FR2482599A2 - 3-Sulphonyl:oxy- or carbalkoxy- vinyl cephalosporin(s) - intermediates for prepn. of 3-thio-vinyl cephalosporin(s) - Google Patents

Abstract

3-R3-CH=CH- 4-R200C- 7-R1-NH 2 or 3-cephem derivs and their 1-oxides of formula (I) are new (where n is 0 or 1 and (A) R1 is a 2-R4NH-4-thiazolyl-C(=N-OR5)-CO-gp (Gp A) , where R5 is vinyl, cyanomethyl or 2-methoxy-2-propyl and R4 is H or a protecting gp or R5 is H, alkyl or a protecting gp and R4 is formyl or trifluoroacetyl; R2 is H, R8-COO-CHR9- (R8 is alkyl or cyclohexyl and R9 is H or alkyl), methoxymethyl, etc and R3 is R'3-SO2-O- or R"3-COO-; R'3 is alkyl, trifluoromethyl, trichloromethyl or phenyl and R"3 is R'3 or acylmethyl,tc or (B) R1 is H or as in (A); R4 is H or a protecting gp and R5 is H, alkyl or a protecting gp), R6 CO-(where R6 is H, alkyl or phenyl), R7-OOC-(where R7 isalkyl nitrophenylthio or R1NH- is replaced by a methyleneimino gp and R2 is as defined in (A) or R1 is H, 1-8C alkanoyl, 2-8C Cl and/or Br substd alkanoyl, azidoacetyl, cyanoacetyl etc. and R2 is 4-6C tert-alkyl, 6-7C tert- alkenyl, 6-7C tert-alkynyl, benzyl etc and R3 is R'3-SO2-O- or R"3-COO, where R'3 is phenyl and R"3 is phenyl, acylmethyl, 2-acylethyl, etc. Unless specifically defined alkyl and acyl gps are 1-4C opt branched gps. When n is 0 (i.e. not the 1- oxide) then the double bond is in position 2- or 3 and when n is 1(the 1-oxide)then the double bond is in position 2-. The 3-group has E. or Z form). (I) are intermediates for 3-thiovinylcephalosporins.

Description

leurs sels et leur preparation. The main patent concerns new vinyl-3 cephalosporins of the general formula

their salts and their preparation.

[dans laquelle R4 est un atome dthydrogène ou un radical protecteur(choisi parmi t.butoxycarbonyle, trichloro-2,2,2 éthoxycarbonyle, chloracétyle, trichloracétyle, trityle, benzyle, dibenzyle, benzyloxycarbonyle, p.nitrobenzyloxycarbonyle et p.méthoxybenzyloxycarbonyle)et R est un atome d'hydrogène, un radical alcoyle ou un groupement protecteur tel que trityle ou tétrahydropyrannyle), un radical acyle de formule générale
R6 CO - (tir) dans laquelle R6 est atome d'hydrogène ou un radical alcoyle [éventuellement
substitué par un ou plusieurs atomes d'halogène ou par un radical phényle ou phénoxy ou phényle,
un radical de formule générale
R7 O CO- (IV) [[dans laquelle R7 est un radical alcoyle ramifié non substitué ou alcoyle droit
ou ramifié portant un ou plusieurs substituants [.hoisis parmi les atomes dthalo-
Se ne ec les radicaux cyano, trialcoylsilyle, phényle et phényle substitué (par
un ou plusieurs radicaux alcoyloxy, nitro ou phényle)], vinyle, allyle ou quino lylej ou bien un radical nitrophénylthio, ou bien R1NE- est replacé par un radical méthylèneimino dans lequel le radical méthylène est substitué par un groupement dialcoylamino ou aryle (lui-même éventuellement substitué par un ou plusieurs radicaux méthoxy ou nitro) et le symbole R2 représente un atome d'hydrogène ou un -radical facilement élimina- ble par voie enzymatique de formule générale

[dans laquelle R8 représente un radical alcoyle ou le radical cyclohexyle et Rg représente un atome hydrogène ou un radical alcoylezou un radical méthoxy- méthyle, t.butyle, benzhydryle, p.nitrobenzyle ou p.méthoxybenzyle, ou bien b) le symbole R1, représente un atome d'hydrogène, un radical alcanoyle contenant 1 à 8 atomes de carbone, alcanoyle contenant 2 à 8 atomes de carbone substitué (par des atomes de chlore ou de brome), azidoacétyle, cyanoacétyle, un radical acyle de formule générale

dans laquelle chaque Q est H ou méthyle et Ar représente un radical thiényl-2, thiényl-3, furyle-2, furyle-3, pyrrolyle-2, pyrrolyle-3 ou phényle [éventuellenient substitué par des atomes d'halogène ou des radicaux trifluorométhyle, hydroxy, alcoyle (contenant 1 à 3 atomes de carbone), alcoyloxy (contenant 1 à 3 atomes de carbone), cyano ou nitro, dont au moins l'un est situé en méta ou en para du phényle], un radical acyle de formule générale
Ar - X - CH2 - CO - (VII) dans laquelle X est l'oxygène ou le soufre et Ar est défini crème ci-dessus ou
X représente le soufre et Ar représente pyridyl-4, un radical acyle répondant à la formule générale ::

dans laquelle Ar est défini comme précédemment et B représente un radical amino, arnino protégé bar un groupement benzyloxycarbonyle, alcoyloxycarbonyle, cyclopentyloxycarbonyle, cyclohexyloxycarbonyle, benzhydryloxycarbonyle, trityle ou trichloro-2,2,2 éthoxycarbonyle), un radical sulfo, un radical hydroxy ou carboxy Eéventuellement protégés par estarification respectivement avec un -acide alcanoïque ou un alcool (contenant 1 à 6 atomes de carbone)), azido, cyano ou carbamoyle, ou un radical (sydnone-3)-2 alcanoyle (dont la partie alcanoyle contient 1 à 3 atomes de carbone) ou un radical de formule générale

dans laquelle ta est 0 à 2 ou un radical amino-5 adipoyletdans lequel le groupement amino est éventuellement protégé par un radical alcanoyle (contenant 1 à 3 atomes de carbone et éventuellement substitué par un atome de chlore) et dans lequel le groupe carboxy est protégé par un groupe benzhydryle, trichloro-2,2,2 éthyle, t-alcoyle (contenant 4 à 6 atomes de carbone) ou nitrobeezyle] et le symbole R2 représente un radical t.alcoyle contenant 4 à 6 atomes de carbone, t.alcényle contenant 6 ou 7 atomes de carbone, t.alcynyle contenant 6 cu 7 atomes de carbone, benzyle, méthoxybenzyle, nitrobenzyle, trichloro-2,2,2 éthyle, benzhydryle, succinimidométhyle ou phtalimidométhyle ou un atome d'hydrogène et le symbole R3 représente un radical de formule générale
R'3 - SO2 O - (X) ou
R'3 - C00- (xI) dans lesquelles R13 représente un radical alcoyle,trifluorométhyle, trichlorométhyle ou phényle substitué par un atome d'halogène ou par un radical alcoyle cu nitro, les portions ou radicaux alcoyles ou acyles cités ci-dessus (ou qui seront cités ci-après) étant (sauf mention spéciale) droits ou ramifiés et contenant 1 à 4 atomes de carbone.The products of general formula (I), in which n is 0 or 1, are in the form of bicyclooctene-2 or -3 (according to the nomenclature of
Chemical Abstracts) when n = O or as bicyclooctene-2 when n = 1, the subscituanc on carbon atom at the 3-position of the cis or trans stereoisomeric preserving bicyclooctene and a) the symbol R1 represents a hydrogen atom, a radical of general formula

[wherein R4 is a hydrogen atom or a protecting group (selected from t.butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, chloroacetyl, trichloroacetyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p.nitrobenzyloxycarbonyl and p.methoxybenzyloxycarbonyl) and R is a hydrogen atom, an alkyl radical or a protective group such as trityl or tetrahydropyranyl), an acyl radical of general formula
R6 CO - (firing) in which R6 is a hydrogen atom or an alkyl radical [optionally
substituted with one or more halogen atoms or with a phenyl or phenoxy or phenyl radical,
a radical of general formula
R7 OCO- (IV) [[wherein R7 is unsubstituted branched alkyl or straight alkyl
or branched bearing one or more substituents [.hoisis among the halogen atoms
Including cyano, trialkylsilyl, phenyl and substituted phenyl radicals (eg
one or more alkyloxy, nitro or phenyl)], vinyl, allyl or quinyl radicals, or a nitrophenylthio radical, or R1NE- is replaced by a methyleneimino radical in which the methylene radical is substituted by a dialkylamino or aryl group (itself even optionally substituted by one or more methoxy or nitro radicals) and the symbol R2 represents a hydrogen atom or a radically easily removable enzymatic of general formula

[wherein R 8 represents an alkyl radical or cyclohexyl radical and R 8 represents a hydrogen atom or an alkyl radical or a methoxymethyl, t-butyl, benzhydryl, p-nitrobenzyl or p-methoxybenzyl radical, or b) the R 1 symbol, represents a hydrogen atom, an alkanoyl radical containing 1 to 8 carbon atoms, alkanoyl containing 2 to 8 carbon atoms substituted (with chlorine or bromine atoms), azidoacetyl, cyanoacetyl, an acyl radical of the general formula

wherein each Q is H or methyl and Ar is thienyl-2, thienyl-3, furyl-2, furyl-3, pyrrolyl-2, pyrrolyl-3 or phenyl [optionally substituted by halogen atoms or radicals trifluoromethyl, hydroxy, alkyl (containing 1 to 3 carbon atoms), alkyloxy (containing 1 to 3 carbon atoms), cyano or nitro, at least one of which is located in meta or para of phenyl], an acyl radical of general formula
Ar - X - CH 2 - CO - (VII) wherein X is oxygen or sulfur and Ar is defined as cream above or
X represents sulfur and Ar represents pyridyl-4, an acyl radical corresponding to the general formula:

in which Ar is defined as above and B represents an amino, protected amino group, benzyloxycarbonyl, alkyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, trityl or 2,2,2-trichloroethoxycarbonyl group), a sulpho radical or a hydroxy or carboxy radical; Possibly protected by estarification respectively with an alkanoic acid or an alcohol (containing 1 to 6 carbon atoms), azido, cyano or carbamoyl, or a (sydnone-3) -2 alkanoyl radical (of which the alkanoyl part contains 1 to 3 carbon atoms) or a radical of the general formula

wherein ta is 0 to 2 or an amino-5 adipoyl radical in which the amino group is optionally protected by an alkanoyl radical (containing 1 to 3 carbon atoms and optionally substituted by a chlorine atom) and wherein the carboxy group is protected by a benzhydryl, 2,2,2-trichloroethyl, t-alkyl (containing 4 to 6 carbon atoms) or nitrosyl group and the symbol R 2 represents a t-alkyl radical containing 4 to 6 carbon atoms, t.alenyl containing 6 or 7 carbon atoms, alkynyl containing 6 to 7 carbon atoms, benzyl, methoxybenzyl, nitrobenzyl, 2,2,2-trichloroethyl, benzhydryl, succinimidomethyl or phthalimidomethyl or a hydrogen atom and the symbol R3 represents a radical of general formula
R'3 - SO2 O - (X) or
R'3 - C00- (xI) wherein R13 represents an alkyl, trifluoromethyl, trichloromethyl or phenyl radical substituted by a halogen atom or by an alkyl or cu nitro radical, the alkyl or acyl portions or radicals mentioned above (or which will be quoted below) being (except special mention) straight or branched and containing 1 to 4 carbon atoms.

 It is understood that mixtures of bicyclooctene-2 and -3 and / or cis and trans isomers are within the scope of the invention described in the main patent.

 In what follows, the trans stereoisomerism is denoted by E and the cis stereoisomerism is denoted by Z.

 Furthermore, it is understood that the -OR5 group of the radical of general formula (II) may be in one of the syn or anti positions and that these isomers and their mixtures are also within the scope of the invention described in main patent.

The syn form is represented by the formula:

The anti form is represented by the formula:

dans laquelle étant défini comr. précédemment, le produit se présente sous forme oxoéthyl-3 bicyclooctène-2 ou -3 ou oxoéthylidène-3 bicyclooctane lorsque n = O et sous forme exoéthyl-3 bicyclooctène-2 ou oxoéthylidene-3 bicyclooctane lorsque n = 1, et R1 est défini comme ci-dessus (à ltexception de représenter
un radical de formule générale (II) dans laquelle R4 est hydrogène) et R2 est
défini comme ci-dessus (a l'exception de représenter lthydrogène) ou sur un
mélange de ses isomères, suivie éventuellement de la réduction du sulfoxyde
obtenu et, le cas échéant, de l'élimination des groupements protecteurs de la
fonction amine du radical de formule générale (II) et/ou éventuellement de la
fonction acide lorsque l'on veut obtenir un produit de formule générale (I)
pour lequel les fonctions amine et/ou acide sont libres.I - According to the main patent the products of general formula (i) for which,
R3 and n being defined as above, a1) R1 and R2 are defined as above in a) with the exception that R1 represents hydrogen or b1) R1 represents an alkanoyl radical containing 1 to 8 carbon atoms, alkanoyl containing 2 to 8 carbon atoms substituted by chlorine or bromine atoms, an acyl radical of general formula (VI) in which
Q is H or methyl and Ar represents a 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl or phenyl optionally substituted with halogen atoms or hydroxy, alkyl ( containing 1 to 3 carbon atoms) or alkyloxy (containing 1 to 3 carbon atoms), at least one of which is in meta or para to the phenyl],
an acyl radical of general formula (VII)
an acyl radical corresponding to the general formula (VIII)
in which Ar is defined as above and B represents a protected amino group [with a benzyloxycarbonyl, alkyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, trityl or 2,2,2-trichloroethoxycarbonyl] group, a sulpho radical or a hydroxy or carboxy radical [ optionally protected by esterification with an alkanoic acid or an alcohol (containing 1 to 6 carbon atoms)], or an amino-5-adipoyl radical in which the amino group is optionally protected by an alkanoyl radical (containing 1 to 3 carbon atoms and optionally substituted by a chlorine atom) and wherein the carboxy group is protected by benzhydryl, 2,2,2-trichloroethyl, alkyl (containing 4 to 6 carbon atoms) or. nitrobenzyl and R2 is defined as previously in can between prepared by action of an activated form of an acid R'3 S03 U or R'3 COOH, typ
(Rt3 SO2) (XII)
R'3 SO2 Hal (XIII)
(R'3 CO) 2 O (XIV)
R'3 CO Hal (Xl)
In these formulas R'3 is defined as above and Hal represents a halogen atom], on a product of general formula

in which being defined comr. previously, the product is in the form of 3-oxo-2-bicyclooctene or 3-oxo-ethylidene-3-bicyclooctane when n = O and 3-exoethyl-2-bicyclooctene or 3-oxo-ethylidene-bicyclooctane when n = 1, and R1 is defined as above (with the exception of representing
a radical of general formula (II) in which R4 is hydrogen) and R2 is
defined as above (with the exception of representing hydrogen) or on a
mixture of its isomers, followed eventually by the reduction of the sulphoxide
obtained and, where appropriate, the elimination of protective groups from the
amine function of the radical of general formula (II) and / or optionally
acid function when it is desired to obtain a product of general formula (I)
for which the amine and / or acid functions are free.

main
11 / - According to the patents, the products of general formula (I), in which
R2, R3 and n are defined as above and R1 represents hydrogen, can be obtained by removal of the radical R1, or optionally elimination
simultaneous radicals R1 and R2, a product of general formula (I) Sedans
which R1 is defined as above in a) with the exception of representing
hydrogen or a radical of general formula (II) or represents an amino-5-adipoyl radical whose amine and acid functions are protected, or radicals of general formula (vi) or (VII) as defined for R1 in bl) and R2 has the corresponding definitions with the exception of representing a hydrogen atom].

main
III / - According to the patent! , the products of general formula (I) [in which
R 3 and n are defined as above, R 1 represents a radical of general formula (II) as defined previously or is defined as previously in b) except for representing hydrogen, and R2 has the corresponding definitions], may be prepared by the action of an acid of the general formula R1OH (Xxx) in which R1 is defined as above, or a reactive derivative of this acid, on a product of the general formula (I) in which R1 is a hydrogen atom, or if necessary on a mixture of the isomers of this product, optionally followed by the reduction of the oxide obtained and optionally the removal of the protective radicals.

main
IV / - According to the patent /, the products of general formula (I) in which
n = i can be prepared by oxidation of the corresponding product of formula
general (I) in which n = 0.

The oxidation can be carried out by any known method which does not alter
not the rest of the molecule, especially by application of the described method
in German Patent DE 2,637,176.

V / - The products of general formula (I) for which R3 and n are defined as
previously, R1 is defined as above in a) and R2 is a radical-of
general formula (V), can be obtained by esterification of the product -corres
of general formula (I) in which R2 is a hydrogen atom, for example
any known method for preparing an ester from an acid without affecting the
rest of the molecule.

dans laquelle a) le symbole R représente un radical alcoyle, phényle, thiadiazol-1,3,4 yl-5 (éventuellement substitué par un radical alcoyle, hydroxyalcoyle, aminoalcoyle, alcoylaminoalcoyl'e, dialcoylaminoalcoyle, carboxyalcoyle, trifluorométhyle, alcoyloxy, alcoylthio, alcoylsulfonyle, amino, alcoylamino, dialcoylamino, acylamino ou carboxy), ou tétrazolyl-5 (éventuellement substitué en position -1 par un radical alcoyle, hydroxyalcoyle dont la partie alcoyle contient 2 à 4 atomes de carbone, alcoyloxyalcoyle, carboxyalcoyle, sulfoalcoyle, aminoalcoyle, alcoylaminoalcoyle, dîalcoylaminoalcoyle, sulfamoylaminoalcoyle ou phényle, le symbole RO représente un radical de formule générale (II) dans laquelle
R4 représente un atome d'hydrogène et R5 est hydrogène ou alcoyle, et le symbole R02 représente un atome d'hydrogène ou un radical de formule générale (V), ou bien ss) le symbole R représente un radical alcoyle ou phényle, le symbole RO, est défini comme R1 précédemment en b) et R 2 prend les définitions correspondantes ; étant entendu que, dans les produits de formule générale (XXXI), le substituant en position -3 présente la stéréoisomérie E ou Z et, lorsque R 1 représente un radical de formule générale (II), celui-ci peut se présenter sous les formes syn ou anti.The products of general formula (i) are useful as intermediates for the preparation of thiovinyl-3 cephalosporins of the general formula

wherein a) R is alkyl, phenyl, 1,3,4-thiadiazolyl (optionally substituted with alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, trifluoromethyl, alkyloxy, alkylthio, alkylsulphonyl, amino, alkylamino, dialkylamino, acylamino or carboxy), or 5-tetrazolyl (optionally substituted in the 1-position by an alkyl, hydroxyalkyl radical, the alkyl part of which contains 2 to 4 carbon atoms, alkyloxyalkyl, carboxyalkyl, sulphoalkyl, aminoalkyl, alkylaminoalkyl, alkylaminoalkyl, sulfamoylaminoalkyl or phenyl, the symbol RO represents a radical of general formula (II) in which
R4 represents a hydrogen atom and R5 is hydrogen or alkyl, and the symbol R02 represents a hydrogen atom or a radical of general formula (V), or else the symbol R represents an alkyl or phenyl radical, the symbol RO, is defined as R1 previously in b) and R 2 takes the corresponding definitions; it being understood that, in the products of general formula (XXXI), the substituent at position -3 has the stereoisomerism E or Z and, when R 1 represents a radical of general formula (II), this radical may be in the forms syn or anti.

 The products of general formula (xxxi) can be in the form of a mixture of these isomers.

1) - Thiovinyl-3 cephalosporins of general formula (XXXI) can be prepared by action of a thiol of general formula
R - SH (XXXII) in which the radical R [which is defined as above in a) or is optionally protected, on a derivative of the cephalosporin or a mixture of the isomers of general formula (I), [in which R1 is a radical of general formula (II) as defined above and R2 has the corresponding definitions, or R1 is defined as previously in b) and R2 has the corresponding definitions], optionally followed by the reduction of the oxide obtained and the elimination of protective radicals.

(dans laquelle n est défini comme précédemment, R1 et R2 sont définis comme ci-dessus et R a les définitions correspondantes). 2) - Thiovinyl-3 cephalosporins of general formula (XXXI) can also be obtained in the following manner
A thiol of general formula (XXXII) is made to act on an isomeric product or mixture of the product of general formula (I) [in which R1 and
R2 have the definitions given above for the preparation of the products of general formula (I) for which R1 is hydrogen, to prepare a product of general formula

(where n is defined as above, R1 and R2 are defined as above and R has the corresponding definitions).

dans laquelle R, R2 et n sont définis comme ci-dessus, par élimination du radical R1 d'un produit de formule générale (XXXIII) tel que défini précédemment, ou éventuellement élimination simultanée des radicaux protecteurs
R1 et R2 de ce produit.A product of general formula is prepared

in which R, R2 and n are defined as above, by removal of the radical R1 from a product of general formula (XXXIII) as defined above, or optionally simultaneous elimination of the protective radicals
R1 and R2 of this product.

The thiovinyl-3-cephalosporin of general formula (XXXI) in which R, R01 and R02 are defined as above, is then prepared by acylation of a 7-amino cephalosporin of general formula (XXXIV) using an acid of general formula
Wherein R 01, which is defined as above, is optionally protected if it contains radicals which may interfere with the reaction, or a reactive derivative of this acid under the conditions described above for the preparation products of general formula (XXXII), then reducing the oxide obtained (when n = t) and eliminates the protective radicals.

 The isomers of the products of general formulas (I), (XVI), (XVIII), (xxxi), (xxxiii) or XXXIV) can be separated by chromatography or by crystallization.

 The products according to the main patent and the products of general formula (XXXI) may be optionally purified by physical methods such as crystallization or chromatography.

 The products of general formula (xxxi) as defined in a), and their salts, have particularly interesting antibacterial properties.

 The cephalosporin derivatives of general formula (XKXI) as defined in p) are described, for their antibacterial properties or as intermediates for the preparation of antibiotic substances, in US Pat. No. 4,065,620.

 The present addition relates to novel 3-vinyl cephalosporins of the general formula (I) and their preparation.

According to the present addition, the products of general formula (I) (which have the same sSeroisomerism as the products of the main patent) are defined as follows n is equal to O or 1, and a ') - the symbol R1 represents a radical of general formula (II) wherein [R5 is vinyl, cyanomethyl or a protecting group such as 2-methoxypropyl-2 and R4 is defined as in the main patent or is a formyl or trifluoroacetyl radical, or
R5 is defined as in the main patent and R4 is a formyl or trifluoroacetyl radical], the symbol R2 is defined as in the main patent in a) and the symbol R3 represents a radical of general formula
R'3 - S020 - (x)
or R "3 - COO- (xIa) in which Rl3 represents an alkyl, trifluoromethyl, trichloromethyl or phenyl radical which is unsubstituted or substituted by a halogen atom or by an alkyl or nitro radical, and R" 3 is defined as R13 or represents an acylmethyl, 2-acylethyl, 2-acylpropyl, 1-alkyloxycarbonylmethyl, 2-alkyloxycarbonylethyl or 2-alkylpropylpropyl radical, or b ') - the R1 symbol is defined as in the main patent, the R2 symbol has the corresponding definition given in the main patent in a) or b) and the symbol R3 is a radical of general formula (X) in which R'3 is phenyl or a radical of general formula (XI a) in which R "3 is a phenyl radical, acylmethyl, 2-acylethyl, 2-acylpropyl, alkyloxycarbonylmethyl, 2-alkyloxycarbonylethyl or 2-alkyloxycarbonylpropyl.

 It is understood that the portions or alkyl or acyl radicals which are involved in the above definition (or which will be mentioned below) are (unless otherwise stated) straight or branched and contain 1 to 4 carbon atoms.

 It is also understood that mixtures of bicyclooctene-2 and -3 and / or cis and trans isomers are within the scope of this addition.

According to the invention, the products of general formula (I) [for which, not being defined as above, a'1) the symbols R1, R2 and R3 are defined as previously in b'l) the symbols R1 and R2 are defined as in the main patent in a) except for R1 to represent a hydrogen atom, or the symbol R1 represents an alkanoyl radical containing 1 to 8 carbon atoms, alkanoyl containing 2 to 8 carbon atoms substituted by chlorine or bromine atoms, an acyl radical of the general formula (VI) wherein Q is H or methyl and Ar is a thienyl-2, thienyl-3, furyl-2, furyl-3, pyrrolyl-2 radical optionally substituted with halogen atoms or hydroxy, alkyl (containing 1 to 3 carbon atoms) or alkyloxy (containing 1 to 3 carbon atoms) radicals, at least one of which is meta or para phenyl, an acyl radical of general formula (VII), an acyl radical corresponding to the general formula (VIII) wherein Ar is defined as above and B represents an amino group protected by a benzyloxycarbonyl, alkyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, trityl or 2,2,2-trichloroethoxycarbonyl group], a radical sulfo, a hydroxy or carboxy radical optionally protected by esterification with an alkanoic acid or an alcohol (containing 1 to 6 carbon atoms)), or an amino-5-adipoyl radical in which the amino group is optionally protected by an alkanoyl radical (containing 1 to 3 carbon atoms and optionally substituted by a chlorine atom) and wherein the carboxy group is protected by benzhydryl, 2,2,2-trichloroethyl, alkyl (containing 4 to 6 carbon atoms) or nitrobenzyl or R1NH is replaced by a cyclic imide group of a dicarboxylic acid and R2 is defined as in b) in the main patent and the symbol R3 is defined as above, and can be prepared by the action of an activated form of an acid R 'S03 H or R "3COOH, of the type ::
3 3 3
(R'3 SO2) 20 (XII)
R'3 SO2 Hai (XIII)
(R'3CO) 20 (XIV) or (R "3 CO) 2 O (XIV a)
Rt3CO Hal (XV) or R "3 CO Hal Cxv a)
In these formulas R'3 and R "3 are defined as above and Hal represents a halogen atom], on a product of general formula (XVI) in which, n being defined as above, the product is in oxoethyl form. 3-bicyclooctene-2 or -3 or 3-oxoethylidene bicyclooctane when n = O and in the form of 3-oxoethyl-2-bicyclooctene or 3-oxo-ethylidene-bicyclooctane when n = 1, and R1 is defined as above (with the exception of a radical of general formula (II) in which R4 is hydrogen) and R2 is defined as above (with the exception of representing hydrogen) or on a mixture of its isomers, followed optionally by the reduction of the sulfoxide obtained and if appropriate, the elimination of the protective groups of the amine function of the radical of general formula (II) and / or optionally of the acid function when it is desired to obtain a product of general formula (i) for which the functions amine and / o u acid are free.

 It is understood that when R 1 is a radical of general formula (II) in which R 5 is a hydrogen atom, it is necessary to protect the oxime by a group as indicated above, which may subsequently be eliminated. under the conditions indicated below.

où X1 Y1 et Z1 représentent des radicaux alcoyle ou phényle, ou éventuellement deux d'entre eux forment un cycle avec l'atome d'azote auquel ils sont rattachés (par exemple en présence de triéthylamine ou de diméthylaniline), dans un solvant organique chloré (par exemple chlorure de méthylène), dans un ester (acétate d'éthyle par exemple), dans un éther (par exemple dioxanne, tétrahydrofuranne), dans un amide (par exemple diméthylacétamide, diméthylformamide ou hexaméthylphosphorotriamide dans l'acétonitrile ou la N-méthylpyrrolidone, ou directement dans un solvant basique comme la pyridine, ou bien on opère en milieu hydroorganique en présence d'un agent alcalin de condensation (bicarbonate alcalin, soude ou potasse par exemple), à une température comprise entre -78 C et la température de reflux du mélange réactionnel.We generally operate in the presence of a tertiary base of the type

where X1 Y1 and Z1 represent alkyl or phenyl radicals, or optionally two of them form a ring with the nitrogen atom to which they are attached (for example in the presence of triethylamine or dimethylaniline), in a chlorinated organic solvent (eg methylene chloride), in an ester (eg ethyl acetate), in an ether (eg dioxane, tetrahydrofuran), in an amide (for example dimethylacetamide, dimethylformamide or hexamethylphosphorotriamide in acetonitrile or N- methylpyrrolidone, or directly in a basic solvent such as pyridine, or one operates in a hydroorganic medium in the presence of an alkaline condensing agent (alkaline bicarbonate, sodium hydroxide or potassium hydroxide for example), at a temperature between -78 C and the temperature reflux of the reaction mixture.

 Optionally, the operation is carried out under nitrogen.

 The reduction of the S-oxide can be carried out under the conditions described in German Patent Application 2,637,176.

 Where appropriate, the removal of the protective radicals from the amine function of the radical of general formula (II) and the acid function is carried out in a single step or in two steps.

By way of example: 1 / - The elimination of amine protecting groups is carried out - when it is a radical t.butoxycarbonyl, trityl, p.methoxy
benzyloxycarbonyl or formyl: by treatment in acidic medium. Of
trifluoroacetic acid is preferably used by operating at a temperature of
between 0 and 20oC, or using formic acid
anhydrous or aqueous, or even para-toluenesulphonic acid or
methanesulfonic acid in acetone or acetonitrile at a temperature
between 20 C and the reflux temperature of the reaction mixture.

Under 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
the amine function by any method known per se to obtain a
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 action of an organic base - in the case of a 2,2,2-trichloroethoxycarbonyl or p.nitro radical
benzyloxycarbonyl: 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 published French patent
under 2 243 199 - in the case of a benzyl, dibenzyl or benzyloxycarbonyl radical
by catalytic hydrogenation - when it acts of a trifluoroacetyl radical: by treatment with
basic medium.

2 / - The elimination of the protective groups of the carboxy radical takes place - when it is a t-butyl group, p.methoxybenzyl or benzhy
dryle: by treatment in an acid medium, under the described conditions
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 - when it acts on a methoxymethyl group:
diluted acidic medium - when it stagnates with a p.nitrobenzyl group: by reduction (notam
treatment with zinc in acetic acid or hydrogenolysis).

31 - The removal of the protective group of the oxime is effected - when it stains trityl group or tetrahydropyranyl
by acidolysis, for example by trifluoroacetic acid, the formic acid
whether aqueous or not, or paratoluenesulphonic acid - when it is the 2-methoxypropyl-2 group: according to the method
described in Belgian Patent 875,379.

 The products of general formula (XVI), for which n = O and R1 and R2 are defined as previously in b'1), can be obtained as described previously in the main patent.

ou du mélange de ses isomères, dans laquelle R1 et R2 sont définis comme en a1 )- dans la présente addition, à l'exception pour R2 et R4 de représenter l'hydrogène et R10 et R11, qui sont identiques ou différents, représentent des radicaux alcoyle (éventuellement substitués par un radical hydroxy, alcoyloxy, amino, alcoylamino ou dialcoyl amino)cuphényle, 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 azote, l'oxygène ou le soufre et éventuellement substitué par un radical alcoyle, étant entendu que l'énamine de de formule générale (XVIII) se se présente sous-forme bicyclo- octène-2 ou -3 et que le substituant sur l'atome de carbone en position -3 du bicyclooctène présente la stéréoisomérie cis ou trans.The products of general formula (XV1) 9 in which n = O and R1 and R2 are defined as above in a ') with the exception of
R2 and R4 represent a hydrogen atom, can be obtained by hydrolysis of an enamne of general formula ::

or a mixture of its isomers, wherein R1 and R2 are defined as in a1) - in the present addition, with the exception that R2 and R4 represent hydrogen and R10 and R11, which are the same or different, represent alkyl radicals (optionally substituted by a hydroxy, alkyloxy, amino, alkylamino or dialkylamino) or phenyl radical, or together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle optionally containing another heteroatom selected from nitrogen, oxygen or sulfur and optionally substituted with an alkyl radical, it being understood that the enamine of general formula (XVIII) is in the form of bicycloctene-2 or -3 and that the substituent on the 3-carbon atom of bicyclooctene has cis or trans stereoisomerism.

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

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

 When operating in an organic medium, the hydrolysis is carried out by adding water to the reaction mixture; 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 can be used are chlorinated solvents, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide, alcohols. It is not absolutely necessary to purify the product of general formula (XVI) obtained for use for the preparation of the products of general formula (I).

 The products of general formula (XVI), for which n = 1, can be obtained by oxidation of products of general formula (XVI) for which n is equal to 0, by application of the method described in German patent application DE 2 637,176.

#dans laquelle 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 (XX) (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 (XX) dans
laquelle X2 est oxygène ou soufre et l'autre un radical amino de formule générale

[dans laquelle R15 et R16 sont définis comme R10 et R11 dans la formule générale (XIX)], soit encore représent chacun des radicaux de formule générale (XXI)] sur un dérivé de céphalosporine de formule générale ::

The products of general formula (XVIII) for which B10 and R11 have the definitions given above (with the exception of representing alkyl substituted with hydroxy, amino or alkylamino) can be obtained by the action of a product optionally prepared in situ of general formula

# in which R10 and R11 are defined as before and R12 and R13, which
are identical or different, or represent groups of general formula
-X2 R14 (XX) (wherein X2 is an oxygen atom and R14 represents an alkyl or phenyl radical), or represents a radical of general formula (XX) in
which X 2 is oxygen or sulfur and the other an amino radical of general formula

[wherein R15 and R16 are defined as R10 and R11 in the general formula (XIX)], still represents each of the radicals of the general formula (XXI)] on a cephalosporin derivative of the general formula:

wherein, R1 and R2 being defined as in a ') - in the present
addition (except for R2 and R4 represent a hydrogen atom), the derivative is in the form of 3-methyl-2-bicyclooctene or 3-methylene-3-bicyclooctane.

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

When choosing a product of general formula (XIX) in
wherein the radical (XXI) is different from -N RloR11, it is preferable to choose such a product so that the HN amine R15R16 is more volatile than HN R10R11.

Products of general formula (XVIII) in which R10 and R11,
which are identical or different, represent alkyl radicals substituted by hydroxy, amino or alkyllanino can be obtained by transénamination from a product of general formula (xviii) wherein R10 and R11 represent alkyl radicals, preferably methyl.

(dans laquelle R10 et R11 ont les définitions correspondantes) sur le produit de formule générale (XVIII), et lton opère dans des conditions analogues à celles décrites précédemment pour l'action d'un produit de formule générale (XIX) sur un dérivé de formule générale (XXII).The reaction is carried out by the action of an amine of general formula

(In which R10 and R11 have the corresponding definitions) on the product of general formula (XVIII), and lton operates under conditions similar to those described above for the action of a product of general formula (XIX) on a derivative of general formula (XXII).

The products of general formula (XIX) can be prepared according to the methods described by H. BREDERECK et al., Chem. Ber. 101 41 (1968),
Chem. Ber. 101, 3058 (1968) and Chem. Ber. 106, 3725 (1973).

Ldans laquelle R2 est défini comme ci-dessus et la position de la double liaison est définie comme pour le produit de formule générale (XXIl)] par action d'un acide de formule générale

Ldans laquelle R4 et R5 sont définis comme dans l'addition en a')- a 11 exception de représenter l'hydrogène], ou d'un dérivé réactif de cet acide.Il est entendu que l'acide de formule générale (XXV) sous forme syn, anti ou leurs mélanges, conduit respectivement aux produits de formule générale (XXII) de forme syn, anti ou leurs mélanges.Cephalosporin derivatives of the general formula (XXII). in
which R 1 represents a radical of general formula (II) may be prepared from the products of general formula

Wherein R2 is defined as above and the position of the double bond is defined as for the product of the general formula (XXIl) by the action of an acid of the general formula

Wherein R4 and R5 are defined as in addition to a ') - with the exception of representing hydrogen, or a reactive derivative thereof. It is understood that the acid of general formula (XXV) in syn, anti form or mixtures thereof, respectively leads to products of general formula (XXII) of syn, anti form or mixtures thereof.

 Generally, the product of general formula (XXV), the free acid function of which is free on 7-cephalosporin of the general formula (XXIV), is condensed in an organic solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride or chloroform, in the presence of a condensing agent such as a carbodiimide (for example dicyclohexylcarbodiimide), N N'-carbonyldiimidazole or 2-ethoxy-ethoxycarbonyl-1-dihydro-1,2-quinoline, at a temperature between -20 and 400C.

(dans laquelle,R4 et R5 étant définis comme précédemment, Z représente un radical succinimido, benzotriazolyl-l, nitro-4 phényle, dinitro-2,4 phényle, pentachlorophényle ou phtalimido], ou bien des dérivés réactifs tels qu'un thioloester défini ci-après par la formule générale (XLV ) ou un halogénure d'acide par exemple le chlorure de l'acide de formule générale (XXV).When a reactive derivative of the acid of general formula (XXV) is used, it is possible to use the anhydride, a mixed anhydride or a reactive ester of general formula

(wherein, R4 and R5 being defined as above, Z is succinimido, benzotriazolyl-1, 4-nitrophenyl, 2,4-dinitrophenyl, pentachlorophenyl or phthalimido), or reactive derivatives such as a defined thioloester hereinafter by the general formula (XLV) or an acid halide for example the acid chloride of the general formula (XXV).

 When using the anhydride, 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 (for example tetrahydrofuran or dioxane), a chlorinated solvent (for example chloroform or methylene chloride), an amide (for example dimethylformamide or dimethylacetamide) or a ketone (for example acetone), or in mixtures of the above solvents, in the presence of an acceptor of acid such as an epoxide (for example propylene oxide) or a nitrogenous organic base such as pyridine, dimethylaminopyridine, N-methylmorpholine or a trialkylamine (for example triethylamine), or in a hydroorganic medium in the presence of an alkaline condensing agent such as sodium bicarbonate, and one operates at a temperature between -40 and 4000. It is also possible to implement a cephalosporin of general formula (X9nV) pre ally silylated by applying the method described in German Patent Application 2,804,040.

 When a reactive ester of general formula (XXVI), or a thiol ester is used, it is generally carried out in the presence of a trialkylamine (for example triethylamine) in an organic solvent such as dimethylformamide, at a temperature of between 0.degree. and 4000.

 The cephalosporin derivatives of general formula (XX2I) and (XXIV), in which R2 represents a radical of general formula (V), may be obtained by esterification of the corresponding acid by any method known per se for preparing an ester with from an acid, without touching the rest of the molecule.

Ldans laquelle R, est défini comme ci-dessus ] ou

Sedans lesquelles la position de la double liaison est définie comme pour les produits de formule générale (XXII) et (XXIV) et le cas échéant la fonction amine du radical R1 est protégée], sur un halogénure de formule générale

dans laquelle R9 et Rlo sont définis comme précédemment et X représente un atome d'halogène, dans un solvant inerte tel que le diméthylformamide, à une température comprise entre O et 3Oc. In general, an alkaline salt or a tertiary amine salt of a product of general formula is reacted with:

Where R, is defined as above] or

Sedans, in which the position of the double bond is defined as for the products of general formula (XXII) and (XXIV) and, where appropriate, the amine function of radical R1 is protected, on a halide of general formula

wherein R 9 and R 10 are as previously defined and X is a halogen atom in an inert solvent such as dimethylformamide at a temperature between 0 and 30 ° C.

 The products of general formula (xxix) can be prepared according to the method described in German Patent Application 2,350,230.

 The products of general formula (XXIV) may be prepared as described in the main patent.

 The acids of general formula (XXV) in which R5 is hydrogen, alkyl or trityl may be prepared according to the method described in patent BE 850 662.

 The acids of general formula (XXV) in which R5 is a vinyl radical can be prepared according to the method described in patent BE 869 079.

 The acids of the general formula (XXV) in which R 5 is cyanomethyl may be prepared according to the method described in German Patent Application 2,812,625.

 The acids of general formula (XXV), in which R 5 is a protective radical, can be prepared by protecting the oxime of such an acid in which R 5 is hydrogen, by any known method which does not affect the rest of the molecule. The protection is carried out in particular by the trityl, tetrahydropyranyl or 2-methoxypropyl-2 groups.

II / - According to the invention, the products of general formula (I), in
which n is defined as above, R3 is a radical of general formula (X) or (XI a), as defined previously in b ') -, R1 represents a hydrogen atom and R2 has the corresponding definition (given in ) or in b) in the main patent) can be obtained by removal of the radical R 1, or optionally simultaneous removal of the radicals R 1 and R 2, of a product of general formula (I) (in which
R1 is defined as previously in the main patent in a1) except to represent a radical of general formula (II) or represents an amino-5-adipoyl radical whose amine and acid functions are protected, or a radical of general formula ( VI) or (VII) as defined for R1 in bl) in the main patent and R2 has a corresponding definition].

 The removal of the protective radical R1 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 1 represents trityl, benzhydryl, trichloroacetyl, chloracetyl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-nitrobenzyloxycarbonyl: according to the methods mentioned above for the liberation of the amino radical of the product of general formula (I). It is advantageous to use p-toluenesulphonic acid in acetonitrile at a temperature between 0 and 50.degree.

when R 1 represents formyl, 2-chloro-dimethyl-1,1-ethoxycarbonyl, 2-cyano-1,1-dimethyl-ethoxycarbonyl, 3,5-dimethoxy-benzyloxycarbonyl, diphenylmethoxycarbonyl, (biphenyl-4-yl) -2-isopropyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, quinolyl- Oxycarbonyl, o-nitro-phenylthio, p-nitrophenylthio, or when R 1 NH is replaced by dimethyl aminomethylene-imino, 3,4-dimethoxy-benzylidene-imino or 4-nitro-benzylidene-imino: by hydrolysis in acidic medium, - when R 1 represents 2,2,2-trichloroethyl or 2,2,2-dimethyl-1,1-ethoxycarbonyl: by treatment with zinc and acetic acid, when R 1 represents acetyl, benzoyl, phenylacetyl, phenoxyacetyl or amino Protected adipoyl: according to the method described in Belgian Patent BE 758,800, when R 1 represents trimethylsilylethoxycarbonyl: according to the method described by H. GERLACH, Helv. Chim. Acta 60 (8), 3039 (1977), when R1 represents p.nitrobenzyloxycarbonyl: by hydrogenolysis in the presence of palladium.

 III / - According to the invention, the products of general formula (I) L in which n is defined as above, R1 is defined as above in a '/ -, R2 has the corresponding definition and R3 is a radical of general formula (X ) or (XI a), or else R1 is a radical of general formula (II) as defined previously in a) - in the main patent, or a radical as defined in b) - in the main patent with the exception to represent the hydrogen atom, R2 has the corresponding definitions and R3 is a radical of the general formula (X) or (XIa) as defined previously in b ')) can be prepared by the action of an acid by the general formula (XXX) wherein R 1 is defined as above, or a reactive derivative of this acid, on a product of general formula (I) wherein R 1 is a hydrogen atom, or where appropriate on a mixture of the isomers of this product, possibly followed by the reduction of the oxide obtained then possibly of the elimination of the protective radicals.

We operate by analogy with the method previously described for
obtaining a product of general formula (xxii) from products of general formulas (XXIV) and (XXV), or according to the methods mentioned in the patent
U.S. 4,065,620.

 If appropriate the reduction of the oxide, as well as the elimination of the protective radicals of the amine function and of the acid function, can be carried out under the conditions described to obtain the product of general formula (I) from a product of general formula (XVI).

IV / - According to the invention, the products of general formula (I) in which n = 1 can be prepared by oxidation of the corresponding product of general formula (I) wherein n = 0.

 The oxidation can be carried out by any known method which does not alter the rest of the molecule, in particular by application of the method described in the German patent DE 2 637 176.

V / - The products of general formula (I) L for which, n being defined as above, R1 and R3 are defined as previously in a ') or R1 is defined as in a) in the main patent and R3 is a radical of formula general (X) or (XI a) as defined above in b ') -, and R2 is a radical of general formula (V), can be obtained by esterification of the corresponding product of general formula (I) in which R2 is a hydrogen atom, by any known method for preparing an ester from an acid without touching the rest of the molecule.

 It is generally carried out by the action of an alkaline salt or a tertiary amine salt of the product of general formula (I) on a halide of general formula (XXIX), under the conditions described above for the preparation of products of general formulas (xxii) or (XXIV) wherein R2 is a radical of general formula (V).

VI / - According to the invention, the products of general formula (I) in which n is defined as above,
R1, R2 and R3 are defined as above in a ') - (except for
R4 to represent chloroacetyl or trichloroacetyl and for R5 to represent vinyl), or
R1 and R2 are defined as in a) - in the main patent, (except for R4 to represent chloroacetyl or trichloroacetyl) and R3 is defined as above in b ') -, may also be prepared by the action of a thiourea of general formula
Wherein R4 is defined as above, on a product or a mixture of the isomers of the product of general formula ## STR3 ##

wherein R2, R3, R5 and n are defined as above and Hal is represented
an atom of chlorine or bromine, possibly followed by
the sulphoxide obtained (when n = 1), and possibly the elimination
protective radicals.

 The operation 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 acetic acid, formic acid), in the presence or absence of a base such as sodium hydroxide, potash, carbonates, acidic carbonates of alkali metals, salts of carboxylic acids and of alkali metals (sodium formate, sodium acetate) or tertiary amines (triethylamine, trimethylamine or pyridine), at a temperature between - 30 and 60 C.

(dans laquelle R2, R3, R4, R5 et n sont définis comme ci-dessus), qui peut etre alors 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 R2, R3, R4, R5 and n are defined as above), which can then be cyclized in acidic medium.

 The reduction of the sulfoxide and the elimination of the protective radicals take place under the conditions described above.

dans laquelle Hal et Hal' sont des atomes de chlore ou de brome et R5 est un radical alcoyle ou cyanométhyle) sur une amino-7 céphalosporine de formule générale (I) dans laquelle R2 a la définition donnée cidessus suivie de la réduction du sulfoxyde obtenu (lorsque n = 1) et de l'élimination des radicaux protecteurs.The products of general formula (XXXVII) in which R5 is an alkyl or cyanomethyl radical may be obtained by the action of an acid halide of general formula

in which Hal and Hal 'are chlorine or bromine atoms and R5 is an alkyl or cyanomethyl radical) on a 7-amino cephalosporin of the general formula (I) in which R2 has the above definition followed by the reduction of the sulfoxide obtained (when n = 1) and the elimination of protective radicals.

 The reaction is generally carried out in a hydroorganic medium, for example water-ether (tetrahydrofuran, dioxane), water-ketone (acetone) or water-chlorinated solvent (chloroform, methylene chloride), in the presence of an alkaline condensing agent such as than an alkaline bicarbonate (for example sodium bicarbonate) at a temperature of between -4 ° and + 40 ° C.

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

The products of general formula (XXXIX) can be obtained by halogenation of a product of general formula

in which R5 and Hal 'are defined as above, by any
method known per se for the preparation of halogenated derivatives, which
does not alter the rest of the molecule.

 When it is desired to obtain a product of general formula (XXXIX) in which Hal represents a bromine atom, bromine is reacted in the presence of a catalyst, an acidic catalyst such as hydrobromic acid or hydrochloric acid. sulfonyl acids (methanesulfonic acid, p-toluenesulfonic acid anhydrous or benensulfonic acid), or in the presence of ultraviolet light.

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

Halogenation is carried out in an organic solvent such as
a chlorinated solvent (for example methylene chloride chloroform, carbon tetrachloride, dichloroethane or trichloroethane) or an ether (for example ethyl ether or dioxane) or in a mixture of these solvents at a temperature of between -40 ° C and the reflux temperature of the reaction mixture.

 The products of general formula (XXXV) can be prepared from the corresponding esters, according to the method described in French Patent Application 2,414,508.

 The esters may themselves be prepared by the method described by R. BUODURT et al., Tetrahedron, 2233 (1978).

dans laquelle R2, R3, Hal et n sont définis comme ci-dessus, 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 (XXXVII) in which R5 is a hydrogen atom can be obtained by nitrosation of a product of general formula

in which R2, R3, Hal and n are defined as above, 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.

Products of general formula (XXXVII) in which
R5 is a protective group can be obtained by protecting the oxime of a product of general formula (XXXVII) for which R5 is a hydrogen atom.

The products of general formula (XLI) can be obtained from a 7-amino cephalosporin of general formula (I) in which
R2 has the definition given above, by action of a product of general formula:
Hal-CH 2 -OOCH 2 -CO Hal (XLII) in which Hal is defined as above, (which may be formed in situ), by operating under the conditions described above for condensing a product of general formula (XXXIX) with a product of formula general (I) or by analogy with the method described in French patent application 2,399,418.

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 Yα et Yα sont identiques ou différents et représent des atomes d'oxygène ou de soufre, et les radicaux Rα; forment ensemble un radical alcoylène con tenant 2 ou 3 atomes de carbone, et et Rss représente un atome d'hydrogène, un radical alcoyle contenant 1 à 3 atomes de carbone,
e) par un radical alcoyle contenant 1 à 5 atoies de carbone substitué par un radical alcoyloxyimino ou hydroxyimino.The novel products of general formula (I) are useful as intermediates for the preparation of thiovinyl-3 cephalosporins of general formula (XOI)
in which -a) the symbol R is chosen from the following meanings:
1) alkyl, L-amino-2-carboxy-2-ethyl or phenyl
2) pyridyl-2, pyridyl-3 or pyridyl-4, optionally N-oxidized,
3) pyrimidinyl-2-pyridazinyl-3 substituted at position -6 (by a radi
cal alkyl, methoxy, amino or acylamino) and optionally N-oxidized
or tetrazolo [4,5-b] pyridazinyl-6
4) dioxo-5,6 1,4,5,6-tetrahydro-1,2,4-triazine-1,3-yl substituted in posi
tino -4, triazol-1,3,4-yl-5 or alkyloxycarbonyl-2-triazol-1,3,4-yl;
substituted in position -1
a) with an alkyl radical containing 1 to 4 carbon atoms which is unsubstituted or substituted by an alkyloxy, alkylthio or phenyl radical,
formyl, carbamoyl, alkylcarbamoyl, dialkylcarbawoyl, acyl, alkyl
loxycarbonyl or thiazolidinyl-2,
b) an allyl radical, 2,3-dihydroxypropyl; dihydroxy-1,3
propyl-2; 2-formyl-2-hydroxyethyl; 3-ammyloxy-2-hydroxypropyl;
2,3-bis-formyloxypropyl or 1,3-bis -formyloxypropyl-2,
(c) an alkyl radical containing 2 to 4 carbon atoms,
killed by hydroxy. carbamoyloxy, acyloxy (the acyl part of which can be
substituted with an amino, alkylamino or dialkylamino radical), alkyl
sulfihyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamino,
alkylsulfonylamino, sulfamoylamino, acylamino (the acyl part of which is
optionally substituted with hydroxy, amino, alkylamino or dialkyl
amino), alkyloxycarbonylamino, ureido, alkylurea, dialkylureido,
d) by a radical corresponding to one of the general formulas

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 alternatively Y 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 and Rss represents a hydrogen atom, an alkyl radical containing 1 to 3 carbon atoms,
e) an alkyl radical containing 1 to 5 carbon atoms substituted by an alkyloxyimino or hydroxyimino radical.

5) 1,4-dialkyl-5,6-dioxo 1,4,5,6-tetrahydro-1,2,4-triazine-1-yl-1-dioxo-5,6-tetrahydro-1,4,5,6-triazine 1,2,4-yl-3-alkyl-2-dioxo-5,6 1,2,5,6-tetrahydro-1,2,4-triazine-3-yl
6) triazol-1,3,4-yl-5, triazol-1,2,3-yl-5 or alkyl-1-triazol-1,2,4
yl-5 unsubstituted or substituted at position -3 by alkyloxycarbonyl
7) a) 1,3,4-thiadiazol-5 unsubstituted or substituted with a radical
alkyl, trifluoromethyl, alkyloxy, alkylthio, hydroxyalkylthio
of which the alkyl part contains 24 carbon atoms, alkylsulphonyl,
hydroxy, hydroxyalkyl, carboxy> carboxyalkyl, amino, alkylamino,
dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,
acylamino or acylaminoalkyl,
b) 1,2,4-thiadiazol-5 substituted with an alkyl radical or
alkyloxy,
8) a) 1,3,4-oxadiazol-5 unsubstituted or substituted with a radical
alkyl, trifluoromethyl, phenyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl or acylaminoalkyl
b) oxazolyl-2 or alkyl-4 oxazolyl-2.

9) 5-tetrazolyl, unsubstituted or substituted at position -1 by
a) an alkyl radical containing 1 to 4 unsubstituted carbon atoms
or substituted with alkyloxy, sulfo, carboxy, formyl or sulfamoyl,
b) an alkyl radical containing 2 to 4 carbon atoms substituted
by hydroxy, amino, alkylamino, dialkylamino, acylamino, carboxy
alkylamino, sulfamoylamino, sulfoamino, ureido, alkylureaido or
dialcoylurédio,
c) an alkyl radical containing 1 to 5 carbon atoms substituted with hydroxyimino or alkyloxyimino,
d) a phenyl radical, 2,3-dihydroxypropyl, 1,3-dihydroxypropyl-2, 2-formyl-2-hydroxyethyl, 3-formyloxy-2-hydroxypropyl, 2,3-bisformyloxypropyl or bis-formyloxy -1,3 propyl-2, or
e) a radical of general formula (XLIII) for which Rss is a hydrogen atom, or a radical of general formula (XLIII b) the symbol
R 01 represents a radical of general formula (II) [wherein R 5 is hydrogen or alkyl, vinyl or cyanomethyl and R 4 represents a hydrogen atom], and the symbol R 02 represents a hydrogen atom or a radical of general formula (V ), or (p) the symbol R represents an alkyl or phenyl radical, and the symbol R01 and the symbol R02 are defined as in the main patent in).

 It is understood that in the products of general formula (XXXI), the 3-position substituent of bicyclooctene has E or Z stereoisomerism, and that when R 1 is a radical of general formula (II), it may to be in syn or anti form.

The products of general formula (XXXI) also exist in the form of mixtures of these isomeric forms.

The products of general formula (XXXI) can be obtained from the products of general formula (I) by operating as follows:
I - Thiovinyl-3 cephalosporins of general formula (XXXI) in which R is defined as in a and ss except for containing a substituent of general formula (XLIII c) may be prepared by action of a thiol of general formula (KXXII) (or an alkali or alkaline earth metal salt thereof) in which the radical RL which is defined as above] is protected as an acetal (as defined by general formulas (XLIII a ) and (XLIII b) when it is desired to obtain a cephalosporin of general formula (XXXI) in which R contains a formyl or acylalkyl radical), on a derivative of cephalosporin or a mixture of isomers of general formula (I), In which n is 0 or 1,
R1, R2 and R3 are defined as above in a '), or
R1 is a radical of general formula (II) (as defined in a) in the main patent) or a radical defined in b) in the main patent,
R2 has the corresponding definition given in the main patent in a) or b) and R3 is defined as previously in b ')], optionally followed by the reduction of the oxide obtained and the elimination of the protective radicals.

it is understood that, when the radical R of the product of general formula (XICXZI) is likely to interfere with the reaction, it is preferable to protect this group, by any method known per se and which does not affect the rest of the molecule (especially when
R contains an amino, alkylamino, hydroxy or carboxy radical).

 When it is amino, alkylamino or carboxy groups, the protection is carried out under the conditions described above.

 In the case of hydroxy groups, the protection is carried out by the radicals mentioned above for the protection of the oxime, or in the form of a cyclic acetal for the protection of the 2,3-dihydroxypropyl or dihydroxy-1 radicals. 3-propyl-2 (for example in the form of 2,2-dimethyl-4-dioxolanylmethyl or 2,2-dimethyl-5-dioxanyl radicals).

 it is also understood that when R5 represents a hydrogen atom, it is preferable to protect the oxime (under the conditions described above).

 Furthermore, it is understood that when the radical R of the product of general formula (XXXI) comprises a hydroxyl or sulfo radical, it is preferable to use a product of general formula (I) in which n = 0.

 The procedure is generally carried out in the presence of a base such as a pyridine or a tertiary organic base of general formula (XVII).

 For example, diisopropylethylamine or diethylphenylamine is used.

 The presence of such a base is not necessary when an alkali or alkaline earth salt of the thiol of the general formula (XXXII) is reacted.

 The reaction is advantageously carried out in an organic solvent, such as dimethylformamide, tetrahydrofuran or acetonitrile or a mixture of the solvents mentioned above.

it is also possible to operate in the presence of bicarbonate
alkali in a solvent as mentioned above, optionally in the presence of water.

We operate at a temperature between -200G and the temperature
the reflux mixture of the reaction mixture, the chosen temperature being
variable according to the thiol used. Similarly, according to the thiol employed,
reaction time can vary from 5 minutes to 48 hours.

 Optionally, the operation is carried out under nitrogen.

 Preferably, when it is desired to use a bicyclooctene-3 of general formula (I) in which R 1 represents a radical of general formula (II), such a product is used for which R2 is other than hydrogen.

 The elimination of the protective radical of R can be carried out indifferently before or after the reduction of the oxide, before, simultaneously with or after the elimination of the other protective radicals.

 The reduction of the oxide and the elimination of the protective groups are carried out according to the methods described above.

 When the dihydroxypropyl radicals are protected in the form of cyclic acetals, the elimination of the protective radicals is carried out by acidolysis (trifluoroacetic acid, aqueous or non-aqueous formic acid, p-toluenesulphonic acid).

 When formic acid, aqueous or not, is used, the release of the protected hydroxyl radicals in the cyclic acetal state can lead at least partially to the corresponding fornic esters, which can be separated, if appropriate, by chromatography.

The elimination of the groups of general formula (XLIII a) and (XLIII b) (when it is desired to obtain a product of general formula (XXXI) in which R contains a formyl or acylalkyl radical is carried out
in the presence of a sulphonic acid (methanesulphonic acid or acid p.

tolensulfonic acid for example) in an organic solvent (acetonitrile or
acetone for example), possibly in the presence of water and possibly
in the presence of an acetalisable reagent such as acetone, glyoxyli acid
benzaldehyde or pyruvic acid, a temperature
200C and the reflux temperature of the reaction mixture - or, when the radical R is a dioxo-5,6-tetrahydro-1,4,5,6 radical
1,2,4-triazine, by the action of aqueous formic acid (containing
less than 10% of water), whether in the presence or absence of silica, or
transacétalisation in the presence of an acetalisable reagent as defined above sua.

Thiols of general formula (XXXII) which can be easily cn
Work in their tautomeric form), can be prepared by app
one of the following methods according to the meaning of the
radical R - when R is a pyridyl-3 radical: according to the method described by
HM WUEST and EH SAKAL, J. Aru. Chem. Soc., 7391210 (1951), when R is a 1-oxide pyridyl-3 radical: according to the method described by BLANK B. 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.sub.1a-3-pyridazinyl radical substituted by alkyl or methoxy and optionally N-oxide: according to the method described in Belgian Patent 787,635, - when R is a substituted pyridazinyl-3 radical; 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 applying the methods described by
Mr. KUSAGAI and Mr. BANDO, Nippon Kagaku Zasshi, 84,995 (1963) and by
T. HORIE and T. UEDA, Chem. Pharnl. Bull., 11, 114 (1963) 1
when R is a tetrazolo radical L4,5-b6-pyridazinyl: according to the method described in Belgian Patent 804251,
when R is a dioxo-5, b-1,4,5,6-tetrahydro-1,2,4-triarine-1,3-yl-substituted or 4-alkyloxycarbonyl-1,3,4-triazol-substituted-5-yl group; in position -1 with a radical -R chosen from:
a) an alkyl radical, alkyl (1 to 4 carbon atoms, itself optionally substituted by an alkyloxy radical, alkylthio,
phenyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, acyl, alkyl
oxycarbonyl or thiazolidin-2)
(b) a 2,3-dihydroxypropyl or 1,3-dibroxy pro radical
pyl-2 (optionally protected as cyclic acetal)
c) an alkyl radical L 2 to 4 carbon atoms, itself
substituted with hydroxy, carbamoyloxy, dialkylamino, alkylsulphinyl,
alkylsulfonyl, alkylsulfonylamino, sulfamoylamino, acylamino (e.g.
optionally substituted), alkyloxycarbonylamino, ureido, alkylureaido,
dialcoyluréido]
d) a radical of general formula (XLIII a) or (XLIII b)
e) a hydroxyiminoalkyl or alkyloxyiminoalkyl radical;
by causing an alkyl oxalate to act on a thiosemicarbazide of
general formula:
RU NH CS NH-NH 2 (XLIV) (wherein R # is defined as above), in the presence of an alkaline alkoxide, for example sodium ethoxide 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 i to release the protected radicals) to use it for the preparation of the products of general formula (XXXI)
The thiosemicarbazide of general formula (XLIV) may be prepared according to one of the methods described by KA JANSSEN et al.
Acta Chim. Scand., 22, 1 (1968), or by the method described by Y. KAZAROV and JY POTOVSKII Doklady Acad. Nauk. SSSR 134, 824 (1966), it being understood that when RY contains an amino radical, the latter is protected.

Protection of the amino radical and elimination of the radical
protector are carried out according to the usual methods which do not alter
not the rest of the molecule. In particular, the grouping is used
t.butoxycarbonyl, which can be removed by acid hydrolysis.

When R is a triazol-1,3,4-substituted-5-yl radical in position -i
with an alkyl, allyl or alkyloxyalkyl radical,
by an alkyl radical (1 to 4 carbon atoms) itself substituted
as defined above in (a) (with the exception of a thiazide radical)
dinyl-2),
by a radical as defined above in c), or
by an alkyloxyiminoalkyl radical;
by applying one of the methods described by M. PESSON and M. ANTOINE,
Bull. Soc. Chim.France 1590 (1970)
- When R is a triazol-1,3,4-yl-5 radical substituted in position -1
by 2-chiazolidinylalkyl or hydroxyiminoalkyl:
by action respectively of cysteamine or hydroxylamine on a
dialkoyloxyalkyl-1-mercapto-5-triazole-1,3,4 which can be obtained
using the method described by N. KNDKA, j. Pharm. Soc.

Japan, 75, 1149 (1955), from a dialkoyloxyalkyl-4 thiosemi
semicarbazide.

- When R is a triazol-1,3,4-yl-5 radical substituted in position -1
2,3-dihydroxypropyl or 1,3-dihydroxypropyl-2 (optionally
protected in the form of acetal resin), or represents a radical of
general formula (XLIII a) or (XLIII b) by application of the method described by M. KANAOKA, J. Pharm. Soc.

Japan, 75, 1149 (1955).

When R is a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 radical substituted in the 4-position or a 2-alkyloxycarbonyl-1,3,4-triazolyl radical, Or triazol-1,3,4-substituted-5-substituted by acyloxyalkyl (optionally substituted): by acylation respectively of the 5-dioxo-4-hydroxyalkyl-3-mercapto-1,4,5-tetrahydro, 1,2,4 triazine-1,2,4-alkoxyoxycarbonyl-1-hydroxyalkyl-5-mercapto-1,3,4-triazol or 1-hydroxyalkyl-1,3,3-mercapto-1,3,4-triazol whose mercapto radical was previously protected (for example according to
CG KRUSE et al., Tet.Lett. 1725 (1976), by any known method
to acylate an alcohol without touching the rest of the molecule, then released
ration of the mercapto group in an acid medium.

When R is a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4 radical
yl-3 substituted in the 4-position or 2-alkyloxycarbonyl-1,3,4-triazol-5-yl
or 1,3,4-triazol-5 substituted in the 1-position with aminoalkyl or
alkylaminoalkyl:
by release of the amine function of the corresponding product, protected
for example by a t.butoxycarbonyl group.

When R is a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4 radical
yl-3 substituted at the 4-position, 2-alkyloxycarbonyl-1,3,4-triazol-5-yl
or 1,3,4-triazol-5 substituted in the 1-position with sulfoaminoalkyl: from the corresponding product substituted with a t-butoxycarbonylaminoalkyl radical, by analogy with the method described in Belgian Pat. No. 4,723,237.

When R is a 1,4-dialkyl-1,4,4,6,6-trietrahydro-1,2,4-triazo-3-yl radical or 1-dioxo-5,6-tetrahydro-1,4,5,6-triazine-alkyl radical. 1,2,4 μl-3; according to the method described in Belgian Patent 830 455.

When R is an alkyl-2-dioxo-5,6-tetrahydro-1,2,5,6-triazine-1,2,4-yl-3 or alkyl-1-alkyloxycarbonyl-3-triazol-1,2,4-yl-5 radical ; according to the method described by M. PESSON and M. UJ'IDINEI ca Acide Sci.,
Ser. C, 267, 25, 1726 (1968).

- When R is a triazol-1,2,3-yl-5 according to the method described in French Patent Application 2 215 942.

 When R is a triazol-1,3,4-yl-5 radical according to the method described by M. KANAOKA, J. Pharm. Soc. Jap.

75, 1149 (1955) - when R is a thiadiazol-1,3,4-yl-5 radical optionally substituted
killed by alkyl, alkyloxy, alkylthio, alkylsulfonyl, amino.

alkylamino, dialkylamino or acylamino: according to the methods described in Belgian Patent 830 821, - when R is a thiadiazol-1,3,4-yl-5 substituted by hydroxy
alkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl;
according to the method described in German Patent Application 2,446,254,
when R is a thiadiazol-1,3,4-yl-5 radical substituted with a
carboxyalkyl radical: by applying the method described in
German Patent Application 1 953 861,
when R is a thiadiazol-1,3,4-yl-5 radical substituted with a
trifluoromethyl radical: according to the method described in the application for
German Patent 2,162,575,
when R is a thiadiazol-1,3,4-yl-5 radical substituted with a
carboxy radical: according to the method described in the patent application
Japanese 77 48666,
when R is a 1,3,4-thiazolyl-substituted 5-yl radical;
acylaminoalkyl radical: according to the method described in the application
Japanese Patent 76,80857, - When R is a thiadiazol-1,3,4-yl-5 radical substituted by a hydroxyalkylthio radical: by application of the method described by
C. NANNINI, Arz. Forsch. 27 (2), 343 (1977).

- When R is a 1,2,4-thiadiazol-5-substituted alkyl or alkyloxy radical. according to the method described in German Patent Application 2,806,226 or according to Chem. ber. 90, 184 (1957).

When R is an oxadiazol-1,3,4-yl-5 radical as described in the definition of the general formula (XXXI) at 8a /: by application of the method described-on E. Hoggarth, -J. Chem. Soc. 4811 (1952).

When R is a 2-oxazolyl or 4-alkyloxazolyl-2 radical by application of the method described previously by C. Bradsher,
J. Org. Chem. 32, 2079 (1967).

- 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 83D 821.

When X is a 5-tetrazolyl radical substituted in the 1-position by alkyloxyalkyl: by addition of sodium azide to an isothiocyanatoalkyloxyalkyl by operating in an organic solvent such as ethanol, at the reflux temperature of the reaction mixture.

Isothiocyanatoalkyloxyalkyl 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 the patent
Belgian 858 112.

- When R is a tetrazolyl-5 radical substituted in position -1 by
a sulphoalkyl radical according to the method described in the patent
Belgian 856 498 or described by DA BERGES et al., J. Het. Chem. 15
981 (1978).

- When R is a tetrazolyl-5 radical substituted in position -1 by
an aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl radical:
by applying the method described in the patent application
German 2,738,711.

When R is a tetrazolyl-5 radical substituted in the -1 position by a sulphamoylalkyl, sulphamoylaminoalkyl or sulphoaminoalkyl radical: according to the method described in Belgian Patent 856,636.

- When R is a tetrazolyl-5 radical substituted by a radical
acylaminoalkyl or 1,3,4-thiadiazol-substituted by hydroxy:
according to the method described in US Pat. No. 4,117,123
- When R is a tetrazolyl-5 radical substituted in position -1 by a
ureidoalkyl, alkylureaalkyl or dialkylureidoalkyl radical
from the corresponding product substituted with aminoalkyl (the
mercapto radical has been previously protected), by treatment with a
alkali isothiocyanate, with an alkyl isocyanate or with a halide
of dialkylcarbamoyl followed by release of the mercapto group
conditions described in Belgian Patent 847 237.

- When R is a tetrazolyl-5 radical substituted in the -I position by a
carboxyalkylaminoalkyl radical: according to the method described in
German Patent Application 2,715,597.

- When R is a tetrazolyl-5 radical substituted in position -1 by
a 2,3-dihydroxypropyl radical: according to the method described in
U.S. Patent 4,064,242.

When R is a tetrazolyl-5 radical substituted in the -t position by a
1,3-dihydroxypropyl-2: by addition of sodium azide to a
2,2-dimethyl-dioxolan-3-isothiocyanate (optionally followed by
release of the hydroxy groups).

- When R is a tetrazolyl-5 radical substituted in position -i by a
radical of general formula (XLIII altar as described in the definition
of the general formula (XXXI) in 9th / - or of general formula
(XLIII b) or a radical defined previously in 9 c / - for the formula
General (XXXI) by action of sodium azide on isothiocyanate
corresponding, by analogy with the method described by RE TORTU, Je Pharm.

Sci. 52 (9), 909 (1963), it being understood that in the case where R contains
a hydroxy or hydroxyiminoalkyl substituent, the alcohol or the oxime are
optionally protected for example by a tetrahydropyranyl group.

Ile) Thiovinyl-3 cephalosporins of general formula (XXXI) in
which R does not contain a substituent of general formula (LIII c)
can also be obtained as follows:
A thiol of general formula (XXXII) as defined in the present addition (or an alkali or alkaline earth salt thereof) is made to act on a product or a mixture of isomers of the product of general formula (I) in which R 1, R 2 and R3 are defined as in II / - for the preparation of the products of general formula (I) for which R1 is a hydrogen atom, or in which R1 is a hydrogen atom and R2 and
R3 have the corresponding definition] then optionally reduces the sulfoxide obtained (when n = 1) and optionally eliminates the protective radicals of R to prepare a product of general formula (XXEIII) in which, n being defined as above, R1 and R2 are defined as previously in II / - and R takes the corresponding definitions.

 The reaction is carried out under the conditions described above for obtaining a product of general formula (xxxi) from a product of general formula (I) and a thiol of general formula (Xxxii).

 It is understood that the radical R of the thiol is (where appropriate) protected as described above and that the elimination of the protective radicals can be carried out under the conditions described above.

 It is, however, preferable to retain the protective groups until the product of the general formula (XXI) is obtained.

 A product of general formula (XXXIV) in which R, R2 and n are defined as above, is prepared by removal of the radical R1 from a product of general formula (XXXIII) in which R1 is other than the atom of hydrogen or optionally simultaneous removal of the protective radicals R1 and R2 of this product.

 The procedure described above is carried out for the preparation of a product of general formula (I), in which R 1 is a hydrogen atom.

The thiovinyl-3-cephalosporin of general formula (XXXI) in which R, R 1 and R 2 are defined as above is prepared by acylation of a 7-amino cephalosporin of general formula (XXXIV) using an acid represented by the general formula (XXXV)
In which R 1, which is defined as above, is optionally protected if it comprises radicals that can interfere with the reaction, or a reactive derivative of this acid, under the conditions described above for the preparation of the products of general formula ( XXIII), then the oxide obtained (when n = 1) is reduced and the protective radicals are eliminated.

It is understood that
the amino or alkoylanino radicals, which exist in certain radicals R, must be protected, and that
the carboxy, hydroxy, formyl or acylalkyl radicals contained in the radicals R can be protected.

 Protection and elimination of the protective radicals are carried out under the conditions described above.

 The reduction of the oxide and the elimination of the other protective radicals are carried out under the conditions described above.

 It is also understood that when R contains a hydroxy, sulpho, sulfinyl or sulphonyl substituent, it is preferred to use a product of general formula (XXXIV) in which n = o.

III - 3-thiovinyl cephalosporins of general formula (XXXI) wherein R does not contain a substituent of general formula (XLIII c) can also be obtained by action of a thioloester of general formula
R @ - SR (XLV) in which R'1 is defined as above in a '/ - or represents a radical of general formula (II) as defined in a / in the main patent, or is defined as in b / in the main patent, and
R is defined according to the addition to a or fi (it being understood that when it contains an amino or alkylamino substituent, it is protected when it contains a hydroxy or carboxy substituent that is free or protected and when it contains a formyl or acylalkyl substituent, which is protected in the form of an acetal of general formula (XLIIIa) or (XLIIIb), on a 7-amino cephalosporin of general formula (I) in which R1 is a hydrogen atom and R2 has the corresponding definition, followed by the reduction of the sulfoxide obtained when n = 1 and, if appropriate, the elimination of the protective radicals.

 It is also understood that the radicals R '1 which contain a group which is capable of interfering with the reaction are protected beforehand. It is the same for the oxime when R'1 represents a radical of general formula (II) in which R5 is a hydrogen atom.

 It is also preferable to use a product in which R'1 does not contain a halogen substituent.

As for the processes described above, when
R contains a hydroxy, sulpho, sulphinyl or sulphonyl substituent, it is preferred to use a product of general formula (I) in which n = 0.

 Protection and elimination of the protective radicals is carried out under the conditions described above.

 The reaction of the thioloester with the 7-amino cephalosporin of general formula (I) 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 base tertiary organic compound of general formula (XVII), especially triethylamine, N, N-diisopropyl N-ethylamine, diethylphenylamine or N-methylmorpholine.

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

 It operates at a temperature between -200C and the reflux temperature of the reaction mixture. The reaction is carried out optionally under nitrogen.

 The reduction of S-oxide is effected under the conditions described above.

Thioloesters of general formula (XLV) can be
prepared by the action of an acid or a reactive derivative of an acid of
general formula:
R'XOH (xxxv a)
on a thiol of general formula (XXXII) (or on an alkaline or alkaline salt
this thiol) followed eventually by the elimination of the radicals
protectors.

In the general formula (XXXV a), R'1 is defined as
above except for R4 and R5 to represent hydrogen atoms.

It is understood that the amino or alkylamino substituents of
R'1 and R are protected and the hydroxy or carboxy substituents are
free or protected.

 It is also understood that the radical R is protected in the form of acetal when it is desired to prepare a product of general formula (XXXI) for which R contains a formyl or acylalkyl radical.

 The procedure described above is carried out for the preparation of a product of general formula (XXII) from a product of general formula (XXIV) and a reactive ester of general formula (XXVI).

When one wants to obtain a product for which R contains a
carboxy radical or sulfo, it is preferable to act a reactive derivative
R'1OH acid on the corresponding thiol.

When lton wants to obtain a thioloester for which R'1, is
a radical of general formula (II) as defined for R 1, it is possible to
remove the protective t.butoxycarbonyl radical of aminothiazole by
treatment in anhydrous acid medium. Preferably the acid is employed
trifluoroacetic acid by operating between 0 and 2000. It is possible to eliminate the radical
trityle protecting the oxime by acidolysis, for example by trifluoric acid
anhydrous acetic acid.

Where appropriate, removal of the trityl protective group
of a hydroxy substituent of thioloester takes place under the conditions
described above for the release of the oxime.

It is advantageous not to eliminate the protective groups
that apax the reaction of the tbioloester on the product of general formula (I)
wherein R1 is the hydrogen atom.

dans laquelle R5 et R sont définis comme ci-dessus et, R2, Hal et n sont définis comme précédemment, à partir d'un produit de formule générale (XXXIV) ou d'un produit de formule générale

[dans laquelle Hal, R2 et n sont définis comme précédemment et R est défini comme ci-dessus], par application des méthodes décrites précédemment pour la préparation du produit de formule générale (XXKvlI)
Lorsque l'on prépare le produit de formule générale (XLVI ) à partir d'un produit de formule générale (XXXIV) le radical R est préalablement protégé lorsqu'il contient un radical amino ou alcoylamino, et il est libre ou protégé lorsqu'il contient un radical hydroxy, carboxy, formyle ou acylalcoyle.IV / - Thiovinyl-3 cephalosporins of general formula (XXXI) in
which RB1 represents a radical of general formula (II) (as defined
previously, except for R5 to represent a vinyl radical),
and R does not contain a substituent of general formula (XLIII c) can
be obtained by operating as follows
A product of general formula is prepared

in which R5 and R are defined as above and R2, Hal and n are defined as above, starting from a product of general formula (XXXIV) or a product of general formula

[in which Hal, R2 and n are defined as above and R is defined as above], by applying the methods described above for the preparation of the product of general formula (XXKvII)
When the product of general formula (XLVI) is prepared from a product of general formula (XXXIV), the radical R is protected beforehand when it contains an amino or alkylamino radical, and it is free or protected when contains a hydroxy, carboxy, formyl or acylalkyl radical.

 When the product of general formula (XLVI) is prepared from a product of general formula CXLVII), the radical R is protected beforehand when it contains an amino, alkylamino or formyl radical, and it is free or protected when it contains a hydroxy, carboxy or acylalkyl radical.

 Protection and elimination of the protective radicals is carried out under the conditions described above.

 A thiourea of general formula (xxxvi) is made to act on the product of general formula (XLVI) under the conditions described above for the preparation of the products of general formula (I) starting from the products of general formula (XXXVII), then reducing the if necessary the sulfoxide obtained and optionally eliminates the protective radicals.

When one wants to obtain a product of general formula
(XXXI) wherein R contains a formylalkyl or acylalkyl radical, this radical may be protected in the form of an acetal, in the form of a radical of general formula (XLIII a) or (XLIII b) as defined above.

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

 The cephalosporin of general formula (XLVII) can be prepared from a cephalosporin of general formula (XXXIV) by analogy with the method described for the preparation of products of the general formula (XLI).

 The 3-thiovinyl cephalosporins of general formula (xxxI) in which R represents a dioxo-5,6-radical 1,4,5,6-tetrahydro-triazine1,2,4-substituted-1,3-yl or triazol -1,3,4-yl-5 or 2-alkylcarbonyl-1,3,4-triazol-1-yl substituted in position -1, with an alkyl radical containing 2 to 4 carbon atoms substituted by a carbamoyloxy or acyloxy group (the acyl part is optionally substituted by an amino, alkylamino or dialkylamino radical and R01 and R02 have the corresponding definitions, which are functional derivatives of the product of general formula (XXXI) in which R is an alk-OH radical selected from dioxo-5, 6-hydroxyalkyl-1,4,5,6-tetrahydro-triazine-r, 2,4-yl-3, hydroxyalkyl-1-triazol-1,3,4-yl-5 or 2-alkyloxycarbonyl-1-hydroxyalkyl-1,3-triazol, 4 yl-5 and R01 and R02 are defined as above, can be obtained from a product of ..

(dans laquelle R4, R5, R2, R-alk'-OH et n sont définis comme précédemment
à l'exception pour R4 de représenter l'atome d'hydrogène)par toute méthode
connue pour obtenir un ester ou un carbamate à partir d'un alcool sans
toucher au reste de la molécule, puis s'il y a lieu, réduction du
sulfoxyde obtenu et élimination des radicaux protecteurs.general formula

(wherein R4, R5, R2, R-alk'-OH and n are defined as above
except for R4 to represent the hydrogen atom) by any method
known to obtain an ester or a carbamate from an alcohol without
touch the rest of the molecule, then, if necessary, reduce the
sulfoxide obtained and removal of the protective radicals.

 The esterification is carried out at a temperature of between -500 ° C. and the reflux temperature of the reaction mixture, in particular by condensation of the anhydride of the acid (or of another reactive derivative, for example a halide) in an organic solvent. inert form such as an ether (for example tetrahydrofuran), a chlorinated solvent (for example methylene chloride), or a mixture of these solvents, in the presence of a nitrogenous base such as pyridine, 4-dimethylaminopyridine or a trialkylamine ( triethylamine) or an alkaline condensing agent (for example sodium bicarbonate) and, where appropriate, reduction of the obtained S-oxide and removal of the protective groups according to the methods described above.

 The carbamate is obtained by any known method which does not alter the rest of the molecule. it is carried out in particular by the action of chlorosulfonyl isocyanate or trichloroacetyl in an inert organic solvent, for example tetrahydrofuran or acetonitrile, at a temperature between -80 and 200C, and then eliminates the protective groups.

dans laquelle R4, R5, R2 et n sont définis comme précédemment, à l'excep- tion pour R4 de représenter l'atome d'hydrogène et -R-NH2 représente un radical dioxo-5,6 tétrahydro-1,4,5,6 triazine-1,2,4 yle3 substitué en position -4, triazol-1,3,4 yl-5 ou alcoyloxycarbonyl-2 triasol-193,4 yl-5 substitués en position -1, par un radical aminoalcoyle dont la partie alcoyle contient 2 à 4 atomes de carbone, ou un radical thiadiazol-1,3,4 yl-5 substitué par un radical amino ou aminoalcoyle, ou un radical oxadiazol-i3,4 yl-5 substitué par un radical amino alcoyle, ou un radical tétrazolyl-S substitué en position -1 par un radical aminoalcoyle dont la partie alcoyle contient 2 à 4 atomes de carbone s par toute méthode connue en soi pour former une fonction amide, sulfamide, carbamate ou urée, sans toucher au reste de la molécule, puis le cas échéant réduction du sulfoxyde et élimination des groupements protec- tueurs.Vle / - Thiovinyl-3 cephalosporins of general formula (XXXI) wherein R represents a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3-substituted in the 4-position, or triazol-1,3,4-yl-5 or 2-alkyl-1-triazol-1,3,4-triazol-1-substituted in 1-position, with an alkyl radical containing 2 to 4 carbon atoms substituted by a sulfoamino group, alkylsulfonylamino sulfamoylamino, acylamino (the acyl part of which is optionally substituted by hydroxy> amino, alkylamino or dialkylamino), alkyloxycarbonylamino, ureido, alkylurea or dialkylureido, or represents a radical-substituted 1,3-thiadiazolyl radical substituted with a radical. acylamino or acylaminoalkyl, or represents an oxadiazol-1,3,4-yl-5 radical substituted by an acylaminoalkyl radical, or represents a tetrazolyl-5 radical substituted in the -1-position by an alkyl radical containing 2 to 4 carbon atoms substituted with a acylamino group> sulfamoylamino, sulfoamino, ureido, alccylureido or dialcoylureido, and R 1 and R 2 have the corresponding definitions, which are all functional derivatives of the corresponding amine, can be obtained from a product of general formula ::

wherein R 4, R 5, R 2 and n are as previously defined, with the exception that R 4 represents the hydrogen atom and -R-NH 2 represents a dioxo-5,6-tetrahydro-1,4,5 radical , 6-triazine-1,2,4-yl3 substituted in the 4-position, triazol-1,3,4-yl-5 or 2-alkyloxycarbonyl-triasol-193,4-yl-5 substituted in position -1, with an aminoalkyl radical whose the alkyl part contains 2 to 4 carbon atoms, or a 1,3,4-thiadiazol-5-radical substituted by an amino or aminoalkyl radical, or a 1,4-oxadiazol-1-yl-5 radical substituted by an aminoalkyl radical, or a tetrazolyl-S radical substituted in the -1 position by an aminoalkyl radical whose alkyl part contains 2 to 4 carbon atoms s by any method known per se to form an amide, sulphonamide, carbamate or urea function, without affecting the rest of the molecule, then, if necessary, reduction of the sulphoxide and elimination of the protective groups.

It is understood that the products which contain a sulpho, sulphonyl or sulphamoyl group are preferably prepared from a product of general formula (XXXI ") in which n
On the other hand, when X is to prepare a product whose radical R contains an amino or hydroxy group, it is necessary to protect these radicals in the reagent used. Similarly, when R 5 represents the hydrogen atom, it is necessary to protect oxime.

 When it is desired to prepare a product of general formula (XXXI) in which the radical R contains a substituent alkylsulfonylamino, sulfamoylamino, acylamino (substituted or unsubstituted), alkyloxycarbonylamino or dialkylureido, the reaction is advantageously carried out by the action, respectively, of the chlorosulfonyl derivative corresponding acid chloride, chloroformate or dialkylcarbamoyl chloride under the conditions described above for the reaction of the acid chloride of the general formula (XXV) with the 7-amino cephalosporin of the general formula (XXIV).

When one wants to prepare a product of general formula
(XXXI3) in which the radical R contains a sulphoamino, alkylsulphonylamino or acylamino substituent (substituted or unsubstituted), the reaction can be carried out using the anhydride of the corresponding acid, under the conditions described above for reacting the product of formula (XXV) as an anhydride.

When one wants to obtain a product of general formula
(XXXI) for which R contains an acylamino radical (substituted or unsubstituted), it is also possible to cause the corresponding acidic action, under the operating conditions described above for the use of the acid of general formula (XXV).

When one wants to obtain a product of general formula
(XXXI) in which R contains a ureido or alkylurea radical, an alkali isocyanate or an alkyl isocyanate are respectively acted on the corresponding product of general formula (XXXI ") in a hydroorganic or organic medium (for example in tetrahydrofuran) at a temperature between -20 and 600C0
The reduction and elimination of the protective radicals is carried out under the conditions described above.

VII / - Thiovinyl-3 cephalosporins of general formula (XXXI) in which R represents a dioxo-5,6-tetrahydro-1,4,5,6-triazine-1,2,4-yl-3 radical substituted in position -4 or triazol-1,3,4-yl-5 or 2-alkyloxycarbonyl-1,3,4-triazol-5-substituted in position -1, with a 2-thiazolidinylalkyl radical, with a radical of general formula (XLIIIc) or with a hydroxyiminoalkyl or alkyloxyiminoalkyl radical in which the iminoalkyl part contains 1 to 5 carbon atoms or represents a tetrazolyl-5 radical substituted in the -1-position by a hydroxyiminoalkyl or alkyloxyiminoalkyl radical, the iminoalkyl part of which contains 1 to 5 carbon atoms, andRO1 and R02 have the corresponding definitions, which are addition derivatives of the product of general formula (XXXI) wherein R is one of the heterocycles mentioned above substituted with a formylalkyl radical (or its hydrate form), can be obtained from a product of general formula rale

in which R2, R and R5 are defined as above and
R-alk'CHO represents a dioxo-5,6-formylalkyl-4-tetrahydro radical
1,4,5,6-triazine-1,2,4-yl-3-formylalkyl-1-triazol-1,3,4-yl-5,
2-alkyloxycarbonylformylalkyl-1,3,4-triazolyl or 5-formylalkyl-5-tetrazolyl, by addition respectively of cysteamine, an alcohol, hydroxylamine or an alkyloxyamine according to known methods to form derivatives of addition of carbonyl functions, then if there is
place elimination of protective radicals.

The reaction is generally carried out in an organic solvent at a temperature of between 20 ° C. and the reflux temperature.
of the reaction mixture.

The organic solvents are chosen according to the
solubility of the products. When using a product of general formula (XXXI "') in which R4 and R2 are other than hydrogen,
solvents such as tetrahydrofuran are advantageously used,
acetonitrile, alcohols, ketones. When implementing a
product of general formula (XXXI "') in which R4 and R2 are
hydrogen atoms, it is advantageous to operate in solvents such as
pyridine, dimethylsulfoxide or dimethylformamide.

When one wants to prepare a product of general formula
(XXXI) for which the radical R contains a substituent of general formula
rale (XLIII c) one operates in acidic medium.

GII / - Thiovinyl-3 cephalosporins of general formula (XXXI), in
which R02 represents a radical of general formula (V) in which R8 and R9 are defined as above, can also be obtained by esterification of a product of general formula (XXXI) in which R02 represents a hydrogen atom and whose function amine has been previously protected, by any method known per se to prepare an ester from an acid without affecting the rest of the molecule.

 It is carried out especially under the conditions described above for the preparation of products of general formula (XXII) or (xxiv) in which R2 is a radical of general formula (V).

 The products of general formulas (XXXIII), (XXXIV), (XXXVII), (XLI), (XLVI) or (XLVII) in which n = 1 can be obtained by oxidation of the corresponding products in which n = 0 according to the described method in the patent application DE 2,637,176.

 The isomers of the products of general formulas I), (XVI), (XVIII), (XXXI), (XXXIII), (XXXIV), (XXXVII), (XLI), (XLVI) or (XLVII) can be fixed by chromatography or by crystallization.

 The new products according to the invention and the products of general formula (XXXI) can be optionally purified by physical methods such as crystallization or chromatography.

 The new products of general formula (I) in which there is an amino radical can be converted into addition salts with acids. According to the processes indicated, the products are optionally obtained in the form of trifluoroacetate, para-toluenesulphonate or solvate with formic acid. The products obtained in the form of these salts can be released and converted into salts of other acids according to the usual methods.

 The products of general formula (I) which contain a carboxy radical may also be converted to metal salts or to addition salts with nitrogenous 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 an amine on a product of general formula (I) in a suitable solvent such as an alcohol, an ether or the like. 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.

 Examples of salts that may be mentioned are salts with alkali metals (such as potassium, sodium or lithium salts) or with alkaline earth metals, salts with nitrogen bases (dimethylamine, diethylamine, diisopropylamine salts). dicyclohexylamine, N-ethylpiperidine and N-methylmorpholine) and addition salts with mineral acids (such as hydrochlorides or hydrobromides) or organic acids (formates, trifluoroacetates, toluenesulfonates, naphthalenesulphonates or oxalates).

 The cephalosporin derivatives of general formula (XXXI) as defined in a) and their pharmaceutically acceptable salts have particularly interesting antibacterial properties.

They exhibit remarkable in vitro and in vivo activity on Gram-positive and Gram-negative organisms.

in vitro, they were active at a concentration of between 0.5 and 15 g / cm3 on strains of penicillin G-sensitive staphylococcus aureus (Smith) at a concentration of between 2 and 30 g / cm3 on staphylococci strains resistant to penicillin G (Staphyococcus aureus M @ 9) at a concentance between 000i and 9 g / cm3 on Escherichia coli strain
Monod and at a concentration of between 0.06 and 30 g / cm3 on
Klebsiella pneumoniae.Moreover, some were active at a concentration of between 0.01 and 30 g / cm3 on Proteus morganii and at a concentration between 0.1 and 30 g / cm3 on Enterobacter aerogenes.

 in vivo, they have been shown to be active in the enteric infections of penicillin-sensitive Staphylococcus aureus Smith mouse G) at a dose of between 0.2 and 5 mg / kg per day subcutaneously, and Escherichia coli (Monod strain) at doses of between 0.001 and 10 mg / kg per day subcutaneously.

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

 The following examples, given in a non-limiting manner, show how the invention can be put into practice.

In these examples, the products are listed according to the Chemical Abstracts nomenclature. It is understood that all the cephalosporin derivatives which are cited in this application exhibit the stereochemistry given by the partial general formula:

EXAMPLE 1
To a cooled solution at -150C of 2.4 g of benzhydryloxy
2-carbonyl-2-oxo-2-oxo-8-oxo [(2-tritylamino-4-thiazolyl) vinyl)
oxyimino-2-acetamido] -7-thia-5-azabicyclo [4.2.0] octene-2-isomer
syn, in 30 cm3 of methylene chloride, 0.65 g of
p-toluenesulfonyl chloride and then, drop by drop in 10 minutes,
a solution of 0.44 cm3 of triethylamine in 5 cm3 of
methylene.The mixture is stirred for 30 minutes at -15 ° C. and allowed to rise to
+ 20 ° C in one hour, the mixture is diluted with 50 cm3 of
methylene, washed with 3 times 50 cm3 of a saturated solution of bicarbonate
sodium, 3 times 50 cm3 of water, dried over sodium sulfate, filter
and concentrated to dryness under 20 mm Hg (2.7 kPa) at 300C.

The residue is taken up in 5 cm3 of ethyl acetate,
add 50 cm3 of isopropyl ether, stir for 10 minutes,
filter and after drying collects 1.6 g of beige powder constituted
mainly 2-benzhydryloxycarbonyl-8-oxo-2-tosyloxyvinyl-3-vinyl
2- (2-Tritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido] thia-5-thia
aza-1 bicyclo [4.2.0] octene-2 and -3, mixture of E and Z forms

4,77 (dd, J = 2 et 16, 1H,

5 > 09 (d, J = 4, 1H, U en 6) ; 5,94 (dd, J = 4 et 9, 1H,
H en 7) i 6,81 (s, 1H, H du thiazole) ; 6,91 (s, 1H, -COOCH-) 7,07 (dd, J = 6 et 16, 1H, -CH=CH2) ; 7 > 74 Cd, J a 8, 2H, H du groupe sulfonyle)
Le benzhydryloxycarbonyl-2 (oxo-2 éthyl)-3 oxo-8 [(tritylamino-2 thiazolyl-4)-2 vinyloxyimino-2 acétamido]-7 thia-5 aza-1 bicyclo[4.2.0] octène-2, isomère syn, peut être préparé de la manière suivante
On agite à 250C, pendant 1 heure, une solution de 2,5 g de benzhydryloxycarbonyl-2 (diméthylamino-2 vinyl) -3 oxo-8[(trityl- amino-2 thiazolyl-4)-2 vinyloxyimino-2 acétamido]-7 thia-5 bicyclo[4.2.0] octène-2, isomère syn, forme E, dans 70 cm3 d'acétate d'éthyle en présence de 50 cm3 d'acide chlorhydrique IN. On décante, lave la phase organique par 2 fois 50 cm3 d'une solution demi-saturée de bicarbonate de sodium et 50 cm3 d'une solution demi-saturée de chlorure de sodium, sèche sur sulfate de sodium, filtre et concentre à sec sous 20 mm de mercure (2,7 kPa) à 20 C. On recueille 2,4 g de meringue brune constituée principalement de benzhydryloxycarbonyl-2 (oxo-2 éthyl)-3 oxo-8 [(tritylamino-2 thiazolyl-4)-2 vinyloxyimino-2 acétamidol-7 thia-5 aza-l bicyclot4.2.0] octène-2, isomère syn.Infrared spectrum (KBr), characteristic bands (cm-)
1790, 1725, 1690, 1640, 1523, 1495, 1450, 1195, 1180, 1075, 1005,
950, 755, 705
Proton NMR Spectrum (350 MHz, CDCl 3, 6 ppm, J in Hz) 2.45 (s, 3H, -CH 2); 3.40 and 3.55 (2d, J = 18, 2H, -SCH 2 -) 4.27 (dd, J = 2 and 6, 1H,

4.77 (dd, J = 2 and 16, 1H,

5> 09 (d, J = 4, 1H, U at 6); 5.94 (dd, J = 4 and 9, 1H,
H at 7) 6.81 (s, 1H, H thiazole); 6.91 (s, 1H, -COOCH-) 7.07 (dd, J = 6 and 16, 1H, -CH = CH 2); 7> 74 Cd, J to 8, 2H, H of the sulfonyl group)
2-Benzhydryloxycarbonyl-2-oxo-2-ethyl-3-oxo-8 [(tritylamino-2-thiazol-4-yl) -vinyloxyimino-acetamido] -7-thia-5-aza-1-bicyclo [4.2.0] octene-2-isomer syn, can be prepared as follows
A solution of 2.5 g of benzhydryloxycarbonyl-2 (2-dimethylamino-vinyl) -3-oxo-8 [(trityl-amino-2-thiazolyl) -2-vinyloxyimino-2-acetamido] is stirred at 250 ° C. for 1 hour. 7 thia-5-bicyclo [4.2.0] octene-2, syn isomer, form E, in 70 cm3 of ethyl acetate in the presence of 50 cm3 of 1N hydrochloric acid. After decanting, the organic phase is washed twice with 50 cm of a semisaturated solution of sodium bicarbonate and 50 cm of a half-saturated solution of sodium chloride, dried over sodium sulphate, filtered and concentrated to dryness under 20 mm of mercury (2.7 kPa) at 20 ° C. 2.4 g of brown meringue consisting mainly of 2-benzhydryloxycarbonyl-2-oxo-2-oxo-8-oxo [(2-tritylamino-4 thiazolyl)) is collected. 2-vinyloxyimino-acetamidol-7-thia-5-aza-1-bicyclot4.2.0] octene-2, syn isomer.

4,78 (dd, J = 2 et 17,

5,12 (d, J = 4, 1H4 H en 6)- ; 6,0 (dd, J = 4 et 9, 1H, H en 7) ; 6,8 (s, 1H, H du chiazole) ; 6,90 (s, 1H, -COOCH-) ; 7,08 (dd, J = 6 et 17, 1H, -CH-CH2) i 9,55 (s, 1H, -CHO)
Le benzhydryloxycarbonyl-2 (dinéthylamino-2 vinyl)-3 oxo-8 [(tritylamino-2 thiazolyl-4)-2 vinyloxyimino-2 acétamido]-7 thia-5 aza-l bicyclo[4.2.0] octène-2, isomère syn, forme E peut être préparé de la manière suivante
A une solution de 2,5 g de benzhydryloxycarbonyl-2 méthyl-3 oxo-8 [(tritylamino-2 thiazolyl-4)-2 vinyloxyimino -2 acétamidol -7 thia-5 aza-1 bicyclo[4.2.0] octène-2, isomère syn, dans 40 cm3 de diméthylformamide, on ajoute à 800C sous azote 0,7 cm3 de t.butoxy bis-diméthyl- aminométhane, on agite pendant 10 minutes à 800C et verse le mélange dans 250 cm3 d'acétate d'éthyle et 250 cm3 d'eau glacée.On decante, lave par 3 fois 150 cm3 d'eau et 150 cm3 d'eau saturée de chlorure de sodium, sèche sur sulfate de sodium, filtre et concentre à sec sous 20 mm de mercure (2,7 kPa) à 300C. On recueille 2,5 g de meringue brune constituée principalemenc de benzhydryloxycarbonyl-2 (diméthylamino-2 vinyl)-3 oxo-8 [(tritylamino-2 thiazolyl-4)-2 vinyloxyimino-2 acétamido]-7 thia-5 aza-1 bicyclo[4.2.0] octène-2, isomère syn, forme E.Infra-red spectrum (KBr), characteristic bands (cm-) 1785, 1725, 1685, 1640, 1530. 1495, 1450, 1000, 950, 755, 700
Proton NMR Spectrum (350 MHz, CDCl3, δ ppm, J in Hz) 3.26 and 3.58 (2d, J = 18, 2H, -SCH2-); 3.53 and 3.69 (2d, J = 18, 2H, -CH 2 -); 4.28 (dd, J = 2 and 6, 1H,

4.78 (dd, J = 2 and 17,

5.12 (d, J = 4, 1H 4 H at 6); 6.0 (dd, J = 4 and 9, 1H, H at 7); 6.8 (s, 1H, chiazole H); 6.90 (s, 1H, -COOCH-); 7.08 (dd, J = 6 and 17, 1H, -CH-CH 2), 9.55 (s, 1H, -CHO)
2-Benzhydryloxycarbonyl-2- (2-dimethylamino-vinyl) -8-oxo-8 - [(tritylamino-4-thiazolyl) -vinyloxyimino-acetamido] -7-thia-5-aza-1-bicyclo [4.2.0] octene-2-isomer syn, form E can be prepared as follows
To a solution of 2.5 g of 2-benzhydryloxycarbonyl-2-methyl-8-oxo-8 [(tritylamino-2-thiazolyl) -2-vinyloxyimino-2-acetamidol-7-thia-5-aza-1-bicyclo [4.2.0] octene-2 , syn isomer, in 40 cm3 of dimethylformamide, 0.7 cm3 of t-butoxy-bis-dimethylaminomethane is added under nitrogen at 800 ° C., the mixture is stirred for 10 minutes at 800 ° C. and the mixture is poured into 250 cm 3 of ethyl acetate. and 250 cm3 of iced water.On decante, washed with 3 times 150 cm3 of water and 150 cm3 of water saturated with sodium chloride, dried over sodium sulfate, filtered and concentrated to dryness under 20 mm of mercury (2 , 7 kPa) at 300C. 2.5 g of brown meringue consisting mainly of 2-benzhydryloxycarbonyl-2-dimethylamino-vinyl-8-oxo [(2-tritylamino-4-thiazolyl) -2-vinyloxyimino-acetamido] -7-thia-5-aza-1 are collected. bicyclo [4.2.0] octene-2, syn isomer, form E.

4,73 (dd, J = 2 et 14, 1H,

5,18 Cd, J = 4, 1H, H en 6) ; 5,60 (dd, J = 4 et 9, 1H, H en 7) ; 6,53 et 6,75 (2d, J = 16, 2H, -CH=CH-) ; 6,88 (s, 1H, -COOCH-) ; 7,10 (dd, J = 6 et 14, 1H, =NOCH=)
Le benzhydryloxycarbonyl-2 méthyl-3 oxo-8 [(tritylamino-2 thiazolyl-4)-2 vinyloxyimino-2 acétamidoj-7 thia-5 aza-l bicyclo[4.2.0]
octène-2, isomère syn est préparé par condensation de l'acide (tritylamino-2 thiazolyl-4)-2 vinyloxyimino-2 acétique, isomère syn (4,ó g) sur l'ester benzhydryle du 7-ADCA (3,8 g) en présence de N,N'-dicyclohexylcarbodiimide (2,3 g) et 0,05 g de diméthylamino-4 pyridine dans 40 cm3 de chlorure de méthylène entre 50C et 200C pendant 4 heures.Infra-red spectrum (KBr), characteristic bands (cm-) 1770, 1670, 1635, 1610, 1530, 1495, 1450, 1000, 945, 755> 700
Proton NMR Spectrum (350 MHz, CDCl 4, 6 ppm, J in Hz) 2.90 (s, 6H, -N (CH 3) 2); 4> 25 (dd, J = 2 and 6, 1h,

4.73 (dd, J = 2 and 14, 1H,

5.18 Cd, J = 4.1H, H at 6); 5.60 (dd, J = 4 and 9, 1H, H at 7); 6.53 and 6.75 (2d, J = 16, 2H, -CH = CH-); 6.88 (s, 1H, -COOCH-); 7.10 (dd, J = 6 and 14, 1H, = NOCH =)
2-Benzhydryloxycarbonyl-3-methyl-8-oxo-4- [(tritylamino-4-thiazolyl) -vinyloxyimino-2-acetamido] -7-thia-5-aza-1-bicyclo [4.2.0]
octene-2, syn isomer is prepared by condensation of 2- (2-trityamino-4-thiazolyl) -2-vinyloxyiminoacetic acid, syn-isomer (4, 6 g) on benzhydryl ester of 7-ADCA (3.8 g) in the presence of N, N'-dicyclohexylcarbodiimide (2.3 g) and 0.05 g of 4-dimethylaminopyridine in 40 cm3 of methylene chloride at 50 ° C. to 200 ° C. for 4 hours.

After chromatography on silica gel (200 g) with methylene chloride, 5 g of the expected product are obtained in the form of yellow meringue.

 Infra-red spectrum (KBr), characteristic bands (cm) 3400, 1785, 1725, 1690, 1640, 1525, 1495, 1450, 1040, 1000, 940, 755, 700.

4,76 (dd, J = 2 et 14, 1H,

5,08 (d, J = 4, 1H, H en 6) ; 5 > 92 (dd, J = 4 et 9, 1H, H en 7) 6,83 (s, 1H, H du thiazole) ; 6,93 (s, 1H,

7,0 (s, 1H, -NH-C(C6H5)3)
t' acide (tritylamino-2 thiazo lyl-4) -2 vinyloxyimino-2 acétique, forme syn, est préparé selon le brevet belge 869 079. Proton NMR Spectrum (350 MHz, CDCl 3, 6 ppm, J in Hz) 2.12 (s, 3H, -CH 3) 3.22 and 3.49 (2d, J = 18, 2H, -CH 2 - ) 4.25 (dd, J = 2 and 6, 1H,

4.76 (dd, J = 2 and 14, 1H,

5.08 (d, J = 4.1H, H at 6); Δ = 92 (dd, J = 4 and 9, 1H, H at 7) 6.83 (s, 1H, H thiazole); 6.93 (s, 1H,

7.0 (s, 1H, -NH-C (C6H5) 3)
(2-Tritylamino-4-thiazolyl-4-yl) -vinyloxyimino-acetic acid, syn form, is prepared according to Belgian Patent 869 079.

EXAMPLE 2
To a solution cooled to -300C under nitrogen with 5 g of 2-benzhydryloxycarbonyl-2-t-butoxycarbonylamino-7 (2-oxoethyl) -3-oxo-5-thia-1-azabicyclo [4.2.0] octene-2 in 50 cm3. 1.4 ml of triethylamine are added to methylene chloride, and a solution of 1.5 g of ethoxymalonyl chloride in 10 cm3 of methylene chloride is added dropwise over 10 minutes. The mixture is stirred for 1 hour at -30 ° C. diluted with 50 cm 3 of methylene chloride, washed with 3 times 50 cm 3 of saturated sodium bicarbonate solution and 3 times 50 cm 3 of water, dried over sodium sulfate filter and concentrated to dryness at 20 g under 20 mm of mercury (2.7 kPa). The residue is taken up in 5 cm 3 of ethyl acetate, the solution is added to 50 cm 3 of diisopropyl ether and the supernatant is decanted. The gumma is taken up in 5 cm 3 of methylene chloride and the solvent is distilled off at 20 ° C. mm Hg (2.7 kPa).

2.4 g of a pale yellow meringue consisting mainly of 2-benzhydryloxycarbonyl-2-butoxycarbonylamino-7 (2-ecoxymalonyloxy-vinyl) -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2 are collected, form E.

Infra-red spectrum (KBr), characteristic bands (cm-1) 3380, 1785, 1720, 1035, 1510, 1500, 1455, 1395, 1370, 1160, 955, 760, 750, 700 Proton NMR spectrum (350 MHz, CDCl3, # in ppm, J in Hz) 1.29 (t, J = 7.3H, -OCH2CH3); 1.48 (s, 9H, -C (CH3) 3); 3.46 (s, 2H, -COCH 2 CD 4.23 (q, J = 7.2H, -OCH 2 -); 5.02 (d, J = H, 1H, H at 6); 5.22 (d, J = 9 1H, -CONH-), 5.64 (dd, J = 4 and 9, 1H, H at 7), 6.95 (s, 1H, -COOCH-), 7.05 and 7.00 ( 2d, J = 12, 1H, -CH = CHS-)
2-Benzhydryloxycarbonyl-2-butoxycarbonylamino-7 (oxo-2-ethyl) -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2 may be prepared as described in the main patent.

EXAMPLE 3
To a cooled solution at -10 ° C., 1.6 g of 2-benzhydroyloxycarbonyl-8-oxo-2- (2-tosyloxy-vinyl) [(2-tritylamino-4-thiazolyl) -vinyloxyimino-2-acetamido] -7-thia-5-aza 1 bicyclo [4.2.0] octene-2 and -3, syn isomer, mixture of E and Z forms in 5 cm3 of methylene chloride, is added dropwise, in 10 minutes, a solution of 0.33 g of 85% m-chloroperbenzoic acid in 7 cm 3 of methylene chloride. It is stirred for 1 hour at -100 ° C., diluted with 30 cm3 of methylene chloride, washed twice with 50 cm3 of a saturated solution of sodium bicarbonate and 50 cm3 of a half-saturated solution of sodium chloride, dried over sodium sulphate, filtered and concentrated to dryness under 20 mm Hg (2.7 kPa) at 30 ° C.The residue is chromatographed on a 20 g column of Merck silica gel (0.06-0.2) ( diameter of the column, 1 cm, height: 10 cm). 500 ml of methylene chloride, 1 liter of a methylene chloride-ethyl acetate mixture 97-3 (vol.) And 1.5 liters of a 95-5 mixture (vol.) Are eluted by collecting 25 cm3. Fractions 14 to 24 are evaporated to dryness under 20 mm Hg (2.7 kPa) at 200 ° C. 0.45 g of 2-benzhydryloxycarbonyl-2-oxo-5-oxide (2-tosyloxy-vinyl) -3 [(tritylamino-2-thiazol-4-yl) -2-vinyloxyimino-2-acetamido] -7-thia-5-azabicyclo [ 4.2.0] octene-2, syn isomer, form E.

4,02 (d, J = 4, 1Hs H en 6) 4,76 (dd, J = 2 et 13, 6,20 (dd, j = 4 et 9, 1H, H en 7)
5,80 (s, 1H, H du thiazole) ; 0,90 (s, 1H, -COOCH-) ; 6,92 et 7,10 (2d,
J = 12, 2H, -CH=CH-) ; 7,05 (dd, J = 6 et 13, 1H, =NOCH=); 7,73 (d,
J = 8, 2H > H en ortho du groupe -OSO2-)
EXEMPLE 4
A une solution refroidie à -10 C de 1,65 g de benzhydryloxycarboayl-2 t.butoxycarbonylamino-7 (6thoxymalonyloxy-2 vinyl)-3 oxo-8 thia-5 aza-1 bicyclo[4.2.0] octène-2, forme E, dans 8 cm3 de chlorure de méthylène on ajoute, goutte à goutte sous agitation en 10 minutes, une solution de 0,63 8 d'acide m.chloroperbenzoïque à 85 % dans 8 cm3 de chlorure de méthylène.Infra-red spectrum (KBr), characteristic bands (cm -1) 1800, 1725, 1690, 1635, 1520, 1495, 1450, 1195, 1180, 1070, 1050, 1000, 945, 740, 700
Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, JHz) 2.45 (s, 3H, -CH2); 3.19 and 3.77 (2d, J = 18, 2H, -SCH 2 -); 4.27 (dd, J = 2 and @,

4.02 (d, J = 4.1Hs H at 6) 4.76 (dd, J = 2 and 13, 6.20 (dd, j = 4 and 9, 1H, H at 7)
5.80 (s, 1H, H thiazole); 0.90 (s, 1H, -COOCH-); 6.92 and 7.10 (2d,
J = 12, 2H, -CH = CH-); 7.05 (dd, J = 6 and 13, 1H, = NOCH =); 7.73 (d,
J = 8, 2H> H in ortho of the group -OSO2-)
EXAMPLE 4
To a solution cooled to -10 ° C. of 1.65 g of 2-benzhydryloxycarbam-2-t-butoxycarbonylamino-7 (6-oxymalonyloxy-2-vinyl) -3-oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, form E, in 8 cm3 of methylene chloride is added dropwise with stirring in 10 minutes, a solution of 0.63 8 of 85% mchloroperbenzoic acid in 8 cm3 of methylene chloride.

Stirring is carried out for 1 hour at -10 ° C. and -15 ° C., the mixture is taken up in 50 cm 3 of methylene chloride, washed with twice 50 cm 3 of saturated sodium bicarbonate solution and 50 cm 3 of a saturated solution of chloride. of sodium, dried over sodium sulphate, filtered and concentrated to dryness at 20 ° C. under 20 mm of mercury. The residue is chromatographed on a column of silica gel
Merck (0.04-0.06) (diameter of the column: 1.5 cm, height: 15 cm). It is diluted with 0.5 liter of a methylene chloride-ethyl acetate mixture 95-5 (by volume) under a pressure of 40 kPa, collecting 20 cm3 fractions. Fractions 5 to 10 are concentrated to dryness at room temperature. 200 ° C. under 20 mm Hg, 0.2 g of 2-benzhydryloxycarbonyl-t-butoxycarbonylamino-7 (6-oxymalonyloxy-vinyl) -3-oxo-8-oxide-5-thia-aza-1-bicyclo [4.2.0] octene are collected. 2, form E, in the form of a yellow powder.

Infra-red spectrum (KBr), characteristic bands (cm-) 3420, 1795, 1725, 1640, 1500, 1460, 1395, 1370, 1160, 1050, 940, 760, 750, 700
Proton NMR Spectrum (350 MHz, CDCl3, B ppm, JHz) 1.29 (t, J = 7.3H, -CH2CH3); 1.48 (s, 9H, -C (CH3) 3); 3.24 and 3.95 (2 d,
J = 18.2H, -SCH 2 -) 1 3.45 (s, 2H, -OCOCH 2 -); 4.23 (q, J = 7, 2H, -OC 2 -); 4.55 (d, J = 4, 1H, H at 6); 5.76 (d, J = 9, 1H, -CONH-); 5.83 (dd, J = 4 and 9, 1H, H at 7); 6.98 (s, 1H, -COOCH-); 7.61 (d, J = 11, 1H, -CH = CHS-)
The products according to the invention can be used as follows
REFERENCE EXAMPLE 1
A mixture of 0.4 g of water is heated at 60 ° C. for 4 hours.
2-benzhydryloxycarbonyl-8-oxo-5-oxide (2-tosyloxyvinyl) (trityl)
2-amino-4-thiazolyl) -vinyloxyimino-2-acetamido-7-thia-5-aza-1
bicyclo [4.2.0] octene-2, syn isomer, E form, 5 cm3 of dimethylformamide,
0.1 g of 5-mercapto-1-methyl-tetrazole and 0.15 cc of N, N-diispropyl
ethylamine. It is taken up in 50 cm3 of ethyl acetate, washed with 50 cm3
of water, 50 cm3 of 0.1 N hydrochloric acid, 50 cm3 of a half solution
saturated with sodium bicarbonate and 50 cm3 of a saturated solution of
sodium chloride, dried over sodium sulphate, filtered and concentrated
dry under 20 mm of mercury (2.7 kPa) at 300C.The residue is chromato
graphed on a 50 g column of Merck silica gel (0.06-0.2)
(diameter of the column, 1.5 cm, height: 15 cm). One elects by 2.5
very much a mixture of methylene chloride and ethyl acetate 90-10 (vol.)
under a pressure of 40 kPa by collecting fractions of 25 cm3.

4,76 (dd, j = 2 et 14,

4,67 (d, J = 4, 1H, H en 6) ; 6,18 (dd, J = 4 et 9, 1H, H en 7) 6,78 (s, 3H, H du thiazole) ; 6,95 (s, 1H,

7,0 (d, J = 15, 1H, -CH=CHS-) ; 7,05 (dd > J = 4 et 6, 1H, -OCH=) ; 7,10 (s, 1H,

7,58 (d, j = 15, 1H, -CH=CHS-)
On traite à -100C, pendant 20 minutes, une solution de 3 g de benzhydryloxycarbonyl-2 [(méthyl-1 rétrazolyl-5) thio-2 vinyl]-3 oxo-8 oxyde-5 L(tritylamino-2 thiazolyl-4)-2 vinyloxyimino-2 acétamido]-7 thia-5 aza-l bicycloL4.2.0] octène-2, isomère syn, forme Et dans 31,7 cm3 de chlorure de méthylène et 1,22 cm3 de diméthylacétamide par 0,554 cm3 de trichlorure de phosphore. On verse le mélange dans 250 cm3 d'acétate d'éthyle, lave par 250 cm3 d'une solution saturée de bicarbonate de sodium, 250 cm3 d'eau et 250 cm3 d'une solution saturée de bicarbonate de sodium, sèche sur sulfate de sodium, filtre et concentre à sec sous 20 mm de mercure (2,7 kPa) à 20 C. On fixe le produit sur 10 g de gel de silice Merck (0,06-0,2) et chromatographie sur une colonne de 30 g de gel de silice Merck (0,06-0,2) (diamètre de la colonne : 1,5 cm). On élue par 250 cm3 d'un mélange cyclohexaneacétate d'éthyle 80-20 (vol.), 250 cm3 d'un mélange 70-30 (vol.) et 250 cm3 d'un mélange 60-40 (vol.) en recueillant des fractions de 60 cm3. On concentre à sec les fractions 5 à 10 sous 20 amide mercure (2 > 7 kPa) à 200C et recueille 1,92 g de benzhydryloxycarbonyl-2 [(méthyl-1 tétrazolyl-5) thio-2 vinyl]-3 oxo-8 [(tritylamino-2 thiazolyl-4)-2 vinyloxyimino-2 acétamido]-7 thia-5 aza-1 bicyclo[4.2.0] octène-2, isomère syn, forme E sous la forme d'une meringue de couleur crème.Fractions 18 to 42 are concentrated to dryness under 20 mm Hg (2.7 kPa) at 20 ° C. 0.15 g of 2-benzhydryloxycarbonyl-2 - [(1-methyl-5-tetrazolyl) -2-thio-vinyl] -3-oxo-5-oxide-5- [(2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido] was thus collected. 7 thia-5-azabicyclo [4.2.0] octene-2, syn isomer, E-form, the characteristics of which are as follows:
Infrared spectrum (KBr), characteristic bands (cm)
3340, 2940, 2860, 1800, 1730, 1690, 1640, 1575, 1525, 1500, 1450,
1215, 1045, 1005, 950, 765, 760
Proton NMR Spectrum (350 MHz, CDCl3, 6 ppm, J in Hz)
3.31 and 4.05 (2d, J = 18, 2H, -SCH 2 -); 3.92 (s, 3H, -CH1); 4.26 (dd,
J = 2 and 6, 1H,

4.76 (dd, j = 2 and 14,

4.67 (d, J = 4, 1H, H at 6); 6.18 (dd, J = 4 and 9, 1H, H at 7) 6.78 (s, 3H, H thiazole); 6.95 (s, 1H,

7.0 (d, J = 15, 1H, -CH = CHS-); 7.05 (dd> J = 4 and 6, 1H, -OCH =); 7.10 (s, 1H,

7.58 (d, j = 15, 1H, -CH = CHS-)
A solution of 3 g of 2-benzhydryloxycarbonyl-1 - [(1-methyl-5-retrazolyl) -2-thio-vinyl] -3-oxo-5-oxide (2-tritylamino-4 thiazolyl) is treated at -100 ° C. for 20 minutes. 2-vinyloxyimino-2-acetamido] -7-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, in form of 31.7 cc of methylene chloride and 1.22 cc of dimethylacetamide per 0.554 cc of trichloride. phosphorus. The mixture is poured into ethyl acetate (250 cc), washed with saturated sodium bicarbonate solution (250 cc), water (250 cc) and saturated sodium bicarbonate solution (250 cc), dried over sodium sulfate. sodium, filtered and concentrated to dryness under 20 mm of mercury (2.7 kPa) at 20 C. The product is fixed on 10 g of Merck silica gel (0.06-0.2) and chromatography on a column of 30 Merck silica gel (0.06-0.2) (column diameter 1.5 cm). 250 cm 3 of a mixture of ethyl cyclohexaneacetate 80-20 (vol.), 250 cm.sup.3 of a mixture of 70-30 (vol.) And 250 cm.sup.3 of a mixture of 60-40 (vol. fractions of 60 cm3. Fractions 5 to 10 were concentrated to dryness under mercury amide (2> 7 kPa) at 200 ° C. and 1.92 g of 2-benzhydryloxycarbonyl-2 - [(1-methyl-5-tetrazolyl) -2-thio-vinyl] oxo-8 was collected. 2- (2-Trityamino-4-thiazolyl) -vinyloxyimino-2-acetamido-7-thia-5-aza-bicyclo [4.2.0] octene-2, syn isomer, Form E as a cream-colored meringue.

Rf = 0.58 [silica gel chromatography plate3 eluent
cyclohexane-ethyl acetate 50-50 (vol.)]
A mixture of 1.92 g of 2-benzhydryloxycarbonyl-2 - [(1-methyl-5-tetrazolylthio) -vinyl] -8-oxo [(2-tritylamino-4 thiazolyl)) is stirred at 50 ° C. for 15 minutes. 2-vinyloxyimino-acetamido] -7 thia-5-aza-bicyclo [4.2.0] octene-2, syn isomer, Form E, 15 cm3 of formic acid and 7 cm3 of water. It is filtered and concentrated to dryness under 0.05 mm of mercury (0.007 kPa) at 30 ° C. The remaining oil is taken up in 100 cm 3 of ethanol, the solvent is removed under 20 mm of mercury (2.7 kPa) at 200 ° C. and is repeated. this operation a second time. It is taken up in 100 cm3 of ethanol, refluxed with stirring, allowed to cool and filtered. After drying, 0.72 g of [(2-emino-4-thiazolyl) -vinyloxyimino-2-acetamido] -7-carboxylic acid are collected. 2 - [(1-methyl-5-tetrazolyl) -2-thio-vinyl] oxo-8-thia-5-aza-bicyclo [4.2.0] octene-2, syn isomer, form E, in the form of a yellow powder .

 Infra-red spectrum (KBr), characteristic bands (cm-) 3340, 1770, 1680, 1620, 1530 and 1380.

4,65 (dd, J = 2 et 14, 1H,

5,22 (d, J = 4 4, li, H en 6) ; 5,82 (dd, J 4,4 4 et 9 1H, H en 7) 6,75 (s, 1H, H du thiazole) ; 0,95 (d, J = 16, 1H, -CH=CHS-); 5,96 (dd, J = 6 et 14, 1H, -OCH-CH2) ; 7,13 (d, J = 16, 1H, =CHS-) 9,83 (d, J = 9, 1H, -CONH-)
EXEMPLE DE REFRRENCE 2
On agite à 250C pendant 3 heures un mélange de 0,8 g de benzhydryloxycarbonyl-2 t-butoxycarbonylamino-7 (éthoxymalonyloxy-2 vinyl)-3 oxo-8 oxyde-5 thia-5 aza-1 bicyclo[4.2.0] octène-2, forme E, 8 cm3 de diméthylformamide, 0,3 g de mercapto-5 méthyl-l tétrazole et 0,45 cm3 de N,N-diisopropyléthylamine.On dilue par 200 cm3 d'acétate d'éthyle, lave par 2 lois 100 cm3 d'eau, 100 cm3 d'acide chlorhydrique 0,1 N, 100 cm3 d'une solution à 2 % de bicarbonate de sodium et 100 cm3 d'une solution saturée de chlorure de sodium , sèche sur sulfate de sodium, filtre et concentre à sec à 200C sous 20 mm de mercure (2,7 kpa). Le résidu est chromatographlé sur une colonne de gel de silice Merck (0,06-0,04) (diamètre de la colonne 1,5 cm, hauteur : 15 cm), on élue par 0,5 litre d'un mélange cyclohexane acétate d'éthyle 50-50 (en volumes) sous une pression de 40 kPa en recueillant des fractions de 25 cm3. Les fractions 10 à 21 sont concentrées à sec à 200C sous 20 mm de mercure (2,7 kPa).On recueille 0,15 g de benzhydryloxycarbonyl-2 t.butoxycarbonylamino-7 [(métyl-1 tétrazolyl-5) chio-2 vinyl]-3 oxo-8 oxyde-5 thia-5 aza-l blcyclo[4.2.0] octène-2, forme E, sous la forme d'une poudre de couleur crème.@MN spectrum of the proton (350 MHz, DMSO d6, 8 ppm, J in Hz) 3.04 and 3.89 (2d, J = 18, 2H, -SCH-); 4.0 (s, 3H, -CH 2); 4.22 (dd,
J = 2 and 6, 1H,

4.65 (dd, J = 2 and 14, 1H,

5.22 (d, J = 44, Li, H at 6); 5.82 (dd, J 4.4, and 1H, H at 7) 6.75 (s, 1H, H thiazole); 0.95 (d, J = 16, 1H, -CH = CHS-); 5.96 (dd, J = 6 and 14, 1H, -OCH-CH 2); 7.13 (d, J = 16, 1H, = CHS-) 9.83 (d, J = 9, 1H, -CONH-)
REFERENCE EXAMPLE 2
A mixture of 0.8 g of benzhydryloxycarbonyl-2-tert-butoxycarbonylamino-7 (ethoxymalonyloxy-2-vinyl) -3-oxo-5-oxide-5-thia-5-aza-1-bicyclo [4.2.0] octene is stirred at 250 ° C. for 3 hours. -2, E form, 8 cm3 of dimethylformamide, 0.3 g of 5-mercapto-1-methyl-tetrazole and 0.45 cm3 of N, N-diisopropylethylamine.Undicated by 200 cm3 of ethyl acetate, washed with 2 100 cm3 of water, 100 cm3 of 0.1 N hydrochloric acid, 100 cm3 of a 2% solution of sodium bicarbonate and 100 cm3 of a saturated solution of sodium chloride, dried over sodium sulfate, filter and concentrated to dryness at 200C under 20 mm of mercury (2.7 kpa). The residue is chromatographed on a column of Merck silica gel (0.06-0.04) (column diameter 1.5 cm, height 15 cm), eluted with 0.5 liter of a cyclohexane acetate mixture. of ethyl 50-50 (by volume) under a pressure of 40 kPa by collecting fractions of 25 cm3. Fractions 10 to 21 are concentrated to dryness at 200 ° C. under 20 mm of mercury (2.7 kPa). 0.15 g of 2-benzhydryloxycarbonyl-2-tert-butoxycarbonylamino-7 - [(1-metyl-5-tetrazolyl) -2-chloro) are collected. vinyl] -3-oxo-5-oxide-5-thia-5-azabicyclo [4.2.0] octene-2, Form E, in the form of a cream-colored powder.

 A mixture of 34.87 g of 2-benzhydryloxycarbonyl-2-butoxycarbonylamino-7 - [(1-methyl-5-tetrazolylthio) -vinyl] -3-oxo-5-oxide-5-thia-aza is stirred for 16 hours at 25 ° C. bicyclo [4.2.0] octene-2 (Form E), 560 cc of acetone nitrile and 21.31 g of p-toluenesulfonic acid monohydrate. The mixture is then concentrated at 200 ° C. under reduced pressure (20 mm Hg) and the residue is taken up in 1 liter of ethyl acetate. It is neutralized by stirring with 300 cm 3 of a 5% solution of sodium bicarbonate, decanted, washed with 3 times 500 cm 3 of a semisaturated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated to dryness. under reduced pressure (20 mm of mercury at 20 ° C., 19.59 g of 7-amino-benzhydryloxycarbonyl-2 - [(1-methyl-5-tetrazolylthio) -vinyl) -3-oxo-5-oxide-thia- Aza-1 bicyclo [4.2.0] octene-2 (E-form) under the form of a raw brown meringue.

Rf = 0.27 [silica gel chromatoplate, solvent: dichloroethane
85-15 methanol (by volume) J.

 3.45 g of 7-Amino-2-benzhydryloxycarbonyl-2 - [(1-methyl-5-tetrazolyl) -2-thio-vinyl] -3-oxo-5-oxide-5-thia-aza-1-bicyclo [4.2.0] octene are condensed. 2, Form E> and 3.1 g of cyanomethoxyimino-2 (2-trityamino-4-thiazol-4-yl) acetic acid, syn isomer (prepared according to the German patent application 2,812,625) in 200 cm3 of methylene chloride in presence of 100 mg of 4-dimethylaminopyridine and 1.48 g of N, N'-dicyclohexylcarbodiimide. 2.01 g of 2-benzhydryloxycarbonyl (2-cyanomethoxyimino-2- (2-trityamino-4-thiazolyl) -acetamido] -7 [(1-methyl-5-tetrazolyl) -2-thio] vinyl is purified in an analogous manner and is collected. 3-oxo-5-oxide-5-thia-5-azabicyclo [4.2.0] octene-2, syn-isomer, Es form as an orange meringue.

Infra-red spectrum (KBr), characteristic bands (cm-) 3330, 1800, 1720, 1685, 1625, 1525, 1495, 1450, 1210, 1040, 750, 700
Proton NMR Spectrum (350 MHz, CDCl3, # in ppm, J in Hz) 3.27 and 4.10 (2d, J = 18, 2H, -SCH2-); 3.90 (s, 311, -CH3); 4.62 (d, J = 4, 1H, H at 6); 4.86 (s, 2H, -OCH 2 -); 6.08 (dd, J = 4 and 9, 1H, H at 7) 6.76 (s, 1H, H thiazole); 6.92 (s, 1H, -COOCH-); 6.99 (d, J = 16, 1H, -CH = CHS-); 7.50 (d, J = 16, 1H, -CHS-); 7.58 (d, J = 9, 1H, -CONH-)
As described in reference example 1, 2.01 g of 2-benzhydryloxycarbonyl [2-cyanomethoxyimino-2- (2-trityamino-4-thiazolyl) acetamido] -7 [(1-methyl-5-tetrazolyl) -2-thio-vinyl] is treated as in the reference example. 3-oxo-5-oxide 5-thia-5-azabicyclo [4.2.0] octene-2 isomer syn, form E, in 21 cm3 of methylene chloride and 0.78 cm3 of dimethylacetamide with 0.365-cm3 of trichloride. phosphorus. Purification is carried out by analogous chromatography and 1.14 g of 2-benzhydryloxycarbonyl-2 [cyanomethoxyimino-2 (2-trityamino-4-thiazolyl) -2-acetamido] -7 [(1-methyl-5-tetrazolyl) -2-thio-vinyl] is collected. 8-oxo-5-thia-azabicyclo [4.2.0] octene-2, syn isomer, E-form, as a cream-colored meringue.

Rf = 0.32 [silica gel chromatoplate, eluent: cyclohexane-acetate
of ethyl 50-50 (in volumes)]
reference 1 but
By proceeding as in Example I, starting with 1.13 g of 2-benzhydryloxycarbonyl-2-cyanomethoxyimino-2-trityamino-4-thiazolyl-2-acetamido] -7 [(1-methyl-5-tetrazolyl) -2-thio-vinyl). ] -3-oxo-8-thia-5-azabicyclo [4.2.0] octene-2, syn isomer, form E, 0.53 g of [(2-amino-4-thiazolyl) -2-cyanomethoxyimino) is obtained. acetamido] -7-carboxy-2 - [(1-methyl-5-tetrazolyl) -2-thio-vinyl] oxo-8-thia-5-aza-1-bicyclo [4.2.0] octene-2, syn isomer, E-form, under the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm-1770, 1680, 1620, 1530, 1380
NMR Spectrum (350 MHz, DMSO 6 ppm, J in Hz) 3.66 and 3.88 (2d, J = 18.2H, -SCH 2 -) i 4.02 (s, 3H, -CH 3) ); 5.0 (s, 2H, -OCH 2 -); 5.22 (d, J = 4, 1H, H at 6); 5.80 (dd, J = 4 and 9, 1H, H at 7); 6.89 (s, 1H, H thiazole); 6.99 (d, J = 16, 1H, -CH = CHS-); 7.12 (d, J = 16, 1H, = CHS-); 9.82 (d, J = 9, 1H, -CONH-)

Claims (8)

1 - A novel 3-vinyl cephalosporin characterized in that it corresponds to the general formula: ## STR2 ## in which n is equal to O or 1, a ') the symbol R 1 represents a radical of general formula: ## STR1 ## wherein R5 is a vinyl, cyanomethyl or 2-methoxy-2-propyl radical and R4 is a hydrogen atom, or a protecting radical, or R5 is a hydrogen atom, an alkyl radical, or a protecting radical, and R4 is a formyl or trifluoroacetyl radical], the symbol R2 represents a hydrogen atom, an easily removable enzymatically radical of general formula in which R8 represents an alkyl radical or the cyclohexyl radical, and Rg represents a hydrogen atom or an alkyl radical, or R2 represents a methoxymethyl, t-butyl, benzhydrylen-p-nitrobenzyl or p-methoxybenzyl radical, and the symbol R3 represents a radical of general formula: R'3-S020 or R "3 -COO in which R '3 represents an alkyl radical, trifluoromethyl, trichloromethyl, or unsubstituted or substituted phenyl (by a halogen atom or an alkyl or nitro radical) and R "3 is defined as R13 or represents an acylmethyl, 2-acylethyl, acyl radical or 2, propyl, alkyloxycarbonylmethyl, 2-alkyloxycarbonylethyl or 2-alkylpropylcarbonyl, or the symbol R1 represents a hydrogen atom, a radical as defined above in a ') for R1 (in which R4 is a hydrogen atom or a protective radical and R5 is a hydrogen atom, an alkyl radical or a protecting group], an acyl radical of the general formula R6CO in which R6 is a hydrogen atom or an alkyl radical [optionally substituted by a or more than one halogen atom or a phenyl or phenoxyl or phenyl radical, or a radical of the general formula: R 70 GO- in which R 7 is an unsubstituted branched alkyl radical or a straight alkyl radical or branched bearing one or more substituents- selected from halogen atoms and cyano, trialkylsilyl, phenyl, substituted phenyl (with one or more alkyloxy nitro or phenyl), vinyl, allyl or quinolyl radicals, or radical nitrophenylthio, or R1NH- is replaced by a methyleneimino radical in which the methylene radical is substituted by a dialkylamino or aryl group (itself optionally substituted by one or more methoxy or nitro radicals) and the symbol R2 is defined as above in a ') or  2- the symbol R1 represents  a hydrogen atom,  an alkanoyl radical containing 1 to 8 carbon atoms, alkanoyl containing  2 to 8 atoms of substituted carbon (with chlorine or bromine atoms), - azidoacetyl, - cyanoacetyl  an acyl radical of general formula

 [wherein Quest® or methyl and Ar represents a thienyl-2 radical,  thienyl-3, furyl-2, furyl-3, pyrrolyl-2, pyrrolyl-3 or phenyl [optional  is substituted by halogen atoms for trifluromethyl radicals,  hydroxy, alkyl (containing 1 1 dt ", carbon) atcoyloxy (containing 2 to 3  carbon atoms), cyaiio or @@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ where at least one is located in  for phenyl] @,  an acyl radical of general formula,  Ar - X - CH2 - CO  where X is oxygen or other IL and Ar is defined as above,  or X represents the sulfur and Ar represents pyridyl-4, an acyl radical corresponding to the general formula:

 wherein Ar is defined as above and B is amino, protected amino [by benzyloxycarbonyl, alkyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, trityl or 2,2,2-trichloroethoxycarbonyl], a sulfo radical, a hydroxy radical or carboxy optionally protected by esterification (respectively with an alkanoic acid or an alcohol containing 1 to 6 carbon atoms)], azido, cyano or carbamoyl, or a radicat (sydnone-3) -2 alkaloyl (the part of which is alkanoyl contains 1 to 3 carbon atoms) to a radical of the general formula:

 wherein m is 0 to 2 or an amino-5-adipoyl radical [wherein amino group is optionally protected by an alkanoyl radical (containing 1 to 3 carbon atoms and optionally substituted by a chlorine atom) and wherein the carboxy group is protected by a benzhydryl, 2,2,2-trichloroethyl, alkyl (containing 4 to 6 carbon atoms) or nitrobenzyl] group, the symbol R2 represents an L.alkyl radical containing 4 to 6 carbon atoms, t. alkenyl containing 6 or 7 carbon atoms, t-alkenyl containing 6 or 7 carbon atoms, benzyl, methoxybenzyl, nitrobenzyl, 2,2,2-trichloroethyl, benzhydryl, succinimidomethyl or phthalimidomethyl or a hydrogen atom and the symbol R3 represents or a radical R'3 S020- in which R'3 is a phenyl radical, or a radical R "3COO - in which R" 3 is a phenyl radical, acylmethyl, 2-acyl ethyl, 2-acyl propyl> alkyloxycarbonylmethyl, alkyloxycarbonyl -2 ethyl or alkoylox 2-propylcarbonyl propyl> the portions or alkyl or alkyl radicals mentioned above being (except special mention) straight or branched and containing 1 to 4 carbon atoms, the product being in the form of bicyclooctene-2 or -3 when n = @ and in bicyclooctene-2 form when n = 1 and the -3 substituent being of E or Z form (as well as mixtures of their isomers) and their salts. 2 - A new product according to claim 1, characterized in that, n, R2 and R3 being defined as in claim 1 in a '), R1 represents a radical of general formula

  in the syn or anti form, in which R 5 is a vinyl, cyanomethyl or 2-methoxypropyl-2 radical and R 4 is a hydrogen atom or a t-butoxycarbonyl radical, 2,2,2-trichloroethoxycarbonyl, chloroacetyl or trichloroacetyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, formyl or trifluoroacetyl, or R 5 is a hydrogen atom, an alkyl, trityl or tetrahydropyranyl radical and R 4 is a formyl or trifluoroacetyl radical. 3 - A new product according to claim 1 characterized in that, n and R3 are defined as in claim i in b ') R1 represents a radical of general formula

 in the syn or anti-form, in which R 4 is a hydrogen atom or a t-butoxycarbonyl, trichloro-2,2,2,2-thoxycarbonyl, chloroacetyl, trichloroacetyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl radical, p.methoxybenzyloxycarbonylX and R5 is a hydrogen atom or an alkyl, trityl or tetrahydropyranyl radical and R2 has the corresponding definition. 4 - A method for preparing a product according to one of claims 1, 2 or 3 for which, n being defined according to claim i, either R1, R2 and R3 are defined as in claim 1 in a ') or in claim 2, wherein R1 and R2 are defined as in claim 1 in b') 1 or in claim 3, except for R1 to represent the hydrogen atom, or R 1 represents a radical-alkanoyl containing 1 to 8 carbon atoms, alkanoyl containing 2 to 8 carbon atoms substituted (with chlorine or bromine atoms), an acyl radical of general formula

 wherein Q is H or methyl and Ar is thienyl-2, thienyl-3, furyl-2, furyl-A-pyrrulyl-2, pyrrolyl-3 or phenyl [optionally substituted with halogen atoms or hydroxy groups, alkyl (containing 1 to 3 carbon atoms) or alkyloxy (containing 1 to 3 carbon atoms), at least one of which is in meta or para to the phenyl]]], an acyl radical of the general formula  Ar - X - CH 2 - CO as defined in claim 1, an acyl radical corresponding to the general formula

 wherein Ar is defined as in claim 1, and B represents a protected amino group [with benzyloxycarbonyl, alkyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzhydryloxycarbonyl, trityl or 2,2,2-trichloroethoxycarbonyl], a sulfo radical, a radical hydroxy or carboxy [optionally protected by esterification, respectively with an alkanoic acid or an alcohol containing 1 to 6 carbon atoms, or an amino-5-adipoyl radical [in which the amino group is optionally protected by an alkanoyl radical (containing 1 to 3 carbon atoms and optionally substituted by a chlorine atom) and wherein the carboxy group is protected by a benzhydryl, 2,2,2-trichloroethyl, alkyl (containing 4 to 6 carbon atoms) or nitrobenzyl group and R2 is defined as above in claim 1 in R3 is defined as in claim 1 in b ') 2, and  characterized in that the product of general formaldehyde (R'3SO2) is roasted.  R'3 SO2 Hal  (R "3 CO) 2 O  or R "3 COHal in which '3 and R" 3 are as above and Hal represents a halogen atom, on a product of the general formula

 wherein, n being defined as in claim 1, the product is in the form of 3-oxo-2-bicyclooctene or 3-oxo-3-ethylbicyclooctane when n = 0 and in the form of 3-oxoethyl-2-bicyclooctene or 3-oxoethylidene bicyclooctane when n = 1, and R1 is defined as above except to represent a radical of general formula

 (in which R4 is hydrogen) and R2 is defined as above except for representing hydrogen, or on a mixture of its isomers, then optionally reduces the sulfoxide obtained, optionally eliminates the protective groups, optionally separates the isomers of the product obtained and eventually converts this product into a salt. 5 - A process for preparing a product according to claim 1 wherein, R2, R3 and n being defined as above, R1 represents hydrogen, characterized in that one eliminates the radical R1 or optionally in that the radicals R1 and R2 are simultaneously removed from a product according to claim 1 wherein R3 and n are defined as in claim 1, R1 and R2 are defined as in claim 1 in b ') i, except for R1 to represent either hydrogen or a radical of general formula

 or else R 1 represents an amino-5 adipolye radical whose amine and acid functions are protected, or a radical

 Ar a - X - CH 2GO as defined in claim 1 and R2 is defined as in claim 1 in b ') 2, then the resulting product is optionally separated into its isomers and optionally converted into a salt. preparation of a product according to one of claims 1, 2 or 3 wherein, n being defined according to claim 1, R1 represents a radical of general formula

 as defined in a ') or b') 1 in claim 1 or claim 2 or 3, or R1 is defined as in b ') 2 in claim 1 except for representing the atom-d hydrogen, and R2 and R3 have the corresponding definition characterized by acylating with an acid represented by the general formula: 1 (wherein R1 is defined as above), or a reactive derivative of this acid, a product according to claim 1 wherein R 1 represents hydrogen, or optionally a mixture of the isomers of this product, then optionally reduces the oxide obtained, optionally eliminates the protective radicals, separates the isomers of the product obtained and transforms it optionally in a salt.  7 - Process for the preparation of a product according to one of claims- I, 2 or 3 for which n is equal to 1, characterized that one oxide a product according to claim 1, 2 or 3 for which n = O by any known method for preparing a sulfoxide from a sulphide without affecting the rest of the molecule, then optionally separates the isomers of the product obtained and eventually converts it into a salt. 8 - Process for the preparation of a product according to one of claims 1,  2 or 3 wherein, R3 and n being defined as in claim 1, R1 is defined as in claim 1 in a) or b '> 1 or in claim 2 or 3 and R2 is a radical of the general formula:

 as defined in claim 1, characterized in that it is esterified a product according to one of claims 1, 2 or 3 wherein, R1, R3 and n being defined as above, R2 is an atom of hydrogen, then optionally reduces the oxide obtained, optionally eliminates the protective groups and optionally separates the product obtained in isomers.  9 - Process for preparing a product according to one of claims 1, 2 or 3 wherein, R3 and n being defined as in claim 1, R1 represents a radical of general formula

  as defined in a ') in claim 1 or 2 [except for R4 represents a chloroacetyl or trichloroacetyl radical and for R5 to represent vinyl, or as defined in b ') r in claim 1 or 3 there the exception for R4 to represent a cetyl chlorine or trichloroacetyl], and R2 has the corresponding definition given in claim 1, characterized in that a thiourea of general formula is made to act  R4NU - -cS NH2 wherein R4 is defined as above, on a cephalosporin derivative of the general formula

 wherein R3 and n are defined as in claim 1, R2 and R5 are defined as above-and Hal represents a chlorine or bromine atom, or optionally on a mixture of the isomers of this product, then optionally reduces the oxide obtained, optionally eliminates the protective groups, optionally separates the isomers of the product obtained and eventually converts it into salt.