FR2475545A1 - 7-Amino-thiazolyl methoxy-imino acetamido 3-thio-vinyl-cephalosporin - antibacterials active against Gram negative and Gram positive bacteria - Google Patents

Abstract

3-Thiovinyl-cephalosporin of formula (I) having syn or anit, E or Z forms and their mixtures including their acid addition, metallic and N-base addition salts are new. In (I) R is e.g. alkyl, L-2-amino-2-carboxy-ethyl; phenyl; 2-, 3- or 4-pyridyl and their (N-oxides) 2-pyrimidinyl; 3-pyridazinyl substd. in position 6 and opt. N-oxidised or tetrazolo(4,5-b)pyridazin-6-cyl; 4) 1,4-dialkyl or 1-alkyl-5,6-dioxo 1,4,5,6-tetrahydro-1, 2,4-trazin-3-yl or 2-alkyl-5,6-dioxo-1,2,5,6-dioxi-1,2,5,6-tetrahydro-1,2,4-triazin-- 3-yl; 6) Ro is H, alkyl, vinyl or cyanomethyl; R1 is H or a group-CH(R2)(OOCR3) (easily removed by enzymes) (where R2=H or alkyl and R3= alkyl or cyclohexyl. The alkyl and acyl radicals above except where specifically specified are opt-branched and contain 1-4C atoms). (I) are a antibacterials active against gram-negative and gram-positive. In vitro tests show (I) are active against penicillin G sensitive Staph aireus (Staph aureus Smith) at 0.5-15 mg/cc and against penicillin G resistant strains (Staph. aureus MB 9) at 1-30 ug/cc. They are active against E. coli Monod at 0.001-ug/cc and against Kledsiella pneumonae at 0.06-30 ug/cc. Some cpds. are active against Proteus morganii (0.01-30ug/cc) and Enterobacter aerogenes (0.1-30ug/cc)sub-cultaneous LD50 of (I) in mice is 1.5-2.5 g/kg. Admin. may be oral, rectat, parenteral or topical.

Description

leurs sels lorsqu'ils existent, leur préparation et leur utilisation.The present invention relates to novel thioloesters of the general formula

their salts when they exist, their preparation and their use.

dans laquelle Ra est hydrogène ou méthyle, qui sont en particulier des intermédiaires pour la préparation de céphalosporines.In European Patent Application No. 4570, the products of general formula have been described

wherein Ra is hydrogen or methyl, which are especially intermediates for the preparation of cephalosporins.

dans laquelle X est entre autres imino, et leurs dérivés réactifs, notai ment les thioesters tels que les thioesters de phényle, de p.nitrophényle, de p.crésyle et de carboxyméthyle, qui sont utilisés pour la préparation de céphalosporines.In Belgian Patent 862,300 have been described acids of general formula

wherein X is inter alia imino, and their reactive derivatives, including thioesters such as phenyl, p-nitrophenyl, p-cresyl and carboxymethyl thioesters, which are used for the preparation of cephalosporins.

dans laquelle alk est un radical alcoylène contenant 1 à 4 atomes de carbone, Xa et Yα; sont identiques et représentent des atomes d'oxygène ou de soufre et R1 représente un radical alcoyle, ou bien X et a sont identiques ou différents et représentent des atomes d'oxygène ou de soufre et les radicaux R1 forment ensemble un radical alcoylène contenant 2 ou 3 atomes de carbone, et le symbole R' représente un atome d'hydrogène ou un radical protecteur choisi parmi t.butoxycarbonyle, trichloro-2,2,2 éthoxycarbonyle, trichloracétyle, trityle, benzyle, dibenzyle, benzyloxycarbonyle, p.nitrobenzyloxycarbonyle, p.methexybenzyloxycarbonyle ou chloracétyle.In the general formula (I), the symbol RO represents a hydrogen atom, an alkyl radical or a protective radical, the symbol R is chosen from the following meanings: 1) alkyl, L-amino-2-carboxy-2 ethyl, the amine function is protected and whose acid function is free or protected, or phenyl 2) 1,3,4-thiadiazol-5 unsubstituted or substituted by an alkyl radical, trifluoromethyl, alkyloxy, alkylthio, alkylsulfonyl, (hydroxy, hydroxyalkyl, carboxy or carboxyalkyl which may be protected), (amino, alkylamino, aminoalkyl or protected alkylaminoalkyl), dialkylamino, dialkylaminoalkyl> acylamino, acylaminoalkyl, 1,2,4-thiadiazol-5 (substituted by alkyl or alkyloxy) 3) triazol 1,2,3-yl-5, triazol-1,3,4-yl-5, or 1-alkyl-1-alkyloxycarbonyl-3-triazol-1,2,4-yl-5,4) tetrazol-5-yl unsubstituted or substituted in position 1 with an alkyl, alkyloxyalkyl, phenyl, sulphoalkyl or (hydroxyalkyl) radical whose alkyl moiety contains 2 to 4 carbon atoms or carboxyalkyl which may be protected), protected aminoalkyl or alkylaminoalkyl, dialkylaminoalkyl, sulfamoylaminoalkyl or acylaminoalkyl, 5) pyridyl-2, pyridyl-3 or pyridyl-4 optionally N-oxidized, 6) 3-pyridazinyl substituted at the -6 position (with an alkyl, methoxy, protected amino or acylamino radical) and optionally N-oxidized or tetrazoloE4.5-bi-pyridazinyl-6,7-dioxo-5,6 1,4,5-tetrahydro 1,2-triazine-1,2,4-yl-3 substituted in the 4-position with a radical of a first group which comprises: alkyl, alkyloxyalkyl, alkylthioalkyl, phenylalkyl, allyl or carbampylalkyl or a radical of a second group which comprises hydroxyalkyl which may be protected, acylaminoalkyl, carbamoyloxyalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl or acyloxyalkyl (the acyl part of which is optionally substituted by an amino or protected alkylamino radical or a dialkylamino radical), Alkyl groups, linked to triazine, radicals of this second group containing 2 to 4 carbonyl atoms, or by a radical of general formula

wherein alk is an alkylene radical containing 1 to 4 carbon atoms, Xa and Y α are identical and represent oxygen or sulfur atoms and R1 represents an alkyl radical, or X and a are identical or different and represent oxygen or sulfur atoms and the radicals R1 together form an alkylene radical containing 2 or 3 carbon atoms, and the symbol R 'represents a hydrogen atom or a protective group selected from t.butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trichloroacetyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p.nitrobenzyloxycarbonyl, p Methexybenzyloxycarbonyl or chloroacetyl.

 It is understood that (except special mention) the portions or alkyl or acyl radicals mentioned above or which will be mentioned below are straight or branched and contain from 1 to 4 carbon atoms.

 The group -OR "of the products according to the present invention may be in one of the syn or anti positions, and these isomers and mixtures thereof are within the scope of the present invention.

The syn form can be represented by the general formula

The anti form can be represented by the general formula

When the radical R is a triazinyl radical as defined above, it can be represented by the two tautomeric forms

Among the meanings of the R symbol above, there may be mentioned in particular methyl, ethyl, propyl, isopropyl, butyl isobutyl, sec.butyl, t-butyl, thiadiazol-1,3,4-yl-5-methyl-2-tniadiazol-1, 3,4-ethyl-2-thiadiazol-1,3,4-yl-5-propyl-2-thiadiazol-1,3,4-yl-5-isopropyl-2-thiadiazol-1,3,4-yl-5-butyl-2-thiadiazole 1,3,4-5-isobutyl-2-thiadiazol-1,3,4-yl-5 sec-butyl-2-thiadiazol-1,3,4-yl-5
t-Butyl-2-thiadiazol-1,3,4-yl-5-hydroxymethyl-thiadiazol-1,3,4-yl-5-hydroxy-2-ethyl-2-thiadiazol-1,3,4-yl-5-butoxycarbonylaminomethyl; 2-thiadiazol-1,3,4-methyl-2-butoxycarbonylaminomethyl-2-thiadiazol-1,3,4-yl-5-dimethylaminomethyl-2-thiadiazol-1,3,4-yl-5 [t-butoxycarbonylamino-2-ethyl] -2-yl thiadiazol-1,3,4-yl-5
2-Ethyl-tert-butoxycarbonylamino-2-ethyl] -thiadiazol-1,3,4-yl-5-dimethylamino-2-ethyl-2-thiadiazol-1,3,4-yl-5-carboxymethyl-1,3,4-thiadiazol-5-yl (2-carboxyethyl) -2-thiadiazol-5-yl-2-methoxythiazol-1,3,4-yl-5-methylthio-2-thiadiazol-1,3,4-yl-5-methylsulfonyl-2-thiadiazol-1 3,4-tert-butoxycarbonylamino-2-thiadiazol-1,3,4-yl-5-methyl-tert-butoxycarbonylamino-2-thiadiazol-1,3,4-yl-5-dimethylamino-2-thiadiazol-1,3,4-yl; 2-acetylamino-thiadiazol-1,3,4-yl-5-hydroxy-thiadiazol-1,3,4-yl-5-acetamidomethyl-2-thiadiazol-1,3,4-yl-5 (2-acetamidoethyl) thiadiazole 1,3,4-methyl-3-methyl-1,2,4-thiadiazol-5-ethyl-3-thiadiazol-1,2,4-l-5-methoxy-3-thiadiazol-1,2,4-yl-5-triazol 1,2,3-triazol-1,3,4-yl-5-methyl-1-methoxycarbonyl-3-triazol-1,2,4-yl-5-methoxy-carbonyl-3-ethyl-1-triazol-1,2,4-yl-5-methyl 1-ethoxycarbonyl-3-triazol-1,2,4-yl-ethyl-1-ethoxycarbonyl-3-triazol-1,2,4-yl-5H-5-tetrazolyl-1-methyl-5-tetrazolylethyl-1-tetrazolylpropyl- l t 5-razolyl-1-isopropyl-5-tetrazol-1-butyl-5-tetrazolyl-2-hydroxyethyl-5-tetrazolyl-3-hydroxypropyl-5-tetrazolyl-1-methoxymethyl-5-tetrazolylcarboxymethyl-5-tetrazolyl 5-sulfomethyl-5-tetrazolyl-5- (2-methylbutylcarbonylaminoethyl) -4-tetrazolyl-5- (2-dimethylaminoethyl) -5-tetrazolyl-5- (2-diethylaminoethyl) -5-tetrazolyl-3-dimethylaminopropyl-1-propyl tetrazolyl-5 (2-sulfamoylaminoethyl) -1-tetrazolyl-5- (2-acetamidoethyl) -5-tetrazolyl-2-pyridyl-3-pyridyl-4-pyridyl-1-oxide 1-pyridyl-6-methyl-3-pyridazinyl-6-methyl-6-oxide 3-pyridazinyl-3-ethyl-6-pyridazinyl-6-ethyl-1-oxide 3-pyridazinyl-6-methoxy-3-pyridazinyl-6-butoxycarbonylamino-3-pyridazinyl 6-acetamido-3-pyridazinyl-tetrazolo [4,5-b] pyridazinyl- 6-dioxo-5,6-methyl-4-tetrahydro-1,4,5,6-triazin-1,2-yl-3-dioxo-5,6-ethyl-1,4,5,6-tetrahydro-1,2-triazine 4α-3-dioxo-5α-propyl-4-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-dioxo-536-isopropyl-4-tetrahydro-1,4,5,6-triazine-1, 2.4 yl-3 allyl-4-dioxo-5,6 1,4,5,6-tetrahydro-1,2,4-triazine-1,3-dioxo-5,6-hydroxy-2-hydroxyethyl-1,4,5-tetrahydro , 6 1,2,4-triazine-1,3-dioxo-5,6-methoxymethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-dioxo-5,6 (2-methoxyethyl) 4-Tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-dioxo-5,6-ethoxymethyl-1,4,5,6-tetrahydro-1,2,4-triazine-3-yl dioxo 5.6 (2-ethoxyethyl) -4,4,6,6-tetrahydro-1,2,4-triazine-3-yl (2-acetamidoethyl) -4,6-dioxo-1,4,5-tetrahydro , 6 triazine-1,2,4-yl-3-benzyl-4-dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-dioxo-5,6-phenethyl-4-tetrahydro-1 , 4,5,6-triazine-1,2,4-yl-3-dioxo-3,6-methylthiomethyl-4-tetrahydro-1,4,5,6-triazin-1,2,4-yl-3-dioxo-5,6-methylthioethyl- 4-Tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-carbamoylmethyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-3-yl (carbamoyl) 2 ethyl-4-dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 (3-carbamoyl-propyl) -4,5-dioxo-1,4,5-tetrahydro, 6 triazine-1,2,4-yl-3 (2-carbamoyloxyethyl) dioxo-53 Tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 (3-carbamoyloxypropyl) -4,5-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine 3-dioxo-5,6-methylsulphinylethyl-4-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-dioxo-5,6-formyloxy-2-ethyl-4-tetrahydro-1,4,5, 6-triazine-1,2,4-yl-3-dioxo-5,6 6 (3-formyloxypropyl) -4-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 (2-acetoxyethyl) 4-dioxo-5,6 1,4,5,6-tetrahydro-1,2,4-triazine-1,3-yl (3-acetoxypropyl) -5,6-dioxo-1,4,5,6-tetrahydro-triazine 1,2,4-yl-3-dioxo-5,6 (t-butoxycarbonylglycyloxy-2-ethyl) -4-tetrahydro-1,4,5,6-triazin-1,2,4-yl-3-dioxo-5,6 (t. butoxycarbonylglycyloxy-3-propyl) -4-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-dioxo-5,6 (2-propanoyloxyethyl) -4,4,5,6-tetrahydro-triazine 1,2,4-yl-3 (2,2-dimethoxyethyl) -4,5-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-1,3-yl (3,3-dimethoxypropyl) 4-dioxo-5,6 1,4,5,6-tetrahydro-1,2,4-triazine-1,3-yl (2-diethoxyethyl) -4,6-dioxo-1,4,5,6-tetrahydro triazine-1,2,4-yl-3 (3,3-diethoxypropyl) -4-dioxo-5 1,2,3-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3- (2-bismethylthio-ethyl) -4,5,6-dioxo-1,4,5,6-tetrahydro-1,2-triazine 4-yl-3 (3,3-bismethylthio-propyl) -4,5-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-3-yl (2-bisethylthioethyl) dioxo -5> 6 1,4,5,6-tetrahydro-1,2,4-triazine-1,3-yl (4-bisethylthio-propyl) -5,6-dioxo 1,4,5,6-tetrahydro-1-triazine 2,4-1,3-dioxo-5> 6 (1,3-dioxolan-2-yl) -4-methyl-1,4,5,6-tetrahydro-triazine1,2,4-dioxo-5,6-dioxo [5-dioxolan] -1,3-yl-2) -2 ethyl] -4-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-dioxo-5,6-dithiolane-1,3-yl-2-methyl 4-Tetrahydro-1,4,5,6-triazine1,2,4-1,3-dioxo-5,6 [(1,3-dithiolane-2-yl) -2-ethyl] -4-tetrahydro-1,4,5,6 triazine 1,2,4 1,3-dioxo-5,6 (1,3-oxathiolan-2-yl) methyl-4-tetrahydro-1,4,5,6-triazin-1,2,4-yl-3-dioxo-5, 1- (1,3-oxathiolane-2-yl) -2-ethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-dioxo-5,6-dioxane-1,3-yl; 2) 4-methyl-1,4,5,6-tetrahydro-triazine1,2,4-yl-3-dioxo-5,6 [(1,3-dioxan-2-yl) -2 ethyl] -4-tetrahyd ro-1,4,5,6-triazine-1,2,4-yl-3-dioxo-56 (dithian-1,3-yl-2) methyl-4-tetrahydro-1,4,5,6-triazine1,2,4-yl 3-dioxo-5,6 [(dithian-1,3-yl-2) -2-ethyl] -4-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3.

 The amino, alkylamino, carboxy and hydroxy groups which exist in certain R radicals are or may be protected by any protective groups normally used for the protection of amines, carboxylic acids or alcohols and whose use does not affect the rest. of the molecule.

 By way of example, the amino and alkylamino groups are protected by radicals such as t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trichloroacetyl, trityl, benzoyl, dibenzyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl or chloroacetyl.

the carboxy groups may be protected by radicals such as methoxymethyl, t-butyl, benzhydryl, p-nitrobenzyl or p-methoxybenzyl.

the hydroxy groups may be protected by radicals such as trityl, tetrahydropyranyl or 2-methoxypropyl-2.

 Among the meanings of the symbol R "above are: hydrogen, methylene, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl.

 When R "is a protective radical, it may be chosen from all the protective groups of o, irnes, usually used, the implementation of which does not affect the rest of the molecule.

 By way of example, it may represent a trityl radical, tetrahydropyranyl or 2-methoxypropyl-2.

 Generally, the syn forms of the products of general formula (I) are the preferred forms.

redans laquelle R représente un radical alcoyle ou un radical protecteur et dans laquelle R" est défini comme R' à l'exception de représenter l'atome d'hydrogène ou, lorsque le dérivé réactif est le chlorure d'acide, R" représente un atome d'hydrogène7 sur un thiol de formule générale
R - SH (v) (dans laquelle R est défini comme ci-dessus) ou sur un de ses sels alcalins ou alcalinoterreux suivie de l'élimination du radical R" protecteur du radical amino lorsque l'on veut obtenir un produit pour lequel R' est un atome d'hydrogène, et éventuellement des autres radicaux protecteurs.According to the invention, the products of general formula (I) in which R is defined as above (with the exception of representing a 4-acyloxyalkyl-5,6-dioxo-tetrahydro-1,4,5,6-triazine-1 group, 2,4-yl-3 whose acyl part is optionally substituted as described above) can be prepared by the action of an acid or a reactive derivative of an acid of general formula

in which R represents an alkyl radical or a protective radical and in which R "is defined as R 'with the exception of representing the hydrogen atom or, when the reactive derivative is acid chloride, R" represents a hydrogen atom7 on a thiol of the general formula
R - SH (v) (in which R is defined as above) or on one of its alkali or alkaline earth metal salts followed by removal of the R "protecting group from the amino radical when it is desired to obtain a product for which R is a hydrogen atom, and optionally other protective groups.

 It is understood that the acid of general formula (IV) of syn, anti form or mixtures thereof, respectively leads to the products of general formula (I) syn or anti form or mixtures thereof.

 when it is desired to obtain a product of general formula (I) for which R is a hydrogen atom, the protection of the oxime can be carried out by any known method which does not alter the rest of the molecule. The trityl group is used in particular.

 Moreover, when it is desired to obtain a product of general formula (I) for which R contains a carboxy or sulpho radical, it is preferable to have a reactive derivative of the acid of general formula (IV) act on the corresponding thiol. .

 When it is desired to obtain a product for which R contains a hydroxyl radical, it is preferable to protect this radical beforehand with a trityl group.

When the product of general formula (IV) is used in acid form, the condensation is generally carried out in an organic solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride, chloroform or acetate. of ethyl, in the presence of a condensing agent such as a carbodiimide (for example dicyclohexylcarbodiimide), NN'-carbonyluiimidazole or 2-ethoxy-ethoxycarboyl-1-dihydro-1,2-quinoline, at a temperature between -20 and 400C, then optionally eliminating the protective groups.

dans laquelle R et R" sont définis comme ci-dessus et Z représente un radical tel que succinimido, benzotriazoîyl-1, nitro-4 phényle, dinitro-2,4 phényle, pentachloropbényle ou phtalimido.B / When a reactive derivative of the acid of general formula (IV) is used, it is possible to use anhydride, a mixed anhydride or a reactive ester of general formula

in which R and R "are defined as above and Z represents a radical such as succinimido, benzotriazolyl-1, 4-nitro-phenyl, 2,4-dinitrophenyl, pentachlorophenyl or phthalimido.

C / When it is desired to obtain a product of general formula (I) in which R 'is a hydrogen atom, it is also possible to use an acid halide, for example acid chloride, while reacting the hydrochloride of the acid chloride of general formula (IV) with the thiol, or a salt thereof.

 When the anhydride is used as a mixed anhydride or an acid halide (which can be prepared in situ), the condensation is carried out in an inert organic solvent such as an ether (tetrahydrofuran or dioxane, for example), a chlorinated solvent (chloroform or methylene chloride for example), an amide (dimethylformamide or dimethylacetamide for example) or a ketone (acetone for example), as well as mixtures of the above solvents> in the presence of an acid acceptor such as an epoxide (for example propylene oxide) or a nitrogen-containing organic base such as pyridine, N-methylmorpholine or a trialkylamine (triethylamine, for example) or in a hydroorganic medium in the presence of an alkaline metal agent. condensation such as sodium bicarbonate, and one operates at a temperature between 40 and +40 C, then optionally eliminating the protective group or groups.

 When a reactive ester of general formula (VI) is used, the operation is generally carried out in the presence of a trialkanolamine (for example triethylamine) in an organic solvent such as dimethylformamide at a temperature of between 0 and 60 ° C., and then optionally the protective group (s) is removed.

 By way of example, the release of the various protected radicals can be carried out under the following conditions - when it is desired to obtain a product of general formula (I) in which R 'is hydrogen, the t.butoxycarbonyl protecting radical is removed. aminothiazole by treatment in an anhydrous acid medium.

In this case, the product is obtained either in the salt state or in the solvate state with the acid employed. Trifluoroacetic acid is preferably used, operating between 0 and 20 ° C. It is also possible to eliminate the benzyl protecting group from aminothiazole by catalytic hydrogenation.

when it is desired to obtain a product of general formula (I) in which the radical R comprises a hydroxyl group and / or in which R is a hydrogen atom, the trityl group (s) are removed by acidolysis with the acid; anhydrous trifluoroacetic acid.

The elimination is carried out before, simultaneously with or after removal of the protective radical of aminothiazole.

 According to the invention, the thioloesters of general formula (I) in which R represents a dioxo-5,6-radical 1,4,5,6-tetrahydro-1,2,4-triazi-yl-3 substituted in the 4-position by a radical carbamoyloxyalkyl or acyloxyalkyl (the acyl part of which is optionally substituted by an amino or protected alkylamino or dialkylamino) and the triaxyl-linked alkyl portion of which contains 2 to 4 carbonyl atoms, may be prepared from a thiol ester of the generic formula (1) wherein R is 5,6-dioxo-4-hydroxyalkyl-1,4,5-tetrahydro-1,2,4-triazine-1,3-yl, the alkyl part of which contains 2 to 4 carbon atoms and wherein the radical R ' and the radical R are other than the hydrogen atom, by any known method to obtain a carbamate or an ester from an alcohol without affecting the rest of the molecule.

 The esterification is carried out at a temperature of between -50 ° C. and the reflux temperature of the reaction mixture, in particular by condensation of the anhydride of the acid (o of another reactive derivative, halide, for example) in a solvent. inert organic such as an ether (tetrahydrofuran for example), a chlorinated solvent (methylene chloride for example), or a mixture of these solvents, in the presence of a nitrogenous base such as pyridine, 4-dimethylaminopyridine, or a trialkylamine (triethylamine for example) or an alkaline condensing agent (sodium bicarbonate for example) and then optionally removing the protective groups according to the methods described above.

 The carbamate is obtained by any known method which does not affect the rest of the molecule. It is carried out in particular by the action of chlorosulfonyl isocyanate or tricbloracetyl in an inert organic solvent, for example tetrahydrofuran or acetonitrile, at a temperature between -80 and 20 C followed by treatment with a base (alkali bicarbonate or sodium hydroxide). example) in an aqueous medium, then removal of the protective groups.

 The products of general formula (IV) can be prepared according to the method described in Belgian Patent 850,662 or by application of the method described in Belgian Patent 877,884. Thiols of general formula (V) (which can be used in their tautomeric form) can be obtained by applying one of the following methods, depending on the meaning of the radical R - when R is a 1,3-thiadiazol, optionally substituted by alkyl, alkyloxy, alkylthio, alkylsulfonyl, aminoalkylamino, dialkylamino or acylamino: according to the methods described in Belgian Patent 830 821, when R is a 1,3,4-thiadiazol-5-substituted by hydroxyalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl according to the method described in the application German Patent 2,446,254, when R is a 1,3,4-thiadiazolyl-5-substituted by a carboxyalkyl radical: by applying the method described in US Pat. German Patent 1,953,861, when R is a 1,3,4-trifluoromethyl-substituted thiadiazol-5-radical: according to the method described in German Patent Application No. 2,162,575, when R is a thiadiazole radical; 1,3,4-yl-5 substituted with a carboxy radical: according to the method described in Japanese Patent Application 77 48666, when R is a 1,3,4-thiadiazolyl radical substituted by an acylaminoalkyl radical: the method described in Japanese Patent Application 7680857, when R is a 1,2,4-thiazolid-1-yl substituted by alkyl or alkyloxy: according to the method described in German Patent Application 2,806,226 or according to Chem .Ber. 90, 184 (1957), when R is a tetrazolyl-5 radical optionally substituted in position -1 by alkyl, hydroxyalkyl or phenyl: according to the methods described in Belgian Patent 830,821, when R is a substituted tetrazolyl-5 radical in position -1 by alkyloxyalkyl: by addition of sodium azide to an isothiocyane toalkyloxyalkyl-operating in an organic solvent such as ethanol at the reflux temperature of the reaction mixture.

 Isotlliocyanatoalkyloxyalkyl can be obtained by application of the method described by E. Schmidt et al., Chem. Ber.

73, 286 (1940).

when R is a tetrazolyl-5 radical substituted in position 1 by a carboxyalkyl radical: according to the method described in Belgian Patent 858,112, when R is a tetrazolyl-5 radical substituted in the -1 position by a sulfoalkyl radical; the method described in Belgian Patent 856,498 or described by DA BERGES et al., J. Het.Chem. 15, 981 (1978), when R is a 5-tetrazolyl radical substituted in the 1-position by an aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl radical by applying the method described in German Patent Application 2,738,711, - when R is a 5-tetrazolyl radical substituted in position -1 by a sulphamoylaminoalkyl radical: according to the method described in Belgian Patent 856 636, when R is a 5-tetrazolyl radical substituted with an acylaminoalkyl or 1,3,4-thiadiazol-5-yl radical; substituted by hydroxy according to the method described in US Pat. No. 4,117,123, - when R is a pyridyl-3 radical: according to the method described by
HM WUEST and EH SAKAL, J. Am.Chem. Soc., 73, 1210 (1951), when R is a 1-oxide-3-pyridyl radical: according to the method described by B. Blanc et al., J. Med. Chem. 17, 1065 (1974), when R is a 1-oxide pyridyl-4 radical: according to the method described by RAY JONES et al., J. Chem. Soc. 2937 (1960), when R is a 3-pyridazinyl radical substituted by alkyl or methoxy and optionally N-oxidized: according to the method described in Belgian Pat. No. 787,635, when R is a 3-pyridazinyl radical substituted with amino and optionally N-oxidized: according to the method described in Belgian Patent 579,291, - when R is a 3-pyridazinyl radical substituted by acylamino and optionally N-oxidized: by application of the methods described by
M. KUMAGAI and M. BANDO, Nippon Kagaku Zasshi, 84,995 (1963) and T. HORIE and T. UEDA, Chem. Pharm. Bull., 11, 114 (1963), when R is a tetrazoloE4,5-bg pyridazinyl-6 radical: according to the method described in Belgian Patent 804251, when R is a 1,2,3-triazolyl radical. -5: according to the method described in the French patent application 2 215 942, - when R is an alkyl-1-alkyloxycarbonyl-3-triazol-1,2,4-yl-5: according to the method described by M. PESSON and M ANTOINE, CR Acad.

Sci., Ser. C, 267, 25, 1726 (1968). According to this method, the corresponding thiol is obtained in the form of a mixture with the corresponding 5-dioxo-2-alkyl-3-thioxo-1-perhydrotriazine-1,2,4, and can be used for the preparation of the products of formula general (I) in this form.

when R is a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 radical substituted in the 4-position by alkyl, allyl or alkyloxyalkyl: according to the method described in the Belgian patent 830 455, when R is a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 radical substituted in the 4-position with a hydroxyalkyl, acylamino-alkyl, phenylalkyl or alkylthioalkyl radical; carbamoylalkyl, or a carbamoyloxyalkyl, alkylsulfinylalkyl or alkylsulphonylalkyl radical, or a radical of the general formula (II): by the action of an alkyl oxalate on a thiosemicarbazide of the general formula
Wherein R2 is hydroxyalkyl, acylaminoalkyl, phenylalkyl, alkylthioalkyl, carbamoylalkyl or a carbamoyloxyalkyl, alkylsulfinylalkyl or alkylsulphonylalkyl radical or a radical of the general formula (II), in the presence of a hydrogen atom. alkali metal alcoholate, for example sodium ethylate or methoxide or potassium t-butoxide, by application of the method described by M. PESSON and
M. ANTOINE, Bull. Soc. Chim. France (1970) 1590.

 It is not absolutely necessary to purify the product obtained to carry it out for the preparation of the products of general formula (I).

 When R2 is phenylalkyl, the thiosemicarbazide of general formula (VII) may be prepared by applying the method described by W. BAIRD et al., J. Chem. Soc., 2527 (1927).

 When R 2 is alkylthioalkyl, the thiosemicarbazide of the general formula (VII) may be prepared by the action of hydrazine hydrate on the corresponding N (methyl alkylthioalkyl dithiocarbamate in ethanol at the reflux temperature of the reaction mixture.

 When R2 is carbamoylalkyl, the thiosemicarbazide of general formula (VII) can be prepared by the action of ammonia in methanol on the corresponding 4-ethoxycarbonylalkyl-thiosemicarbazide at a temperature between 20 and 30 C.

 Ethoxycarbonylalkyl-4 thiosemicarbazide can be obtained by application of the method described by Gante and Lantsch, Chem. Ber.

97, 989 (1964).

 When R2 represents a radical of general formula (II), the thiosemicarbazide of general formula (VII) may be prepared by the action of hydrazine hydrate on the corresponding isothiocyanate in ethanol at a temperature between 0 and 10 C.

When R2 is carbamoyloxyalkyl, alkylsulfinylalkyl or alkylsulphonylalkyl, the thiosemicarbazide may be obtained from an amine of the general formula
R2 - NH2 (pathway) in which R2 has the corresponding definition, by application of the method described by Y. KAZAKOV and JY POTOVSKII, Doklady Akad. Nauk
SSSR 134, 824 (1960).

 The product of general formula (VIII) in which R 2 is carbamoyloxyalkyl may be obtained by the action of chlorosulfonyl isocyanate on the corresponding alcohol whose amine function has been previously protected, and then removal of the protective radical.

 The protection of the amino radical and the elimination of the protective radical are carried out according to the usual methods which do not affect the rest of the molecule. In particular, the t-butoxycarbonyl group is used, which is removed by acid hydrolysis.

 The reaction of the chlorosulfonyl isocyanate is carried out in a solvent such as dry tetrahydrofuran or dimethylformamide, at a temperature of between -70 and 0 ° C. followed by treatment with a base in aqueous solution (for example with sodium hydroxide or a bicarbonate). alkaline).

 The product of general formula (VIII) in which R 2 is alkylsulfinylalkyl or alkylsulphonylalkyl may be prepared by the action of one or two equivalents of metachloro perbenzoic acid respectively on the corresponding alkyl aminothioamoylamine, the amine function of which has previously been protected, and then the release of the amine function. The reaction is carried out in a chlorinated solvent (methylene chloride, chloroform, for example). The blocking and then the unblocking of the amine function take place under the usual conditions, in particular with a t-butoxycarbonyl radical.

dans laquelle le symbole RO représente un atome d'hydrogène ou un radical alcovle, le symbole R est choisi parmi les significations suivantes:: 1) alcoyle, L-amino-2 carboxy-2 éthyle ou phényle 2) thiadiazol-i,3,4 yl-5 non substitué ou substitué par un radical alcoyle, trifluorométhyle, alcoyloxy, alcoylthio, alcoylsulfonyle, hydroxy, hydroxyalcoyle, carboxy, carboxyalcoyle, amino, alcoylamino, aminoalcoyle, alcoylaminoalcoyle, dialcoylamino, dialcoylaminoalcoyle, acylamino ou acylaminoalcoyle, thiadiazol-1,2,4 yl-5 (substitué par un radical alcoyle ou alcoyloxy), 3) triazol-1,2,3 yl-5, triazol-1,3,4 yl-5 ou alcoyle alcoyloxycarbonyl-3 triazol-1,2,4 yl-5 4) tétrazolyl-5 non substitué ou substitué en position -1 par un radical alcoyle, alcoyloxyalcoyle, phényle, hydroxyalcoyle dont la partie alcoyle contient 2 à 4 atomes de carbone, carboxyalcoyle,-sulfoalcoyle, aminoalcoyle, alcoylaminoalcoyle, dialcoylaminoalcoyle, sulfamoylaminoalcoyle ou acylaminoalcoyle 5) pyridyl-2, pyridyl-3 ou pyridyl-4 cventuellement N-oxydés, 6) pyridazinyl-3 substitué en position -6 (par un radical alcoyle, méthoxy, amino ou acylamino) et éventut-llemtnt N-oxydé ou tétrazolot4,5-bJ pyridazinyl-6 7) dioxo-516 tétrahydro-1,4,5,6 triazine-1,2,4 yl-3 substitué en position -4 par un radical d'un premier groupe qui comprend : alcoyle, alcoyloxyalcoyle, alcoylthioalcoyle, phénylalcoyle, allyle, formylalcoyle ou carbamoylalcoyle ou par un radical d'un second groupe qui comprend hydroxyalcoyle, acylaminoalcoyle, carbamoyloxyalcoyle, alcoylsulfinylalcoyle, alcoylsulfonylalcoyle ou acyloxyalcoyle (dont la partie acyle est éventuellement substituée par un radical amino, alcoylamino ou dialcoylamino), les parties alcoyles, liées à la triazine, des radicaux de ce second groupe contenant 2 a 4 atomes de carbonyle, ou encore par un radical de formule générale (II) tel que défini ci-avant, et le symbole R3 représente un atome d'hydrogène ou un radical facilement éliminable par voie enzymatique de formule générale

dans laquelle R4 représente un atome d'hydrogène ou un radical alcoyle et R5 représente un radical alcoyle ou le radical cyelohexyle. The products of general formula (I) are useful for the preparation of cephalosporins of general formula

in which the symbol RO represents a hydrogen atom or an alcovle radical, the symbol R is chosen from the following meanings: 1) alkyl, L-amino-2-carboxy-2-ethyl or phenyl 2) thiadiazol-i, 3, 4-yl-5 unsubstituted or substituted by alkyl, trifluoromethyl, alkyloxy, alkylthio, alkylsulfonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, amino, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, acylamino or acylaminoalkyl, 1,2-thiadiazole , 4-yl-5 (substituted by alkyl or alkyloxy), 3) triazol-1,2,3-yl-5, triazol-1,3,4-yl-5 or alkyl-3-alkyloxycarbonyl-1,2,4-triazol 4-tetrazol-5-unsubstituted or substituted in the 1-position with an alkyl, alkyloxyalkyl, phenyl or hydroxyalkyl radical, the alkyl portion of which contains 2 to 4 carbon atoms, carboxyalkyl, -sulfoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfamoylaminoalkyl, and the like; or acylaminoalkyl 5) pyridyl-2, p optionally pyridazinyl-3-pyridazinyl-6 (substituted by the alkyl, methoxy, amino or acylamino radical) and optionally N-oxide or tetrazolot4,5-bj pyridazinyl-6 7) dioxo-516 1,4,5,6-tetrahydro-1,2,4-triazine-1,3-yl substituted in the 4-position with a radical of a first group which comprises: alkyl, alkyloxyalkyl, alkylthioalkyl, phenylalkyl, allyl, formylalkyl or carbamoylalkyl or by a radical of a second group which comprises hydroxyalkyl, acylaminoalkyl, carbamoyloxyalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl or acyloxyalkyl (the acyl part of which is optionally substituted with an amino, alkylamino or dialkylamino radical), the alkyl parts, linked to the triazine, radicals of this second group containing 2 to 4 carbonyl atoms, or by a radical of general formula (II) as defined above, and the symbol R3 represents a hydrogen atom or an easily removable radical p ar enzymatic route of general formula

wherein R4 represents a hydrogen atom or an alkyl radical and R5 represents an alkyl radical or the cyelohexyl radical.

 In the general formula (IX), the substituent at position -3 can be in cis or trans form or in the form of a mixture of cis and trans forms. In what follows, the trans stereoisomerism will be denoted by E and the cis stereoisomerism will be denoted by Z.

dans laquelle n est 0 ou 1 lorsque n = O le produit se présente sous forme bicyclooctène-2 ou -3 et lorsque n = 1 le produit se présente sous forme bicyclooctène-2 (selon la nomenclature des Chemical Abstracts)], le substituant sur l'atome de carbone en position -3 du bicyclooctène présente la stéréoisomérie E ou Z,
R'3 représente un atome d'hydrogène, un radical de formule générale (X) ou un radical protecteur facilement éliminable (par exemple méthoxyméthyle, t.butyle, benzhydryle, p.nitrobenzyle ou p.méthoxybenzyle) et R6 représente un radical de formules générales
- O SO2 R'6 (XII)
ou - O CO R'6 (xiii) dans lesquelles R'6 est un radical alcoyle, trifluoromXthyle, trichlorométhyle ou phényle substitué (par un atome d'halogène ou par un radical alcoyle ou nitro), puis le cas échéant on réduit le sulfoxyde obtenu (lorsque n =1) et élimine le cas échéant les radicaux protecteurs.The preparation of the products of general formula (IX) can be carried out as follows
a product of general formula (I), optionally in the form of salt, is made to act on a 7-amino cephalosporin (or, if appropriate, on a mixture of the isomers of this product) of general formula

where n is 0 or 1 when n = 0 the product is in the form of bicyclooctene-2 or -3 and when n = 1 the product is in the form of bicyclooctene-2 (according to the nomenclature of Chemical Abstracts)], the substituent on the carbon atom at the 3-position of the bicyclooctene has E or Z stereoisomerism,
R'3 represents a hydrogen atom, a radical of general formula (X) or an easily removable protecting group (for example methoxymethyl, t-butyl, benzhydryl, p-nitrobenzyl or p.methoxybenzyl) and R6 represents a radical of formulas General
- O SO2 R'6 (XII)
or - O CO R '6 (xiii) in which R' 6 is an alkyl, trifluoromethyl, trichloromethyl or substituted phenyl radical (by a halogen atom or by an alkyl or nitro radical), then if necessary the sulphoxide is reduced; obtained (when n = 1) and eliminates if necessary the protective radicals.

 When it is desired to obtain a product of general formula (IX) for which R is 4-dioxo-4-formylalkyl-1,4,5,6-tetrahydro-1,2,4-triazine-1,3-yl, the corresponding product is prepared. in which the formylalkyl radical is protected in the form of an acetal in the form of the radical of general formula (II) and then the protective group is removed before, after or simultaneously with the other protective groups present in the molecule, by any known method of desacalisation which does not alter the rest of the molecule.

 It is advantageous to operate simultaneously by the action of aqueous formic acid (preferably containing less than 10% of water), either in the presence or absence of silica, or by transacetalization in the presence of an acetalisable reagent such as acetone. , glyoxylic acid, benzaldehyde or pyruvic acid. it is also possible to operate in an organic solvent (for example acetonitrile or acetone) in the presence of ptoluenesulphonic acid and in the presence or absence of an acetalisable reagent as defined above.

 When in the product of general formula (IX), the radical R represents a dioxo-6-formylalkyl-1,4,6,4-tetrahydro-1,2,4-triazine-3-yl radical, it may be in its form. form free aldehyde or aldehyde hydrate. These forms are especially observed under the conditions described below.

 Nuclear magnetic resonance studies show in particular that - in acidic solvent, such as formic acid or trifluoroacetic acid (deuterated), in the presence or absence of water (heavy) the product is mainly in the form of free aldehyde.

in basic solvent such as water (heavy) with added sodium bicarbonate, it is mainly in the form of aldehyde hydrate.

in a neutral solvent such as dimethylsulfoxide (d6), the free aldehyde and aldehyde hydrate forms are present, the addition of water gradually leading to the conversion of the free aldehyde form into an aldehyde hydrate form.

The reaction of the products of general formula (I) with the 7-amino cephalosporins of general formula (XI) is generally carried out in the presence of an acid acceptor such as an organic base, more particularly in the presence of a pyridine or a nitrogenous organic base of the type

X1, Y1 and Z1 being alkyl or phenyl radicals or 2 of them forming a mixture with the nitrogen atom to which they are attached. For example, triethylamine, N, N-diisopropylethylamine, diethylphenylamine or N-methylmorpholine are used.

 The reaction is advantageously carried out in an organic solvent such as an amide (dimethylformamide> dimethylacetamide for example), an ether (tetrahydrofuran, dioxane for example), a chlorinated solvent (chloroform, methylene chloride for example), a ketone (acetone for example) or a nitrile (acetonitrile for example) or in a mixture of these solvents.

 It is also possible to operate in the presence of an alkaline bicarbonate in one of the solvents mentioned above, optionally in the presence of water.

 When using a product of general formula (I) in which R 'and / or R are hydrogen, it is preferable to protect the amine and / or the oxime beforehand.

 It operates at a temperature between -20C and the reflux temperature of the reaction mixture. The reaction is carried out optionally under nitrogen.

 The reduction of the S-oxide is carried out for example under the conditions described in the German patent application 2,637,176.

The elimination of the different protective radicals can be carried out simultaneously or successively.

By way of example, 1 / the elimination of the protective amine groups is carried out
when it is a t-butoxycarbonyl, trityl or p-methoxybenzyloxycarbonyl radical: by treatment in an acid medium. Trifluoroacetic acid is preferably used at a temperature of between 0 and 20 ° C., or anhydrous or aqueous formic acid or para-toluenesulphonic acid is used. Under these conditions, the product of general formula (I) is obtained in the form of trifluoroacetate, of solvate with formic acid or of para-toluenesulphonate, the amine function of which can be released by any method known per se for obtaining an amine from one of its salts without affecting the rest of the molecule.On operates in particular by placing in contact with an ion exchange resin or by action of an organic base.

when it is a 2,2,2-trichloroethoxycarbonyl or p-nitrobenzyloxycarbonyl radical: by reduction (in particular treatment with zinc in acetic acid)
when it is a chloroacetyl or trichloroacetyl radical: by application of the method described in the French patent published under No. 2,243,199
when it is a benzyl, dibenzyl or benzyloxycarbonyl radical: by catalytic hydrogenation.

2 / The elimination of the protective groups of the carboxy radical is carried out
when it is a t-butyl, p-methoxybenzyl or benzyhydryl group: by treatment in an acid medium, under the conditions described above for the removal of the amino-protecting trityl radical. In the case of the benzhydryl radical, it is possible to operate in the presence of anisole
- in the case of a methoxymethyl group: by treatment in a dilute acidic medium
in the case of a p-nitrobenzyl group: by reduction (in particular treatment with zinc in acetic acid or hydrogenolysis).

3 / The elimination of the protective groups of the oxime and / or the hydroxyl radicals is carried out
in the case of trityl or tetrahydropyranyl group: by acidolysis, for example by trifluoroacetic acid, formic acid, aqueous or otherwise, or paratoluenesulphonic acid
when it is the 2-methoxypropyl-2 group according to the method described in Belgian Patent 875,379.

(dans laquelle, R6 et n étant définis comme préeédemment, la position de la liaison est définie comme précédemment pour les produits de formule générale (XI), R"3 est défini comme R'3 à l'exception de représenter l'atome d'hydrogène et R7 est un radical facilement éliminable), par élimination du radical R7 ou éventuellement élimination simultanée des radicaux R7 et R"3 lorsque l'on.veut obtenir un produit de formule générale (XI) dans lequel R'3 est un atome d'hydrogène.The products of general formula (XI) can be obtained from a product or a mixture of isomers of general formula

(wherein, R6 and n being defined as previously, the position of the bond is defined as above for the products of general formula (XI), R "3 is defined as R'3 with the exception of representing the atom of hydrogen and R 7 is an easily removable radical), by elimination of the radical R 7 or optionally simultaneous elimination of the radicals R 7 and R "3 when it is possible to obtain a product of general formula (XI) in which R '3 is an atom hydrogen.

By easily removable R7 radical is meant a benzhydryl or trityl radical, a 2,2,2-trichloroethyl radical, an acyl radical of general formula
R8 - CO - (xvi) (in which R8 is a hydrogen atom or an alkyl radical optionally substituted by one or more halogen atoms or by a phenyl or phenoxy or phenyl radical), or a radical of general formula
Wherein R 9 is an unsubstituted branched alkyl radical, a straight or branched alkyl radical leaving one or more substituents selected from halogen atoms, a cyano, trialkylsilyl, phenyl, substituted phenyl radical (for example: one or more alkyloxy, nitro or phenyl)], vinyl, allyl or quinolyl] or nitrophenylthio radicals.

In addition, the radical R 7 NH may be replaced by a methyleneimino radical in which the methylene radical is substituted by a dialkylamino or aryl group, the latter optionally substituted by one or more methoxy or niter radicals.

Examples of R 7 radicals which may be used include the following radicals: formula, acetyl, chloroacetyl, trichloroacetyl, phenylacetyl, phenoxyacetyl, benzoyl, t. butoxycarbonyl 2-chloro-dimethyl-1,1-ethoxycarbonyl-2,2,2-trichloroethoxycarbonyl-2,2,2-trichloro-1,2-dimethyl-2-ethoxycarbonyl 2-cyano-dimethyl-1,1-ethoxycarbonyl-2-trimethylsilyl ethoxycarbonyl benzyloxycarbonyl p-methoxybenzyloxycarbonyl dimethoxy 3,5-benzyloxycarbonyl p-nitrobenzyloxycarbonyl diphenylmethoxycarbonyl (biphenyl-4-yl) -2-isopropyloxycarbonyl vinyloxycarbonyl allvloxycarbonyl-8-quinolyl-oxycarbonyl n-nitrophenylthio p-nitrophenylthio
Examples of methyleneimino radicals that may be mentioned are dimethylaminomethylene thyleneimino 3,4-dimethoxybenzylideneimino-4-nitro benzylideneimino
Removal of the radical R is carried out by any known method to release an amine function without affecting the rest of the molecule.

 By way of example, mention may be made of the following methods when R 7 represents trityl, benzhydryl, trichloroacetyl, chloroacetyl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, 3-methoxybenzyloxycarbonyl and p-nitrobenzyloxycarbonyl, according to the methods mentioned above for the release of the amino radical from product of general formula (IX) - when R7 represents formyl, 2-chloro-dimethyl-1,1 ethoxycarbonyl, 2-cyano-dimethyl-1,1 ethoxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, (biphenylyl-4) -2 isopropyloxycarbonyl , vinyloxycarbonyl, allyloxycarbonyl, 8-quinolyloxycarbonyl, o-nitro-phenylthio, p-nitrophenylthio, and - when R7NH is replaced by dimethylaminomethyleneimino, 3,4-dimethoxybenzylideneimino or 4-nitro-benzylideneimino: by hydrolysis in an acidic medium, - when R7 represents 2,2,2-trichloro-2-ethyl or 2,2,2-trichloro-1,1-dimethyl-ethoxycarbonyl: by treatment with zinc in the acetic acid - when R7 represents acetyl benzoyl, phenylacetyl or phenoxyacetyl: according to the method described in Belgian Patent 758,800, - when R7 represents trimethylsilylethoxycarbonyl: according to the method described by H.GERLACH, Belv. Chim. Acta 60 (8), 3039 (1977), when R7 represents p.nitrobenzyloxycarbonyl: by hydrogenolysis in the presence of palladium.

(dans laquelle R"3, R7 et n sont définis comme précédemment, étant entendu que lorsque n = O le produit se présente sous forme bicyclooctène-2 ou -3 ou oxoéthylidène-3 bicyclooctane et lorsque n = 1 le produit se présente sous forme bicyclooctène-2 ou oxoéthylidène-3 bicyclooctane) suivie éventuellement de la réduction du sulfoxyde obtenu si l'on veut préparer un produit de formule générale (XV) dans laquelle n = O à partir d'un produit de formule générale (XXII) dans laquelle n = 1.The products of general formula (XV) can be prepared by the action of an activated derivative of the acids R '6SO 3 H and R' 6 COOH, of the type
(R'6SO2) 20 (xvIII)
R'6S02 Hal (xix) (R'6CO) 20 (XX)
R'6CO Hal (xxi) (R'6 being defined as above and Hal representing a halogen atom) on a product (or a mixture of isomers) of general formula

(wherein R "3, R7 and n are defined as above, it being understood that when n = 0 the product is in the form of 2-bicyclooctene or -3 or 3-oxoethylidene bicyclooctane and when n = 1 the product is in the form of bicyclooctene-2 or 3-oxoethylidene bicyclooctane) optionally followed by the reduction of the sulfoxide obtained if it is desired to prepare a product of general formula (XV) in which n = 0 from a product of general formula (XXII) in which n = 1.

 It is generally carried out in the presence of a tertiary base. as defined by the general formula (XIV), for example triethylamine or NN-dimethylaniline, in a chlorinated organic solvent (methylene chloride for example), in an ether (dioxane, tetrahydrofuran, for example), in an amide ( dimethylacetamide, dimethylformamide, acetonitrile or N-methylpyrrolidone, or directly in a basic solvent such as pyridine at a temperature between -780C and the reflux temperature of the reaction mixture.

 It is not absolutely necessary to have purified the intermediate of general formula (XXII) to carry out this reaction.

dans laquelle, R"3 et R7 étant définis comme précédemment, le produit se présente sous forme lsicyclooctène-2 ou -3, et le substituant sur l'atome de carbone en position -3 du bicyclooctène présente la stéréoisomerie E ou Z, et
R10 et R11 qui sont identiques ou différents représentent des radicaux alcoyle (éventuellement substitués par un radical hydroxy, alcoyloxy, amino, alcoylamino ou dialcoylamino) ou phényle, ou forment ensemble avec l'atome d'azote auquel ils sont rattachés un hétérocycle saturé à 5 ou 6 chaînons, contenant éventuellement un autre hétéroatome choisi parmi l'azote, l'oxygène ou le soufre et éventuellement substitué par un radical alcoyle.The products of general formula tXXII), in which n is 0, can be obtained by hydrolysis of the stamen (or the mixture of isomeric stamines) of general formula

wherein, wherein R "3 and R 7 are defined as above, the product is in the form of licyclooctene-2 or -3, and the substituent on the carbon atom at the -3 position of bicyclooctene has E or Z stereoisomery, and
R 10 and R 11 which are identical or different represent alkyl radicals (optionally substituted with a hydroxy, alkyloxy, amino, alkylamino or dialkylamino radical) or phenyl, or together with the nitrogen atom to which they are attached form a saturated heterocyclic ring; or 6-membered, optionally containing another heteroatom selected from nitrogen, oxygen or sulfur and optionally substituted by an alkyl radical.

 Preferably, an enamine of general formula (XXIII) in which R10 and R11 each represent a methyl radical is hydrolyzed.

 It is generally carried out in an organic acid (formic acid, acetic acid for example) or mineral (hydrochloric acid, sulfuric acid for example) in the presence or absence of a solvent, in aqueous or organic medium, at a temperature between -20 C and the reflux temperature of the reaction mixture. When operating in an organic medium, the hydrolysis is carried out by adding water to the reaction mixture and then optionally treated with a mineral base (alkaline bicarbonate) or organic (tertiary amine or pyridine).

 When operating in the presence of a solvent, it is not necessary that the solvent is miscible with the acidic aqueous phase. The contact is then carried out by vigorous stirring.

 Among the solvents that may be used, mention may be made of chlorinated solvents, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide and alcohols. it is not absolutely necessary to have purified the intermediate of general formula (XXIII) to implement this reaction.

 The products of general formula (XXII), in which n is equal to 1, are obtained by oxidation of the products of general formula (XXII) for which n is equal to 0 by application of the method described in German Patent Application 2,637 176.

 Similarly, the products of general formulas (XI) or (XV) in which n is equal to 1 can be obtained respectively by oxidation of the products of general formulas (XI) or (XV) in which n is equal to 0 by application of method described in German Patent Application 2,637,176.

éventuellement préparé in situ, tpour lequel R10 et R11 sont définis comme précédemment et R12 et R13, qui sont identiques ou différents, soit représentent des groupements de formule-générale
-x2 R14 (xxv) dans laquelle X2 est un atome d'oxygène et R14 représente un radical alcoyle ou phényle, soit représentent l'un un radical de formule générale (XXV) (dans laquelle
X2 représente un atome d'oxygène ou de soufre et R14 est alcoyle ou phényle), et l'autre un radical amino de formule générale

dans laquelle R15 et R16 sont définis comme R10 et R11, soit encore R12 et R13 représentent chacun un radical de formule générale (XXVI) sur un dérivé de céphalosporine de formule générale

dans laquelle, R"3 et R7 étant définis comme précédemment, le produit se présente sous forme bicyclooctène-2 ou -3 ou méthylène-3 bicyclooctane.The products of general formula (XXIII) in which R10 and R11 have the above definition, with the exception of representing alkyl substituted with hydroxy, amino or alkylamino, may be obtained by the action of a product of general formula

optionally prepared in situ, for which R10 and R11 are defined as above and R12 and R13, which are identical or different, or represent groups of general formula
in which X 2 is an oxygen atom and R 14 represents an alkyl or phenyl radical, or represents a radical of general formula (XXV) (in which
X 2 represents an oxygen or sulfur atom and R 14 is alkyl or phenyl), and the other an amino radical of general formula

in which R15 and R16 are defined as R10 and R11, or else R12 and R13 each represent a radical of general formula (XXVI) on a cephalosporin derivative of general formula

wherein, R "3 and R7 being defined as above, the product is in the form of bicyclooctene-2 or -3 or methylene-3-bicyclooctane.

 When a product of general formula (XXIV) in which the radical (XXVI) is different from -NRIoRll is chosen, it is preferable to choose such a product so that the amine HNR15R16 is more volatile than HNR10R11.

 It is generally carried out in an organic solvent such as dimethylformamide, or in a mixture of solvents (dimethylformamidetetrahydrofuran, dimethylformamide dimethylacetamide, dimethylformamide-ether or dimethylformamide-dioxane for example) at a temperature between 200C and the reflux temperature of the reaction mixture.

 The products of general formula (XXIII) in which R "3 and R 7 are defined as above and R 10 and R 11 represent hydroxyl, amino or alkylamino substituted alkyl radicals can be obtained by transenamination from a product of general formula (XXIII). ) in which R10 and R11 represent alkyl radicals, preferably methyl.

dans laquelle R'lo et R'11 qui sont identiques ou différents, représentent des radicaux alcoyle substitués par hydroxv, amino oualcoylamino, sur le produit de formule générale (XXIII) et l'on opère dans les conditions décrites précédemment pour l'action d'un produit de formule générale (XXIV) sur un dérivé de formule générale (XXVII).The reaction is carried out by the action of an amine of general formula

in which R'lo and R'11 which are identical or different, represent alkyl groups substituted by hydroxv, amino or alkylamino, on the product of general formula (XXIII) and one operates under the conditions described previously for the action of a product of general formula (XXIV) on a derivative of general formula (XXVII).

 The products of general formula (XXIV) can be prepared according to the methods described by H. BREDERECK et al., Chem.

Ber. 41 (1968), Chem. Ber. 101, 3058 (1968) and Chem. Ber. 106, 3725 (1973).

 The cephalosporin derivatives of general formula (XXVII) in which R "3 represents a radical of general formula (X) can be obtained by esterification of the corresponding acids by any known method to obtain an ester from an acid, without touching to the rest of the molecule.

(dans laquelle R7 est défini comme précédemment) sur un produit de formule générale

(dans laquelle R4 et R5 sont définis comme précédemment et Z2 représente un atome d'halogène) dans un solvant inerte tel que le diméthylformamide à une température comprise entre O et 300C. Generally, an alkali metal salt or a tertiary amine salt of a product of general formula is reacted.

(in which R7 is defined as above) on a product of general formula

(In which R4 and R5 are defined as above and Z2 represents a halogen atom) in an inert solvent such as dimethylformamide at a temperature between 0 and 300C.

dans laquelle la position de la double liaison est définie comme précédemment, selon les méthodes connues ou décrites dans la littérature : - lorsque R7 est un radical formyle : selon J.C. SHEENAN et coll.,
J. Amer. Chem. Soc. 80 1156 (1958), - lorsque R7 est acétyle, chloracétyle, trichloracétyle, phénylacétyle, phénoxyacétyle ou benzoyle : selon E.H. FLYNN, Cephalosporins and
Penicillins, Ac. Press (1972), - lorsque R7 est un radical t.butoxycarbonyle : selon L. MORODER et coll., Hoppe Seylers's Z. Physiol. Chem. 357 1651 (1976), - lorsque R7 est trichloro-2,2,2 diméthyl-l,l éthoxycarbonyle : selon
J. UGI et coll., Angew. Chem. Int. Ed.Engl. 17(5) 361 (1978), - lorsque R7 est trichloro-2,2,2 éthoxycarbonyle, chloro-2 diméthyl1,1 éthoxycarbonyle, cyano-2 diméthvl-l,l éthoxycarbonyle, triméthylsilyl-2 éthoxycarbonyle, benzyloxycarbonyle, p.méthoxybenzyloxycarbonyle, diméthoxy-3,5 benzyloxycarbonyle, p.nitrobenzyloxycarbonyle, vinyloxycarbonyle : par action d'un chloroformiate en milieu hydroorganique en présence d'un bicarbonate alcalin, ou selon le brevet belge 788 885, - lorsque R7 est diphénylméthoxycarbonyle : par action de l'azidoformiate correspondant en milieu hydroorganique, en présence d'un bicarbonate alcalin, - lorsque R7 est (biphénylyl-4)-2 isopropyloxycarbonyle : par analogie avec la méthode décrite par Helv. Cnim. Acta, 51, 924 (1968), - lorsque R7 est quinolyl-8 oxycarbonyle ou allyloxycarbonyle : par action du carbonate correspondant en milieu hydroorganique basique, - lorsque R7 est o.nitrophénylthio ou p.nitrophénylthio : par analogie avec la méthode décrite par L. ZERVAS et coll., J. Amer. Chem. Soc. 85, 3660 (1963), - lorsque R7NH est remplacé par diméthylaminométhylèneimino : par analogie avec la méthode décrite par J.F. FITT, J. Org. Chem. 42(15), 2639 (1977), - lorsque R7NH est remplacé par nitro-4 benzylidèneimino ou diméthoxy-3,4 benzylidèneimino : selon la méthode décrite par R.A. SIRESTONE, Tetrahedron Lett., 33, 2915 (1977), - lorsqu'e R"3 est méthoxyméthyle : selon S. SEKI et coll., Tetrahedron
Lett. 33, 2915 (1977), - lorsque R"3 est t.butyle : selon R.J. STEDMAN, J. Med.Chem., 9, 444 (1966), - lorsque R"3 est benzhydryle : selon la demande de brevet néerlandais 73 03263, - lorsque R"3 est p.nitrobenzyle ou p.méthoxybenzyle : selon R.R.The introduction of the protective groups R "3 and R 7 of the product of general formula (XXVII) fou (XXIX) for RX can be carried out on a 7-amino cephalosporin of general formula

in which the position of the double bond is defined as above, according to known methods or described in the literature: when R 7 is a formyl radical: according to JC SHEENAN et al.,
J. Amer. Chem. Soc. 80 1156 (1958), - when R7 is acetyl, chloroacetyl, trichloroacetyl, phenylacetyl, phenoxyacetyl or benzoyl: according to EH FLYNN, Cephalosporins and
Penicillins, Ac. Press (1972), when R7 is a t.butoxycarbonyl radical: according to L. MORODER et al., Hoppe Seylers' Z. Physiol. Chem. 357 1651 (1976), when R7 is 2,2,2-trichloro-1,1-dimethyl-ethoxycarbonyl: according to
J. UGI et al., Angew. Chem. Int. Ed.Engl. 17 (5) 361 (1978), when R7 is 2,2,2-trichloroethoxycarbonyl, 2-chloro-dimethyl-1,1-ethoxycarbonyl, 2-cyano-dimethyl-1,1-ethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl , 3,5-dimethoxybenzyloxycarbonyl, p.nitrobenzyloxycarbonyl, vinyloxycarbonyl: by action of a chloroformate in a hydroorganic medium in the presence of an alkaline bicarbonate, or according to Belgian Patent 788,885, when R7 is diphenylmethoxycarbonyl: by action of the corresponding azidoformate in a hydroorganic medium, in the presence of an alkaline bicarbonate, - when R7 is (biphenylyl-4) -2 isopropyloxycarbonyl: by analogy with the method described by Helv. Cnim. Acta, 51, 924 (1968), - when R7 is 8-quinolyloxycarbonyl or allyloxycarbonyl: by the action of the corresponding carbonate in a basic hydroorganic medium, - when R7 is o.nitrophenylthio or p.nitrophénylthio: by analogy with the method described by L ZERVAS et al., J. Amer. Chem. Soc. 85, 3660 (1963), when R7NH is replaced by dimethylaminomethyleneimino: by analogy with the method described by JF FITT, J. Org. Chem. 42 (15), 2639 (1977), when R7NH is replaced by 4-nitrobenzylideneimino or 3,4-dimethoxybenzylideneimino: according to the method described by RA SIRESTONE, Tetrahedron Lett., 33, 2915 (1977), when e R "3 is methoxymethyl: according to S. SEKI et al., Tetrahedron
Lett. 33, 2915 (1977), when R "3 is t.butyl: according to RJ STEDMAN, J. Med. Chem., 9, 444 (1966), - when R" 3 is benzhydryl: according to the Dutch patent application 73 03263, - when R "3 is p.nitrobenzyl or p.methoxybenzyl: according to RR

CHAUVETTE et al., J. Org. Chem. 38 (17) 2994 (1973).

 The isomers of the products of general formulas (xi), (XV), (xxII), (XXIII), (xxix) and (xxxI) can be separated by chromatography or by crystallization.

 The cephalosporin derivatives of general formula (IX) and their pharmaceutically acceptable salts have particularly advantageous anti-bacterial properties. They exhibit remarkable in vitro and in vivo activity on Gram-positive and Gram-negative organisms.

 In vitro, the products of general formula (IX) were active at a concentration of between 0.25 and 15 μg / cm 3 on strains of penicillin G-sensitive staphylococci (Staphylococcus aureus Smith) at a concentration of between 0.degree. , 5 and 30 μg / cm3 on staphylococci strains resistant to penicillin G (Staphylococcus aureus MB 9), at a concentration of between 0.0005 and 1 μg / cm3 on Escherichia coli strain Monod, at a concentration between 0, 06 and 30 μg / cm3 on Klebsiella pneumoniae.

In addition, some of them have been active at a concentration of between 0.01 and 30 μg / cm3 on Proteus morganii and at a concentration between 0.1 and 30 μg / cm3 on Enterobacter aerogenes.

In vivo, the products of general formula (IX) have been shown to be active on experimental infections of the mouse with
Staphylococcus aureus Smith (penicillin G sensitive) at a dose of 0.2 to 15 mg / kg daily subcutaneously, at
Escherichia coli (Monod strain) at doses of 0.001 to 10 mg / kg daily subcutaneously.

 Furthermore, the LD50 of the products of general formula (IX) is between 1.5 g / kg and doses greater than 2.5 g / kg subcutaneously in mice.

 The novel products produced according to the invention may be optionally purified by physical methods such as crystallization or chromatography.

 The general tormile products (I) in which R contains a carboxy or sulfo radical can also be converted to metal salts or addition salts with tertiary nitrogen organic bases by methods known per se. These salts can be obtained by the action of a metal base (for example alkaline or alkaline earth) or of a tertiary amine on a product of general formula (I) in a suitable solvent such as an alcohol or an ether or by exchange reaction with a salt of an organic acid. The salt formed precipitates, after optional concentration of its solution, it is separated by filtration or decantation.

 Examples of salts which may be mentioned are salts with alkali metals (such as potassium, sodium or lithium salts) or with alkaline earth metals and tertiary nitrogen base salts (salts of pyridine, triethylamine, diisopropylethylamine, N-ethylpiperidine and N-methylmorpholine).

 These salts can be used, in the same way as the corresponding acids, for the preparation of cephalosporins of general formula (IX).

 The following examples, given by way of non-limiting example, illustrate the present invention.

EXAMPLE 1-
To a cooled suspension at 4 ° C. of 8.88 g (2-trityamino-4-thiazolyl) -2-acetic acid, syn isomer and of 2.64 g of 5-mercapto-2-methyl-1,3,4-thiadiazole in 200 cm 3 of To ethyl acetate, 4.96 g of N, N'-dicyclohexylcarbodiimide are added with stirring in one go. It is stirred for 4 hours at 40 ° C., the suspension is filtered, the mixture is washed twice with 200 cm 3 of water, twice with 100 cm 3 of a half-saturated solution of sodium bicarbonate and 100 cm 3 of a saturated solution of sodium chloride. sodium sulfate, filter, concentrated at 20 cm3 at 200C under 20 mm Hg (2.7 kPa) and filtered. The filtrate is diluted with 200 cm3 of petroleum ether, filtered and collected 6.2 g of yellow powder corresponding to the expected crude product.

 the puritication is carried out as follows: or refluxing the preceding product with 200 cm 3 of cyclohexane, heat filter, concentrate the filtrate to 3 () cm3 (20 C under 20 mm of mercury, 2.7 kPa) , filter and collect 4.5 g of [2-methoxyimino-2- (2-trityamino-4-thiazolyl) -2-acetylthio] methyl-2-thiadiazole-1,3-isomer syn.

Proton NMR Spectrum (80 MHz, CDCl 3, 6 ppm, J in Hz) 2.85 (s, 3H, (-CH 3); 4.08 (s, 311, = NOCH 3); 6.60 (s, 1H, H thiazole)
Infra-red spectrum (CHBr3), characteristic bands (cm-1) 1695, 1605, 1580, 1530, 1490, 1450, 1050, 900.

EXAMPLE 2
To a cooled solution at 4 ° C of 0.89 g of 2-methoxyimino-2 (2-trityamino-4-thiazolyl) acetic acid, syn isomer, and 0.47 g of (2,2-dimethoxyethyl) 4-dioxo-5,6 thioxo-3-perhydrotriazine-1,2,4 in 20 cm3 of dimethylformamide is added at once 0.50 g of
N, N'-dicyclohexylcarbodiimide; the mixture is stirred for 1 hour at 4 ° C. and then for 3 hours at 200 ° C. The reaction suspension is filtered, the filtrate is diluted with 100 cm 3 of ethyl acetate, washed with twice 50 cm 3 of water, twice with 50 cm 3 of a 1% solution of sodium bicarbonate and twice with 50 cm 3. of a half-saturated solution of sodium chloride, dried over sodium sulphate, filtered and concentrated to dryness at 200 ° C. under 20 mm of mercury (2.7 kPa). The residue is triturated in 10 cm 3 of sodium oxide. isopropyl and obtained after filtration and drying 0.91 g of 2- (2,6-dimethoxyethyl) -5,5-dioxo-2-methoxyimino (2-tritylamino-4-thiazolyl) acetylthio] -3-tetrahydro-1,4, 5.6 1,2,4-triazine, syn isomer, as a yellow powder.

Proton NMR Spectrum (80 MHz, CDCl3, 6 ppm, JHz) 3.30 (s, 6H, -OCH3); 4.05 (s, 3H, = NOCH3); 4.28 (d, J = 5.2H,> NCH 2 -); 4.66 (J = 5, 1H, -CH =); 6.68 (s, 1H, thiazole H)
Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3380, 1720, 1585, 1525, 1490, 1450, 1040, 900, 750, 730.

2- (2-Dimethoxyethyl) -4,5-dioxo-3-thioxo-1,2,4-perhydrotriazine can be prepared in the following manner
A solution of sodium methylate is prepared by dissolving 4.15 g of sodium in -140 cm3 of methanol, adding 32.3 g of (2,2-dimethoxyetllyl) -4 thiosemicarbazide and adding 26.3 g of ethyl oxalate. Refluxed with stirring for 4 hours and allowed to cool. After one night, the suspension obtained is filtered and the precipitate washed with 3 times 25 cm3 of ether. The solid is dissolved in 40 cm3 of water and, after cooling to 4 ° C., the solution is acidified to pH 3 with 4N hydrochloric acid and left at 4 ° C. for 30 minutes. After filtration and drying, 12 g of 4- (2,2-dimethoxyethyl) -5,5-dioxo-3-thioxo-1,2,4-perhydrotriazine are collected in the form of a white solid. inst. (Kofler) = 172 C (dec.).

Intra-red spectrum (KBr), characteristic bands (cm) 3280, 3250, 1695, 1380, 1130, 1050
NMR spectrum of C80 MHz proton, DMSO d6.6 in ppm, J in Hz) 3.30 (s, 6H, -OCP13); 4.38 (d, J = 5.5, 2H, NCH 2 -); 4.94 (t, J = 5.5, 1H, -CH (OCH3) 2).

(2,2-Dimethoxyethyl) thiosemicarbazide can be prepared in the following manner
To a solution of 14.35 g of hydrazine hydrate in 40 cm3 of ethanol, 37.7 g of dimethoxy-2 isothiocyanate are added over 1 hour, with stirring at a temperature of between 5 and 9 ° C. 2 ethyl.

After 12 hours at 4 ° C., the mixture is concentrated to dryness at 200 ° C. under reduced pressure (20 mm Hg, 2.7 kPa). The yellow syrup obtained crystallizes after priming. The solid is dissolved in hot in 50 cm3 of methanol, filtered and diluted with 200 cm3 of diethyl ether. After about 10 hours at 4 ° C., 32.3 g of (2,2-dimethoxyethyl) -4-thiosemicarbazide are collected in the form of a white solid. F. inst. (Kofler) = 69 C.

REFERENCE EXAMPLE A
The product of Example 1 can be used as follows
A mixture of 1.16 g of 7-amino-2-benzhydryloxycarbonyl-2-oxo-5-oxide (2-tosyloxy-vinyl) -5-thia-5-azabicyclo [4.2.0] is stirred for 1 hour at 60 ° C. under nitrogen. ] Octene-2, Form E, 35 cm3 of dimethylformamide, 1.67 g of 2-methoxyimino-2 (2-trityamino-4-thiazolyl) -2-acetylthio] -5-methyl-thiadiazole-1,3,4 isomer syn and O, 35 cm3 of N, N-diisopropylethylamine. The mixture is diluted with ethyl acetate (140 cc), the solution is washed with water (3 × 70 cc), dried over sodium sulphate, filtered and concentrated to dryness at 200 ° C. under 20 mm Hg (2.7 kPa). The residue is taken up in 25 cm3 of methylene chloride, 5 g of Merck silica gel (0.06-0.2 mm) are added, the mixture is concentrated to dryness at 200 ° C. under 20 mm of mercury (2.7 kPa) and the mixture is removed. the powder on a 35 g column of Merck silica gel (0.06-0.2) (column diameter 2 cm). 80 cm (vol.), 250 cm.sup.3 of a 60-40 (vol.) Mixture, 500 cm.sup.3 of a 40-60 (vol.) Mixture are successively eluted with 100 cm.sup.3 of a mixture of ethyl cyclohexaneacetate (vol. 500 cm3 of a mixture of 20-80 (vol.) And 500 cm3 of pure ethyl acetate collecting 60 cm3 fractions. Concentrated to dryness at 200C under 20 mm of mercury (2.7 kPa) fractions 17 to 26 and collected 0.56 g of 2-benzhydryloxycarbonyl-2-methoxyimino-2 (2-trityamino-4-thiazolyl) acetamido] -7 C (2-methyl-1,3,4-thiadiazol-5-thio) -vinyl 3-oxo-8-oxide-5-thia-5-azabicyclo [4.2.2] octene-2, syn isomer, E-form as a pink meringue.

Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3380, 1800, 1725, 1680, 1515, 1490, 1445, 1045, 935, 750
Proton NMR Spectrum (350 MHz, CDCl 3, 6 ppm, J in Hz) 2.72 (s, 3H, -CH 3); 3.28 and 4.08 (2d, J = 18, 2H, -SCH 2 -); 4.07 (s, 3H, -OCH3); 4.60 Cd> J = 4, 1H, H at 6); 6.16 (dd, J = 4 and 9, 1H, H at 7); 6.71 (s, 1H, H thiazole); 6.95 (s, 1H, -COOCH-); 7.07 (s, 1H, -NH C (C6H5) 3); 7.23 and 7.33 (2d, J = 16, -CH = CH-).

 To a solution of 5.11 g of 2-benzhydryloxycarbonyl-2-methoxyimino (2-trityamino-4-thiazolyl) acetamidyl-7- (2-methylthiadiazol-1,3,4-yl-5) thio-2-vinyl] -3 8-oxo-5-thia-5-aza-1 bicyclos [4.2.0] octene-2, syn isomer, E-form and 2.1 cm3 of dimethylacetamide in 50 cm3 of methylene chloride, is added at -8 ° C. and with stirring 0.93 cm3 of phosphorus trichloride. The mixture is stirred for 1 hour at -80 ° C. and the mixture is diluted with 1 liter of ethyl acetate, washed twice with 250 cm 3 of half-saturated sodium bicarbonate solution and twice with 250 cm 3 of a half solution of sodium bicarbonate. saturated with sodium chloride, dried over sodium sulphate and concentrated to dryness at 200C under 20 mm of mercury (2.7 kPa) .The product, dissolved in 50 cm3 of a cyclohexane-ethyl acetate mixture. 60 (vol.), Is chromatographed on a column of 150 g of Merck silica gel (0.04-0.06) (column diameter: 5 cm). The mixture is eluted with 3 liters of the above mixture under a pressure of 4 kPa, collecting 125 cm3 fractions. Fractions 10 to 20 are concentrated to dryness at 200C under 20 mm of mercury (2.7 kPa). 2.69 g of 2-benzhydryloxycarbonyl-2-imethoxyimino-2- (2-trityamino-4-thiazolyl) -acetamido] -7 [(2-methyl-thiadiazol-1,3,4-yl-5) -thio-2-vinyl-3-oxo) are collected. 8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E as a yellow meringue.

Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3390, 1785, 1720, 1685, 1515, 1495, 1445, 1045, 940, 755
Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, JHz) 2.75 (s, 3H, -CH3); 3.60 and 3.69 (2d, J = 18, 2H, -SCH 2 -); 4.09 (s, 3H, -OCH3); 5.09 (d, J = 4.1H, H at 6); 5.93 (dd, J = 4 and 9, 1H, H at 7); 6.75 (s, 1H, H thiazole); 6.98 (s, 1H, -COOCH-) 7.0 (s, 1H, -NH C (CH) 3); 7.22 (d, J = 14, 1H, -CH = CHS-).

 A mixture of 2.37 g of 2-benzhydryloxycarbonyl [2-methoxyimino-2-tritylamino-4-thiazolyl] -2-acetamido] -7-methyl-1,3,4-thiadiazol-5-yl is stirred at 50 ° C. for 15 minutes. 2-thio-viny-3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E in 30 cc of formic acid supplemented with 14 cm3 of water. Allowed to cool, diluted with 16 cm3 of water and filtered. The filtrate is concentrated to dryness at 30 ° C. under 0.05 mm of mercury (0.007 kPa) and the residue is taken up with 3 times 50 cm 3 of ethanol, while concentrating to dryness each time. The solid obtained is stirred at 500C in 35 cm3 of ethanol for 25 minutes, filtered, washed with twice 20 cm3 of ethyl ether and dried. 1.18 g of [(2-amino-4-thiazolyl)) are collected. -2-Methoxyimino-2-acetamido-7-carboxy-2 - [(2-methyl-thiadiazol-1,3,4-yl) -5-thio-vinyl] -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene 2, syn isomer, form E in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm-1) 3400-, 3200, 3100, 2200, 1775, 1675, 1530, 1045, 940
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 2.74 (s, 3H, -CH3); 3.67 and 3.94 (2d, J = 18, 2H, -SCH 2 -); 3.86 (s, 3H, -OCH 3); 5.21 (d, J = 4, 1H, H at 6); 5.80 (2d, J = 4 and 9, 1H,
H in 7); 6.75 (s, 1H, H thiazole); 7.12 and 7.17 (2d, J = 16, 2H, -CH = GHS-); 7.20 (s, 2Hs-Nil 2); 63 (d, J = 9, 1H, -CONH-).

7-Amino-2-benzhydryloxycarbonyl-5-oxo-5-oxide (2-tosyloxyvinyl) thia-5-aza-1-bicyclo [4.2.0] octene-2, form E can be obtained as follows
A solution of 54.3 g of 2-benzhydryloxycarbonyl-2-butoxycarbonylamino-7-oxo-5-oxide (2-tosyloxy-vinyl) -3-thia-5-azabicyclo [4.2.0] is stirred at 35 ° C. for 2 hours. octene-2, E-form and 30.4 g of p-toluenesulphonic acid hydrate in 1.4 liters of acetonitrile.A concentrated to dryness at 300c under 20 mm of mercury (2.7 kPa), resumes in 1 liter of ethyl acetate, washed twice with 500 cm3 of a semisaturated solution of sodium bicarbonate and twice with 500 cm3 of a semisaturated solution of sodium chloride, dried over sodium sulphate and concentrated to dryness at 20 ° C. under 20 mm of mercury (2, j kPa). The residue is triturated in 200 cm3 of ether. There is obtained 28.13 g of 4-amino-2-benzhydryloxycarbonyl-5-oxo-5-oxide (2-tosyloxyvinyl) -5-thia-5-aza-1-bicyclo [4.2.0] octene-2, form E in the form of a light brown powder.

Rf = 0.32 silica gel chromatoplate [methylene chloride
methanol 85-15 (vol.) j.

2-Benzhydryloxycarbonyl-2-tert-butoxycarbonylamino-7-oxo-5-oxide (2-tosyloxyvinyl) thia-5-aza-1-bicyclo [4.2.0] octene-2 can be prepared in the following manner
In a cooled solution at 100 ° C. of 180.56 g of 2-benzhydryloxycarbonyl-2-t-butoxycarbonylamino-7-oxo-8 (tosyloxy-2-vinyl) -3-thia-5-aza-1-bicyclo [4.2.0 octene-2 (or -3) ) (mixture of E and Z forms) in 1.4 liter of methylene chloride, a solution of 55.22 g of 85% mchloroperbenzoic acid in 600 cm 3 of methylene chloride is added dropwise over 2 hours. . The mixture is washed with 1.5 liters of a 5% solution of sodium bicarbonate and twice with 1.5 liters of water, dried over sodium sulphate and concentrated at 200 ° C. under reduced pressure (20 mm Hg; , 7 kPa) up to the volume of 300 cm3. This solution is chromatographed on a column of 3 kg of Merck silica gel (0.05-0.2) (diameter of the column: 9.2 cm height: 145 cm). Eluted with cyclohexane-acetate mixtures. ethyl, successively: 15 liters 80-20 (vol.) Jet 32 liters [70-30 (vol.)) collecting 600 cc fractions. Fractions 27 and 28 are collected and evaporated to give 5.56 g of the Z form of 2-benzhydryloxycarbonyl-2-tibutoxycarbonylamino-7-oxo-5-oxide (2-tosyloxy-vinyl) -3-thia-5-azabicyclo [4.2 .0] octene-2.

Infra-red spectrum (CHBr3), characteristic bands (cm) 3420, 1800, 1720, 1505, 1380, 1370, 1195, 1180, 1050, 1010, 730
Proton NMR Spectrum (350 MHz, CDCl 3, 6 ppm, J in Hz) 1.49 (s, 9H, -C (CH 3) 3); 2.44 (s, 3H, -CH3); 3.36 and 4.04 (2d, J = 19, 2H, -SCH 2 -); 4.44 (d, J = 4.5, 1H, H at 6); 5.73 (d, J = 9, 1H, -CONH-); 5.81 Cdd, J = 4.5 and 9, 1H, H at 7); 6.42 (d, J = 7, H, -CH = CH-OSO 2 -) 6.46 (d, J = 7.1H = CH-OSO 2 -); 6.89 (s, 1H, -COOCH #); 7.77 (d, J = 9, 2H, H ortho ortho tosyl).

 Fractions 29 to 34 give 26 g of the mixture of Z and E forms.

Finally, in fractions 35 to 58, 43 g of the product form E are obtained.
Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3420, 1800, 1720, 1505, 1380, 1370, 1195, 1180, 1075, 935, 745
Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, JHz) 1.48 (s, 9H, (CH3) 3C-); 2.46 (s, 3H, -CH3); 3.16 and 3.81 (2d, J = 18, 2H, -SCH 2 O, 4.46 (d, 1 = 4.5, 1H, H at 6), 5.73 (d, J = 9, 1H); , -CONH-); 5.8 (dd, J = 9 and 4.5, 1H, H at 7); 6.83 (d, J = 13, 1H, -CH-CH-OSO 2 -) 6.83 (s, 1H, -COOCH #); 7.08 (d, J = 13, 1H, = CH-OSO 2 -); 7.73 (d, J = 9, 2H, H in tosyl ortho).

2-Benzhydryloxycarbonyl-tert-butoxycarbonylamino-7-oxo-8 (2-tosyloxyvinyl) thia-5-aza-1-bicyclo [4.2.0] octene-2 (or -3) (mixture of E and Z forms) can be obtained in the following manner
To a solution of 113.7 g of 2-benzhydryloxycarbonyl-2-t-butoxycarbonylamino-7 (2-dimethylamino-vinyl) -3-oxo-5-thia-5-aza-1-bicyclo [4.2.0] octene-2 (Form E) in 1 liter of tetrahydrofuran, a solution of 50 cm3 of formic acid in 500 cm3 of water is added.

The homogeneous solution is stirred at 20 ° C. for 20 minutes and then concentrated to a quarter of its volume under reduced pressure (20 mm of mercury, 2.7 kPa at 200 ° C.). The concentrate is taken up in 2 liters of ethyl acetate, washed with twice 500 cm 3 of a 5% solution of sodium bicarbonate, 2 times 500 cm 3 of water and 2 times 500 cm 3 of a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness at 200C under reduced pressure (20 mm Hg, 2.7 kPa). 112.4 g of crude product are treated, which are treated in solution in 250 cm 3 of pyridine at 50 ° C. with 57.2 g of tosyl chloride. After 30 minutes at SOC and 1 hour at 200 ° C., the solution is poured into 1 liter of a crushed ice-water mixture. The aqueous phase is separated off and the insoluble material is washed with 300 cm 3 of distilled water. The pasty product is dissolved in 200 cm 3 of ethyl acetate, washed twice with 750 cm 3 of 1N hydrochloric acid, twice. 750 cc of a 5% solution of sodium bicarbonate and 4 times 750 cc of dry water over sodium sulfate and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa at 200C). 121 g of 2-benzhydryloxycarbonyl-2-tert-butoxycarbonylamino-7-oxo-8 (2-tosyloxy) -vinyl-5-aza-1-bicycloE4.2.02-octene-2 (or -3) (mixture of E and Z forms) are obtained. the shape of a raw brown meringue.

The mixture of E and Z forms of benzhydryloxycarbonyl-2-t-butoxycarbonylamino-7 (2-dimethylamino-vinyl) -3-oxo-5-thia-5-aza-1-bicyclo [4.2.0] octene-2 and -3 can be obtained by operating as follows
90.5 g of 2-benzhydryloxycarbonyl-4-butoxycarbonyl-7-amino-3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2 are dissolved in 400 cm 3 of anhydrous N, N dimethylformamide. The solution obtained is heated at 80 ° C. under a nitrogen atmosphere. A solution of 36.1 g of bis-dimethylamino t.butoxymethane in 60 cm3 of anhydrous N, N dimethylformamide preheated to 800 ° C. is then added rapidly. The reaction mixture is maintained at 800 ° C. for 5 minutes and then poured into 3 liters of ethyl acetate. After addition of 1 liter of distilled water, the organic phase is decanted, washed with 4 times 1 liter of distilled water, dried. over sodium sulphate and filtered in the presence of bleaching black. It is concentrated to dryness under reduced pressure (20 mm of mercury 2.7 kPa) at 300 ° C. to give 101 g of 2-benzhydryloxycarbonyl-2-tert-butoxycarbonylamino-7 (2-dimethylamino-vinyl) -3-oxo-5-thia-aza-1-bicyclo [4.2.0] octene-2 (E-form) as an orange meringue.

Rf = 0.29; silica gel chromatoplate [cyclohexane-acetate
50-50 (vol.)].

The 2-benzilydryloxy-2-carboxy-2-butoxycarbonylamino-3-methyl-8-oxo-5-thia-aza-1-bicyclo [4.2.0] octene-2 can be obtained in the following manner
To a solution of 188.6 g of t-butoxycarbonylamino-7-carboxy-2-methyl-3-oxo-8-thia-5-aza-1-bicycloE4.2.0 octene-2 in 2100 cm3 of acetonitrile is added dropwise in 45 minutes. at a temperature between 25 and 30 C, a solution of 116.5 g of diphenyldiazomethane in 800 cm3 of acetonitrile. The reaction mixture is stirred for 16 hours at 22 ° C and then concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 40 ° C. The residue is redissolved in 2 liters of ethyl acetate and the solution is dissolved in water. is washed with 700 cm 3 of 2N hydrochloric acid, then with 700 cm 3 of saturated aqueous sodium bicarbonate solution and with 700 cm 3 of saturated aqueous sodium chloride solution, the solution is dried over sodium sulphate, treated with decolourising black and filtered and then concentrated to dryness under reduced pressure (20 mm of mercury, 2.7 kPa) at 40 ° C. The residue is dissolved in 600 cm 3 of ethyl acetate to boiling point, 1 liter of cyclohexane is added, the mixture is heated at reflux and then The resulting crystals are filtered off, washed with diethyl ether (3 × 250 cc) and dried.) 191 g of 2-benzhydryloxycarbonyl-2-tert-butoxycarbonylamino-7-methyl-3-oxo-5-thia-5-azabicyclo [4] are obtained. .2.01 octene-2 in the form of white crystals (F = 1790C).

Concentration of the mother liquors at 500 cm 3 gives a second product fraction (32.6 g, mp = 178 ° C.).

T-Butoxycarbonylamino-7-carboxy-2-methyl-8-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2 can be obtained as follows
371 g of 7-amino-2-carboxymethyl-3-oxo-5-thia-4-azabicyclo2.2.2 octene-2 are dissolved in a solution of 307 g of sodium bicarbonate in a mixture of 2 liters of distilled water. and 2 liters of dioxane. A solution of 421 g of di-butyldicarbonate in 2 liters of dioxane is added over 10 minutes. The reaction mixture is stirred for 48 hours at 25 ° C. The suspension obtained is concentrated under reduced pressure (20 mm of mercury, 2.7 kPa) at 500 ° C. to a residual volume of approximately 2 liters, then diluted with 1 liter of ethyl acetate and 2 liters of distilled water. The aqueous phase is decanted, washed with 500 cm3 of ethyl acetate and acidified to pH = 2 with 6N hydrochloric acid in the presence of 1500 cm3 of ethyl acetate. The aqueous phase is extracted with 2 times 1 liter of ethyl acetate. The combined organic phases are washed with twice 250 cm3 of saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is evaporated under reduced pressure (20 niai of mercury, 2.7 kPa) at 50 ° C. 486 g of t-butoxycarbonylamino-7-carboxy-2-methyl-3-oxo-8-thia-5-aza-1 are obtained. bicyclor4.2.02 octene-2 in the form of yellow crystals (F = 1900C, decomposition).

REFERENCE EXAMPLE B
The product of Example 2 can be used as follows
A mixture of 0.23 g of 7-amino-2-benzhydryloxycarbonyl-5-oxo-5-oxo-2-tosyloxy-vinyl-5-thia-5-azabicycloic acid is stirred for 5 hours at 60 ° C. under nitrogen. [4.2.0] octene-2, form E, 15 cm3 of dimethylformamide, 0.40 g of (2,2-dimethoxy-ethyl) -4-dioxo-5,6 [2-methoxyimino-2-tritylamino-4-thiazolyl] 2 acetylthio] -3,4,6,6-tetrahydro-1,2,4-triazine, syn-isomer, and 0.07 cc of N, N-diisopropylethylamine, diluted with 60 cm3 of ethyl acetate, the solution was washed with 3 times 30 cm3 of water and then 2 times 30 cm3 of a half-saturated solution of sodium chloride, dried over sodium sulphate, filtered and concentrated to dryness at 20 ° C. under 20 mm of mercury (2.7 kPa) The residue is taken up in 10 cm3 of methylene chloride, 2 g of Merck silica gel (0.06-0.2) are added and the mixture is concentrated to dryness at 20 ° C. under 20 mm of mercury (2.7 kPa).

The powder obtained is deposited on a column of 8 g of silica gel
Merck (0.06-0.2) (column diameter: 1.2 cm). 50 cm3 of a cyclohexane-ethyl acetate mixture 80-20 (vol.), 100 cm3 of the mixture 60-40 (vol.), 100 cm3 of the mixture 40-60 (vol.), 200 cm3 are eluted successively. mixture 20-80 (vol) and 200 cm3 of pure ethyl acetate collecting 25 cm3 fractions. The fractions 1-2 to 19 are concentrated to dryness at 200 ° C. under 20 mm of mercury (2.7 kPa) and 0.19 g of 2-benzhydryloxycarbonyl-2- [1- (dimethoxy-2,2-ethyl) dioxo-5 are collected. Tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-thio-2-vinyl] -3 [2-methoxyimino-2-tritylamino-4-thiazolyl] acetamidol-7-oxo-8-oxide 5-thia-5-azabicyclo [4.2.0] octene-2, syn-isomer, E-form as a beige meringue.

Infra-red spectrum (KBr), characteristic bands (cm) 3380, 3250, 1795, 1720, 1685, 1520, 1490, 1445, 1040, 940, 760, 700
Proton NMR Spectrum (350 MHz, CDCl3, # in ppm, J in Hz) 3.34 and 4.12 (2d, J = 18, 2H, -SCH2-); 3.40 (s, 6H, -OCH 3); 3.94 to 4.06 (m, 5H, -OCH 3 and XNCH 2 -); 4.60 to 4.68 Cm> 2H, H at 6 and -CH (OCH3) 2); 6.07 (dd, J = 4 and 9, 1H, H at 7); 6.70 (s, 1H,
Thiazole); 6.82 (d, J = 16, 1H, -CH = CHS-); 6.96 (s, 1H, -COOC-).

 A solution of 8.5 g of 2-benzhydryloxycarbonyl {[(1- (dimethoxy-2,2-ethyl) -4,6-dioxo-1,4,5,6-tetrahydro-1-triazine) is treated at -100 ° C. with stirring. 2,4-yl-3-thio-2-vinyl) -3 [2-methoxyimino-2-tritylamino-4-thiazolyl] acetamido] -7-oxo-5-oxide-5-thia-5-aza-1-bicyclo [4.2.0] octene -2, syn isomer, E form and 3 cm3 of dimethylacetamide in 100 cm3 of methylene chloride per 1.40 cm3 of phosphorus trichloride; after 1 hour 30, then 2 hours, 0.7 cm3 of phosphorus trichloride are added (each time). The mixture is diluted with 600 cm 3 of ethyl acetate, washed twice with 150 cm 3 of a 2% solution of sodium bicarbonate and twice 150 cm3 of a half-saturated solution of sodium chloride, dried over sodium sulphate, filtered and concentrated to dryness at 200 ° C. under a pressure of 20 mm of mercury (2, 7 kPa). The residue is taken up in 50 cm3 of ethyl acetate and the solution is chromatographed on a column of 100 g of Merck silica gel (0.05-0.2) (diameter of the column: 3 cm, height: 25 cm). Eluted with 1 liter of ethyl acetate, collecting fractions of 200 cm3. Fractions 3, 4 and 5 are concentrated to dryness (20 mm Hg, 2.7 kPa) at 200 ° C. 7.5 g of 2-benzhydryloxycarbonyl-2- [2- (dimethoxy-2,2-ethyl) dioxo-5 are collected. Tetrahydro-1,4,5,6-triazin-1,2,4-yl-7-thio-2-vinyl-3-one [2-methoxyimino-2-tritylamino-4-thiazolyl] acetamido] -7-oxo-8-thia- Aza-1 bicyclo 4.2.Q7 octene-2, syn isomer, form E in the form of an orange meringue.

Infra-red spectrum (CHBr3), characteristic bands (cm-1) 3380, 1780, 1720, 1680, 1515, 1490, 1445, 755, 740
Proton NMR Spectrum (350 MHz, CDCl 3, δ ppm, J in Hz) 3.40 (s, 6H, -OCH 3); 3.54 and 3.66 (2d, J = 18, 2H, -sch 2 -); 3.98 (d, J = 5, ZH, # NCH 2 -); 4.02 (s, 3H, = NOCH3); 4.65 (t, J = 5, 1H, -CH ((OCH 3) 2), 5.08 (d, J = 4.1H, H at 6), 5.92 (dd, J = 4 and 9, 1H,
H in 7); 6.73 (s, 1H, H thiazole); 6.83 (d, J = 16, 1H, = CH-CHS-); 6.95 (s, 1H, -COOCH-).

 (a) A solution of 1.05 g of 2-benzhydryloxycarbonyl {[(2,2-dimethoxy-ethyl) -4,5-dioxo-1,4,5,6-tetrahydro-triazine-1) is treated at 500 ° C. for 30 minutes. 2,4-yl-3-thio-2-vinyl] -3 [2-methoxyimino-2-tritylamino-4-thiazolyl) acetamido] -7-oxo-8-thia-5-azabicyclo [4.2.0] octene-2 , syn isomer, Form E in 20 cm3 of 98% formic acid. The mixture is concentrated to dryness at 500 ° C. under a pressure of 0.05 mm Hg (0.007 kPa), taken up in 50 cm3 of acetone, concentrated to dryness at 30 ° C. under reduced pressure (20 mm Hg, 2.7 kPa). ) and repeat this operation a second time.

 The solid obtained is treated at 600C for 10 minutes with stirring with 50 cm3 of acetone, the cooled suspension is filtered, the residue is dried and 0.51 g of 1 (2-amino-4-thiazolyl) -2-methoxyimino-2 is obtained. acetamido] -7 carbox-2 {[(4,4-dioxo-4-formylmethyl) -4,4,6,6-tetrahydro-triazin-1,2,4-yl-37-thio-2-vinyl] -3-oxo-8-thia-5-aza; bicyclo [4.2.0] octene-2, syn isomer, form E.

Infrared spectrum (KBr), characteristic bands (cm-1) 3500, 2300, 1770, 1715, 1680, 1540, 1050, 950
Proton NMR Spectrum (350 MHz, CF3COOD, 6 ppm, JHz) 3.87 (AB limit, 2H, -SCH2-); 4.30 (s, 3H, -OCH 3); 5.20 (brs, 2H, NCH 2 -); 5.38 (d, J = 4.1H, H at 6); 6.03 (d, J = 4.1H, H at 7); 7.22 (d, J = 16, 1H, -CH = CHS-); 7.50 (s, 1H, H thiazole); 7.72 (d,
J = 16, 1H, = CHS-); 9.74 (brs, 1H, -CHO).

Proton NMR spectrum (350 Mhz, CF3COOD + D20, 6 ppm,
J in Hz) 3.82 (AB limit, 2H, -SCH 2 -); 4.26 (s, 1H, -OCH3); 5.10 (brs, 2H, ncH 2 -); 5.31 (d, J = 4, 1H, H at 6); 5.96 (d, J = 4, 1H, H at 7); 7.06 (d, J = 16, 1H, -CH = CH 2 -); 7.43 (s, 1H, H thiazole); 7.56 (d, J t 16, 1H, = CHS-); 9.67 (bs, 1H, -CHO).

b) It is also possible to operate as follows
A mixture of 1 g of 2-benzhydryloxycarbonyl {[(2,2-dimethoxy-ethyl) -4-dioxo-5,6-tetrahydro-1,4,5,6-triazine-1 is stirred at 50 ° C. for 30 minutes under stirring. 2,4-yl-3-thio-2-vinyl] -3 [2-methoxyimino-2-tritylamino-4-thiazolyl) acetamido] -7-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene 2, syn isomer, Form E, 40 cm3 of pure formic acid, 1.27 cm3 of water and 6 g of Merck silica gel (0.05-0.2). It is concentrated to dryness at 30 ° C. under 20 mm of mercury (2.7 kPa) and the resulting powder is deposited on a column of 20 g of silica gel.
Merek (0.05-0.2) (diameter of the column: 2 cm, height: 17 cm).

It is eluted with an ethyl acetate-formic acid-water 3-1-1 (vol.) Mixture, collecting the 10 cm3 fractions. The Oractions 3 are concentrated to dryness at 26 ° to 27 ° C. under 0.05 mm of mercury (0.007 kPa) The yellow solid obtained is triturated in 60 cm 3 of ether, the residue is filtered and the residue is dried and Q 4 g is obtained. [2-Amino-2-thiazlyl-4-methoxyimino-2-acetamido] -7-carboxy-2 - [(4,6-dioxo-4-formylmethyl) -4,4,6,6-tetrahydro-1,2,4-triazine) 3) 2-thio-vinyl] -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form whose NMR and infra-red characteristics are identical to those of the product prepared according to (3) at).

 c) A mixture of 0.297 g of [(2-amino-4-thiazolyl) -2-methoxyimino-2-acetamido] -7-carboxy-2 - [(4,6-dioxo-4-formylmethyl) tetrahydro is stirred until dissolved and under nitrogen. -1,4,5,6-triazine1,2,4-yl-3-triol-2-vinyl-3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form, 10 cm3 of water and 0.042 g of sodium bicarbonate, filter and lyophilize the solution. 0.28 g of the sodium salt of [(2-amino-4-thiazolyl) -2-methoxyimino-2-acetamido] -7-carboxy-2 - [(4,6-dioxo-4-formylmethyl-1,4,5-tetrahydro) , 6-triazine-1,2,4-yl-3-thio-2-vinyl] -3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer. form E, aldehyde hydrate.

Infra-red spectrum (KBr), characteristic bands in cm-1 3420, 3200, 1760, 1710, 1670, 1600, 1530, 1040, 945
Proton NMR spectrum (350 Mtlz, DMSO d6 + D20, 6 ppm,
J in Hz) 3.54 (AB limit, 2H, -SCH2-); ; 5.06 (d, J = 4, 1H, H at 6); 5.08 (s, 1h, -CH (OH) 2); 5.63 (d, J = 4, 1H, H at 7); 6.44 (d, J = 16, 1, -CH = CHS-); 6.76 (s, 1H, H thiazole); 7.24 (d, J = 16, 1H, = CHS-); 9.60 (s, 0.0511, -CHO).

 The NMR spectrum of this sodium salt, aldehyde hydrate, drawn in CF3COOD shows that in solution in this solvent the product is in aldehyde form Spectrum identical to that described above in (a)].

 By operating in the same manner from the appropriate starting materials, c - {[(2-acetamidoethyl) -1-tetrazolyl-5-thio-2-vinyl] -3 [(2-amino-1,3-thiazolyl)} -4) -2-methoxyimino-2-acetamido-2-carboxy-2-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, Form E, yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3500, 2500, 1775, 1660, 1540, 1040, 945
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 1.90 (s, 3H, -CH3); 3.44 (t, 2H,> N CH 2 -); 3.60 (q, 2H, -CH2NHCO-) 3.64 and 3.76 (2d, J = 18, 2H, -S CH2-); 4.0 (s, 311, -OCH3); 5.18 (d, J = 4, 1H, H at 6); 5.82 (dd, J = 4 and 9, 111, H at 7) 6.60 (s, 3H, -NH3 +); 6.78 (s, 1H, H thiazole); 6.96 (d, J = 16, LiI, -CH = CH s-); 7.37 (d, J = 16, 111, = CHS-); 7.86 (t, J = 5, 1H, -NHCOCH3); 9.50 (d, J = 9, 1H, -CON-).

D - [(2-acetamidomethyl-1,3,4-chiadiazol-5-yl) -2-vinyl]] - [(2-amino-thiazol-1,3-yl) -4-methoxyimino-2-acetamido] -7-carboxylic acid 2-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form, cream-colored powder.

Infrared spectrum (KBr), characteristic bands (cm-1) 3320, 1770, 1660, 1540, 1380, 1040
Proton NMR Spectrum (350 MHz, DMSO d6, δ ppm, J in Hz) 1.90 (s, 3H, -COCH3); 3.68 and 3.92 (2d, J = 18, 2H, -S CH 2 -); 3.87 (s, 3H, -OCH 3); 4.22 (d, J = 4, 1H, H at 6) d 4.60 (AB limit, 2H, -CH 2 NHCO-); 5.82 (dd, J = 4 and 9, 1H, H at 7); 6.75 (s, 1H, -OCH3) 7.15 (d, J = 16, 1H, -CH = CHS-); 7.20 ts, 3H, -NH 3 +) -; 7.25 (d, J = 16, 1H, = CHS-); 9.63 (d, J = 9, 1H, -CONH-).

 # - [(2-amino-1,3-thiazolyl-4-yl) -2-methoxyiminoacetamido] -7-carboxy-2 (3-methyl-thiadiazol-1,2,4-yl-5) thio-2 vinyl] - 3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn-isomer, Form E, yellow powder.

Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 2.57 (s, 3H, -CH3); 3.65 and 3.95 (2d, J = 18, 2H, -SCH 2 -); 3.86 (s, 3H, -OCH 3); 5.23 (d, J = 4, 1H, H at 6); 5.82 (dd, J = 4 and 9, 1H, H at 7); 6.75 (s, 1H, H thiazole); 7.04 (d, J - 16, 1H,
CH = CHS-); 7, 36 (d, J = 16, 1H, = CHS-); 9.63 (d, J = 9, 1H, -CONH-).

F - [(2-Amino-1,3-thiazol-4-yl) -2-methoxyiminoacetamidyl] -2-carboxy-8-oxo [(2-pyridyl) -2-thio-vinyl] -5-thia-1-azabicyclic [4.2.0] octene-2, syn isomer, form E.

Infra-red spectrum (KBr), characteristic bands [cm-1 3500, 2820, 2600, 1775, 1670, 1650, 1630, 1575, 1450, 1415, 1380, 1040, 940, 765
Proton NMR spectrum (350 MHz, DMSO, δ ppm, J in Hz) 3.72 and 3.95 (2d, J = 18, 2H, 4H); 3.85 (s, 3H, -OCH 3); 5.20 (d, J = 4.1H, H at 6); 5.77 (dd, J = 4 and 9, 1H, H at 7), 76 (s, 1H, H thiazole); 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 4 of the pyridine); 8.50 (t, 1H, J = 4, H2 of pyridine) 9.50 (d, J = 9, 1H, -CONH-).

G - [(6-acetamido-3-pyridazinyl) -2-thio-vinyl] [(2-aminothiazol-1,3-yl-4) -2-methoxyimino-2-acetamido] -7-carboxy-2-oxo-8-thia-5 aza-1 bicyclo [4.2.0] octene-2, syn isomer, E-form, cream-colored solid.

Infrared spectrum (KBr), characteristic bands (cm-1) 3300, 1760, 1660, 1550, 1510, 1035, 940
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 2.10 (s, 3H, CH3CONH-); 3.72 and 3.98 (AB, J = 17, 2H, -SCH 2 -); 3.86 (s, 3H, = NOCH3); 5.2 (d, J = 4.1H, H at 6); 5.78 (dd, J = 4 and 9, 1H, H at 7); 6.76 (s, 1H, H thiazole); 7.20 (s, 2H, -NH 2); 7.19 (d, J-10, 1H, -CH = CH-S-); 7.33 (d, J = 10, 1H, -CH = CH-S-); 7.78 (d, J = 9, 1H, H on pyridazine); 8.12 (s, 1H, CH3CONH-) 9.65 (d, J-9, 1H, -CONH-); 8.27 (d, J e 9, 1H, H at 4 on pyridine); 11.1 (brs, 1H, -CO2H).

H - (2-amino-1,3-thiazolyl-4-yl) -methoxyimino-2-acetamido] -7-carboxy-2 - [(4,6-dioxo-4-methyl-1,4,5,6-tetrahydro-triazine-1, 2,4-yl-3-thio-2-vinyl] -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form, cream-colored solid.

Rf = 0.37, silica gel chromatoplate; eluting
ethyl acetate-water-acetic acid 3-2-2 (vol.)
Infrared spectrum (KBr), characteristic bands (cm-1)
3300, 3260, 2600, 1770, 1705, 1680, 1630, 1585, 1530, 1375, 1040, 950
Proton NMR Spectrum (350 MHz, DMgO d6, 6 ppm, J in Hz)
3.35 (s, 3H, -CH 3 triazine); 3.65 and 3.88 (ab, J = 18, 2h, -sch 2 -); 3.87 (s, 3H, = NOCH 3); 5.22 (d, J = 4, 1H, H at 6); 5.80 (dd, J - 4 and 1H, H at 7); 6.75 <s> (s, 1H, H thiazole); 6.83 (d, J = 16, -CH = CH-S-); 7.11 (d, J = 16, 1H, -CH = CH-S-); 7.20 (brs, 3H, -NH 3 +); 9.58 (d, J-9, 1H, -CONH-).

I - (2-amino-1,3-thiazolyl-4-yl) -2-methoxyimino-7-acetamido-2-carboxy [5- (4,6-dioxoethyl) -4,4,5,6-tetrahydro-1,2-triazine , 4-yl-3) 2-thio-vinyl] -3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E.

Infrared spectrum (KBr), characteristic bands (cm-1) 3500, 2200, 1770, 1700, 1680, 1530, 1040, 940
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 1.22 (t, J - 7, 3H, -CH3); 3.65 and 3.80 (2d, J = 18, 2H, -SCH 2 -) 3.80 (q, J = 7, 2H,> NCH 2 -); 3.86 (s, 3H, -OCH 3); 5.20 (d, J = 4.1H, H at 6); 5.78 (dd, J = 4 and 9, 1H, H at 7); 6.75 (B, 1H, H thiazole); 6.95 (d, 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-).

N - [(2-amino-1,3-thiazol-4-yl) -2-methoxyimino-7-acetamido-2-carboxy] - [(4,6-dioxo-4-isopropyl-1,4,5,6-tetrahydro-1-triazine), 2,4-yl-3-thio-2-vinyl] -3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form
E, yellow powder.

-1
Infrared spectrum (KBr), characteristic bands (cm) 3500, 2200, 1775, 1705, 1680, 1530, 1050, 950
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 1.48 (d, J = 7.6H, -CH (CH3) 2); 3.64 and 3.82 (2d, J188, 2H, -SCH2-) 3.85 (s, 3H, -OCH3); 4.42 (mt, 1H, -CH (CH3) 2); 5.22 (d, J = 4, 1H, H at 6); 5.78 (dd, J = 4 and 9, 1H, H at 7); 6.74 (s, 1H, H thiazole); 6.93 (d, J = 16, 1H, -CH = CHS-); 7.07 (d, J = 16, 1H, = CHS-); 7.18 (s, 3H, -NH 3 +); 9.62 (d, J = 9, 1H, -CONH-); 12.55 (s, 1H, = NNHCO- or = NN = 9-OH).

K - {E (allyl-3) -4-dioxo-S, 6-tetrahydro-1,4,5,6-triazin-1,2,4-yl-3-thio-2-vinyl) -3 [(2-aminothiazol)} 1,3-yl-4) -2-methoxyimino-2-acetamido] -7-carboxy-2-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, Form E, yellow powder.

Infrared spectrum (KBr), characteristic bands (cm-1) 3600, 2300, 1775, 1710, 1680, 1535, 1040, 945
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.63 and 3.80 (2d, J = 18, 2H, -SCH2-); 3.88 (s, 3H, -OCH 3); 4.48 (d,
J = 4, 2H,> CH = CH 2; 5.19 to 5.27 (mt, 3H, CH 2 and H at 6); 5.74 to 5.92 (mt, 2H, 6.91 and H at 7); 6.74 (s, 1H, H thiazole) d, J = 16, 1H, -CH = CHS-); 7.09 (d, J = 16, 1H, = CHS-) 7.18 (s, -NH3 +); 9.60 (d, J = 9, 1H, -CONH-); 12.61 (s, 1H, = N-NHCO or = NN - # -).

L - [(Amino-2-thiazol-1,3-yl) -4-methoxyimino-2-acetamido] -1-carboxy-2 {[dioxo-5,6-hydroxy-2-ethyl] -4-tetrahydro-1,4,5 1,2,4-triazine-1-yl-3-thio-2-vinyl-3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form, light yellow crystals.

Proton NMR Spectrum (350 MHz, DMSO d6, # in ppm, J in Hz) 3.60 (t, J = 5.2H, # N-CH2-CH-2OH); 3.84 (s, 3H, = NOCH3); 3.92 Ct,
J = 5.2H, # N-CH-2CH2OH); 5.10 (d, J = 4, 1H, H at 6); 5.65 (dd,
J - 4 and 9, 1H, H at 7); 6.39 (d, J = 16, 1H, -CH = CH-S-); 6.73 (s, 1H, H in 5 thiazole); 7.17 (brs, 2B, NH 2); 7.37 (d,
J = 16, 1H, -CH 2 CH-S-); 9.54 (d, J = 9, 1H, -CONH-C7).

M-carboxy-2 - [(2-methoxyethyl) -4,5,5-dioxo-1,4,5,6-tetrahydro-1,2,4-triazo-3-yl] -2-thio-vinyl} -3 [methoxyimino-2] (2-amino-1,3-thiazolyl-4-yl) acetamido] -7-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form, yellow solid.

Infra-red spectrum (KBr), characteristic bands (cm-1) 3480, 2830, 1775, 1710, 1680, 1635, 1590S 1535, 1380, 1110, 1040, 940
Proton NMR Spectrum (350 MHz, DMSO d 6, ppm, J an Hz) 3.36 (s, 3H, -CH 2 OCH-3); 3.56 (t, J = 5, 2H, -CH-20-); 4.10 (t, J = 5.2H, -CH2N #); 3.62 and 3.73 (2d, J = 18, 2H, -SCH 2 -); 3.96 (s, 3H, = NOCH3); 5.18 (d, J = 4, 1H, H at 6); 5.81 (dd, J = 4 and 9, 1H,
H in 7); 6.78 (s, 1H, tiaziazole); 6.87 (d, J = 15, 1H, -CH = CH-S-) 7.29 (d, J = 15, 1H, -CH = CH-S-); 6.70 (br s, 3H, -NH 3 +); 9.55 (d,
J - 9, 1H, -CONH-); 12.64 (s, 1H, -OH).

N - {[(2-acetamidoethyl) -4-dioxo-5,6-tetrahydro-1,4,5,6-triazin-1,2,4-yl-3-thio-2-vinyl] -3 [(2-amino-thiazol) -1,3-yl-4) -2-methoxyimino-2-acetamido] -7-carboxy-2-oxo-8-thia-5-aza-1-icyclo [4.2.0] octene-2, syn isomer, E-form, yellow powder.

Infra-red spectrum (KBr), characteristic bands (cm-1 ~ 3500, 2500, 1775, 1710, 1685 to 1630, 1540, -1045, 950
Proton NMR Spectrum (350 MHz, DMSO d6, # in ppm, J in Hz) 1.90 (s, 3H, -CH3); 3.48 (m, 2H, -CH-2NH-); 3.62 and 3.73 (2d, J = 18, 2H, -SCH 2 -); 4.0 (s, 3H, -OCH 3); 5.15 (d, J = 4, 1H, H at 6); 5.82 (dd, J = 4 and 9, 1H, H at 7); 6.78 (s, 1H, H thiazole) 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, 1H, -CONHN = or -C = NN =).

6H
O - [(2-Amino-4-thiazolyl) -2-methoxyimino-2-acetamido] -2-carboxy-2 - [[(2H) methoxycarbonyl-2-methyl-2-triazol-1,2,4-yl] -3-thio-vinyl} 3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, Form E, cream-colored powder.

-1
Infra-red spectrum (KBr, characteristic bands in cm) 3450, 3320, 2200, 1770, 1735, 1660, 1630, 1535, 1385, 1220, 1040, 945
Proton NMR spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.66 and 3.90 (2d, J = 18, 2H, -SCH2-); 3.85 (s, 3H = NOCH 3); 3.87 (s, 3H, -CO 2 CH 3), 3.90 (s, 3H, # NCH 3 triazole); 5.20 (d, J = 9, 1H,
H in 6); 5.79 (dd, J = 4 and 9, 1H, H at 7); 6.74 (s, 1H, H thiazole) 6.98 and 7.03 (AB, J = 14, 2H, -CH = CH-S-); 7.20 (brs, 2H, -NH 2); 9.63 (d, J = 9, 1H, -CONH-C7).

p - [(2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -7 [(4-benzyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine-3-yl)) tio-2-vinyl] -3-carboxy-2-oxo-8-thia-5-aza-1-bicyclofi4.2.0] octene-2, syn isomer, E-form, yellow powder.

Infrared spectrum (KBr), characteristic bands in cm-1 3500, 2300, 1770, 1710, 1680, 1585, 1530, 1045, 945
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.58 and 3.78 (2d, J = 18, 2H, -SCH2-); 3.88 (8, 3H, -OCH 3); 5.10 (s, 2H, # NCH 2); 5.18 Cd, J - 4, 1H, H at 6); 5.78 (dd, J = 4 and 9, 1H, H at 7); 6.75 (s, 1H, H thiazole); 6.86 (d, J = 16, 1H, -CH = CHS-); 7.05 (d, J = 16, 1H, = CHS-); 7.20 (s, 3H, -NH 3 +); 9.60 (d, J = 9, 1H, -CONH-); 12.69 (s, 1H, = NNHCO-).

Q - [(2-Amino-2-thiazolyl) -2-methoxyimino-2-acetamido] -7-carboxy-2 {[dioxo-5,6 (methylthio-2-ethyl) -4-tetrahydro-1,4,5,6-triazine-1 2,4-yl-3-thio-2-vinyl-3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E.

Infrared spectrum (KBr), characteristic bands in cm-1 3600, 2200, 1770, 1710, 1680, 1585, 1535, 1040, 945
Proton RM Spectrum (350 MHz, DMSO d6, # in ppm, J in Hz) 2.12 (s, 3H, -SCH3); 2.73 (t, J = 7, 2H, -CH-2S-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,> NCH 2 -) -; 5.20 (d, J = 4.1H, H at 6); 5.78 (dd, J = 4 and 9, 1H,
H in 7); 6.73 (s, 1H, it thiazole); 6.92 (d, J = 16, 1H, -CH = CHS-) 7.12 (d, J = 16, 1H, = CHS-); 7.15 (s, 3H, -N3 +); 9.66 (d, J = 9, 1H, -CONH-); 12.61 (s, 111, # n-hco-).

2 - [(2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -7 - [(4-carbamoylmethyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine) -3-yl) 2-thio-vinyl] -3-carboxy-2-oxo-8-thia-5-aza-1 bicyclo [4.2.0] octene-2, syn isomer, E-form, beige powder.

Infra-red spectrum (KBr), characteristic bands (cm-1) 3410, 3320, 3200, 3100, 2000, 1770, 1710, 1680, 1630, 1590, 1380, 1040, 945
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.63 and 3.83 (AB, J = 18, 2H, -SCII2-); 3.87 (s, 3H, = NOCH 3); 4.45 (brs, 2H, -CH-2 CONH 2); 5.20 (d, J = 4.1H, H an 6); 5.78 (dd,
J = 4 and 9, 1H, H at 7); b, 75 (s, 1H, H thiazole); 6.90 and 7.08 (2d, J = 16, 2 x 111, -CH = CH-S-); 7.32 (bs, 211, -NH 2 thiazole); 7.70 (brs, 211, -CONH 2); 9.60 (d, J = 9, 1H, -CONH-C7); -N = C-OH triazine, #> 12 ppm.

S - [(2-amino-4-thiazolyl) -2-methoxyimino-7-acetamido-2-carboxy [{((2,2-dimethoxyethyl) -4,6-dioxo-1,4,5,6-tetrahydro-triazine] 1,2,4-yl-3-thio-2-vinyl-3-oxo-5-thia-5-azabicyclo [4.2.0] oct-2-ene, syn isomer, Form E, yellow powder.

-1
Infrared spectrum (KBr), characteristic bands in cm 3500, 3300, 1780, 1715, 1680, 1590, 1535, 1050, 950
Proton NMR Spectrum (350 MHz, DMSO d6, δ in ppm, J in Hz) 3.62 and 3.81 (2d, j = 18, -SCH2-); 3.84 (s, 3H, -OCH 3); 3.97 (d,
J = 3.2H, # NCH2-); 4.58 (t, J = 3, 1H, -CH (OCH3) 2); 5.20 (d, J = 4.1H, H at 6); 5.77 (dd, J = 4 and 9, 1H, H at 7); 6.74 (s, 1H, H thiazole); 6.91 (d = 16, 1H, -CH = CHS-); 7.09 (d, J = 16, 1H, = CHS-); 7.17 (s, 3H, -NH 2)); 9.60 (d, J = 9, 1H, -CONH-); 12.64 (s, 1H, = NNHCO-).

T - [(4-Amino-2-thiazolyl) -2-methoxyimino-2-acetamido] -7- [2 - [(2-carbamoyloxyethyl) -4,4,5,5-tetrahydro-1,4,5,6-triazine-1,2,4 yl-3-thio-2-vinyl-3-carboxy-2-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form, cream-colored powder.

triazine). -1
Infrared spectrum (KBr), characteristic bands in cm 3550, 2200, 1770, 1710, 1680, 1050, 940
Proton NMR Spectrum (350 MHz, DMSO d6, # in ppm, J in Hz) 3.62 and 3.82 (2d, J = 18, 2H, -SCH2-); 3.86 (s, 3H, = NOCH3); 4.06 and 4.15 (2t, J = 5, 2 x 2H, # NCH 2 CH 2 O-); 5.21 (d, J = 9, 1H, H at 6) 5.78 (dd, J = 4 and 9, 1H, H at 7); 6.50 (bs, 2H, -OCONH 2); 6.75 (s, 1H, H thiazole); 6.92 and 7.08 (2d, J = 16, 2H, -CH = CH-S-); 7 to 7.50 (brs, 2H, -NH 2 thiazole); 9.66 (d, J = 9, 111, -CONH-C7); 12.62 (s, 1H,

triazine).

 2 - [(2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -carboxy-2 - [[dioxo-5,6-formyloxy-2-ethyl] -4-tetrahydro-1,4,5,6-triazine-1] 2,4-yl-3-thio-2-vinyl-3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, Form E, yellow powder.

Intra-red spectrum (KBr), characteristic bands in cm-1 3400, 3200, 2200, 1776, 1710, 1680, 1530, 1040, 945
Proton NMR Spectrum (350 MHz, DMSO d6, # in ppm, J in Hz) 3.62 and 3.82 (AB, J = 18, 2H, -SCH2-); 3.84 (s, 3H, -NOCH3); 4.15 and 4.32 (2t, J = 5, 2 x 2H, # NCH-2CH-2-OCHO); 5.21 (d, J = 4, 1H, H at 6); 5.78 (dd, J = 4 and 9, 1H, H at 7); 6.73 (s, 1H, H thiazole); 6.89 and 7.10 (2d, J = 6, 2H, -CH = CII-S-); 7.16 (brs, 2H, -NH 2) 8.18 (s, 1H, HCOO-); 9.59 (d, J = 9, 1H, -CONH-C7); 12.60 (brs, 1H, -N-COH triazine).

V - [(2-acetoxyethyl) -4,5-dioxo-tetrahydro-1,4,5,6-triazin-1,2,4-yl-3-thio-2-vinyl] -3 [(2-amino-thiazolyl) -2- 4) -2-2-metoxyimino-7-acetamidol-8-oxo-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, Form E, pale yellow powder.

 Infra-red spectrum (KBr), characteristic bands in cm-1 3320, 3220, 3150, 2300, 1780, 1740, 1720, 1680, 1635, 1590, 1535.

1375, 1210, 1040, 950
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 2.0 (s, 3H, CH-3CO2-); 3.63 and 3.82 (AB, J = 18, 2H, -SCH 2 -) 3.85 (s, 3H, = NOCH 3); 4.08 (t, J = 5.2H, # NCH-2CH2OCOCH3, 4.25 (t, J = 5.2H, # NCH2CH-2OCOCH3), 5.20 (d, J = 4.1H, H at 6); 5.78 (dd, J = 4 and 9, 1H, 11 at 7), 6.73 (s, 1H, thiazole) 6.90 (d, J - 16, 1H, -CH = CH-S) 7.12 (d, J = 16, 1H, = CH = CHS-) 7.18 (bs, 211, -Nil2); 9.60 (s, J = 9, 1H, -CONH-C7); 12.6 (brs, 111, -NC-OH triazine).

2 - [(2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2-carboxy-2 - [[dioxo-5,6-glycyloxy-2-ethyl] -4-tetrahydro-1,4,5,6 -formate) 1,2,4-triazine-3-yl-2-thio-vinyl-3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E in the form of a light yellow powder .

Infrared spectrum (KBr), characteristic bands in cm-1 3550, 2200, 1755, 1705, 1675, 1580, 1530, 1035
Proton NMR Spectrum (1SO MHz, DMSO d6, ppm, J in Hz) 3.51 and 3.62 (AB, J = 18, 2H, -SCH2-); 3.72 (mt, 2H, -COCH 2 NH 2) 3.82 (s, 3H, = NOCH 3); 4.12 and 4.40 (2 Mt, 2 x 2H, # NCH 2 CH 2 OCO 3) 5.10 (d, J = R, 111, H at 6); 5.67 (dd, J = 4 and 9, 1H, 7) 6.44 (d, J = 16, 1H, -CH = CH-S-); 6.72 (s, 1H, H thiazole); 7.18
(broad s, 3H, -NH3 + thiazole); 8.12 (s, 1H, HCO2-); 9.56 (d, J = 9, 1H, -CONH-C7).

X - [(2-Amino-1,3-thiazolyl) -2-methoxyimino-2-acetamido] -7-carboxy-2 - [(1-methyl-5-tetrazolylthio) -vinyl] -3-oxo-trifluoroacetate
thia-5-azabicyclo [4.2.0] octene-2, syn isomer, Z-form.

 Rf = 0.50, silica gel chromatoplate, solvent: ethyl acetate, acetone, acetic acid, water 50-20-10-10 (by volume).

Infrared spectrum (RBr), characteristic bands (cm) 3300, 1785, 1675, 1180, 1140, 1050
Proton NMR Spectrum (350 MHz, DMSO d6, δ in ppm, J in Hz) 3.8 and 3.85 (AB, J = 17.5, 2H, -SCH2); 3.93 (s, 3H, # NCH 3); 4.0 (s, 3H, -OCH 3); 5.26 (d, J = 4, 1H, H at 6); 5.85 (dd, J = 4 and 10, H at 7);
6.75 (d, J = 11, 1H, -CH = CH S-); 6.87 (s, 1H, H 5 thiazole); 6.91
(d, J = 11, 1H, = CH S-); 9.34 (d, J = 10, 1H, -CONH-).

2 - [(2-Amino-1,3-thiazolyl) -2-methoxyimino-2-acetamido] -7-carboxy-2 - [(2-methyl-5-tetrazolylthio) -vinyl] -3-oxo-trifluoroacetate
thia-S aza-1 bicyclo [4.2.0] octene-2, syn isomer, form E.

 Rf = 0.49; silica gel chromatoplate, solvent: ethyl acetate, acetone, acetic acid, water 50-20-10-10 (by volume).

Infrared spectrum (KBr), characteristic bands Ccm) 3320, 1780, 1675, 1200, 1140, 1040, 950
Proton NMR spectrum (350 MHz, DMSO d6, 6 ppm, J in Hz)
3.66 and 3.86 (2d, J = 17, -SCH 2 -); 3.90 (s, 3H, # NCH 3); 4.0 (s, 3H, -OCH 3); 5.20 (d, J = 4.1H, H at 6); 5.80 (dd, J = 4 and 9, 1H, H at 7);
6.83 (s, 1H, H in 5 thiazole); 7.0 (d, J = 16, 1H, -CH = CH 2 -); 7.1
(d, J = 16, 1H, = CHS); 9.7 (d, J = 9, 1H, -CONH-).

Z - Internal salt of f (2-amino-1,3-thiazolyl) -2-methoxyimino-2
7-acetamidol 2-carboxy-2-hydroxy-1-ethyl-5-tetrazolylthio
vinyl-3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn-isomer,
E-form, pale yellow solid.

Infra-red spectrum (KBr); characteristic bands (cm-1) 3350, 1770, 1720, 1675, 1530, 1390, 1040, 940
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.63 and 3.87 (AB, J = 19, 2H, -SCH2); 3.77 and 4.41 (2t, 4H, -CH 2 CH 2 O-); 3.84 (s, 311, -OCH3); 4.19 (d, J = 4.1H, H at 6); 5.89 (dd, J = 4 and 9, 1H, H at 7); 6.73 (s, 1H, H at 5 thiazole); 6.94 (d, J = 16, 1H, CH = CHO-); 7.25 (d, J = 16, 1H, = CHS-); 9.61 (d, J = 9, 1H, -CONH-).

AA - [(2-amino-1,3-thiazolyl) -4-hydroxyiminoacetamidyl] -7-carboxy-2 - [(1-methyl-5-tetrazolyl) -2-thio-vinyl] -8-oxo-5-thia-aza -1 bicyclo [4.2.0] octin-2 (syn isomer, form E) in the form of a yellow powder.

Infrared spectrum (KBr) characteristic bands (cm) 3440, 3360, 3200, 1785, 1720, 1680, 1610, 1405
Proton NMR Spectrum (350 MHz, DMSO d6, # in ppm, J in Hz) 3.65 and 3.91 (2d, J = 18, 2H, -S CH2); 4.97 (s, 3H, # NCH 3); 5.25 (d, J = 4, 1H, H at 6); 5.90 (dd, J = 4 and 9, 1H, H at 7); 6.76 (s, 1H, H in 5 thiazole); 6.96 (d, J = 14, 1H, -CH = CHS-; 7.07 (d, J = 14, 1H, = CHS-) 9.50 (d, J = 9, 1H, -COH-) .

Ail - [(2-amino-4-thiazolyl) -2-methoxyimino-2-acetamidol-2-carboxy-2 - [[(2-dimethylaminoethyl)] -4-tetrazolyl] -thio-2-vinyl] -3-oxo-8-thia-5-aza bicyclo [4.2.0] octene-2, syn isomer, form E, formate
Infrared spectrum (KBr), characteristic bands (cm) 2820, 1770, 1670, 1530, 1610, 1385, 1030
Proton NMR Spectrum (350 MHz, DMSO d6, # in ppm, J in Hz) 2.70 (s, 6H, -N (CH3) 2); 2.75 and 3.95 (2 t, J = 7.4H, -CH 2 CH 2 -); 3.85 (s, 3H, = NOCH3); 5.16 (d, J = 4, 1H, H at 6); 5.85 (dd, J = 4 and 9, 1H, H at 7); 6.8 and 6.9 (2d, J = 16, 2H, -CH = CH-S-); 9.63 (d, J = 9.

1H, -CONH-); 7.20 (brs, 2H, -NH 2 thiazole).

AC - (2-amino-4-thiazolyl) -2-methoxyimino-acetamidyl-7-carboxy-2 - [(5-dimethylaminomethyl-thiadiazol-1,3,4-yl) -2-thio-vinyl] oxo-8-thia-5 aza-1 bicyclo [4.2.0] octene-2, syn isomer, form E, formate.

 Proton NMR spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 2.36 (s, 6H, -N (CH3) 2); 3.67 and 3.92 (AB, J = 18, 2H, -SCH 2 -); 3.88 (s, 3H, = NOCH3); 5.20 (d, J = 4.1H, H at 6); 5.80 (dd, J = 4 and 9, 1H, H at 7); 6.76 (s, 1H, H thiazole); 7.10 and 7.25 (2d, J = 16, 2H, -CH = CH-S-); 7.20 (brs, 2H, -NH 2); 9.60 (d, J = 9, 1H, -CONH-).

2 - [(2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -7-carboxy-2 [5-aminomethyl-1,3,4-thiadiazol-2-yl] -vinyl] -3-oxo-8-thiophenone Aza-1 bicyclo [4.2.0] octene-2, isomer sy, form E.

Infra-red spectrum (KBr), characteristic bands (cm-1) 3400, 3200, 3100, 2300, 2820, 1765, 1665, 1610, 1530, 1380, 1040, 945
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.56 and 3.76 (AB, J = 18, 2H, -SCH2-); 3.84 (s, 3H, = NOCH 3 O, 4.38 (bs, 2H, -CH 2 NH 2), 5.15 (d, J = 4, 1H, H at 6), 5.72 (dd, J = 4 and 9, 1H, H at 7), 6.73 (s, 1H, H thiazole), 6.83 and 7.27 (d, J = 16, 2H, -CH = CH-S-); (Broad, 2H, -NH 2 thiazole), 9.60 (d, J = 9, 1H, -CONH-).

AE - [(2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -7-carboxy-2 - [(thiadiazol-1,3,4-yl-2) thio-2-vinyl] -3-oxo-8-thia-5-aza bicyclo [4.2.0] octene-2, syn isomer, E-form,
Infrared spectrum (KBr), characteristic bands (cm) 2820, 1775, 1675, 1630, 1530, 1370, 1040
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm # J in Hz) 3.68 and 3.96 (AB, J = 18, 2H, -SCH2-); 3.84 (s, 3H, = NOCH3); 5.21 (d, J = 4.1H, H, en6); 5.80 (dd, J = 4 and 9, 1H, H at 7); 6.73 (s, 1H,
Thiazole); 7.20 (AB limit, 2H, -CH = CH-S-); 7.20 (s large, 2H,
NH2); 9.60 (s, 1H, H thiadiazole); 9.63 (d, J = 9, 1H, -CONH-).

AF - [(5-amino-thiadiazol-1,3,4-l-2) -thio-2-vinyl] -3 [(2-amino-thiazol-4-yl) -2-methoxyimino-2-acetamido] -7-carboxy-2-oxo-8 thia -5 aza-1 bicyclo [4.2.0] octene-2, syn isomer, E form.

Infra-red spectrum (KBr), characteristic bands (cm-1) 3320, 3200, 3100, 2820, 2000, 1770, 1670, 1610, 1530, 1380, 1040, 940
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 3.83 (s, 3H, = NOCH3); 5.12 (d, J = 4.1H, H at 6); 5.76 (dd, J = 4 and 9, 1H, H at 7); 6.74 (s, 1H, H thiazole); 7.16 (brs, 2H, -NH 2 thiazole); 7.48 (bs, 2H, -NH 2 thiadiazole); 6.95 and 7.02 (2d,
J = 16.2H, -CH = CH-S-); 9.60 (d, J = 9, 1H, -CONH-).

Claims (12)

 1 - A new thioloester characterized in that it meets the general formula

 in which the symbol R "represents a hydrogen atom, an alkyl radical or a protective radical, the symbol R is chosen from the following meanings: 1) alkyl, L-amino-2-carboxy-2-ethyl, the amine function of which is protected and of which the acid function is free or protected, or phenyl 2) 1,3,4-thiadiazol-5 unsubstituted or substituted with alkyl, trifluoromethyl, alkyloxy, alkylthio, alkylsulfonyl, (hydroxy, hydroxyalkyl, carboxy or carboxyalkyl) radicals which may protected), Camino, alkylamino, aminoalkyl or protected alkylaminoalkyl), dialkylamino, dialkylaminoalkyl, acylamino, acylaminoalkyl, 1,2,4-thiadiazol-5 substituted with an alkyl or alkoxy radical, and 3) 1,2,3-triazol-1-yl; 5, triazol-1,3,4-yl-5 or alkyl-1-alkyloxycarbonyl-3-triazol-1,2,4-yl-4) tetrazol-5-yl unsubstituted or substituted in the -1 position by an alkyl, alkyloxyalkyl or phenyl radical , sulfoalkyl, hydroxyalkyl, the alkyl part of which contains 2 to 4 carbon atoms or carboxyalkyl which may be protected), (protected aminoalkyl or alkylaminoalkyl), dialkylaminoalkyl, sulfamoylaminoalkyl or acylaminoalkyl 5) pyridyl-2, pyridyl-3 or pyridyl-4 optionally N-oxidized, 6) substituted pyridazinyl-3 at position -6 (with alkyl, methoxy, protected amino or acylamino) and optionally N-oxidized or tetrazoloE4,5-b] pyridazinyl-5,7) dioxo-5,6 1,4,5,6-tetrahydro-triazine- 1,2,4-yl-3 substituted in the 4-position by a radical of a first group which comprises: alkyl, alkyloxyalkyl, alkylthioalkyl, phenylalkyl, allyl or carbamoylalkyl or by a radical of a second group which comprises hydroxyalkyl which may to be protected, acylaminoalkyl, carbamoyloxyalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl or acyloxyalkyl (the acyl part of which is optionally substituted by an amino or protected alkylamino radical or a dialkylamino radical), the alkyl parts, triazine radicals, radicals of this second group containing 2 to 4 carbon atoms or a radical of general formula

 wherein alk is an alkylene radical containing 1 to 4 carbon atoms, a and Y are the same and represent oxygen or sulfur atoms, and R1 represents an alkyl radical, or and and Y &alpha; are identical or different and represent oxygen or sulfur atoms and the radicals R 1 together form an alkylene radical containing 2 or 3 carbonyl atoms, and the symbol R 'represents a hydrogen atom or a protective radical chosen from t.butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, chloroacetyl, trichloroacetyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and p-methoxybenzyloxyearbonyl, it being understood that (except where otherwise stated) the alkyl moieties or acyl groups referred to above or which will be quoted below are straight or branched and contain from 1 to 4 carbon atoms; its syn, anti isomers and mixtures thereof and, when the radical R contains a carboxy or sulfo group, their metal salts and their addition salts with tertiary nitrogen bases.  2 - A novel thioloester according to claim 1, characterized in that R is a protective radical selected from trityl, tetrahydropyranyl and 2-methoxypropyl-2.  3 - A novel thioloester according to claim 1, characterized in that, when R has an amino, alkylamino, aminoalkyl or protected alkylaminoalkyl radical, the protective group is chosen from t.butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, chloroacetyl, trichloroacetyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and p-methoxybenzyloxycarbonyl.  4 - A new thioloester according to claim 1, characterized in that, when R has a protected carboxy radical, the protective group is selected from methoxymethyl, t.butyl, benzhydryl, p.nitrobenzyl and p.methoxybenzyl.  5 - A novel thioloester according to claim 1, characterized in that, when R comprises a protected hydroxy radical, the protective group is chosen from trityl, tetrahydropyranyl and 2-methoxypropyl-2.  6 - A process for the preparation of a product according to claim 1, characterized in that an acid (or a reactive derivative of the acid) of general formula is reacted

 in which R is defined as in the claim, it being understood that the oxime is protected beforehand if R "represents hydrogen, and R "is defined as R 'in claim 1 except for representing hydrogen (or represents a hydrogen atom when the reactive derivative is the acid chloride) on a thiol (free or in the form of alkaline or alkaline earth salt) of the general formula  R - SH in which R is as defined in claim 1 except for representing a 4-acyloxyalkyl-dioxo-S, 6 -tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 group whose portion acyl is optionally substituted, then if necessary eliminates the protective radicals and optionally converts the product obtained into a metal salt or an addition salt with a tertiary nitrogen organic base when R contains a carboxy or sulfo radical.  7 - A process according to claim 6, characterized in that the acid of general formula

 is used in the form of a reactive derivative selected from the anhydrides a mixed anhydride, a reactive ester or acid chloride.  8 - A method according to claim 7, characterized in that the reactive derivative of the acid of general formula

 a reactive ester of general formula

 wherein R "is defined as R 'in claim 1 except for representing hydrogen, R is defined as in claim 1 and Z is a succinimido radical, benzotriazolyl-1-nitro-4-phenyl, 2,4-dinitrophenyl, pentachlorophenyl or phthalimido.  9 - A process for preparing the products according to claim 1, for which R is a dioxo-S> 6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 radical substituted in the -4 position by a carbamoyloxyalkyl or acyloxyalkyl radical (the acyl portion of which is optionally substituted by an amino or protected alkylamino radical or a dialkylamino radical) and the triaxine-linked alkyl part of which contains 2 to 4 carbon atoms, characterized in that A thioloester according to claim 1 wherein R is 5-dioxo-4-hydroxyalkyl-4-tetrahydro-s, 5,6-triazine-1,2,4-yl-3, the alkyl part of which contains 2 to 4 carbon atoms, and for which the radicals R 'and R0 are other than hydrogen, by any known method for obtaining a carbamate or an ester from an alcohol without touching the rest of the molecule, and then optionally eliminating the protective groups.  10 - A method according to claim 9, characterized in that the carbamate conversion is carried out by the action of chlorosulfonyl isocyanate or trichloroacetyl, followed by treatment with a base.  11 - A method according to claim 9, characterized in that the esterification is carried out by condensation of a reactive derivative of the acid in the presence of a nitrogen base or an alkaline condensing agent.  12 - Use of a thioloester according to claim 1 for the preparation of a cephalosporin of general formula

 in which R represents a hydrogen atom or an alkyl radical, R is selected from the following meanings: I) alkyl, L-amino-2-carboxy-2-ethyl or phenyl 2) thiadiazol-1,3,4-yl-5 (unsubstituted or substituted by alkyl, trifluoromethyl, alkyloxy, alkylthio, alkylsulfonyl, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, amino, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, acylamino or acylaminoalkyl), 1,2,4-thiadiazol-5 (substituted with alkyl or alkyloxy radical), 3) triazol 1,2,3-yl-5, triazol-1,3,4-yl-5 or alkyl-3-alkyloxycarbonyl-1,2,4-triazol-5,4-tetrazolyl-5 (unsubstituted or substituted in the -1-position) by an alkyl, alkyloxyalkyl, phenyl, hydroxyalkyl radical, the alkyl part of which contains 2 to 4 carbon atoms, carboxyalkyl, sulfoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfamoylaminoalkyl or acylaminoalkyl), 5) pyridyl-2, pyridyl-3 or pyridyl-4 optionally N-oxidized, 6) pyridazinyl-3 substituted in position - 6 (with an alkyl radical, methoxy, amino or acylamino) and optionally N-oxidized or tetrazolof4,5-b2 pyridazinyl-6,7) dioxo-5,6 1,4,5,6-tetrahydro-1,2-triazine, 4-substituted-4-yl by a radical of a first group which comprises: alkyl, alkyl-oxyalkyl, alkylthioalkyl, phenylalkyl, allyl, formylalkyl or carbamoylalkyl or by a radical of a second group which comprises hydroxyalkyl, acylaminoalkyl, carbamoyloxyalkyl, alkylsulphinylalkyl, alkylsulphinylalkyl or acyloxyalkyl (the acyl portion of which is optionally substituted by an amino, alkylamino or alkylalkyl radical), the alkyl portions, linked to triazina, radicals of this second group containing 2 to 4 carbon atoms, or again by a radical of general formula

 as defined in claim 1 and R3 represents a hydrogen atom or an easily removable enzymatic radical of general formula

 in which R 4 represents a hydrogen atom or an alkyl radical and R 5 represents an alkyl radical or the cyclohexyl radical, it being understood that the substituent at the 3-position of the cephalosporin is in cis or trans form or in the form of a mixture cis and trans forms, that the group -ORO is in the syn or anti position or in the form of their mixture, and that unless otherwise indicated the alkyl and acyl radicals are straight or branched and contain from 1 to 4 carbon atoms, characterized in that the thiol ester is activated on a 7-amino cephalosporin (or optionally on a mixture of the isomers of this product) of general formula

 where n is 0 or 1 When n = 0 the product is in 2-bicyclooctene or -3 form and when n = 1 the product is in the bicyclooctene-substituted form on the 3-carbon atom of bicyclooctene has E or Z stereoisomerism, R'3 is defined as R3 or represents a protective radical and R6 represents a radical of general formulas  - O S02 R'6  or - O CO R '6 in which R' 6 is an alkyl, trifluoromethyl, trichloromethyl or substituted phenyl radical (by a halogen atom or by an alkyl or nitro radical)> then, if necessary, the sulphoxide obtained is reduced (when n = 1), if necessary, the protective radicals are removed and, if appropriate, the product obtained is converted into a salt.