazol-4- Yl) -acetamido-8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (9.02 g) Methylene (85 cc) diluted, the mixture was washed with half saturated sodium bicarbonate (250 cc), washed again with saturated brine (250 cc), dried over sodium sulfate, concentrated to dryness at 20 ° C. under reduced pressure (20 mmHg).

The brown solid is dissolved in a mixture of ethyl acetate, methylene chloride, and methanol (120: 120: 80 cc), and the solution is chromatographed on a column (4 cm) of Melksilica gel (0.04-0.06 mm). The developing solution is developed at 40 kPa pressure with a 95: 5 (volume) mixture of ethylacetate and methanol (1.5 L). Collect 125 cc milk powder and concentrate dry milk powder 6-10 at reduced pressure (20mm Hg) at 20 ° C to give beige solid 3- {2- [4- (2-acetamidoethyl) -5,6-di Oxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2 -(2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer , Form E) (3.33 g).

Infrared spectrum (CHBr ₃ ): Characteristic band (cm ⁻¹ ) is 3380, 1785, 1710, 1680, 1520, 1495, 1445, 755, 740.

).Proton NMR spectrum (350MHz, DMSO, d ₆ , ppm δ, Hz J): 1.75 (s, 3H, -COCH ₃ ): 3.32 (mt, 2H, -CH ₂ NHCO:): 3.62 , J = 8, 2H, -SCH _2- ): 3.86 (t,, 2H,> NCH ₂ ): 3.86 (s, 3H, -CCH ₃ ): 5.05 (d, J = 4, 1H, H in 6 positions ): 5.85 (dd, J = 4 and 9, 1H, H at 7th position): 6.80 (s, 1H, H of toothbrush): 6.96 (d, J = 16, 1H, -CH = CHS-): 6.97 (s, 1H, -COOJ-): 7.12 (d, J = 16, 1H, = CHS-): 7.98 (t, J = 6, 1H, -NHCOCH ₃ ): 8.75 (s, 1H, -NHC (C ₆ H ₅ ) ₃ ): 9.04 (d, J = 9, 1H, -CONH-): 12.60 (s, 1H, = -N-NHCO- or

).

The beige solid product (syn isomer, Form E) (3.15 g) is dissolved in formic acid (80 cc), water (30 cc) is added and the mixture is heated at 60 ° C. for 30 minutes with stirring. After cooling, filtering, and concentrated to dryness under reduced pressure (0.05mmHg) 50 ℃. The residue is dissolved in ethanol (250 cc) and the mixture is concentrated to dryness at 30 ° C. under reduced pressure (20 mmHg). This operation is repeated and the solids are absorbed in ethanol (40 cc) with stirring at 40 ° C. After cooling, filtration and drying, yellow powder of 3- {2- [4- (2-acetamidoethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4 -Triazin-3-yl] -thiovinyl} -7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxo- 5-Tia-1-aza-bicyclo- [4,2,0] oct-2-ene (syn isomer, Form E) (1.56 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3500, 2500, 1775, 1710, 1685, 1630, 1540, 1045, 950.

=N-N=).Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 1.90 (s, 3H, -CH ₃ ): 3.48 (m, 2H, -CH ₂ NH-): 3.62 and 3.73 (2d, J = 18, 2H, -SCH _2- ): 4.0 (s, 3H, -OCH ₃ ): 5.15 (d, J = 4, 1H, 6 position H): 5.82 (dd, J = 4 and 9, 1H , H at position 7: 6.78 (s, 1H, H of toothbrush): 6.86 (d, J = 16, 1H, -CH = CHS-) 7.31 (d, J = 16, 1H, = CHS-7.73 ( s, 3H, -NH ⁺ ₃ ): 9.50 (d, J = 9, 1H, -CONH-): 12.54 (s, wide area, 1H, -CONHN = or

= NN =).

A portion of the product (0.128 g) is dissolved in 0.1 M sodium bicarbonate solution (2 cc), filtered and lyophilized to obtain soda salt (0.127 g) of the material.

4- (2-acetamidoethyl) -5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (3.61 g) is 4- (2-acetamidoethyl ) -Chiosemi carbazide (4.41 g) and ethyloxalate (3.4 cc) in the presence of methylsoda. Peson and M. Antoine, Bull. Soc. Chim. It is obtained by applying the method described in France 1590 (1970). Product characteristics are as follows. Immediate melting point [Kofler]> 260 ° C: Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3365, 3050, 2000, 1710, 1630, 1600-1580, 1545, 1350, 1330 and 1200: Proton to NMR spectrum (80 MHz, DMSO d ₆ , ppm is δ, Hz is J): 1.7 (s, 3H, -CH ₃ ): 3-3.7 (mt, -CH ₂ NHCO- and H ₂ O): 4.3 (t, 2H, > -NCH ₂ ): 7.85 (t, 1H, -NHCO-): 12.5 (m, 2H, -NH- of the ring).

Thiosemicarbazide starting materials can be prepared as follows.

Aqueous alcohol (300cc) solution of methyl N- (2-acetamidoethyl) -dithiocarbamate (57.5 g) and hydrazine hydrate (14.6 cc) was heated under reflux for 2 hours to give 4- (2-acetamido Obtain white crystals of ethyl) -thiosecarbazide (39.5 g).

Immediate m.p. [Kofler] = 171 ° C

Infrared Spectrum (KBr): Characteristic band (cm ^-1 ) is from 3280, 2180, 1650, 1560 to 1535, 1360 and 1280.

Example 30

2-benzhydroxycarbonyl-7- [2-methoxyimino-2- (2tritylamino-thiazol-3-yl) -acetamido] -8-oxo-5-oxide-3- (2 -Tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (10.04 g), dimethylformamide (50 cc), 1- (2,2-dimethoxyethyl) -5-mercapto-2-methoxycarbonyl-1,3,4-triazole (3.95 g) and N, N-diisoprophylethylamine (1.19 cc) ) Is stirred for 6 h at 60 ° C. and 8 h at 20 ° C. Inject into ethyl acetate (700cc) and wash the mixture with water (2x125cc), 0.1N hydrochloric acid (150cc), half-saturated sodium bicarbonate solution (2x150cc), half-saturated saline (2x150cc), and then dry over sodium sulfate. After filtration and concentrated to dryness at 20 ℃, 20mmHg (2.7kPa). The product is fixed to Melk Sealica gel (0./06-0.2mm) (50g) and chromatographed on the column (4cm in diameter, 46cm in height) of Melksilica Gel (0.06-0.2mm) (200g) and 250cc milk powder Collect it. Dry milk 5-14 was evaporated to dryness at 20 DEG C and 20 mmHg (2,7 kPa) to give 2-benzhydryloxycarbonyl-3- {2- [1- (2,2-dimethoxyethyl)-as an orange solid. 2-methoxycarbonyl-1,3,4-triazol-5-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -Acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-syn isomer, Form E) (4.35 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3400, 1800, 1730, 1685, 1515, 1495, 1450, 1210, 945, 755, 700.

Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 3.30 (s, 6H,> C (OCH ₃ ) ₂ ): 3.86 (s, 3H, CH ₃ ON =) 3.94 (s, 3H, CH ₃ OCO-): 3.64 and 4.35 (2d, J = 18, 2H, -SCH _2- ): 4.35 (d, J = 6, 2H,> CH-CH ₂ N <): 4.58 (t, J = 6, 1H,> CH-CH ₂ N): 5.05 (d, J = 4, 1H, H at 6 position): 5.86 (dd, J = 4 and 9, 7H ₇ ): 6.80 (s, 1H, tooth H) of the sol: 6.98 (s, 1H, -COOCH =): 7.06 (d, J = 16, -CH = CH-): 7.17 (d, J = 16, 1H, -CH = CH-s-): 8.72 (s, 1H, -NH- of dental labware): 9.0 (d, J = 9, 1H, -CONH-).

The solution of the orange solid product (syn isomer, Form E) (4.15 g) of methylene chloride (60 cc) and dimethylacetamide (146 cc) was treated with phosphorus trichloride (0.67 cc) at -80 ° C. for 1 hour 20 minutes. do.

The mixture was diluted with ethyl acetate (700cc), washed with water (150cc), saturated sodium bicarbonate (150cc) and saturated brine (150cc), dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C and 20mmHg (2.7kPa). I was.

The residue is chromatographed on a column of Melk silica gel (0.06-0.2 mm) (150 g) (4.5 cm in diameter and 28 cm in height). After development with ethyl acetate (1.7 L), 250 cc milk powder is collected and the milk powders 2-6 are evaporated to dryness at 20 ° C. and 20 mm Hg (2.7 kPa). Obtain orange foam (4 g). This was dissolved in ethyl acetate (70 cc), diisopurophyl ether (450 cc) was added with stirring, filtered, and dried to yield 2-benzhydryloxycarbonyl-3- {2- [1- (2) as a beige solid. , 2-dimethoxyethyl) -2-methoxycarbonyl-1,3,4-triazol-5-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethyl Amino-thiazol-4-yl) -acetamido] -8-oxo-5-thia-1-aza- = bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) ( 3.4 g).

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) appear at 3400, 1790, 1730, 1690, 1520, 1495, 1450, 1210, 1090, 1050, 945, 755 and 705.

Proton NMR spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 3.29 (s, 6H, C- (OCH ₃ ) ₂ ): 3.65 and 3.87 (2d, J = 18, 2H, -SCH ₂ -): 3.86 (s, 3H, = N-OCH ₃ ): 3.94 (s, 3H, CH ₃ OCO-): 4.35 (d, J = 6, 2H,> NCH ₂ CH <): 4.57 (t, J = 6, 1H,> NCH ₂ CH-): 5.23 (d, J = 4, 1H, H ₆ ): 5.77 (dd, J = 4 and 9, 1H, H ₇ ): 6.73 (s, 1H, Chiazole H): 6.94 (s, 1H, -COOCH): 7.0 (d, J = 12, 1H, -CH = CH-s-): 7.10 (d, J = 12, 1H, -CH = CH-s) ): 8.77 (s, 1 H, NH): 9.57 (d, J 9, 1 H, -CONH-).

The beige solid product (syn isomer, E-type) (3.3 g) dissolved in 100 cc of formic acid was stirred at 50 ° C. for 40 minutes, concentrated to dryness at 30 ° C. and 0.05 mmHg (0.007 Kpa), and the residue was then washed with acetone. (60 cc) and the mixture is concentrated to dryness again at 20 ° C., 20 mm HG (2.7 Kpa).

This operation is repeated twice and the remaining solids are treated with acetone at 40 ° C., the mixture is cooled and filtered. Dry after filtration to dry 7- [2- (2-amino-thiazol-4-yne) -2-methoxyimino-acetamido] -2-carboxy-3- {2- [1- (2 , 2-dimethoxyethyl) -2-methoxycarbonyl-1,2,4-triazol-5-yl] -thiovinyl} -8-oxo-5-thia-1-aza-bicyclo [4 , 2,0] oct-2-ene (syn isomer, Form E).

Infrared Spectrum (KBr): Characteristic band (cm ^-1 ) appears at 3200, 1775, 1735, 1680, 1620, 1535, 1385, 1050, 945.

Proton NMR spectrum (350 MHz, CF ₃ COOD, ppm δ, Hz J): 3.65 (s, 6H, CH (OCH ₃ ) ₂ ): 4.21 (s, 3H, -COOCH ₃ ): 4.29 (s, 3H , = NOCH ₃ ): 5.38 (d, J = 4, 1H, H at 6 position): 6.08 (d, J = 4, 1H, H at 7 position): 7.05 and 7.95 (2d, J = 16, 2H, -CH = CHS-): 7.48 (s, 1H, H of toothazole).

1- (2,2-dimethoxyethyl) -5-mercapto-2-methoxy-carbonyl-1,3,4-triazole is 4- (2,2-dimethoxyethyl) -5, 6-dioxo-3-thioxo-perhydro-1,2,4-triazine (4- (2,2-dimethoxyethyl)-thiosemicarbazide (100 g) and ethyloxalate in Example 16 (81.6 g) is mentioned in the process of condensing in the presence of methylol (440 g) solution of methanol (440 g). At the end of the reaction, the water mixture is filtered and triazine soda salt is collected. The filtrate is concentrated to dryness at 20 ° C. and 20 mm HG (2.7 kPa), and the residue is taken up in ethyl acetate (300 cc) and acidified with stirring with 1N hydrochloric acid (200 cc).

The organic phase was decanted, washed with saturated brine (3 × 100 cc), dried over sodium sulfate, filtered and concentrated filtered at 20 ° C. and 20 mmHg (2.7 kPa).

The residue is chromatographed with Melk Sealica gel (0.06-0.2 mm) (200 g) (column: 4.5 cm in diameter, 25 cm in height). Develop with a mixture of cyclohexane and ethyl acetate (1L) 30:70 (volume) and take 100cc of milk powder.

Condensate 2-9 was concentrated to dryness at 20 ° C. and 20 mm Hg (2.7 kPa) to obtain crystalline white solid component (14.3 g) (melting point 123 ° C.).

Infrared spectrum (CHBr ₃ ): Characteristic band (cm ^-1 ) is 3420, 3200, 2840, 2600, 1745, 1450, 1086, 1065, 980.

Example 31

1,4-Dimethyl-5,6-dioxo-3-thioxo-perhydrot-1,2,4-triazine (0.75 g) was converted to 2-benzhydryloxycarbonyl-7- [2- Methoxy-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [ 4,2,0] Dry N, N-dimethylformamide (75 cc) solution of oct-2-ene (syn isomer, Form E) (2.37 g) was heated to 60 ° C. and N, N-diisopurophyll The solution was introduced dropwise into anhydrous N, N-dimethylmethylamide (25 cc) solution of ethylamine (0.42 cc) for 15 minutes. The reaction mixture was stirred at 60 ° C. for 25 minutes, diluted with ethyl acetate (400 cc), washed with distilled water (3 × 200 cc), saturated sodium bicarbonate solution (100 cc) and saturated brine (200 cc), dried over magnesium sulfate, and the organic phase was 40 ° C., Concentrate to dryness under reduced pressure (30 mmHg, 4 kPa). Orange blister (2 g) was obtained and purified by chromatography on a column of melk silica gel (0.04-0.06 mm) (diameter 4 cm, height 30 cm). Develop with a 30:70 (volume) mixture of cyclohexane and ethyl acetate (2 L) and collect 50 cc milk powder. Combine the powdered product 15-14 and concentrate at reduced pressure (30mmHg, 4kPa) at 40 ° C to give 2-benzhydryloxycarbonyl-3- [2- (1,4-dimethyl-5,6-dioxo-1,4 , 5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl ) -Acetamido] -8-oxo-5-thio-1-aza-bicyclo [4,2,0] oct-2-ene (50:50 mixture of Anti isomers with E-type syn) ( 0.85 g).

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3400, 1790, 1720, 1680, 1585, 1520, 1506, 1450, 1035, 1025, 945, 760.

Proton NMR spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): syn isomers: 3.43 and 3.58 (2s, 2 × 3H, 2CH _{3 of} triazine): 3.61 and 3.70 (2d, J = 18, 2H , -SCH ₂ ): 4.08 (s, 3H, = NOCH ₃ ): 5.12 (d, J = 4, 1H, H at 6 position): 5.95 (dd, J = 4 and 9. 1H, H at 7 position) : 6.77 (s, 1H, H of chiazole): 6.81 (d, J = 16, 1H, -CH = CH-s-6.98 (s, 1H, -CO ₂ CH (C ₆ H ₅ ): 7.0 (s Anti-isomers: 3.43 and 3.50 (2s, 2 × 3H, tree), 7.2 to 7.50 (hump, 27H, aromatic, -CONH-C _7- , -CH = CH-s). 2CH ₃ ): 3.50 and 3.58 (2d, J = 18, 2H, -SCH ₂ ) of azine: 4.12 (s, 3H, = NOCH ₃ ): 5.13 (d, J = 4, 1H, H at 6 position) ‥ 6.08 (dd, J = 4 and H at position 0, 1H, 7): 6.75 (d, J = 16, 1H, -CH = CH-s-): 6.98 (s, 1H, -CO ₂ CH (C ₆ H ₅ b): 7.18 (s, wide, 1H, -NH- of Trichil): 7.2 to 7.50 (hump, 26H, directional, -CH = CH-s-): 7.42 (s, 1H, H of chiazole ): 9.60 (d, J = 9, -CONH-C ₇ ).

98% of the syn and Anti isomer mixtures (50:50) (0.8 g) were added distilled water (10 cc) to a solution of formic acid (20 cc) and heated at 60 ° C. for 25 minutes. After concentration at 40 ° C. under reduced pressure (10 mmHg, 1.44 kPa), the residue was dissolved in anhydrous alcohol (25 cc) and concentrated at 40 ° C. under reduced pressure (10 mmHg, 1.44 kP a). Repeat this operation two more times. The solid residue is taken up in boiling ethanol (20 cc), the solids are heat filtered and dried under reduced pressure (10 mmHg, 1.33 kPa).

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-30 [2- (1,4-dimethyl-5,6-di Oxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2, 0] oct-2-ene (a mixture of Form E syn and Anti isomer 50:50) (0.34 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3500, 2300, 1770, 1710, 1670, 1575, 1530, 1030, 940.

Proton NMR spectra (350 MHz, DMSO d ₆ , ppm δ, Hz J): syn isomers: 3.35 and 3.48 (2s, 2 × 3H, 2-CH _{3 of} triazine): 3.66 and 3.80 (2d, J = 18, 2H, -SCH _2- ): 3.87 (s, 3H, = NOCH ₃ ): 5.18 (d, J = 4, 1H, H at 6 position): 5.82 (dd, J = 4 and 9, 1H, 7 H) in position: (6.74 (s, 1H, H of toothbrush): 6.95 and 7.14 (2d, J = 16, 2H, -CH = CH-s-): 7.18 (s, wide area, 2H, -NH ₂ ): 9.64 (d, J = 9, 1H, -CONH-).

Anti isomer:

3.35 and 3,48 (2s, 2x3, 2-CH ₃ of triazine: 3.66 and 3.90 (2d, J = 18, 2H, -SCH ₂ ): 3.98 (s, 3H, = NOCH ₃ ): 5.19 ( d, J = 4, 1H, H at 6 position: 5.81 (dd, J = 4 and 9, 1H, H at 7 position): 6.95 and 7.15 (2d, J = 16, 2H, -CH = CH-s -: 7.09 (s, wide area, 2H, -NH ₂ ): 9.48 (d, J = 9, 1H, -CONH-):

1,4-Dimethyl-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine can be prepared according to the method described in Belgian patent 830,455.

Example 32

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -oct-2-ene (syn isomer, E Type) (1 g) and dimethylformamide (10 cc), 5,6-dioxo-1-ethyl-3-thioxo-perhydro-g, 2,4-triazine (0.345 g) and N, N- Extract a mixture of diisopropyl ethylamine (0.35cc) with (2 × 30cc) and wash the organic phase with 0.05N hydrochloric acid (50cc), wash with half-saturated saline (50cc), wash with half-saturated saline (50cc) and sulfuric acid Dry in soda. It is filtered and concentrated to dryness at 20 ° C., 20 mmHg (2.7 kPa). The residue is chromatographed on a column of Melksilica gel (0.04-0.06 mm) (diameter 1.5 cm, height 30 cm). Develop with ethyl acetate (0.5) at 40 kPa. Collect 25 cc milk powder and evaporate to dry 15 at 20 ° C., 20 mm Hg (2.7 kPa) in yellow foam to 2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-) as a yellow foam. 1-Ethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -7- [2-methoxyimino-2- (2-triethylamino -Thiazol-4-yl) -aminoamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (sym isomer, Form E) (0.75 g Get)

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3410, 1795, 1720, 1625, 1605, 1560, 1505, 1455, 1245, 1205, 940, 760, 745.

Proton NMR spectra (350 MHz, DMSO d ₆ , ppm δ, Hz J): 1.25 (t, J = 7, -CH ₂ CH ₃ ): 3.68 and 3.88 (2d, J = 18, 2H, -SCH ₂ -): 3.80-3.90 (hump, 5H, -CH ₃ CH ₃ and -OCH ₃ ): 5.22 (d, J = 4, 1H, H in 6 position): 5.74 (dd, J = 4 and 9, 1H, H) at position 7: 6.75 (s, 1H, H of toothbrush): 6.94 (s, 1H, -COOCH-): 6.95 (d, J = 16, 1H, -CH-CHS-), 8.80 (s, 1H, NH (C ₆ H ₅ ) ₃ ) 9.60 (d, J = 9, 1H, -CONH):

The mixture of the yellow foam product (0.72 g), formic acid (12 cc) and water (6 cc) was treated at 50 ° C. for 45 minutes. The cold mixture is filtered and concentrated to dryness at 35 ° C., 0.05 mmHg (0,007 kPa), the residue is taken up in ethanol (2 × 20 cc) and the mixture is evaporated to dryness at 20 ° C., 20 mmHg (2.7 kPa). The solid residue was dissolved in ethanol (10 cc) at 60 ° C. for 10 minutes, the cooling suspension was filtered, the filter residue was washed with diethyl ether (2 × 5 cc) and dried to give a yellow 7- [2- (2-amino-thiazole). -4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2- (5,6-dioxo-1-ethyl-1,4,5,6-tetrahydro-1 , 2,4-triazin-3-yl] -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct 2-ene (syn isomer, Form E) ( 0.39 g).

Infrared Spectrum (KBr): Characteristic band (cm ^-1 ) appears at 3700, 2200, 1770, 1720, 1665, 1630, 1590, 1040, 945.

Proton NMR spectra (350 MHz, DMSO d ₆ , ppm δ, Hz J): 1.25 (t, J = 7, 3, -CH ₂ CH ₃ ): 3.71 and 3.88 (2d, J = 18, 2H,- SCH _2- ): 3.80 to 3.90 (hump [5H, -CH ₂ CH ₃ and -OCH ₃ ): 5.19 (d, J = 4, 1H, H at 6 position): 5.75 (dd, J = 4 and 9, H at position 1H, 7): 6.77 (s, 1H, H of toothbrush): 7.10 (s, wide area, 2H, -CH = CH-): 7.20 (s, 2H, -NH ₂ ): 9.62 (d, J = 9, 1H, -CONH- (.

1-Ethyl-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine can be prepared as follows.

A sodium (1.5 g) solution was prepared in methanol (25 cc) and 1-ethyl-1-ethoxy-thiocemiccarbazide (11 g) was added and the reaction mixture was heated at reflux for 1 hour.

Concentrate to dryness at 20 ° C., 20 mmHg (2.7 kPa) and the residue was triturated and dissolved in diethyl ether (50 cc). The yellow solid is dissolved in water (15 cc) and the solution is acidified to pH 2 with 2N hydrochloric acid. Scratch around to start crystallization. The mixture is left at 4 ° C. for 1 hour and filtered. 1-Ethyl-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (52) is obtained as a pale yellow solid having a melting point of 214-216 占 폚.

1-Ethyl-1-ethoxyaryl-thiosemicarbazide can be prepared as follows. Ethos aryl chloride (10.6 cc) was added to acetone (200 cc) solution of 1-ethyl-thiocemiccarbazide (11.9 g) at 22 ° C. for 10 minutes, the temperature was raised to 43 ° C. and the mixture was stirred for 1 hour without heating. Concentrate to dryness at 20 ° C., 20 mmHg (2.7 kPa). The residue was taken up in methanol (30 cc) and crystallization started. After filtration and drying, 1-ethyl-1-ethoxy-aryl-thiocemiccarbazide (13.2 g) having a white solid melting point of 170 ° C. was obtained. 1-Ethyl-Chiomyemicarbazide is prepared by reducing acetaldehyde thiosemicarbazone (52 g) to sodium protective hydride (26 g) in ethanol (2 ° C.). (52.5 g) is prepared by condensing a solution of ethanol (1 L) of thiosemicarbazide (45.5 g) and acetaldehyde (42.4 cc) The reaction mixture is partially concentrated to crystallize and has a melting point of 153 ° C.

Example 33

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (7.03 g), dimethylformamide (70 cc), A mixture of 5,6-dioxo-2-methyl-3-thioxo-perhydro-1,2,4, -triazine (1.23 g) and N, N-diisofurophylethylamine (1.34 cc) Was stirred for 20 minutes at 60 ° C. in nitrogen, poured into ethyl acetate (300cc), washed with water (4 × 150cc), dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C and 20mmHg (2.7kPa). . Purification is performed by chromatography on a column of Melksilica gel (0.04-0.06 mm) (2 00 g) (diameter 6 cm, height 30 cm). A mixture of cyclohexane and ethyl acetate (3.5 L) 20:80 (volume) is developed under 40 kPa pressure. Collect 125 cc milk powder and concentrate dry powder 17 to 25 at 20 ° C., 20 mmHg (2.7 kPa) in creamy foam to form 2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-2). -Methyl-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -7- [2-methoxyimino-2- (2-trimethylamino- Chiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-0-ene (syn isomer, Form E) (0,05 g) is obtained.

Infrared spectrum (CHBr ₃ ): Characteristic band (cm ⁻¹ ) is 1800, 1725, 1685, 1595, 1515, 1495, 1450, 1040, 750, 700.

) : 7.73(d, J=9, 1H-CONH-).Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 3.24 and 3.88 (2d, J = 18, 2H, -SCH _2- ): 3.80 (s, 3H, -CH ₃ ): 4.09 ( s, 3H-) CH ₃ ): 4.60 (a, J = 4, 1H, H at 6 position): 6.15 (dd, J = 4 and 9, 1H, 7 position H): 6.74 (s, 1H, tooth H) of the sol: 6.95 (s, 1H,

): 7.73 (d, J = 9, 1 H-CONH-).

A solution of the above-mentioned cream-colored product (syn isomer, E-type) (0.5 g) of methylene chloride (30 cc) and dimethylacetamide (0.192 cc) was phosphorus trichloride (0.176 cc) for 1 hour and 40 minutes at -9 ° C. To be processed.

The mixture was diluted with ethyl acetate (250cc), washed with water (2x100cc) saturated sodium bicarbonate solution (100cc) and water (100cc), dried over sodium sulfate and concentrated to dryness at 20 占 폚, 20mmHg (2.7kPa).

Purified by chromatography on a column of Melksilica gel (0.06-0.28 mm) (950 g) (diameter 2.5 cm, height 15 cm). At this time, develop with ethyl acetate (50cc) and collect the 30cc milk powder. Concentrate to dry powder 6 to 10 at 20 ° C., 20 mmHg (2.7 kPa), to obtain 2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-2-methyl-1,2,5, 6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acet Amido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E (0.4 g) is obtained in the form of an orange-yellow foam.

Infrared spectrum (CHBr ₃ ): characteristic bands (cm ⁻¹ ) are 3400, 1780, 1725, 1680, 1595, 1520, 1495, 1450, 1040, 755.

) : 7.18(d, J=16, 1H, -CH=CH-S-) : 7.20(s, 1H, -NHC(C₆H₅)₃).Proton NMR Spectrum (350MHz, CDCl ₃ , ppm δ, Hz J): 3.52 and 3.61 (2d, J = 18, 2H, -SCH _2- ): 3.84 (s, 3H, -CH ₃ ): 4.08 ( s, 3H, -OCH _3- ): 5.12 (d, J = 4, 1H, H at 6 position): 5.84 (dd, J = 4 and 9, 1H, H at 7 position): 6.78 (s, 1H, Tooth sol H): 6.81 (d, J = 9, 1H, -CONH-): 6.98 (s, 1H, -COOH

): 7.18 (d, J = 16, 1H, -CH = CH-S-): 7.20 (s, 1H, -NHC (C ₆ H ₅ ) ₃ ).

The orange yellow foam product (syn isomer, Form E) (0.18 g) formic acid (15 cc) was treated at 50 ° C. for 30 minutes, the mixture was filtered and concentrated to dryness at 30 ° C., 0.05 mmHg (0.007 kPa). The residue was taken up in ethanol (4 × 25 cc) and the mixture was evaporated to dryness (20 ° C., 20 mmHg (2.7 kPa) each time. The residue was triturated in ethanol (100 cc) at 60 ° C., filtered and filtered and dried. -(2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2- (5,6-dioxo-2-methyl-1,2, 5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo- [4,2,0] oct-2 -N (syn isomer, Form E) (0.062 g) is obtained as a yellow powder.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3600, 2300, 1765, 1720, 1670, 1600, 1525, 1280, 1075, 1040, 930.

Proton NMR spectrum (350 MHz, CF ₃ COOD, ppm δ, Hz J): 3.77 and 3.88 (2d, J = 18, 2H, -SCH _2- ): 4.0 (C, 3H, -CH ₃ ): 4.30 (s, 3H, -OCH ₃ ): 5.41 (d, J-4, 1H, H at 6 position): 6.0 (d, J = 4, 1H, H at position 7): 7.50 (s, 1H, toothbrush H):

5,6-Dioxo-2-methyl-3-thioxo-perhydro-1,2,4-triazine can be prepared as follows.

A sodium (4.6 g) solution was prepared in methanol (200 cc) in nitrogen, 2-methyl- thiosemicarbazide (21.03 g) was added at 40 ° C. and dimethyloxalate (27.1 cc) was added dropwise for 10 minutes. The mixture is heated to reflux for 5 hours with stirring. After cooling to 5 ° C. for 1 hour and filtering, the obtained crystals are washed with methanol (25 cc) and ether (3 × 25 cc). The soda salt thus obtained is stirred at 20 ° C. for 15 minutes in the presence of 2N hydrochloric acid (50 cc) and then stirred at 5 ° C. for 1 hour. After filtration a white solid (10.7 g)) consisting of a thiosemicarbazide starting material and 5-mercapto-3-methoxycarbonyl-1-methyl-1,2,4-triazole) is obtained. Dissolve the product under reflux in methylene chloride (200 cc), cool the solution and filter to afford the expected product and 2-methyl- thiosemicarbazide mixture (9.63 g). Final purification of this product is carried out by conversion to soda salt (product is added to methanol (200 cc) and filtered by adding 4N sodium (2-ethylhexanoate solution (10cc) and filtered). 2N hydrochloric acid (10cc) in water (10cc) Acidification with 20 cc) liquid D. 5,6-oxo-2-methyl-3-thioxo-perhydro-1,2,4-triazine (5.5 g) to obtain a white powder (melting point of 185 ° C.) 2 Methyl-Chiosemicarbazide is manufactured according to KA Ensen (Acta Chem. Scand. 22, 1-50 (1968).

Example 34

With N, N-diisopropylethylamine solution (1.21cc), 3-methoxycarbonyl-1-methyl-5-thioxo-1,2,4-triazolin and 5,6-dioxo-2 M-pexone and M. antoin, CR Acad, Sci. C. 267, 25, 1726-a solution of an equivalent mixture (2.2 g) of methyl-3-thioxo-perhydro-1,2,4-triazine (1968)) anhydrous N, N-dimethylmethylamide (35 cc) solution in 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-tri) in nitrogen Cylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0 Oct-2-ene (syn isomer, Form E) (6.92 g) was added dropwise at 65 ° C for 40 minutes. The reaction mixture is stirred at 65 ° C. for 5 hours 30 minutes and washed with distilled water (2 × 100 cc). After drying over magnesium sulfate, the mixture is filtered and the organic phase is concentrated to dryness at 40 DEG C under reduced pressure (30 mmHg: 4 kPa). The residue is chromatographed on a column of silica gel (0.02-0.04 mm) (diameter 4 cm, height 35 cm).

A mixture of cyclohexane and ethyl acetate (4.5) (30:70) (volumes) is developed under 40 kPa pressure and 100 cc milk powder is collected. Combined milk powders 2, 3 and 4, concentrated to dryness at 40 ° C. under reduced pressure (30 mmHg: 4 kPa), yellow foamed 2-benzhydryloxycarbonyl-3- {2- [3-methoxycarbonyl-1 -Methyl-1,2,4-triazol-5-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-tucciamiro-thiazol-4-yl) -acetami 8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (3 g).

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3360, 1800, 1730, 1670, 1515, 1495, 1450, 1210, 1040, 950, 755, 740.

Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 3.30 and 4 (2d, J = 18, 2H, -S (O) CH ₂ ): 3.84 (s, 3H, = NOCH ₃ ) : 4.63 (d, J = 9, 1H, H at 6 position): 6.13 (dd, J = 4 and 9, 1H, H at 7 position): 6.72 (s, 1H, -CH (C ₆ H ₅ ) ₂ ): 7.0 and 7.50 (2d, J = 16, 2H, -CH = CH-S-): 7.09 (s, 1H, (C ₆ H ₅ ) ₃ (NH-)): 7.15-7.45 (Mt, 26H, Directional and -CONH-C ₇ ).

The yellow foamed product (syn isomer, E-type) (3 g) was added to a mixed solution of anhydrous methylene chloride (30 cc) and N, N-dimethylacetamide, cooled at -25 ° C and phosphorus trichloride ( 0.57 cc). After stirring for 30 minutes at a temperature between -25 ° C and -10, the reaction mixture is diluted with ethyl acetate (150cc), washed with saturated sodium bicarbonate (100cc) and washed again with saturated brine (100cc). The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 40 ° C. under reduced pressure (30 mmHg, 4fkPa). The residue is filtered over a column of silica gel (0.02-0.04 mm) (4 cm in diameter, 25 cm in height), developed with a mixture of cyclohexane and ethyl acetate (2.5 L) 50: 50 (volume) under 40 kPa pressure and the 100 cc milk powder collected. . Milk powder 9-24 was combined and concentrated under reduced pressure at 40 ° C. (30 mmHg: 4 kPa) to give a yellow foamed 2-benzhydryloxycarbonyl-3- {2- [3-methoxycarbonyl-1-methyl-1, 2,4-triazol-5-yl] -thiovinyl] -7-[2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo -5-chia-1 -aza- (2.35 g) is obtained.

Infrared spectrum (CHBr ₃ ): characteristic band (cm ⁻¹ ) is 3490, 1785, 1735, 1685, 1515, 1495, 1450, 1210, 1040, 755, 740.

NCH) : 4.08(s, 3H, =NOCH₃) : 5.12(d, J=9, 1H, 6위치에 H)‥5.98(dd, J=4와 9, 1H, 7위치에 H) : 6.78(s, 1H, 트리아졸의 H) : 6.96(s, 1H, -CH(C₆H₅)₂) : 6.94와 7.03(2d, J=14, 1H, -CH=CH-S-) : 7.15-7.50(Mt, 27H, 방향성, -CONH-, C₇), (C₆H₅)₃CNH-).Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 3.62 and 3.72 (2d, J = 18, 2H, -SCH _2- ): 3.87 (s, 3H, -COOCHH _3- ): 4.0 (s, 3H, triazole

NCH): 4.08 (s, 3H, = NOCH ₃ ): 5.12 (d, J = 9, 1H, H at 6 position) ‥ 5.98 (dd, J = 4 and 9, 1H, H at 7 position): 6.78 ( s, 1H, triazole H): 6.96 (s, 1H, -CH (C ₆ H ₅ ) ₂ ): 6.94 and 7.03 (2d, J = 14, 1H, -CH = CH-S-): 7.15- 7.50 (Mt, ₂₇ H, aromatic, -CONH-, C ₇ ), (C ₆ H ₅ ) ₃ CNH-).

The yellow fume type product (syn isomer, E-type) (2.2 g) is dissolved in formic acid (40 cc), diluted with distilled water (25 cc), heated at 50 ° C. for 20 minutes, and diluted with distilled water (15 cc). Insoluble material is filtered off and the reaction mixture is concentrated at 40 ° C. (decompression 5 mmHg, 0.67 kPa). The residue was triturated and dissolved in ethanol (50 cc) and evaporated sequentially under reduced pressure at 40 ° C. (30 mmHg: 4 kPa).

This operation is repeated twice and the residue is taken up in ethanol (50 cc), the solids are filtered off, washed with ethanol (10 cc) and washed again with isofurophyll ether (2 x 25 cc). 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-1,2,4-triazol5-yl) -thiovinyl-8-oxo as a creamy powder after drying Obtain 5-5-thia-1-aza-bicyclo-4,2,0-oct-2ene (syn isomer, Form E) (1.1 g).

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3450, 3320, 2200, 1770, 1735, 1660, 1630, 1535, 1220, 1040 and 945.

NCH₃) : 5.20(d, J=9, 1H, 6위치에 H) : 5.79(dd, -4와 9, 1H , 7위치에서 H) : 6.74(s, 1H, 치아졸의 H) : 6.98와 7.03(AB, J=14, 2H, -CH=CH-S -) : 7.20(s, 광역, 2H, -NH₂-) : 9.63(d, J=9, 1H, -CONH-C₇).Proton NMR Spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 3.66 and 3.90 (2d, J = 18, 2H, -SCH _2- ): 3.85 (s, 3H, = NOCH ₃ ): 3.87 (s, 3H, -CO ₂ CH ₃ ): 3.90 (s, 3H, of triazole

NCH ₃ ): 5.20 (d, J = 9, 1H, H at 6 position): 5.79 (dd, -4 and 9, 1H, H at 7 position): 6.74 (s, 1H, H of toothbrush): 6.98 And 7.03 (AB, J = 14, 2H, -CH = CH-S-): 7.20 (s, wide area, 2H, -NH _2- ): 9.63 (d, J = 9, 1H, -CONH-C ₇ ) .

Example 35

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (tritylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2 -Tosyloxyvinyl) -5-thia-1-aza-bicyclo- [4,2,0] oct-2-ene (syn isomer, E-type) (6.02 g) with dimethyl-formamide (60 cc) ), A mixture of 2-acetamidomethyl-5-mercapto-1,3,4-thia-diazole (2.27 g) and diisopropylethyleneamine (1.15 cc) in nitrogen at 60 ° C. for 30 hours. Stir for minutes. Dilute the cooled mixture with ethyl acetate (250cc), wash with water (150cc), 0.1N hydrochloric acid (100cc), saturated sodium bicarbonate solution (100cc) and water (2x100cc), dry over sodium sulfate, filter, and decompress at 20 ℃. Concentrate dry under (20 mmHg). The residue was fixed on the melt silica gel (0.05-0.2 mm) (20 g), accumulated in a column of silica gel (0.0 5-0.2 mm) (70 g) (diameter 2.5 cm), developed with ethyl acetate (2.51), and then 100 cc milk powder was collected. Collect. Dry milk 9-23 was evaporated to dryness at 20 ° C. under reduced pressure (20 mmHg) to obtain brown foamy 3- [2- (2-acetamidomethyl-1,3,4-thiadiazol-5-yl) -cio Vinyl] -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide -5-Cia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (3 g) is obtained.

Infrared spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3400, 1795, 1720, 1670, 1525, 1495, 1450, 1370, 1040, 940, 750 and 700.

Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.00 (s, 3H, -COOCH ₃ ): 3.58 and 3.68 (2d, J = 18, 2H, SCH _2- ): 4.08 (S ,, 3H, OCH ₃ ): 4.75 (d, J = 5, 2H, -CH ₂ NHCO-): 5.10 (d, J = 4, 1H, H in 6 position): 5.97dd, J = 4 and 9, H at 1H, 7 position: 6.55 (t, J = 5, 1H, -NHCO-): 6.76 (s, 1H, H of toothbrush): 7.0 (s, 1H, -COOCH-): 7.05 (s, 1H, -NH-C (C ⁹ H ₅ ) ₃ ): 7.18 (d, J = 16, 1H, -CH = CHS-).

The yellow foamed product (syn isomer, E-form) (2.1 g) is dissolved in formic acid (21 cc), water (12 cc) is added and the mixture is heated at 50 ° C. for 30 minutes. After cooling to 20 ° C. and filtration, it is concentrated to dryness under 50 ° C. pressure (0.05 mmHg). The residue is taken up in ethanol (50 cc) and the solvent is removed at 20 ° C. under reduced pressure (20 mmHg). This operation is repeated twice and the residue is taken up in ethanol (50 cc) under reflux and the mixture is thermally filtered to remove some insoluble material and the filtrate is concentrated to 20 cc under 20 ° C. reduced pressure (20 mmHg) and filtered. Cream to dry, 3- [2- (2-acetamido-methyl-1,3,4-thiadiazol-5-yl) -thiovinyl] -7-2 [-(2-amino-teeth Zol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn Isomer, Form E) (0.75 g) is obtained.

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3320, 1770, 1660, 1540, 1380, and 1040.

Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.00 (s, 3H, -CO CH ₃ ): 3.68 and 3.92 (2d, J = 18, 2H, 3.87 (s, 3H,-) OCH ₃ ): 4.22 (d, J = 4, 1H, H at 6 position): 4.60 (AB, limit, 2H, -CHNNCO-): 5.82 (dd, J = 4 and 9, 1H, H at 7 position) : 6.7 5 (s, 1H, -OCH ₃ ): 7.15 (d, J = 16, 1H, -CH = CHS-): 7.20 (s, 3H, -NH ₃ ⁺ ): 7.25 (d, J = 16, 1H, = CHS-): 9.63 (d, J = 9, 1H, -CONH-).

2-acetamidomethyl-5-mercapto-1,3,4-thiadiazole can be prepared by the method disclosed in Japanese Patent Application 51/80, 857 (Derwent 65961X).

Example 36

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethyl-amino-thiazol-4-yl) -acetamido]-according to the method described in Example 35. 8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E-form (4 g) N, N-diisofurophyllylamine in dimethylformamide (50 cc) solution of 2-3-butoxycarbonylamino-5-mercapto-1,3,4-thiazol (1.86 g) (0.83cc) in the presence of chromatograph on silica gel (using a 40:60 (volume) mixture of cyclohexane and ethyl acetate) followed by creamy foam 2-benzhydryloxycarbonyl- 3- (2-Triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E-form) (2.6 g) is obtained.

Infrared Spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3380, 2820, 1800, 1720, 1530, 1490, 1445, 1390, 1370, 1050, 940, 760 and 605.

Proton NMR spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 1.43 (s, 9H, -C (CH ₃ ) ₃ ): 3.24 and 4.46 (2d, J = 19, 2H, -SCH _2- ): 4.04 (δ, 3H, -OCH ₃ ): 4.64 (d, J = 4, 1H, H at 6 position): 6.14 (dd, J = 4 and HH at 9, 1H, 7 position): 6.70 (s , 1H, H azole: 6.94 (s, 1H, -COOCH-): 7.11 (d, J = 16, 1H, -CH = CHS-): 7.34 (d, J = 9, 1H, -CON H -): 7.37 (d, J = 10, 1H, = CH-S-).

Dimethylacetamide (0.95) was dissolved in phosphoric trichloride (0.46 cc) in which the cream foam product (syn isomer, Form E) (2.55 g) was dissolved in methylene chloride (50 cc) using the conditions described in Example 35. cc) processing in the presence of. Chromatography is carried out with silica gel (using a 30:70 (volume) mixture of cyclohexane and ethyl acetate as the developing solution).

2-benzhydryloxycarbonyl-3- [2- (2-tert-butoxycarbonylamino-1,3,4-thiadiazol-5-yl) -thiovinyl] -7- [2- Methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2 -En (syn isomer, Form E) (2.1 g) is obtained as a cream foam form.

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3400, 1785, 1725, 1685, 1530, 1495, 1450, 1250, 1210, 1050, 940, 755, 740.

Proton NMR spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 1.53 (s, 9H, -C (CH ₃ ) ₂ ): 3.52 and 3.62 (2d, J = 18, 2H, 4.06 (s, 3H, OCH ₃ ): 5.06 (d, J = 4, 1H, H at 6 position): 5.92 (dd, J = 4 and 9, 1H, 7 position 7): 6.72 (s, 1H, H of toothbrush ): 7.03 (d, J = 16, 1H, -CH = CHS-): 7.07 (d, J = 9, 1H, -CONH-).

Using the conditions of Example 35, the cream foam product (syn isomer, Form E) (2 g) was treated with a mixture of formic acid (40 cc) and water (15 cc).

3- [2- (2-Amino-1,3,4-thiadiazol-5-yl) -thiovinyl] -7- [2- (2-amino-thiazol-4-yl) -methoxyimino Acetamido] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo- [4,2,0] oct-2-ene (syn isomer, Form E) (0.74 g) yellow Obtained as a powder.

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3320, 3200, 3100, 2820, 2000, 1770, 1670, 1610, 1380, 1040 and 940.

Proton NMR spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 3.83 (s, 3H, -OCH ₃ ): 5.12 (d, J = 4, 1H, H in 6 position): 5.76 (dd , J = 4 and 9, 1H, H at 7 positions: 6.74 (s, 1H, H of toothbrush): 6.95 (d, J = 16, 1H, -CH = CHS-: 7.02 (d, J = 16 , 1H, = CHS-): 7.18 (s, wide, 2H, -NH ₂ of chiazole; 7.48 (s, wide, 2H, -NH ₂ of toothazole: 9.60 (d, J = 9, 1H, -CONH-).

The 2-tert-butoxycarbonylamino-5-mercapto-1,3,4-thiadiazole was 25 ° C. in the presence of sodium bicarbonate in accordance with J. Che m. Soc. 1508 (1958). Hours Prepared by condensation of tert-butylcarcarbonate with 2-amino-5-mercapto-1,3,4-thiadiazole in a water / dioxane mixture.

The product is recrystallized from acetonitrile. m.p. (kofler) = 200.

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 1725, 1390, 1370, 1240, 1170 and 1070.

Proton NMR spectrum (60 MHz, DMSO d ₆ , ppm δ, Hz J): 1.53 (s, 9H, —C (CH ₃ ) ₃ ).

Example 37

2-Dimethylaminomethyl-5-mercapto-1,3,4-thiadiazole (1.3 g) was purified using 2-benzhydryloxycarbonyl-7- [2- using the conditions described in Example 35. Methoxy-imino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia- Dimethylformamide (60 cc) solution of 1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (6.02 g) was purified by N, N-diisopurophylethylamine (1.15). react in the presence of cc). Chromatography is carried out on silica gel [developing liquid: 20:80 (volume) of cyclohexane and ethyl acetate]]. 2-benzhydryloxycarbonyl-3- [2- (2-dimethylaminoethyl-1,3,4-thiadiazol-5-yl) -thiovinyl] -7- [2- on orange foam Methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct 2-en (syn isomer, Form E) (2.7 g) is obtained.

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3380, 2820, 2780, 1790, 1715, 1665, 1515, 1445, 1200, 1040, 970, 750, 735.

Proton NMR spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.34 (s, 6H, -N (CH ₃ ) ₂ ): 3.28 and 3.98 (2d, J = 18, 2H, -SCH _2- ) ₂ : 3.85 (s, 2H, NCH-): 4.07 (s, 3H, -OCH): 4.62 (d, J = 4, 1H, H in 6 position): 6.15 (dd, J = 4 and 9, 1H , HH at 7 position): 6.71 (s, 1H, H of toothbrush): 6.96 (s, 1H, -COOCH).

2-benzhydryloxycarbonyl-3- [2- (2-dimethylaminomethyl-1,3,4-thiadiazol-5-yl) -thiovinyl] -7- [2-methoxyimino- 2- (2-trimethylamino-thiadiazol-4-yl) -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (2.7 g) was reduced to methylene chloride (27 cc) to phosphorus trichloride (0.468 cc) in the presence of dimethylacetamide (0.995) under the conditions described in Example 35 and chromatographed with silica gel. Developing solution: 30:70 (volume) mixture of cyclohexane and ethyl acetate] -2-benzhydryloxycarbonyl-3- [2-triethylamino-thiadiazol-4-yl) -acetamido] Obtain a pink foamy phase of -8-oxo-3-thia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (1.6 g).

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3400, 2820, 2780, 1790, 1715, 1685, 1515, 1450, 1205, 1040, 755 and 740.

Proton NMR spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.35 (s, 6H, -N (CH ₃ ) ₂ ): 3.62 and 3.72 (2d, J = 18, 2H, -SCH _2- ): 3.86 (s, 2H, = NCH ₂ ): 4.09 (s, 3H, -OC _2- ): 5.12 (d, J = 4, 1H, H in 6 position): 5.95 (dd, J = 4 and 9 , 1H, H at position 7): 6.76 (s, 1H, H of toothbrush): 6.88 (d, J = 9, 1H, -CONH-): 7.22 (d, J = 16, 1H, -CH = CHS -): 7.42 (d, U = 16, 1H, = CHS-).

2-benzhydryloxycarbonyl-3- [2- (2-versylaminomethyl-1,3,4-thiadiazol-5-yl) -thiovinyl] -7 using the conditions of Example 35 -[2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct 2-en (Syn isomer, Form E) (1.6 g) was treated with a mixture of formic acid (16 cc) and water (8 cc) to give a yellow powder 7- [2- (2-amino-thiazol-4-yl)- 2-methoxyimino-acetamido] -2-carboxy-3- [2- (2-diketylaminomethyl-1,3,4-thiadiazol-5-yl) thiovinyl] -8-oxo- Obtained with a formate of 5-chia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (0.92 g).

Infrared Spectrum (KBr): Characteristic Band (cm ⁻¹ ) 3400, 3300, 3250, 2000, 1765, 1665, 1600, 1530, 1035 and 960.

Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 2.36 (s, 6H, -N (CH ₃ ) ₂ ): 3.67 and 3.92 (d, J = 18, 2H, -SCH ₂ -): 3.88 (s, 3H, = OCH ₃ ): 5.28 (d, J = 4, 1H, H at 6 position): 5.80 (dd, J = 4 and 9, 1H, 7 position H): 6.76 ( s, 1H, H of toothbrush: 7.10 (d, J = 16, 1H, -CH = CHS-): 7.20 (s, 2H, -NH ₂₎ : 7.25 (d, U = 16, 1H, = CHS -): 9.60 (d, J = 9, 1 H. -CONH).

Example 38

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-2-tosyl Oxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (4 g), 5-mercapto-3-methyl-1,2, A mixture of 4-thiadiazole (1.05 g), N, N-diisopropylethylamine (0.83 cc) and dimethylformamide (50 cc) is stirred in nitrogen at 60 ° C. for 2 hours. The mixture was cooled to 20 ° C. and diluted with ethyl acetate (600 cc) and the organic phase washed with distilled water (100 cc) and 0.1 N hydrochloric acid (150 cc) 5 ° C. sodium bicarbonate (2 × 150 cc) and saturated brine (2 × 150 cc). Dry over sodium sulfate, filter, and terminate under 20 ° C. reduced pressure (20 mmHg). The brown residue is placed in a mixture of cyclohexane and ethyl acetate (10 cc) and 40:60 (volume), and the solution is chromatographed on a column (4 cm in diameter) of Melk Silica gel (0.04-0.06 mm) (150 g).

Develop at 40 kPa with a 40:60 (volume) mixture of cyclohexane and ethyl acetate. 50 cc milk powder and milk powder 24-30 were evaporated to dryness under reduced pressure (20 mmHg) at 20 ° C. to 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazole -4-yl) -acetamido] -3- [2- (3-methyl-1,2,4-thiadiazol-5-yl) -thiovinyl] -8-oxo-5-oxide-5- Chia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (1.8 g) is obtained.

Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.63 (s, 3H, -CH ₃ ): 3.29 and 4.07 (2d, J = 18, 2H, -SCH ₂ ): 4.08 (s , 3H, -OCH ₃ ): 4.61 (d, J = 4, 1H, 6 position H): 6.18 (dd, J = 4 and 9, 1H, 7 position H): 6.71 (s, 1H, H): 6.89 (s, 1H, -COOCH): 7.05 (d, J = 14, 1H, -CH = CHS-): 7.48 (d, J = 9, 1H, -CONH-): 7.58 (d, J = 14, 1 H. = CHS-).

Phosphorous trichloride (0.35 cc) was injected into the solution of the product (syn isomer, Form E) (1.75 g) and dimethylacetamide (0.72 g) by dropwise injection of phosphorus trichloride (0.35 cc). The mixture was stirred for 1 hour at -10 ° C, a little more phosphorus trichloride (0.17cc) was added, and the stirring was continued for 10 minutes.

Dilute with ethyl acetate (500cc), wash with 2% sodium bicarbonate (2x150cc) and half-saturated saline (2x150cc), dry over sodium sulfate, filter, and concentrated to dryness under reduced pressure (20mmHg) at 20 ℃. The residue is dissolved in a 30:70 (volume) mixture of cycloacid and acetylacetate (15 cc) and the solution is chromatographed on a column (diameter cc) of Melk silica gel (0.05-0.2 mm) (60 g). The developing solution is carried out with the mixture (300 cc). 20 cc milk powder is collected and milk powders 6 to 13 are combined and concentrated to dryness under 20 ° C. reduced pressure (20 mmHg). 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2 (2-triethylamino-thiazol-4-yl) -acetamido] -3- [2- (3-methyl-1 , 2,4-thiadiazol-5-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E (1.18 g).

Proton NMR spectrum (350MHz, CDCl ₃ , ppm δ, Hz J): 2.62 (s, 3H, -CH ₃ ): 3.60 and 3.68 (2d, J = 18, 2H, -CH _2- ): 4.07 ( s, 3H, = OCH ₃ ): 5.11 (d, J = 4, 1H, 6 position H): 5.95 (dd, J = 4 and 9, 1H, 7 position H): 6.75 (s, 1H, toothbrush H): 6.88 (d, J = 9, 1H, -CONH): 6.98 (d, J = 16, 1H, -CH = CHS-): 6.99 (s, 1H, -COOCH): 7.0 (s, 1H , -NH-).

The product (syn isomer, Form E) (1.1 g) is dissolved in formic acid (30 cc), distilled water (13c c) is added and the mixture is heated at 50 ° C. for 30 minutes. The suspension is cooled to 20 ° C., filtered and the filtrate is concentrated under 20 ° C. reduced pressure (0.05 mmHg). The residue is taken up in ethanol (30 cc) and the mixture is concentrated under reduced pressure at 20 ° C. and the previous operation repeated three times. The solids are treated with ethanol (100 cc) under reflux, some insolubles are filtered off and the filtrate is concentrated to 5 cc and diluted with diethyl ether (20 cc). The mixture was cooled to + 4 ° C., filtered and dried to give 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- in yellow powder. [2- (3-Methyl-1,2,4-thiadiazol-5-yl) -thiovinyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (0.44 g) is obtained.

Proton NMR spectrum (350 MHz, DMSOd ₆ , ppm δ, Hz J): 2.57 (s, 3H, -CH ₃ ): 3.65 and 3.96 (2d, J = 18, 2H, -SCH _2- ): 3.86 ( s, 3H, -OCH ₃ ): 5.23 (d, J = 4, 1H, 6 position H): 5.82 (dd, J = 4 and 9, 1H, 7 position H): 6.75 (s, 1H, toothbrush H): 7.04 (d, J = 16, 1H, -CH = CHS-): 7.36 (d, J = 16, 1H, = CHS-): 9.63 (d, J = 9, 1H, = CONH-) .

5-mercapto-3-methyl-1,2,4-thiadiazole can be prepared according to the method described in Chem. Ber. 90. 184 (1957).

Example 39

N-Ethyl-N, N-diisofurophylamine (1.4 cc) to 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (trisilamine-thiazol-4-yl) Acetamido] -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E ) (4.0 g) and 2-mercapto-5-phenyl-1,3,4-oxadiazole- (1.4 g) were added to a dimethylformamide (40 cc) solution and heated at 60 ° C. for 6 hours. After cooling, dilute with ethyl acetate (500 cc) and wash the mixture with 0.1 N hydrochloric acid (150 cc), distilled water (150 cc), 3% sodium bicarbonate (150 cc), and finally brine (150 cc). The organic extract is dried over magnesium sulfate, filtered and concentrated under reduced pressure (30 mmHg, 3.3 kPa) at 30 ° C. The obtained material is chromatographed under a pressure of 50 kPa on a column of Melk Sealica (0.020-0.063 mm) (45 cm in diameter and 300 cm in height). A 50:50 (volume) mixture of cyclohexane and ethyl acetate (3 L) is developed as a developing solution. Combine milk powder 43-39 and concentrate under reduced pressure (25 mmHg, 3.3 kPa) to yield 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl ) -Acetamido] -8-oxo-5-oxide-3- [2- (5-phenyl-1,3,4-oxadiazol-2-yl) -thiovinyl] -5-thia-1- Aza-bicyclo [4.20] oct-2-ene (syn isomer, Form E) (1.0 g) is obtained. E type) (1.2 g) is obtained.

The material (1.2 g) is heated for 30 minutes with a solution of formic acid (10 cc) and distilled water (3 cc). After cooling the suspension is filtered and the filter cake is washed with distilled water (2 x 3 cc) and the filtrate is concentrated under reduced pressure (30 mmHg, 0.07 kPa) at 30 ° C.

The solid thus obtained is taken up in ethanol (40 cc) and the suspension is concentrated under reduced pressure (30 mmHg, 0.07 kPa) at 30 ° C. This operation is repeated twice and the obtained solid is dissolved in a mixture of acetonitrile (10 cc) and ethanol (5 cc). It was filtered, washed with acetonitrile (2 × 5 cc) and dried at 20 ° C. under reduced pressure (0.02 mmHg, 0.03 kPa) 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino Acetamido] -2-carboxy-8-oxo-3- [2- (5-phenyl-1,3,4-oxadiazol-2-yl) -thiovinyl] -5-thia-1-aza -Bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (0.25 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3400, at 2000, 3300, 1760, 1630, 1540, 1380, 1055, 750, 710, 695.

NMR spectrum (350 MHz, DMSOd ₆ , ppm δ, Hz J): 3.68 and 3.94 (2d, J = 1 8, 1H, -SCH-): 3.86 (s, 3H, = NOCH ₃ ): 5.22 (d, H at 1H, 6 position: 5.82 (H at dd, 1H, 7 position): 6.74 (s, 1H, H at tooth position): 7.10 (d, J = 16, 1H, -CH = CHS-) 7.18 ( s, 2H, -NH ₂ ): 7.26 (d, J = 16, 1H, CH = CHS-): 7.83 (mt, 3H, P and m-proton of C ₆ H ₅ ): 8.0 (d, J = 7, 2H, furotone of -C ₆ H ₅ ): 9.61 (d, J = 9, 1H. -CONH-).

2-mercapto-5-phenyl-1,3,4-oxadiazole can be prepared according to the method described by Hogart, J. Chem. Soc. 4811 (1952).

Example 40

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide- (2 2-mercapto-3-methyl with a solution of tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (4.0 g) To an oxal (0.92 g) solution of dimethylformamide (40 cc) is added N-ethyl-N, N-diisofurophylamine (1.4 cc). The solution is heated at 55 ° C. for 2 hours. After cooling, dilute with ethyl acetate (500cc) and wash sequentially with 0.1N hydrochloric acid (150cc), 3% sodium bicarbonate solution (2x150cc), and finally brine (150cc). The organic extract is dried over sodium sulfate, filtered and concentrated at 20-25 ° C. under reduced pressure. Chromatography was carried out at 50 kPa pressure on a column of Melksilica (0.02-0.063 mm) (diameter 3 cm).

The developing solution uses 40:60 (volumes) of cyclohexane and ethyl acetate (1.5 L). Fifty milk powders are collected, combined in milk powders 14 for 23 days and concentrated under reduced pressure at 40 ° C. (25 mmHg, 3.3 kPa). Dry at 20 ° C. under 0.2 mmHg (0.03 kPa). 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -3- [2- (4-methyloxa Zol-2-yl) -thiovinyl] 8-oxo-5-oxide-5-aza-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1.15 g ) Is obtained in the form of a yellow foam.

In a solution of anhydrous methylene chloride (10 cc) and N, N-dimethylacetamide (0.43 cc) of the product (syn isomer, Form E) (1.1 g), phosphorus trichloride (0.202 cc) was cooled. Add. The solution is stirred at -15 ° C for 1 hour 30 minutes. Dilute with ethyl acetate (250 cc) and wash the mixture sequentially with 3% sodium bicarbonate (250 cc) and saturated brine (250 cc). The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure (25 mmHg, 3.3 kPa) at 30 ° C. to 2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino -Thiazol-4-yl) -acetamido] -3- [2- (4-methyloxazol-2-yl) -thiovinyl-8-oxo-5-thia-1-aza-bicyclo [4 , 2,0] oct-2-ene (syn isomer, Form E) (1.08 g).

The material (syn isomer, Form E) (1.08 g) is heated for 45 minutes at 50 ° C. with a solution of formic acid (10 cc) and distilled water (6 cc). After cooling, the suspension is filtered, the solids are washed with distilled water (3 cc) and the filtrate is concentrated to dryness under reduced pressure (30 mmHg, 0.07 kPa) at 30 ° C. The obtained solid is taken up in ethanol (75 cc) and concentrated under reduced pressure (0.5 mmHg, 0.075 kPa) at 30 ° C. Repeat the previous operation twice.

The obtained solid is dissolved in acetonitrile (50 cc), filtered, washed, and dried under reduced pressure of 20 ° C. (0.2 mmHg, 0.03 kPa).

7- [2- (2-amino-thiazol-4-yl) -2-methoxyamino-acetamido] -2-carboxy-3-[2- (4-methyl-oxazol-2-yl) -Thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.41 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3300, 2940, 1770, 1675, 1530, 1380, 1040, 940, 730, 700.

Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.10 (s, 3H, -CH ₃ ): 3.66 and 3.90 (2d, J = 18, 2H, -SCH _2- ): 3.86 ( s, 3H, -NOCH ₃ ): 5.19 (d, 1H, H at 6 position): 5.78 (dd, 1H, H at 7 position): 6.74 (s, 1H, H of toothbrush ring): 7.0 (d, J = 16, 1H, -CH = CHS-): 7.14 (d, J = 16, 1H, CH = CHS-): 7.20 (s, 2H, -NH ₂ ): 7.94 (s, 1H, H of oxazole ring) : 9.72 (d, J = 9, 1H, -CONH-).

2-mercapto-4-methyl-oxazole can be prepared by the method described by C, Bradsch (J. Org. Chem. 32 2079 (1967)).

Example 41

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-3- (2-tosyl Oxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) ((0.57 g) with dimethylformamide (15 cc) and 1- ( A mixture of 2-hydroxyethyl) -5-mercapto-tetrazole (0.17 g) is heated in nitrogen to 60 ° C. Dimethylformamide of ethyl-N, N-diisofurophylamine (0.1 cc) (5cc) solution is slowly added dropwise with stirring for 15 minutes After 3 1/2 hours at 60, the mixture is diluted with ethyl acetate (100cc), washed with distilled water (5x50cc), dried over soda sulfate and filtered. Concentrate under reduced pressure (20 mm Hg) at 20 ° C. The residue is dissolved in methylene chloride (5 cc) and on a column (2 cm in diameter, 15 cm in height) of melksilica gel (0.04-0.06 mm) (80 g), the developing solution Expanded under 40kPa pressure with 25:75 (volume) mixture of ethylacetate (300cc) Perform chromatograph Collect 60 cc of milk powder.

A little (0.06 g) of starting material is obtained in milk powder 1. Condensate 2-4 was concentrated to dryness under reduced pressure (20 mmHg) at 20 ° C. to 2-benzhydryloxycarbonyl-3- {2- (1- (2-hydroxyethyl) -tetrazol-5-yl) -Ciovinyl} -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamino) -8-oxo-5-thia-1-aza-bicyclo [ 4.2.0] oct-2-ene (syn isomer, Form E) (0.4 g).

Infrared spectrum (KBr): Characteristic bands (cm ^-1 ) are 3400, 1785, 1720, 1580, 1525, 1370, 1210, 1035, 940, 755 and 700.

Proton NMR spectra (350 MHz, CDCl ₃ , ppm δ, Hz J): 3.57 and 3.67 (AB, A = 18, 2H, -5CH ₂ ): 4.07 (s, 3H, -CH _3- ): 4.1 and 4.35 (2t, 4H, -CH ₂ CH ₂ O): 5.09 (d, J = 4, 1H, H at 6 position): 5.94 (dd, J = 4 and 9, 1H, 7 position H): 6.84 ( s, 1H, H at position 5): 6.95 (s, 1H, -COOCH-): 6.97 (s, 1H, (C ₆ H ₅ ) ₃ CHN-): 7.00 (d, J = 16, 1H , -CH = CHS-).

The product (syn isomer, Form E) (0.39 g) is dissolved in formic acid, the solution is diluted with water (4 cc) and heated at 50 ° C. for 30 minutes. After cooling, filtering, and concentrated to dryness under reduced pressure (0.05mmHg) at 20 ℃. The residue was triturated in diisofueroether (10 cc), filtered and dried to 7- [2- (2-amino-thiazol-4-yl) -2-methoxy-imino-acetamido] -2- Carboxy-3- {2-[1- (2-hydroxyethyl) -tetrazol-5-yl) -thiovinyl} -8-oxo-5-thia-1-aza-bicyclo [4.2.0] Octate-2-ene (formic acid lysate (syn isomer, Form E) (0.2 g) is obtained as a pale yellow solid.

The above product (dissolved) (0.9%) was treated with ethanol (50 cc) under reflux, some insoluble material was removed by filtration, and the filtrate was left to cool at 20 ° C. for 2 hours, and then left at 4 ° C. for 2 hours. The mixture is filtered and the material (0.41 g) is obtained in the form of an internal salt.

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3250, 1770, 1720, 1675, 1530, 1390, 1040 and 940.

Proton NMR spectrum (350MHz, DMSOd ₆ , ppm δ, Hz J): 3.63 and 3.37 (AB, J = 19, 2H, -SCH _2- ): 3.77 and 4.41 (2t, 4H, -CH ₂ CH ₂ O): 3.84 (s, 3H, -OCH ₃ ): 5.19 (d, J = 4, 1H, H in 6 position): 5.89 (dd, J = 4 and H in 9, 1H, 7 position): 6.73 ( s, 1H, H at position 5 of the toothbrush: 6.94 (d, J = 16, 1H, -CH = CHS-): 7.25 (d, J = 16, 1H, = CHS-): 9.61 (d, 1H , -CONH-).

The internal salt (0.27 g) is suspended with distilled water (2 cc) and sodium bicarbonate (0.042 g) is added and the mixture is stirred at 20 ° C. for 15 minutes. After lyophilization, soda salt of the product (0.27 g) is obtained.

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-2- (2-tosyl Oxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) can be obtained by the method described in Example 3.

Example 42

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-Tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (10.04 g) with dimethylformamide (200 cc), 1- A mixture of (acetamidoethyl) -5-mercapto-tetrazole (3.74 g) and diisofurophylethylamine (3.5 cc) is stirred at 60 ° C. for 6 hours in nitrogen. Dilute with ethyl acetate (800 cc) and wash the mixture with water (# x 400 cc), dry over sodium sulfate, filter, and concentrate to dry at 20 ° C, 20 mmHg. The product first adhered to Melk Sealica gel (0.05-0.2 mm) (50 g) is dipped into a column (100 g) of the same gel (3 cm in diameter). The whole solution is carried out with a 25:75 (volume) mixture of cyclohexane and ethyl acetate (1 L) and ethyl acetate (3 L). 125 cc milk powder is collected and concentrated to dry powder 19 to 20 at 20 ° C., 20 mm Hg. Brown foamy 3- [2-ethoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-chia-1-azabi Obtain a [4.2.0] oct-2-ene (syn isomer, Form E) (5.05 g).

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3440, 3380, 1800, 1720, 1670, 1510, 1495, 1445, 1370, 1045, 940, 750 and 735.

Proton NMR Spectrum (350MHz, CDCl ₃ , ppm Hz J): 1.84 (s, 3H, -COCH ₃ ): 3.72 and 4. (2d, J = 18, 2H, -SCH _2- ): 3.62 (mt , 2H, -CH ₂ NHCO-): 4.05 (s, 3H, -OCH ₃ ): 4.35 (t, 2H, -NCH _2- (: 4.62 (d, J = 4, 1H, H in 6 position): 6.07 (dd, J = 4 and 9, 1H, H at 7 positions): 6.50 (t, J = 7, 1H, -NHCO-) 6.69 (s, 1H, -COOH): 6.96 (d, J = 16, 1H , -CH = CHS-): 7.10 (s, 1H, -NHC (C ₆ H ₅ ) ₃ ).

Dimethylacetamide (1.95cc) and phosphorus trichloride (0.86cc) were added to the mixture of the methyl foamed product (syn isomer, Form E) (4.99 g), and then cooled to -10 ° C. Stir at -10 ° C for 2 hours. Dilute with ethyl acetate (300 cc) and wash the mixture with half-saturated sodium bicarbonate (200 cc) and saturated brine (200 cc) and dry over sodium sulfate. Filter and concentrate at 20 ° C., 20 mmHg. The material thus obtained was melksilica gel (0.04-0.06 mM); Chromatography is carried out in kelam (6 cm in diameter).

At this time, a 20:80 (volume) mixture of cyclohexane and ethyl acetate (5 L) was developed under a 40 kPa pressure as a developing solution. Collect 125 cc milk powder. Dry milk from 19 to 32 was evaporated to dryness at 20 ° C., 20 mmHg, to give a yellow foam of 3- {2- [1- (2-acetamido-itchel) -tetrazol-5-yl] -thiovinyl} -2- Benzhydryloxycarbonyl-7- [2--methoxy imino-2- (2-trimethyl-amino-thiazol-4-yl) -acetamido] -8-oxo-5-thia-1 Obtain aza-microcyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2.3 6 g).

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ⁻¹ ) are 3440, 3400, 1785, 1720, 1680, 1515, 1495, 1450, 1370, 1040, 945, 755, 740.

):7.00(s, 1H, (C₆H₅)₃C-NH-).Proton NMR spectrum (350MHz, CDCl ₃ , ppm δ, Hz J): 1.93 (s, 3H, -CH ₃ ): 3.54 and 3.60 (2d, J = 18, 2H, -SCH _2- ): 3.70 ( m, 2H, -CH ₂ NHCO-): 4.04 (s, 3H, -OCH ₃ ): 4.35 (t, J = 5, 2H, -NCH _2- ): 5.10 (d, J = 4, 1H, 6 position H): 5.94 (dd, J = 4 and 9, 1H, H in 7 position): 6.40 (t, J = 5, 1H, -NHCOCH ₃ ): 6.73 (s, 1H, Hicazole H): 6.93 (s, 1H, COO

): 7.00 (s, 1 H, (C ₆ H ₅ ) ₃ C-NH-).

The yellow foamed product (syn isomer, Form E) (2.32 g) is dissolved in formic acid (60 cc), water (6 cc) is added and the mixture is heated with stirring at 50 ° C. for 15 minutes. Cool to 20 ° C, filter, and dry under 50 ° C, 0.05mmHg. The residue is taken up in ethanol (3 x 150 cc) and the solvent is removed each time at 20 DEG C under reduced pressure (20 mmHg). The residue is taken up in ethanol (50 cc) and the solvent is removed each time under reduced pressure (20 mmHg) at 20 ° C. The residue is taken up in ethanol (50 cc) and the suspension is stirred at 40 ° C. for 1 hour and then cooled to 20 ° C.

Filtration to give pale yellow powder of 3- {2- [1- (2-acetamido-ethyl) -tetrazol-5-yl] -thiovinyl} -7- [2- (2-amino-thiazol-4 -Yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E (0.86 g).

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3500, 2500, 1775, 1660, 1540, 1040 and 945.

NCH₂) : 360(q, 2H, -CH₂NHCO-) : 3.64와 3.76(2d, J=18, 2H, -SCH₂-) : 4.0(s, 3H, -OCH₃) : 5.16(d, J=4, 1H, 6위치에 H) : 5.82(dd, J=4와 9, 1H, 7위치에 H) : 6.60(s, 3H, -NH³⁺) : 6.78(s, 1H, 치아졸의 H) : 6.90(d, J=16, 1H, -CH=CH-S-) : 7.37(d, J=16, 1H, -CHS-) : 7.86(t, J=5, 1H, -NHCOCH₃) :9.50(d, J9, 1H, -CONH-).Proton NMR spectrum (35 MHz, DMSO d ₆ , ppm δ, Hz J): 1.90 (s, 3H, -CH ₃ ): 3.44 (t, 2H,

NCH ₂ ): 360 (q, 2H, -CH ₂ NHCO-): 3.64 and 3.76 (2d, J = 18, 2H, -SCH _2- ): 4.0 (s, 3H, -OCH ₃ ): 5.16 (d, J = 4, 1H, H at 6 position: 5.82 (dd, J = 4 and 9, 1H, H at 7 position): 6.60 (s, 3H, -NH ³⁺ ): 6.78 (s, 1H, toothbrush H): 6.90 (d, J = 16, 1H, -CH = CH-S-): 7.37 (d, J = 16, 1H, -CHS-): 7.86 (t, J = 5, 1H, -NHCOCH ₃ ): 9.50 (d, J9, 1H, -CONH-).

1- (2-acetamido-ethyl) -5-mercapto-tetrazole may be prepared according to the methods described in US Pat. No. 4,117,123.

Example 43

2-benzhydryloxycarbonyl-7 [2-methoxy imino-2- (2-trimethyl amino-thiazol-4-yl) -acetamido] -8-oxo-3- (2-tosyl Oxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E (1.04 g) and 1- (2-dimethylaminoethyl) 5- The mixed solution of the dimethylformamide solution of mercapto-tetrazole (0.35 g) (manufactured by German patent application 2,738,711) is stirred in nitrogen at 60 ° C. for 5 hours. After extraction with ethyl acetate as described in Example 42, chromatography on silica gel is carried out. The developing solution is a 20:80 (volume) mixture of cyclohexane and ethyl acetate.

2-benzhydryloxycarbonyl-3- {2- [1- (2-dimethylamido ethyl) -tetrazol-5-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethyl amino-thiazol-4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E) (0.3 g) is obtained as a light brown foam.

Infrared spectrum (CHBr ₃ ): Characteristic band (cm ^-1 ) is 3390, 2820, 2780, 1715, 1680, 1510, 1445, 1205, 1045, 940, 750, 735.

Proton NMR spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 2.25 (s, 6H, -N (CH ₃ ) ₂ : 2.73 (t, J = 7, 2H, -CH ₂ N (CH) ₃ ) ₂ ): 3.61 and 3.68 (d, J = 18, 2H, -SCH _2- ): 4.08 (s, 3H, = NOCH ₃ ): 4.3 (t, J = 7, 2H, -CH ₂ CHN (CH ₃ ) ₂ ): 5.11 (d, J = 4, 1H, H at 6 position): 5.95 (dd, J = 4 and 9, 1H, H at position 7): 6.76 (s, 1H, H of toothbrush) : 6.86 (dJ, J = 9, 1H, -CONH-): 6.95 (s, 1H, -COOCH-): 6.99 (s, 1H, -NHC (C ₆ H ₅ ) ₃ ): 7.07 (d, J = 16, 1H, -CH = CHS-): 7.42 (d, J = 16, 1H, = CHS-).

The pale brown foamy product (syn isomer, Form E) (0.59 g) was treated with a mixture of formic acid (30 cc) and water (30 cc) according to the procedure described in Example 42 to give 7- [2- (2-amino -Thiazol-4-yl) -2-ethoxyimino-acetamido] -2-carboxy-3- {2- [1- (2-dimethylamino ethyl) -tetrazol-5-yl) -thio Vinyl} -8-oxo-5-thia-1-aza-bicyclo [4,2,0] octro-2-ene (syn isomer, Form E) (0.38 g) is obtained as a yellow powdered formate.

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3400, 3200, 2000, 1770, 1670, 1615, 1530 and 1035.

Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 2.70 (s, 6H, -N (CH ₃ ) ₂ : 2.75 (t, J = 7, 2H, -CH ₂ NC): 3.85 (s, 3H, -OCH ₃ ): 3.95 (t, J = 7, 2H, -CH ₂ CH ₂ N (CH ₃ ) ₂ ): 5.16 (d, J = 4, 1H, H at 6 position): 5.85 (dd, J = 4 and H at position 9, 1H, 7): 6.74 (s, 1H, H of toothbrush): 6.80 (d, J = 16, 1H, -CH = CHS-): 6.90 (d , J = 16, 1H, -CHS-: 7.20 (s, 2H, -NH ₂ ): 9.63 (d, J = 9, 1H, -CONH-).

Example 44

2-benzhydryloxycarbonyl-7- [2-methoxy imino-2- (2-trimethyl amino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3 -(2-tosyloxy vinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (10 g) and dimethylformamide (200 cc) The mixture of 1- (2,2-dimethoxy ethyl) -5-mercapto-tetrazole (5.75 g) is stirred at 50 ° C. in nitrogen for 24 hours. Dilute with ethyl acetate (200 cc) and water (200 cc), decanter the organic phase, wash with water (3 x 20 cc) and wash with saturated brine (100 cc). Concentrate to dryness at 20 ° C., 20 mmHg (2.7 k Pa).

The residue is chromatographed on a column (6 cm in diameter and 30 cm in height) of Melx silica gel (0.04-0.06 mm). The developing solution is either a 25:75 (volume) mixture (4.6 L) or a 50:50 (volume) mixture (3.8 L) of cyclohexane and ethyl acetate. Collect 120 cc milk powder and concentrate 69 at milk powder 40 to 20 ° C., 20 mmHg (2.7 kPa), and dry to 2-benzhydryloxycarbonyl-3- {2- [1- (2,2-dimethoxyethyl) -Tetrazol-5-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5- Oxide-5-chia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (3.4 g) is obtained as a brown foam. The obtained material is used for the next operation.

The obtained material (3.37 g) was dissolved in a solution of methylene chloride (25 cc) and dimethylacetamide (1.31 cc) and treated with phosphorus trichloride (0.58 cc) for 30 minutes at -3 ° C with stirring. The mixture was diluted with methylene chloride (75 cc), washed with semisaturated sodium bicarbonate (2 x 50 cc) and water (2 x 50 cc), dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C and 20 mmHg (2.7 kPa). .

The residue is chromatographed on a column (melt 4 cm, height 20 cm) of Melx silica gel (0.04-0.06 mm). A 50:50 (volume) mixture of cyclohexane and methyl acetate (1.8 L) is developed at 40 kPa pressure. Collect 60 cc of dry milk and evaporate dry milk from 16 to 24 to form a creamy foam of 2-benzhydryloxycarbonyl-3- {2- [1- (2,2-dimethoxy ethyl) -tetrazol-5 -Yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl-(acetamido) -8-oxo-5-thia-1-aza Bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1.1 g) is obtained.

Infrared spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3400, 1790, 1725, 1690, 1520, 1450, 1210, 1050, 945 and 705.

NCH₂CH

) : 4.70(t, J=6,

NCH₂CH

) : 5.25(d, J=4, HO) : 5.78(dd, J=4와 9, H₇) : 6.74(s, 치아졸의 H) : 9.96(s, -COOCH) : 7.02와 7.08(d, J=16, 2H, -CH=CHS-) : 8.79(s, -NH-) : 9.60(d, J=9, -NHCC-).Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): (s, 6H, -C (OC H ₃ ) ₂ ): 3.65 and 3.91 (2d, J = 18, 1H, -SCH- ): 3.83 (s, 3H, = NOCH ₃ ): 4.48 (dm J = 6, 2H,

NCH ₂ CH

): 4.70 (t, J = 6,

NCH ₂ CH

): 5.25 (d, J = 4, HO): 5.78 (dd, J = 4 and 9, H ₇ ): 6.74 (s, H of toothbrush): 9.96 (s, -COOCH): 7.02 and 7.08 (d , J = 16, 2H, -CH = CHS-): 8.79 (s, -NH-): 9.60 (d, J = 9, -NHCC-).

The cream colored foam material (syn isomer, Form E) (1.06 g) was heated in a solution dissolved in formic acid (42 cc) at 50 ° C. for 30 minutes. Concentrate to dryness at 30 ° C. (0.05 mmHg, 0.007 kPa) and the residue is taken up in acetone (100 cc) and the mixture is concentrated to dryness at 20 ° C., 20 mmHg (2.7 kPa). This operation is repeated four times. The yellow solid is treated with acetone (30 cc) under reflux, cooled and filtered. 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2- [1- (2,2-dimethy) after drying Methoxyethyl) -tetrazol-5-yl] -thiovinyl} -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.42 g) is obtained as a yellow powder.

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3350, 1780, 1680, 1655, 1620, 1530, 1120, 1040 and 940.

C(OCH)₂): 3.92(s, 광역, 2H, -SCH₂-) : 4.31(s, 3H, =NOCH₃) : 4.73(d, J=6, 2H,

NCH₂) : 5.0(t, J=6, 1H,-CH₂-CH

) : 5.38(d, J=4, 6H) : 6.05(dd, J=4와 9, H₇) : 7.16와 7.88(2d, J=16, -CH=CH-) : 7.50(s, 치아졸의 H).Proton's NMR spectrum (350 MHz, OF ₃ CO ₂ D, ppm δ, Hz J): 3.61 (s, 6H,

C (OCH) ₂ ): 3.92 (s, broad, 2H, -SCH _2- ): 4.31 (s, 3H, = NOCH ₃ ): 4.73 (d, J = 6, 2H,

NCH ₂ ): 5.0 (t, J = 6, 1H, -CH ₂ -CH

): 5.38 (d, J = 4, 6H): 6.05 (dd, J = 4 and 9, H ₇ ): 7.16 and 7.88 (2d, J = 16, -CH = CH-): 7.50 (s, toothbrush H).

1- (2,2-dimethoxyethyl) -5-mercapto-tetrazole can be prepared as follows.

A solution of sodium azide (65 g) in 95% ethanol (1,680 cc) was heated under reflux and a solution of 2,2-dimethoxyethyl isothiocyanate (147.2 g) dissolved in 95% ethanol (320 cc) was added. Dropped with stirring for 1 hour 30 minutes. The mixture is heated at reflux for 12 h and concentrated to dryness at 40 ° C., 20 mm Hg (2.7 kPa). The residue is taken up in acetone (600 cc) and the mixture is filtered and diethyl ether (1 L) is added.

The decision starts and add more ethylethyl (2.5 L). It is left for 24 hours at 20 DEG C, filtered and dried to obtain a hydrate (208.2 g) of 1- (2,2-dimethoxyethyl) -5-mercapto-tetrazole.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3480, 3220, 2840, 1660, 1400, 1290, 1115, 1070, 1025, 790.

Example 45

2-benzhydryloxycarbonyl-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -7- [2- (2-trimethylamino-thiazol-4-yl) -2-vinyl Oxyimino-acetamido] -5-chia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.4 g), dimethylformamide (5 cc), A mixture of 5-mercapto-1-methyl-tetrazole (0.1 g) and N, N-diisopropylethylamine (0.15 cc) is heated at 60 ° C. for 4 hours. It was taken up in ethyl acetate (50cc), and the organic phase was washed with water (50cc), 0.1N hydrochloric acid (50cc), semisaturated brine (50cc) and saturated brine (50cc), dried over sodium sulfate, filtered and filtered at 30 ° C, 20mmHg ( 2.7 kPa).

The residue is chromatographed on a column (melt 1.5 cm, height 15 cm) of Melx silica gel (0.06-0.2 mm) (50 g). A 90:10 (volume) mixture of methylene chloride and acetylacetate (2 L) is developed under 40 kPa pressure and 25 cc milk powder is collected. Condensate 18-42 concentrated to dryness at 20 ° C., 20 mmHg (2.7 kPa), 2-benzhydryloxycarbonyl-2- [2- (1-methyl-tetrazol-5-yl) -thiovinyl] -8 -Oxo-5-oxide-7- [2- (2-trimethyl amino-thiazol-4-yl) -2-vinyloxyimino-acetamido] -5-thia-4-aza-bicyclo [4 , 2,0] oct-2-ene (syn isomer, Form E) (0.15 g).

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3340, 2940, 2860, 1800, 1730, 1690, 1640, 1575, 1525, 1500, 1450.

) : 4.76(dd, J=2-14, 1H,

) : 4.67(d, J=4, 1H, 6위치의 H) : 6.18(dd, J=4-9, 1H, 7위치 의 H) : 6.7(s, 3H, 치아졸의 H) : 6.95(s, 1H,

) : 7.0(d, J=15, 1H, -CH=CHS -) : 7.05(dd, J=4-6, 1H, -OCH=) : 7.10(s, 1H,

CNH) : 7.58(d, J=15, 1H, -CH=C HS-) :Proton NMR spectrum (350MHz, CDCl ₃ , ppm δ, Hz J): 3.31-4.05 (2d, J = 18, 2H, -SCH _2- ): 3.92 (s, 3H, -CH ₃ ): 4.26 ( dd, J = 2-6, H, H

): 4.76 (dd, J = 2-14, 1H,

): 4.67 (d, J = 4, 1H, H in 6 position): 6.18 (dd, J = 4-9, 1H, H in 7 position): 6.7 (s, 3H, H of toothbrush): 6.95 ( s, 1H,

): 7.0 (d, J = 15, 1H, -CH = CHS-): 7.05 (dd, J = 4-6, 1H, -OCH =): 7.10 (s, 1H,

CNH): 7.58 (d, J = 15, 1H, -CH = C HS-):

2-benzhydryloxycarbonyl-3- [2- (1-methyl-tetrazol-5-yl) -thiovinyl] -8-oxo-5-oxide-7- [2- (2-trimethylamino -Thiazol-4-yl) -2-vinyloxyimino-acetamido] -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) ( 3 g) of methylene chloride (31.7 cc) and dimethylacetamide (1.22 cc) solution were treated with phosphorus trichloride for 20 minutes at -10 ° C. Ethyl acetate (250cc) was added dropwise to the mixture, and the mixture was washed with saturated sodium bicarbonate solution (250cc), water (250cc), saturated sodium bicarbonate solution (250cc), dried under sodium sulfate, filtered and filtered to 20 mmHg (2.7kPa). Concentrated to dryness at 20 ° C.

The obtained product was adjusted to Melk silica gel (0.06-0.2 mm) (10 g) and chromatographed on Melk silica gel (0.06-0.2 mm) (30 g) column (diameter 1.5 cm).

60 cc of fractions were collected by evolving a mixture of cyclohexane and ethyl acetate, i.e., 80: 20 (volume) (250cc), 70: 30 (volume) (250cc), 60:40 (volume) (250cc), respectively. do.

The milk powder was concentrated to dryness at 5-10 at 20 ° C. and 20 mmHg (2.7 kPa) to give cream-containing 2-benzhydryloxycarbonyl-3- [2- (1-methyl-tetrazol-5-yl)- Thiovinyl] -8-oxo-5-oxide-7- [2- (2-trimethyl amino-thiazol-4-yl) -2-)-vinyloxyimino-acetamido] -5-thia-4 Aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1.92 g) is obtained.

Rf = 0.58 (on silica gel chromatography)

Developing solution: 50:50 (volume) of cyclohexane, ethyl acetate and mixed solution

A mixture of the creamy foam material (syn isomer, Form E) (1.92 g), formic acid (15 cc), and water (7 cc) was filtered by stirring at 50 ° C. for 15 minutes and filtered at 0.05 mm Hg (0.007 kPa) at 30 ° C. Concentrate to dryness. The remaining oil phase is taken up in ethanol (100 cc), the solvent is removed at 20 ° C. and 20 mm Hg (2.7 kPa) and this operation is repeated twice. The residue was taken up in ethanol (100 cc), heated to reflux with stirring, and cooled by filtration and dried to give a yellow powder of 7- [2- (2-amino-thiazol-4-yl) -2-vinyloxy imino-acetamido ] -2-carboxy-3- [2- (1-methyl-tetrazol-5-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct 2-en (syn isomer, Form E) (0.72 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3340, 1770, 1680, 1620, 1530, 1380.

) : 4.65(dd, J=2-14, 1H

) : 5.22(d, J=4, 1H, 6위치의 H) : 5.82(dd, J=4-9, 1H, 7위치의 H) : 6.75(s, 1H, 치아졸의 H) : 6.95(d, J=16, 1H, -CH=CHS-) : 6.96(dd, J=6-14 , 1H, -OCH=CH₂) : 7.13(d, J=16, 1H, -CHS-) : 9.83(d, J=9, 1H, -CONH-).Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 3.64-3.89 (2d, J = 18, 2H, 2SCH _2- ): 4.0 (s, 3H, -CH ₃ ): 4.22 ( dd, J = 2-6, 1H,

): 4.65 (dd, J = 2-14, 1H

): 5.22 (d, J = 4, 1H, H at 6 position): 5.82 (dd, J = 4-9, 1H, H at 7 position): 6.75 (s, 1H, H of toothbrush): 6.95 ( d, J = 16, 1H, -CH = CHS-): 6.96 (dd, J = 6-14, 1H, -OCH = CH ₂ ): 7.13 (d, J = 16, 1H, -CHS-): 9.83 (d, J = 9, 1H, -CONH-).

2-benzhydryloxycarbonyl-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -7- [2- (2-tritylamino-thiazol-4-yl) -2-vinyl Oxy-imino-acetamido] -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) can be prepared by the following method.

A solution of methylene chloride (7 cc) and 85% of steel M-chloroperbenzoic acid (0.33 g) was cooled to −10 ° C. for 10 minutes, followed by 2-benzhydryloxycarbonyl-8 of methylene chloride (5 cc). -Oxo-3- (2-tosyloxy vinyl) -7- [2- (2-trityl amino-thiazol-4-yl) -2-vinyloxyimino-acetamido] -5-thia-1- Aza-bicyclo [4,2,0] oct-2-ene and oct-3-ene (syn isomers, mixtures of E and Z-form) solutions are added dropwise. The mixture was stirred at −10 ° C. for 1 hour, diluted with methylene chloride (30 cc), washed with saturated sodium bicarbonate solution (2 × 50 cc) and half-saturated saline solution (50 cc), filtered under dry sulfuric acid, and filtered at 30 ° C. and 20 mm Hg (2.7 g). kPa) and concentrated to dryness. The residue is chromatographed on a column (1cm in diameter, 10cm in height) of Melk silica gel (0.06-0.22mm). The development was carried out by developing a mixed solution of methyl chloride (500 cc), 97: 3 (volume) (1 L), 95: 5 (volume) (1.5 L) of methyl chloride and ethyl acetate, and 25 cc of milk powder was collected. Dry evaporation of the milk powder 14-24 at 20 ° C., 20 mmHg (2.7 kPa) gave 2-benzhydryloxycarbonyl-8-oxo-5-oxide-3- (2-tosyloxy vinyl) -7- [2- (2-trityl amino-thiazol-4-yl) -vinyloxyimino-acetamido] -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E) (0.45 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 1800, 1725, 1690, 1635, 1520, 1495, 1450, 1195, 1180, 1070, 1050, 1000, 945, 740, 700.

) : 4.62 (d, J=4, 1H, 6위치의 H) :4.76(dd, J=2-13, 1H,

) : 6.20(dd, J=4-9, 1H, 7위치의 H) : 6.80(s, 1H, 치아졸의 H) : 6.90(s, 1H, -COOCH=) : 6.92-7.10(2d, J=12, 2H, -CH=CH-) : 7.05(dd, J=6-13 , 1H, =NOCH=) : 7.73(d, J=8, 2H, -OSO₂기의 오르토 위치 H).Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.45 (s, 3H, -CH ₃ ): 3.19 and 3.77 (2d, J = 18, 2H, -SCH _2- ): 4.27 ( dd, J = 2-6, 1H,

): 4.62 (d, J = 4, 1H, H in 6 position): 4.76 (dd, J = 2-13, 1H,

): 6.20 (dd, J = 4-9, 1H, H at 7 position): 6.80 (s, 1H, H of toothbrush): 6.90 (s, 1H, -COOCH =): 6.92-7.10 (2d, J = 12, 2H, -CH = CH-): 7.05 (dd, J = 6-13, 1H, = NOCH =): 7.73 (d, J = 8, 2H, ortho position H of the -OSO ₂ group).

2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -7- [2- (2-tritylamino-thiazol-4-yl) -2-vinyloxyimino-acet Amido] -5-chia-1-aza-bicyclo [4,2,0] oct-2-ene and 3-ene (a mixture of Form E and Form Z) may be prepared by the following method. 2-benzhydryloxycarbonyl-3- (2-oxoethyl) -8-oxo-7- [2] of methylene chloride (30 cc) while cooling to para-toluene sulfonyl (0.65 g) at -15 占 폚. -(2-tritylamino-thiazol-4-yl) -2-vinyloxyimino-acetamido] -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene ( syn isomer) (2.4 g) solution, followed by dropwise injection of a solution of methylene chloride (5 cc) and triethylamine (0.44 cc) for 10 minutes. The mixture is stirred for 30 minutes at -15 ° C and left for 1 hour at + 20 ° C. The mixture was diluted with methylene chloride (50 cc), washed with saturated sodium bicarbonate solution (3 x 50 cc) and water (3 x 50 cc), dried under sodium sulfate and concentrated to dryness at 30 ° C and 20 mmHg (2.7 kPa) under filtration. . The residue was taken up in ethyl acetate (5 cc), diisopropyl ether (50 cc) was added, and the mixture was stirred for 10 minutes, followed by filtration and drying. 2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxy vinyl ) -7- [2- (2-tritylamino-thiazol-4-yl) -vinyloxyiminoacetamido] -5-thia-1-aza-bicyclo [4,2,0] oct- Beige powder (1.6 g) containing 2-ene and oct-3-ene (a mixture of Form E and Form Z) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 1790, 1725, 1690, 1640, 1525, 1495, 1450, 1195, 1180, 1075, 1005, 950, 755, 705.

) : 4.77(d, J=2-16, 1H,

) :5.09(d, J=4, 1H, 6위치의 H) : 5.94(dd, J=4-9, 1H, 7위치의 H) : 6.81(s, 1H, 치아졸의 H) : 6.91(s, 1H, -COOCH-) : 7.07(dd, J=6-16 , 1H, -CH=CH₂-) : 7.74(d, J=8, 2H, 설폰기의 H).Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.45 (s, 3H, -CH ₃ ): 3.40-3.55 (2d, J = 18, 2H, -SCH _2- ): 4.27 ( dd, J = 2-6, 1H,

): 4.77 (d, J = 2-16, 1H,

): 5.09 (d, J = 4, 1H, H in 6 position): 5.94 (dd, J = 4-9, 1H, H in 7 position): 6.81 (s, 1H, H of toothbrush): 6.91 ( s, 1H, -COOCH-): 7.07 (dd, J = 6-16, 1H, -CH = CH _2- ): 7.74 (d, J = 8, 2H, H of sulfone group).

2-benzhydryloxycarbonyl-3- (2-dimethylaminovinyl) -8-oxo-7- [2- (2-tritylamino-thiazol-4-yl) -2-vinyloxyimino- Acetamido] -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2.5 g) was dissolved in 1 N hydrochloric acid (5 0cc) washed with half-saturated saline (50cc), dried over sodium sulfate, filtered, and concentrated to dryness at 20 ° C and 20mm Hg (2.7kPa) 2-benzhydryloxycarbonyl-3- (2-oxyethyl)- 8-oxo-7- [2- (2-tritylamino-thiazol-4-yl) -vinyloxyiminoacetamido] -5-thia-1-aza-bicyclo [4,2,0] Obtain a brown foamy material of oct-2-ene (syn isomer).

Infrared spectrum (KBr): Characteristic band (cm ^-1 ): 1785, 1725, 1685, 1640, 1530, 1495, 1450, 1000, 950, 755, 700.

) : 4.78(d, J=2-17, 1H,

) : 5.12(d, J=4, 1H, 6위치의 H) : 6.0(dd, J=4-9, 1H, 7위치의 H) :6.8(dd, J=4-9, 1H, 7위치의 H) : 6.90(s, 1H,

) : 7.08(dd , J=6-7, 1H, -CH=CH₂-) : 9.55(s, 1H, -CHO-).Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 3.26-2.58 (2d, J = 18, 2H, -SCH _2- ): 3.53-3.69 (2d, J = 18, 2H,- CH _2- ): 4.28 (dd, J = 2-3, 1H,

): 4.78 (d, J = 2-17, 1H,

): 5.12 (d, J = 4, 1H, 6 position H): 6.0 (dd, J = 4-9, 1H, 7 position H): 6.8 (dd, J = 4-9, 1H, 7 position H): 6.90 (s, 1H,

): 7.08 (dd, J = 6-7, 1H, -CH = CH _2- ): 9.55 (s, 1H, -CHO-).

2-benzhydryloxycarbonyl-3- (2-dimethylaminovinyl) -8-oxo-7- [2- (2-tritylamino-thiazol-4-yl) -2-vinyloxyimino- Acetamido] -5-chia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) can be prepared by the following method.

Tet-butoxy-bis-dimethylaminomethane (0.7 cc) was extracted with 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7- of dimethylsulfonamide (40 cc) in the presence of nitrogen at 80 ° C. 2- (2-tritylamino-thiazol-4-yl) -2-vinyl-oxyimino-acetamido] -5-thia-1-aza-bicyclo [4, 2,0] oct-2- A solution of en (syn isomer, Form E) (2.5 g) was added, stirred at 80 ° C. for 10 minutes, and ethyl acetate (250 cc) and ice water (250 cc) were added thereto. The organic phase was separated by tilting, washed with water (3 × 150 cc) and saturated brine (150 cc), dried over sodium sulfate, filtered and concentrated to dryness at 30 ° C. and 20 mmHg (2.7 kPa). 2-benzhydryloxycarbonyl-3 -(2-Dimethylaminovinyl) -8-oxo-7- [2- (2-tritylamino-thiazol-4-yl) -2-vinyloxyimino-acetamido] -5-thia-1 Obtain a brown foam (2.5 g) material of aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E).

Infrared spectrum (KBr): Characteristic band (cm ^-1 ): 1770, 1670, 1635, 1610, 1530, 1495, 1450, 1000, 945, 755, 700.

) : 5.18(dm J=4, 1H , 6위치의 H) : 5.60(dd, J=4-9, 1H, 7위치의 H) : 6.53-6.75(2d, J=16, 2H, -CH=C H-) : 6.88(s, 1H,

) : 7.10(dd, J=6-14, 1H, =NOCH=).Proton NMR spectrum (350MHz, CDCl ₃ , ppm δ, Hz J): 2.90 (s, 6H, -N (CH ₃ ) ₂ ): 4.25 (dd, J = 2 = 6, 1H,): 4.73 ( dd, J = 2-14, 1H,

): 5.18 (dm J = 4, 1H, H in 6 position): 5.60 (dd, J = 4-9, 1H, H in 7 position): 6.53-6.75 (2d, J = 16, 2H, -CH = C H-): 6.88 (s, 1 H,

): 7.10 (dd, J = 6-14, 1H, = NOCH =).

2-benzhydryloxycarbonyl-3-methyl-8-oxo-7- [2- (2-trityl amino-thiazol-4-yl) -2-vinyloxyimino-acetamido] -5- Chia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer) is in the presence of N, N-dicyclohexylcarbodiimide (2.3 g) at 5-20 ° C. for 4 hours. Benzhydryl ester of 2- (2-tritylamino-thiazol-4-yl) -2-vinyloxyimino-acetyl acid (syn isomer) (4.6 g) with 7-ADCA and 4 of methylene chloride (40 cc) Prepared from dimethylaminopyridine (0.05 g).

After chromatographing with silica gel (200 g), a yellow foam material is obtained using methylene chloride.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ): 3400, 1785, 1725, 1690, 1640, 1525, 1495, 1450, 1040, 1000, 940, 755, 700.

) : 4.76(dd, J=2 -14, 1H,

) : 5.08(d,J=4, 1H , 6위치의 H) : 5.92(dd, J=4-9, 1H, 7위치의 H) : 6.85(s, 1H, 치아졸의 H) : 6.93(s, 1H, -COOCH) : 7.0(2, 1H, -NH-C(C₆H₅)₃).Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 2.12 (s, 3H, -CH ₃ ): 3.22-3.49 (2d, J = 18, 2H, -CH _2- ): 4.25 ( dd, J = 2-6, 1H,

): 4.76 (dd, J = 2 -14, 1H,

): 5.08 (d, J = 4, 1H, H in 6 position): 5.92 (dd, J = 4-9, 1H, H in 7 position): 6.85 (s, 1H, H of toothbrush): 6.93 ( s, 1H, -COOCH): 7.0 (2, 1H, -NH-C (C ₆ H ₅ ) ₃ ).

2- (2-tritylamino-thiazol-4-yl) -2-vinyloxyimino-acetic acid (syn isomer) is prepared by Belgian patent 869,079.

Example 46

2-benzhydryloxycarbonyl-3- {2- [5,6-dioxo-4- (2-hydroxyethyl) -1,4,5, 6-tetra hydro-1,2,4, -Triazin-3-yl] -thiovinyl} -7- [2- (2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo Anhydrous tetrahydrofuran (250 cc) of -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2.5 g) was cooled to -50 deg. Treated with crorosulfonyl isocyanate (11 cc).

The mixture is stirred for 55 minutes while slowly rising to -5 ° C. Saturated sodium bicarbonate solution (100cc) and ethyl acetate (250cc) are added. The aqueous layer is extracted with ethyl acetate (100 cc) and the combined organic extracts are washed with saturated saline solution (2 x 100 cc). Dry over magnesium sulfate and filter. Evaporate and dry the solvent under reduced pressure (30 mmHg, 4 kPa) (40 ° C.) to 2-benzhydryloxycarbonyl-3-{[4- (2-carbamoyloxyethyl) -5,6-dioxo-1 , 4,5,6-tetra hydro-1,2,4, -triazin-3-yl] -thiovinyl} -7- [2- (2-methoxyimino-2- (2-trimethylamino-) Chiazol-4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2.6 g) To yellow powder.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ): 3350, 2600, 1785, 1720, 1685, 1530, 1490, 755 and 700.

).Proton NMR spectrum (350 MHz, DMSOd ₆ , ppm δ, Hz J): 3.30 and 3.64 (2d, J = 18, 2H, -SCH _2- ): 3.84 (s, 3H, = NOCH ₃ ): 4.03 4.11 (2t, J = 5, 2 × 2H> NCH ₂ CH ₂ OC O) 5.24 (d, J = 4, 1H, H at 6 position): 5.77 (dd, J = 4 and 9, 1H, 7 position H): 6.71 (s, 1H, H of toothbrush): 6.94 (s, 1H, -CH ((C ₆ H ₅ ) ₂ ): 6.93 and 7.02 (AB, J = 16, 2H, -CH = CH- S): 7.15-7.60 (Mt, 25H, Directional): 8.25-8.80 (2S, 2H, -OCHONH ₂ ): 9.60 (d, J = 9, 1H, = CONH-C ₇ ): 12.60 (s, 1H, -N = C-OH or triazine

).

2-benzhydryloxycarbonyl-3- {2- [4- (2-carbamoyloxyethyl) -5,6-dioxo-1,4, 5,6-tetra hydro-1,2,4 , -Triazin-3-yl] -thiovinyl} -7- [2- (2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8- Formic acid (47 cc) of oxo-5-thia-1-aza-bicyclo [4, 2,0] oct-2-ene (syn isomer, Form E) (2.6 g) was diluted with distilled water (20 cc) and 50 DEG C. Heated for 20 minutes and further diluted with distilled water (27 cc) Filter the insoluble material and concentrate the filtrate under reduced pressure at 30 ° C. (5 mmHg: 0.67 kPa) The residue was triturated and dissolved in anhydrous ethanol (50 cc) and reduced to 40 ° C. ( Evaporate under 30 mmHg: 4 kPa) Repeat this procedure twice more, take the residue in ethanol (40 cc), filter, wash with water, and dry to obtain 7- [2- (2-amino-thiazol-4-yl) -2-. Methoxyimino-acetamido] -3- {2- [4- (2-carbamoyloxyethyl) -5,6-dioxo-1,4,5,6-tetra hydro-1,2,4 , -Triazin-3-yl] -thiovinyl} 2-Carboxy-7-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1.5 g) is obtained in the form of a creep powder. .

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3350, 2200, 1770, 1710, 1680, 1050 and 940.

).Proton NMR spectra (350 MHz, DMSOd ₆ , δ at Hz, Hz are J): 3.62 and 3.82 (2d, J = 18, 2H, -SCH _2- ): 3.86 (s, 3H, = NOCH ₃ ): 4.60 and 4.15 (2t, J = 5, 2 × 2H> NCH ₂ CH ₂ O-): 5.21 (d, J = 9, 1H, H at 6 position): 5.78 (dd, J = 4 and 9, 1H, 7 position H): 6.50 (s, Wide, 2H, -OCONH ₂ of Chiazole; 6.75 (s, 1H, H of Chisol): 6.92 and 7.08 (2d, J = 16, 2H, -CH = CH-s -): 7-7.50 (s, wide area, 2H, -NH ₂ of chiazole): 9.66 (d, J = 9, 1H, H, -CONH-C ₇ ): 12.62 (s, 1H,

).

2-benzhydryloxycarbonyl-3- {2- [5,6-dioxo-4- (2-hydroxyethyl) -1,4,5,6-tetrahydro-1,2,4, -Triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5- Chia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) can be obtained by the following method.

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino) to N, N-dimethylformamide (50 cc) of N, N-diisofurophylethylamine -Thiazol-4-yl) -acetamido] -8-oxo-3- (2-tosyloxyvinyl) -5-chai-1-aza-bicyclo [4.2.0] oct-2-ene (syn Isomer, Form E) (5.5 g) and 5,6-dioxo-4- (2-hydroxyethyl) -3-thioxo-perhydro-1,2,4-triazine (2.08 g) , N-dimethylmethylamide (150 cc) solution mixture is added at 60 ° C. for 15 minutes. The mixture is stirred at 60 ° C. for 3 hours and diluted with ethyl acetate (600 cc). The organic layer is washed with saturated brine (150cc), distilled water (3 × 150cc) and dried over magnesium sulfate. After filtration, concentrated to dryness at 40 ℃, reduced pressure (30mmHg, 4kPa).

The residue was chromatographed on a Melk Sealica gel (0.04-0.06 mm) column (6 cm in diameter and 30 cm in height) and the developing solution was 4 kPa in a mixture of 15:85 (volume) of cyclohexane and ethyl acetate (7.5 L). Develop under pressure. Collect 100 cc milk powder, combine 70 in milk powder 24 and concentrate to dryness under reduced pressure (30 mmHg, 4 kPa) (40 ° C.). 2-benzhydryloxycarbonyl-3- {2-5,6-dioxo-4- (2-hydroxyethyl) -1,4,5,6-tetrahydro-1,2,4-tri Azin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia- 1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (3.31 g) is obtained as a pale yellow solid.

Rf = 0.33 [Silica gel chromatography plate: 10:90 (volume) mixture of cyclohexane and ethyl acetate]

Infrared spectrum (CHBr): Characteristic bands (cm ⁻¹ ) are 3380, 1785, 1715, 1680, 1585, 1520, 1495, 1450, 940, 755 and 740.

Proton NMR spectrum (350 MHz, CDCl ₃ , ppm δ, Hz J): 3.44 and 3.60 (AB, J = 18, 2H, -SCH _2- ): 3.81 (mt, 2H, -CH ₂ OH): 4.00 (s, 3H, = NOCH ₃ ): 5.00 (dd, J = 4, 1H, H in 7 position): 6.70 (s, 1H, H of toothbrush): (6.81 (d, J = 15, 1H,- CH = CH-S)-): 6.90 (s, 1H, -CH (C ₆ H ₅ ) ₂ ) 5.72-7.6 (mt, directional, -CONH-, CH = HHS-, (C ₆ H ₅ ) ₃ CNH -).

Example 47

A solution of methylene chloride (10 cc) of trimylamino (0.38 cc) and 4-N, N-dimethylaminopyridine (0.05 g) formic anhydride (4.9 mmol) was prepared using G.A. Ola, Angew. Manufactured by Chem 91,649 (1 979).

2-benzhydryl oxycarbonyl-3- {2- [5,6-dioxo-4 (2-hydroxyethyl) -1,4,5, 6-tetrahydro-1,2,4-tri Azin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl-acetamido] -8-oxo-5-oxide-5 To anhydrous tetrahydrofuran (100 cc) of -chia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (2.5 g) was added under cooling to -10 ° C. The reaction mixture was stirred at 20 ° C. for 3 hours, filtered, and diluted with ethyl acetate (450 cc).

Wash 0.2N hydrochloric acid (50cc), distilled water (100cc), and saturated sodium bicarbonate solution (100cc) in this order. The organic phase is dried over magnesium sulphate, filtered and concentrated under 40 [deg.] C. pressure (30 mmHg, 4 kPa).

2-benzhydryl oxycarbonyl-3-2- [5,6-dioxo-4- (2-formyloxy ethyl) -1,4,5,6-tetrahydro-1,2,4-triazine -3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethyl-amino-thiazol-4-yl-acetamido] -8-oxo-5-oxide-5 -Cia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (2.7 g) is obtained as a brown powder.

Rf = 0.68 [silica gel chromatography: developing solution: 80:20 (volume) mixture of ethyl acetate and methanol]].

The crude product thus obtained (3.35 g) was dissolved in methylene chloride (50 cc) and N, N-dimethylacetamide (1.42 cc) was added. The mixture is cooled at -10 [deg.] C. and treated with phosphorus trichloride (0.1 cc) and after -10 [deg.] C., 20 minutes the reaction mixture is diluted with ethyl acetate (500 cc) and saturated sodium bicarbonate (150 cc). The organic layer was decanted, washed with distilled water (2 x 50 cc) and saturated brine (100 cc), dried over magnesium sulfate and filtered. Evaporate at 40 ° C. under reduced pressure (35 mmHg, 4.7 kPa), and residue (3.6 g) is chromatographed on a column of Melksilica gel (0.06-0.04 mm) (diameter 5 cm, height 30 cm) and is treated with cyclohexane under 40 kPa pressure. Develop with ethyl acetate (4 L) 40:60 (volume) mixture. Collect 50 cc of milk powder. The milk powder 38 to 76 is evaporated to dryness at 40 ° C. under reduced pressure (35 mmHg, 4.7 kPa). 2-benzhydryloxycarbonyl-3- {2-[5,6-dioxo-4- (2-formyloxyethyl) -1,4,5,6-tetrahydro-1,2,4- Triazin-3-yl] -thiovinyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia- 1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (1.3 g) is obtained as a pale yellow powder.

)Proton NMR spectra (350 MHz, DMSOd ₆ , ppm δ, Hz J): 3.65 and 3.88 (AB, J = 18, 2H, -SCH ₂ ): 3.84 (s, 3H, = NOCH ₃ ) 4.10 and 4.32 ( 2t, J = 5, 2 × 2H,> NCH ₂ CH ₂ OCHO): 5.21 (d, J = 4, 1H, H at 6 position): 5.75 (dd, J = 4 and 9, 1H, H at 7 position ): 6.72 (s, 1H, H of toothbrush): 6.94 (s, 1H, -CH (C ₆ H ₅ ) ₂ ): 6.93 and 7.02 (AB, J = 16, 2H, = CH = CH-S) : 7.1 to 7.5 (Mt, 25H, Directivity): 8.80 (s, Wide Area, 1H, (C ₆ H ₅ ) ₃ NH-): 9.60 (d, J = 9, 1H, -CONH-G): 12.60 (s , Wide area, 1H, = NN = C-OH or

)

The pale yellow substance (syn isomer, Form E) (1.25 g) is added to formic acid (15 cc), diluted with distilled water (4 cc), heated at 50 ° C. for 25 minutes, and further diluted with mid-water (11 cc). Insoluble material is filtered off and the filtrate is concentrated at reduced pressure (5 mmHg; 0.67 kPa) (30 ° C.). The residue was triturated in ethanol and evaporated under reduced pressure (40 mmHg, 4.7 kPa) at 40 ° C.

After repeating this operation four times, the solid residue is taken up in ethanol (20 cc), filtered, washed with isoprophyl ether (2 x 25 cc) and dried.

Dissolve in pure formic acid (10 cc) and heat the solution at 45 ° C. for 1 hour 30 minutes. Concentrate to dryness at 40 ° C. under reduced pressure (5 mmHg, 0.67 kPa). The residue was triturated and dissolved in anhydrous ethanol (30 cc) and evaporated at 40 ° C. under reduced pressure (30 mmHg, 4 kPa). Repeat this operation twice. 7- [2- (amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2- [5,6-dioxo-4- (2-formyl Oxyethyl) -1,4,5,6-tetra hydro-1,2,4-triazin-3-yl] -thiovinyl} -8-oxo-5-thia-1-aza-bicyclo [4.2 .0] Octet-2-ene (syn isomer, Form E) (0.54 g) is obtained as a yellow powder.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3400, 3200, 2200, 1775, 1710, 1680, 1530, 1040, 945.

).Proton NMR spectrum (350 MHz, DMSOd ₆ , ppm δ, Hz J): 3.62 and 3.82 (AB, J = 18, 2H, -SCH _2- ): 3.84 (s, 3H, = NOCH ₃ ): 4.15 4.32 (2t, J = 5, 2 × 2H, NCH ₂ CH ₂ -OCHO): 5.21 (d, J = 4, 1H, H in 6 position): 5.78 (dd, J = 4 and 9, 1H, 7 position H): 6.9 3 (s, 1H, H azole): 6.89 and 7.10 (2d, J = 16, 2H, -CH-CH = S-): 6.17 (s, wide area, 2H, -NH ₂ ) : 8.18 (s, 1H, HCOC-): 9.59 (d, J = 9, 1H, -CONH-C ₇ ): 12.60 (1, wide area, 1H,

).

2-benzhydryl oxycarbonyl-3- {2- (5,6-dioxo-4- (2-hydroxyethyl) -1,4,5, 6-tetrahydro-1,2,4- Triazine-3-yl] -thiovinyl} -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) It may be prepared in the same manner.

5,6-Dioxo-4- (2-hydroxyethyl) -perhydro-1,2,4-triazine- (7 g) is substituted with 2-benzhydryloxycarbonyl-7- [2-methoxy Mino-2- (2-trimethyl amino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza- To anhydrous N, N-dimethylmethylamide (490 cc) solution of bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (18 g) was added at 65 ° C. and added to N, N-diisopurophyll. Anhydrous N, N-Dimethylformamide (160 cc) solution of Chillamine (2.32 g) is introduced dropwise for 10 minutes. The reaction mixture is stirred at 65 ° C. for 2 hours, diluted with ethyl acetate (2 L) and washed with distilled water (4 × 500 cc). The organic layer is dried over magnesium sulfate and concentrated under reduced pressure (40 mmHg, 4.7 kPa) at 40 ° C. The residue is chromatographed on Melk Sealica gel (0.2-0.04 mm) (column diameter 4 cm) (200 g). Develop with a mixture of cyclohexane and ethyl acetate 20:80 (volume) and collect 250 cc milk powder. Concentrate dryness of the milk powder 6 at 40 ° C. under reduced pressure (35 mmHg, 4.7 kPa) to 2-benzhydryloxycarbonyl-3- {2- [5,6-dioxo-4- (2-hydroxy). 7) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethylamino- Chiazol-4-yl-acetamido] -8-oxo-5-oxide-5-thia-1-aza-expensive micro [4.2.0] oct-2-ene (syn isomer E type) (17.16 g To a pale yellow powder.

Infrared spectrum (KBr): Characteristic bands (cm ^-1 ) are 1800, 1720, 1685, 1525, 1495, 1450, 1045, 945, 755 and 700.

).Proton NMR spectra (350 MHz, DMSOd ₆ , ppm δ, Hz J): 3.60 and 4.28 (2d, J = 17.5, 2 × 1H, -S (O) CH _2- ): 3.57 and 3.88 (2Mt, 2 × 2H, NCH ₂ CH ₂ OH): 3.84 (s, 3H, = NOCH ₃ ) 5.04 (d, J = 4, 1H, H in 6 position): 5.84 (dd, J = 4 and 9, 1H, 7 position H): 6.96 and 7.09 (AB, J = 16, 2 × 1H, -CH = CH-S-) 7.15 to 7.60 (Mt, 25H, directional): 8.72 (s, 1H,

).

Example 48

2-benzhydryl oxycarbonyl-3- {2- (4- (2-hydroxyethyl) -5,6-dioxo-1,4,5, 6-tetrahydro-1,2,4- Triazin-3-yl] -thiovinyl} -7- [2-setamido-2- (2trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide- To anhydrous tetrahydrofuran (25cc) solution of 5-chia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, Form E) (2.05 g) at 22 ° C. (0.64 g) Was added and 15 ml of anhydrous tetrahydrofuran (5 cc) solution of acyl anhydride (0.4 cc) was introduced.

4-Dimethylaminopyridine (0.05 g) was dissolved in anhydrous tetrahydrofuran (1 cc), and the reaction mixture was stirred at 25 ° C for 10 minutes. Dilute with distilled water (50cc) and ethyl acetate (120cc), decanter the organic layer, wash sequentially with 0.5N hydrochloric acid (80cc), saturated sodium bicarbonate (80cc) and saturated brine (100cc), dry over magnesium sulfate, and depressurize to 40 ℃. Concentration under (30mMHg, 4kPa) affords the crude (2.05g) as a yellow powder. The crude product (2.5 g) obtained above was chromatographed on a column (4 cm in diameter and 30 cm in height) of Melx silica gel (0.04-0.06 mm) and developed into a 40:60 (volume) mixture of cyclohexane and ethyl acetate (31). do. Collect 100 cc milk powder and concentrate dry milk powder 11-26 at 40 ° C. at reduced pressure (30 mmHg, 4 kPa).

3- {2- [4- (2-acetoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thio Vinyl} -2-benzhydryl oxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-teeth A yellow foamy substance of [4,2,0] oct-2-ene (syn isomer, Form E) (1.84 g) is obtained as -1-aza-bicyclo.

Infrared spectrum (CHBr ₃ ): Characteristic band (cm ^-1 ) 3400, 2820, 1790, 1720, 1685, 1590, 1495, 1450, 1050, 940, 760, 740.

).Proton NMR spectrum (350MHz, DMSOd ₆ , ppm δ, Hz J): 3.63 and 3.88 (AB, J = 18, 2H, -SCH _2- ): 3.83 (s, 3H, = NOCH ₃ ): 4.06 ( t, J = 5, 2H, ∧N-CH ₂ CH ₂ OC OCH ₃ ): 4.23 (t, J = 5, 2H,> NCH ₂ -CH ₂ OCOCH ₃ ): 5.21 (d, J = 4, 1H, H at 6 position: 5.76 (dd, J = 4 and 9, 1H, H at 7 position): 6.71 (s, 1H, H of toothazole): 6.91 (d, J = 16, -CH = CH-S -): 6.93 (s, 1H, -CH (C ₆ H ₅ ) ₂ ): 7.0 (d, J = 16, 1H, -CH = CH-S-): 7.2 to 7.5 (mt, 25H, directional): 9.60 (d, J = 9, 1H, -CONH-): 12.58 (S, wide 1H, = NN = C-OH or

).

The pale yellow foam type product (syn isomer E type) (1.8 g) was dissolved in formic acid (40 cc), distilled water (15 cc) was added, and the reaction mixture was heated at 60 ° C. for 30 minutes, filtered, and then mixed at 40 ° C. (5 mmHg, 0.67 kPa). Concentrated to dryness).

The residue was triturated and dissolved in ethanol (50 cc), evaporated under reduced pressure (30 mmHg, 4 kPa) at 40 ° C., and this operation was repeated twice more. The residue is dissolved in boiling ethanol (150 cc), the filtrate is filtered and the filtrate is left to cool at 5 ° C. for 2 days. The solids were filtered off, washed with diethyl ether (20 cc) and dried to afford 3- {2- [4- (2-acetoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro- 2,2,4-triazin-3-yl] -thiovinyl} -7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -8-oxo -5-Cia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.65 g) is obtained as a pale yellow powder.

Infrared Spectrum (KBr): Characteristic bands (ccm- ¹ ) are 3320, 3220, 3150, 2300, 1780, 1740, 1720, 1680, 1625, 1590, 1535, 1375, 1310, 1040 and 950.

).Proton NMR Spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 2.0 (s, 3H, CH ₃ CO _2- ): 3.63 and 3.82 (AB, J = 18, 2H, -SCH _2- ) : 3.85 (s, 3H, = NOCH ₃ ): 4.08 (t, J = 5, 2H,> NCH ₂ OCOCH ₃ ): 4.25 (t, J = 5, 2H,> NCH ₂ CH ₂ OCOCH ₃ ): 5.20 ( d, J = 4, 1H, H at 6 position): 5.78 (dd, J = 4 and 9, 1H, H at 7 position): 6.73 (s, 1H, H of toothbrush): 6.90 (d, J = 16, 1H, -CH = CH-S-): 7.12 (d, J = 16, 1H, -CH = CH-S-): 7.18 (S, wide area, 2H, -NH ₂ ): 9.60 (s, J = 9, 1H, -CONH-C ₇ ): 12.6 (s, wide area, 1H,

).

Example 49

A solution of methyl chloride (20 cc) of N, N-dihexylcarbodiimide (0.72 g) was added to anhydrous methyl chloride (30 cc) solution of N-3 grade butoxycarbonylglycine (1.12 g). Add 5 minutes at and stir at 0 ° -5 ° C. for 30 minutes. The filtrate was washed with 2-benzhydryloxycarbonyl-3- {2- [5,6-dioxo-4- (2-hydroxyethyl) -1,4,5,6-tetrahydro-1,2, 4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5 To a tetrahydrofuran (70 cc) solution of -oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (3 g) is added for 10 minutes. Cool to 0 ° C. The reaction mixture was stirred at 20 ° C. for 45 minutes, diluted with ethyl acetate (500 cc), washed with distilled water (2000), saturated sodium bicarbonate solution (100 cc), distilled water (1100 cc) and saturated brine (50 cc), and the organic layer was dried over sodium sulfate, After filtration, the mixture was concentrated under reduced pressure (30 mmHg, 4 kPa) at 40 ° C. 2-benzhydryloxycarbonyl-3- [2- (2-N-tert-butoxycarbonylgrisyloxy-ethyl) -5,6-dioxo-1,4,5,6-tetrahydro -1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2triethylamino-thiazol-4-yl) -acetamido] -8 -Oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (3.45 g) is obtained as a brown powder. This crude product (3.3.g) is dissolved in anhydrous methylene chloride (45 cc), cooled to -10 deg. C, treated with N, N-dimethylacetamide (1.24 cc) and treated with phosphorus trichloride (0.6 cc). After 1 hour 30 minutes (at -10 ° C), the mixture was diluted with ethyl acetate (600 cc), washed sequentially with saturated aqueous sodium bicarbonate solution (100 cc), distilled water (2 x 100 cc) and saturated brine (2 x 200 cc), and dried over sodium sulfate. Filtered. The organic solution was concentrated to dryness at 40 ° C. under reduced pressure (30 mmHg, 4 kPa), and the residue was chromatographed on a column (4 cm in diameter and 30 cm in height) of Melksilica gel (0.04-0.062 mm).

Cyclohexane and ethylethyl (1.51) were developed under a 40 kPa pressure with a 10:90 (volume) mixture. Collect 50 cc of milk powder. Combine milk powders 7 to 22 and concentrate to dry at 30 ° C. under reduced pressure (30 mm Hg, 4 kPa). 2-benzhydryloxycarbonyl-3- {2- [4- (N-2-tert-butoxycarbonyl-glycyloxyethyl) -5,6-dioxo-1,4,5, 6-tetrahydro-1,2,4-triazine-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) acetami 8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1.44 g) is obtained as a yellow powder.

Infrared spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 1785, 1685, 1530, 1495, 1445, 1160, 1030, 945, 755 and 700.

).Boroton NMR Spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 1.36 (s, 9H, (CH ₃ ) ₃ CC-): 3.25 and 3.86 (2d, J = 18, 1H, -SCH ₂ 3.65 (d, J = 9, 2H, -CONH ₂ NH-): 3.84 (s, 3H, = NOCH ₃ ): 4.05 and 4.26 (st, J = 5, 2 × 2H, = NCH ₂ CH ₂ OCO-): 5.23 (d, J = 4, 1H, H at position): 5.56 (d, J = 9, 1H, -CH ₂ NHCO-): 5.76 (dd, J = 4 and 9, 1H, 7 position H): 6.71 (s, 1H, H of toothbrush): 6.91 (s, 1H, -CH (C ₆ H ₅ ) ₂ ): 6.90 and 7 (2d, J = 16, 2H, -CH = CH- S-): 7.15-7.5 (mt, 25H, Directional): 8.78 (s, Wide Area, 1H, (C ₆ H ₅ ) ₃ CNH-): 9.60 (d, J = 9, 1H, -CONH-): 12.60 (s, 1H, = NH = C-OH or

).

Formic acid (15 cc) of the yellow powder-type product (syn isomer, E-type) (1.5 g) is diluted with distilled water (4c c) and heated at 50 ° C. for 30 minutes. Dilute with distilled water (11 cc), filter the insoluble material, and distill the filtrate under reduced pressure (30 mmHg, 0.67 kPa) at 30 ° C. The residue was dissolved in anhydrous ethanol (60 cc) and evaporated at 40 ° C. under reduced pressure (30 mmHg: 4 kPa). Repeat all three operations. The residue is taken up in isoprofil ether (50 cc), filtered, washed with ethyl ether (3 x 20 cc) and dried. 7- [2- (2 amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3-2-5,6-dioxo-4- (2-glycyl Oxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -8-oxo-5thia-1-aza-bicyclo [4, 2,0] Formate (0.8 g) of oct-2-ene (syn isomer, Form E) is obtained as a pale yellow powder.

Infrared spectrum (KBr): Characteristic band (c ^-1 ) is 3350, 2200, 1755, 1705, 1675, 1580, 1530, 1035.

) : 5.10(d, J=4, 1H, 6위치에서 H) : 5.67(dd, J=4와 9, 1H, 7위치에서 H) : 6.44(d, J=16, 1H, -CH=CH-S-) : 6.72(s, 1H, 치아졸의 H) : 7.18(S, 광역 3H, 치아졸의 -NH₃ ⁺) : 8.12(s, 1H, HCO₂-) : 5.96(d, J=9, 1H, -CONH-C₇).Proton's NMR spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 3.50 and 3.62 (AB, J = 18, 2H, -SCH _2- ): 3.72 (mt, 2H, -COCH ₂ NH ₂ ) : 3.82 (s, 3H, = NOCH ₃ ): 4.12 and 4.40 (2Mt, 2 × 2H,

): 5.10 (d, J = 4, 1H, H at 6 position): 5.67 (dd, J = 4 and 9, 1H, H at 7 position): 6.44 (d, J = 16, 1H, -CH = CH -S-): 6.72 (s, 1H, H of toothbrush): 7.18 (S, wide 3H, -NH ₃ ⁺ of toothazole): 8.12 (s, 1H, HCO _2- ): 5.96 (d, J = 9, 1H, -CONH-C ₇ ).

Example 50

Methylsulfonyyl chloride (0.28 cc) and triethylamine (0.2 cc) were added at −20 ° C. in 3- {2- [4- (2-aminoethyl-5,6-dioxo-1,4,5, 6-tetrahydro 1,2,4-triazin-3-yl] -thiovinyl} -2 -benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trimethylamino-thia Zol-4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2 g) ( Solution of tetrahydrofuran (prepared by the method of example 28) and allowed to rise to -5 ° C. for 1 h 30 min.The mixture is added to water (500 cc) with vigorous stirring and filtered. Wash and dry with ethanol (30 cc) and diethyl ether (10 cc) Pre-fixed to melksilica gel (0.06-0.2 mm) (5 g) and onto a column (0.5 cm in diameter and 10 cm in height) of the same silica gel (10 g). Perform the chromatography The development is carried out with ethyl acetate (200 cc) Collect 15 cc milk powder and weigh 5 to 11 milk powder. Crude 2-benzhydryloxycarbonyl-3- {2- [6,6-dioxo-2-methylsulfonyl-amino-ethyl) -1,4,5,6-tetrahydro-1,2, 4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5 -Cia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.3 g) is obtained as a yellow powder.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3300, 1790, 1715, 1695, 1590, 1525, 1495, 1450, 1320, 1160, 1035, 945, 755, 700.

The yellow powder-type product (syn isomer, E-type) (0.7 g) is treated with a mixture of formic acid (10 cc) and water (5 cc) at 50 ° C. for 30 minutes. The mixture is filtered and the filtrate is concentrated at 50 ° C., 20 mm Hg (2.7 kPa) and the residue is taken up in ethanol (4 × 50 cc) and evaporated to dryness at 20 ° C., 20 mm Hg. The solid was triturated in ethanol (50 cc), filtered and washed with diethyl ether (2 x 10 cc) and 7- [2- (2-amino-thiazol-4-yl) 2-methoxyimino-acetamido]- 2-carboxy-3- [2- 5,6-dioxo-4- (2-methylsulfonylaminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazine-3 -Yl-thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2ene (syn isomer, Form E) (0.4 g) Yellow powder.

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3400, 3300, 3200, 1775, 1710, 1680, 1590, 1530, 1320, 1150, 1140 and 945.

H-CH₂-) : 5.17(d, J=4, 1H, 6위치에서 H) : 5.73(dd, J=4와 9, 1H, 7위치에서 H) : 6.74(s, 1H, 치아졸의 H) : 6.79(d, J=16, 1H, -CH=CHS-) ‥7.17(s, 2H, -NH₇) : 9.60(d, J=9, 1H, -CONH-).Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 2.90 (s, 3H, -SO ₂ CH ₃ ): 3.20 (mt, 2H, -CH ₂ NH-): 3.61 and 3.61 3.78 (2d, J = 18, 2H, -SCH _2- ): 3.96 (s, 3H, = NOCH ₃ ): 3.96 (t, J = 5, 2H,

H-CH _2- ): 5.17 (d, J = 4, 1H, H at 6 position): 5.73 (dd, J = 4 and 9, 1H, H at 7 position): 6.74 (s, 1H, of toothbrush H): 6.79 (d, J = 16, 1H, -CH = CHS-) .7.17 (s, 2H, -NH ₇ ): 9.60 (d, J = 9, 1H, -CONH-).

Example 51

A solution of methylene chloride (10 cc) of N, N'-dihexylcarbodiimide (0.5 g) was added to a solution of methylene chloride (20 cc) of N -tert-butoxycarbonylglycine (0.84 g). Cool at 10 ° C and add dropwise for 10 minutes. The mixture is stirred at 5 ° C. for 30 minutes and filtered. The filtrate was washed with 3- {2- [4- (2-aminoethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine- at 5 ° C. for 20 minutes. 3-yl] -thiovinyl} -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8 Oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2.04 g) and tricylylamine (0.34 cc) To a solution of dimethylaminopyridine (50 mg) of methylene chloride (100 cc) is added dropwise. The temperature is raised to 20 ° C. with stirring and after 1 h the mixture is concentrated at 20 ° C. to 20 cc at 20 mmHg (2.7 kPa). The residue is diluted with ethyl acetate (70 cc) and the mixture is washed with saturated aqueous sodium bicarbonate (2X 60 cc) and water (3X 50 cc), dried over sodium sulfate and filtered. Concentrate at 20 ° C., 20 mmHg (2.7 kPa), and add the residue to tetrahydrofuran (10 cc) and leave the mixture at 4 ° C. for 48 hours. The filtrate is concentrated to dryness at 20 ° C., 20 mm Hg (2.4 kPa). The residue was triturated and dissolved in diethyl ether (50 cc), filtered and dried to give 2-benzhydryloxycarbonyl-3- {2- [4- (tert-butoxycarbonylglycosylamino-ethyl)- 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2- Trimethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (1.72 g) is obtained as a brown powder.

N-CH₂-CH₂NH-) : 3.54(t, J=5, 2H,

NCH₂CH₂NH-) : 3.63(d, J=5, 2H, -COCH₂NH-) : 3.6과 4.3(2d, J=18, 2H, -SCH₂-) : 3.86(s, 3H, =NOCH₃) : 5.06(d, J=4, =H, H₆) : 5.86(dd, J=4와 9, 1H, H₇) : 6.78(s, 1H, 치아졸의 H) : 6.85와 7.12(2d, J=16, 2H, -CH=CH-) : 6.97(s, 1H, -COOCCHC) : 7.18(s, 1H, 치아졸의 NH) : 8.0(t, J=5, 1H, -COCH NH-) : 8.75(s, 광역, 1H, NCH₂CH₂NH-) : 9.03(d, J=9, 1H, -CONH-) : 12.6(s, 1H, 트리아진의 -NH).Infrared Spectrum (KBr): Characteristic band (cm ^-1 ) is 3380, 1800, 1710, 1690, 1590, 1515, 1495, 1450, 1210, 1165, 1050, 1040, 945, 755 and 700. Proton NMR spectrum (350MHz , DMSO d ₆ , ppm is δ, Hz is J): 1.35 (s, 9H,-(CH ₃ ) ₃ ): 3.33 (m, 2H,

N-CH ₂ -CH ₂ NH-): 3.54 (t, J = 5, 2H,

NCH ₂ CH ₂ NH-): 3.63 (d, J = 5, 2H, -COCH ₂ NH-): 3.6 and 4.3 (2d, J = 18, 2H, -SCH _2- ): 3.86 (s, 3H, = NOCH ₃ ): 5.06 (d, J = 4, = H, H ₆ ): 5.86 (dd, J = 4 and 9, 1H, H ₇ ): 6.78 (s, 1H, H of toothbrush): 6.85 and 7.12 (2d, J = 16, 2H, -CH = CH-): 6.97 (s, 1H, -COOCCHC): 7.18 (s, 1H, NH of chiazole): 8.0 (t, J = 5, 1H, -COCH NH-): 8.75 (s, broad, 1H, NCH ₂ CH ₂ NH-): 9.03 (d, J = 9, 1H, -CONH-): 12.6 (s, 1H, -NH of triazine).

The brown powder (syn isomer, Form E) (1.65 g) is treated with a solution of methylene chloride (30 cc) and dimethylacetamide (0.56 cc) with phosphorus trichloride at 10 ° C. for 1 hour 30 minutes.

The mixture was diluted with methylene chloride (150 cc), washed with half saturated sodium bicarbonate (2 x 100 cc) and half saturated saline (2 x 200 cc), dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C, 20 mmHg (2.7 kPa). Let's do it.

The product is chromatographed on a column (2 cm in diameter and 34 cm in height) of melt silica gel (0.06-0.2 mm) (50 g).

It is developed with a mixture of 50:50 (volume), 25:75 (volume) (500c c) of hexane and ethylacetate (250cc) and ethylacetate (1.5 ₁ ). Collect 60 cc milk powder and concentrate dryness from dry milk 9 to 24 to 2-benzhydryloxycarbonyl-3- {2- [4- (tert-butoxycarbonylgrisylamino-ethyl) -5,6 -Dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethylamino- Chiazol-4-yl] -acetamido] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.78 g) Obtained as a cream foam.

Infrared spectrum (KBr): Characteristic bands (cm ^-1 ) are 3400, 3300, 1785, 1710, 1680, 1590, 1530, 1495, 1450, 1200, 1165, 1050, 950, 755 and 700.

NCH₂CH₂-NH-) : 3.45(d, J=5, 2H, -COCH₂NH) : 3.65와 3.88(2d, J=16, 2H, -SCH₂-) : 3.85(t, J=6, 2H,

NCH₂CH₂NH-) : 3.85(s,3H, =NOCH₃) : 5.24(d, J=4, H₆) : 5.76(dd, J=4와 9, H₇) : 6.92와 7.00(2d, J=16, 2H, -CH=CH-) : 6.93 (s,

) : 7.79(t, J=5, 1H, -CH₂NHCC-) : 8.80(s, 치아졸의 NH) : 9.59(d, J=9, -CONH-) : 12.53(s, 1H, 트리아진의 -NH-).Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 1.38 (s, 9H, -C (CH ₃ ) ₃ ): 3.30 (m, 2H,

NCH ₂ CH ₂ -NH-): 3.45 (d, J = 5, 2H, -COCH ₂ NH): 3.65 and 3.88 (2d, J = 16, 2H, -SCH _2- ): 3.85 (t, J = 6 , 2H,

NCH ₂ CH ₂ NH-): 3.85 (s, 3H, = NOCH ₃ ): 5.24 (d, J = 4, H ₆ ): 5.76 (dd, J = 4 and 9, H ₇ ): 6.92 and 7.00 (2d , J = 16, 2H, -CH = CH-): 6.93 (s,

): 7.79 (t, J = 5, 1H, -CH ₂ NHCC-): 8.80 (s, NH of chiazole): 9.59 (d, J = 9, -CONH-): 12.53 (s, 1H, triazine -NH-).

The solution dissolved in a mixture of formic acid (15 cc) and water (15 cc) of the cream foam (syn isomer, E type) (0.73 g) was treated at 50 ° C. for 30 minutes. Concentrate to dryness at 50 ° C., 0.05 mmHg (0.007 kPa), and remove the residue in ethanol (3 × 150 cc) and evaporate at 20 ° C., 20 mmHg (2.7 kPa) each time. Solids are taken at ethanol (25 cc) 45 ° C. and the mixture is stirred for 30 minutes. Cool and filter. 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carbocy- {3- [2-5,6-dioxo-4 after drying -(2-Glycosylaminoethyl) -1,4,5,6-tetra-1,2, -triazin-3-yl] -thiovinyl-8-oxo-5-thia-1-avava-expensive The micro [4,2,0] oct-2-ene (syn isomer, Form E) (0.39 g) is obtained as a yellow powder.

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3700, 2200, 765, 1705, 1675, 1610, 1585, 1530, 1035 and 930.

CH₂N

와-COCH₂N

) : 3.85(s, =NOCH₃) : 5.12(d, J=4, H₆) : 5.67(dd, J=4와 9, H₇) : 6.35(d, J=16, -CH=CHS-) : 6.73 (s, 치아졸의 H) : 7.15(s, 광역, -NH₂) : 8.2(s, 포르메이트의 H) : 8.6(m, -CH₂NHCO-) : 9.54(d, J=0, -NHCO-).Proton Tone NMR Spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 3.2-3.6 (m, 8H, = SCH _2- ,

CH ₂ N

And -COCH ₂ N

): 3.85 (s, = NOCH ₃ ): 5.12 (d, J = 4, H ₆ ): 5.67 (dd, J = 4 and 9, H ₇ ): 6.35 (d, J = 16, -CH = CHS- ): 6.73 (s, H of chiazole): 7.15 (s, wide, -NH ₂ ): 8.2 (s, H of formate): 8.6 (m, -CH ₂ NHCO-): 9.54 (d, J = 0, -NHCO-).

3- {2- [4- (2-aminoethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl } -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide- 5-Cia-1-aza-bicyclo [4,2,0] -oct-2-ene (syn isomer, Form E) can be obtained as follows.

A solution of p-toluenesulfonic acid hydrate (1.14 g) was added to 2-benzhydryloxycarbonyl-3- {2- [4- (2-tert-butoxycarbonyl-amino-ethyl) -5,6- Dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-trimethylamino- Chiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) To a solution of acetonitrile (45 cc) (3.36 g) (prepared as described in Example 28) was added dropwise at 40 ° C. for 10 minutes. The mixture is stirred at 40 ° C. for 2 hours and cooled. The half-saturated sodium bicarbonate solution (100 cc) was added, stirred vigorously for an hour, filtered and dried to obtain 3- {2- [4- (2-aminoethyl-5,6-dioxo-1,4,5,6- Tetrahydro-1,2,4-triazine-3-yl] -thiovinyl} -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol -4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (2.73 g) is obtained as a brown powder.

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) range from 3250 to 2300, 1800, 1715, 1685, 1595, 1520, 1500, 1450, 1215, 1180, 1040, 945, 755 and 700.

CH₂CH₂-NH₂) : 3.63과 4.30(2d, J=18, 2H, -SCH₂-) : 3.86(s, 3H, =NOCH₃) : 4.09(t, J=6, 2H,

NCH₂CH₂) : 5.07(d, J=4, H₆) : 5.87(t, J=4와 9, H₇) : 6.80(s, 치아졸의 H) : 6.90(s,-COOCH

) : 7.07과 7.13(2d, J=16, -CH=CH-) : 9.0(d, J=9, -NHCO-) : 12.62(s, 광역 : 치아졸의 -NH-).Proton's NMr spectrum (350 MHz, DMSO, d ₆ , ppm is δ, Hz is J): 3.08 (m, 2H,

CH ₂ CH ₂ -NH ₂ ): 3.63 and 4.30 (2d, J = 18, 2H, -SCH _2- ): 3.86 (s, 3H, = NOCH ₃ ): 4.09 (t, J = 6, 2H,

NCH ₂ CH ₂ ): 5.07 (d, J = 4, H ₆ ): 5.87 (t, J = 4 and 9, H ₇ ): 6.80 (s, H of toothbrush): 6.90 (s, -COOCH

): 7.07 and 7.13 (2d, J = 16, -CH = CH-): 9.0 (d, J = 9, -NHCO-): 12.62 (s, wide area: -NH- of toothbrush).

Example 52

3- {2- [4- (2-aminoethyl) -5,6-dioxo-1 in urea dissolved in water (1.5 cc) and methyl chloroformate (0.16 cc) , 4,5,6-tetrahydro-1,2,4-triazine-3-yl] -thiovinyl} -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2 -Triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] -oct-2-ene ( Syn isomer, Form E) (2 g) was added to a solution dissolved in tetrahydrofuran (60 cc) with stirring at 20 ° C. The mixture was stirred at 20 ° C for 1 hour 30 minutes, methylchloroformate (0.32cc) was added, and after 1 hour 30 minutes, the mixture was distilled off with tetrahydrofuran (100cc), the mixture was dried over sodium sulfate, filtered and 30 ° C. Concentrate to dryness at 20 mmHg (2.7). The product is fixed on Melk Sealica gel (0.06-0.2 mm) (5 g) and subjected to chromatography on a column of gel (25 g) (1.5 cm in diameter, 15 cm in height). The developing solution is developed with 40:60 (volume), 20:80 (500cc) and ethyl acetate (500cc) of cyclohexane and ethyl acetate (500cc) and a 25 ° C. milk powder is collected.

Dry milk 19 to 32 are evaporated to dryness at 20 ° C., 20 mmHg (2.7 kPa). 2-benzhydryloxycarbonyl-3- {2- [5,6-dioxo-4- (2-methoxycarbonylaminoethyl) -1,4,5,6-tetrahydro-1,2 , 4-triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethylaminothiazol-4-yl) -acetamido] -8-oxo-5 -Cia-1-aza-bicyclo [4,2,0] -oct-2-ene (syn isomer, Form E) (0.7 g) is obtained as a yellow powder.

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3400, 3300, 1790, 1720, 1690, 1590, 1525, 1495, 1450, 1040, 755, 740 and 700.

The mixture of the yellow powder product (syn isomer, Form E) (0.7 g), formic acid (10 cc) and water (5 cc) was treated at 50 ° C. for 40 minutes. After filtration and concentrated to dryness at 30 ° C., 0.05 mm Hg (0.007 kPa), the residue was taken up in ethanol (4 × 50 cc) and the mixture was concentrated to dry at 20 ° C., 20 mm Hg (2.7 kPa) each time. The residue is again dissolved in ethanol (30 cc), filtered off, washed with diethyl ether (2 × 20 cc) and dried.

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2- [5,6-dioxo-4- (2 -Methoxycarbonylaminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -8-oxo-5-thia-1-aza Bicyclo 4,2,0 oct-2-ene (syn isomer, Form E) (0.35 g) as yellow powder.

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3340, 3210, 3100, 2200, 1770, 1685, 1625, 1590, 1530, 1035 and 945.

) : 5.19(d, J=4, 1H, 6위치에서 H) : 6.74(s, 1H, 치아졸의 H) : 9.58(d, J=9, 1H, =NNHCO- 혹은

).Proton NMR spectrum (350 MHz, DMSO, d ₆ , ppm δ, Hz J): 3.55 (s, 3H, -COOCH ₃ ): 3.62-3.79 (2d, J = 18, 2H, -SCH ₂ ): 3.85 -3.93 (mt, 5H, = NOCH ₃ and

): 5.19 (d, J = 4, 1H, H at 6 position): 6.74 (s, 1H, H of toothbrush): 9.58 (d, J = 9, 1H, = NNHCO- or

).

3- {2- [4- (2-aminoethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl } -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia- 1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) can be prepared as follows.

2-benzhydryloxycarbonyl-3- {2- [4- (tert-butoxycarbonyl-amino-ethyl) -5,6-dioxo-1,4,5,6-tetrahydro -1,2,4-triazine-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethylamino-thiadiazol-4-yl) -acetamido] -8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (25 g) (obtained by the method of Example 28) Acetonitrile (170 cc) solution is treated with acetonitrile (100 cc) solution of -toluenesulfonic acid (8.4 g) at 40 DEG C for 1 hour. The rubbery precipitate is separated by decantation and treated with stirring with saturated sodium bicarbonate (800 cc). Filter, wash with water (2 x 50 cc) and dry in air.

3- {2- [4- (2-aminoethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl } -2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5-thia- 1-Aza-bicyclo [4,2,0] -oct-2-ene (syn isomer, Form E) (15.3 g) is obtained as a yellow powder.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3400, 3150, 2200, 1785, 1715, 1690, 1585, 1520, 1495, 1445, 1205, 1180, 1160, 1030, 940, 750, 700.

Example 53

The tetrahydrofuran (25 cc) solution of the yellow powder product (syn isomer, Form E) (2 g) obtained in Example 52 was treated with methyl isocyanate (0.35 cc) at 4 ° C. The mixture is stirred at 5 ° C. for 2 hours. Concentrate to dryness at 20 ° C., 20 mmHg (2.7 kPa), and remove the residue into diethyl ether (20 cc) and filter. Yellow powder (1.4g) is fixed to Melk Sealica gel (0.06-0.2mm) (10g) and chromatographed on column (1.5cm diameter, 15cm height) of Melk Sealica gel (0.06-0.2mm) (20g). Develop with a 20:80 (volume) mixture of cyclohexane and ethyl acetate (200 cc) and ethyl acetate (500 cc) and collect the 25 cc milk powder. Dry matter 15 to 25 are evaporated to dryness at 20 ° C., 20 mmHg (2.7 kPa).

2-benzhydryloxycarbonyl-3- {2- [5,6-dioxo-4- [2- (3-methylureido) -ethyl] -1,4,5,6-tetrahydro-1 , 2,4-triazin-3-yl] -thiovinyl} -7- [methoxyimino-2- (2-trimethylamino-thiazol-4-yl) -acetamido] -8-oxo- 5-Tia-1-aza-bicyclo [4,2,0] -oct-2-ene (syn isomer, Form E) (0.5 g) is obtained as a yellow powder.

Infrared spectrum (KBr): characteristic band (cm ^-1 ): 3400, 1785, 1710, 1685, 1585, 1535, 1495, 1445, 1030, 940, 760, 700.

The mixture of yellow powder (syn isomer, Form E) (0.5 g), formic acid (8 cc) and water (4 cc) was treated at 50 ° C. for 40 minutes, filtered and concentrated to dryness at 30 ° C., 0.05 mm Hg (0.007 kPa). The residue is dissolved in ethanol (4 × 50 cc) and concentrated to dryness at 20 ° C., 20 mm Hg (2.7 kPa). The residue is dissolved in ethanol (40 cc), filtered and washed with diethyl ether (2 × 10 cc) and dried.

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2-[5,6-dioxo-4- [2 -(3-methylureido) -ethyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -thiovinyl} -8-oxo-5-thia-1 Aza-bicyclo [4,2,0] -oct-2-ene (syn isomer, Form E) (0.3 g) is obtained as a yellow powder.

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3320, 3200, 1775, 1710, 1680, 1635, 1585, 1535, 1040 and 945.

NCH₃) : 3.60와 3.73(2d, J=18, 2H, -SCH₂-) : 3.85(s, 광역, 5H =NOCH와₃

NCH₂-) :5.18(d, J=4, 1H, H₆) : 5.74(dd, J=4와 9, 1H, H₇) : 6.09(t, J=6, 1H, -NH- CH₂) : 6.74(s, 1H, 치아졸의 H) : 6.82와 7.62(2d, J=16, 2H, -CH=CH-) : 9.58, J=9, 1H, -CONH-) : 12.52(s, 1H, 치아졸의 -NH-.Proton's NMR spectrum (350 MHz, DMSO, d ₆ , ppm is δ, Hz is J): 3.30 (m, 5H, -CH ₂ NH and

NCH ₃ ): 3.60 and 3.73 (2d, J = 18, 2H, -SCH _2- ): 3.85 (s, wide area, 5H = NOCH and ₃

NCH _2- ): 5.18 (d, J = 4, 1H, H ₆ ): 5.74 (dd, J = 4 and 9, 1H, H ₇ ): 6.09 (t, J = 6, 1H, -NH-CH ₂ ): 6.74 (s, 1H, H of toothbrush): 6.82 and 7.62 (2d, J = 16, 2H, -CH = CH-): 9.58, J = 9, 1H, -CONH-): 12.52 (s, 1H, -NH- of chiazole.

Example 54

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2--(5,6-dioxo-4-formylmethyl -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0 A pyridine (30 cc) solution of] -oct-2-ene (syn isomer, Form E) (1.19 g) and cisacamine hydrochloride (0.247 g) is stirred at 50 ° C. for 30 minutes. The resultant was concentrated to dryness at 30 DEG C, 0.05 mmHg (0.007 kPa), the residue was taken up in ethanol (20 cc), and the product was filtered and washed with ethanol (2 x 20 cc) and dimethyl ether (2 x 20 cc).

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2-[5,6-dioxo-1,4, 5,6-tetrahydro-4- (2-thiaziridin-2-yl) -ethyl] -1,2,4-triazin-3-yl) -thiovinyl} -8-oxo-5-thia- The pyridine salt of 1-aza-bicyclo [4,2,0] -oct-2-ene (syn isomer, Form E) (1.3 g) is obtained in the form of a yellow powder.

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3400, 3280, 3200, 2000, 1775, 1410, 1680, 1610, 1380, 1035, 750 and 685.

Proton to NMR spectra (350 MHz, COOD, ppm δ, Hz J): 6.04 (d, J = 4, H at position 7): 7.257 and 7.78 (2d, J = 16, 2H, -CH = CH- ): 7.50 (s, 2H, H of toothazole).

Example 55

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2--(5,6-dioxo-4-formylmethyl -1,4,5,6-tetrahydro-1,2,5-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0 ] -Oct-2-ene (syn isomer, Form E) (1.78 g) A mixture of pyridine (50 cc) and hydroxylamine hydrochloride (0.42 g) is heated at 50 ° C. for 20 minutes. Concentrate to dryness at 30 ° C., 0.05 mmHg (0.007 kPa). The residue is taken up in ethanol (20 cc) and the product is filtered off, washed with ether (2 x 20 cc) and dried. The resulting solids (1.3 g) were heated in water at 60 ° C., some insoluble material was filtered off, the filtrate was cooled and the pH was added to acetic acid (3 cc) to pH 3. The mixture is heated to 70 ° C. to elute. Filter and allow to 20 ° C. It is left for 2 hours at 4 ° C, filtered and dried. 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido [-2-carboxy-3- {2- (5,6-dioxo-4- (2 -Hydroxyimino-ethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-expensive Micro [4,2,0] -oct-2-ene (synsyn, E and syn, Anti), E isomer (0.8 g) are obtained in the form of a cream powder.

Infrared Spectrum (KBr): Characteristic bands (cm ^-1 ) are 3700, 3200, 1770, 1710, 1680, 15 85, 1530, 1040 and 940.

Proton NMR spectrum (350MHz, CF ₃ COOD, ppm δ, Hz is J): 3.89 (s, 3H, -OCH ₃ ): 5.39 (d, J = 4, 1H, H at 6 positions): 6.04 ( d, J = 4, 1H, H at 7 positions): 7.28 and 7.77 (2d, J = 16, 2H, -CH = CHS): 7.50 (s, 1H, H of azole).

Example 56

2-benzhydryloxycarbonyl-3- [2- (4-2,2-dimethoxyethyl) -5,6-dioxo-1,4, 5,6-tetrahydro-1-2-4 -Triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5- Chia-1-aza-bicyclo [4,2,0] oct-2-ene (syn, isomer, Form E) (2.9 g), tetrahydrofuran (50 cc) and methoxyamine hydrochloride (0.49 g) Heat at reflux for 24 hours. Concentrate to dryness at 30 ° C., 20 mmHg (2.7 kPa). The residue is triturated and dissolved in water (20 cc), filtered and washed with ethanol (2 x 10 cc).

2-benzhydryloxycarbonyl-3- [2- (5,6-dioxo-4- (2-methoxyimino-ethyl) -1,4,5, 6-tetrahydro-1-2-4 -Triazin-3-yl] -thiovinyl} -7- [2-methoxyimino-2- (2-triethylamino-thiazol-4-yl) -acetamido] -8-oxo-5- Chia-1-aza-bicyclo [4,2,0] oct-2-ene (a mixture of Syn, E, Syn and Anti, E, Syn isomers) (0.92 g) is obtained.

Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3700, 2500, 1785, 1715, 1685, 1585, 1550, 1495, 1450, 950, 745, 700.

).Proton NMR spectrum (350MHz, DMSOd ₆ , ppm δ, Hz J): 3.35 (s, 3H, -CH = nO-CH ₃ ): 3.70 and 3.90 (2d, J = 18, 2H, -SCH _2- ): 3.95 (s, 3H, = NOCH ₃ ): 5.30 (d, J = 4, 1H, H at 6 position): 5.88 (dd, J = 4 and 9, 1H, 7 position H): 6.95 and 7.05 (2d, J = 16, 2H, -CH = CH-): 9.84 (d, J = 9, 1H, -CONH-): 12.70 (s, 1H, = NNHCC- or

).

The solution of formic acid (20 cc) and water (15 cc) of the above product (a mixture of Syn, Syn, E, Syn, Anti, and isomer) (0.85 g) is stirred at 50 ° C for 30 minutes. Concentrate to dry (0.007 kPa) at 45 ° C., 0.05 mmHg and the residue is taken up in ethanol (40 cc) and the mixture is evaporated to dryness at 20 ° C., 20 mmHg (2.7 kPa). Repeat this operation twice. The yellow solid is dissolved in ethanol (20 cc) at 50 ° C. and the mixture is cooled and filtered.

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- {2-[5,6-dioxo-4- (2 -Methoxyiminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl} -8-oxo-5-thia-1-aza-expensive Micro [4,2,0] -oct-2-ene (a mixture of Syn, Syn, E and Syn, Anti, E isomers) (0.44 g) is obtained as a yellow powder. Infrared spectrum (KBr): Characteristic band (cm ^-1 ) is 3700-200, 1715, 1710, 1690, 1690, 1655, 1585, 1550, 1650, 345.

Proton's NMR spectrum (350MHz, DMSOd ₆ , ppm δ, Hz J): 5.24 (d, J = 4, 1H, H at 6 positions): 5.80 (dd, J = 4 and 9, 1H, 7 positions H): 6.95 and 7.10 (2d, J = 16, 2H, -CH = CH-): 9.77 (d, J = 9, 1H, -CONH-).

The invention also relates to a medicament containing the substance of the general formula (I) as an active substance in a pure state (at least in free or salt form) or in a composition with a pharmaceutically applicable adduct.

Such agents can be used orally, by injection, or by suppository. Tablets, pills, powders, granules and the like are used for oral administration and in such compositions, according to the present invention, the active ingredient is mixed with one or several inert diluents or with adjuvants such as sucrose, lactose or starch. Such compositions may contain substances other than diluents or lubricants such as magnesium stearate.

Pharmaceutically used inert substances such as suspensions, emulsions, syrups or eryryls such as those containing diluents such as water and paragin oils can be used for oral administration. It may also contain other humidifiers, sweeteners or flavorings. Injectables include aqueous or non-aqueous sterile liquids or suspensions or emulsions, and solvents or carriers may include propylene glycol, polyethylene glycol, polyethylene glycol, vegetable oils, in particular olive oils, and injectable organic esters such as ethanol. Such compositions may contain auxiliaries, in particular humidifiers, emulsifiers or diffusion agents. Sterilization can be carried out by bacterial filtration or addition of a sterilizing agent to the composition for several days, or by irradiation or heating, and can be prepared by injectable powder and dissolved in distilled water for injection or other sterile medium for injection. As a suppository, it is made by adding an active substance to cacao butter or suppository wash. According to the invention in the treatment of humans it is particularly effective for the treatment of bacterial infections. In general, the physician will determine the appropriate dosage based on the patient's age, weight, the intensity of the infection, and other particulars. Oral intravenous intramuscular administration at a dose between 1 and 10 g in adults as an effective daily ingredient. The composition according to the present invention is given as follows as an example of not administering restriction.

[Example]

Injectable solutions are prepared with the following composition:

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2 -5,6-dioxo-formylmethyl-1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] -oct Soda salt of 2-ene (Syn isomer, Form E), 267 mg (as aldehyde hydrate)

Salt 1.5 mg, base solution for injection 2 cm ³

This solution contains 250 mg of active substance (calculated as free acid aldehyde).

According to the invention the following compounds can also be prepared.

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2--(2-methyl-1,3,4-teeth Diazol-5-yl) -thiovinyl} -8-oxo-5-thia-1-aza-bicyclo [4,2,0] -oct-2-ene (Syn isomer, mixture of Form E and Z) Trifluoroacetate (1 g) is obtained.

Rf = 0.50 (Sililica gel chromatography: 50: 20: 10 (volume) mixture of developing solution: ethyl acetate, acetone, vinegar acid, and water).

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3380, 3300, 1780, 1675, 1200, 1140, 1050 and 945.

Proton NMR (350 MHz, CDCl ₃ , ppm δ, Hz J): Form E: 2.74 (s, 3H, -CH ₃ ): 3.69 and 3.83 (2d, J = 17, 2H, -SCH _2- ): 3.91 (s, 3H, -CH ₃ ): 5.23 (d, J = 4, 1H, H at 6 positions): 5.82 (dd, J = 4 and H at 10, 1H, 7 positions): 6.85 (s, 1H , H) at position 5 of the toothbrush: 7.16 and 7.32 (2d, J = 16, 2H, -CH = CHS-): 9.75 (d, J = 10, 1H, -CONH-). Form Z: 3.88 and 3.92 (2d, J = 17, 2H, SCH ₂ ): 6.91 (AB, limiting, 2H, -CH = CH-).

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3-2- (1-methyltetrazol-5-yl) -thio Vinyl-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (Syn isomer, Z-type) tripururoacetyl chloride (0.33 g) is obtained.

Rf = 0.50 [Sillika gel chromatography: solvent: ethyl acetate, acetone, vinegar, water: 50: 20: 10: 10 (volume) mixture].

Infrared Spectrum (KBr): Characteristic bands (cm ⁻¹ ) are 3300, 1785, 1675, 1180, 1140 and 1050.

NCU₃) : 4.0(s, 3H, -OCU₃) : 5.26(d, J=4, 1H, 6위치에서 H) : 5.85(dd, J=4와 10, 1H, 7위치에서 H) : 6.75(d, J=11, 1H, =CH=CH=S-) : 6.87(s, 1H, 치아졸의 5위치에서 H) : 6.91(d, J=11, 1H, =CH-S- ) :9.34(d, J=10, 1H, -CONH-).Protonone NMr (350 MHz, DMSO d ₆ , ppm δ, Hz J): 3.8 and 3.85 (AB, J = 17.5H, 2H, -SCU ₂ ): 3,93 (s, 3H,

NCU ₃ ): 4.0 (s, 3H, -OCU ₃ ): 5.26 (d, J = 4, 1H, H at 6 position): 5.85 (dd, J = 4 and H at 10, 1H, 7 position): 6.75 (d, J = 11, 1H, = CH = CH = S-): 6.87 (s, 1H, H at 5 positions of the toothbrush): 6.91 (d, J = 11, 1H, = CH-S-): 9.34 (d, J = 10, 1H, -CONH-).

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-3- [2- (1-methyl-tetrazol-5-yl) -Thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2 -ene (syn isomer, Form E), trifururo acetate (4.57 g) is obtained.

Rf = 0.49 [silica gel chromatography, solvent: ethyl acetate, acetone, vinegar, (volume) mixture of water 50: 20: 10: 10].

Infrared spectrum KBr): Characteristic bands (cm ^-1 ) are 3320, 1780, 1675, 1200, 1140, 1040 and 950.

NCH₂) : 4.0(s, 3H, -OCH₃) : 5.20(d, J=4, 1H, 6위치에서 H) : 5.80(dd, J=4와 9, 1H, 7위치에서 H) : 6.83(s, 1H, 치아졸의 5위치에서 H) : 7.0(d, J=16, 1H, -CH=CHS-) : 7.1(d, J=16, 1H=CHS) : 9.7(d, J=9, 1H, -CONH-).Proton's NMr spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 3.66 and 3.86 (d, J = 17, 2H, -SCH _2- ): 3,90 (s, 3H,

NCH ₂ ): 4.0 (s, 3H, -OCH ₃ ): 5.20 (d, J = 4, 1H, H at 6 position): 5.80 (dd, J = 4 and 9, 1H, H at 7 position): 6.83 (s, 1H, H at 5 positions of the toothbrush): 7.0 (d, J = 16, 1H, -CH = CHS-): 7.1 (d, J = 16, 1H = CHS): 9.7 (d, J = 9, 1H, -CONH-).

7- [2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido] -2-carboxy-8-oxo-3- [2- (1,3,4-teeth Diazol-2-yl) -thiovinyl] -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E (1.5 g) is obtained.

Infrared spectrum (KBr): Characteristic bands (cm ^-1 ) are 2820, 1775, 1675, 1630, 1530, 1490, 1450, 1370, 1040, 750 and 700.

Proton's NMR spectrum (350MHz, DMSO d ₆ , ppm δ, Hz J): 3.68 and 3.96 (2d, J = 18, 2H, -SCH _2- ): 3,84 (s, 3H, -OCH ₃ ) : 5.21 (d, J = 4, 1H, H at 6 position): 5.80 (dd, J = 4 and 9, 1H, H at 7 position): 6.73 (s, 1H, H of toothbrush): 7.18-7.22 (hump 4H, -NH ₂ and CH = CH-) 9.03 (d, J = 9, 1H, -CONH-): 9.60 (s, 1H, H of thiadiazole).

7- [2- (2-amino-thiazol-4-yl) -2-hydroxyimino-acetamido] -2-carboxy-3-[2- (1-methyl-tetrazol-5-yl) -Thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.24 g) is obtained.

Infrared Spectrum (KBr): Characteristic band (cm ^-1 ) is 3440, 3360, 3200, 1785, 1720, 1680, 1610 and 1405

Proton NMR spectra (350 MHz, DMSO d ₆ , ppm δ, Hz J): 3.65 and 3.91 (2d, J = 18, 2H, -S-CH _2- ): 4.97 (s, 3H, NCH ₃ ): 5.25 (d, J = 4, 1H, H at 6 position): 5.90 (dd, J = 4 and 9, 1H, H at 7 position): 6.76 (s, 1H, H at 5 position of toothbrush): 6.96 (d, J = 14, 1H, -CH = CHS-): 7.07 (d, J = 14, 1H, = CHS-): 9.50 (d, J = 9, 1H, -CONH-).

2-benzhydrosoloxycarbonyl-7-2-hydroxyimino-2- (2-amino-thiazol-4-yl) -ceamido-3- [2- (2-methyl-1,3, 4-thiadiazol-5-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct2-ene (syn isomer, Form E) (0.9 g ) Is obtained in the form of a beige solid.

Infrared spectrum (KBr): Characteristic bands (cm ^-1 ) are 3380, 3200, 3100, 1785, 1720, 1685, 1630, 1535, 1500, 1445, 1210, 950, 760, 745 and 705.

) : 7.05(d, J=16, 1H, -CH=CHS-7.26(d, J=16, 1H, -CH=CHS- ) : 9.65(d, J=9, 1H, -CONH-11.85(s, 광역, 1H, =NOH).Proton NMR spectra (350 MHz, DMSO d ₆ , ppm δ, Hz J): 2.71 (s, 3H, -CH ₃ Het): 3.72 and 3.98 (2d, J = 18, 2H, + SCH _2- ): 5.28 (d, J = 4, 1H, H at 6 position): 5.90 (dd, J = 4 and 9, 1H, H at 7 position): 6.80 (s, 1H, H of toothbrush): 6.98 (s, 1H,

): 7.05 (d, J = 16, 1H, -CH = CHS-7.26 (d, J = 16, 1H, -CH = CHS-): 9.65 (d, J = 9, 1H, -CONH-11.85 (s , Wide area, 1H, = NOH).

2-carboxy-7- [2-hydroxyimino-2- (2-amino-thiazol-4-yl) acetamido] -3-[2- (2-methyl-1,3,4-thiadia Zol-5-yl) -thiovinyl] -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Form E) (0.07 g) yellow Obtained as a solid.

Infrared spectrum (CHBr ₃ ): Characteristic bands (cm ^-1 ) are 3600, 2200, 1770, 1660, 1630, 1530, 1390 and 950

Proton NMR spectrum (350 MHz, DMSO d ₆ , ppm δ, Hz J): 2.74 (s, 3H, -CH ₃ , Het): 3.64 and 3.90 (2d, J = 18, 2H, -SCH _2- ) : 5.20 (d, J = 4, 1H, H at 6 position): 5.80 (dd, J = 4 and 9, 1H, H at 7 position): 6.65 (s, 1H, H of toothbrush).

6.80 (s, wide area, 2H, -NH ₂ ): 7.10 and 7.20 (2d, J = 14, 2H, -CH = CH-S-): 9.46 (d, J = 9, 1H, -CONH-): 11.28 (s, wide, 1H, = NOH).

Claims (1)

Reacting a thiol of the following structural formula in free or alkaline metal salt form or alkaline earth metal salt with a cephalosporin derivative or mixture of isomers thereof, reducing the resulting oxide, or 3-thiovinyl-sephalosporin of the following structural formula (I) in the form of Syn- or ant i-, E- or Z-, and mixtures thereof, addition salts of metal salts and nitrogen-containing bases; How to make it.

In the above formula (I), R is selected from the following list. 1) alkyl, L-2-amino-2-carboxy-ethyl and phenyl. 2) pyrid-2-yl, pyrid-3-yl or pyrid-4-yl and their N-oxides, 3) pyrimidin-2-yl, pyridazin-3-yl (substituted with alkyl, methoxy, amino or acylamino groups in the 6-position), N-oxides and tetrazolo [4,5-b ] Pyridazine-6-day, 4) 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl is in the 4-position, 1,3,4-triazol-5-yl or 2-alkoxy-carbonyl-1,3,4-triazol-5-yl are each substituted at the 1-position with the following groups, In other words, a) an alkyl group substituted or unsubstituted with an alkoxy, alkylthio, phenyl, formyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl, or thiazoridin-2-yl group, b) allyl, 2,3-dihydroxyfurophyll, 1,2-dihydroxyfurop-2-yl, 2-formyl-2-hydroxy-ethyl, 3-formyloxy-2-hydroxyfuro Phil, 2,3-bisporyloxyfurophyll, or 1,3-bisporyloxy-furofur-2-yl group, c) an alkyl group containing 2-4 carbon atoms, wherein hydroxyl, carbamoyloxy, asyloxy (the acyl moiety may be substituted with amino, alkylamino, or dialkylamino groups). Alkylserfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfamino, alkylsulfonylamino, stoolamoylamino, asalamino (assholes may be optionally substituted with hydroxyl, amino, alkylamino or dialkylamino groups) Alkoxycarbonyl amino, ureido, alkylureido or dialkylureido groups, d) any of the following structural formulas,

(In the structural formula, alk denotes an alkylene group containing 1-4 carbon warmers, X ^α and Y ^α are the same and are oxygen or sulfur uae, R ^α represents an alkyl group, or X ^α and Y ^α are The same may be an oxygen or sulfur atom and may form an alkylene group containing R 2-3 with R ^α, and R ^β represents a hydrogen atom or an alkyl group having 1-3 carbon atoms.) e) an alkyl group having 2-5 carbon atoms, substituted with an alkoxyimino or hydroxy amino group. 5) 1,4-Dialkyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 1-alkyl-5,6-dioxo -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl or 2-alkyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2 4-triazin-3-yl, 6) 1,3,4-triazol-5-yl, 1,2,3-triazol-5-yl or 1-alkyl-1,2,4-triazol-5-yl, (alkoxy at 3-position Carbonyl group may or may not be substituted). 7) a) alkyl groups, trifluoromethyl, alkoxy, alkylthio, hydroxyalkylthio (alkyl moieties have 2-4 carbon atoms), alkylsulfonyl, hydroxyl, hydroxyalkyl, carboxyl, carboxyalkyl, amine 1,3,4-thiadiazol-5-yl, unsubstituted or substituted with alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, asylamino or asylaminoalkyl group, b) 1,2,4-thiadiazol-5-yl substituted with an alkyl or alkoxy group, 8) a) 1,3,4-oxadiazol-5-yl, unsubstituted or substituted by alkyl, trifluoromethyl, phenyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or acylaminoalkyl groups, b) oxazol-2-yl or 4-alkyl-oxazol-2-yl, 9) tetrazol-5-yl unsubstituted or substituted in the 1-position with the groups listed below; a) an alkyl group substituted or unsubstituted with an alkoxy, scallop, carboxyl, formyl or scholdamoin group, b) an alkyl group having 2-4 carbon atoms, which is hydroxyl, amino, alkylamino, dialkylamino, asylamino, carboxyalkylamino, stoolamoylamino, sulfonylamino, ureido, alkylureido or dialkyl ureido Alkyl group substituted by. c) an alkyl group having 2-5 carbon atoms and substituted with a hydroxyimino or alkoxyimino group, d) phenyl, 2,3-dihydroxyfurophyll, 1,3-dihydroxyfurop-2yl, 2-formyl-2-hydroxy-ethyl, 3-formyloxy-2-hydroxyfurofill, 2,3-bispotyloxy-furophyll or 1,3-bisformyloxyfurov-2-yl group, e) a group of formula (II) wherein R ^β is a hydrogen atom, or a group of formula (III) R ⁰ represents a hydrogen atom or an alkyl, vinyl or cyanomethyl group; R 'represents a group of the following formula (V) which can be easily removed by a hydrogen atom or an enzyme.

(Wherein R 'represents a hydrogen atom or an alkyl group, and R' 'represents an alkyl group or a cyclohexyl group.) In the above formula (R), R is as defined initially, and when R is to obtain a product containing a formyl group or acylalkyl group, the R group is acetal [general formula -alk-CR ^β (X ^α R ^α) ) (Y ^α R ^α ) and —CH ₂ CHOH—CH (X ^α R ^α ) (defined as Y ^α R ^α ). R ⁰ in the formula (VII) is the same as in formula (I); R ₁ is a hydrogen atom, a group of formula (V), or a protecting group that can be easily removed; n is 0 or 1; Derivatives of this structural formula are bicyclooct-2-ene or bicyclooct-3-ene when n = 0, and bicyclooct-2-ene when n = 1. Substituents on the carbon atom at the 3-position of octene show the E- or Z-stereoisomeric form. In this structural formula (V), R <_2> is a hydrogen atom or a protecting group with respect to an amino group; R <_3> is group of following structural formula (VIIa) or structural formula (VIIb). -O-SO ₂ R ' ₃ (Ⅸa) -O-COR ₃ ＂(Ⅸb) Wherein R ₃ 'is a straight or branched chain alkyl group of 1-4 carbon atoms, trifluoromethyl, trichloromethyl, or phenyl [substituted or unsubstituted by a halogen atom or an alkyl or nitro group] R ₃ 와 is the same as R ₃ ′ or is acylmethyl, 2-acylethyl, 2-acylporophyll, alkoxycarbonylmethyl, 2-alkoxycarbonylethyl, or 2-alkoxycarbonylfurophil group) The alkyl moiety, the acyl moiety, the alkyl group, or the acyl moiety is a straight or branched chain of 1-4 carbon atoms unless otherwise specified.