FR2482600A2 - 7-Amino-thiazolyl hydroxy-imino acetamido 3-thio-vinyl cephalosporin - by reaction of thiourea with 7-4-halo-2-hydroxy-imino-3-oxo-butyramido cpd. to form antibacterials - Google Patents

Abstract

Process for prepn of 7-Q-C6=N-OR5)-CO-NH- 3-R-S-CH=CH- 4-R'OOC- 3-cephem derivs of formula (I), (where Q is 2-amino- 4-thiazolyl; R5 is H or alkyl and R is (1) alkyl, L-2-amino- 2-carboxy-ethyl or phenyl, (2) amt substd 1,3,4-thiadiazol-5- yl 1,2,4-thiadiazol-5-yl substd by alkyl or alkoxy; (3)1,2,3- triazol-5-yl, 1,3,4-triazol-5yl etc;(4) 5-tetrazolyl opt substd in position 1 by alkyl, alkoxyalkyl, phenyl etc; (5)2-, 3- or 4-pyridyl and their N-oxides;(6)3-pyridazinyl substd in position 6 by alkyl, methoxy, amino or acylamino or the N-oxide deriv or tetrazolo(4,5-b)-pyridazin-6yl;(7)5,6-dioxo- 1,4,5,6-tetrahydro-1,2,4- triazin-3-yl substd in position 4 R1 is H or a readily enzymatically removable gp -CHR2-OOCR3, where R2 is H or alkyl and R3 is alkyl or cyclohexyl. In the above definitions alkyl gps are 1-4C opt branched unless specified) by reaction of a thiourea R4-NH-CS-NH2 (where R4 is H or a protecting gp)with (II) (where R1 is R' or a protecting gp, n is 0 or 1 and Hal is Cl or Br), then if necessary reduce the 1-ozide, remove protecting groups and convert the prod to a salt. New preparation of antibacterials active against gram-negative and gram-positive bacteria.

Description

dans laquelle le symbole R 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-1,3,4 yl-5 non substitué ou substitué par un radical alcoyle, trifluorométhyle, alcoyloxy, alcoylthio, alcoylsulfonyle, hydroxy, hydroxyalcoyle, carboxy > carboxyalcoyle, amine, alcoylamino, aminoalcoyle, alcoylaminoalcoyle, dialcoylamino, dialcoylaminoalcoyle.In the main patent, the first and second additians have been described the thiovinyl-3 cephalosporins of general formula:

in which the symbol R 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-1,3,4 yl-5 unsubstituted or substituted by alkyl, trifluoromethyl, alkyloxy, alkylthio, alkylsulfonyl, hydroxy, hydroxyalkyl, carboxycarboxyalkyl, amine, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl.

acylamino or acylaminoalkyl.

-dans laquelle alk est un radical alcoylène contenant 1 à 4 atomes de carbone, Xα et Yα sont identiques et représentent des atomes d'oxygène ou de soufre, et Rα représente un radical alcoyle, ou bien Xα et Yα sont identiques ou différents et représentent des atomes d'oxygène ou de soufre et les radicaux Rα; forment ensemble un radical alcoylène contenant 2 ou 3 atomes de carbone et le symbole R' représente un atome d'hydrogène ou un radical facilement éliminable par voie enzymatique de formule générale

dans laquelle R" représente un atome d'hydrogène ou un radical alcoyle et R"1 représente un radical alcoyle ou le radical cyclohexyle, étant entendu que les portions ou radicaux alcoyles ou acyles cités ci-dessus (ou qui seront cités ci-après) sont (sauf mention spéciale) droits ou ramifiés et contiennent 1 à 4 atomes de carbone
Il est également entendu que le substituant en position (-3) des produits de formule générale (i) peut se présenter sous forme cis ou trans ou d'un mélange des formes cis et trans.1,2,4-thiadiazol-5 (substituted by alkyl or alkyloxy radical), 3) 1,2,3-triazol-5-yl, 1,3,4-triazol-5-yl or 1-alkyl-3-alkyloxycarbonyl 1,2,4-triazol-4-yl) 4-tetrazol-5-unsubstituted or 1-position substituted by alkyl, alkyloxyalkyl, phenyl, hydroxyacoyl, the alkyl portion of which contains 2 to 4 carbon atoms, carboxyalkyl, sulfoalkyl, amino - alkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfamoylaminoalkyl or acylaminoalkyl 5) pyridyl-2, pyridyl-3 or pyridyl-4 optionally N-oxidized, 6) 3-pyridazinyl substituted in the -h position (by an alkyl, methoxy, amino or acylamino radical) and optionally N-oxidized or tetrazolo [4,5-b] pyridazinyl-b 7) dioxo-5,6 1,4,5,6-tetrahydro-1, 4-triazine-1,3-yl-3 substituted in the 4-position with a radical of a first group which comprises: alkyl, alkyloxyalkyl, alkylthioalkyl, phenylacoyl, allyl, formylalkyl or carbanyloyl or a radical of a second group which comprises hydroxyalkyl, acyl; aminoalkyl, carbamoyloxyalkyl, alkylsulinylalkyl, alkylsulioylalkyl or acyloxyalkyl (the acyl part of which is optionally substituted by an amino, alkylamino or dialkylamino radical), the alkyl portions, linked to the triazine, radicals of this second group containing 2 to 4 carbon atoms; or by a radical of general formula

wherein alk is an alkylene radical containing 1 to 4 carbon atoms, X α and Y α are identical and represent oxygen or sulfur atoms, and R α represents an alkyl radical, or else X α and Y α are identical or different and represent oxygen or sulfur atoms and radicals R α; together form an alkylene radical containing 2 or 3 carbon atoms and the symbol R 'represents a hydrogen atom or an easily removable enzymatic radical of general formula

in which R "represents a hydrogen atom or an alkyl radical and R" 1 represents an alkyl radical or the cyclohexyl radical, it being understood that the alkyl or acyl moieties or radicals mentioned above (or which will be mentioned below) are (except special mention) straight or branched and contain 1 to 4 carbon atoms
It is also understood that the substituent in position (-3) of the products of general formula (i) can be in cis or trans form or a mixture of cis and trans forms.

In what follows, the trans stereoisomerism is denoted by E and the cis stereoisomerism is denoted by Z.
on the other hand, it is understood that the ORO group can be in one of the syn or anti positions.

The syn form is represented by the formula

The anti form is represented by the formula:

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

 When the radical R represents a dioxo-5,6-formylalkyl-1,4,4,6,6-triazine-1,2,4-yl-3-tetrahydro, it may be in its free aldehyde or aldehyde hydrate form. 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.

dans laquelle R est défini comme précédemment, et dont la fonction amine est préalablement protégée (ainsi que l'-oxime lorsque R0 représente lthydrogène), ou dtun dérivé réactif de cet acide sur une amino-7 céphalosporine de formule générale

(dans laquelle R est défini comme précédemment, et R1 représente un atome d'hydrogène, un radical de formule générale (III) ou un radical protecteur facilement éliminable, par exemple méthoxyméthyle, t.butyle, benzhydryle, p.nitrobenzyle, p.méthoxybenzyle, et n représente O ou l), suivie de la réduction du sulfoxyde obtenu lorsque n- 1, puis de l'élimination des radicaux protecteurs.According to the main patent, the first and second additions, the products of general formula (I) can be prepared by the action of an acid of general formula:

in which R is defined as above, and whose amine function is protected beforehand (as well as oxime when R0 represents hydrogen), or a reactive derivative of this acid on a 7-amino cephalosporin of general formula

(wherein R is defined as above, and R 1 represents a hydrogen atom, a radical of general formula (III) or an easily removable protecting group, for example methoxymethyl, t-butyl, benzhydryl, p-nitrobenzyl, p-methoxybenzyl; and n represents O or 1), followed by reduction of the sulfoxide obtained when n-1, followed by removal of the protective radicals.

dans laquelle, R , R1 et n étant définis comme précédemment, lorsque n = O le produit se présente sous forme bicyclooctène-2 ou -3 et lorsque rt = 1 le produit se présente sous forme bicycloctène-2 (selon la nomenclature des Chemical Abstracts), le substituant sur l'atome de carbone en position -3 du bîcyclooctène présente la stéréoisomérie E ou Z,
R2 représente un atome d'hydrogène ou un radical protecteur du groupement amino, choisi parmi t.butoxycarbonyle, trichloro-2,2,2 échoxycarbonyle, chloracétyle, trichloracétyle, trityle, benzyle, dibenzyle, benzyloxycarbonyle, p. uitrobenzyloxycarbonyle ou p.méthoxybenzyloxycarbonyle,
R3 représente un radical de formule générale
- O - SO2 - R'3 (IX)
ou - O - CO - Rt
3 (x) dans lesquelles R'3 est un radical alcoyle, trifluorométhyle,trichlo- rométhyle ou phényle substitué (par un-atome d'halogene ou par un radical alcoyle ou nitro), suivie de la réduction de l'oxyde-obtenu (lorsuqe n = 1) puis éventuellement de l'élimination des radicaux protecteurs.According to the main patent, the first and second additions, the products of general formula (I) in which R and R 1 are defined as above and R is defined as above except for representing a 4-acyloxyalkyl-5-dioxo radical. , 6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 (of which the acyl part is optionally substituted), may also be prepared by the action of a thiol or an alkaline salt of a thiol of general formula
R - SH (VII) [wherein R, which is defined as above, is protected as an acetal when it is intended to prepare a product of the general formula (1) in which R contains a formyl radical], on a cephalosporin derivative (or if appropriate on a mixture of the isomers of this derivative) of general formula

wherein, R, R1 and n being defined as above, when n = 0 the product is in the form of bicyclooctene-2 or -3 and when rt = 1 the product is in the form of bicycloctene-2 (according to the nomenclature of Chemical Abstracts ), the substituent on the carbon atom at the 3-position of the cyclooctene has E or Z stereoisomerism,
R 2 represents a hydrogen atom or a radical protecting the amino group, chosen from t-butoxycarbonyl, 2,2,2-trichloroalkoxycarbonyl, chloroacetyl, trichloroacetyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p. uitrobenzyloxycarbonyl or p.methoxybenzyloxycarbonyl,
R3 represents a radical of general formula
- O - SO2 - R'3 (IX)
or - O - CO - Rt
3 (x) in which R'3 is an alkyl, trifluoromethyl, trichlo- romethyl or substituted phenyl radical (by a halogen atom or by an alkyl or nitro radical), followed by reduction of the oxide-obtained ( when n = 1) and eventually the elimination of the protective radicals.

(dans laquelle R , R1 et n sont définis comme précédemment, R'2 est défini comme R2 à l'exception de représenter l'hydrogène et alk' est un radical alcoyle droit ou ramifié, contenant 2 à 4 atomes de carbone), par toute méthode connue pour obtenir un carbamate ou un ester à partir d'un alcool sans toucher au reste de la molécule, suivie, s'il y a lieu, de la réduction du sulfoxyde et de l'élimination des radicaux protecteurs.According to the second addition, the products of general formula (I) in which, R and R 'being defined according to the main patent,
R represents a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 radical substituted with a carbanyoyloxyalkyl or acyloxyalkyl group (the acyl part of which is optionally substituted); by an amino, alkylamino or dialkylamino radical), the triazine-linked alkyl part of which contains 2 to 4 carbon atoms, which are functional derivatives of the product of general formula (I) in which R and R 'are as defined above and R represents a dioxo-5,6-hydroxyalkyl-1,4,4,6,6-triazo-1,2,4-yl-3-tetrahydro radical, can be obtained from a product of general formula

(wherein R, R 1 and n are defined as above, R 2 is defined as R 2 except for representing hydrogen and alk 'is a straight or branched alkyl radical containing 2 to 4 carbon atoms), any known method for obtaining a carbamate or an ester from an alcohol without affecting the rest of the molecule, followed, if necessary, by the reduction of the sulfoxide and the elimination of the protective radicals.

 According to the main patent and its additions the products of general formula (I) in which R 'represents a radical of general formula (III) in which R "and R"' are defined as above, can also be obtained by esterification of a product of general formula (I) in which R 'represents a hydrogen atom and whose amine function has been previously protected.

 Where appropriate, the isomers of the products of general formula (I), (VI) or (XI) are separated by chromatography or crystallization.

The products according to the main patent and its additions can be transtruded into acid addition salts. According to the methods of the main patent and its patents, the products can be obtained in the form of trifluoroacetate, solvate with
Formic acid or water or para-toluenesulphonate. The products of general formula (L) obtained in the form of these salts may be released and converted into salts of other acids according to the usual methods.

 The products according to the main patent and its additions can also be converted to metal salts or addition salts with nitrogenous bases according to the methods known per se.

These salts can be obtained by the action of a metal base (for example alkaline or alkaline earth), ammonia Qu of an amine on a product according to the addition in a suitable solvent such as an alcohol, an ether or water 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.

 As examples of pharmaceutically acceptable salts, mention may be made of addition salts with mineral acids (hydrochlorides, hydrobromides, sulphates, nitrates, phosphates) or organic acids (succinates, fumarates, maleates, toluenesulfonates), salts with sodium alkali metals. potassium, lithium) or with alkaline earth metals (magnesium, calcium), ammonium salt, nitrogen base salts (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, NN-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-s-phenethylamine, N, N'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine, dibenzylamine).

 The products according to the main patent and its additions may be optionally purified by physical methods such as crystallization or chromatography.

The cephalosporin derivatives according to the main patent and its additions and their pharmaceutically acceptable salts have particularly interesting anti-bacterial properties. They exhibit remarkable activity in vitro and in vivo on germs
Gram-positive and Gram-negative.

dans laquelle RO, R, R1 et n sont définis comme précédemment dans le brevet principal et ses additions et Hal représente un atome de chlore ou de brome, suivie s il y a lieu de la réduction du sulfoxyde et de l'éli- mination des radicaux protecteurs.It has now been found and this is the subject of the present addition, that the products of general formula (I) can be obtained by action of a thiourea of general formula
R2NHCSNH2 (fold) [wherein R2 represents a hydrogen atom, or an amino protecting group selected from t.butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p.nitrobenzyloxycarbonyl or p methoxybenzyloxycarbonyl], on a product of general formula

wherein RO, R, R1 and n are defined as previously in the main patent and its additions and Hal represents a chlorine or bromine atom, followed by the reduction of the sulfoxide and the elimination of protective radicals.

 The procedure is generally carried out in an aqueous, organic or hydroorganic medium, for example in solvents or mixtures of solvents such as alcohols (methanol, ethanol), ketones (acetone), chlorinated solvents (chloroform, ethylene chloride), nitriles (acetonitrile), amides (dimethylformamide, dimethylacetamide), ethers (tetrahydrofuran, dioxane), esters (ethyl acetate) or acids (acetic acid, formic acid), in the presence or absence of a base such as sodium hydroxide, potassium hydroxide, carbonates, acidic carbonates of alkali metals, salts of carboxylic acids and alkali metals (sodium formate, sodium acetate) or tertiary amines (triethylamine, trimethylamine or pyridine), at a temperature of between -30 and 60 ° C.

dans laquelle R0 > R", R, R1 et n sont définis comme précedemment, qui peut alors être cyclisé en milieu acide.When operating in the presence of a base, depending on the nature of the latter and the quantity introduced, the intermediate of general formula is isolated or not

wherein R0> R ", R, R1 and n are defined as previously, which can then be cyclized in acidic medium.

 When it is desired to obtain a product of general formula (I) in which R contains a formylalkyl radical, this radical may be protected in the form of an acetal} in the form of a radical of general formula (II) as defined previously in the 2nd addition.

 The reduction of the sulfoxide and the elimination of the protective radicals is carried out under the conditions described previously in the main patent and its additions.

The elimination of protective radicals is carried out in particular under the following conditions
The liberation of the amino groups is effected: when it is a t.butoxycarbonyl trityl, p-methoxybenzyloxycarbonyl or formyl radical: by treatment in acidic medium. Trifluoroacetic acid is preferably used at a temperature of between 0 and 200 ° C., or anhydrous or aqueous formic acid or para-toluenesulphonic or methanesulphonic acid in acetone or acetonitrile are used at a temperature between 200C and the reflux temperature of the reaction mixture.In these conditions the product of general formula (I) can be obtained in the form of trifluoroacetate, solvate with formic acid, methylsulfonate or para-toluenesulphonate, which can be released. amine function by any method known per se to obtain an amine from one of its salts without affecting the rest of the molecule. It is carried out in particular by placing in contact with an ion exchange resin or by the action of an organic base - when it is a radical-2,2,2-trichloroethoxycarbonyl or p.nitrobenzyloxycarbonyl: by reduction (including treatment with zinc in acetic acid), when it is a benzyl, dibenzyl or benzyloxycarbonyl radical by catalytic hydrogenation, when it is a trifluoroacetyl radical: by treatment in a basic medium.

 The liberation of the carboxy radical is effected - when it is a t-butyl, p-methoxybenzyl or benzhydryl group: by treatment in an acidic medium, under the conditions described above for the removal of the trityl protecting radical amino.

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).

dans laquelle Hal est défini comme précédemment, R'" est défini comme Ro à l'exception de représenter l'atome d'hydrogène et Bal' représente le chlore ou le brome, sur une amino-7 céphalosporine de formule générale (VI), suivie éventuellement de la réduction du sulfoxyde obtenu (lorsque n = 1) et de l'élimination des radicaux protecteurs.The products of general formula (XIII) in which RO is an alkyl radical can be obtained by the action of an acid halide of general formula

in which Hal is defined as above, R '"is defined as Ro except for representing the hydrogen atom and Bal' represents chlorine or bromine, on a 7-amino cephalosporin of general formula (VI), optionally followed by the reduction of the sulfoxide obtained (when n = 1) and the elimination of the protective radicals.

 The reaction is generally carried out in a hydroorganic medium, for example water-ether (tetrahydrofuran, dioxane), water-ketone (acetone) or chlorinated water-solvent (chloroform, methylene chloride), in the presence of an alkaline condensing agent such as alkaline bicarbonate (eg, sodium bicarbonate) at a temperature between -40 and + 40 ° C.

 It is also possible to operate by analogy with the method described in the French patent application 2,399,418.

 It is understood that when the radical R of the 7-amino cephalosporin contains an amino or alkylamino radical, it is protected, and when the radical R contains a hydroxyl, carboxy or formyl radical the latter is free or protected.

 The protection of the amino or alkylamino groups may be carried out by radicals as described above for the blocking of the aminothiazole.

 Protection of the carboxy groups can be carried out by protective radicals as defined above for R1.

 The protection of the hydroxyl groups is carried out in particular by trityl, tetrahydropyranyl or 2-methoxypropyl-2 radicals.

 When it is desired to obtain a product of general formula (XIII) in which R contains a formylalkyl radical, this radical may optionally be protected in the form of an acetal, in the form of a radical of general formula (II).

 The removal of the protective radicals is carried out under the conditions described above for the amino, alkylamino and carboxy radicals.

 The removal of the protective group of the hydroxy radical is carried out - when it is a trityl or tetrahydropyranyl group: by acidolysis, for example by trifluoroacetic acid, aqueous or non-aqueous formic acid or para-toluenesulphonic acid, in the case of the 2-methoxypropyl-2 group: according to the method described in Belgian Patent 875,379.

 The elimination of the protective group of general formula (II) [when it is desired to obtain a product of general formula (XIII) in which the radical R contains a formylalkyl radical] is carried out - in the presence of a sulphonic acid (acid methanesulphonic or p-toluenesulphonic acid for example) in an organic solvent (acetonitrile or acetone for example), optionally in the presence of water and optionally in the presence of an acetalisable reagent such as acetone, glyoxylic acid, benzaldehyde or pyruvic acid, at a temperature of between 20 ° C. and the reflux temperature of the reaction mixture, or else by the action of aqueous formic acid (preferably containing less than 10% of water), or in the presence of or not silica, or by transacétalîsation in the presence of an acetalisable reagent as defined above.

 It is not absolutely necessary to isolate and purify the product of general formula (XIII) obtained, to react with the thiourea of general formula (XII).

peuvent être obtenus sous forme de l'un ou l'autre des isomères (pur), en opérant de la manière suivante : on prépare un halogénure d'acide de formule générale

dans laquelle R' et Hal' sont définis comme précédemment en faisant agir un agent d'halogénation sur l'acide, (un sel ou un ester silylique de l'acide) de formule générale

dans laquelle R'O est défini comme précédemment, en présence d'un produit de formule générale ::

dans laquelle X3, Y3 et Z3 sont identiques ou différents et teprésentent des radicaux alcoyle ou phényle, ou 2 d'entre eux forment ensemble avec les atomes auxquels ils sont rattachés un hétérocycle à 5 ou 6 chatnons contenant éventuellement un autre hétéroatome choisi parmi l'oxygène, l'azote ou le soufre, ou bien X3 et Y3 représentent des radicaux alcoyle tels que définis précédemment et Z3 représente un atome d'hydrogène ou un radical dialcoylamino.The products of general formula (XV) which have been described in the French application 2 414 508 in the form of a mixture of syn and anti isomers, prepared according to the scheme

can be obtained in the form of one or the other isomers (pure), operating in the following manner: an acid halide of general formula is prepared

wherein R 'and Hal' are defined as above by reacting a halogenating agent with the acid, (a salt or silyl ester of the acid) of the general formula

in which R'O is defined as above, in the presence of a product of general formula:

wherein X3, Y3 and Z3 are the same or different and represent alkyl or phenyl radicals, or 2 of them together with the atoms to which they are attached a 5- or 6-membered heterocycle optionally containing another heteroatom selected from oxygen, nitrogen or sulfur, or X3 and Y3 represent alkyl radicals as defined above and Z3 represents a hydrogen atom or a dialkylamino radical.

 The halogenating agent may be chosen from phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride or phosgene when it is desired to obtain the acid chloride, or else from phosphorus pentabromide. phosphorus oxybromide or thionyl bromide when it is desired to obtain the acid bromide.

 Among the products of general formula (tVIII), dimethylacetamide, diethylacetamide, dimethylpropionamide, diethylpropionamides, dimethylformamide, N-acetylmorpholine, N-acetylpiperidine, N-acetyl N-methylaniline, N-methylpyrrolidone or tetramethylurea.

 When a salt of the acid of general formula (XVII) is reacted, an alkaline salt or a tertiary amine salt (for example triethylamine) is preferably used.

 When a silyl ester is reacted, a trimethylsilyl or t.butyldimethylsilyl ester is advantageously used.

This ester may optionally be prepared by application of the method described by A. WISSNER et al., J. Org. Chem., 43 (20), 3972 (1978), or generated in situ.

 The preparation of the halide of the acid of general formula (XVII) is generally carried out in an organic solvent such as a chlorinated solvent (for example methylene chloride, chloroform), in an ester (for example ethyl acetate ), an aromatic hydrocarbon (for example toluene, xylene), or in an ether (for example ethyl ether, isopropyl ether or tetrahydrofuran), at a temperature of between -70 and +30 ° C.

 It is understood that the acids of general formula (XVII) of syn form lead to acid halides of syn form and that the acids of general formula (XVII) of anti form lead to acid halogens of general formula (XVI) of anti form.

 The products of general formula (XV) are then prepared by halogenation of a product of general formula (XVI) by any method known per se for the preparation of halogenated derivatives, which does not affect the rest of the molecule.

 When it is desired to obtain a product of general formula (XV) in which Hal represents a bromine atom, bromine is reacted in the presence of a catalyst, an acidic catalyst such as hydrobromic acid, hydrochloric acid, sulphonic acids (methanesulphonic acid, anhydrous p-toluenesulphonic acid or benzenesulphonic acid), or in the presence of ultraviolet light.

 When it is desired to obtain a product of general formula (XV) in which Hal is a chlorine atom, the chlorine is reacted in the presence of a catalyst as mentioned above, or sulfuryl chloride.

 The halogenation is carried out in an organic solvent such as chlorinated solvents (for example methylene chloride, chloroform, carbon tetrachloride, dichloroethane or trichloroethane) or the ethers (for example ethyl ether or dioxane) or in a mixture of these solvents at a temperature between -400C and the reflux temperature of the reaction mixture.

 The products of general formula (XV) thus obtained, which are respectively of syn form when they are prepared from a product of general formula (XVI) of syn form, or of anti form when they are prepared from a product of general formula (XVI) of anti-form are pure isomeric forms. They are therefore new and come within the scope of the present invention.

dans laquelle R'O est défini comme précédemment et Alk représente un radical alcoyle. The acids of general formula (XVII) can be obtained by acid hydrolysis or by saponification of an ester of general formula

in which R'O is defined as above and Alk represents an alkyl radical.

The esters of general formula (XIX) may be prepared by applying the method described by R. BUCOURT et al.
Tetrahedron, 34, 2233 (1978) or by the method described in J. Am. Chem. Soc., 60, 1328 (1938) or J. Indian Chem. Soc., 42, 677 (1965).

dans laquelle R, R1, Hal et n sont définis comme précédemment, par analogie avec la méthode décrite dans la demande de brevet français 2 399 418, puis éventuellement réduction du sulfoxyde et élimination des radicaux protecteurs.The products of general formula (XIII) in which R "represents a hydrogen atom can be obtained from a product of general formula

in which R, R1, Hal and n are defined as previously, by analogy with the method described in the French patent application 2,399,418, then optionally reduction of the sulfoxide and elimination of the protective radicals.

 It is understood that when the radical R of the product of general formula (XX) contains an amino, alkylamino or formyl radical, it is protected, and when the radical R contains a hydroxy or carboxy substituent, it is free. or protected.

 If necessary, the reduction of the sulfoxide and the elimination of the protective radicals is carried out under the conditions described above.

 The products of general formula (XX) can be obtained from a 7-amino cephalosporin of general formula (VI) by the action of a product of general formula Hal-CH 2 COCH 2 -COHal (xxI) in which Hal is defined as above (which can be formed in situ), by operating under the conditions described above to condense a product of general formula (XV) with a product of general formula (V), or by analogy with the method described in the French patent application 2,399,418.

 The preparation of the product of general formula (vit) has been described previously in the main patent and its additions.

EXAMPLE 1
0.18 g of thiourea are added to a solution of 1.4 g of benzhydryloxycarbonyl-2 (4-bromo-4-hydroxyimino-3-oxo-butyramido) -7 (2-methylthiadiazol-1,3,4-yl-5) thio -2-vinyl-3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, Form E, in 25 cm3 of ethanol, 25 cm3 of tetrahydrofuran and 5 cm3 of water and stirred for 4 hours. hours at 20 ° C. The solution is concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa). The residue is triturated with 10 cm3 of water, brought to pH 7 with sodium bicarbonate solution, the precipitate is filtered off, washed with water (5 cc) and dried. 1.3 g of a light beige solid which is dissolved in 10 cm3 of chloroform is obtained. The solution obtained is added dropwise to 100 cm3 of isopropyl ether with stirring. The insoluble material formed is filtered, redissolved in 25 cm3 of tetrahydrofuran, the solution formed is filtered in the presence of bleaching black, and concentrated to a volume of 5 cm3 under reduced pressure (20 mm of mercury, 2.7 kPa). 25 cm3 of ethyl acetate are added to this solution. The solid formed is filtered, washed with 10 cm3 of ethyl acetate and dried. 0.9 g of benshydryloxy-2-carbonyl-2-hydroxyimino (2-amino-4-thiazolyl) -2-acetamido] -7 ((2-methyl-thiadiazol-1,3,4-yl) -5-thio-2-vinyl) are thus obtained. 3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E, as a beige solid.

7,05 Cd, J = 16, 1H, -CH=CHS-) ; 7,26 (d, J = 16, 1H, -CH=HS-) 9,65 (d, J = 9, 1H, -CONH-) ; 11,85 (s large, lu, =NOH).Infra-red spectrum (KBr), characteristic bands (cm-1) 3380, 3200, 3100, 1785, 1720, 1685, 1630, 1535, 1500, 1445, 1210, 950, 760, 745, 705
Proton NMR Spectrum (350 MHz, DMSO d6.6 in ppm, J in Hz) 2.71 (s, 3H, -CH2 Het); 3.72 and 3.98 (2d, J = 18, 2H, -SCH2-) 5.28 (d, J = 4.1HH at 6); 5.90 (dd, J = 4 and 9, 1H, H at 7) 6.80 (1, 1H, H thiazole); 6.98 (s, 1H,

7.05 Cd, J = 16, 1H, -CH = CHS-); 7.26 (d, J = 16, 1H, -CH = HS-) 9.65 (d, J = 9, 1H, -CONH-); 11.85 (s wide, read, = NOH).

 0.3 g of 2-benzhydryloxycarbonyl [2-hydroxyimino-2- [2-amino-4-thiazolyl] -2-acetamido] [(1-methyl-thiadiazol-1,3,4-yl) -5-thio-2-vinyl] -3-is dissolved 8-oxo-5-thia-aza-1 bicyclo [4.2.0] octene-2, syn isomer, E-form, in 6 cm3 of 98% formic acid, 6 cm3 of distilled water and 15 minutes C. The cloudy solution is cooled, filtered in the presence of bleaching black and the filtrate is evaporated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) Etc (10 cc) is added to the residue, concentrated to dryness under reduced pressure (20 mm of mercury, 2.7 kPa), repeat this operation twice and then reflux the suspension of the residue with 10 cm3 of ethanol, cool, filter and dry under reduced pressure (0.5 mm Hg) 0.07 kPa).

0.07 g of 2-carboxy-2-hydroxyimino (2-amino-4-thiazolyl) acetamido] -7 [(2-methyl-thiadiazol-1,3,4-yl) -5-thio-2-vinyl] are thus obtained. 3-oxo-8-thia-5-azabicyclo (4.2.0) octene-2, syn isomer, form E, as a yellow solid.

Infrared spectrum (KBr), characteristic bands (cm-1) 3600, 2200, 1770, 1660, 1630, 1530, 1390, 950
Proton NMR spectrum (350 MHz, DMSO d6, δ ppm, J in Hz) 2.74 (s, 3H, -CH3 Het); 3.64 and 3.90 (2d, J = 18, 2H, -SCH 2 -); 5.20 (d, J = 4.1H, H at 6); 5.80 (dd, J = 4 and 9, 1H, H at 7) 6.65 (s, 1H, H thiazole); 7.08 (-: broad, 2H, -NH 2) 7.10 and 7.20 (2d, J = 14, 2H, -CH = CH-S-); 9.46 (d, J = 9, 1H, -CONH-); 11.28 (bs, 1H, = NOH)
Benzhydryloxycarbonyl-2 (4-bromo-2-hydroxyimino-3-oxo-butyramido) -7 [(2-methyl-thiadiazol-1,3,4-yl) -5-thio-2-vinyl] -3-oxo-5-chia-aza-1 bicyclo [4.2.0] octene-2, syn isomer, form E, may be prepared in the following manner
1.8 g of benzhydryloxycarbonyl-2 (4-bromo-3-oxo-butyramido) -7 ((2-methyl-thiadiazol-1,3,4-yl-5-thio-2-vinyl] -3 are suspended at 100 [deg.] C. 8-oxo-5-thia-azabicyclo [4.2.0] octene-2, isomer E, in a mixture of 23 cm 3 of tetrahydrofuran and 4.7 cm 3 of water, then 7.8 cm 3 of acid are added. acetic acid, cooled to 0.degree. C. with ice, a solution of 0.187 g of sodium nitrite in 2.3 cm.sup.3 of water is added and the reaction mixture rises to 200.degree. C. for 4 hours. The resulting solution is diluted with 150 cm.sup.3 of water. The precipitate is filtered, dissolved in 100 cm 3 of ethyl acetate, the organic phase is washed twice with 25 cm 3 of a saturated solution of sodium bicarbonate, twice with 25 cm 3 of a saturated solution. sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 ml of mercury, 2.7 kPa) to give 1.5 g of benzhydryloxycarbonyl-2 (4-bromo-2-hydroxyimino). oxo-3 butyram ido) 7 E (2-methyl-1,3,4-thiadiazol-5-yl) -5-vinyl-3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, form E, in the form of a brown solid.

Infrared spectrum (KBr), characteristic bands (cm-1) 1785, 1715, 1685, 1540, 1495, 1455, 1205, 950, 760, 745, 700
Proton NMR Spectrum (350 MHz, CNCl3, 6 ppm, JHz) 2.76 (s, 3H, CU3 Het); 4.53 (s, 2H, -COCH 2 Br); 5.12 (d, J 2, 4, 1H,
H at 6): 5.85 (dd, J = 4 and 9, 1H, H at 7); 7.01 (s, 1H, -COOCH <) 9.43 (d, J = 9, 1H, -CONH-); 16.50 (s large, 1H, = NOH)
A solution of 5.79 g of bromine in 3.53 cm3 of methylene chloride is added dropwise to a solution of 3.04 g of diketene in 3.53 cm3 of methylene chloride at -300 ° C. in 35 minutes.

This solution is stirred at the same temperature for 30 minutes.

One tenth of this solution is taken and added dropwise to a stirred solution of 1.38 g of 7-amino-2-benzhydryloxycarbonyl [(2-methyl-thiadiazol-1,3,4-yl-5) thio). 2 vinyl] -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, isomer E and 1.11 cm3 of bistrimethylsilylacetamide in 20 cm3 of ethyl acetate at -15 ° C. in 10 minutes and the solution is stirred at the same temperature for 30 minutes, then 20 cm3 of water are added, decanted, the organic phase is washed three times with 10 cm 3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. to dryness under reduced pressure (20 mm of mercury, 2.7 kPa) is thus obtained 1.9 g of benzhydryloxycarbonyl-2 (4-bromo-3-oxo-butyramido) -7 [(2-methyl-1,3-thiazole) 4-yl-5-thio-2-vinyl] -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2 isomer E as a brown solid.

Infrared spectrum (KBr), characteristic bands (cm) 1780, 1720, 1680, 1535, 1490, 1450, 1250, 940, 760, 700
Proton NMR spectrum (350 MHz, CDc13, 6 ppm, JHz) 2.75 (s, 3H, -CH3 heterocycle); 3.58 and 3> 84 (2d, J-19, 2H, -SCH 2 -); 3.75 (s, 2H, -CQCH 2 CO-); 4.03 (s, 2H, -CH 2 Br); 5.04 (d, J = 4.1H,
H in 6); 5.85 (dd, J = 4 and 9, - 1H, H at 7); 6.98 (s, 1H, -COOCH @)
7-aminobenzhydryloxycarbonyl-2 - [(2-methyl-thiadiazol-1,3,4-yl-5-thio-2-vinyl] -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, isomer E can be prepared as follows:
To a suspension of 9.2 g of 2-benzhydryloxycarbonyl-t-butoxycarbonylamino-7 [(2-methyl-thiadiazol-1,3,4-yl-5) -thio-2-vinyl] -3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, isomer E, in 138 cm3 of acetonitrile at 35 ° C., a solution of 8.43 g of p-toluenesulphonic acid monohydrate in 46 cm3 of acetonitrile is added over a period of 3 minutes.

The mixture is homogeneous and maintained at 38 ° C. for 40 minutes and then poured into a solution of 7.44 g of sodium bicarbonate in 600 cm 3 of water. The mixture is extracted with 300 cm3 of ethyl acetate and then with three times 100 cm3 of ethyl acetate. The organic phases are combined, washed with 100 cm 3 of saturated sodium bicarbonate solution and then twice with 100 cm 3 of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure ( 20 mm Hg, 2.7 kPa).

6.8 g of 7-amino-2-benzhydryloxycarbonyl (2-methyl-thiadiazol-1,3,4-yl-5) -thio-2-vinyl [3-oxo-8-thia-5-azabicyclo [4.2. 0] octene-2, isomer E, as a brown gum.

Infra-red spectrum (KBr); characteristic bands (cm-1) 3400, 3340, 1780, 1720, 1670, 1560, 1500, 1455, 950, 760, 745, 700
Proton NMR spectrum (80 MHz, CDCl 3, 6 ppm> J in Hz) 2.72 (s, 3H, cH 3 heterocycle); 3.46 (s, broad, 2H, -SCH 2 -) 4.77 (d, J = 4, 1H, H at 6); 5.00 (d, J = 4.1H, H at 7) 7.00 (s, 1H, -COOCH 3); 7.18 (bs, 2H, -CH = CH-)
Benzhydryloxycarbonyl -2-butoxycarbonylamino-7 [(2-methyl-thiadiazole-1,3,4-yl-5) thio-2-vinyl] -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, isomer E, can be prepared from the following dewlap
To a solution of 17 g of 2-benzhydryloxycarbonyl-2-t-butoxycarbonylamino-7 - [(2-methyl-thiadiazol-1,3,4-yl-5) -thio-2-vinyl] -3-oxo-5-oxide-5-thia-5-aza-1 bicycloE4.2.0] octene-2, isomer E, and 10.9 cm3 of dimethylacetamide in 170 cm3 of methylene chloride at -10 C is added in 5 minutes 4.7 cm3 of phosphorus tri chloride and maintained at -10 C The reaction mixture is diluted with 2000 cm 3 of ethyl acetate at 0 ° C., washed three times with 250 cm of saturated sodium bicarbonate solution, with 250 cm of saturated sodium chloride solution and dried. on magnesium sulphate, filtered and evaporated to dryness under reduced pressure The residue is chromatographed on a column of 291 g of silica gel Verse (0.063-0.2) (column diameter: 4.5 cm, height 37 cm) ) eluting with 3 liters of a mixture of methylene chloride and ethyl acetate 92.5-7.5 (by volume) and collecting fractions of 100 cm3. The product is then evaporated to dryness under reduced pressure (20 mm Hg, 2.7 kPa). 9.25 g of benshydryloxycarbonyl-2-tert-butoxycarbonylamino-C (2-methyl-1,3,4-chiadiazol) are thus obtained. yl-5) 2-thio-vinyl] -3-oxo-8-thia-5-aza-1 bicyclo [4.2.0] octene-2, isomer E, as a light yellow solid.

Infra-red spectrum (KBr); characteristic bands (cm-1) 3370, 1790, 1715, 1700, 1520, 1160, 945, 740, 700
Proton NMR Spectrum (80 MHz, CDC 13> 6 in ppm, J in Hz) 1.50 (s, 9H, (CH 3) 3 C-); 2.75 (s, 3H, -CH3 heterocyclic), 3.68 (bs, 2H, -SCH2-); 5.03 (d, J = 4.1H, H at 6) 5.28 (d, J = 9, 1H, -CONH-); 5.65 (dd, J = 4 and 9, 1 H H at 7) 7> 00 (1H, s, -COOCH)
Benzhydryloxycarbonyl-2-t-butoxycarbonylamino-7 - ((2-methyl-thiadiazol-1,3,4-yl-5) thio-2-vinyl] -3-oxo-5-oxide-5-thia-aza-1-bicyclo C4.2.01 octene 2, isomer E, can be obtained from the following dewlap
A solution of 20 g of 2-benzhydryloxycarbonyl-2-tert-butoxycarbonylamino-7-oxo-7-oxide (2-tosyloxyvinyl) -3-thia-5-aza-1-bicycloC4.2.0] octene-2 is stirred at 60 ° C. for 2 hours. E isomer, 4.87 g of 2-methyl-thiadiazoline-1,3,4 thione-5 and 5,04 cm3 of diisopropylethylamine in 200 cm3 of dimethylformamide.The mixture is poured on 2000 cm3 of ice water, extracted by 2000 cm3 then 500 cm3 of ethyl acetate, the organic phases are combined, washed with 250 cm3 of a saturated solution of sodium bicarbonate, with four times 250 cm3 of distilled water and then with 250 cm3 of a saturated solution of chloride of sodium, dried over magnesium sulphate, filtered in the presence of bleaching black and concentrated to dryness under reduced pressure (30 mm of mercury, 4 kPa) at 300 ° C. This gives 17 g of 2-benzhydryloxycarbonyl-3-butoxycarbonylamino-7 (2-methyl-1,3,4-thiadiazol-5-yl) -5-thio-vinyl] -5-oxo-5-oxide-5-thia-aza-1-bicyclo [4.2.0] octene-2, isomer E, in the form of 'a brown-green eraser. It is redissolved in 60 cm3 of ethyl acetate, reprecipitated with 600 cm3 of isopropyl ether, filtered and dried.

The expected product is thus obtained in the form of a yellow powder.

4,55 (d, J = 4, 1H, H en 6) ; 5,7 à 5,9 (m, 2H, -CONH- et H en 7) ; 6,97 (s, 1H,

7,53 (d J = 16, 1H, -CH=CHS-)
La préparation du benzhydryloxycarbonyl-2 t.butoxycarbonylamino-7 oxo-8 oxyde-7 (tosyloxy-2 vinyl)-3 thia-5 aza-l bicyclo[4.2.0] octène-2, isomère E a été décrite dans le brevet principal.Infrared spectrum (KBr), characteristic bands (cm-1)
3410, 1795, 1720, 1500, 1160, 1050, 940, 755, 740, 700
Proton NMR Spectrum (350 MHz, CDCl3, δ ppm, J-Hz) 1.50 (s, 9H, (CH2) CC-) 2.75 (s, 3H, -CH3 Het) '; 3.30 and 4.15 (2 d,
J = 18, 2H,

4.55 (d, J = 4, 1H, H at 6); 5.7 to 5.9 (m, 2H, -CONH- and H at 7); 6.97 (s, 1H,

7.53 (d J = 16, 1H, -CH = CHS-)
The preparation of 2-benzhydryloxycarbonyl-2-tert-butoxycarbonylamino-7-oxo-7-oxide (2-tosyloxyvinyl) thia-5-aza-1bicyclo [4.2.0] octene-2, isomer E has been described in the main patent .

EXAMPLE 2
0.51 S-amino-7-carboxy-2 - [(1-methyl-5-tetrazolyl) -2-thio-vinyl] -3-oxo-8α-hia-5-aza-1-cicyclo [4.2.0] octene-2 is dissolved. form Es in a mixture of 10 cm3 of water, 0.63 g of sodium bicarbonate and 7.5 cm3 of acetone. It is cooled to -80 ° C. and a solution of 0.363 g of 4-bromo-2-methoxyimino-3-oxo-butyryl chloride, in 5 ml of acetone, is added dropwise over a period of 5 minutes. The mixture is stirred for 50 minutes while allowing to warm from -8 ° C. to +5 ° C. It is filtered, the acetone is evaporated at 200 ° C. under 20 mm of mercury (2.7 kPa), diluted with 50 cm 3 of water, washed with 50 cm 3 of ethyl acetate, dilute the aqueous phase with 100 cm3 of water, add 150 cm3 of ethyl acetate and acidify to pH = 2.3 with a 4 N solution of hydrochloric acid. The organic layer is washed with 100 cm 3 of a semisaturated solution of sodium chloride, dried over sodium sulphate and concentrated to dryness at 200 ° C. under 20 mm of mercury (2.7 kPa).

 (4-Bromo-2-methoxyimino-3-oxo-butyramido) -7-carboxy-2 - [(1-methyl-5-tetrazolyl) -2-thiocyclo] oxo-8-thia-5-aza-1-bicyclo [4.2.0 ] octene 2, form E thus obtained in 5 cm 3 of ethanol is added at 20 ° C. to a solution of 0.11 g of thiourea in 5 cm 3 of ethanol and 10 cm 3 of water. 35 mm at + 20 ° C is stirred, the pH is then adjusted to 6 by addition of sodium bicarbonate and acidified by adding 1 cm3 of formic acid, the mixture is concentrated to dryness at 200 ° C. under 20 mm of mercury (2 , 7 kPa), and the residue is taken up with 3 times 50 cm3 of ethanol by dry evaporating each time at 200C under 20 mm of mercury.

4,0 (s, 3H, -OCH3) ; 5,20 (d, J = 4, 1H, H en 6) ; 5,80 (dd, J = 4 et 9, 1H, H en 7) ; 6,83 (s, 1H, H en 5 du thiazole) ; 7,0 (d, J = 16, 1H, -CH=CHS-) ; 7,1 (d, J = 16, 1H, =CHS-) ; 9,7 (d, J = 9, 1H, -CONH-).The residue is extracted with 250 cm3 of refluxing ethanol, filtered, concentrated at 25 cm3 at 20 ° C. under 20 mm of mercury (2.7 kPa), left for 15 minutes at 5 ° C., filtered again, and washed for 5 minutes. solid with 5 cm3 of ethanol and 2 times 10 cm3 of ether. 0.28 g of 2 - [(2-amino-4-thiazolyl) -2-methoxyiminoacetamido] carboxy-2 - [(1-methyl-5-tetrazolyl) -2-thio] -vinyl) oxo-8-thiophene are collected. Aza-1 bicyclo [4.2.0] octene-2, syn isomer, form E, in the form of a yellow powder whose characteristics are as follows
Rf = 0.49; silica gel chromatography, solvent: ethyl acetate, acetone, acetic acid, water 50-20-10-10 (by volume)
NMR spectrum of the proton (350 MHz, DMSO + CF3COOD, ben ppm,
J in Hz): 3.66 and 3.86 (2d, J = 17, 2H, -SCH 2 -); 3.90 (s, 3H,

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 = CHS-); 7.1 (d, J = 16, 1H, = CHS-); 9.7 (d, J = 9, 1H, -CONH-).

7-Amino carboxy-2 - [(1-methyl-5-tetrazol-5-yl) -vinyl] oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2,. form E can be prepared as follows:
A mixture of 3 g of 7-amino-2-benzhydryloxycarbonyl [1- (1-methyl-5-tetrazolylthio) -3-vinyl] -3-oxo-5-thia-aza-1-bicyclo [4.2.0] is treated at 500 ° C. for 30 minutes. ] Octene-2, Form E, with 105 cm3 of formic acid and 40 cm3 of water. It is concentrated to dryness at 200 ° C. under 0.05 t of mercury (0.007 kPa), taken up twice with 100 cm3 of ethanol and concentrated to dryness each time at 20 ° C. under 20 mm of mercury (2.7 kPa), triturated. the solid obtained in 50 cm3 of ethanol, filtered and washed twice with 25 cm3 of diethyl ether.

 1.5 g of 7-amino-2-carboxy-2 - [(1-methyl-5-tetrazolylthio) -vinyl] oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2 are obtained, which forms E, in formate form.

Proton RtS spectrum (350 MHz, DMSO d6, # in ppm, J in Hz)
3.64 and 3.89 (2d, J = 18, 2H, = SCH 2 -); 4.02 (s, 3H, 5.15 (d, J = 4, 1H, H at 6), δ> 77 (dd, J = 4 and 9, 1H> H at 7), 6.97 and 7, 13 (2d, J = 16, 2H, -CH = CH-); 9.07 (d, J = 9, 1H, -CONH-)
Amino- 2-benzhydryloxycarbonyl-2 - [(1-methyl-5-tetrazolyl-2-thio-vinyl] -3-oxo-5-thia-aza-1-bicyclo [4.2.0] octene-2, Form E, can be obtained in the following manner
8 g of 2-benshydryloxycarbonyl-tert-butoxycarbonylamino-7 - [(1-methyl-5-tetrazolyl) -2-thio-vinyl] -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] E-form are usually treated under the usual conditions. in solution in 80 cm3 of acetonitrile with 4.9 g of p-toluenesulphonic acid hydrate. After this treatment, 5.7 g of 7-amino-2-benzhydryloxycarbonyl [(1-methyl-tetrazolyl) 5) 2-thio-vinyl] -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2-octene-2, Form E, as a light brown solid.

 Infra-red spectrum (KBr), characteristic bands (cm 1) 1775, 1710, 1495, 1455, 1210, 755, 705.

 A solution of 13.8 g of 2-benzhydryloxycarbonyl-2-butoxycarbonylamino-7 - [(1-methyl-5-tetrazolylthio) -vinyl] -3-oxo-5-oxide-5-thia-aza is treated at -200 ° C. for 10 minutes. -1 bicyclo [4.2.0] octene-2, form And in 250 cm3 of methylene chloride and 7.65 g of dimethylacetamide with 11.9 g of phosphorus tribromide. The mixture is poured into 250 cm 3 of saturated potassium bicarbonate solution with vigorous stirring, the organic phase is washed with saturated sodium chloride solution (100 cc), dried over sodium sulphate, filtered and concentrated to dryness to dryness. C under 20 mm Hg (2.7 kPa).

The residue is chromatographed on a column of 260 g of Merck silica gel (0.06-0.2) (column diameter: 3 cm, height: 32 cm).

The mixture is eluted with 1.5 liters of a cyclohexane-ethyl acetate mixture 70-30 (by volume), collecting 100 cm3 fractions. Fractions 7 to 14 at 20 ° C. under 20 mm of mercury (2.7 kpa) are concentrated to dryness and 8.5 g of 2-benzhydryloxycarbonyl-2-t-butoxycarbonylamino [(1-methyl-5-tetrazolyl) thio-2) are concentrated to dryness. vinyl] -3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, form E, in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3340, 1790, 1705, 1690, 1510, 1160, 940, 730, 700
The preparation of 2-benzhydryloxycarbonyl-2-tert-butoxycarbonylamino-7 - [(1-methyl-5-tetrazolyl) -2-vinyl]] oxo-5-oxide-5-thia-aza-1-bicyclo [4.2.0] octene-2, form E has been described in the main patent.

4-bromo-2-methoxyimino-3-oxo-butyryl chloride, syn isomer, can be prepared in the following manner
To a solution at 20 C of 4.08 g of 2-methoxyimino-3-oxo-butyric acid, syn isomer, in 50 cm3 of diethyl ether, 2 drops of dimethylformamide are added, followed by dropwise dropwise, in 15 minutes, 2 cm3. of oxalyl chloride in solution in 5 cm3 of diethyl ether.

It is stirred for 1 hour at 200 ° C., another 1 drop of dimethylformamide is added and the reaction is continued for 15 minutes. It is concentrated to dryness at 20 ° C. under 20 mm of mercury (2.7 kPa) and is taken up twice with 30 cm 3 of petroleum ether, each time evaporating the solvent at 200 ° C. under 20 ° of mercury (2.7 kPa). . 2-methoxyimino-3-oxo-butanoyl chloride, syn isomer, thus obtained is dissolved in 50 cm3 of methylene chloride, 0.2 cc of 5.4 N hydrochloric ether is added to this solution at 20 ° C. and 1.14 cm3 of bromine. It is stirred for 20 hours at 200 ° C., concentrated to dryness at 20 ° C. under 20 mm of mercury (2.7 kPa) and 5.42 g of a brown oil consisting mainly of 4-bromo-2-methoxyimino-3-oxo-chloride are obtained. butyryl, syn isomer

 Proton NMR Spectrum (60 MHz, CDCl3, 6 ppm, JHz) 4.25 (s, 3H, -OCH3); 4.34 (s, 2H, -CH 2 -).

2-Methoxyimino-3-oxo-butyric acid, syn isomer, can be prepared in the following manner
A mixture of 52 g of 2-methoxyimino-3-oxo-butyrate of ethyl, syn isomer, 300 cm 3 of ethanol and 330 cm 3 of 1N sodium hydroxide is refluxed for 15 hours. The ethanol is concentrated at 200 ° C. under a pressure of 20 mm of mercury (2.7 kPa) and extracted with 150 cm 3 of methylene chloride. The aqueous phase is treated with 1 g of animal black, filtered, saturated with sodium chloride, cooled to 4 ° C. and acidified to pH -2 with 2N hydrochloric acid in the presence of 200 cm 3 of methylene chloride. aqueous phase with 2 times 100 cm3 of the same solvent and then with 6 times 200 cm3 of ethyl acetate The organic phases are dried over sodium sulfate and concentrated to dryness separately at 20 ° C. under 20 moles of mercury (2.7 kPa) .

The residues are collected and treated with vigorous stirring with 80 cm 3 of diisopropyl ether for 4 hours. The crystals obtained are drained and dried, thereby obtaining 8.9 g of 2-methoxyimino-3-oxo-butyric acid, syn isomer.

Infra-red spectrum (CHCl3), characteristic bands (cm-1) 3400, 2830, 2300, 1730, 1695, 1370, 1035
Proton NMR Spectrum (60 MHz, CDCl3, 6 ppm, JHz) 2.18 (s, 3H, CH3CO-); 4.18 (s, 3H, -OCH 3); 11.2 (s, 1H, -COOH).

 Ethyl 2-methoxyimino-3-oxo-butyrate, syn isomer, is prepared according to R. BUCOURT et al., Tetrahedron, 34, 2233 (1978).

EXAMPLES 3 TO 6
By operating in a similar manner, the products of general formula (I) corresponding to the structure are prepared.

Ex. <SEP> R <SEP> 1) <SEP> Spectrum <SEP> Infra-red
<tb><SEP> 2) <SEP><SEP> Spectrum of <SEP> NMR
<tb><SEP> 1) <SEP> Spectrum <SEP> infre-red <SEP> (KBr, <SEP> bands <SEP> characteristics <SEP> (cm-1)
<tb><SEP> 3500, <SEP> 2300, <SEP> 1770, <SEP> 1715, <SEP> 1680, <SEP> 1540, <SEP> 1050, <SEP> 950
<tb><SEP> 2) <SEP> Spectrum <SEP> of <SEP><SEP> NMR <SEP> proton <SEP> (350 <SEP> MHz, <SEP> CF3COOD, <SEP>#in<SEP> ppm, <SEP> J <SEP> in <SEP> Hz)
<tb><SEP> 3.87 <SEP> (AB <SEP> limit, <SEP> 2H, <SEP> -SCH2-) <SEP>;<SEP> 4.30 <SEP> (s, <SEP> 3H, <SEP> -OCH3) <SEP>;<SEP> 5.20 <SEP> (s <SEP> large,
<tb><SEP> 2H, <SEP>> NCH2-) <SEP>;<SEP> 5.38 <SEP> (d, <SEP> J <SEP> = <SEP> 4, <SEP> 1H, <SEP> H <SEP> in <SEP> 6) <SEP>;<SEP> 6.03 <SEP> (d, <SEP> J <SEP> = <SEP> 4, <SEP> 1H,
<tb><SEP> 3 <SEP>#<SEP> H <SEP> in <SEP> 7) <SEP>;<SEP> 7.22 <SEP> (d, <SEP> J <SEP> = <SEP> 16, <SEP> 1H, <SEP> -CH = CHS-) <SEP>;<SEP> 7.50 <SEP> (s, <SEP> 1H, <SEP> H <SEP> of <SEP> thia
<SEP> zole) <SEP>;<SEP> 7.72 <SEP> (d, <SEP> J <SEP> = <SEP> 16, <SEP> 1H, <SEP> = CHS-) <SEP>;<SEP> 9.74 <SEP> (s <SEP> wide, <SEP> 1H, <SEP> -CHO).
<tb><SEP> Spectrum <SEP> of <SEP><SEP> NMR <proton <SEP> (350 <SEP> MHz, <SEP> CF3COOd <SEP> + <SEP> D2O, <SEP># in <SEP> ppm, <SEP> J <SEP> in <SEP> Hz)
<tb><SEP> 3.82 <SEP> (Ab <SEP> limit, <SEP> 2H, <SEP> -SCH2-) <SEP>;<SEP> 4.26 <SEP> (s, <SEP> 1H, <SEP> -OCH3) <SEP>;<SEP> 5,10 <SEP> (s <SEP> large,
<tb><SEP> 2H, <SEP>> NCH2-) <SEP>;<SEQ> 5.31 <SEP> (d, <SEP> J <SEP> = <SEP> 4, <SEP> 1H, <SEP> H <SEP> in <SEP> 6) <SEP>;<SEP> 5.96 <SEP> (d, <SEP> J <SEP> = <SEP> 4, <SEP> 1H, <SEP> H
<tb><SEP> in <SEP> 7) <SEP>;<SEP> 7.06 <SEP> (d, <SEP> J <SEP> = <SEP> 16, <SEP> 1H, <SEP> -CH = CHS-) <SEP>;<SEP> 7.43 <SEP> (s, <SEP> 1H, <SEP> H <SEP> of <SEP>thiazole);
<tb><SEP> 7.56 <SEP> (d, <SEP> J <SEP> = <SEP> 16, <SEP> 1H, <SEP> = CHS-) <SEP>;<SEP> 9.67 <SEP> (s <SEP> wide, <SEP> 1H, <SEP> -CHO).
<Tb>

<SEP> Ex. <SEP> R <SEP> 1) <SEP> Spectrum <SEP> IR <SEP> (KBR <SEP> bands <SEP> characteristics <SEP> cm-1
<tb><SEP> 2) <SEP><SEP> Spectrum of <SEP><SEP> NMR <SEP> proton <SEP> 350 <SEP> MHz, <SEP> DMSO <SEP> d6, <SEP># in <SEP> ppm, <SEP> J <SEP> in <SEP> Hz
<tb><SEP> 1) <SEP> 3480, <SEP> 2830, <SEP> 1775, <SEP> 1710, <SEP> 1680, <SEP> 1635, <SEP> 1590, <SEP> 1535, <SEP > 1380, <SEP> 1110, <SEP> 1040, <SEP> 940
<tb><SEP> 2) <SEP> 3.36 <SEP> (s, <SEP> 3H, <SEP> -CH2OCH3) <SEP>;<SEP> 3.56 <SEP> (t, <SEP> J <SEP> = <SEP> 5, <SEP> 2H, <SEP> -CH2O-) <SEP>;<SEP> 4.10 <SEP> (t, <SEP> J <SEP> = <SEP> 5,
<tb><SEP> 2H, <SEP> -CH2N <);<SEP> 3.62 <SEP> and <SEP> 3.73 <SEP> (2d, <SE> J <SEP> = <SEP> 18, <SEP> 2H, <SEP> - <SEP> SCH2-) <SEP>;<SEP> 3.96 <SEP> (s, <SEP> 3H,
<tb><SEP> 4 <SEP>#<SEP> = NOCH3) <SEP>;<SEP> 5,18 <SEP> (d, <SEP> J <SEP> = <SEP> 4, <SEP> 1H , <SEP> H <SEP> in <SEP> 6) <SEP>;<SEP> 5.81 <SEP> (dd, <SEP> J <SEP> = <SEP> 4 <SEP> and <SEP> 9, <SEP> 1H,
<tb><SEP> H <SEP> in <SEP> 7) <SEP>;<SEP> 6.78 <SEP> (s, <SEP> 1H, <SEP> H <SEP> of <SEP> thiazole) <SEP>;<SEP> 6.87 (d, <SEP> J <SEP> = <SEP> 15, <SEP> 1H, <SEP> -CH = CH-S);
<tb><SEP> 7.29 <SEP> (d, <SEP> J <SEP> = <SEP> 15, <SEP> 1H, <SEP> -CH = CH-S-) <SEP>;<SEP> 6.70 <SEP> (s <SEP> wide, <SEP> 3H, <SEP> -NH3 +) <SEP>;<SEP> 9.55 <SEP> (d,
<tb><SEP> J <SEP> = <SEP> 9, <SEP> 1H, <SEP> - <SEP> -CONH-) <SEP>;<SEP> 12.64 <SEP> (s, <SEP> 1H, <SEP> -OH).
<tb><SEP> 1) <SEP> 3500, <SEP> 2500, <SEP> 1775, <SEQ> 1710, <SEQ> 1685 <SEP> to <SEP> 1630, <SEQ> 1540, <SEP> 1045 , <SEP> 950
<tb><SEP> 2) <SEP> 1.90 <SEP> (s, <SEP> 3H, <SEP> = CH3) <SEP>;<SEP> 3.48 <SEP> (m, <SEP> 2H, <SEP> -CH2NH-) <SEP>;<SEP> 3.62 <SEP> and <SEP> 3.73 <SEP> (2d, <SEP> J <SEP> = <SEP> 18,
<tb><SEP> 5 <SEP>#<SEP> 2H, <SEP> -SCH2-) <SEP>;<SEP> 4.0 <SEP> (s, <SEP> 3H, <SEP> -OCH3) <SEP>;<SEP> 5.15 <SEP> (d, <SEP> J <SEP> = <SEP> 4, <SEP> 1H, <SEP> H <SEP> into <SEP> 6) <SEP>;
<tb><SEP> 5.82 <SEP> (dd, <SEP> J <SEP> = <SEP> 4 <SEP> and <SEP> 9, <SEP> 1H, <SEP> H <SEP> into <SEP> 7) <SEP>;<SEP> 6.78 <SEP> (s, <SEP> 1H, <SEP> H <SEP> of <SEP> thiazole) <SEP>;
<tb><SEP> 6.86 <SEP> (d, <SEP> J <SEP> = <SEP> 16, <SEP> 1H, <SEP> -CH = CHS-) <SEP>;<SEP> 7.31 <SEP> (d, <SEP> J <SEP> = <SEP> 16, <SEP> 1H, <SEP> = CRS-) <SEP>;<SEP> 7.73
<tb><SEP> (s, <SEP> 3H, <SEP> -NH3 +) <SEP>;<SEP> 9.50 <SEP> (d, <SEP> J <SEP> = <SEP> 9, <SEP> 1H, <SEP> -CONH-) <SEP>;<SEP> 12.54 <SEP> (s <SEP> wide, <SEP> 1H,
<tb><SEP> -CONHN = <SEP> or <SEP> -C = N = N).
<tb><SEP> OH
<tb><SEP> 1) <SEP> 3400, <SEP> 3200, <SEP> 2200, <SEP> 1775, <SEP> 1710, <SEP> 1680, <SEP> 1530, <SEP> 1040, <SEP > 945
<tb><SEP> 2) <SEP> 3.62 <SEP> and <SEP> 3.82 <SEP> (AB, <SE> J <SEP> = <SEP> 18, <SE> 2H, <SEP > -SCH2-) <SEP>;<SEP> 2.84 <SEP> (s, <SEP> 3H, = NOCH3) <SEP>;<SEP> 4.15 <SEP> and
<tb><SEP> 4.32 <SEP> (2t, <SEP> J <SEP> = <SEP> 5, <SEP> 2 <SEP> x <SEP> 2H, <SEP>> NCH2CH2-OCHO) <SEP>;<SEP> 5.21 <SEP> (d, <SEP> J <SEP> = <SEP> 4, <SEP> 1H, <SEP> H <SEP> in <SEP> 6) <SEP>;
<tb><SEP> 6 <SEP>#<SEP> 5.78 <SEP> (dd, <SEP> J <SEP> = <SEP> 4 <SEP> and <SEP> 9, <SEP> 1H, <SEP> H <SEP> in <SEP> 7) <SEP>;<SEP> 6.73 <SEP> (s, <SEP> 1H, <SEP> H <SEP> of <SEP> thiazole) <SEP>;
<tb><SEP> 6.89 <SEP> and <SEP> 7.10 <SEP> (2d, <SEP> J <SEP> = <SEP> 16, <SEP> 2H, <SEP> -CH = CH -S-) <SEP>;<SEP> 7.16 <SEP> (s <SEP> wide, <SEP> 2H, -NH2) <SEP>;
<tb><SEP> 8,18 <SEP> (s, <SEP> 1H, <SEP> HCOO-) <SEP>;<SEP> 9.59 <SEP> (d, <SEP> J <SEP> = <SEP> 9, <SEP> 1H, <SEP> -COHN-C7) <SEP>;<SEP> 12.60 <SEP> (s <SEP> wide,
<tb><SEP> 1H, <SEP> -N = COH <SEP> triazine).
<Tb>

Claims (3)

1 - A process for preparing a product of general formula

 in which the symbol RO represents a hydrogen atom or an alkyl radical, the symbol R is chosen from the following meanings: 1) alkyl, L-amino-2-carboxy-2-ethyl or phenyl 2) thiadiazol-1,3,4-yl Unsubstituted or substituted by alkyl, trifluoromethyl, alkyloxy, alkylthio, alkylsulfonyl, hydroxy, hydroxyalkyl, carboxyalkoxyalkyl, amino, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, acylamino or acylaminoalkyl, thiadiazol-1,2,4 yl; -5 (substituted by alkyl or alkyloxy), 3) 1,2,3-triazolyl, 1,3,4-triazol-5-yl or 1-alkyl-1-alkyloxycarbonyl-1,2,4-triazolyl 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 or acylaminoalkyl radical; 5) pyridyl-2, p optionally pyridazinyl-3-pyridazinyl-3 (with an alkyl radical, methoxy, amino or acylamino) and optionally N-oxide or tetrazolo [4,5-b] pyridazinyl- 7) 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazo-1,3-yl substituted by a radical of a first group which includes alkyl, alkyloxyalkyl, alkylthioalkyl, phenylalkyl, allyl, formylalkyl or carbamoyl by a radical of a second group which comprises: hydroxyalkyl, acylaminoalkyl, carbamoyloxyalkyl, alkylsulfinylalkyl, alkylsulphonylalkyl or acyloxyalkyl (the acyl part of which is optionally substituted with an amino, alkylamino or dialkylamino radical), the parts alkyl, linked to the triazine, radicals of this second group containing 2 to 4 carbon atoms, or by a radical of general formula

 wherein alk is an alkylene radical containing 1 to 4 carbon atoms, X &alpha; and Y &alpha; are identical and represent oxygen or sulfur atoms, and R &alpha;; represents an alkyl radical, or else X &alpha; and Y &alpha; are identical or different and represent oxygen or sulfur atoms and radicals R &alpha; together form an alkylene radical containing 2 or 3 carbon atoms and the symbol R 'represents a hydrogen atom or an easily removable enzymatic radical of general formula

 in which R "represents a hydrogen atom or an alkyl radical and R" 'represents an alkyl radical or the cyclohexyl radical (the abovementioned alkyl or acyl radicals or radicals being straight or branched and contain 1 to 4 carbon atoms ) characterized in that a thiourea of general formula: R2NHCSNH2 in which R2 is a hydrogen atom or a protecting group is reacted, on a product of formula

  where R and R are defined as above, R1 is defined as R 'above or represents a protective radical, n is 0 or 1, and Hal represents a chlorine or bromine atom, then reduces if necessary the sulfoxide obtained, optionally eliminates the protective radicals and optionally converts the product obtained in a salt. 2 - A process according to claim 1, characterized in that a thiourea of general formula is made to act  R2NHCSNH2 wherein R2 is a protecting group selected from t.butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl or p.methoxybenzyloxycarbonyl. 3 - A method according to claim 1, characterized in that a product of general formula is made to act

 wherein Hal, R ", R and n being defined as in claim 1 R1 is a protecting group selected from methoxymethyl, t.butylylbenzhydryl, p.nitrobenzyl or p.methoxybenzyl.