GB2095238A

GB2095238A - 7-Acylamido-3-cephem-4-carboxylic acid compounds

Info

Publication number: GB2095238A
Application number: GB8205260A
Authority: GB
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1981-02-27
Filing date: 1982-02-23
Publication date: 1982-09-29
Also published as: ES8307822A1; PT74498B; FI820618L; DK84982A; ES509956A0; GB2095238B; EP0059683A3; NO820618L; IL65108A0; AU8093482A; EP0059683A2; GR78230B; PT74498A

Description

SPECIFICATION 7-Acylamido-3-cephem-4-carboxylic acid compounds, processes for the manufacture thereof pharmaceutical preparations containing these compounds and the use of the latter The present invention relates to novel 7P-acylamido-3-cephem-4-carboxylic acid compounds, processes for the manufacture thereof, pharmaceutical preparations containing these compounds and their use for the manufacture of pharmaceutical preparations or as pharmacologically active compounds.

The present invention relates to 7P-acylamido-3-cephem-4-carboxylic acid compounds of the formula

in which I represents an integer from 0 to 2, m represents an integer from 0 (direct bond) to 4, n represents an integer from 1 to 4, X represents oxygen, sulphur or the group -NH-, W represents a group -CO-, -CONHSO2- or -SO2NHCO-, or X and W together represent a group -CO- or -CONHSO2-, Y represents hydrogen or an unsubstituted or substituted organic radical, R1 represents hydrogen,.lower alkyl, lower alkoxy, halogen or a group of the formula -CH2-fl2 in which R2 represents a free, esterified or etherified hydroxy or mercapto group or a quaternary ammonium group, R3 represents hydrogen or lower alkoxy, and R4 represents carboxy or protected carboxy, hydrates and salts of compounds of the formula I, processes for the manufacture of compounds of the formula I, pharmaceutical preparations containing compounds of the formula I and the use of compounds of the formula I for the manufacture of pharmaceutical preparations or as pharmacologically active compounds.

In the description of the present invention, the term "lower" used in connection with groups, for example lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl etc., means that the corresponding groups contain up to 7, and preferably up to 4, carbon atoms unless expressly defined otherwise.

In the above formula I, the index I, represents especially 0. If I has the value 1 , the corresponding 1-oxide compound of the formula I is in the a- or p-configuration or there may be a mixture of compounds in both configurations.

If the index m represents 0, a direct bond is present. If m represents an integer of from 1 to 4, the group (CrnH2rn) is-an unbranched or branched alkylene chain and represents, for example, methylene, 1,2-ethylene, 1,3-propylene or 1 ,4-butylene.

A group (CnH2) is an unbranched or branched alkylene chain and is, for example, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1 ,1-ethylene, 1,1-propylene, 1,2-propylene, 1,1 -butylene or 1,1 -isobutylene.

An unsubstituted or substituted organic radical Y has up to 1 8 carbon atoms and is a lower aliphatic hydrocarbon radical that is unsubstituted or substituted by one or more functional groups or is a cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aliphatic hydrocarbon radical or an unsubstituted or substituted heterocyclic or heterocyclic-aliphatic radical.

A lower aliphatic hydrocarbon radical Y is, for example, lower alkyl having from 1 to 7, preferably from 1 to 4, carbon atoms, for example methyl, ethyl, propyl or butyl, or is lower alkenyl having from 2 to 5 carbon atoms, for example vinyl or allyl.

A lower aliphatic radical Y substituted by one or more functional groups is, for example, lower alkyl substituted by hydroxy, etherified hydroxy, for example lower alkoxy, for example methoxy or ethoxy, by esterified hydroxy, for example lower alkanoyloxy, for example acetyloxy, by halogen, for example chlorine, by carboxy, esterified carboxy, for example lower alkoxycarbonyl, for example methoxycarbonyl, by sulpho, amidated sulpho, amino, mono- or di-alkylamino, for example methylamino or ethylamino, or by acylamino, for example lower alkanoylamino, for example acetylamino: for example hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-acetoxyethyl, 2-chloroethyl, carboxymethyl, 2-carboxyethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, sulphomethyl, 2sulphoethyl, sulphamoylmethyl, 2-sulphamoylethyl, 2-aminoethyl, 2-dimethylaminoethyl or 2acetylaminoethyl.

A cycloaliphatic hydrocarbon radical Y is, for example, cycloalkyl having from 3 to 8, especially from 3 to 6, carbon atoms, for example cyclopropyl, cyclopentyl or cyclohexyl, or is cycloalkenyl having from 3 to 8, especially from 3 to 6, carbon atoms, for example 1 -cyclohexenyl or 1 ,4-cyclohexadienyl.

A cycloaliphatic-aliphatic hydrocarbon radical Y is, for example, one of the mentioned aliphatic radicals that is substituted by one of the mentioned cycloaliphatic radicals, for example cyclopropylmethyl or -ethyl or cyclohexyl-methyl or -ethyl.

An aromatic hydrocarbon radical Y is, for example, phenyl.

An aromatic-aliphatic hydrocarbon radical Y is, for example, one of the mentioned aliphatic radicals that is substituted, for example by phenyl, for example benzyl or phenethyl.

A heterocyclic radical Y is, for example, a monocyclic aza-, thia, oxa, thiaza-, thiadiaza-, diaza- or tetraaza- cyclic radical of aromatic character.

A heterocyclic radical Y is especially an aromatic monoaza-, monothia- or monooxa-cyclic radical, for example pyridinium, thienyl, for example 2-or 3-thienyl, or furyl, for example 2- or 3-furyl, a monocyclic thiaza-, thiadiaza-, diaza- or tetraaza-cyclic radical, for example thiazolyl, for example 2thiazolyl, isothiazolyl, for example 2- or 4-isothiazolyl, thiadiazolyl, for example 1 ,2,4-thiadiazol-3-yl or 1 ,3,4-thiadiazol-2-yl, imidazolyl, for example 2-imidazolyl, or tetrazolyl, for example 1 or 5-tetrazolyl.

Substituents of the mentioned heterocyclic radical Y are, for example, lower alkyl, especially methyl, and also ethyl, n-propyl, isopropyl or straight-chain or branched butyl, or lower alkyl that is substituted by hydroxy, esterified hydroxy, for example lower alkanoyloxy, halogen, for example chlorine, phosphono that is present in salt form and is optionally esterified by one or two lower alkyl groups, carboxy, esterified carboxy, for example lower alkoxycarbonyl, sulpho, amidated sulpho, amino, mono- or di-lower alkylamino, acylamino, for example lower alkanoylamino, or lower alkanoylamino substituted by carboxy or halogen: for example 2-hydroxyethyl, 2-acetoxyethyl, 2-chloroethyl, carboxymethyl, 2-carboxyethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, sulphomethyl, 2sulphoethyl, sulphamylmethyl, 2-sulphamylethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2acetylaminoethyl, 3-carboxypropionylamino or 3-chloropropionylamino.

Functiqnal groups or modified, for example protected, functional groups, for example halogen, for example fluorine, chlorine or bromine, unsubstituted or substituted amino, for example amino that is unsubstituted or mono- or di-substituted by lower alkyl, for example amino, methylamino or dimethylamino, acylamino, for example lower alkanoylamino or lower alkylsulphonylamino, or lower alkanoylamino substituted by halogen or carboxy, for example acetylamino, methylsulphonylamino or ethylsulphonylamino, 3-chloropropionylamino or 3-carboxypropionylamino, nitro, hydroxy, lower alkoxy, for example methoxy or ethoxy, carboxy, esterified carboxy, for example lower alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, optionally substituted, for example mono- or di-lower alkylated, carbamoyl, for example methylcarbamoyl or dimethylcarbamoyl, or cyano, and also oxo or oxido, are likewise substituents of the heterocyclic radical Y.

Preferred unsubstituted or substituted heterocyclyl radicals Y are, for example, thienyl, for example 2- or 3-thienyl, furyl, for example 2- or 3-furyl, tetrazolyl, for example 1 -tetrazolyl, aminothiazolyl, for example 2-amino-4-thiazolyl, aminothiadiazolyl, for example 5-amino-1,2,4thiadiazol-3-yl, and N-lower alkylaminothiadiazolyl, for example 5-N-methylamino-1 ,2,4-thiadiazol-3yl.

A heterocyclic-aliphatic radical Y is, for example, one of the mentioned aliphatic radicals, for example methyl that is substituted by one of the mentioned heterocyclic radicals, for example tetrazolyl, for example tetrazol-5-ylmethyl.

A lower alkyl group R1 contains from 1 to 4 carbon atoms and is, for example, ethyl, propyl, butyl or especially methyl.

A lower alkoxy group R, contains from 1 to 4 carbon atoms and is, for example, methoxy, ethoxy, propoxyorbutoxy.

R, representing halogen is fluorine, bromine or iodine but preferably chlorine.

An esterified hydroxy or mercapto group R2 is esterified by a lower aliphatic carboxylic acid or by an optionally N-substituted carbamic acid.

A hydroxy group R2 esterified by a lower aliphatic carboxylic acid is especially lower alkanoyloxy, for example acetyloxy, also formyloxy, propionyloxy, valeryloxy, hexanoyloxy, heptanoyloxy, pivaloyloxy or acetoacetoxy.

A mercapto group R2 esterified by a lower aliphatic carboxylic acid is especially lower alkanoylthio, for example acetylthio, formylthio, propionylthio, valeroylthio, hexanoylthio, heptanoylthio or pivaloylthio.

In a hydroxy or mercapto group R2 esterified by an optionally N-substituted carbamic acid, an Nsubstituent is, for example, lower alkyl that is unsubstituted or substituted by halogen, for example chlorine, or by lower alkanoyloxy, for example acetoxy or propionyloxy, for example methyl, ethyl, 2chloroethyl or 2-acetoxyethyl.

A hydroxy group R2 esterified by an optionally N-substituted carbamic acid is, for example, carbamoyloxy, N-methylca rbamoyloxy, N-ethylcarbamoyloxy, N-(2-chloroethyl)-carbamoyloxy or acetoxyethyl)-carbamoyloxy.

A mercapto group R2 esterified by an optionally N-substituted carbamic acid is, for example, carbamoylthio, N-methylcarbamoylthio, N-ethylcarbamoylthio, N-(2-chloroethyl)-carbamoylthio or N (2-acetoxyethyl)-carbamoylthio.

An etherified hydroxy or mercapto group R2 is, for example, etherified by an aliphatic hydrocarbon radical and is especially lower alkoxy having from 1 to 4 carbon atoms, especially methoxy, and also ethoxy, n-propoxy or isopropoxy, also straight-chain or branched butoxy, or is lower alkylthio having from 1 to 4 carbon atoms, especially methylthio, and also ethylthio, n-propylthio or isopropylthio, also straight-chain or branched butylthio.

An etherified mercapto group R2 is especially etherified by an unsubstituted or substituted heterocyclic radical that has from 1 to 4 nitrogen hetero atoms and optionally an additional oxygen or sulphur hetero atom and that is bonded via a ring carbon atom to the sulphur atom of the mercapto group.

A heterocyclic radical of this type is especially an unsubstituted or substituted monocyclic, fivemembered or six-membered diaza-, triaza-, tetraaza-, thiaza-, thiadiaza-, thiatriaza-, oxaza- or oxadiazacyclic radical of aromatic character.

Substituents of a heterocyclic radical of this type are the same as those mentioned above for the heterocyclic radical Y.

A heterocyclylthio group R2 in which the heterocyclic radical is a monocyclic five-membered radical, is, inter alia, imidazolylthio, for example 2-imidazolylthio, triazoiylthio that is unsubstituted or substituted by lower alkyl and/or phenyl, for example 1 H-l ,2,3-triazol-5-ylthio, l-methyl-l H-1,2,3- triazol-4-ylthio, 1 H- 1 ,2,4-triazol-3-ylthio, 5-methyl-1 H-1 ,2,4-triazol-3-ylthio or 4,5-dimethyl-4H1 ,2,4-triazol-3-ylthio, tetrazolylthio that is unsubstituted or substituted as indicated, for example 1 H tetrazol-5-ylthio, 1 1-methyl- 1 H-tetrazol-5-ylthio, 1 -phosphonomethyl-1 H-tetrazol-5-ylthio that is present in salt form, for example in the form of the sodium salt, or that is optionally esterified by one or two lower alkyl groups; for example ethyl groups, 1-carboxymethyl-1H-tetrazol-5-ylthio, 1-(2 carboxyethyl)- 1 H-tetrazol-5-ylthio, 1 -sulphomethyl-1 H-tetrazol-5-ylthio, 1 -(2-sulphoethyl)- 1 Htetrazol-5-ylthio or 1 -(2-dimethylaminoethyl)-l H-tetrazol-5-ylthio, thiazolylthio or isothiazolylthio that is unsubstituted or substituted by lower alkyl, for example 2-thiazolylthio, 4,5-dimethyl-2-thiazolylthio, 3-isothiazolylthio, 4-isothiazolylthio or 5-isothiazolylthio, especially thiadiazolylthio that is unsubstituted or substituted as indicated, for example 1 ,2,3-thiadiazol-4-ylthio, 1 ,2,3-thiadiazol-5ylthio, 1 ,3,4-thiadiazoi-2-ylthio, 2-methyl-l ,3,4-thiadiazol-5-ylthio, 1 ,2,4-thiadiazol-5-ylthio or 1,2,5thiadiazol-3-ylthio, thiatriazolylthio, for example 1 ,2,3,4-thiatriazolyl-5-ylthio, oxazolylthio or isoxazolylthio that is unsubstituted or substituted as indicated, for example 5^oxazolylthio, 4-methyl-S- oxazolylthio, 2-oxazolylthio or 3-methyl-5-isoxazolylthio, and oxadiazolylthio that is unsubstituted or substituted as indicated, for example 1 ,2,4-oxadiazol-5-ylthio or 2methyl1 ,3,4-oxadiazol-5-ylthio.

A heterocyclylthio group R2 in which the heterocyclic radical is a monocyclic six-membered radical contains from 1 to 3 nitrogen atoms and is, for example, 5,6-dioxotetrahydro-as-triazinylthio that is unsubstituted or substituted by lower alkyl, for example methyl, carboxylower alkyl, for example carboxymethyl, or by sulpholower alkyl, for example sulphomethyl, for example 1- or 2-methyl-5,6dioxo- 1 ,2,5,6-tetrahydro-as-triazin-3-ylthio, 4-methyl-5,6-dioxo- 1 ,4,5,6-tetrahydro-as-triazin-3-ylthio, 1- or 2-carboxymethyl-5,6-dioxo-l ,2,5,6-tetrahydro-as-triazin-3-ylthio, 4-carboxymethyl-5,6-dioxo- 1 ,4,5,6-tetrahydro-as-triazin-3-ylthio, 1- or 2-sulphomethyl-5,6-dioxo- 1 ,2,5,6-tetrahydro-as-triazin-3- ylthio or 4-su lphomethyl-5,6-dioxo- 1 ,4,5,6,-tetrahydro-as-triazin-3-ylthio.

A quaternary ammonium group R2 is derived from a tertiary organic base, for example from an aliphatic amine or preferably from an unsubstituted or substituted heterocyclic nitrogen base and is bonded via the nitrogen atom to the methylene group in the 3position of the cephem nucleus. The positive charge at the quaternary nitrogen atom is compensated for, for example by the negatively charged carboxylate in the 4-position of the cephem nucleus.

A quaternary ammonium group R2 that is derived from an aliphatic amine is, for example, trilower alkylammonium, for example trimethyl- or triethyl-ammonium.

A quaternary ammonium group R2 that is derived from an unsubstituted or substituted heterocyclic nitrogen base is, for example, 1 -pyrazolium that is unsubstituted or substituted in the 2position by lower alkyl, for example methyl or ethyl, lower alkenyl, for example vinyl or allyl, carboxylower alkyl, for example carboxymethyl, lower alkoxycarbonyl-lower alkyl, for example methoxycarbonylmethyl, sulpho-lower alkyl, for example sulphomethyl, amino-lower alkyl, for example 2-aminoethyl, or di-lower alkylamino-lower alkyl, for example 2-dimethylaminoethyl: for example 2methyl or 2-ethyl-1 -pyrazolium, 2-allyl- or 2-vinyl-1 -pyrazolium, 2-carboxymethyl-l -pyrazolium, 2 methoxycarbonylmethyl-1 -pyrazolium, 2-sulphomethyl- 1 -pyrazolium, 2-(2-aminoethyl)- 1 -pyrazolium or 2-(2-dimethylaminoethyl)-1 -pyrazolium.

A quaternary ammonium group R2 that is derived from an unsubstituted or substituted heterocyclic nitrogen base is likewise, for example, 1-triazolium that is unsubstituted or substituted in the 3-position by lower alkyl, for example methyl or ethyl, carboxy-lower alkyl, for example carboxymethyl, or di-lower alkylamino-lower alkyl, for example 2-dimethylaminoethyl: for example 3 methyl -triazolium, 3-carboxymethyl-1 -triazolium or 3-(2-dimethylaminoethyl)- -triazolium.

A quaternary ammonium group R2 that is derived from an unsubstituted or substituted heterocyclic nitrogen base is likewise, for example, pyridinium that is unsubstituted or mono- or di substituted by lower alkyl, for example methyl, carbamoyl, lower alkylcarbamoyl, for example methylcarbamoyl, hydroxy-lower alkyl, for example hydroxymethyl, lower alkoxy-lower alkyl, for example methoxymethyl, cyano-lower alkyl, for example cyanomethyl, carboxy-lower alkyl, for example carboxymethyl, sulpho-lower alkyl, for example 2-sulphoethyl, carboxy-lower alkenyl, for example 2carboxyvinyl, carboxy-lower alkylthio, for example carboxymethylthio, thiocarbamoyl, halogen, for example bromine or chlorine, carboxy, sulpho or cyano: for example lower alkylpyridinium, for example 2-, 3- or 4-methylpyridinium or 2-, 3- or 4-ethylpyridinium, carbamoylpyridinium, for example 3- or 4-carbamoylpyridinium, lower alkylcarbamoylpyridinium, for example 3- or 4-methylcarbamoylpyridinium, di-lower alkylcarbamoylpyridinium, for example 3- or 4-dimethylcarbamoylpyridinium, hydroxy-lower alkylpyridinium, for example 3- or 4-hydroxymethylpyridinium, lower alkoxy-lower alkylpyridinium, for example 4-methoxymethylpyridinium, cyano-lower alkylpyridinium, for example 3cyanomethylpyridinium, carboxy-lower alkylpyridinium, for example 3-carboxymethylpyridinium, sulpho-lower alkylpyridinium, for example 4-(2-sulphoethylpyridinium), carboxy-lower alkenylpyridinium, for example 3-(2-carboxyvinyl)-pyridinium, carboxy-lower alkylthiopyridinium, for example 4-carboxymethylthiopyridinium, thiocarbamoylpyridinium, for example 4-thiocarbamoylpyridinium, halopyridinium, for example 3-bromo- or 4-bromo-pyridinium, carboxypyridinium, for example 4-carboxypyridinium, sulphopyridinium, for example 3-sulphopyridinium, cyanopyridinium, for example 3-cyanopyridinium, carboxy-lower alkylcarbamoylpyridinium, for example 3-carboxymethyl-4carbamoylpyridinium, aminocarbamoylpyridinium, for example 2-amino-5-carbamoylpyndinium, carboxycarbamoylpyridinium, for example 3-carboxy-4-carbamoylpyridinium, cyanohalomethylpyridinium, for example 3-cyano-4-trifluoromethylpyridinium, and aminocarboxypyridinium, for example 2-amino-3-carboxypyridinium.

A quaternary ammonium group R2 is preferably 2-lower alkyl-1 -pyrazolium, for example 2 methyl -pyrazolium, 2-carboxy-lower alkyl-1 -pyrazolium, for example 2-carboxymethyl-1 -pyrazolium, 3-lower alkyl-1-triazolium, for example 3-methyl-1-triazolium,or pyridinium that is unsubstituted or substituted by hydroxy-lower alkyl, for example hydroxymethyl, carboxy, carboxy-lower alkyl, for example carboxymethyl, halogen, for example chlorine or bromine, or by carbamoyl, for example 3- or 4-hydroxymethylpyridinium, 4-carboxypyridinium, 3- or 4-carboxymethylpyridinium, 3- or 4chloropyridinium, 3- or 4-bromopyridinium or 3- or 4-carbamoylpyridinium.

Lower alkoxy R3 is, for example, methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy.

R4 representing "protected carboxy" is carboxy that can be cleaved under physiological conditions or is carboxy that is esterified by the protecting groups described below.

The functional groups in the compounds of the formula I, especially carboxy and amino, and also hydroxy and sulpho, groups, are optionally protected by conventional protecting groups used in penicillin, cephalosporin and peptide chemistry.

Such protecting groups can be readily removed, that is to say without undesired secondary reactions taking place, for example by solvolysis, reduction, photolysis or alternatively under physiological conditions.

Protecting groups of this type and the manner in which they are removed are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, in "Protective Groups in Organic Chemistry", Willy, New York, 1974, in "The Peptides", vol. I. Schröder and Lübke, Academic Press, London, New York, 1965, and in "Methoden der organischen Chemie", Houben-Weyl, 4th edition, vol 1 5/t, Georg Thieme Verlag, Stuttgart, 1 974.

Thus carboxy groups, for example the carboxy group R4 or the carboxy group in the aaminocarboxylic acid grouping, and also carboxy groups in R, and Y, are generally protected in esterified form, such ester groupings being readily cleaved under mild conditions. Carboxy groups protected in this manner are esterified especially by lower alkyl groups that are branched in the 1position or substituted in the 1- or 2-position by suitable substituents.

Preferred protected carboxy groups that are esterified by lower alkyl branched in the 1-position are, for example, tert.-iower alkoxycarbonyl, for example tert.-butoxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals in which the aryl is phenyl that is unsubstituted or mono- or polysubstituted, for example, by lower alkyl, for example tert.-lower alkyl, for example tert.-butyl, lower alkoxy, for example methoxy, hydroxy, halogen, for example chlorine, and/or by nitro, for example benzyloxycarbonyl that is unsubstituted or substituted, for example as mentioned above, for example 4-nitrobenzyloxycarbonyi or 4-methoxybenzyloxycarbonyl, or diphenylmethoxycarbonyl that is unsubstituted or substituted, for example as mentioned above, for example diphenylmethoxycarbonyl or di-(4-methoxyphenyl)-methoxycarbonyl.

Preferred protected carboxy groups that are esterified by lower alkyl suitably substituted in the 1or 2-position are, for example, 1-lower alkoxy-lower alkoxycarbonyl, for example methoxymethoxycarbonyl, 1 -methoxyethoxycarbonyl or 1 -ethoxymethoxycarbonyl, 1-lower alkylthiolower al koxycarbonyl, for example 1 -methylthiomethoxycarbonyl or 1 -ethylthioethoxycarbonyl, aroylmethoxycarbonyl in which the aroyl group is benzoyl that is unsubstituted or substituted, for example by halogen, such as bromine, for example phenacyloxycarbonyl, and also 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxywarbonyl or 2iodoethoxycarbonyl. Carboxy groups are likewise protected in the form of silyloxycarbonyl groups.

A silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, for example trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group can alternatively be substituted by only two lower alkyl groups, for example methyl groups, and the carboxy group or amino group or a second molecule of the formula I. Compounds having such protecting groups can be manufactured, for example, by using dimethyldichlorosilane as silylating agent.

Preferred protected carboxy groups are tert.-lower alkoxycarbonyl, such as tert.-butoxycarbonyl, and especially benzyloxycarbonyl that is optionally substituted, for example as mentioned above, for example 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl.

An esterified carboxy group R4 that can be cleaved under physiological conditions is especially an acyloxymethoxycarbonyl group in which acyl is, for example the acyl group of an organic carboxylic acid, especially of an optionally substituted lower alkanecarboxylic acid, or in which acyloxymethyl forms the radical of a lactone.Such groups are lower alkanoyloxymethoxycarbonyl, for example acetyloxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, lower alkoxycarbonyloxy-lower alkoxycarbonyl, for example 1 -ethoxycarbonyloxyethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, especially a-amino-lower alkanoyloxymethoxycarbonyl, for example glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl or L-leucyloxymethoxycarbonyl, also phthalidyloxycarbonyl, for example 2-phthalidyloxycarbonyl, or indanyloxycarbonyl, for example 5indanyloxycarbonyl.

Amino groups, for example the amino group in the a-aminocarboxylic acid grouping, and amino groups in RI and Y can be protected, for example, in the form of a readily cleavable acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group.

In a readily cleavable acylamino group, acyl is, for example, the acyl group of an organic carboxylic acid having up to 1 8 carbon atoms, especially of an alkanecarboxylic acid that is unsubstituted or substituted, for example by halogen or aryl, or of a benzoic acid that is unsubstituted or substituted, for example by halogen, lower alkoxy or nitro, or of a carbonic acid semiester.Such acyl groups are, for example, lower alkanoyl, for example formyl, acetyl or propionyl, halo-lower alkanoyl, for example 2-haloacetyl, especially 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl, benzoyl that is unsubstituted or substituted, for example by halogen, lower alkoxy or nitro, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl that is branched in the 1-position of the lower alkyl radical or suitably substituted in the 1- or 2-position.

Lower alkoxycarbonyl branched in the 1-position of the lower alkyl radical is, for example, tert.lower alkoxycarbonyl, for example tert.-butoxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals in which aryl is preferably phenyl that is unsubstituted or mono- or polysubstituted, for example by lower alkyl, especially tert.-lower alkyl, for example tert.-butyl, lower alkoxy, for example methoxy, hydroxy, halogen, for example chlorine, and/or by nitro, for example unsubstituted or substituted benzyloxycarbonyl, for example 4-nitro-benzyloxycarbonyl or unsubstituted or substituted diphenylmethoxycarbonyl, for example benzhydryloxycarbonyl or di-(4-methoxyphenyl)methoxycarbonyl.

Lower alkoxycarbonyl suitably substituted in the 1- or 2-position is, for example, tri-lower alkylsilyloxycarbonyl, for example trimethylsilyloxycarbonyl, a royl methoxycarbonyl in which aroyl is benzoyl that is -unsubstituted or substituted, for example by halogen, for example bromine, for example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2bromoethoxycarbonyl or 2-iodoethoxycarbonyl or 2-(tri-substituted silyl)-ethoxycarbonyl in which each of the substituents, independently of one another, represents an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical having up to 1 5 carbon atoms that is unsubstituted or substituted, for example by lower alkyl, lower alkoxy, aryl, halogen or by nitro, for example lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl each of which is unsubstituted or substituted as mentioned above: for example 2-tri-lower alkylsilylethoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl or 2-(di-n butyl-methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, for example 2 triphenylsilylethoxycarbonyl.

Further acyl groups coming into consideration as amino-protecting groups are also acyl groups of organic phosphoric, phosphonic or phosphinic acids, such as di-lower alkylphosphoryl, for example dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or dilsopropyiphosphoryl, dicycloalkylphosphoryl, for example dicyclohexylphosphoryl, diphenylphosphoryl, diphenyl-lower alkylphosphoryl that is unsubstituted or substituted, for example by nitro, for example dibenzylphosphoryi or di4-nitrobenzylphosphoryl, phenoxyphenylphosphonyl, di-lower alkylphosphinyl, for example diethylphosphinyl, or diphenylphosphinyl.

In an arylmethylamino group that is mono-, di- or especially tri-arylmethylamino, the aryl radicals are especially phenyl radicals. Such groups are, for example, benzyl-, diphenylmethyl- and especially trityl-amino.

In an etherified mercaptoamino group, the etherified mercapto group is especially arylthio or aryllower alkylthio in which aryl is especially phenyl that is unsubstituted or substituted, for example by lower alkyl, for example methyl or tert.-butyl, lower alkoxy, for example methoxy, halogen, for example chlorine, and/or nitro. Such an amino-protecting group is, for example, 4-nitrophenylthio.

In a 2-acyl-lower alk-1-enyl group that may be used as an amino-protecting group, acyl is, for example, the acyl group of a lower alkanecarboxylic acid, or of a benzoic acid that is unsubstituted or substituted, for example by lower alkyl, for example methyl or tert.-butyl, lower alkoxy, for example methoxy, halogen, for example chlorine, and/or nitro, or especially the acyl group of a carbonic acid semiester, for example of a carbonic acid lower alkyl semiester. Such amino-protecting groups are especially 1-lower alkanoylprop-1 -en-2-yl, for example 1 -acetylprop-1 -en-2-yl, or 1-lower alkoxycarbonylprop- 1 -en-2-yl, for example 1 -ethoxycarbonylprop-1 -en-2-yI.

A silylamino group is, for example a tri-lower alkylsilylamino group, for example trimethylsilylamino. The silicon atom of the silylamino group can alternatively be substituted by only two lower alkyl groups, for example methyl groups, and the amino group or carboxy group of a second molecule of the formula I. Compounds having such protecting groups can be manufactured, for example, by using dimethyldichlorosilane as silylating agent.

An amino group may also be protected in protonated form. As anions there come into consideration especially those of strong inorganic acids, such as hydrohalic acids, for example the chlorine or bromine anion, or of organic sulphonic acids, such as p-toluenesulphonic acid.

Preferred amino-protecting groups are acyl radicals of carbonic acid semiesters, especially tert.butoxycarbonyl, or benzyloxycarbonyl that is unsubstituted or substituted, for example as indicated, for example 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, or trityl or formyl.

Hydroxy groups, for example hydroxy groups in R, and Y, may be protected, for example in the form of acyl groups, for example lower alkanoyl substituted by halogen, for example 2,2-dichloroacetyl, or they may be protected especially by the acyl radicals of carbonic acid semi-esters mentioned in connection with protected amine groups.Preferred hydroxy-protecting groups are, for example, 2,2,2trichloroethoxycarbonyl, organic silyl radicals having the above-mentioned substituents, also readily removable etherifying groups, such as tert.-lower alkyl, for example tert.-butyl, 2-oxa- or 2-thiaaliphatic or -cycloaliphatic hydrocarbon radicals, for example 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, for example methoxymethyl, 1 -methoxyethyl, 1 -ethoxyethyl, 1-methylthiomethyl, 1-methylthioethyl or 1 -ethylthioethyl, or 2-oxa- or 2-thia-cycloalkyl having from 5 to 7 ring atoms, for example 2-tetrahydrofuryl or 2-tetrahydropyranyl or corresponding thia analogues, and also unsubstituted or substituted 1 -phenyl-lower alkyl, for example unsubstituted or substituted benzyl or diphenylmethyl, the phenyl radicals being substituted, for example by halogen, such as chlorine, lower alkoxy, for example methoxy, and/or nitro.

Sulpho groups, for example sulpho groups in R1 and Y, are preferably esterified by an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol, for example by lower alkanol, or by a silyl group, for example by tri-lower alkylsilyl. A sulpho group is protected analogously to a carboxy group.

Salts of compounds according to the invention are especially pharmaceutically acceptable nontoxic salts of compounds of the formula Such salts are formed, for example, from the acid groups in compounds of the formula I, for example carboxy or sulpho groups, and are especially metal or ammonium salts, for example alkali metal and alkaline earth metal salts, for example sodium, potassium magnesium or calcium salts, and also ammonium salts that are formed with ammonia or suitable organic amines, there being suitable for the salt formation especially aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or poly-amines, and also heterocyclic bases.Such bases are, for example, lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid 2-diethyidiaminoethyl ester, lower alkyleneamines, for example 1 -ethylpiperidine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example N,N'-dibenzylethylenediamine, also bases of the pyridine type, for example pyridine, collidine or quinoline.

The basic groups in the compounds of the formula I, for example amino groups, can form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulphuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, for example trifluoroacetic acid, and also with amino acids, such as arginine and lysine.

If several acid groups, for example two carboxy groups, or basic groups are present in compounds of the formula I, mono- or poly-salts can be formed, Since the compounds of the formula I have at least one acid group, for example the carboxy group in the a-aminocarboxylic acid grouping, and at least one basic group, for example the amino group in the a-aminocarboxylic acid grouping, compounds of the formula I may be in the form of internal salts, that is to say in zwitterion form. In compounds of the formula I, one acid and one basic group may be in the form of an internal salt and additional acid and/or basic groups may be in the form of, for example, acid addition and or base addition salts.

For the purposes of isolation or purification, it is also possible to use pharmaceutically unacceptable salts, Only pharmaceutically acceptable non-toxic salts are used therapeutically and these are therefore preferred.

The compounds of the formula I in which the functional groups are in free form and the carboxy groups are optionally in physiologically cleavable esterified form, and their pharmaceutically acceptable non-toxic salts are valuable antibioticaily active substances that can be used especially as antibacterial antibiotics.For example, they are effective in vitro against gram-positive and gram-negative microorganisms, including strains producing ,-lactamase, for example against cocci, such as Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Neisseria gonorrhoeae and Neisseria meningitidus, in minimum concentrations of from approximately 0.01 to approximately 64 ssug/ml, and against enterobacteria, such as Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Proteus spp., Enterobacter cloacae, Serratia marcescens, Haemophilus influenzae and Pseudomonas aeruginosa, in minimum concentrations of from approximately 0.01 ssg/ml to approximately 64 Clg/ml.

In vivo, when administered subcutaneously to mice, they are effective, for example, against systemic infections caused by staphylococci in minimum doses of approximately 30 mg/kg and against systemic infections caused by enterobacteria in a dosage range of from approximately 0.3 mg/kg to approximately 85 mg/kg.

In the following test report, the effectiveness of compounds of the formula I is demonstrated with reference to selected compounds: Test report I. Tested compounds The antibiotic activity of the following compounds was tested: 1. The sodium salt of 3-acetoxymethyl-7ss-[2-((2R)-2-amino-2-carboxyethoxycarbonylamino)- acetamido]-3-cephem-4-carboxylic acid (Example 1 c)).

2. The sodium salts of 3-acetoxymethyl-7α-methoxy-7ss-[2-((2R)-2-amino-2- carboxyethoxyzarbonyla mino)-acetamido]-3-cephem-4-carboxylic acid (Example 1 d)).

3. The sodium salt of 3-( 1-methyl- 1 H-tetrazol-5-ylthiomethyl)-7α-methoxy-7ss-[2-((2R)-2- amino-2-carboxy-ethoxycarbonylamino)-acetamido]-3-cephem- 4-carboxylic acid (Example 1 e)).

4. The disodlum salt of 3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl)-7α-methoxy-7ss-[2- ((2R)-2-a mino-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid (Example 1 f)).

5. The sodium salt of 3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl]-7α-methoxy-7ss [2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid (Example 1g)).

6. The disodium salt of 3-(1-sulphomethyl-1H-tetrazol-5-ylthiomethyl)-7α-methoxy-7ss-[2-((2R)- 2-amino-2-ca rboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid (Example 1 h)).

7. 3-(4-carbamoylpyridiniomethyl)-7 a-methoxy-7p-[2-((2 R)-2-amino-2- carboxyethoxycarbonylamino)-aceta mido]-3-cephem-4-carboxylate (Example 1 i)).

8. The sodium salt of 3-carbamoyloxymethyl-7a-methoxy-7p-[2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid (Example 2d)).

9. The sodium salt of 7α-methoxy-7ss-[2-((2R)-2-amino-2-carboxyethoxycarbonylamino)- acetamido]-3-cephem-4-carboxylic acid (Example 3c)).

10. The sodium salt of 3-acetoxymethyl-7a-methoxy-7p-[(2R)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-2-methylacetamido]-3-cephem-4-carboxylic acid (Example 5c)).

11. The sodium salt of 3-( 1-methyl- 1 H-tetrazoI-5-ylthiomethyl)-7a-methoxy-7-[(2Fl)-2-((2 Fl)-2- amino-2-carboxyethoxycarbonylamino)-2-methylacetamide]-3-cephem-4-carboxylic acld (Example 5d)).

12. The sodium salt of 3-acetoxymethyl-7ss-[(2R,S)-2-amino-2-carboxyethoxycarbonylamino)-2- (2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid (Example 8c)).

13. The sodium salt of 3-( 1-methyl- 1 H-tetrazol-5-ylthiomethyl)-7p-[(2R,S)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid (Example 8d)).

14. The sodium salt of 3-( 1 -methyl-1 H-tetrazol-5-ylthiomethyl)-7α-methoxy-7ss-[(2R)-2-((2R)- 2-amino-2-carboxyethoxycarbonylamino)-2-methoxymethylacetamido]-3-cephem-4-carboxylic acid (Example 12e)).

15. The sodium salt of 3-( 1-methyl- 1 H-tetrazol-5-ylthiomethyl)-7a-methoxy-7p-[(2R)-2-((2R)-2- amino-2-carboxyethoxycarbonylamino-2-hydroxymethylacetamido]-3-cephem-4-carboxylic acid (Example 1 2g)).

1 6. The sodium salt of 3-acetoxymethyl-7ss-[(2R)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamidoi-3-cephem-4-carboxylic acid (Example 9d)).

17. The sodium salt of 3-acetoxymethyl-7ss-[(2S)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid (Example 9e)).

18. The sodium salt of 3-[1 -(2-dimethylaminoethyl)-1 H-tetrazol-5-ylthiomethyl]-7ss-[(2R,S)-2- ((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4carboxylic acid (Example 9f)).

19. The sodium salt of 3-(1 -carboxymethyl-1 H-tetrazol-5-ylthiomethyl)-7,B-[(2R,S)-2-((2R)-2- amino-2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]- 3-cephem-4-carboxylic acid (Example 9g)).

20. The sodium salt of 3-(1-sulphomethyl-1 H-tetrazol-5-ylthiomethyl)-7p-[(2R.S)-2-((2R)-2- amino-2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid (Example 9h)).

21. The sodium salt of 3-( 1 -methyl-1 H-tetrazol-5-ylthiomethyl)-7α-methoxy-7ss-[(2R)-2-((4R)-4- amino-4-carboxybutyrylamido)-2-methylacetamido]-3-cephem-4-carboxylic acid (Example 11 f)).

22. The sodium salt of 3-(1-methyl-1 H-tetrazol-5-ylthiomethyl)-7p-[(2R,S)-2-((3R)-3-amino-3- carboxypropionamido)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid (Example 1 Od)).

23. The sodium salt of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2S)-2((2R)-2-amino-2carboxyethoxycarbonylamino)-2-phenylacetamido]-3-cephem-4-carboxylic acid (Example 14b)).

24. The sodium salt of 3-(1-methyl-1 H-tetrazol-5-yithiomethyl)-7ss-[(2R)-2-((2R)-2-amino-2- ca rboxyethoxycarbonyl amino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid (Example 15b)).

25. The sodium salt of 3-(1-methyi-1 H-tetrazol-5-ylthiomethyl)-7p-[(2S)-2-((2R)-amino-2- carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid (Example 15c)).

26. 3-(4-carbamoylpyridiniomethyl)-7ss-[(2R,S)-2-((2R)-2-amino-2carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate (Example 16)).

27. The sodium salt of 3-acetoxymethyl-7-methoxy-7,ss-[4-((2R)-2-amino-2- carboxyethoxycarbonyla mino)-butyramido]-3-cephem-4-carboxylic acid (Example 18c)).

28. The sodium salt of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7α-methoxy-7ss-[4-((2R)-2- ami no-2-carboxyethoxycarbonylamino)-butyramido]-3-cephem-4-carboxylic acid (Example 18e)).

29. The sodium salt of 3-acetoxymethyl-7ss-[4[((2R)-2-amino-2-carboxyethoxycarbonylamino)- butyramido]-3-cephem-4-carboxylic acid (Example 18d)).

30. The sodium salt of 3-(1-methyl-1- H-tetrazol-5-ylthiomethyl)-7,B-[4-((2R)-2-amino-2- carboxyethoxycarbonylamino)-buWramido]-3-cephem-carboxylic acid (Example 18f)).

II. Experimental A. The antibiotic activity of the test compounds in vitro was established by the agar dilution method according to Ericsson, H. M. and Sherris, S. C., 1971, Acta Path. Microb. Scand. Section B, Suppl. No. 21 7, vol. 1-90, in DST agar. The minimum concentration still inhibiting the growth of the test organisms (MIC=minimum inhibiting concentrations) are given in micrograms per millilitre (,ug/ml) for the tested compounds in Table 1.

B. The chemotherapeutic activity in vivo against systemic infections in female SPF, MF2 mice was established according to the method of Zak, O., et al., 1979, Drugs Exptl. Clin. Res.5,45-59. The ED50 values found in milligrams substance per kilogram mouse (mg/kg) against a number of microorganisms are indicated in Table 2 for the test compounds administered orally (p.o.) or subcutaneously (s.c.).

III. Test results Table 1: antibiotic activity (in vitro)

MIC [yg/mlY Pseudomonas test Escherichia Klebsiella Salmonella aeruginosa compound coli 205 pneumoniae 327 typhimurium 277 799/61 1 4 4 4 4 2 1 1 1 0.5 3 1 1 1 0.5 4 1 1 0.5 0.5 S 2 2 2 1 6 2 2 1 1 7 8 8 4 1 8 1 1 1 1 9 4 8 4 16 10 1 1 1 1 11 1 1 1 1 12 0.05 0.05 0.05 0.1 13 0.02 0.05 0.02 0.05 Table 1 (contd.) antibiotic activity (in vitro)

MIC [yg/mil Pseudomonas test Escherichia Klebsiella Salmonella aeruginosa compound coli 205 pneumoniae 327 typhimurium 277 799/61 14 8 8 2 1 15 8 2 2 1 16 0.1 0.1 0.1 0.5 17 0.002 0.002 0.002 0.1 18 0.1 0.1 0.1 0.2 19 0.2 0.2 0.2 0.1 20 0.2 0.2 0.2 0.1 21 2 2 1 0.5 22 0.02 0.1 0.1 0.1 23 2 2 1 1 24 0.1 0.2 0.1 0.1 25 0.02 0.02 0.02 0.05 26 0.2 0.5 0.2 0.5 27 1 1 1 0.5 28 1 0.5 0.5 0.2 29 32 4 2 11 30 2 0.5 0.5 . 0.5 Table 2: chemotherapeutic activity (in vivo)

ED50[mg/kg, s,c,] Staphylococcus Escherichia Proteus test compound anvens 10B coli 205 morganli 2359 1 30 85 > 100 2 > 30 6 15 3 40 6 8 4 > 30 5 10 5 30 7 10 6 20 5.5 10 7 10 30 85 8 > 30 6 10 9 > 30 > 30 > 30 10 > 30 > 16 12 11 30 10 5.5 12 30 1 35 13 > 30 0.2 13 14 20 15 17 15 > 30 12 10 16 > 30 1 70 17 30 0.4 15 18 > 30 n.t. 14 19 > 30 n.t. 22 20 > 30 n.t. 25 21 > 30 5.5 5 22 > 30 < 1 3-10 23 > 30 13 50 24 > 30 #1 5 25 > -,30 0.28 c.3 26 15 9 10 27 > 30 14 8 28 > 30 4 5 29 > 30 7 75 30 #30 1.7 10 n.t.=not tested Compounds of the formula I in which the functional groups are protected are used as starting materials for the manufacture of compounds of the formula I in which functional groups are in free form or in physiologically cleavable form.

The present invention relates preferably to those compounds of the formula I in which functional groups are in free form or in physioiogically cleavable protected form, and the pharmaceutically acceptable salts thereof, since it is mainly these compounds that have the activity indicated and can be used for the purpose indicated.

Attention is drawn to those compounds the formula I in which I represents an integer of from 0 to 2, m represents an integer from 0 (direct bond) to 4, n represents an integer from 1 to 4, the groups (CmH2mA and (CH2) are unbranched, X represents oxygen or the group -NH-, W represents the group -CO-, or X-W- together represent the group -CO-, Y represents hydrogen, lower alkyl, for example methyl, unsubstituted or amino-substituted furyl, thienyl, thiazolyl or thiadiazolyl, for example furyl, thienyl, aminothiazolyl or aminothiadiazolyl, R1 represents hydrogen, lower alkoxy, for example methoxy or ethoxy, halogen, for example chlorine, or a group of the formula -CH2-Fl2 in which R2 represents lower alkanoyloxy, for example acetyloxy; carbamoyloxy; N-lower alkylcarbamoyioxy; triazolythio, tetrazolylthio, thiazolylthio, thiadiazolylthio, oxazolylthio, oxadiazolylthio or 5,6-dioxotetrahydro-as-triazinylthio each of which is unsubstituted or substituted by lower alkyl, for example methyl, di-lower alkylamino-lower alkyl, for example dimethyl-aminomethyl, carboxy-lower alkyl, for example carboxymethyl, amino, carboxy-lower alkylamino, for example 2carboxyethylamino or by carbamoyl: for example 1H-1,2,3-triazol-5-ylthio, 1H-tetrazol-5-ylthio, 1,3,4thiadiazol-5-ylthio, 5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio or 5,6-dioxo-1,4,5,6-tetrahydroas-triazin-3-ylthio; 2-lower alkyl-1-pyrazolium, for example 2-methyl-1-pyrazolium; 2-carboxy-lower alkyl-1 -pyrazolium, for example 2-carboxymethyl-1 -pyrazolium; 3-lower alkyl-1 -triazolium, for example 3-methyl-1 -triazolium; or pyridinium that is unsubstituted or substituted by hydroxy-lower alkyl, for example hydroxymethyl, carboxy, carboxy-lower alkyl, for example carboxymethyl, halogen, for example chlorine or bromine, or by carbamoyl, for example 3-or 4-hydroxymethylpyridinium, 4- carboxypyridinium, 3- or 4-carboxymethylpyridinium, 3- or 4-bromopyridinium or 3- or 4carbamoylpyridinium, R3 represents hydrogen or lower alkoxy, for example methoxy, and R4 represents carboxy, pivaloyloxymethoxycarbonyl or 1 -ethoxycarbonyloxycarbonyl, and to hydrates and pharmaceutically acceptable salts of such compounds.

Special attention is drawn to those compounds of the formula I in which / represents 0, m represents an integer from 0 (direct bond) to 4, n represents an integer from 1 to 4, the groups (CH2m) and (CH2) are unbranched, X represents oxygen or the group -NH-, W represents the group -CO-, or X-W together represent the group CO-, Y represents hydrogen, lower alkyl, for example methyl, furyl, for example 2- or 3-furyl, thienyl, for example 2- or 3-thienyl, aminothiazolyl, for example 2-aminothiazol-4-yl, or aminothiadiazolyl, for example 5-amino-l ,2,4-thiadiazolyl-3-yl, R represents hydrogen, lower alkoxy, for example methoxy, halogen, for example chlorine, or a group of the formula -CH2-Fl2 in which R2 represents lower alkanoyloxy, for example acetyloxy; carbamoyloxy; triazolylthio, tetrazolylthio, thiadiazolylthio or 5,6-dioxotetrahydrotriazin-3-ylthio, each of which is unsubstituted or substituted by lower alkyl, for example methyl, di-lower alkylamino-lower alkyl, for example 2-dimethylaminoethyl, sulpho-lower alkyl, for example sulphomethyl, carboxy-lower alkyl, for example carboxymethyl, or by carbamoyl: for example 1H-1,2,3-triazol-5-ylthio, 1H-tetrazol5-ylthio. 1-methyl-1H-tetrazol-5-ylthio, 1-sulphomethyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1Htetrazol-5-ylthio, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthio, 1,3,4-thiadiazol-5-ylthio, 2-methyl 1,3,4-thiadiazol-5-ylthio, 2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-methyl-5,6 dioxo-l ,4,5,6-tetrahydro-as-triazin-3-ylthio;; or pyridinium that is unsubstituted or substituted by hydroxy-lower alkyl, for example hydroxymethyl, carboxy, carboxy-lower alkyl, for example carboxymethyl, halogen, for example chlorine or bromine, or by carbamoyl, for example 3- or 4 hydroxymethylpyridinium, 4-carboxypyridiniu m, 3- or 4-carboxymethylpyridinium, 3- or 4chloropyridinium, 3- or 4-bromopyridinium or 3- or 4-carbamoylpyridinium, R3 represents hydrogen or methoxy and R4 represents carboxy, and to hydrates and pharmaceutically acceptable salts of such compounds.

Preferred are compounds of the formula I in which / represents 0, m represents an integer from 0 (direct bond) to 3, n represents 1 or 2, the group (CrnH2rn) is unbranched, X represents oxygen, W represents the group -CO-, or X-W together represent the group -CO-, Y represents hydrogen, lower alkyl, for example methyl, furyl, for example 2- or 3-furyl, aminothiazolyl, for example 2aminothiazol-4-yl, or aminothiadiazolyl, for example 5-amino-1 ,2,4-thiadiazol-3-yl, R, represents hydrogen, lower alkoxy, for example methoxy, halogen, for example chlorine, or a group of the formula CH2-Fl2 in which R2 represents lower alkanoyloxy, for example acetyloxy, carbamoyloxy, tetrazolylthio, for example 1 H-tetrazol-5-ylthio, tetrazolylthio substituted by lower alkyl, for example methyl, di-lower alkylamino-lower alkyl, for example dimethylaminoethyl, sulpho-lower alkyl, for example sulphomethyl, or by carboxy-lower alkyl, for example carboxymethyl, for example 1 -methyl-1 -tetrazol-5-ylthio, 1 -(2- dimethylaminoethyl)-1 H-tetrazol-5-ylthio, 1 -sulphomethyl- 1 H-tetrazol-5-ylthio, or 1 -carboxymethyl1 H-tetrazol-5-ylthio, thiadiazolylthio, for example 1 ,3,4-thiadiazol-5-ylthio, or thiadiazolylthio substituted by lower alkyl, for example methyl, for example 2-methyl-i ,3,4-thiadiazol-5-ylthio, 5,6- dioxotetrahydro-as-triazinylthio or 5,6-dioxotetrahydro-as-trizinylthio substituted by lower alkyl, for example methyl, for example 2-methyl-5,6-dioxo- 1 ,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-methyl 5,6-dioxo- 1 ,4,S,6-tetrahydro-as-triazin-3-ylthio, pyridinium or pyridinium substituted by hydroxy-lower alkyl, for example hydroxymethyl, carboxy, carboxy-lower alkyl, for example carboxymethyl, halogen, for example chlorine or bromine, or by carbamoyl, for example 3- or 4-hydroxymethylpyridinium, 4carboxypyridinium, 3- or 4-carboxymethylpyridinium, 3- or 4-chloropyridinium, 3- or 4bromopyridinium or 3- or 4-carbamoylpyridinium, R3 represents hydrogen or methoxy, and R4 represents carboxy, and hydrates and pharmaceutically acceptable salts of such compounds.

The invention relates especially to the compounds of the formula I described in the Examples, their pharmaceutically acceptable salts, and the starting materials and intermediates described therein.

The invention relates more especially to the pharmaceutically acceptable salts of compounds of the formula I, or their enantiomers, listed in the Test Evaluation.

Manufacturing process Compounds of the formula I in which the carboxy groups are in free form or are esterified in physiologically cleavable form, hydrates and salts of such compounds that have a salt-forming group, are manufactured, for example, by a) in a compound of the formula

in which I, R1, R3 and R4 have the meanings given under formula I and the 7amino group is optionally protected by a group allowing acylation, acylating the amino group by reaction with a carboxylic acid of the formula

in which m and n and X, W and Y have the meanings given under formula I and the a-aminocarboxylic acid grouping H0OCCH(NH2)- and functional groups in the group Y are in protected form, or with a reactive functional acid derivative or a salt thereof, or b) in a compound of the formula

in which I, m, Y, R, and R4 have the meanings given under formula I and the a-amino group is optionally protected by a group allowing the acylation reaction and functional groups in the group Y are optionally in protected form, acylating the amino group by reaction with a reactive functional derivative of an acid of the formula

in which n, X and W have the meanings given under formula I and the a-aminocarboxylic acid grouping HOOC-CH(NH2)- is in protected form, or, if X-W together represent the group -CO-, alternatively with a corresponding free acid or with a salt thereof, or c) in a compound of the formula

in which n and X have the meanings given under formula I and the a-aminocarboxylic acid grouping HOOC-CH(NH2)- is in protected form, acylating the group -X-H by reaction with a reactive functional derivative of an acid of the formula

in which /, m, W, Y, R1, R3 and R4 have the meanings given under formula I and functional groups in the group Y are optionally in protected form, or d) isomerising a 2-cephem compound of the formula

in which m, n, X, W, Y, R1, R3 and R4 have the meanings given under formula I and the aaminocarboxylic acid grouping HOOC-CH(NH2)- and functional groups in the group Y are in protected form, to form the corresponding 3-cephem compound of the formula I and, if desired, converting a compound of the formula I obtainable according to the invention into a different compound of the formula I and/or, if desired, converting a compound of the formula I obtainable according to the invention in which / represents 0 into a compound of the formula I in which / represents 1 or 2, and/or converting a compound of the formula I in which / represents 1 or 2 into a compound of the formula I in which / represents 0, and/or converting functional groups present in protected form in a compound of the formula I into free functional-groups, and/or converting a resulting salt into the free compound or into a different salt, and/or converting a resulting free compound having a salt-forming group into a salt, and/or separating a resulting mixture of isomeric compounds of the formula I into the individual isomers.

Processes a), b) and c) (acylations) In starting materials of the formulae II and IV, the amino groups are optionally protected by groups that permit acylation. Such groups are, for example, organic silyl groups, and also ylidene groups, which, together with the amino group, form a Schiff's base. The mentioned organic silyl groups are, for example, those that are also capable of forming a protected carboxy group with a carboxy group R4. These are especially tri-lower alkylsilyl, especially trimethylsilyl. In the silylation for the protection of a 4-carboxy group in a starting material of the formula II or V, if an excess of the silylating agent is used, the amino group may likewise be silylated.The mentioned ylidene groups are especially 1-aryl-lower alkylidene groups, especially 1-arylmethylene groups, wherein aryl represents especially a carbocyclic, primarily a monocyclic, aryl radical, for example phenyl optionally substituted by lower alkyl, hydroxy, lower alkoxy and/or nitro.

The remaining functional groups present in the starting materials of the formulae Il-VIl may be protected, for example, by the protecting groups mentioned for the compounds of the formula II.

Preferably, the functional groups not participating in the acylation reaction, especially optionally present acylatable amino, hydroxy and mercapto groups, are correspondingly protected.

In compounds of the formulae Ill, IV, V, VI and VII, any amino group present may also be protected in ionic form, i.e. the starting material in question having such an amino group can be used in the form of an acid addition salt, preferably with a strong inorganic acid, such as a hydrohalic acid, for example hydrochloric acid, or sulphuric acid, or with an organic acid, for example p-toluenesulphonic acid.

If a free acid of the formula Ill, in which any functional groups apart from the carboxyl group participating in the reaction may be protected, or a free acid of the formula V in which X-W represents the group -CO-, is used for acylation, the reaction is usually carried out in the presence of suitable condensation agents, such as carbodiimides, for example N,N'-diethyl-, N,N'-dipropyl-, N,N'dicyclohexyl- or N-ethyl-N'-3-dimethylaminopropyl-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-l ,2-oxazolium 3'-sulphonate or 2-tert.-butyl-5-methyl-l ,2-oxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1 -ethoxycarbonyl-l 2-dihydroquinoline.

The condensation reaction is carried out preferably in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, for example methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, if desired or necessary while cooling or heating, for example within a temperature range of from approximately40 C to approximately + 1 000C, preferably from approximately20 C to approximately +500C and/or in an inert gas atmosphere, for example a nitrogen atmosphere.

A reactive, i.e. amide-forming, or ester-forming functional derivative of an acid of the formula Ill, V or VII in which any functional groups present apart from the carboxyl group participating in the reaction may be protected, is especially an anhydride of such an acid, including and preferably a mixed an hydride. Mixed anhydrides are, for example, those with inorganic acids, such as hydrohalic acids, i.e.

the corresponding acid halides, for example chlorides or bromides, and also those with hydrazoic acid, i.e. the corresponding acid azides, with a phosphorus-containing acid, for example phosphoric acid, diethylphosphoric acid or phosphorous acid, or with a sulphur-containing acid, for example sulphuric acid, or with hydrocyanic acid. Further mixed anhydrides are, for example, those formed with organic carboxylic acids, for example with lower alkanecarboxylic acids optionally substituted, for example, by halogen, such as fluorine or chlorine, for example pivalic acid or trichloroacetic acid, or with semiesters, especially lower alkyl semiesters of carbonic acid, such as the ethyl or isobutyl semiester of carbonic acid, or with organic, especially aliphatic or aromatic, sulphonic acids, for example p-toluenesulphonic acid.

Further derivatives of acids of the formulae Ill, V and VII in which any functional groups present apart from the carboxyl group participating in the reaction may be protected, that are suitable for reaction with the corresponding amino, hydroxy or mercapto groups are activated esters, for example esters with vinylogous alcohols, i.e. enols, such as vinylogous lower alkenols, or iminomethyl ester halides, for example dimethyliminomethyl ester chloride, manufactured from the carboxylic acid and, for example, dimethyl-( 1 -chloroethylidene)-iminium chloride of the formula [(CH3)2N&commat;;=(CI)CH3]CIs, which can in turn be obtained, for example, from N,N-dimethylacetamide and phosgene or-oxalyl chloride, or aryl esters, for example phenyl esters substituted by halogen, such as chlorine, and/or nitro, for example 4-nitrophenyl or 2,3-dinitrophenyl, or pentachlorophenyl ester, N-heteroaromatic esters, such as N-benztriazole esters, for example 1 -benztriazole ester, or N-diacylimino esters, such as Nsuccinylimino or N-phthalylimino ester.

The acylation with a reactive functional derivative of an acid of the formula Ill, V or VII, for example with a corresponding anhydride, especially an acid halide, is carried out preferably in the presence of an acid-binding agent, for example an organic base, such as an organic amine, for example a tertiary amine, such as tri-lower alkylamine, for example trimethylamine, triethylamine or ethyldiisopropylamine, or N,N-di-lower alkylaniline, for example N,N-dimethylaniline, or a cyclic tertiary amine, such as an N-lower alkylated morpholine, such as N-methylmorpholine, or a base of the pyridine type, for example pyridine, or an inorganic base, such as, for example, an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a 1,2-lower alkylene oxide, such as ethylene oxide or propylene oxide.

The above acylations are preferably carried out in an inert, preferably anhydrous, solvent or solvent mixture, for example in a carboxylic acid amine, such as a formamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, a cyclic ether, for example tetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or mixtures thereof, if necessary or desired at reduced or elevated temperature, for example in a temperature range of from approximately -400C to approximately +1000C, preferably from approximately --100C to approximately +500 C, and/or in an inert gas atmosphere, for example a nitrogen atomsphere.

The acylation of a compound of the formula II can also be effected by using a suitable derivative of the acid of the formula Ill in the presence of a suitable acylase. Such acylases are known and can be formed by a number of microorganisms, for example by acetobacter, such asAcetobacter aurantium, achromobacter, such as Achromobacter aeris, aeromonas, such asAeromonas hydrophila, or bacillus, such as Bacillus meqaterium 400.In such an enzymatic acylation, there are used as suitable derivatives especially amides, esters or thioesters, such as lower alkyl esters, for example methyl or ethyl esters, of the carboxylic acid of the formula III. Acylation of this kind is usually carried out in a nutrient medium containing the corresponding microorganism, in a filtrate of the culture broth or, optionally after isolation of the acylase, including after adsorption on a carrier, in an aqueous medium optionally containing a buffer, for example in a temperature range of from approximately 200C to approximately 400C, preferably at approximately 370C.

A reactive functional derivative of an acid of the formula III used in the acylation reaction may, if desired, be formed in situ. Thus, for example, a mixed anhydride can be obtained by reacting an acid of the formula ill or an acid of the formula V in which X-W represents the group -CO-, optionally having appropriately protected functional groups, or a suitable salt thereof, for example an ammonium salt, which is formed, for example, with an organic base, such as pyridine or 4-methylmorpholine, or a metal salt, for example an alkali metal salt, with a suitable acid derivative, for example a corresponding acid halide of an optionally substituted lower alkanecarboxylic acid, for example trichloroacetyl chloride, with a semiester of a carbonic acid semihalide, for example chloroformic acid ethyl ester or isobutyl ester, or with a halide of a di-lower alkyiphosphoric acid, for example diethylphosphorobromidate, which can be formed by reacting triethyl phosphite with bromine. The mixed anhydride so obtained can be used in the acylation reaction without isolation.

An acid chloride derived from an acid of the formula V in which X-W represents an --OO-CCO-, -S-CO or -NH-CO- grouping and in which the aminocarboxylic acid grouping HOOC- CH(NH2)- is in protected form can, for example, be formed in situ by treating an aminocarboxylic acid of the formula VI in which X represents oxygen, sulphur or the group -NH- and the grouping HOOC-CH(NH2)- is in protected form, with phosgene in the presence of a hydrochloric acid acceptor in an inert organic solvent or solvent mixture.The hydrochloric acid acceptors, solvents and reaction conditions are the same as those mentioned for the acylation of compounds of the formula II or IV; for example, the reaction can be carried out in the presence of pyridine in methylene chloride and toluene at approximately 0 to approximately 1 OOC.

In the same manner it is possible, for example in situ, to produce an acid chloride of an acid of the formula VII in which W represents the group -SO2NHCO- and the 4-carboxy group and functional groups present in the groups Y and R, are protected, from a correspondingly protected compound of the formula IV by treatment with chlorosulphonyl isocyanate.

Process d) (isomeration) In a 2-cephem starting material of the formula VIII, the optionally protected 4-carboxyl group is preferably in the a-configuration.

2-Cephem compounds of the formula VIII can be isomerised by treating with a weakly basic agent and isolating the corresponding 3-cephem compound. Suitable isomerising agents are, for example, organic, nitrogen-containing bases, especially tertiary heterocyclic bases of aromatic character, especially bases of the pyridine type, such as pyridine itself, and picolines, collidines or lutidines, and also quinoline, tertiary aromatic bases, for example those of the aniline type, such as N,Ndi-lower alkylanilines, for example N,N-dimethylaniline or N,N-diethylaniline, or tertiary aliphatic, azacycloalipharic or araliphatic bases, such as N,N,N-tri-lower alkylamines, for example N,N;;Ntrimethylamine or N,N-diisopropyl-N-ethylamine, N-lower alkylazacycloalkanes, for example Nmethylpiperidine, or N-phenyl-lower alkyl-N,N-di-lower alkylamines, for example N-benzyl-N,Ndimethylamine, and also mixtures of such basic agents, such as the mixture of a base of the pyridine type and an N,N,N-tri-lower alkylamine, for example pyridine and triethylamine. Furthermore, inorganic or organic salts of bases, especially of medium-strength to strong bases with weak acids, such as alkali metal or ammonium salts of lower alkane-carboxylic acids, for example sodium acetate, triethylammonium acetate or N-methylpiperidine acetate, and other analogous bases or mixtures of such basic agents can also be used.

Isomerisation of 2-cephem compounds of the formula VIII with basic agents is carried out preferably in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, for example chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, it being possible for the bases used as reactants which are liquid under the reaction conditions to serve, at the same time, as solvents, optionally while cooling or heating, preferably within a temperature range of from approximately30 C to approximately +1 000C, in an inert gas atmosphere, for example a nitrogen atmosphere, and/or in a closed vessel.

3-cephem compounds of the formula I obtainable in this manner can be separated from 2cephem starting materials which may still be present in a manner known per se, for example by adsorption chromatography and/or crystallisation.

The isomerisation of 2-cephem compounds of the formula Vlil to corresponding 3-cephem compounds is preferably carried out by oxidising these in the 1-position, optionally separating isomeric mixtures of the 1 -oxides formed and reducing the resulting 1 -oxides of the corresponding 3-cephem compounds.

Suitable oxidising agents for the oxidation in the 1-position of 2-cephem compounds of the formula IV are inorganic peracids that have a reduction potential of at least 1.5 volts and consist of non-metallic elements, organic peracids or mixtures consisting of hydrogen peroxide and acids, especially organic carboxylic acids, having a dissociation constant of at least 10-5. Suitable inorganic peracids are periodic acid and persulphuric acid. Organic peracids are corresponding percarboxylic and persulphonic acids which are added as such or may be formed in situ by using at least one equivalent of hydrogen peroxide and a carboxylic acid. In this case, it is expedient to use a large excess of the carboxylic acid if, for example, acetic acid is used as solvent.Suitable peracids are, for example, performic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid 3chloroperbenzoic acid, mono-perphthalic acid orp-toluenepersulphonic acid.

The oxidation can likewise be effected using hydrogen peroxide with catalytic amounts of an acid having a dissociation constant of at least 10-5, it being possible to use low concentrations, for example 12% and lower, or alternatively relatively large amounts of the acid. In this case, the effectiveness of the mixture depends chiefly on the strength of the acid. Suitable mixtures are, for example, those of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.

The above oxidation may be carried out in the presence of suitable catalysts. Thus, for example, the oxidation with percarboxylic acids can be catalysed by the presence of an acid having a dissociation constant of at least 10-5, the effectiveness of this acid being dependent on its strength. Acids suitable as catalysts are, for example, acetic acid, perchloric acid and trifluoroacetic acid. Usually, at least equimolar amounts of the oxidising agent, and preferably a slight excess of from approximately 10% to approximately 20%, are used, it being possible alternatively to use relatively large excesses, i.e. up to 10 times the amount or more of the oxidising agent.The oxidation is carried out under mild conditions, for example at temperatures of from approximately50 C to approximately + 1 000C, preferably from approximately --1 OOC to approximately +400 C.

The reduction of 1-oxides of 3-cephem compounds can be carried out in a manner known per se by treating with a reducing agent, if necessary in the presence of an activating agent. As reducing agents there come into consideration, for example: catalytically activated hydrogen, there being used noble metal catalysts that contain palladium, platinum or rhodium and which are optionally employed together with a suitable carrier, such as carbon or barium sulphate; reducing tin, iron, copper or manganese cations, which are used in the form of corresponding compounds or complexes of an inorganic or organic kind, for example in the form of tin(ll) chloride, fluoride, acetate or formate, iron(ll) chloride, sulphate, oxalate or succinate, copper(l) chloride, benzoate or oxide, or manganese(ll) chloride, sulphate, acetate or oxide, or in form of complexes, for example with ethylenediaminetetraacetic acid or nitrolotriacetic acid; reducing dithionite, iodide or iron(ll) cyanide anions, which are used in the form of corresponding inorganic or organic salts, such as alkali metal dithionite, iodide or iron(ll) cyanide, for example sodium or potassium dithionite, sodium or potassium iodide or sodium or potassium iron(Il) cyanide, or in the form of the corresponding acids, such as hydriodic acid; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, also esters, amides and halides of phosphonous, phosphinous or phosphorous acid, and also phosphorus-sulphur compounds corresponding to these phosphorus-oxygen compounds, in which organic radicals are especially aliphatic, aromatic or araliphatic radicals, for example optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, such as, for example, triphenylphosphine, tri-n-butylphosphine, diphenylphosphonous acid methyl ester, diphenylchlorophosphine, phenyidichlorophosphine, benzenephosphonous acid dimethyl ester, butanephosonous acid methyl ester, phosphoric acid triphenyl ester, phosphorous acid trimethyl ester, phosphorus trichloride, phosphorus tribromide, also phosphorous acid triphenylester-halogen adducts, for example chlorine or bromine adducts, in which the phenyl radicals are optionally substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, or halogen, for example chlorine, etc.; reducing halosilane compounds that have at least one hydrogen atom bonded to the silicon atom and which may contain, apart from halogen, such as chlorine, bromine or iodine, also organic radicals, such as aliphatic or aromatic groups, for example optionally substituted lower alkyl or phenyl, such as chlorosilane, bromosilane, di- or tri-chlorosilane, di- or tri-bromosilane, diphenylchlorosilane or dimethylchlorosilane, or also halosilane compounds in which all the hydrogen atoms are replaced by organic radicals, such as a tri-lower alkylhalosilane, for example tri-methylchlorosilane or trimethyliodosilane, or cyclic sulphur-containing silanes, such as 1,3dithia-2,4-disilacyclobutanes or 1,3,5-trithia-2 ,4,6-trisilacyclohexanes, of which the silicon atoms are substituted by hydrocarbon radicals, such as, especially, lower alkyl, for example 2,2,4,4-tetramethyl 1 ,3-dithia-2,4-disilacyclobutane or 2,2,4,4,6,6-hexamethyl- 1 ,3,5-trithia-2,4,6-trisilacyclohexane, etc.; reducing quaternary chloromethylene-iminium salts, especially chlorides or bromides, in which the iminium group is substituted by one bivalent or two monovalent organic radicals, such as optionally substituted lower alkyiene or lower alkyl, such as N-chloromethylene-N,N-diethyl-iminium chloride or N-chloromethylene-pyrrolidinium chloride; or complex metal hydrides, such as sodium borohydride, in the presence of suitable activating agents, such as cobalt(ll) chloride, and also borane dichloride.

As activating agents which are used with those of the above-mentioned reducing agents that do not themselves have the properties of Lewis acids, i.e. those which are used primarily with the dithionite, iodide or iron(ll) cyanide reducing agents and the trivalent phosphorus reducing agents that do not contain halogen, or are used in the catalytic reduction, there may be mentioned especially organic carboxylic and sulphonic acid halides, also sulphur, phosphorus or silicon halides having a second order hydrolysis constant which is the same as or greater than that of benzoyl chloride, for example phosgene, oxalyl chloride, acetyl chloride or bromide, chloroacetyl chloride, pivaloyl chloride, 4-methoxybenzoyl chloride, 4-cyanobenzoyl chloride, p-toluenesulphonyl chloride, methanesulphonyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenephosphonous acid dichloride, dimethylchlorosilane or trichlorosilane, also suitable acid anhydrides, such as trifluoroacetic acid anhydride, or cyclic sultones, such as ethanesultone, propanesultone, 13-butanesultone or 1 ,3-hexanesultone.

The reduction is carried out preferably in the presence of solvents or mixtures thereof, the choice of which is determined primarily by the solubility of the starting materials and the chosen reducing agent; thus, for example, lower alkanecarboxylic acids or esters thereof, such as acetic acid and ethyl acetate, in the case of catalytic reduction and, for example, optionally substituted, such as halogenated or nitrated, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, for example benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives, such as lower alkanecarboxylic acid esters or nitriles, for example ethyl acetate or acetonitrile, or amides of inorganic or organic acids, for example dimethylformamide or hexamethylphosphoramide, ethers, for example diethyl ether, tetrahydrofuran or dioxan, ketones, for example acetone, or suiphones, especially aliphatic sulphones, for example dimethylsulphone or tetramethylenesuiphone, etc., together with the chemical reducing agents, these solvents preferably containing no water. The reaction is usually carried out at temperatures of from approximately20 C to approximately 1000C, it being possible, when using very reactive activating agents, to carry out the reaction also at lower temperatures.

Subsequent operations In a resulting compound of the formula í, in a customary manner known per se functional groups that are not protected can be protected, or protecting groups can be exchanged for other protecting groups, for example by splitting off the protecting group present and introducing the desired other protecting group.

R1 conversions In a resulting compound of the formula I in which functional groups are optionally protected, in a manner known per se a group R, can be replaced by another radical R, or converted into another radical R1. Thus, for example, it is possible in a compound of the formula I in which Rr represents a group of the formula -CH2-Fl2 and R2 represents, for example, a radical replaceable by nucleophilic substituents, or in a salt thereof, to replace such a radical R2 by an etherified or esterified mercapto group R2 by treatment with a corresponding mercaptan compound or a thiocarboxylic acid compound.

A suitable radical replaceable by an etherified mercapto group is, for example, a hydroxy group esterified by a lower aliphatic carboxylic acid. Such esterified hydroxy groups are especially acetoxy and acetoacetoxy.

The reaction of such a compound of the formula I with a suitable mercaptan compound can be carried out under acidic, neutral or weakly basic conditions. In the case of acidic conditions the reaction is carried out in the presence of concentrated sulphuric acid, which is optionally diluted by an inorganic solvent, for example polyphosphoric acid. In the case of neutral or weakly basic conditions the reaction is carried out in the presence of water and optionally a water-miscible organic solvent.

The basic conditions can be established, for example, by the addition of an inorganic base, such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium, potassium or calcium hydroxide, carbonate or bicarbonate. There may be used as organic solvents, for example, water-miscible alcohols, for example lower alkanols, such as methanol or ethanol, ketones, for example lower alkanones, such as acetone, amides, for example lower alkanecarboxylic acid amides, such as dimethylformamide, or nitriles, for example lower alkanoic acid nitriles, such as acetonitrile, and the like.

Esterified hydroxy groups R2 in a compound of the formula I in which R, represents -CH2Fl2, R2 representing a hydroxy group esterified by the acyl radical of an optionally substituted semiamide of carbonic acid, can be introduced, for example, by reacting a corresponding compound of the formula I in which R2 represents free hydroxy (which can be liberated, for example, by splitting off the acetyl radical from an acetoxy group R2, for example by hydrolysis in a weakly basic medium, such as with an aqueous sodium hydroxide solution at a pH of 9-10, or by treating with a suitable esterase, such as a corresponding enzyme selected from Rhizobium tritolii, Rhizobium lupinii, Rhizobium japonicum or Bacillus subtilis, or with a suitable citrus esterase, for example from orange peel) with a suitable carbonic acid derivative, especially with an isocyanate or carbamic acid compound, such as a silyl isocyante, for example silyl tetraisocyanate, a sulphonyl isocyanate, for example chiorosulphonyl isocyanate, or a carbamic acid halide, for example carbamic acid chloride (which result in N unsubstituted 3-aminocarbonyloxymethyl compounds), or with an N-substituted isocyanate or with an N-mono- or N,N-di-substituted carbamic acid compound, such as a corresponding carbamic acid halide, for example carbamic acid chloride, the reaction usually being carried out in the presence of a solvent or diluent and, if necessary, while cooling or heating, in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.

Also, a compound of the formula I in which R, represents a CH2-Fl2 group, R2 representing, for example, the above-defined radical replaceable by nucleophilic substitution, can be reacted with a tertiary organic base, especially an optionally substituted pyridine, under neutral or weakly acidic conditions, preferably at a pH value of approximately 6.5, in the presence of water and optionally in a water-miscible organic solvent, to form compounds of the formula I in which R, represents a radical of the formula -CH2-Fl2 and R2 represents a quaternary ammonium group. The weakly acidic conditions can be established by the addition of a suitable organic or inorganic acid, for example acetic acid, hydrochloric acid, phosphoric acid or, alternatively, sulphuric acid. There may be used as organic solvents, for example, the afore-mentioned water-miscible solvents. To increase the yield certain salts may be added to the reaction mixture, for example alkali metal salts, such as sodium and, especially, potassium salts, of inorganic acids, such as hydrohalic acids, for example hydrochloric acid and especially hydriodic acid, as well as thiocyanic acid, or of organic acids, such as lower alkanecarboxylic acids, for example acetic acid. Representatives of such salts are, for example, sodium iodide, potassium iodide and potassium thiocyanate.Salts of suitable anion exchangers can also be used for this purpose, for example liquid ion exchangers in salt form, such as, for example, Amberlite LA-i (liquid secondary amines with a molecular weight of 351-393; oil-soluble and water-insoluble; meq/g=2.5--2.7, for example in acetate form), with acids, for example acetic acid.

Quaternary ammonium groups R2 can advantageously be produced using an intermediate of the formula I in which R2 represents a substituted, but especially an aromatic substituted, carbonylthio group and, more especially, a benzoylthio group. Such an intermediate, which can be obtained, for example, by reacting a compound of the formula I in which R2 in the radical R, represents an esterified hydroxy group, especially a lower alkanoyloxy group, for example acetoxy, with a suitable salt, such as an alkali metal salt, for example a sodium salt, of a thiocarboxylic acid, such as an aromatic thiocarboxylic acid, for example thiobenzoic acid, is reacted with a tertiary amine, especially a tertiary heterocyclic base, such as an optionally substituted pyridine, to yield the quaternary ammonium compound.The reaction is usually carried out in the presence of a suitable desulphurising agent, especially a mercury salt, for example mercury(ll) perchlorate, and of a suitable solvent or diluent or a mixture thereof, is necessary while cooling or heating, in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.

Introduction of 7a-methoxy In a resulting intermediate of the formula I or IV in which R3 represents hydrogen and all functional groups are present in protected form, the 7a-methoxy group R3 can be introduced in a manner known per se, for example by treating the mentioned intermediate in succession in an anionforming agent, a N-halogenating agent and methanol.

A suitable anion-forming agent is especially a metal organic base, especially an alkali metal, more especially a lithium, organic base. Such compounds are especially corresponding alcoholates, such as suitable lithium lower alkanolates, especially lithium methanolate, or corresponding metal hydrocarbon bases, such as lithium lower alkanes and lithium phenyl. The reaction with the anion-forming metal organic base is carried out usually while cooling, for example at from approximately OOC to approximately --800C, and in the presence of a suitable solvent or diluent, for example an ether, such as tetrahydrofuran, when using lithium methanolate also in the presence of methanol and, if desired, in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.

There is usually used as N-halogenating agent a sterically hindered organic hypohalite, especially hypochlorite, and more especially a corresponding aliphatic hypohalite, for example hypochlorite, such as a tert.-lower alkyl hypohalite, for example hypochlorite. Primarily the tert.-butyl hypochlorite is used, and this is reacted with the non-isolated product of the anionisation reaction.

The N-halogenated intermediate compound is converted under the reaction conditions and without being isolated, in the presence of an excess of anion-forming base, especially lithium methanolate, into a 7-acylimino cephem compound, and this is converted into a 7a-methoxy-cephen compound by the addition of methanol.If necessary, the elements of the hydrohalic acid, especially hydrochloric acid, must be split off from the N-halogenated intermediate; this is carried out by the addition of a base that splits off hydrogen halide, such as a suitable alkali metal lower alkanolate, for example lithium tert.-butanolate, the reaction usually taking place under the conditions of the anionand N-halogen compound-forming reaction, it being possible to carry out the reaction in the presence of methanol and, instead of the acylimino compound, obtain the 7a-methoxy-cephem compound directly.The starting material is usually a compound of the formula I in which functional groups are in protected form, and this is reacted with an excess of anion-forming agent, for example lithium methanolate or phenyl lithium, in the presence of methanol, then treated with the N-halogenating agent, for example tert.- butyl hypochlorite, and thus the desired compound of the formula I in which functional groups are protected is obtained directly. It is also possible to add the methanol subsequently, it being possible to carry out the dehydrohalogenation and the addition of methanol at slightly higher temperatures than the anion- and N-halogen compound-forming reactions, for example at from approximately OOC to approximately 200 C, if necessary in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.

Conversion to the 1-oxide, 1-dioxide and 1-sulphide A compound of the formula I in which the index / is 0 can be converted by the oxidising agents described in process d) into the corresponding 1-oxide in which index I is 1.

1-oxides of the formula I that are in the p-configuration can be produced in a manner known per se according to the process known from German Offenlegungsschrift 30 1 3 996, that is to say, by.

oxidation of a 1 -sulphide of the formula I or VIII (1=0) with a percarboxylic acid, for example peracetic acid or m-chloroperbenzoic acid.

1-oxides of the formula I that are in the a- or p- configuration can be produced in a manner known per se according to the process known from German Offenlegungsschrift 30 1 3 996, that is to say, by oxidation of a 1 -sulphide of the formula II in which the 7amino group is protected, for example, by ylidene groups which together with the amino group form a Schiff's base, with a percarboxylic acid, for example m-chloroperbenzoic acid, chromatographic separation of the resulting - and ,B-1-oxides of the formula II and subsequent acylation with a carboxylic acid of the formula Ill.

A compound of the formula I in which the index / is O or 1 can be converted into the corresponding 1-dioxide in which / is 2 by reaction with agents that convert sulphide or sulphoxide groups into sulphone groups.

Such agents are especially hydrogen peroxide, organic peracids, especially aliphatic percarboxylic acids, for example peracetic acid, perbenzoic acid, chloroperbenzoic acid, for example mchloroperbenzoic acid, or monoperphthalic acid, oxidising inorganic acids or their salts, for example nitric acid, chromic acid, potassium permanganate, or alkali metal hypochlorite, for example sodium hypochlorite, or anodic oxidation may be used.The oxidation is carried out preferably in a suitable inert solvent, for example a halogenated hydrocarbon, for example methylene chloride, chloroform or carbon tetrachloride, an alcohol, for example methanol or ethanol, a ketone, for example acetone, an ether, for example diethyl ether, dioxan or tetrahydrofuran, an amide, for example dimethylformamide, a sulphone, for example dimethyl sulphone, a liquid organic carboxylic acid, for example acetic acid, or in water or a mixture of these solvents, especially an aqueous mixture, for example aqueous acetic acid, at room temperature, or while cooling or gently heating, i.e. at from approximately 200 to approximately +900, preferably at from approximately +180 to approximately +300.The oxidation can also be carried out in stages by first of all oxidising at low temperature, that is to say at from approximately --200 to approximately 00, to the sulphoxide stage, which is optionally isolated, then, in a second stage, oxidising the sulphoxide to the sulphone, that is the 1,1-dioxide of the formula (I), preferably at elevated temperature, for instance at room temperature.

For working up, excess oxidising agent that may still be present can be eliminated by reduction, especially by treatment with a reducing agent, such as a thiosulphate, for example, sodium thiosulphate.

A 1-oxide of the formula I in which the index I is 1, and a 1 -dioxide in which the index / is 2, can be converted by the reducing agents described in process d) into the corresponding 1 -sulphide in which the index I is 0.

The splitting off of protecting groups In a resulting compound of the formula I in which one or more functional groups are protected, these, for example, protected carboxyl, amino, hydroxy and/or sulpho-groups, may be liberated in a manner known per se, optionally in stages or simultaneously, by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis or chemical reduction.

A protected carboxyl group is liberated in a manner known per se and, depending on the nature of the protecting groups, by various methods, but preferably by means of solvolysis or reduction. Thus, tert.-lower alkoxycarbonyl, or lower alkoxycarbonyl substituted in the 2-position by an organic silyl group or in the 1-position by lower akoxy or lower alkylthio, or optionally substituted diphenylmethoxycarbonyl can be converted into free carboxyl, for example, by treating with a suitable acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol, anisole or ethylenethioglycol. Optionally substituted benzyloxycarbonyl can be liberated, for example, by means of hydrogenolysis, i.e. by treating with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst.Furthermore, suitably substituted benzyloxy-carbonyl, such as 4-nitrobenzyloxycarbonyl, can be converted into free carboxyl also by means of chemical reduction, for example by treating with an alkali metal dithionite, for example sodium dithionite, or with a reducing metal, for example zinc, or a reducing metal sait, such as a chromium(ll) salt, for example chromium(ll) chloride, usually in the presence of a hydrogen-yielding agent that, together with the metal, is capable of producing nascent hydrogen, such as an acid, especially a suitable carboxylic acid, such as a lower alkanecarboxylic acid optionally substituted, for example, by hydroxy, for example acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or of an alcohol or thiol, water preferably being added. By treating with a reducing metal or metal salt, as described above, it is also possible to convert 2-halo-lower alkoxy-carbonyl (optionally after converting a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl into free carboxyl, it being possible to split aroylmethoxycarbonyl also by treating with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide.Substituted 2-siíylethoxywarbonyl can also be converted into free carboxyl by treating with a salt of hydrofluoric acid yielding the fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride, in the presence of a macrocyclic polyether ("Crown ether"), or with a fluoride of an organic quaternary base, such as tetra-iower alkylammonium fluoride or tri-lower alkylarylammonium fluoride, for example tetraethylammonium fluoride or tertrabutylammonium fluoride, in the presence of an aprotic polar solvent, such as dimethyl sulphoxide or N,Ndimethylacetamide. Carboxyl esterified by an organic silyl group, such as tri-lower alkylsilyl, for example trimethylsilyl, can be liberated in the customary manner by solvolysis, for example by treating with water, an alcohol or an acid.

A protected amino group is liberated in a manner known perse and, depending on the nature of the protecting groups, by various methods, but preferably by solvolysis or reduction. 2-halo-lower alkoxycarbonylamino, optionally after converting a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group, aroy!methoxycarbonylamino or 4nitrobenzyloxycarbonylamino can be split, for example by treating with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid.

Aroylmethoxycarbonylamino can also be split by treating with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treating with an alkali metal dithionite, for example sodium dithionite. Optionally substituted diphenylmethoxycarbonylamino, tert.lower alkoxycarbonylamino or 2-tri-substituted silylethoxycarbonylamino can be liberated by treating with a suitable acid, for example formic acid or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino can be liberated, for example, by hydrogenolysis, i.e. by treating with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, optionally substituted triarylmethylamino, formylamino or 2-acyl-lower alk-1 -enylamino can be liberated, for example, by treating with an acid, such as a mineral acid, for example hydrochloric acid, or an organic acid, for example formic acid, acetic acid or trifluoroacetic acid, optionally in the presence of water, and an amino group protected by an organic silyl group can be liberated, for example, by hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl, for example 2-chloroacetyl, can be liberated by treating with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate, of thiourea and by subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting condensation product.An amino group protected by 2-substituted silylethoxycarbonyl can also be converted into the free amino group by treating with a salt of hydrofluoric acid yielding fluoride anions as indicated above in connection with the liberation of a correspondingly protected carboxyl group. A phosphoramido, phosphonamido or phosphinamido group can be converted into the free amino group, for example by treating with a phosphorus-containing acid, such as a phosphoric, phosphonic or phosphinic acid, for example orthophosphoric acid or polyphosphoric acid, an acid ester thereof, for example monomethyl, monoethyl, dimethyl or diethyl phosphate, or monomethylphosphonic acid, or an anhydride thereof, such as phosphorus pentoxide.

An amino protected in the form of an azido group is converted into the free amino group, for example by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel, or alternatively by treating with zinc in the presence of an acid, such as acetic acid. The catalytic hydrogenation is carried out preferably in an inert solvent, such as a halogenated hydrocarbon, for example methylene chloride, or alternatively in water or a mixture of water and an organic solvent, such as an alcohol or dioxan, at approximately 200C to 250 C, or alternatively while cooling or heating.

A hydroxy group protected by a suitable acyl group, an organic silyl or stannyl group or by optionally substituted 1-phenyl-íower alkyl is liberated in the same manner as a correspondingly protected amino group. A hydroxy group protected by 2,2-dichioroacetyl is liberated, for example by basic hydrolysis, while a hydroxy group etherified by tert.lower alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is liberated by acidolysis, for example by treating with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid.

A protected, especially esterified, sulpho group is liberated analogously to a protected carboxyl group.

The splitting reactions described are carried out under conditions known perse, if necessary while cooling or heating, in a closed vessel and/or in an inert gas atmosphere, for example a nitrogen atmosphere.

Preferably, when several protected functional groups are present, the protecting groups are so selected that more than one such group can be split off simultaneously, for example by acidolysis, such as by treating with trifluoroacetic acid or formic acid, or by reduction, such as by treating with zinc and acetic acid, or with hydrogen and a hydrogenation catalyst, such as a palladium-on-carbon catalyst.

Esterification of a free carboxyl group The conversion of a free carboxyl group in a compound of the formula (I) into esterified carboxyl, especially into an esterified carboxyl group that can be split under physiological conditions, is effected according to esterification methods known perse, for example by reacting a compound of the formula (I) in which other functional groups present are optionally in protected form, or a reactive functional carboxy derivative, including a salt, thereof, with a corresponding alcohol or a reactive functional derivative thereof.

The esterification of free carboxyl with the desired alcohol is carried out in the presence of a suitable condensation agent. Customary condensation agents are, for example, carbodiimides, for example N,N'-diethyl-, N,N'-dipropyl-, N,N'-dicyclohexyl- or N-ethyl-N'-(3-dimethylaminoprnpyl)- carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1 ,2-oxazolium-3'-sulphonate and 2-tert.-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1 -ethoxycarbonyl 1 2-dihydroquinoline. The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, for example methylene chlorine, dimethylformamide, acetonitrile or tetrahydrofuran and, if necessary, while cooling or heating and/or in an inert gas atmosphere.

Suitable reactive functional derivatives of the carboxyl compounds of the formula I to be esterified are, for example, anhydrides, especially mixed anhydrides, and activated esters.

Mixed anhydrides are, for example, those with inorganic acids, such as hydrohalic acids, i.e. the corresponding acid halides, for example chlorides or bromides, also hydrazoic acid, i.e. the corresponding acid azides, as well as phosphorus-containing acids, for example phosphoric acid, diethylphosphoric acid or phosphorous acid, or sulphur-containing acids, for example sulphuric acid, or hydrocyanic acid. Further mixed anhydrides are, for example, those with organic carboxylic acids, such as with lower alkanecarboxylic acids optionally substituted, for example by halogen, such as fluorine or chlorine, for example pivalic acid or trichloroacetic acid, or with semiesters, especially lower alkyl semiesters of carbonic acid, such as ethyl or isobutyl semiesters of carbonic acid, or with organic, especially aliphatic or aromatic, sulphonic acids, for example p-toluenesulphonic acid.

Activated esters suitable for reaction with the alcohol are, for example, esters with vinylogous alcohols (i.e. enols), such as vinylogous lower alkenols, or iminomethyl ester halides, such as dimethyliminomethyl ester chloride, manufactured from carboxylic acid and dimethylchloromethylidene-iminium chloride of the formula [(CH3)2N=NHCIjCl0-, or aryl esters, such as pentachlorophenyl, 4-nitrophenyl or 2,3-dinitrophenyl esters, heteroaromatic esters, such as benztriazole esters, for example 1 -benztriazole ester, or diacylimino esters, such as succinylimino or phthalylimino ester.

The acylation with such an acid derivative, such as an anhydride, especially with an acid halide, is preferably carried out in the presence of an acid-binding agent, for example an organic base, such as an organic amine, for example a tertiary amine, such as a tri-lower alkylamine, for example trimethylamine, triethylamine or ethyldiisopropylamine, or an N,N-di-lower alkylaniiine, for example N,N-dimethyl-aniline, or a cyclic tertiary amine, such as a N-lower alkylated morpholine, such as N methylmorpholine, or a base of the pyridine type, for example pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2alkylene oxide, such as ethylene oxide or propylene oxide.

A reactive functional derivative of the esterifying alcohol is especially a corresponding ester, preferably with a strong inorganic or organic acid, and is especially a corresponding halide, for example chloride, bromide or iodide, or a corresponding lower alkylsulphonyloxy or arylsulphonyloxy compound, such as methylsulphonyloxy or 4-methylphenylsulphonyloxy.

Such a reactive ester of an alcohol can be reacted with the free carboxyl compound of the formula i or with a salt, such as an alkali metal or ammonium salt, thereof, the reaction preferably being carried out in the presence of an acid-binding agent when using the free acid.

The above esterification reactions are carried out in an inert, usually anhydrous, solvent or solvent mixture, for example in a carboxylic acid amide, such as a formamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, a cyclic ether, for example tetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or mixtures thereof, if necessary while cooling or heating, for example within a temperature range of from approximately -400C to approximately +1 000C, preferably at from approximately-I 00C to approximately +400C and/or in an inert gas atmosphere, for example a nitrogen atmosphere.

Furthermore, the acid derivative may, if desired, be formed in situ. For example, a mixed anhydride is obtained by treating the carboxylic acid compound having appropriately protected functional groups, or a suitable salt thereof, such as an ammonium salt, for example with an organic amine, such as pyridine or 4-methylmorpholine, or a metal salt, for example an alkali metal salt, with a suitable acid derivative, such as the corresponding acid halide of an optionally substituted lower alkanecarboxylic acid, for example trichloroacetyl chloride, with a semiester of a carbonic acid semihalide, for example chloroformic acid ethyl ester or isobutyl ester, or with a halide of a di-lower alkylphosphoric acid, for example diethyl phosphorobromidate, and the mixed anhydride so obtained is used without isolation.

Salt formation Salts of compounds of the formula I can be manufactured in a manner known per se. Thus, salts of compounds of the formula I can be formed, for example, by reaction of the acid groups with metal compounds, such as-alkali metal salts of suitable carboxylic acids, for example the sodium salt of aethylcaproic acid, or sodium bicarbonate, ar with ammonia or a suitable organic amine, preferably stoichiometric quantities or only a small excess of the salt-forming agent being used. Acid addition salts of compounds of the formula I are obtained in the customary manner, for example by treating with an acid or a suitable anion exchange reagent. Internal salts of compounds of the formula I can be formed, for example, by neutralising salts, such as acid addition salts, to the isoelectric point, for example with weak bases, or by treating with liquid ion exchangers.

Salts can be converted in the customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treating with suitable acids, and acid addition salts can be converted, for example, by treating with a suitable basic agent.

In all of the reactions mentioned hereinbefore that are carried out under basic conditions, all or some 3-cephem compounds can be isomerised to 2-cephem compounds. A resulting 2-cephem compound or a mixture of a 2- and a 3-cephem compound can be isomerised in a manner known per se to the desired 3-cephem compound.

Mixtures of isomers can be separated into the individual isomers in a manner known per se, for example by fractional crystallisation, chromatography, etc.

The process also includes those embodiments according to which compounds formed as intermediates are used as starting materials and the remaining process steps are carried out with these, or the process is discontinued at any stage; furthermore, starting materials may be used in the form of derivatives or formed during the reaction.

Preferably, the starting materials and the reaction conditions are so chosen that the compounds described above as being especially preferred are obtained.

Pharmaceutical preparations The pharmacologically acceptable compounds of the formula I, their hydrates or salts, can be used for the manufacture of pharmaceutical preparations.

Pharmaceutical preparations contain an effective amount of the pure active ingredient of the formula I alone or an effective amount of the active ingredient of the formula I in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are preferably suitable for parenteral administration.

Preferably, the active ingredients of the formula I of the present invention are used in the form of injectable, for example intravenously administrable, preparations or in the form of infusion solutions.

Such solutions are preferably isotonic aqueous solutions or suspensions which can be produced before use, for example from lyophilised preparations that contain only the active ingredient or the active ingredient together with a carrier, for example mannitol. The pharmaceutical preparations are preferably sterilised and may contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The pharmaceutical preparations in question which, if desired, may contain other pharmacologically valuable substances, contain from approximately 0.1% to 100%, especially from approximately 1% to approximately 50%, and in the case of lyophilisates up to 100%, of the active ingredient.

The pharmaceutical preparations are produced in a manner known per se, for example by means of conventional dissolving or lyophilising processes.

Use Compounds of the formula I, their hydrates or pharmaceutically acceptable salts can be used as antibiotically active agents in the form of pharmaceutical preparations in a method for the therapeutic treatment of the human or animal body, for example for the treatment of infections that are caused by gram-positive or gram-negative bacteria and cocci, for example by enterobacteria, for example Escherichia coli, Klebsiella pneumoniae or Proteus spy,.

Depending on the nature of the infection and the condition of the infected organism, daily doses of from approximately 0.5 g to approximately 5 g are used s.c., i.v. or i.m. for the treatment of warm biooded animals weighing approximately 70 kg.

Starting materials The starting materials used in the process for the manufacture of compounds of the present invention are either known or, if novel, can be produced in a manner known per se.

Starting materials of the formula II and corresponding compounds having protected functional groups are known or can be produced in a manner known per se.

Compounds of the formula Ill in which the index n and the symbols X, W and Y have the meanings given under formula I and the a-aminocarboxylic acid grouping HOOC-CH(NH2)- and functional groups which may be present in the group r are optionally in protected form, are produced, for example, by acylating a compound of the formula V, in which n, X and W have the meanings given under formula I and the a-aminocarboxylic acid grouping HOOC-CH(NH2)- is in protected form, or, when X-W together represent the group -CO-, alternatively a free acid or a reactive functional acid derivative or a salt thereof, with an acid of the formula

in which m and Y have the meanings given for formula I, and in which the amino group is optionally protected by a group allowing acylation and functional groups present in the group Y are protected and the carboxyl group is intermediately protected, and, if desired, converting a resulting compound of the formula Ill into a different compound of the formula Ill having correspondingly protected functional groups.

Protecting groups that allow the acylation reaction, and the protecting groups of the a- aminocarboxylic acid grouping and of functional groups present in the group Y are the same protecting groups as those mentioned for the compounds of the formulae I, II, IV, V, VI, VII and VEIL.

For the intermediate protection of the carboxyl group in a compound of the formula IX it is likewise possible in principle to use the carboxyl-protecting groups already mentioned, but the carboxyl-protecting groups used for intermediate protection in the acylation in question must be different in the manner in which they can be split off, from the other protecting groups which are necessarily to remain present in the compounds of the formula III, so that they can be split off selectively after the acylation reaction.If, for example, a protecting group that can be split off by hydrogenolysis is used for the intermediate protection of the carboxyl group, such as one of the mentioned optionally substituted benzyl groups, for example the benzyl orp-nitrobenzyl group, then it must not be possible for the other protecting groups to be split off by hydrogenolysis; those may then, for example, by the mentioned tert-lower aikyl groups, such as tert-butyl, or tert-lower alkoxycarbonyl groups, such as tert.-butoxycarbonyl, which can be split off only by acidolysis.

The acylation can otherwise be carried out analogously to that of compounds of the formula IV with an acid of the formula V, or an appropriately protected and reactive functional derivative thereof.

In a resulting compound of the formula Ill having appropriately protected functional groups, a protecting group can be split off, optionally selectively, or a functional group that may have been freed during the acylation reaction can be protected. The compounds of the formula IV, V, VI, and VII are known, and corresponding compounds having protected functional groups are known or can be produced in a manner known per se.

2-cephem starting compounds of the formula Vlil are novel. They can be produced analogously to the acylation and condensation processes a) to d) starting from the 2-cephem compounds of the formula

which are known or can be produced in a manner known per se. Furthermore, they may be formed as by-products in processes a) to d), especially if basic conditions are employed.

The following Examples serve to illustrate the invention; temperatures are given in degrees Centrigrade. The wave lengths of the UV spectra are given in nanometers (nm).

The following abbreviations are used in the Examples: BOC: tert.-butoxycarbonyl.

mp: melting point.

TLC: thin layer chromatogram, on ready-made silica gel plates SL 254 produced by Messrs.

Antec, Birsfelden, Switzerland.

Rf96: Rf value in the solvent system sec.-butanol/glacial acetic acid/water 67:10:23.

Example 1 1 a) 58.26 g of 3-acetoxymethyl-7,B-(2-aminoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl esterp-toluenesulphonic acid salt are stirred for 1 hour at 0 in 750 ml of tetrahydrofuran with 16.11 ml of pyridine and 67 g of (2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonyl chloride. The mixture is taken up in ethyl acetate and washed in succession with 1 N aqueous hydrochloric acid, saturated aqueous NaCI solution, saturated aqueous NaHCO3 solution and again with NaCI solution until neutral. After drying over sodium sulphate and concentration by evaporation, the resulting crude product is chromatographed over 2000 g of silica gel (eluant:toluene/ethyl acetate (1 :1); 1000 ml fractions).After combining the fractions containing the product,3-acetoxymethyl-7p-[2-((2 Fl)-2-BOC-amino-2-diphenylmethoxycarbonyl- ethoxyca rbonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[aj20'-+21 a+1 (0.90% in CHCI3); IR: 3390, 1785, 1740--1690 (broad), 1510(shoulder), 1495 cm-l (CH2CI2); UV: 258 (7800), 263 (7800; EtOH).

1 b) To a solution of 45 g of 3-acetoxymethyl-7,B-[2-((2R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonylamino)-acetamido]-3-cepehem-4-carboxylic acid diphenylmethyl ester in 4500 ml of tetrahydrofuran, cooled to 750 under a nitrogen atmosphere, there is added dropwise, while stirring vigorously, in the course of 1 minute, a pre-cooled solution of 1.5 g of lithium in 270 ml of methanol. Stirring is then continued for 2 minutes and, at -750, 3.33 ml of tert-butyl hypochlorite are added, stirring is carried out for 1 5 minutes, another 3.33 ml of tert-butyl hypochlorite are added, stirring is carried out for 1 5 minutes and 1.86 ml of tert-butyl hypochlorite are added.The mixture is then stirred for another 15 minutes at -750, then, while stirring, 68.4 ml of acetic acid and a solution of 19.8 g of sodium thiosulphate in 30 ml of water are added dropwise in succession. The mixture is allowed to warm to room temperature, is concentrated in vacuo to approximately 1 litre, taken up in ethyl acetate and washed in succession with water, saturated aqueous NaHCO3 solution and with saturated aqueous NaCI solution until neutral. The crude product obtained after drying over sodium sulphate and concentration by evaporation is chromatographed over 2000 g of silica gel (eluant: toluene/ethyl acetate (2:1); 1000 ml fractions).By combining the fractions containing the product there is obtained, after re-precipitation from CH2Cl2/diethyl ether/hexane, 3 acetoxymethyl-7-methoxy-7,B-[2-((2R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonyliamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester.

[CE]2D =+49 +1 (0.87% in CHCl3); IR: 3380, 1782, 1740-1 690 (broad), 1495 cm- (CH2CI2); UV: 251(4700), 258 (4800), 264 (4950), 268 (4800; EtOH).

1c) 0.9 g of of 3-acetoxymethyl-7ss-[2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-acetamide]-3-cephem-4-carboxylic acid diphenylmethyl ester are dissolved at room temperature in a mixture of 1.95 ml of CH2CI2 and 0.713 ml of anisole. 9.3 ml of trifluoroacetic acid cooled to 0 are added to the solution and the mixture is stirred, without cooling, for 15 minutes. After the addition of 120 ml of hexane/ether (2:1), the mixture is stirred for 5 minutes, and the precipitate is filtered with suction and washed with 100 ml of hexane/ether (2:1) mixture. The filter residue is dissolved in 70 ml of methanol, 70 ml of water are added, and the mixture is adjusted to pH 7 by adding 1 N aqueous sodium hydroxide solution and extracted with ethyl acetate.The organic phase is washed three times with water, and all the aqueous phases are combined and concentrated in vacuo to approximately 10 ml. By adding approximately 300 ml of ethanol a white precipitate is obtained which is filtered with suction, washed twice with ethanol and twice with ether and dried in vacuo. The hydrate of the sodium salt of 3-acetoxymethyl-7ss-[2-((2R)-2-amino-2-carboxyethoxycarbonylamino)- acetamido]-3-cephem-4-carboxylic acid is obtained.

Decomposition from 1 500; [α]D20 =+100 #1 (0.76% in H2O); IR: 3600-2400 (broad), 1776, 1732, 1650 (shoulder), 1610, 1557, 1540 cm~1 (Nujol); UV: 259 (6800; EtOH).

Id) Analogously to Example 1 c), 8.83 g of 3-acetoxymethyl-7α-methoxy-7ss-[2-((2R)-2-BOC- a mino-2-diphenyl methoxycarbonylethoxycarbonylamino)-acetamide]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 18.5 ml of CH2CI2 and 6.77 ml of anisole with 88.3 ml of trifluoroacetic acid and worked up. The hydrate of the sodium salt of 3-acetoxymethyl-7a-methoxy-7,3- [2-((2R)-2-a mino-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid is obtained.

Decomposition from 1 550; [α]D20 =+153 #1 (0.74% in H2O); IR: 3600--2400 (broad), 1777, 1735, 17l0(shoulder), 1612(loroad), 1538(broad) cm-l (Nujol); UV: 240 (6400), 264 (7800; EtOH).

1 e) 1.6 g of the sodium salt of 3-acetoxymethyl-7a-methoxy-7p-[2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid and 0.93 g of the sodium salt of 1-methyl- 5-mercapto-1 H-tetrazole are suspended in 8 ml of water and brought into solution at pH 6.8 by adding 1 N aqueous sodium hydroxide solution. The solution is then stirred under nitrogen for 4 hours at 650, cooled and introduced into 800 ml of ethanol. The resulting precipitate is filtered with suction, dissolved in a little water and chromatographed over 150 g of silylated silica gel (Antec Opti Up C,2) (eluant: water; fraction size 30 ml). The fractions containing the product are combined, concentrated to a volume of approximately 10 ml and introduced into 400 ml of ethanol.The precipitated product is filtered off, washed twice with ethanol and twice with diethyl ether and dried.

The hydrate of the sodium salt of 3-(1 -methyl-1 H-tetrazol-5-ylthiomethyl)-7 a-methoxy-7P-[2-((2 R)-2- amino-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid is obtained.

Decomposition from 1 500; [α]D20 =+81 #1 (0.81% in H20); IR: 3600-2400 (broad), 1770, 1730, 1692, 1616 (broad), 1532 cm-l (Nujol); UV: 238 (7400), 270 (9200; EtOH).

lfl As described in Example 1 e), 1.5 g of the sodium salt of 3-acetoxymethyl-7a-methoxy-7P-[2- ((2R)-2-amino-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid and 1.0 g of 1 -carboxymethyl-5-mercapto-1 H-tetrazole are reacted in 8 ml of water, worked up and chromatographed. The hydrate of the disodium salt of 3-( 1 -carboxymethyl-1 H-tetrazol-5 ylthiomethyl)-7α-methoxy-7ss-[2-((2R)-2-amino-2-carbpxyethoxycarbonylamino)-acetamido]-3- cephem-4-carboxylic acid is obtained.

Decomposition from 1 600; [α]D20 =+71 #1 (0.58% in H20); R:3600-2400 (broad), 1770, 1720, 1690, 1627, 1535 cm- (Nujol); UV: 233 (8860), 268 (8800).

1 g) As described in Example 1 e), 1.5 g of the sodium salt of 3-acetoxymethyl-7α-methoxy-7ss-[2- ((2R)-2-amino-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid and 1.09 g of 1 -dimethylaminoethyl-5-mercapto-1 H-tetrazole are reacted in 8 ml of water, worked up and chromatographed. The sodium salt of 3-[1-(2-dimethylaminoethyl)-1 H-tetrazol-5-ylthiomethyl]-7α- methoxy-7p-[2-((2R)-2-a mino-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1450; [α]D20 =+86 #1 (0.71% in H20); IR: 3600-2400 (broad), 1770, 1725, 1695, 1622 (broad), 1532 cm- (Nujol); UV: 240 (7480), (8200; H20).

1 h) As described in Example 1 e), 2.0 g of the sodium salt of 3-acetoxymethyl-7α-methoxy-7ss-[2- ((2R)-2-amino-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid and 2.0 g of 1 -sulphomethyl-5-mercapto-1 H-tetrazole are reacted in 12 ml of water, worked up and chromatographed. The disodium salt of 3-(1 -sulphomethyl-1 H-tetrazol-5-ylthiomethyl)-7α-methoxy- 7ss-[2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carbocylic acid is obtained in the form of the hydrate.

Decomposition from 1650; [aj200'=+640*1 0 (0.73% in H20); IR: 3600-2400 (broad), 1 770, 1 722-1690 (broad), 1 632, 1 533 cm- (Nujol); UV: 240 (7640), 268 (8200; H20).

li) 1.5 g of the sodium salt of 3-acetoxymethyl-7a-methoxy-7,B-[2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid, 0.523 g of isonicotinamide, 4.74 g of sodium iodide and 0.516 g of trichloroacetic acid in 3.15 ml of water are heated at 700 for 11/2 hours. The mixture is then cooled and introduced into 800 ml of ethanol. The resulting precipitate is filtered off, washed with ether and dried. It is then dissolved in a little water and the aqueous phase is extracted in succession with 175 ml in each case of liquid ion-exchanger LA1 (HOAc-form), hexane and ethyl acetate (twice).The aqueous phase is then concentrated to dryness by evaporation in vacuo and the resulting crude product, in water, is adjusted to pH 2.2 with 1 N hydrochloric acid and subsequently chromatographed over 100 g of silylated silica gel (Antec Opti-Up C12). The fractions containing the product are further treated as described in Example 1 e). 3-(4-carbarmoylpyridiniomethyl)-7α-methoxy- 7jB-[2-((2R)-2-a mino-2-carboxyethoxycarbonylamino)-acetamidoj-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1400; [α]D20 =+39 #1 (0.89% in H2O); IR: 3600-2400 (broad), 1778, 1818 (shoulder), 1690, 1637, 1565, 1530 cm- (Nujol); UV: 264(9300; H20).

1 k) As described in Example 1 e), 1.5 g of the sodium salt of 3-acetoxymethyl-7α-methoxy-7ss-[2- ((2R)-2-amino-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid and 1 g of 2 methyl-3-mercapto-5,6-dioxo-l ,4,5,6-tetrahydro-as-triazine are reacted in 8 ml of water, worked up and chromatographed. The disodium salt of 3-(2-methyl-5,6-dioxo- 1 ,4,5,6-tetrahydro-as-triazin-3- ylthiomethyl)-7α-methoxy-7ss-[2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-acetamido]-3- cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1700; [α]D20 =+62 #1 (0.69% in H20); IR: 3600-2400 (broad), 1770, 1720, 1650 (broad), 1 570, 1 510 cm- (Nujol); UV: 234 (17200), 277 (23900; H20).

The starting material for Examples 1 a)-1 k) can be manufactured as follows: 11) 20 g of BOC-glycine are dissolved in 900 ml of tetrahydrofuran, the solution is cooled to 200 and 14.5 ml of N-methylmorpholine and 14 ml of chloroformic acid isobutyl ester are added in succession.The mixture is stirred for 3 hours at 200, the temperature is then reduced to 400, 45 g of 3-acetoxymethyl-7ss-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in solid form are added, the mixture is stirred for 10 minutes at-40 and for 21/2 hours at 0 and working up is then carried out as follows: the reaction mixture is taken up in ethyl acetate and washed in succession with 1 N aqueous hydrochloric acid, saturated aqueous NaCI solution, saturated aqueous NaHCO3 solution and again with NaCI solution until neutral. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo and the residue is chromatographed over 2000 g of silica gel (eluant: toluene/ethyl acetate (1:1); fraction size 1000 ml).By combining the fractions containing the product there is obtained, after re-precipitation from CH2Cldiethyl ether/hexane, 3-acetoxymethyl-7P- (2-BOC-aminoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester.

[α]D20 =+19#1 (0.90% in CHCI3); IR: 3390, 1782, 1740 (shoulder), 1720, 1690 (shoulder), 1512 (shoulder), 1495 cm~1 (CH2CI2); UV: 262 (7500; EtOH).

1 m) 61.73 g of 3-acetoxymethyl-7ss(2-BOC-aminoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester are stirred for 21/2 hours at room temperature with 46 g of p-toluenesulphonic acid monohydrate in 250 ml of acetonitrile. After the additon of 2500 ml of ether, filtering off the precipitate with suction, washing with 1000 ml of ether and drying in vacuo, 3-acetoxymethyl-7ss-(2- aminoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate is obtained.

[α]D20 =+25 #1 (0.93% in CH3OH); IR: 3200-2800 (broad), 1780, 1740-1720 (broad), 1700 cm- (CH2Cl2); UV: 261(7200; EtOH).

Example 2 2a) 10.5 g of 3-carbamoyloxymethyl-7ss-(2-aminoacetamido)-3-cephem-4-c acid diphenylmethyl esterp-toluenesulphonic acid salt are reacted with 12.0 g of (2R)-2-BOC-amino-2 diphenylmethoxycarbonylethoxycarbonyl chloride (2.9 ml of pyridine, 1 50 ml of tetrahydrofuran), worked up and chromatographed, as described in Example 1 a). In so doing, 3-carbamoyloxymethyl-7p- [2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-acetamido]-3-cephem-4carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+20 #1 (0,75% in CHCl3); IR: 3460, 3370, 1782, 1 740-1 690 (broad), 1582, 1494 cm- (CH2CI2); UV: 257 (8200), 263 (8200; EtOH).

2b) 7.6 g of 3-carbamoyloxymethyl-7,B-[2-((2R)-2-BOC-amino-2diphenyl- methoxycarbonylethoxycarbonylamino)-aceta mido]-3-cephem-4-carboxylic acid diphenylmethyl ester are methoxylated in 760 ml of tetrahydrofuran (0.253 g lithium in 45 ml of methanol; 1.478 ml of tertbutyl hypochlorite divided into two portions of 0.562 and one portion of 0.354 ml), worked up and chromatographed (eluant: toluene/ethyl acetate (1:1); fraction size 500 ml) as described in the Example 1 b). 3-carbamoyloxymethyl-7α-methoxy-7ss-[2-((2R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[aj20'-+490*1 0 (0.87% in CHCí3); IR: 3480, 3390, 1780, 1 740-1 700 (broad), 1585, 1493 cm-1 (CH2CI2); UV: 246 (5000), 252 (5000), 258 (5000), 264 (5200; EtOH).

2c) 0.9 g of 3-carbamoyloxymethyl-7jB-[2-((2R)-2-BOC-amino-2-diphenyl- methoxycarbonylethoxycarbonylamino)-acetamido]-3-caphem-4-carboxylic acid diphenylmethyl ester are reacted in 2 ml of CH2CI2 and 0.72 ml of anisole with 10 ml of trifluoroacetic acid and worked up, analogously to Example 1 c). The sodium salt of 3-carbamoyloxymethyl-7ss-[2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

IR: 3600-2400 (broad), 1780, 1735, 1710 (shoulder), 1612 (broad), 1 538 (broad) cm- (Nujol); UV: 240 (6600), 264 (7900; EtOH).

2d) 5 g of 3-carbamoyloxymethyl-7 cL-methoxy-7P-[2-((2R)-2-BOC-amino-2- diphenyl methoxyca rbonylethoxycarbonylmino)-acetamido]-3-cephem-4-ca rboxylic acid diphenylmethyl ester are reacted in 10 ml of CH2CI2 and 3.83 ml of anisole with 50 ml of trifluoroacetic acid and worked up, analogously to Example 1 c). The sodium salt of 3-carbamoyloxymethyl-7a- methoxy-7ss-[2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1750; [a]20"-+1430*1 0 (0.84% in H2O); IR: 3600-2400 (broad), 1770, 1715 (broad), 1610 (broad), 1535 (broad) cm- (Nujol); UV: 239 (6100), 623 (7400: H2O).

The starting material for Examples 2a)-2d) can be manufactured as follows: 2e) 4.4 g of BOC-glycine and 10 g of 3-carbamoyloxymethyl-7,B-amino-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted (3.2 ml of N-methylmorpholine; 3 ml of chloroformic acid isobutyl ester; 200 mi tetrahydrofuran), worked up and chromatographed, as described in Example 11).

3-carbamoyloxymethyl-7ss-(2-BOC-aminoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+16 #1 (0.70% in CHCl3); IR: 3470, 3380, 1781, 1740 (shoulder), 1720-1680 (broad), 1582, 1493 cm-' (CH2CI2); UV: 260 (7700; EtOH).

2f) 11.5 g of 3-carbamoyloxymethyl-7ss-(2-BOC-aminoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted with 7.4 g of p-toluenesulphonic acid monohydrate in 100 ml of acetonitrile and worked up, analogously to the method described in Example 1 m). 3 carbamoyloxymethyl-7P-(2-a minoacetamido)-3-cephem-4-ca rboxylic acid diphenylmethyi ester ptoluenesulphonic acid salt is obtained.

[α]D20 =+23 #1 (0.80% in H3CH); IR: 3500-2500 (broad), 1780, 1722, 1710, 1690 (shoulder), 1603, 1537 cm- (Nujol); UV:218(27000),258(6600),281(6600;EtOH).

Example 3 3a) 6.2 g of 7ss-(2-aminoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester p- toluenesulphonic acid salt are reacted with 9 g of (2R)-2-BOC-amino-2-diphenylmethoxy carbonylethoxycarbonyl chloride (2.5 ml of pyridine; 150 ml of tetrahydrofuran), worked up and chromatographed (eluant: toluene/ethyl acetate (9:1) and (1:1); fraction size 500 ml), as described in Example 1 a). 7ss-[2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)- acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

IR: 3465, 3371, 1781, 1740-1690 (broad), 1 581, 1494 cm- (CH2CI2).

3b) 8 g of 7ss-[2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)- acetamidoj-3-cephem-4-carboxylic acid diphenylmethyl ester are methoxylated in 800 ml of tetrahydrofuran (0.29 g of lithium in 30 ml of methanol; 2.2 ml of tert.-butyl hypochlorite divided into two portions of 0.8 and one portion of 0.6 ml), worked up and chromatographed (eluant: toluene/ethyl acetate (4:1); fraction size 500 ml), as described in Example 1 b). 7α-methoxy-7ss-[2-((2R)-2-BOC- amino-2-diphenylinethoxycarbonylethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+78 #1 (0.87% in EtOH); IR: 3464,3368, 1779, 1740-1690 (broad), 1581, 1494 cm- (CH2Cl2).

UV: 251(5000), 257 (4900), 264 (4700), 268 (4500; EtOH).

3c) 1.55 g of 7cr-methoxy-7p-[2-((2R)-2-BOC-amino-2-diphenylmethoxy- carbonylethoxycarbonylamino)-acetamidoj-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 3 ml of CH2CI2 and 1.3 ml of anisole with 10 ml of trifluoroacetic acid and worked up, analogously to Example 1 c). The sodium salt of 7a-methoxy-7P-[2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1 600; [a]200"=+1 73011 0 (0.62% in H2O) IR: 3600-2400 (broad), 1779, (broad), 1620 (broad), 1530 (broad) cm- (Nujol); UV: 261 (3440:H2O).

The starting material for Examples 3a)-3c) can be manufactured as follows: 3d) 3.6 g of BOC-glycine and 7 g of 7P-a m ino-3-cephem4-ca rboxylic acid diphenylmethyl ester are reacted (2.7 ml of N-methylmorpholine; 2.6 ml of chloroformic acid isobutyl ester; 160 ml of tetrahydrofuran), worked up and chromatographed (eluant: toluene/ethyl acetate (4:1); fraction size 500 ml). as descrlbed in Example @@). 7ss-2-BOC-amino-acetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =1 #1 (1,30% in CHCl3); IR: 3475, 3380, 1782, 1740 (shoulder), 1720-1690 (broad), 1580, 1495 cm- (CH2Cl2).

3e) 6.8 g of 7ss (2 BOC aminoaoctamido)-3-cephom-4-carboxylic acid diphenylmethyl ester are reacted with 4.9 g of p-toluenesulphonic acid monohydrate in 70 ml of acetonitrile and worked up, as described in Example 1 m). 7ss-(2-aminoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonic acid salt is obtained which is further processed (Example 3a) without being characterised.

Example 4 4a) 45.5 g of (2R)-2-((2R)-2-BOC-amino-2-diphenyimethoxycarbonylethoxycarbonylamino)-2 phenylacetic acid are dissolved in 1 200 ml of tetrahydrofuran, the solution is cooled to 200 and 9.6 ml of N-methylmorpholine and 9.1 ml of chloroformic acid isobutyl ester are added in succession. The mixture is stirred for 3 hours at-20 C. the temperature is then reduced to 400, 29 g of 3acetoxymethyl-7ss-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in solid form are added, the mixture is stirred for 10 minutes at 400 and for 2+ hours at 0 and is worked up as described in Example 1 a). The resulting crude product is chromatographed over 2000 g of silica gel (eluant: methylene chloride/ethyl acetate (98:2); fraction size 1000 ml).By combining the fractions containing the product and re-precipitating from methylene chloride/hexane, 3-acetoxymethyl-7ss-[(2R)-2-((2R)-2- BOC-amlno-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-phenylacetamido]-3-cephem-4carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =1 #1 (1,30% in CHCl3); IR; 3490, 1785, 1745, 1690 (broad), 1595 cm- (CH2Cl2); UV: 257 (7200)263 (7100; EtOH).

4b) 7.3 of 3-acetoxymethyl-7,B-[(2R)-2-((2R)-2-BOC-amino-2-diphenyl- methoxycarbonylethoxycarbonyla mino)-2-phenylacetamido]- 3-cephem-4-carboxyl ic acid diphenylmethyl ester are methoxylated in 730 ml of tetrahydrofuran (0.21 g of lithium in 30 ml of methanol; 1.7 ml of tert-butyl hypochlorite divided into two portions of 0.6 and 1 portion of 0.5 ml), worked up and chromatographed (eluant: toluene/ethyl acetate (4:1)), as described in Example 1 b). 3 acetoxymethyl-7α-methoxy-7ss-[(2R)-2-((2R)-2-BOC-amino-2-diphenylmethoxy- carbonylethoxycarbonylamino)-2-phenylacetamiodo]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

IR: 3360, 1780, 1722 (broad), 1495 cm- (Nujol); UV: 246 (6400), 252 (6500), 258 (6600), 264 (6600; EtOH).

4c) 6.6 g of 3-acetoxymethyl-7-methoxy-7p-[(2R)-2-((2R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonylamino)-2-phenylacetamido]- 3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 10 ml of CH2CI2 and 4.3 ml of anisole with 20 ml of trifluoroacetic acid and worked up, as described in Example 1 c). The sodium salt of 3-acetoxymethyl-7a-metoxy-7,3- [(2R)-2-((2R)-2-amino-2-carbxoyethoxycarbonylamino)-2-phenylacetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1 600; [α]D20 =+73 #1 (0.63% in H2O); IR: 3500-2500 (broad), 1775, 1732, 1712 (shoulder), 1700 (shoulder), 1625 (broad), 1525 (broad) cm-' (Nujol); UV: 263 (6360; H20).

The starting material for Examples 4a)-4c) can be manufactured as follows: 4d) 12.5 g of D-phenylglycine are suspended in 300 ml of CH3CN/H2O (1:1) mixture. The suspension is then adjusted to pH 10.5 with 1 N sodium hydroxide solution whereupon a clear solution forms. To this there is then added dropwise, in the course of 20 minutes, at 00, a solution of 39.4 g of (2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxywarbonyl chloride, the pH being maintained constant at pH 7.5 by simultaneously adding 1 N NaOH (titrator). The mixture is then stirred at the same pH for a further hour at 00.The mixture is then adjusted to pH 3 by adding concentrated hydrochloric acid, immediately extracted with ethyl acetate, washed four times with saturated aqueous NaCI solution, dried over sodium sulphate and concentrated by evaporation in vacuo. (2R)-2-((2R)-2-BOCamino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-phenylacetic acid is obtained which is further processed (Example 4a) without being characterised.

Example 5 5a) 21 g of 3-acetoxymethyl-7ss-((2R)-2-amino-2-methylacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulfonate are reacted with 23.4 g of (2R)-2-BOC-amino-2 diphenylmethoxycarbonylethoxycarbonyl chloride (5.7 ml of pyridine; 300 ml of tetrahydrofuran), worked up and chromatographed (eluant: toiuane/ethyl acetate (3:2); fraction size 1000 ml), as described in Example 1 a). 3-acetoxymethyl-7ss0[(2R)-2-((2R)-2-BOC-amoino-2- diphenyl methoxywarbonylethoxywarbonylamino)-2-methylacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+20 #1 (0.79% in CHCl3); IR: 3370, 1790, 1722 (broad), 1495 cm- (CH2CI2); UV: 258 (7600; EtOH).

5b) 16.5 g of 3-acetoxymethyl-7p-[(2R)-2-((2R)-2-BOC-amino-2-diphenyi- methoxycarbonylethoxycarbonyla mino)-2-methylacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are methoxylated in 1650 ml of tetrahydrofuran (0.542 g of lithium in 96.5 ml of methanol; 3.1 ml of tert-butyl hypochlorite divided into-2 portions of 1.20 and 1 portion of 0.70 ml), worked up and chromatographed (eluant: toluene/ethyl acetate (4:1)), as described in Example 1 b). 3 acetoxymethyl-7a-methoxy-7P-[(2R)-2-((2R 2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-methylacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+63 #1 (0.88% in CHCI3); IR: 3380, 1782, 1740-1 700 (broad), 1495 cm~1 (CH2CI2); UV: 246 (5400), 251(5400), 257 (5500), 263 (5600), 267 (5500; EtOH).

5c) 14 g of 3-acetoxymethyl-7cg-methoxy-7,B-[(2R)-2-((2R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonylamino)-2-methylacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 27.5 ml of CH2CI2 and 10.5 ml of anisole with 138 ml of trifluoroacetic acid and worked up, analogously to Example 1 c). The sodium salt of 3-acetoxymethyl 7a-methoxy-7P-[(2 R)-2-((2 R)-2-a mino-2- carboxyethoxyca rbonylam ino)-2-methylacetam ido]-2cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1600; [α]D20 =+180 #1 (0.74% in H20); IR: 3600-2400 (broad), 1772, 1720, 1690 (shoulder), 1610, 1530 cm- (Nujol); UV: 239 (6300), 254 (7400; H20).

6d) 1,77 g of the sodium sait of 3-scetoxymethyl-7α-methoxy-7ss0[(2R)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-2-methylacatamido]-3-cephem-4-carboxylic acid are reacted with 1 g of the sodium salt of 1 -methyl-5-mercapto-1 H-tetrazole, as described in Example 1 e). The sodium salt of 3-(1-methyl-1H-totrazol-5-ylthiomethl)-7α-methoxy-7ss-[(2R)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-2-methylacetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1 650; [α]D20 =+91 #1 (0.76% in H2O); IR: 3610-2400 (broad), 1771, 1722, 1690 (shoulder), 1610, 1530 cm-l (Nujol); UV: 270 (7400;H2O).

The starting material for Examples 5a-5d) can be manufactured as follows: 5e) 7.54 9 of BOC-(D)-aianine and 15.8 g of 3-acetoxymethyl-7ss-amino-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted (5.11 ml of N-methylmorpholine; 4.94 ml of chloroformic acid isobutyl ester; 300 ml of tetrahydrofuran), worked up and chromatographed (eluant: toluene/ethyl acetate (4:1); fraction size 1000 ml), as described in Example 11). 3-acetoxymethyl-7P-((2R)-2-BOC- amino-2-methylacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[a]20"=+l70*l (0.93% in CHCl2); IR: 3390, 1788, 1722 (broad), 1500 cm~1 (CH2CI2); UV: 264 (7000; EtOH).

5f) 21 g of 3-acetoxymethyl-7ss-((2R)-2-BOC-amino-2-methylacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted with 13.1 g of p-toluenesulphonic acid monohydrate in 50 ml of acetonitrile and worked up, as described in Example 1 m). 3-acetoxymethyl-7P-((2R)-2-amino-2- methylacetamido)-3-cephem-4-carboxylic acid diphenylmethyi ester p-toluenesulphonate is obtained.

[α]D20 =+24 #1 (0.73% in CH3OH); IR: 3600-2400 (broad), 1785, 1725, 1690, 1 550 (broad), 1485 cm~1 (Nujol); UV: 218 (25800), 260 (6800; EtOH).

Example 6 6a) To a solution of 5.79 g of (3R)-3-BOC-amino-3-tert-butoxycarbonylpropionic acid and 2.2 ml of N-methylmorpholine in 150 ml of absolute methylene chloride, cooled to --200, there are added, under a nitrogen atmosphere, 2.6 ml of chloroformic acid isobutyl ester and, after one hour, 13.36 g of 3-acetoxymethyl-7ss-(2-a minoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester ptoluenesulphonic acid salt and 2.2 ml of N-methylmorpholine. After stirring for three hours at room temperature, the reaction mixture is diluted with 800 ml of ethyl acetate, washed twice with ice-water and twice with saturated sodium chloride solution, dried over sodium sulphate and freed of solvents in a rotary evaporator.The residue is purified over silica gel with diethyl ether/ethyl acetate (1:1) as eluant to yield 3-acetoxymethyl-7ss-[2-((3 R)-3-BOC-a mino-3-tert-butoxycarbonyliproplonylamino)- acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester as a colourless amorphous powder. TLC (silica gel, identification with iodine): Rf#0.44 (ethyl acetate).

6b) To a solution of 9.97 g of the compound obtained according to Example 6a) in 1000 ml of absolute tetrahydrofuran, cooled to 750, there is added, in the course of 2 minutes, while stirring under a nitrogen atmosphere, a solution of 361 mg of lithium in 72 ml of absolute methanol. Then, after 2, 5 and 15 minutes, 2.1 ml, 0.8 ml and 0.5 ml of tert-butyl hypochlorite are added to the reaction mixture. After a further 15 minutes at --750, 17.9 ml of acetic acid and then 4.55 g of sodium thiosulphate dissolved in 6.5 ml of water are added to the reaction mixture and the whole is heated to 00. The solution, diluted with ethyl acetate, is washed twice with ice-water, twice with 5% sodium bicarbonate solution and twice with saturated sodium chloride solution, dried over sodium sulphate and freed of solvents in a rotary evaporator.The residue is purified over silica gel with diethyl ether/ethyl acetate 1:1 as eluant to yield 3-acetoxymethyl-7a-methoxy-7,B-[2-((3R)-3-BOC-amino-3- tert-butoxycarbonylpropionylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester in the form of an amorphous powder that is uniform according to thin-layer chromatography.

TLC (silica gel, identification with iodine): Rf-0.47 (ethyl acetate).

6c) A solution of 4.3 g of the compound obtained according to Example 6b) in 43 ml of trifluoroacetic acid is stirred in the presence of 4.3 ml of anisole for 90 minutes at room temperature under a nitrogen atmosphere. After the addition of 400 ml of diethyl ether, the corresponding precipitate is filtered off, washed with a little diethyl ether and dried under reduced pressure. The trifluoroacetic acid salt so obtained is dissolved in 20 ml of ice-water and extracted with ethyl acetate (3x 10 ml). The acid aqueous phase is adjusted to pH 5.5 by adding dropwise 2N aqueous sodium hydroxide solution and, at 00, isopropanol (100 ml) is added. The resulting precipitate is filtered off, washed with ethanol, re-dissolved in water in order to remove organic solvents and concentrated in a rotary evaporator.After drying (16 hours, room temperature, 0.05 torr), the sodium salt of 3 acetoxymethyl-7Q-methoxy-7P-[2-((3 R)-3-a mino-3-carboxypropionylamino)-aceta mido]-3-cephem-4- carboxylic acid is obtained in the form of a 1.5 hydrate.

mp: from 1680 (with decomposition); TLC (silica gel, development with ninhydrin): R1-0.16; UV spectrum (0.1 N aqueous hydrochloric acid): 264 nm (E=7000); [aC12DOO=+116 +1 (0.1 N aqueous hydrochloric acid, c=1.22%).

6d) In a manner analogous to that of Example 6c), 3-acetoxymethyl-7ss-[2-((3R)-3-amino-3- carboxyproplonyiamino)-acetamido]-3-cephem-4carboxylic acid is obtained in the form of a 1.5 hydrate by treating 1.9 g of 3-acetoxymethyi-7,B-[2-((3R)-3-BOC-amino-3-tert-butoxycarbonyl- propionylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester with 20 ml of trifluoroacetic acid and 2 ml of anisole.

mp: from 1320 (with decomposition); TLC (silica gel, development with ninhydrin): Rf#0.16; UV spectrum (0.1 N aqueous hydrochloric acid): 258 nm #=7500); [a120"=+720*l 0 (0.1 N aqueous hydrochloric acid, c=1.22%i.

Example 7 7a) To a solution of 4.76 g of 3-acetoxymethyl-7ss-[2-BOC-amino-acetamido]-3-cephem-4- carboxylic acid diphenylmethyl ester in 476 ml of absolute tetrahydrofuran, cooled to 750, there is added, in the course of about 2 minutes, while stirring vigorously under a nitrogen atmosphere, a solution of 222 mg of lithium in 44 ml of absolute methanol. Then, after 2 and 5 minutes, 0.5 ml of tert-butyl hypochlorite is added each time and, after 1 5 minutes, 0.3 ml of tert-butyl hypochlorite is added, similarly art 750 After a further 1 5 minutes, 11 ml of acetic acid and then 2.8 g of sodium thiosulphate dissolved in 4 ml of water are added to the reaction mixture and the whole is heated to room temperature.The solution, diluted with ethyl acetate, is washed twice with ice-water, twice with 5% sodium bicarbonate solution and twice with saturated sodium chloride solution, dried over sodium sulphate and freed of solvent in a rotary evaporator. The crude product is purified over silica gel with methylene chloride/ethyl acetate 3:1 as eluant to yield 3-acetoxymethyl-7ss-(2-BOC- aminoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester.

mp: 124-126 (from diethyl ether); TLC (silica gel, identification with iodine): Rf~0.71; (diethyl ether/ethyl acetate 2:1).

7b) A solution of 1.93 g of 3-acetoxymethyl4a-methoxy-7-(2-B0C-aminoacetamido)-3- cephem-4-carboxylic acid diphenylmethyl ester and 1.1 g of p-toluenesulphonic acid monohydrate in 1 5 ml of absolute acetonitrile is stirred at room temperature for 3 hours. After the addition of diethyl ether (90 ml), the resulting precipitate is filtered off, stirred again with diethyl ether (30 ml) and, after filtration, dried in a high vacuum. The resulting 3-acetoxymethyl-7α-methoxy-7ss-(2-aminoacetamido)- 3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonic acid salt can be used in the next reaction step without further purification.

mp: from 11 00 (decomposition); TLC (silica gel, identification with iodine): Rf#0.10; (ethyl acetate/ethanol 9:1).

7c) Analogously to Example 6a),3-acetoxymethyl-7cg-methoxy-7p-[2-((3R)-3-BOC-amino-3-tert- butoxycarbonylpropionylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained by treating the mixed anhydride, manufactured from 637 mg of (3R)-3-BOC-amino-3-tertbutoxycarbonylpropionic acid and 0.29 ml of chloroformic acid isobutyl ester in the presence of 0.24 ml of N-methylmorpholine in 20 ml of absolute methylene chloride at-i 5, with 1.4 g of 3acetoxymethyl-7 -methoxy-7p-(2-a minoacetamido)-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonic acid salt, followed by 0.24 ml of N-methylmorpholine.

Example 8 8a) 17.8 g of (2R,s)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2 (2-trichloroethoxycarbonylaminothiazol-4-yl)-acetic acid and 9.4 g of 3-acetoxymethyl-7p-amino-3- cephem-4-carboxylic acid diphenyl ester are dissolved in 180 ml of absolute tetrahydrofuran together with 1.8 g of hydroxybenztriazole. Then, immediately and after 11/2 hours and after 3 hours, 1.63 g of dicyclohexyl carbodiimide in 50 ml of tetrahydrofuran are added each time and the mixture is stirred at room temperature for a total of 6 hours. The reaction mixture is poured onto 4 litres of hexane, filtered with suction and washed with hexane. The suction-filter residue is introduced into 4 litres of ethyl acetate and the mixture is stirred.The dicyclohexylurea which is insoluble in ethyl acetate is filtered off and the ethyl acetate solution is washed in succession with saturated sodium bicarbonate and sodium chloride solutions. After drying over sodium sulphate and concentration by evaporation, the resulting crude product is re-precipitated once from methylene chloride/ether/hexane to yield 3-acetoxymethyl7ss-[(2R,s)-2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylathoxycarbonylamino)-2-(2trichloroethoxycarbonylaminothiazo(-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyimethyl ester.

[a]2D =+5 ~1 (1.01% in C2H50H); IR: 3300--3400, 1787, 1740--1690 (broad), 1495 cm-l (CH2CI2); UV: 258 (15300, C2H5OH).

If desired, the resulting binary (2R,S)-product mixture can be separated into its (2R)- and (2S)enantiomers by chromatography over silica gel.

8b) 19 g of zinc dust are added in portions while stirring at 00, in the course of 10 minutes, to a solution of 19 g of 3-acetoxymethyl-7ss-[(2R,s)-2-((2R)-BOC-amino-2-diphenylmethoxycarbonyl ethoxycarbonylamino)-2-(2-trichloroethoxywarbonylaminothiazol-4-yl)-aceta mido]-3-cephem-4- carboxylic acid diphenylmethyl ester in 190 ml of an acetic acid/acetonitrile mixture (1 :1) and the whole is then stirred for a further 3 hours at 00. The reaction solution is then filtered off from the zinc residue with suction, washed with acetonitrile and concentrated in a rotary evaporator. Water is added to the residue and the mixture is adjusted to pH 8 with 2N NaOH, extracted with ethyl acetate and washed neutral with NaCI solution.The crude product obtained after drying over sodium sulphate and concentration by evaporation is chromatographed over 900 g of silica gel with fractions of 500 ml each being taken. Eluant: ether, ether/ethyl acetate (9:1), ether/ethyl acetate (1:1) and ethyl acetate. By combining the fractions containing the product, concentrating them by evaporation and reprecipitating the evaporation residue from CH2Cl2/hexane, 3-acetoxymethyl-7ss-[(2R,s)-2-((2R)-2-BOC- amino-2-diphenyl methoxyca rbonylethoxycarbonyla mino)-2-(2-a minothiazol-4-yl)-aceta mido]-3cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+31 #1 (1.07% in CHCIs); IR: 3370, 1785, 1740-1696 (brosd), 1600, 1595 cm- (CH2Cl2); UV: 256 (11000; EtOH).

8c) 5 g of 3-acetoxymethyl-7ss-[(2R,s)-2-((2R)-2-BOC-amino-2-diphenylmethoxy- carbonylethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 10 ml of CH2CI2 and 6.5 ml of anisole with 30 ml of trifiuoroacetic acid and worked up, analogously to Example 1 c). The hydrate of the sodium salt of 3-acetoxymethyl7ss-[(2R,s)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-(2aminothiazol-4-yl)-acatemido]-3cephem-4-carboxylic acid is obtained.

Decomposition from 1500; [a]2o0'=+l030*1 0 (0.90% in H20); IR: 3600-3100 (broad), 1760, 1720, 1680, 1615, 1527, 1460 cm- (Nujol); UV: 252 (11200; H20).

8d) 1.8 g of the sodium salt of 3-acetoxymethyl-7ss-[(2R,S)-2-amino-2- carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acstamido]-3-caphem-4-carboxylic acid and 0.86 g of the sodium salt of 1 -methyl-5-mercapto-1 H-tetrazol are reacted in 10 ml of water, worked up and chromatographed, as described in Example 1 e). The hydrate of the sodium salt of 3-( 1-methyl- 1H-tetrazol-5-ylthiomethyl)-7ss-[(2R,S)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-(2aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid is obtained.

Decomposition from 220 ; [aj2000=+180*1 0 (0.85% in H2O); IR: 3600-3080 (broad), 1760, 1713, 1680, 1609, 1520, 1460 cm- (Nujol); UV: 256 (10500; H2O).

The starting material for Examples 8a)-8d) can be manufactured as follows: 8e) 10 g of (2R,S)-2-(2-trichloroethoxycarbonylaminothiazol-4-yl)-glyclne, which is obtained according to Japanese Patent Application 52,083,836 (Derwent No. 61588Y/36), are suspended in 250 ml of acetonitrile/water (1:1) and brought into solution at pH 9.5 by adding 1N sodium hydroxide solution. Then, at 00, 13.6 g of (2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonyl chloride in 100 ml of acetonitrile are added dropwise, while stirring, in the course of 15 minutes, the pH being maintained constant at 9.5 by adding 1 N sodium hydroxide solution.Stirring is continued under the same conditions for 3 hours, the mixture is adjusted to pH 3 with 2N hydrochloric acid, extracted with ethyl acetate, washed four times with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated by evaporation in vacuo. (2R,S)-2-[(2R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonylamino]-2-[2-trichloroethoxycarbonylaminothlazol-4-yl)-acetic acid is obtained which is further processed in crude form without being characterised.

If, instead of the 7ss-[(2R,s)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-(2-aminothazol- 4-yl)-acetamido] derivatives described in Example 8a)-8d), the corresponding (R)- or (S)-compounds are to be synthesised, the racemic starting material must be separated, in a manner known per se, into its antipodes.

Example 9 9a) 30 g of 3-acetoxymethyl-7P-[(2R,S)-2-((2R)-2-BOC mino-2- diphenylmethoxycarbonylethoxywarbonylamino)-2-(2-trichloroethoxywarbonylaminothiazol-4-yl)- acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (see Example 8a) for manufacture) are chromatographed over 2 kg of silica gel (1 litre fractions). In fractions 33-36 there is eluted (eluant: toluene/ethyl acetate 85:15 mixture) 3-acetoxymethyl-7ss-[(2R)-2-((2R)-2-BOC-amino-2 diphenylmethoxycarbonylethoxycarbonyla mino)-2-(2-trichloroethoxycarbonylaminothiazol-4-yl) acetamidoj-3-cephem-4-carboxylic acid diphenylmethyl ester.

The assignment of configuration at the carbon atom of the acetyl radical in the 7ss-acyl side chain is made on the basis of rotatory shifts and NMR comparisons (CH-7) with ureidocephalosporins, cf., for example, H. Breuer et al., J. Antibiot. 31, 546-560, and DOS 2,924,296; [α]D20 =-7 #1 0 (0.87% in CHCI3); IR: 3300-3400, 1787, 1740-1690, 1495 cm- (CH2CI2); UV: 258 (15300; C2HsOH).

The next eluted fractions, 37-45, consist of a binary mixture of the above-mentioned (2R)compound and the corresponding (2S)-isomer (cf. fractions 46-60).

Fractions 46-60 yield 3-acetoxymethyl-7ss[(2S)-2-((2R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonylamino)-2-(2-trichloroethoxycarbonylaminothiazol-4-yl)- acstamido]-3-cephem-4-carboxylic acid diphenylemthyl ester. The configuration at the α-carbon atom in the 7ss-acyl side chain is assigned according to the method described above.

[α]D20 =+1 (0.76% in CHCl3); IR: 3300-3400, 1 787, 17401690, 1495 cm- (CH2CI2); UV: 258 (15000; C2H,OH).

9b) 4.68 g of 3-acetoxymethyl-7/3-[(2R)-2-((2R)-2-BOC-amino-2-diphenyl- methoxycarbonylethoxycarbonyla mino)-2-(2-trichloroethoxycarbonyla minothiazol-4-yl)-acetamido]-3- cephem-4-carboxylic acid diphenylmethyl ester are reacted with 4.68 g of zinc dust in 46.8 ml of acetic acid/acetonitrile (1:1) mixture, worked up and chromatographed, as described in Example 8b). 3 acetoxymethyl-7P-[(2 R)-2-((2 R)-2-BOC-a mino-2-diphenylmethoxyca rbonylethoxycarbonylam ino)-2- (2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 -15 #1 (0.92% in CHCl3); IR: 3370, 1785, 1740-1696, 1600, 1585 cm-1 (CH2CI2); UV: 256 (11500; C2H5OH).

9c) 6.54 g of 3-acetoxymethyl-7ss-[(2S)-2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-(2trichlorosthoxycarbonylaminothiazol-4-yl)-acetamido]-3-cephem4-carboxylic acid diphenylmethyl ester are reacted with 6.54 g of zinc dust in 65.4 ml of acetic acid/acetonitrile (1:1) mixture, worked up and chromatographed, analogously to Example 8b). 3 acetoxymethyl-7P-[(2S)-2-((2R)-2-BOC-a mino-2-diphenylmethoxyca rbonylethoxyca rbonylamino)-2 (2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyi ester is obtained.

[a]200"=*200*1 0 (0.69% in CHCI3); IR: 3370, 1785, 1 740-1 696, 1600, 1595 cm- (CH2Cl2); UV: 256 (10900; C2H5OH).

9d) 2.9 g of 3-acetoxymethyl-7ss-[(2R)-2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonyl- ethoxycarboonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 5 ml of CH2Cl2 and 2.5 ml of enisole with 20 ml of trifluoroacetic acid and worked up, analogously to Example [c]. The hydrate of the sodium salt of 3-acetoxymethyl7ss-[(2R)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3cephem-4-carboxylic acid is obtained.

Decomposition from 1 650C; [α]D20 =+52 #1 (0.84% in H2O); IR: 3600--3100, 1760, 1720, 1680, 1615, 1527, 1460 cm-' (Nujol); UV: 252 (11500; H2O).

9e) 3.95 g of 3-acetoxymethyl-7,B-[(2R)-2-((2R)-2-BOC-amino-2-diphenyl- methoxycarbonylethoxycarbonylamino)-2-(2-a minothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 7 ml of CH2CI2 and 4.5 ml of anisole with 25 ml of trifluoroacetic acid and worked up, analogously to Example 1 c). The hydrate of the sodium salt of 3 acetoxymethyl-7p-[(2S)-2-((2R)-2-amino-2-carboxyethoxywarbonylamino)-2-(2-aminothiazol-4-yl)- acetamido]-3-cephem-4-carboxylic acid is obtained.

Decomposition from 1650; [α]D20 =+86 #1 (0.85% in H20); IR: 3600-3100, 1760, 1720, 1680, 1615, 1527, 1460 cm- (Nujol); UV: 252 (11200; H2O).

9f) 2 g of the sodium salt of 3-acatoxymethyl-7ss-[(2R,S)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino]-2-(2-aminmothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid and 1.28 g of 1-dimethylaminoathyl-5-mercepto-1H-tetrazole are rescted in 6 ml of water, worked up and chromatographed, as described in Example 1 e). 3-[1 -(2-dimethylaminoethyl)-1 H-tetrazol-5ylthiomethyl]-7ss-[(2R,S)-2-((2R)-2-amino-2-careboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid is obtained.

Decomposition from 1600; [α]D20 =+20 #1 (0.82% in H2O); IR: 3600-2500 (broad), 2770, 1712, (ehoulder). 1680 (shoulder), 1615,1508cm~' (Nujol); UV: 254 (13500; H2O).

9g) 2 g of the sodium salt of 3-acetoxymethyl-7ss-[(2R,S)-2-((2R)-2-amino-2carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid and 1.19 g of 1 -carboxymethyl-5-mercapto-1 H-tetrazole are reacted in 6 ml of water, worked up and chromatographed, as described in Example 1 e). The hydrate of the disodium salt of 3-( 1 - carboxymethyl-1 H-tetrazol-5-ylthiomethyl)-7,5-[(2R,S)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-caphem-4-carboxylic acid is obtained.

Decomposition from 1750; [α]D20 =+11 #1 (0.98% in H2O); IR: 3600-2600 (broad), 1765, 1 740-1 570 (broad), 1520 cm- (Nujol); UV: 258 (13500; H2O)- 9h) 2 g of the sodium salt of 3-acetoxymethyl-7ss-[(2R,S)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid end 1.9 g of 1 -sulphomethyl-5-mercapto-1 H-tetrazole are reacted in 6 ml of water, worked up and chromatographed, as described in Example 1 e).The disodium salt of 3-( 1 -sulphomethyl-1 H-tetrazol-5 ylthiomethyl)-7P-[(2R,S)-2-((2 R)-2-amino-2-carboxyethoxycarbonylamino)-2-(2-a minothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1650; [α]D20 =+12 #1 (0.90% in H20); IR: 3800-2500 (broad), 1765, 1730 (shoulder), 1680 (shoulder), 1625 cm- (Nujol); UV:258 (14200; H2O).

Example 10 1 Oa) Analogously to Example 8a), 14.52 g of (2R,S)-2-((3R)-3-BOC-amino-3-tertbutoxycarbonylpropionamido)-2-(2-trichloroethoxycarbonylaminothiazol-4-yl)-acetic acid and 9.1 g of 3-acetoxymethyl-7ss-amino-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 180 ml of tetrahydrofuran with 1.8 g of hydroxybenztriazole and 5.1 g of dicyclohexyl carbodiimide and worked up. After chromatography over 900 g of silica gel, 3-acetoxymethyl-7ss-[(2R,S)-2-((3R)-3-BOC-amino- 3-tert-butoxyCarbonylpropionamido)-2-(2-trichloroethoxyCarbonylaminothiazol-4-yl)-acetamido]-3- cephem-4-carboxylic acid diphenylmethyl ester is obtained from the toluene/ethyl acetate (7:3) eluates.

[α]D20 =+15 #1 (0.90% in CHCI3); IR: 3395, 3300 (shoulder), 1780, 1 750-1650 (broad), 1550 (shoulder). 1490 cm- (CH2CI2); UV: 258 (1600: C2HsOH).

1 Ob) Analogously to Example 8b), 6.75 g of 3-acetoxymethyl-7,B-[(2R,S)-2-((3R)-3-BOC-amino- 3-tert-butoxycarbonylpropionamido)-2-(2-trichloroethoxycarbonylaminothiazol-4-yl)-acetamido]-3cephem-4-carboxylic acid diphenylmethyl ester are reacted with 7.6 g of zinc dust in 67 ml of acetic acid/acetonitrile (1:1) mixture, worked up and chromatographed. 3-acetoxymethyl-7ss0[(2R,S)-2-((3R)- 3-BOC-amino-3-tert-butoxycarbonylpropionamido)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =-7 #1 (0.98% in CHCl3); IR: 3480 (shoulder), 3390, (shoulder), 1780,1740-1650 (broad), 1600, 1487 cm- CH2CI2); UV: 258 (12600; C2H5OH).

1 0c) Analogously to Example 1 c), but with the reaction period being extended to 2 hours, 2.5 g of 3-acetoxymethyl-7,B-[(2 R,S)-2-((3 R)-3-BOC-amino-3-tert-butoxycarbonylpropionamido)-2-(2aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 4.3 ml of CH2CI2 and 1.4 ml of anisole with 30 ml of trifluoroacetic acid and worked up. The hydrate of the sodium salt of 3-acetoxymethyl-7ss-[(2R,S)-2-((3R)-3-amino-3-carboxypropionamidl]-2-(2- aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid is obtained (decomposition from 1 800) which is further processed (Example 1 Od)) without being characterised.

1 Od) As described in Example 1 e), 1.45 g of the sodium salt of 3-acetoxymethyl-7P-[(2R,S)-2- ((3R)-3-amino-3-carboxypropionamido)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid and 0.76 g of the sodium salt of 1 -methyl-5-mercapto-1 H-tetrazole are reacted in 5 ml of water, worked up and chromatographed. The sodium salt of 3-(1-methyl-1 H-tetrazol-5-ylthiomethyl)-7ss- [(2R,S)-2-((3R)-3-a m ino-3-carboxypropionamido)-2-( 2-aminothiazol-4-yl)-acetamido]-3-cephem-4carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1 800; [a]20'=-90 +10(0.70%inH2O); IR: 3600-2400 (broad), 1765, 1710-1575 (broad), 1500 cm- (Nujol); UV: 258 (12040; H2O).

The starting material for Examples 1 Oa1- Od) can be manufactured as follows: 10e) 7.04 g of (3R)-3-BOC-amino-5-tert-butoxycarbonylpropionic acid are dissolved in 150 ml of tetrahydrofuran, the solution is cooled to 200 and 3.13 ml of N-methylmorpholine and 3.0 ml of chloroformic acid isobutyl ester are added in succession. The mixture is then stirred for 4 hours at -20 . At the same time, 8.6 g of (2R,S)-2-(2-trichloroethoxycarbonylaminothiazol-4-yl)-glycine are made into a slurry in 150 ml of tetrahydrofuran, 7 ml of N,O-bis(trimethylsilyl)-acetamide are added immediately and another 7 ml of N,O-bis(trimethylsilyl)-acetamide are added after 30 minutes and the mixture is stirred at room temperature for a total of 11/2 hours.In so doing, a clear solution is produced which is added dropwise to the first-described reaction solution when the 4 hour reaction period at -20 had elapsed. The mixture is then stirred at 0 for a further 3 hours. The mixture is then poured onto ice-water, adjusted to pH 2 with 2N hydrochloric acid, extracted with ethyl acetate and washed neutral with saturated aqueous NaCl solution. The crude (2R,S)-2-((3R)-3-BOC-amino-3-tertbutoxycarbonylpropionamidel-2-(2-trichloroethoxycarbonylaminothlazol-4-yl)- acetic acid obtained after drying over Na2SO4 and concentration by evaporation is further processed directly (Example 1 Oa)).

Example 11 11 a) Analogously to Example 4a), 3.4 g of (2R)-2-((4R)-4-BOC-amino-4-tert butoxycarbonylbutyramido)-2-methylacetic acid and 3 g of 3-acetoxymcthyl-7ss-amino 3-cophem-4 carboxylic acid diphenylmethyl ester are reacted with 0.92 ml of N-methylmorpholine and 0.88 ml of chloroformic acid isobutyl ester in 65 ml of tetrahydrofuran and worked up. The resulting crude product is chromatographed over 200 g of silica gel (eluant: methylene chloride/ethyl acetate (1:1), fraction size 100 ml). By combining the fractions containing the product and re-precipitating from methylene chloride/ether/hexane, 3-acetoxymethyl-7,B-[(2R)-2-((4R)-4-BOC-amino-4-tert- butoxycarbonylbutyramido)-2-methylacatamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+5 #1 (0.87% in CHCl3); IR: 3340, 1785, 1730, 1697, 1645, 1530 cm-' (Nujol); UV: 260 (7600; C2H5OH).

11 b) As described in Example 1 a), 13.0 g of 3-acetoxymethyl-7p-[(2R)-2- ((4R)-4-BOC-amino-4tert-butoxycarbonylbutyramido)-2-methlacatamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are methoxylated in 1300 ml of tetrahydrofuran (0.45 g of lithium in 50 ml of methanol; 3.5 ml of tertbutyl hypochlorite divided into two portions of 1.45 and one portion of 0.6 ml), worked up and chromatographed (eluant: ether/ethyl acetate (9:1); fraction size 150 ml). 3-acetoxymethyl-7a- methoxy-7ss-[(2R)-2-((4R)-4-BOC-amino-4-tert0butoxycarbonylbutyramido)-2-methylacetamido]-3cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+75 #1 (1.03% in CHCl3); IR: 3340, 1785,1730 (broad), 1655, 1520 cm (Nujol); UV: 247 (5600), 264 (5800), 269 (5800; C2HSOH).

1 1 c) Analogously to Example 1 0c), 2 g of 3-acetoxymethyl-7ss-[(2R)-2-((4R)-4-BOC-amino-4-tert- butoxycarbonylbutyramido)-2-methylacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 3 ml of CH2CI2 and 0.43 ml of anisole with 8 ml of trifluoroacetic acid and worked up. The hydrate of the sodium salt of 3-acetoxymethyl- 7ss-[(2R)-2-((4R)-4-amino-4-carboxybutyramido)-2- methylacetamido]-3-cephem-4-carboxylic acid is obtained.

Decomposition from 1 900; [a]20"-+81 0*1 0 (0.86% in H2O); IR: 3600-2400 (broad), 1772, 1720-1 600 (broad), 1550 (shoulder) cm- (Nujol); UV: 263 (6020; C2H5OH).

1 1 d) Analogously to Example 1 Oc), 6.7 g of 3-acetoxymethyl-7α-methoxy-7ss-[(2R)-2-((4R)-4- BOC-amino-4-tert-butoxycarbonylbutyramido)-2-methylacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 10 ml of CH2Cl2 and 2 ml of anisole with 25 ml of trifluoroacetic acid and worked up. The hydrate of the sodium salt of 3-acetoxymethyl-7α-methoxy-7ss-[(2R)-2-((4R)- 4-a mino-4-ca rboxybutyramido)-2-methylacetamido]-3-cephem-4-carboxylic acid is obtained.

Decomposition from 1700; [α]D20 =+145 #1 (0.87% in H20); IR: 3600-2400, 1769, 1 720-1630 (broad), 1540 (shoulder) cm- (Nujol); UV: 238 (5480), 264 (6460; H2O).

11 e) As described in Example 1 e), 1.7 g of the sodium salt of 3-acetoxymethyl-7p-[(2R)-2-((4R)- 4-amino-4-carboxybutyramido)-2-methylacetamido]-3-cephem-4-carboxylic acid and 0.8 g of the sodium salt of 1 -methyl-5-mercapto- 1 H-tetrazole are reacted in 10 ml of water, worked up and chomatographed. The sodium salt of 3-(1 1-methyl-1 H-tetrazol-5-ylthiomethyl)-7ss-[(2R)-2-((4R)-4- amino-4-carboxybutyramido)-2-methylacetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1950; [ < *]2D0 =11 +1 (0.95% in H2O); IR: 3600-2400 (broad), 1768, 1750-1 580 (broad), 1550 (shoulder) cm- (Nujol); UV: 285 (6800; H2O).

1 if) As described in Example 1 e), 3.2 g of the sodium salt of 3-acetoxymethyl-7 a-methoxy-7P- [(2R)-2-((4R)-4-amino-4-carboxybutyramido)-2-methylacetamido]-3-cephem-4-cerboxylic acid and 1.6 g of the sodium salt of 1-methyl-5-mercspto-1 H-tetrazole are reacted in 20 ml of water, worked up and chromatographed. The sodium salt of 3-( 1-methyl-1 H-tetrazol-5-ylthiomethyl]-7α-methoxy-7ss- [(2R)-2-((4R)-4-amino-4-carboxybutyramido)-2-methylacetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1950; [α]D20 =+89 #1 0 (0.82% in H20); IR: 3600-2400 (broad), 1769, 1750-i 675 (broad), 1530 cm- (Nujol); UV: 272 (3540; H20).

The starting material for Examples 11a)-11f) can be manufactured as follows: 11g) 3 g of (4R)-4-BOC-amino-4-tert-butoxycarbonylbutyric acid are dissolved in 60 ml of tetrahydrofuran, the solution is cooled to-20 and 1.27 ml of N-methylmorpholine and 1.22 ml of chloroformic acid isobutyl ester are added in succession. The mixture is then stitred for 4 hours at 200. At the same time, 0.81 g of D-aianine are made into a slurry in 30 ml of acetonitrile, 8 ml of N,O-bis(trimethylsilyl)-acetamide are added and the mixture is heated under reflux for 3 hours. In so doing, a clear solution is produced which is concentrated to dryness by evaporation in a rotary evaporator. The evaporation residue is dissolved in 30 ml of tetrahydrofuran and the resuiting solution is then added dropwise, at-20 , to the first-described reaction solution.The mlxture is then stirrsd at 0 for a further 3 hours. The mixture is then poured nonto ice-weter, adjusted to pH 2 with 2N hydrochloric acid, extracted with ethyl acetate and washed neutral with saturated aqueous NaCI solution The crude (2R)-2-[(4R)-4-BOC-amino-4-tert-butoxycarbonylbutyramido)-2-methylacetic acid obtained after drying over Na2SO4 and concentration by evaporation is further processed directly (Example 11 a)).

Example 12 12a) As described in Example 1 a), 1 5 g of 3-acetoxymethyl-7P-[(2R)-2-amino-2- hydroxymethylacetylamino]-3-cephem-4-carboxylic acid diphenylmethyl esterp-toluenesulphonic acid salt are reacted in 200 ml of tetrahydrofuran together with 4.1 ml of pyridine and 18.6 g of (2R)-2 BOC-amino-2-diphenylmethoxycarbonylathoxycarbonyl chlorlde, worked up and chromatographed. 3acetoxymethyl-7ss-[(2R)-2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2hydroxymethylacetamido]-3-cephem-4-cartboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+17 #1 (0.84% in CHCl3); IR: 3370, 1780, 1740-1 680 (broad), 1495 cm- (CH2CI2); UV: 258 (7800), 264 (7800; C2H5OH).

12b) Analogously to Example 1a), 11,3 g of 3-acetoxymethyl-7ss-[(2R)-2-((2R)-2-BOC-emino-2diphenylmethoxycarbonylethoxycarbonylamino)-2-hydroxymethylacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 130 ml of tetrahydrofuran and 1.424 ml of pyrldine with 2.44 ml of 2,2,2-trichloroethyl chloroformate and worked up. After re-procipltating the crude product from methylene chloride/ether/hexane, 3-acetoxymethyl-7ss-[(2R)-2-BOC-amino-2diphenyl methoxycarbonylethoxyca rbonylamino)-2-trichlornethoxycarbonyloxymethyIacetamidoj3 cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+5 #1 (0.79% in CHCl3); IR: 3370, 1780, 1760, 1740-1700 (broad), 1690 (shoulder), 1595 cm- (CH2Cl2); UV: 258 (8000), 264 (8000; C2H6OH).

12c) As described in Example 1b), 12.95 g of 3-acetoxymethyl-7ss-[(2R)-2-((2R)-2-BOC-amino 2-diphenylmethoxycarbonylethoxycarbonylamino)-2-trichloroethoxycarbonyloxy)-methylacetamido] 3-cephem-4-carboxylic acid diphenylmethyl ester are methoxylated in 1295 ml of tetrahydrofuran (0.35 g of lithium in 62.3 ml of methanol; 1.985 ml of tert-butyl hypochlorite divided into two portions of 0.775 ml and one portion of 0.435 ml). worked up and chromatographed. Using a toluene/ethyl scetate (9:1) mixture as eluant, 3-acetoxymethyl-7α-methoxy-7ss-[(2R)-2-((2R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonylamino]-2-trichloroethoxycarbonyloxymethylacetamido]-3 cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+#1 90.90% in CHCl3); IR: 3380, 1780 (shoulder), 1770-1 695 (broad), 1490 cm-l (CH2CI2); UV: 247 (6600), 251 (6700), 257 (6900), 263 (7000), 267 (6800; C2H5OH).

From the toluene/ethyl acetate (85:15) fractions, 3-acetoxymethyl-7α-methoxy-7ss-[(2R)-2- ((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-methoxymetholacetamido]3-cephem-4-carboxylic acid diphenyimethyl ester is isolated, [α]E20 =+41 #1 (1.07% in CHCl3); IR: 3375, 1780, 1760-1690 (broad), 1590 cm- (CH2Cl2); UV: 247 (5400), 251 (5500), 257 (5700), 263 (6700), 267 (5600; C2H5OH), 12d) Analogousiy to Example 1c). 5.2 g of 3-acetoxymethyl-7α-methoxy-7ss-[(2R)-2-((2R)-2- BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylemino)-2-methoxymethylacetamido]-3caphem-4-carboxylic acid diphenylmethyl ester are reacted in 10 ml of CH2Cl2 and 3.78 ml of anisole with 49.66 ml of trifluoroacetic acid and worked up.The sodlum salt of 3-acetoxymethyl-7α-methoxy- 7ss-[(2R)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino]-2-methoxymethylacetamido]-3-cephem-4 carboxylic acid is obtanined in the form of the hydrate.

Decomposition from 1550; [α]D20 =+120 #1 (0.80% in H2O); IR: 3600-2500 (broad), 1760,1730,1683,1632, 1607,1512, 1460cm (Nujol); UV:240 (6000), 264(7200;H2O).

12e) As described in Example 1e), 1.75 g of the sodium sait of 3-acetoxymethyl-7α-methoxy-7ss- [(2R)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino]-2-methoxymethylacetamido]-3-caphem-4carboxylic acid are reacted with 0.93 g of the sodium salt of 1 -methyl-5-mercapto-1 H-tetrazole, worked up and chromatographed. The sodium salt of 3-[1-methyl-1 H-tetrazol-5-ylthiomethyl)-7amethoxy-7ss-[(2R)-2-((2R)-2-amino-2-carboxyathoxycarbonylamino)-2-methoxyathylacetamido]-3cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 135 ; [α]D20 =+62 #1 (0.75% in H2O); IR: 3600-2500, 1760, 1710, 1673, 1520, 1462 cm-' (Nujol); UV: 240 (7100), 268 (8200; H2O).

12f) As described in Examplc 8b), 4.8 g of 3-acetoxymethyl-7α-methoxy-7ss-[(2R)-2-((2R)-2- BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylemino)-2-trichloroethoxycarbonylioxymethylacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reduced with 7.2 g of zinc dust in 55 ml of acetonitrile/acetic acid (1:1), worked up and chromatographed. 3-acetoxymethyl-7a methoxy-7A-[(2R)-2-((2R)-2-BOC-amine-2-diphenylmethoxyCarbonylethoxyCarbonylamino)-2- hydroxymethylacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+46 #1 (0.73% in CHCl3); IR: 3380, 1780, 1740-1 700 (broad), 1690 (shoulder) 1590 cm- (CH2CI2); UV: 251 (5200), 257 (6300), 263 (5400), 267 (5200; C2H3OH).

12g) Analogously to Example 1c), 4.1 g of 3-acetoxymethyl-7α-methoxy-7ss-[(2R)-2-((2R)-2- BOC-amino-2-diphenyl methoxycarbonylethoxycarbonylamino)-2-hydroxymethylaceta mido]-3cephem-4-carboxylic acid diphenylmethyl ester are reacted in 7.5 ml of CH2Cl2 and 2.98 ml of anisole with 39.1 5 ml of trifluoroacetic acid and worked up. The sodium salt of 3-acetoxymethyl-7a-methoxy7ss-[(2R)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-hydroxymethylacetamido]-3-cephem-4carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1550; [aj20'=+1430*10 (0.76% in H2O); IR: 3600-2500 (broad), 1770,1730,1695,1611, 1532, 1467 cm-' (Nujol); UV: 240 (6400), 266 (7700; H2O).

1 2h) As described in Example 1 e), 1.5 g of the sodium salt of 3-acetoxymethyl-7a-methoxy-7p- [(2R)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-hydroxymethylacetamido]-3-cephem-4carboxylic acid are reacted with 0.82 g of the sodium sait of 1-methyl-5-mercapto-1H-tetrazole, worked up and chrnmatographed The sodium salt of 3-(1-methyl-1 H-tetrazol-S-ylthiomethyl)-7a- methoxy-7p-[(2 R)-2-((2R)-2-am ino-2-carboxyethoxycarbonylamino)-2-hydroxymethylacetamido]-3- cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1500; [α]D20 =+75 #1 (0.93% in H2O); IR: 3600-2500 (broad), 1770, 1725, 1692, 1620, 1533, 1466 cm- (Nujol); UV: 238 (8000), 270 (9200; H2O).

The starting material for Examples 1 2a)-1 2) can be manufactured as follows: 12I) Analogously to Example 8a), 10.4 g of N-BOC-[D]-serine and 20 g of 3-acetoxymethyl-7ssamino-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 240 ml of dioxan and 160 ml of tatrahydrofuran with 3.92 g of hydroxybenztriazols and 3x3.4 g of dicyclohexyl carbodiimide, worded up and chromatographed. 3-acetoxymethyl-7ss-[(2R)-2-BOC-smino-2hydroxymethylacetamido]-3-cephem-4-carboxylic acid diphenylimethyl ester is obtained.

[aj20,=+ 1 30 * 1 (1.03% in CHCl3) IR: 3500, 3370, 1780, 1720, 1690, 1488 cm-' (CH2CI2); UV: 260 (7200; C2H6OH).

12J) As des cribed in Example 1ml, 18 g of 3-acetoxymethyl-7ss-[(2R)-2-BOC-amino-2hydroxymethylacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted with 10.9 g of p-toluenesulphonic acid monohydrate 100 ml of acetonitrile and worked up. 3-acetoxymethyl-7ss [(2R)-amino-2-hydroxymethylacetamido]-3-cephem-4-carboxylic acid diphenyimethyl ester toluensulphonic acid salt is obtained.

[α]D20 =+22 #1 (0.74% in CH3OH); IR: 3600-2500 (broad), 1785, 1732, 1693, 1550, 1490, 1461 cm- (Nujol); UV: 260 (7200; C2H5OH).

Example 13 1 3a) Analogously to Example 4a), 3.412 g of the (2R)-2-((2R)-2-BOC-amino-2diphenylmethoxycarbonylethoxycarbonylamino)-2-phenylacetic acid obtainable according to Example 4d) and 2.45 g of 3-(1-methyl-1 H-tetrazol-5-ylthiomethyl)-7ss-amino-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted (0.72 ml of N-methylmorpholine+0.68 ml of chloroformic acid isobutyl ester in 90 ml of tetrahydrofuran), worked up and chromatographed (200 g of silica gel; eluant: toluene/ethyl scetate [4:1], fraction slze 25 ml). By combining the fractions containing the product and reprecipitating from methylene chlorolde/hexane, 3-(1-methyl-1H-tetrazol-5-ylthlomethyl)7ss-[(3R)-2-((2R)-2-BOC-amino-3-diphenylmethoxycarbonylethoxycarbonylamino)-2phenylacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =-94 #1 (1,11% in CHCl3); IR: 3360, 1790, 1728, 1705 (shouider), 1500 cm-' (Nujol); UV: 262 (9000), 267 (8900; C,HSOH).

1 3b) Analogously to Example 1 c), 2 g of 3-(1-methyl-1 H-tetrazol-5-ylthlomethyl)-7ss-[(2R)-2- (2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-phenylacetamido]-3cephem-4-carboxylic acid diphenylmethyl ester are reacted in 4 ml of trifluoroacetic acid and worked up. The sodium salt of 3-(1-methyl-1 H-tetrazol-5-ylthiomethyl)-7,B-[(2R)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-2-phenylacetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1800; [aj20'=260+1 (0,91% in H2O); IR: 3600-2500, 1770, 1718 (shoulder), 1682 (shoulder), 1611, 1532, 1465 cm- (Nujol); UV: 265 (9600; H2O).

Example 14 1 4a) Analogously to Example 4a), 4 g of (2S)-2-((2R)-2-BOC-amino-2 diphenylmethoxycarbonylethoxycarbonylamino)-2-phenylacetic acid and 3.12 g of 3-( 1 -methyl-1 H tetrazol-5-yEthiomethyl)-7,B-amino-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted (0.92 ml of N-methylmorpholine+0.87 ml of chloroformic acid isobutyl ester in 1 50 ml of tetrahydrofuran), worked up, chromatographed and re-precipitated. 3-( 1-methyl- 1 H-tetrazol-5-ylthiomethyl)-7ss-[(2S)- 2-[(2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-phenylacetamido]-3cephem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =-65 #1 (1.05% in CHCI3); IR: 3355, 1790, 1727, 1692 (shoulder), 1500, 1458 cm- (Nujol); UV: 264 (9000), 268 (8900; C2HsOH).

1 4b) Analogously to Example 1 c), 2 g of 3-(1-methyl-1- H-tetrazol-5-ylthiomethyl]-7ss-[(2S)-2- ((2R)-2-BOC-amino-2-diphenyimethoxycarbonylethoxycarbonylamino)-2-phenylacetamido]-3cephem-4-carboxylic acid diphenylmethyl ester are reacted and worked up. The sodium salt of 3-(1methyl-1H-tetrazol-5-ylthoomethyl)-7ss-[(2S)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2phenylacetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1780; [α]D20 =+44 #1 (1.03% in H2O); IR: 3600-2500,1770,1721 (shoulder), 1682 (shoulder), 1612, 1531, 1463 cm- (Nujol); UV: 265 (9500; H2O).

The starting material for Examples 1 4a)-1 4b) can be manufactured as follows: 1 4c) As described in Example 4d), 1.25 g of L-phenylglycine and 3.94 g of (2R)-2-BOC-amino-2 diphenylmethoxycarbonylethoxycarbonyl chloride are reacted and worked up. (2S)-2-((2R)-2-BOC a mino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-phenylacetic acid is obtained which is further processed (Example 1 4a)) without being characterised.

Example 15 1 5a) Analogously to Example 8a), 15 g of (2R,S)-2-((2R)-2-BOC-amino-2-diphenyl methoxycarbonylethoxycarbonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid and 10 g of 3-(1 methyl H-tetrazol-5-ylthiomethyl)-7,B-amino-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 150 ml of tetrahydrofuran (1.76 g of hydroxybenztriazole+3 x1 .63 g of dicyclohexyl carbodiimide in 50 ml of tetrahydrofuran in each case) and worked up. The resulting crude product is chromatographed in 5 portions over 450 g of silica gel in each case on graded columns (eluant: toluene/ethyl acetate 85:5 mixture; 25 ml fractions).First of all there is eluted 3-(1-methyl-1 Htatrazol-5-ylthiomethyl)-7ss-[(2R)-2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonyletoxycarbonyl amino)-2-(2-BOC-aminothiazol-4-yl)-acetamidoj-3-cephem-4-carboxylic acid diphenylmethyl ester which is re-precipitated from CH2Cl2/ether/hexane. The assignment of configuration at the a-carbon atom of the acetyl radical in the 7P-acyl side chain is made using the methods mentioned in Example 9a).

[α]D20 =-68 #1 (1.03% in CHCl3); IR: 3400, 1784, 1730-1 690 (broad), 1520 (shoulder), 1490 cm-' (CH2CI2); UV: 260 (17000; C2HsOH).

The next eluted fractions consist of a binary mixture of the above-mentioned compound and the corresponding (2S)-isomer which can be further separated by repeating chromatography once more.

Finally, pure 3-(1-methyl-1 H-tetrazol-5-ylthiomethyl)-7P-[(2S)-2-(( R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonylami no)-2-(2-B0C-amino-thiazol-4-yl)-aceta mido]-3-cephem- 4-carboxylic acid diphenylmethyl ester is eluted which can be re-precipitated from CH2Cl2/ether/hexane. The assignment of configuration at the carbon atom of the acetyl radical in the 7ss-acyl side chain is made using the methods mentioned in Example 9a).

[α]D20 =-36 #1 (0.82% in CHCl3); IR: 3400, 1796, 1730-1690 (broad), 1540 (shoulder), 1495 cm- )CH2Cl2); UV: 260 (17400; C2HsOH).

1 5b) Analogously to Example 1 c), 2.8 g of 3-(1-dimethyl-1- H-tetrazol-5-ylthiomethyl)-7ss-[(2R)-2- ((2R)-2-BOC-amino-2diphenylmethoxycarbonyletoxycarbonylamino)-2-[2-BOC-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 4.8 ml of CH2CI2 and 2.4 ml of anisole with 1 9.6 ml of trifluoroacetic acid (reaction period: 1 hour) and worked up. The hydrate of the sodium salt of 3-(1-methyl-1 H-tetrazol-5-ylthiomethyl)-7p-[(2R)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4carboxylic acid is obtained.

Decomposition from 1 680; [α]D20 C=-1 #1 (0.93% in H20); IR: 3600-2500 (broad), 1770, 1715 (shoulder), 1680 (shoulder), 1622, 1523, 1465 cm- (Nujol); UV: 258 (13000; H20).

15c) As described in Example 1 c), 1.83 g of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2S)-2- ((2R)-2-BOC-amino-2-diphenylmethoxywarbonylethoxywarbonylamino)-2-(2-BOC-aminothiazol-4-yl)- acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 3.2 ml of CH2CI2 and 1.6 ml of anisole with 12.8 ml of trifluoroacetic acid and worked up. The hydrate of the sodium salt of 3-(1methyl 1 H-tetrazol-S-ylthiomethyI)-7-[(2S)-2-((2Fl)-2-amino-2-carboxyethoxycarbonylamino)-2-(2- aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid is obtained.

Decomposition from 1700; [a]20"=+S20*l 0 (0.75% in H2O); IR: 3600-2500 (broad), 1770, 1719 (shoulder), 1625, 1525, 1467 cm- (Nujol); UV: 255 (12100; H2O).

Example 16 As described in Example 1 i), 3.4 g of the sodium salt of 3-acetoxymethyl-7ss-[(2R,S)-2-(2R)-2- amino-2-carboxyethoxyarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid obtainable according to Example 8c), 1.046 g of isonicotinamide, 9.48 g of sodium iodide and 1.032 g of trichloroacetic acid are reacted in 6.3 ml of water, worked up and chromatographed. 3-(4carbamoylpyridiniomethyl)-7ss-[(2R,S)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-(2 aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1600; [α]D20 =+10 #1 (0.84% in H2O); IR: 3600-2500, 1772, 1620 (shoulder), 1687 (broad), 1520 cm- (Nujol); UV: 258 (14300; H2O).

Example 17 1 7a) Analogously to Example 8a), 3 g of (2R,S)-2-((4R)-4-BOC-amino-4-tertbutoxycarbonylbutyramido)-2--(2-BOC-aminothiazol-4-yl)-acetic acid and 2.47 g of 3-(1-methyl-1- H tetrazoi-5-ylthiomethyl)-7p-amino-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 40 ml of tetrahydrofuran (0.43 g of hydroxybenztriazole+3x0.38 g of dicyclohexyl carbodiimide in 50 ml of tetrahydrofuran in each case) and worked up.After chromatography of the crude product over 200 g of silica gel (eluant: ether/ethyl acetate 4:1; fraction size 100 ml), 3-(1-methyl-1 H-tetrazol-5ylthiomethyl)-7ss-[(2R,S)-2-((4R)-4-BOC-amino-4-tert-butoxycarbonylbutyramido)-2-(2-BOC aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained which is re-precipitated from CH2CI3/ether/hexane.

[α]D20 =-88 #1 (0.91% in CHCl3); IR: 3430, 3315, 1790, 1722, 1688, 1547, 1503 cm- (CH2CI2); UV: 260 (16200; C2H5OH).

1 7b) As described in Example 1 c), 3.8 g of 3-(1-methyl-1 H-tetrazol-5-ylthiomethyl)-7ss-[(2R,S)- 2-( (4R)-4-BOC-am ino-4-tert-butoxycarbonylbutyra mido)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3cephem-4-carboxylic acid diphenylmethyl ester are reacted in 5 ml of CH2CI2 and 1.1 ml of anisole with 20 ml of trifluoroacetic acid and worked up. The hydrate of the sodium salt of 3-(1 -methyl-1 H-tetrazol5-ylthiomethyl)-7ss-[(2R,S)-2-((4R)-4-amino-4-carboxybutyramido)-2-(2-aminothiazol-4-yl) acetamido]-3-cephem-4-carboxylic acid is obtained.

Decomposition from 2100; [α]D20 =-10 #1 (1.15% in H2O); IR: 3600-2500,1770,1718, 1530 cm- (Nujol); UV: 258 (13400; H2O).

The starting material for Examples 1 7a)-1 7b) can be manufactured as follows: 1 7c) 3 g of (4R)-4-BOC-amino-4-tert-butoxycarbonylbutyric acid are dissolved in 200 ml of tetrahydrofuran, the solution is cooled to 200 and 1.35 ml of N-methylmorpholine and 1.3 ml of chloroformic acid isobutyl ester are added in succession. The mixture is stirred at 200 for 3 hours, 2.9 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-glycine methyl ester are added, the mixture is stirred at O 0 for a further 3 hours and worked up as described in Example 11). The crude product is chromatographed over 200 g of silica gel (eluant: ether; fraction size 100 ml).Combination of the fractions containing the product yields (2R,S)-2-((4R)-4-BOC-amino-4-tert-butoxycarbonylbutyramido)-2-(2-BOCaminothiazol-4-yl)-acetic acid methyl ester which is further processed (Example 1 7d)) without being characterised.

1 7d) 50 ml of 1 N aqueous NaOH are added to 2.7 g of (2R,S)-2-((4R)-4-BOC-amino-4-tert- butoxycarbonylbutyramido)-2-(2-BOC-aminothiazol-4-yl)-acetic acid methyl ester in 50 ml of methanol and the mixture is stirred at room temperature for 30 minutes. It is then extracted with ethyl acetate and washed twice with water. The ethyl acetate phase is eliminated. The combined aqueous portions are adjusted at 0 to pH 3 with 4N HCI, extracted with ethyl acetate and washed four times with saturated aqueous NaCI solution. The crude (2R,S)-2-((4R)-4-BOC-amino-4-tert- butoxycarbonylbutyramido)-2-(2-BOC-aminothiazol-4-yl)-acetic acid obtained after drying of the organic phase and concentration thereof by evaporation is further processed (Example 1 7a)) without being characterised.

Example 18 1 8a) Analogously to Example 1 a), 13.7 g of 3-acetoxymethyl-7ss-(4-aminobutyramido)-3- cephem-4-carboxylic acid diphenylmethyl esterp-toluenesulphonic acid salt are reacted in 350 ml of tetrahydrofuran together with 5 ml of pyridine and 18.8 g of (2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonyl chloride, worked up and chromatographed. After combining the fractions containing the product, 3-acetoxymethyl-7,6-[4-((2R)-2-BOC-amino-2-diphenylmethoxy- carbonylethoxycarbonylamino)-butyramido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

IR: 3390, 1782, 1 740-1 690 (broad), 1 511 (shoulder), 1496 cm-' (CH2CI2); UV: 258 (7900), 264 (7750; EtOH).

1 8b) Analogously to Example 1 b), 9.2 g of 3-acetoxymethyl-7ss-[4-((2R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonylamino)-butyramido]-3-cephem-4-carboxylic acid diphenylmethyl ester are methoxylated in 920 ml of tetrahydrofuran (0.28 g of lithium in 35 ml of methanol; 2.2 ml of tert-butyl hypochlorite divided into two portions of 0.85 and one portion of 0.5 ml), worked up and chromatographed. 3-acetoxymethyl-7cr-methoxy-7,B-[4-((2R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonylamino)-butyramido]-3-caphem-4-carboxylic acid diphenylmethyl ester is obtained.

[α]D20 =+47 #1 (1.21% in CHCI3); IR: 3465, 1790, 1730, 1695 (shoulder), 1498 cm-t (CH2CI2); UV: 246 (5100), 251(5200), 258 (5200), 263 (5400; CH2CI2).

1 8c) Analogously to Example 1 c), 10.1 g of 3-acetoxymethyl-7α-methoxy-7ss0[4-((2R)-2-BOC- amino-2-diphenylmethoxycarbonyletoxycarbonylamino)-butyramido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 10 ml of CH2CI2 and 2.6 ml of anisole with 25 ml of trifluoroacetic acid and worked up. The sodium salt of 3-acetoxymethyl-7α-methoxy-7ss-[4-((2R)-2-amino-2- carboxyethoxycarbonylamino)-butyrnmidoi-3-cephem-4carboxyIic acid is obtained in the form of the hydrate.

Decomposition from 180 ; [c]20O=+126 ~ 1 (0.75% in H2O); IR: 3600-2400 (broad), 1770, 1725, 1612, 1532 cm- (Nujol); UV: 240 (5600), 265 (6600; H2O).

1 8d) Analogously to Example 1 c), 7.2 g of 3-acetoxymethyl-7ss-[4-((2R)-2-BOC-amino-2- diphenylmethoxycarbonylethoxycarbonyla mino)-butyramido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 10 ml of CH2CI2 and 1.9 ml of anisole with 12 ml of CF3COOH and worked up. The sodium salt of 3-acetoxymethyl-7,B-[4-((2R)-2-amino-2-carboxyethoxy- carbonylamino)-butyramido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1800; IR: 3600-2400 (broad), 1765,1712,1656,1611, 1539 cm- (Nujol); UV: 257 (6800; H2O).

1 8e) Analogously to Example 1 e), 2.5 g of the sodium salt of 3-acetoxymethyl-7a-methoxy-7X5- [4-((2R)-2-amino-2-ca rboxyethoxyca rbonyla mino)-butyramido]-3-cephem-4-carboxylic acid are reacted with 1.2 g of the sodium salt of 1 -methyl-5-mercapto-1 H-tetrazole. The sodium salt of 3-(1methyl- 1 H-tetrazol-S-ylthiomethyl)-7 a-methoxy-7-[4-((2R)-2-amino-2- carboxyethoxycarbonylamino)-butyramido]-3-cephem-4-carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1850; [z]2 D=+72O+ 1 (0.92% in H2O); IR: 3600-2400 (broad), 1772, 1712, 1610 (broad), 1535 cm-' (Nujol); UV: 238 (7000), 270 (8700; H2O).

1 8f) Analogously to Example 1 e), 2.5 g of the sodium salt of 3-acetoxymethyl-7P-I4-((2R)-2- amino-2-carboxyethoxycarbonylamino)-butyramido]-3-cephem-4-carboxylic acid are reacted with 1.3 g of the sodium salt of 1 -methyl-5-mercapto-1 H-tetrazole. The sodium salt of 3-( 1 -methyl-1 H-tetrazol 5-ylthiomethyl)-7p-[4-((2R)-2- amino-2-carboxyethoxycarbonylamino)-butyramido]-3-cephem-4carboxylic acid is obtained in the form of the hydrate.

Decomposition from 1900; [α]D20 =+1 #1 (1.04% in H20); IR: 3600-2400, 1 770, 1 711, 1 665-1600 (broad), 1540 cm~1 (Nujol); UV: 267 (9700; H20).

The starting material for Examples 18a)--18f) can be manufactured as follows: 1 8g) Analogously to Example 11). 30.5 g of N-BOC-4-aminobutyric acid and 65.7 g of 3 acetoxymethyl-7,3-amino-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted (20.5 ml of Nmethylmorpholine; 20 ml of chloroformic acid isobutyl ester; 1100 ml of tetrahydrofuran) and worked up. By crystallisation of the crude product from ether, 3-acetoxymethyl-7-(4-BOC-aminobutyramido)- 3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

IR: 3385, 1 780, 1740-1 690 (broad), 1512(shoulder), 1492 cm- (CH2CI2); UV: 262 (7900; EtOH).

18h) Analogously to Example 1 m), 87 g of 3-acetoxymethyl-7p-(4-BOC-aminobutyramido)-3- cephem-4-carboxylic acid diphenylmethyl ester are reacted with 53 g of p-toluenesulphonic acid monohydrate in 725 ml of acetonitrile and worked up.3-acetoxymethyl-7p-(4-aminobutyramido)-3- cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonic acid salt is obtained.

IR: 3600--2400 (broad), 1781, 1727, 1690, 1550(broad), 1485 cm-' (Nujol); UV: 260 (6900; EtOH).

Example 19 1 9a) Analogously to Example 8a), 7.5 g of (2R,S)-2-((2R)-2-BOC-amino-2 diphenylmethoxycarbonylethoxycarbonylamino)-2-(5-BOC-amino-1 ,2,4-thiadiazol-3-yl)-acetic acid and 5 g of 3-(1-methyl-1 H-tetrazol-5-ylthiomethyl)-7,5-amino-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 75 ml of tetrahydrofuran, worked up and re-precipitated. 3-(1methyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2R,S)-2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonyl ethoxyca rbonylamino)-2-(5-BOC-a mino- ,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained.

IR: 3400, 1782, 1735-1690 (broad), 1521 (shoulder), 1490 cm-1 (CH2CI2); UV: 260 (16800; EtOH).

19b) Analogously to Example 1 c), 5.6 g of 3-( 1 -methyl-1 H-tetrazol-5-ylthiomethyl)-7p-[(2R,S)- 2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-(5-BOC-amino-1,2,4thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 9.6 ml of CH2CI2 and 4.8 ml of anisole with 40 ml of trifluoroacetic acid (reaction period 1 hour) and worked up.

The hydrate of the sodium salt of 3-( 1 -methyl-1 H-tetrazol-5-ylthiomethyl)-7p-[(2R,S)-2-((2R)-2- amino-2-carboxyethoxycarbonylamino)-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4carboxylic acid is obtained.

IR: 3600-2400 (broad), 1 771, 1720-1 680 (broad), 1620, 1520, 1465 cm- (Nujol); UV:258 (12900; H2O) The starting material for Examples 1 9a)-1 9b) can be manufactured as follows: 19c) 14 g of 2-(5-BOC-amino-1,2,5-thiadiazol-3-yl)-2-Z-methoxyiminoacetic acid methyl ester are exhaustively hydrogenated in the presence of 10 g of 5% palladium-on-carbon in 550 ml of methanol/acetic acid (1 :1) mixture. The mixture is then filtered from the catalyst with suction and concentrated to dryness by evaporation in vacuo. The residue is dissolved in water, adjusted to pH 7 with 2N aqueous NaOH, extracted with ethyl acetate and washed three times with water. The organic phase is then extracted three times with 50 ml of 2N HCI each time.The ethyl acetate phase is eliminated. and the aqueous portions are again adjusted to pH 7 with 2N NaOH while cooling with ice.

The mixture is then extracted again with ethyl acetate, washed neutral with saturated NaCI solution, dried over Na2SO4 and concentrated by evaporation in vacuo. (2R,S)-2-(5-BOC-amino-l ,2,4-thiadiazol- 3-yl)-2-aminoacetic acid methyl ester is obtained which is further processed directly.

19d) 7.6 g of (2R,S)-2-(5-BOC-amino-l ,2,4-thiadiazol-3-yl)-2-amino-acetic acid methyl ester are stirred for one hour at room temperature in a mixture of 25 ml of methanol and 71 ml of 0.75N sodium hydroxide solution. The mixture is then adjusted to pH 7 with 1 N HCI, and concentrated to dryness by evaporation in vacuo. The evaporation residue is dissolved in 50 ml of water and the solution is adjusted to pH 9.5 with 2N NaOH. Then, at 00, a solution of 9.2 g of (2R)-2-BOC-amino-2 diphenylmethoxycarbonylethoxycarbonyl chloride in 60 ml of acetonitrile is added dropwise, in the course of 15 minutes, while stirring, the pH being maintained constant at 9.5 by adding 2N NaOH (titrator). Stirring is then continued at pH 9.5 and 0 for 2 hours. The mixture is then adjusted to pH 3 with 2N HCI while cooling with ice, extracted with ethyl acetate, washed neutral with saturated aqueous NaCI solution, dried over Na2SO4 and concentrated by evaporation. (2R,S)-2-((2R)-2-BOCamino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)acetic acid is obtained which is further processed directly.

Example 20 20a) 2.27 g of dicyciohexyl carbodiimide dissolved in 25 mi of tetrahydrofuran are added, while stirring, in the course of 10 minutes, to a solution, cooled to 0 , of 6.7 g of (2R,S)-2-((2R)-2-BOC amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-(2-BOC-aminothiazol-4-yI)-acetic acid and 1.35 g of 1 -hydroxybenztriazole in 75 ml of tetrahydrofuran. After two hours, there are added to this suspension 3.57 g of 3-methoxy-7ss-amino-3-cephem-4-carboxylic acid diphenylmethyl ester. After a reaction time of one hour at 0 and 3 hours at room temperature, the precipitate that has formed is filtered off and the solvent is distilled off.The residue is then taken up in ethyl acetate (500 ml) and washed three times in each case with 50 ml of ice-water, 1 N hydrochloric acid and saturated sodium chloride solution. The mixture is dried over sodium sulphate, and the crude product is freed of solvent and purified over silica gel using methylene chloride/ethyl acetate (4:1) as eluant to yield 3-methoxy 7p-[(2R,S)-2-((2R)-BOC-amino-2-diphenylmethoxyCarbonylethoxycarbonylamino)-2-82BOC-amino- thiazol-4-yl)-aceta mido]-3-cephem-4-carboxylic acid diphenylmethyl ester.

TLC (silica gel, identification with iodine): Rf#0.58 (methyiene chloride/ethyl acetate 1:1).

20b) Analogously to Example 20al, 7ss-[(2R)-BOC-amino-2-diphenylmethoxycarbonyl- rtoxycarbonylamino)-2-(2-BOC-aminothiazol-4-yl)-acstamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained by treating 6.7 g of (2R,S)-2-((2R)-2-BOC-amino-2-diphenylmethoxy- carbonylethoxycarbonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid and 3.29 g of 7ss-amino-3- cephem-4-carboxylic acid diphenylmethyl ester with 1.35 g of 1 -hydroxybenztriazole and 2.27 g of dicyclohexyl carbodiimide in tetrahydrofuran (100 ml) as solvent.

TLC (silica gel, identification with iodine): Rf#0.68 (methylene chloride/ethyl acetate (1:1).

20c) Analogously to Example 20b),3-carbamoyloxymethyl-7p-[(2R,S)-2-((2R)-BOC-amino-2- diphenylmethoxycarbonylamino)-2-[2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained by treating 4.02 g of (2R,S)-2-((2R)-2-BOC-amino-2-diphenyl methoxycarbonylethoxycarbonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid and 2.42 g of 3 carbamoyloxymethyl-7,B-amino-3-cephem-4-carboxylic acid diphenylmethyl ester with 0.81 g of 1hydroxybenztriazole and 1.24 g of dicyciohexyl carbodiimide in tetrahydrofuran (65 ml) as solvent.

TLC (silica gel, identification with iodine): Rf#0.48 (methylene chloride/ethyl acetate 1:1).

20d) 18.5 ml of trifluoroacetic acid are added to a solution of 3.70 g of the 3-methoxy-7p- [(2R,S)-2-((2R)-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-(2-BOC.

aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester obtainable according to Example 20a) and 3.7 ml of anisole in 18.5 ml of methylene chloride, the mixture is stirred at room temperature for one hour and then, at 00, diethyl ether (200 ml) is added in the course of 15 minutes.

The resulting precipitate of the trifluoroacetic acid salt is dissolved, after filtration, in water (12 ml) and extracted with ethyl acetate (3x5 ml). The acid aqueous phase (pH 1.5) is adjusted to pH 7 at 0 by adding 2N sodium hydroxide solution and ethanol (45 ml) is added. The resulting precipitate is filtered off, taken up in water to remove the organic solvent and concentrated in a rotary evaporator. After drying (16 hours, room temperature, 0.05 torr), the sodium salt of 3-methoxy-7/3-[(2R,S)-2-((2R)- amino-2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid is obtained in the form of a dihydrate.

mp:from 2100 (with decomposition); TLC (silica gel OPTI-UPC,2, identification with ninhydrin): Rf#0.33 (water).

20e) Analogously to Example 20d), the sodium salt of 7P-[(2R,S)-2-((2R)-2-amino-2- ca rboxyethoxycarbonylamino)-2-(2-a minothiazol-4-yi)-acetamido]-3-cephem-4-carboxylic acid is obtained in the form of a trihydrate by treating 8.2 g of the 7P- [(2R,S)-2-((2 R)-BOC-a mi no-2- diphenylmethoxycarbonylethoxycarbonyla mino)-2-(2-BOC-a minothiazol-4-yl)-acetamido]-3-cephem- 4-carboxylic acid diphenylmethyl ester obtainable according to Example 20b) in the presence of 8 ml of anisole with 40 ml of trifluoroacetic acid in 40 ml of methylene chloride.

mp: from 2000 (with decomposition); [a]200=+860*1 (1.195% in 0.1 N hydrochloric acid); UV: 252 nm (13100) in 0.1N hydrochloric acid; TLC (silica gel, OPTI-UPC,2, identification with ninhydrin): Flf""'0.78 (water/acetonitrile 9:1).

20f) Analogously to Example 20d), the sodium salt of 3-carbamoylmethyl-7p-[(2R,S)-2-((2R)- amino-2-ca rboxyethoxycarbonylamino)-2-(2-a minothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid is obtained in the form of a dihydrate by treating 3.9 g of the 3-carbamoyloxymethyl-7p-[(2R,S)-2- ((2R)-BOC-amino-2-diphenylmethoxyCarbonyiethoxycarbonylamino)-2-(2-BOC-aminothiazol-4-yl)- acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester obtainable according to Example 20c) in the presence of 4 ml of anisole with 20 mT of trifluoroacetic acid in 20 ml of methylene chloride.

mp: from 2000 (with decomposition); [a]2,0",+540 +1 (n 0.1N hydrochloric acid); UV: 252 nm (14900) in 0.1N hydrochloric acid; TLC (silica gel, OPTI-UPCt2, identification with ninhydrin): Ref~0.77 (water/acetonitrile 9:1).

The starting material for Examples 20a) to 20c) can be manufactured as follows: 20g) A mixture of 43.1 g of 2-(2-aminothiazol-4-yl)-2-syn-methoximinoacetic acid methyl ester and 131 g of di-tert-butyl dicarbonate is heated at 1100 for 2 hours while removing by distillation the tert-butanol being formed. Another 43.6 g of di-tert-butyl di-carbonate are then added. After a total reaction time of 4 hours, the crude product is purified over silica gel with hexane/diethyl ether (1 :1) as eluant to yield 2-(2-BOC-aminothiazol-4-yl)-2-syn-methoximinoacetic acid methyl ester in the form of an amorphous powder.

TLC (silica gel, identification with iodine): Rf#0.67 (diethyl ether); IR (CH2CI2) inter alia characteristic absorption bands at 3395, 1730, 1645, 1155 and 942 cm~'.

20h) A solution of 26.8 g of 2-(2-BOC-aminothiazol-4-yl)-2-syn-methoximinoacetic acid methyl ester in 1.1 litres of acetic acid/methanol (1:1) is hydrogenated in the presence of 13.4 g of palladiumon-carbon (10%) as catalyst. When the theoretical amount of hydrogen has been absorbed, the reaction mixture is filtered over Celite and freed of solvent under reduced pressure. The residue is taken up in ethyl acetate (1 litre) and washed twice with 5% sodium bicarbonate and sodium chloride solution each time. After drying of the organic phase with sodium sulphate and removal of the solvent, 2-(2R,S)-amino-2-(2-BOC-aminothiazol-4-yl)-acetic acid methyl ester which is uniform according to thin-layer chromatography is obtained and is used directly in the next reaction step.

TLC (silica gel, identification with iodine): Rf#0.60 (sec-butanol/acetic acid/water 67:10:23).

20i) 32.4 g of potassium hydroxide dissolved in 276 ml of water are added, while stirring at room temperature, to a solution of 28.94 g of 2-(2R,S)-amino-2-(2-BOC-aminothiazol-4-yl)-acetic acid methyl ester in 650 ml of ethanol. After 1.5 hours, the reaction mixture, cooled to 00, is adjusted to pH 7 with 4N hydrochloric acid and concentrated under reduced pressure to approximately 350 ml. After acidifying this solution to pH 4.5 with 4N hydrochloric acid, the resulting precipitate is filtered off and dried over phosphorus pentoxide (16 hours, room temperature, 0.01 torr). The resulting 2-(2R,S)amino-2-(2-BOC-aminothiazol-4-yl)-acetic acid contains 0.5 mol of water.

mp: 159162 (with decomposition); TLC (silica gel, identification with ninhydrin): Rf#-0.48 (sec-butanol acetic acid/water 67:10:23).

20k) A suspension of 10.92 g of 2-(2R,S)-amino-2-(2-BOC-aminothiazol-4-yl)-acetic acid in 300 ml of acetonitrile/water (1:1) cooled to 0 is adjusted to pH 9.5 with 1 N sodium hydroxide solution and, in the course of 10 minutes, 19.07 g of (2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonyl chloride dissolved in 100 ml of acetonitrile are added. During the total reaction time of 3 hours, the pH is maintained constant at 9.5 by adding dropwise 1 N sodium hydroxide solution. The reaction mixture is then adjusted to pH 2 with 2N hydrochloric acid, diluted with ethyl acetate and washed with ice-water.After drying the organic phase over sodium sulphate, the solvent is distilled off, and the residue is purified over silica gel with methylene chloride/ethyl acetate (4:1) as eluant to yield (2R,S)-2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-2-(2- BOC-aminothiazol-4-yl)-acetic acid.

TLC (silica gel, identification with iodine): R,~0.75 (chloroform/methanol/acetic acid 75:22:13).

Example 21 Analogously to the preceding Examples, the following compounds can be manufactured starting from appropriate starting materials and intermediates: 3-(4-methyl-5,6-dioxo- 1 ,4,5,6-tetrahydro-as-triazin-3-yithiomet carboxyethoxyca rbonylamino)-aceta mido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1770,1718,1648 (broad), 1570,1510 cam~' (Nujol); UV: 234 (16800). 278 (24100; H20).

3-pyridiniomethyl-7ss-[2-((2R)-2-carboxyethoxycarbonylamino)-acetamido]-3-cephem4-carboxylic acid.

IR: 3600-2400 (broad), 1770, 1725, 1655 (broad),1570,1510 cm-l (Nujol); UV: 234 (16900), 277 (23600; H20).

3-pyridiniomethyl-7p-[(2S)-2-((2R)-2-amino-2-carboxyethoxyCarbonyla mino)-2-(2-a minothiazol- 4-yl)-acetamido]-3-cephem-4-carboxylate.

IR: 3600-2450 (broad), 1770, 1720 (shoulder), 1690 (broad), 1615 (broad), 1 520 cm-l (Nujol); UV:259(14100;H20).

3-(2-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-2-ylthiomethyl)-7ss-[(2S)-2-((2R)-2-amino2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2390 (broad), 1772, 1720, 1650, (broad), 1575, 1510 cm- (Nujol); UV: 279 (21200; H2O).

3-(4-methyl-5,8-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthoomethyl-7ss-[(2S)-2-((2R)-2-amino 2-carboxyethoxywarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400, 1775, 1722, 1 655 (broad), 1570, 1510 cm-' (Nujol); UV: 278 (20900; H2O).

7ss-[(2S)-2-((2R)-2-amino-2-carboxyethoxylamino)-2-(5-amino-1,2,4-thladiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2500 (broad), 1770, 1715, 1680, 1610, 1520 1460 cm- (Nujol); UV: 256 (11000; H2O).

3-acetoxymethyl-7P-[(2S)-2-((2R)-2-a mino-2-carboxyethoxycarbonylamino)-2-(5-amino-1 ,2,4 thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2500, 1775, 1725, 1715, 1683, 1610, 1520 cm- (Nujol); UV: 252 (12000; H2O).

3-(4-carbamoylpyridiniomethyl)-7ss-[(2S)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2 (5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylate.

IR: 3600-2400 (broad), 1772, 1720 (shoulder), 1690 (broad), 1615 (broad), 1520 cm- (Nujol); UV: 259 (13900; H2O).

3-carbamoyloxymethyl-7ss-[(2S)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-(5-amino 1,2,4-thiadiazol-3-yi)-aceta mido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1769, 1720, 1690 (broad), 1620 (broad), 1620 (broad), 1520 cm-l (Nujol); UV: 252 (14000; H2O).

3-pyrldiniomethyl-7ss-[(2S)-2-((2R)-2-amino-2-carboxyethoxycarbonylamlno)-2-(5-amino-1,2,4thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylate.

IR: 3600-2400 (broad), 1770, 1720, 1690 (broad), 1610(broad), 1515 cm~1 (Nujol); UV: 259 (13300; H2O).

3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2S)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2600 (broad), 1 765, 1740-1570 (broad), 1520 cm- (Nujol); UV: 258 (13400; H2O)- 3-(1-sulphomethyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2S)-2-((2R)-2-amino-2-carboxyethoxycarbonylemino)-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2500 (broad), 1765, 1728 (shoulder). 1681 (shoulder), 1625, 1520 cm- (Nujol); UV: 258 (14000; H2O).

3-(2-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthio)-7ss-[(2S)-2-((2R)-2-amino-2 carboxyethoxycarbonylamino)-2-(5-a m ino-l ,2,4-thiadiazol-3-yl)-aceta mido]-3-cephem-4-ca rboxyl ic acid.

IR: 3600-2400 (broad), 1770, 1720, 1650 (broad), 1575 cm- (Nujol); UV: 278 (20900; H2O).

3-(4-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7ss-[(2S)-2-((2R)-2-amino2-carboxyethoxycarbonylamino)-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1771, 1715 (shoulder), 1650 (broad) cm-l (Nujol); UV: 279 (19200; H2O).

3-[ 1 -(2-dimethylaminoethyl)- 1 H-tetrazol-5-ylthiomethyl]-7ss-[(2S)-2-((2 Fl)-2-amino-2- carboxyethoxycarbonylamino)-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600--2500 (broad), 1770, 1712 (shoulder), 1680 (shoulder), 1615, 1508 cm-' (Nujol); UV: 254 (13900; H2O).

7j-[(2S)-2-((3 R)-3-a mino-3-carboxypropiona mido)-2-(2-amino-thiazol-4-yl)-aceta mido]-3cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1765, 1710--1575 (broad), 1500 cm- (Nujol); UV: 259 (12000; H2O).

3-(4-carbamoylpyridiniomethyl)-7P-[(2 S)-2-((3R)-3-amino-3-carboxypropionamido)-2-(2-a minothiazol-4-yl)-acetamido]-3-cephem-4-carboxylate.

IR: 3600-2400 (broad), 1770, 1719, 1685 (broad), 1620 (broad), 1520 cm- (Nujol); UV: 252 (14000; H2O).

3-carbamoyloxymethyl-7ss-[(2S)-2-((3 R)-3-a mino-3-ca rboxypropiona mido)-2-(2-amino-thiazol4-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1772, 1721, 1690 (broad), 1620 (broad), 1520 cm- (Nujol); UV: 252 (13900; H2O)- 3-pyridiniomethyl-7p-[(2S)-2-((3R)-3-amino-3-carboxypropionamido)-2-(2-amino-thiazol-4-yi)- acetamido]-3-cephem-4-carboxylate.

IR: 3600-2400 (broad), 1770, 1720, 1690 (btoad), 1620 (broad) cm- (Nujol); UV: 251 (13800: H2O).

3-(1-carboxymethyl-1H-tetrazol-5-ylthlomethyl)-7ss-[(2S)-2-((3R)-3-amino-3-carboxypropionamido)-2-(2-amino-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1768, 1740, 1570 (btoad), 1620 cm- (Nujol); UV: 258 (14800: H2O).

3-(1-sulphomethyl-1H-tetrazol-5-ylthlomethyl)-7ss-[(2S)-2-((3R)-3-amino-3-carboxypropionamido)-2-(2-amino-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2500 (broad), 1766, 1728, (shoulder), 1680 (shoulder). 1625, 1520 cm- (Nujol); UV: 258 (13500: H2O).

3-(2-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7ss-[(2S)-2-((3R)-3-amino3-carboxypropionamido)-2-(2-amino-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1770, 1720, 1650 (broad), 1575 cm- (Nujol); UV: 278 (20100: H2O).

3-[1 -(2-dimethyla minoethyl)- 1 H-tetrazol-5-ylthiomethyl]-7ss-[(2S)-2-((3 Fl)-3-amino-3-carboxy- propionamido)-2-(2-amino-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600 (broad), 1770, 1712 (shoulder), 1680 (shouder), 1615, 1508 cm- (Nujol); UV: 254 (14000; H2O).

7ss-[(2S)-2-((4R)-4-amino-4-carbxoybutyramido)-2-(2-amino-thiazol-4-yl)-acetamido]-3cephem-4-carboxylic acid.

IR: 2600-2400 (broad), 1766, 1710-1570 (broad), 1500 cm- (Nujol); UV: 258 (11400; H2O).

3-acetoxymethyl-7p-[(2S)-2-((4R)-4-amino-4-carboxybutyramido)-2-(2-amino-thiazol-4-yl)- acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1768, 1725--1570 (broad), 1500 cm- (Nujol); UV: 259 (14700;H2O).

3-(4-ca rba moylpyridi nlomethyl)-7ss-[(2S)-2((4R)- 4-a mino-4-carboxybutyramido)-2-(2-amino thiazol-4-yl)-aceta mido]-3-cephem-4-carboxylate.

IR: 3600-2400 (broad), 1771, 1720, 1680 (broad), 1620 (broad), 1520 cm- (Nujol); UV: 253 (12900; H2O).

3-carbamoyloxymethyl-7ss-[(2S)-2-((4R)-4-amino-4-carboxybutyramido)-2-(2-amino-thiazol-4yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1771, 1720, 1690 (broad), 1620 (broad), 1515 cm- (Nujol); UV: 252 (13000; H2O).

3-pyridiniomethyl-7p-[(2S)-2-((4R)-4-amino-4-carboxybutyramido)-2-(2-amino-thiazol-4-yl)- acetamido]-3-cephem-4-carboxylate.

IR: 3600-2400 (broad), 1789, 1722, 1690 (broad), 1615 9broad) cm- (Nujol); UV: 252 (11900; H2O).

3-( 1 -carboxymethyl- 1 H-tetrazol-4-ylthiomethyl)-7ss-[(2S)-2- (4R)-4-a mino-4carboxybutyramldo)-2-(2-amino-thiazol-4-yl)-acetamido]-3-cep;hem-4-carboxylic acid.

IR: 3600--2600, 1769, 1740--1570 (broad), 1520 cm- (Nujol); UV: 258 (14500; H2O).

3-(1-sulphomerthyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2S)-2-((4R)-4-amino-4carboxybutyra mido)-2-(2-amino-thiazol-4-yl)-aceta mido]-3-cephem-4-carboxylic acid.

IR: 3600-2500 (broad), 1 768, 1 727 (shoulder), 1680(shoulder), 1625, 1520 cm- (Nujol); UV: 258 (13700; H2O).

3-(2-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthiomethyl]-7ss-[(2S)-2-((4R)-4-amino4-carboxybutyra mido)-2-(2-a minothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600--2400 (broad), 1769, 1718, 1655(broad), 1575 cm-l (Nujol); UV: 278 (20000; H2O).

3-[ 1 -( 2-dimethylaminoethyl)- 1 H-tetrazol-5-ylthiomethyl]-7p-[(2S)-2-((4R)-4-amino-4- carboxybutyramido)-2-(2-amino-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600 (broad), 1771, 1715 (shoulder), 1680, 1615, 1510cm- (Nujol); UV: 254 (13300; H2O).

7ss-[(2S)-2-((3R)-3-amino-3-carboxypropionsmido)-2-(6-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1766, 1712-1 577 (broad), 1500 cm- (Nujol); UV: 2158 (11800; H2O).

3-acetoxymethyl-7p-[(2 S)-2-((3R)-3-amino-3-carboxypropion amido)-2-(5-amino- 1,2,4thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1771, 1720, 1690 (broad), 1615 (broad), 1515cm- )Nujol); UV: 253 (14200; H2O).

3-(4-carbamoylpyridiniomethyl)-7ss-[(2S)-2-((3 R)-3-amino-3-carboxypropiona mido)-2-(5-amino 1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxcylate.

IR: 3600-2400 (broad), 1769, 1718, 1680 (broad), 1620 (broad), 1515 cm- UV: 252 (13500; H2O).

3-carbamoyloxymethyl-7ss-[(2S)-2-((3R)-3-amino-3-carboxypropionamido)-2-(5-amino- 1,2,4 thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1771, 1720, 1690 (broad), 1620 (broad), 1518 cm- (Nujol); UV: 252 (13900; H2O)- 3-pyridiniomethyl-7ss[(2S)-2-((3R)-3-amino-3-carboxypropionamido)-2-(5-amino-1,2,4thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1769, 1720, 1690 (broad), 1620 (broad) cm- (Nujol): UV: 251 (13700: H2O).

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2S)-2-((3R)-3-amino-3-carboxypropionamido)-2 (5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2600 (broad), 1769, 1740-1570 (broad), 1520 cm- (Nujol): UV: 259 (14200; H2O).

3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2S)-3-amino-3carboxypropionamido)-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2600 (broad), 1770, 1740-1670 (brodd), 1520 cm- (Nujol): UV: 259 (12850; H2O).

3-(1-suiphomethyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2S)-2-((3R)-3-amino-3-carboxy propionamido)-2-(5-amino- ,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2500 (broad), 1768, 1730 (shoulder), 1685 (shoulder), 1625, 1519 cm- (Nujol): UV: 258 (14200; H2O).

3-(2-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7ss-[(2S)-2-((3R)-3-amino3-carboxypropionamido)-2-(5-amino-1,2,4-thiadiazol-2-yl)-acetamido]-3-cephem-4-carboxylic acid IR: 3600-2400 (broad), 1768, 1722, 1650 (broad), 1 15715 cm1 (Nujol); UV: 279 (22000; H2O).

3-[1 -(2-di methylaminoethyl)- 1 H-tetrazol-5-ylthiomethyl]-7ss-[(2S)-2-((3 Fl)-3-amino-3- carboxypropionamido)-2-(5-amino-1,2,4-thiadiazol-3-yl]-acetamio]-3-cephem-4-carboxylic acid.

IR: 3600-2600 (broad). 1771, 1712 (shoulder), 1680 (shoulder), 1617, 1510cm- (Nujol): UV: 255 (13000; H2O).

7ss-[(2S)-2-((4R)-4-a mino-4-carboxybutyramido)-2-( 15-amino- 1 ,2 ,4-thiadiazol-3-yl)-aceta mido]- 3-cephem-4-carboxylic acid.

IR: 3600-2450 (broad), 1767, 1710-1570 (broad), cm- (Nujol); UV: 257 (12400; H2O).

3-acetoxymethyl-7ss-[(2S)-2-((4R)-4-amino-4-carboxybutyramido)-2-95-amino-1,2,4-thiadiazol3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1767, 1720-1570 (broad), 1502 cm- (Nujol); UV: 259 (14400; H2O).

3-(4-carbamoylpyridiniomethyl)-7p-[(2S)-2-((4R)-4-amino-4-carboxybutyramido)-2-(5-amino- 1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-ca rboxylate.

IR: 3600-2420 (broad), 1770, 1720, 1680 (broad), 1620 (broad), 1520 cm- (Nujol): UV: 254 (13100;H2O).

3-carbamoyloxymethyl-7ss-[(2S)-2-((4R)-4-amino-4-carboxybutyramido)-2-(5-amino-1,2,4 thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2400 (broad), 1771, 1720, 1690 (broad), 1615 (broad), 1520 cm- (Nujol); UV:252 (14200; H2O).

3-pyridiniomethyl-7ss-[(2S)-2-((4R)-4-amino-4-carboxybutyramido)-2-(5-amino-1,2,4-thiadiazol 3-yl)-acetamido]-3-cephem-4-carboxylate.

IR: 3600-2400 (broad), 1770, 1724, 1695 (broad), 1625 (broad) cm- (Nujol); UV: 251 (12900; H2O).

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2S)-2-((4R)-4-amino-4-carboxybutyramido)-2-(5emino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 2600-2600 (broad), 1770, 1740-1570 (broad), 1520 cm- (Nujol); UV: 259 (13950; H2O).

3-(1-carboxymethyl-1H-tetrazol-5-ylthlomethyl]-7ss-[(2S)-2-((4R)-4-amino-4-carboxybutyramido]-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2600 (broad), 1772, 1740--1570 (broad), 1520 cm (Nujol); UV: 258 (12800; H2O).

3-(1-sulphomethyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2S)-2-((4R)-4-amino-4carboxybutyramido)-2-(5-amino- 1 ,2,4-thiadiazol-3-yl)-aceta midoj-3-cephem-4-ca rboxylic acid.

IR: 3600-2500 (broad), 1768, 1725 (shoulder). 1680 (shoulder), 1625, 1519 cm- (Nujol); UV: 258 (14000; H2O).

3-(2-methyl-5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7ss-[(2S)-2-((R)-4-amino 4-carboxybutyramido)-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR:3600-2400 (broad), 1769, 1725, 1650 (broad), 1575cm- (Nujol): UV: 279 (21300; H2O).

3-[ 1 -(2-dimethylaminoethyl)-1 H-tetrazol-5-ylthiomethyl]-7JB-[(2S)-2-((4R)-4-amino-4-carboxy- butyramido)-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylic acid.

IR: 3600-2600 (broad), 1769, 1712 (shoulder), 1680 (shoulder), 1615, 1512 cm- (Nujol); UV: 256 (12910; H2O), and the corresponding 7a-methoxy compounds and the corresponding R-mnd R,S-derivatives and the salts thereof, for example the sodium salts.

Example 22 Dry ampoules or vials containing 0.5 g of the sodium salt of 3-(1 -methyl-1 H-tetrazol-5ylthiomethyl)-7ss-[(2S)-2-((2B)-2-amlno-2-carboxyethoxycerbonylamino)-2-(2-aminothiazol-4-yl) acetamido]-3-cephem-4-carboxylic acid are manufactured as follows: sodium salt of 3-( 1 -methyl-1 H-tetrazol-5-ylthiomethyl)-7ss-[(2S)-2-((2R).

2-amino-2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)- acetamido]-3-cephem-4-carboxylic acid 0.5 g mannitol 0.05 g A sterile aqueous solution of the sodium salt of 3-( 1 -methyl-1 H-tetrazol-5-ylthiomethyl)-7P- [(2S)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3cephem-4-carbxoylic acid and mannitol is sealed in 5 ml ampoules or 5 ml vials undar aseptic conditions and tested.

Claims

1. Compounds of the formula

in which I represents an integer from 0 to 2, m represents an integer from 0 (direct bond) to 4, n represents an integer from 1 to 4, X represents oxygen, sulphur or the group -NH-, W represents a group -CO-, -CONHSO2- or -SO2NHCO-, or X and W together represent a group -CO- or -CONHSO2-, Y represents hydrogen or an unsubstituted or substituted organic radical, R1 represents hydrogen, lower alkyl, lower alkoxy, halogen or a group of the formula -CH2-Fl2 in which R2 represents a free, esterified or etherified hydroxy or mercapto group or a quaternary ammonium group, R3 represents hydrogen or lower alkoxy, and R4 represents carboxy or protected carboxy, hydrates and salts of compounds of the formula I.

2. Compounds of the formula I according to claim 1, in which I represents an integer from 0 to 2, m represents an integer from 0 (direct bond) to 4, n represents an integer from 5 to 4, the groups (CmH2m) and -(CH2) are unbranched, X represents oxygen or the group -NH-, W represents the group -CO-, or X-W- together represent the group -CO-,Y represents hydrogen, lower alkyl, for example methyl, unsubstltuted or amino-substituted furyl, thlonyl, thiszolyl or thiadiazolyl, for example furyl, thienyl, aminothiazolyl or aminothiadiazolyl, R1 represents hydrogen, lower alkoxy, for example methoxy or ethoxy, halogen, for example chlorine, or a group of the formula -CH2-Fl2 in which R2 represents lower alkanoyloxy, for example acetyloxy; carbamoyloxy; N-lower alkylcarbamoyloxy; triazolylthio, tetrazolylthio; thiazolylthio, thiadiazolylthio, oxazolylthio, oxadiazolylthio or 5,6-dioxotetrahydro-as-triazinylthio, each of which is u nsubstituted or substituted by lower alkyl, for example methyl, di-lower alkylamino-lower alkyl, for example dimethylaminomethyl, carboxy-lower alkyl, for example carboxymethyl, amino, carboxy-lower alkylamino, for example 2carboxyethylamino or by carbamoyl: for example 1 H-1 ,2,3-triazol-5-ylthio, 1 H-tetrazol-5-ylthio, 1,3,4- thiadiazol-5-ylthio, 5,6aioxo-1 ,2,5,6-tetrahydro-as-triazin-3-ylthio or 5,6-dioxo-1,4,5,6-tetrahydro-as- triazin-3-ylthio; 2-lower alkyl-1-pyrazolium, for example 2-methyl-1-pyrazolium; 2-carboxy-lower alkyl-1 -pyrazolium, for example 2-carboxymethyl-1 -pyrazolium; 3-lower alkyl-1 -triazolium, for example 3-methyl-1-triazolium; or pyridinium that is unsubstituted or substituted by hydroxy-lower alkyl, for example hydroxy-methyl, carboxy, carboxy-lower alkyl, for example carboxymethyl, halogen, for example chlorine or bromine or by carbamoyl, for example 3- or 4-hydroxymethylpyridinium, 4- carboxypyridinium, 3- or 4-carboxymethylpyridinium, 3 or 4-bromopyridinium or 3- or 4carbamoylpyridinium, Rs represent hydrogen or lower alkoxy, for example methoxy, and R4 represents carboxy, pivaloyloxymethoxycarbonyl or 1 -ethoxycarbonyloxyethoxycarbonyl, and hydrates and pharmaceutically acceptable salts of such compounds.

3. Compounds of the formula I according to claim 2 in which I represents 0, m represents an integer from 0 (direct bond) to 4, n represents an integer from 1 to 4, the groups (CmH2m) and are unbranched, X represents oxygen or the group -NH-, W represents the group -CO-, or X-W together represent the group -CO-, Y represents hydrogen, lower alkyl, for example methyl, furyl, for example 2- or 3-furyl, thienyl, for example 2- or 3-thienyl, aminothiazolyl, for example 2-aminothiazol-4-yl, or aminothiadiazolyl for example Ei-amino-l ,2,4-thiadiazol-3-yl, R, represents hydrogen, lower alkoxy, for example methoxy, halogen, for example chlorine, or a group of the formula -CH2-Fl2 in which R2 represents lower alkanoyloxy, for example acetyloxy; carbamoyloxy; triazolylthio, tetrazolylthio, thiadiazolylthio or 5,6-dioxotetrahydrotriazin-3-ylthio, each of which is unsubstituted or substituted by lower alkyl, for example methyl, di-lower alkyl-amino-lower alkyl, for example 2-dimethylaminoethyl, sulpho-lower alkyl, for example sulphomethyl, carboxy-lower alkyl, for example carboxymethyl or by carbamoyl: for example 1 H-1 ,2,3-triazol-5-ylthio, 1 H-tetrazol-5-ylthio, 1- methyl-1 H-tetrazol-15-ylthio, 1 -sulphomethyl-1 H-tetrazol-15-ylthio, 1 -carboxymethyl-1 H-tetrazol-5ylthio, 1 -(2-di methyla minoethyl)-1 H-tetrazol-5-yithio, 1 ,3,4-thiadiazol-5-yithio, 2-methyl-1,3,4- thiadiazol-5-ylthio, 2-methyl-5,6-dioxo- 1 ,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-methyl-5,6-dioxo 1,4,5,6-tetrahydro-as-triazin-3-ylthio;; or pyridinium that is unsubstituted or substituted by hydroxy lower alkyl, for example hydroxy-methyl, carboxy, carboxy-lower alkyl, for example carboxymethyl, halogen, for example chlorine or bromine, or by carbamoyl, for example 3- or 4-hydroxymethyl pyridinium, 4-carboxypyridinium, 3- or 4-carboxymethylpyridinium, 3- or 4-chloropyridinium, 3- or 4 bromopyridinium or 3- or 4-carbamoylpyridinium, R3 represents hydrogen or methoxy and R4 represent carboxy, andchydrates and pharmaceutically acceptable salts of such compounds.

4. Compounds of the formula I according to claim 3 in which / represent 0, m represents an integer from 0 (direct bond) to 3, n represents 1 or 2, the group (CmH2m) is unbranched, X represents oxygen, W represents the group -CO-, or X-W together represent the group -CO-, Y represent hydrogen, lower alkyl, for example methyl, furyl, for example 2- or 34uryl, aminothiazolyl, for example 2-aminothiazol-4-yl, or aminothiadiazolyl, for example 5-amino-1 ,2,4-thiadiazol-3-yl, R, represents hydrogen, lower alkoxy, for example methoxy, halogen, for example chlorine, or a group of the formula CH2-Fl2 in which R2 represents lower alkanoyloxy, for example acetyloxy, carbamoyloxy, tetrazolylthio, for example 1 H-tetrazol-5-ylthio, tetrazolylthio substituted by lower alkyl, for example methyl, di-lower alkylamino-lower alkyl, for example dimethylaminoethyl, sulpho-lower alkyl, for example sulphomethyl, or by carboxy-lower alkyl, for example carboxymethyl, for example 1 -methyl-1 - tetrazol-5-ylthio, 1 -(2-dimethylaminoethyl)-1 H-tetrazol-5-ylthio, 1 -sulphomethyl-1 H-tetrazol-5-ylthio, or 1 -carboxymethyl-1 H-tetrazol-5-ylthio, thiadiazolylthio, for example 1,3,4-thiadiazol-5-ylthio, or thiadiazolylthio substituted by lower alkyl, for example methyl, for example 2-methyl-1 3,4-thiadiazol 5-ylthio, 15,6-dioxotetra hydro-as-triazinylthio or 5,6-dioxotetrahydro-as-triazinylthio substituted by lower alkyl, for example methyl, for example 2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-methyl-5,6-dioxo, 1 ,4,5,6-tetrahydro-as-triazin-3-ylthio, pyridinium or pyridinium substituted by hydroxy-lower alkyl, for example hydroxymethyl, carboxy, carboxy-lower alkyl, for example carboxymethyl, halogen, for example chlorine or bromine, or by carbamoyl, for example 3- or 4 hydroxymethylpyridinium, 4-carboxypyridinium, 3- or 4-carboxymethylpyridinium, 3- or 4 chloropyridinium, 3- or 4-bromopyridinium or 3- or 4-carbamoylpyridinium, R3 represents hydrogen or methoxy, and R4 represents carboxy, and hydrates and pharmaceutically acceptable salts of such compounds.

5. The sodium salt of 3-acetoxymethyl-7a-methoxy-7p-[2-((2R)-2-amino-2-carboxyethoxy- carbonylamino)-acetylamino]-3-cephem-4-carboxylic acid according to claim 4.

6. The sodium salt of 3-( 1-methyl- 1 H-tetrazol-5-ylthiomethyl)-7cr-methoxy-7p-[2-((2R)-2- amino-2-carboxyethoxyca rbonylamino)-acetyla mino]-3-cephem-4-carboxylic acid according to claim 4.

7. The sodium salt of 3-( 1-methyl-1 H-tetrazol-5-ylthiomethyl)-7,B-[(2R,S)-2-((4R)-4-amino-4- carboxybutyramido)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid according to claim 4.

8. The sodium salt of 3-acetoxymethyl-7,B-[(2R,S)-2-((2R)-2-amino-2-carboxyethoxy- carbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid according to claim 4.

9. The sodium salt of 3-( 1 -methyl-1 H-tetrazol-5-ylthiomethyl)-7p-[(2R,S)-2-((2R)-2-amino-2- carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid according to claim 4.

10. The sodium salt of 3-acetoxymethyl-7p-[(2R)-2-((2R)-2-amino-2-carboxyethoxy- carbonylamino)-2-(2-a minothiazol-4-yI)-acetyla minoj-3-cephem-4-carboxylic acid according to claim 4.

11. The sodium salt of 3-acetoxymethyl-7ss-[(2S)-2-((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetylamino]-3-cephem-4-carboxylic acid according to claim 4.

12. The sodium salt of 3-[.1 -(2-dimethylaminoethyl)-l H-tetrazol-5-ylthiomethyl]-7p-[(2R,S)-2- ((2R)-2-amino-2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetylamino]-3-cephem-4carboxylic acid according to claim 4,

13. The sodium eait of 3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2R,S)-2-((2R)-2 amino-2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetylamino]-3-cephem-4-carboxylic acid according to claim 4.

14. The sodium salt of 3-(i -sulphomethyl-1 H-tetrazol-5-ylthiomethyl)-7,B-[(2R,S)-2-((2R)-2- amino-2-carboxyethoxycarbonyla mino)-2-(2saminothiazol-4-yl)-acetylamino]-3-cephem-4-carboxyl ic acid according to claim 4.

15. The sndium salt of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7ss-[(2R,S)-2-((3R)-3-amino-3carboxypropionylamino]-2-[2-aminothiazol-4-yl)-acetylamino]-3-cephem-4-carboxylic acid according to claim 4.

16. The sodium ealt of 3-(1-methyl-1H-tetrazol-5-ylthlomethyl)-7ss-[(2R)-2-((2R)-2-amino-2carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetylamino]-3-cephem-4-carboxylic acid according to claim 4.

17. The sodium salt of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl]-7ss-[(2S)-2-((2R)-2-amino-2carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetylamino]-3-cephem-4-carboxylic acid according to claim 4.

18. 3-(4-ca rbamoylpyridiniomethyl)-7p-[(2 R,S)-2-((2 R)-2-amino-2-carboxyethoxycarbonylamino)-2-(2-aminothiazol-4-yl)-acetylamino]-3-cephem-4-carboxyiate according to claim 4,

19. The sodium salt of 3-(1-methyl-1H-tetrazol-5-ylthlomethyl)-7ss-[4-((2R)-2-amino-2carboxyethoxvcarbonylamino)-butyramido]-3-caphem-4-carboxylic acid according to claim 4,

20. Pharmaceutical preparations containing compounds of the formula I according to claim 1, hydrates or pharmaceutically acceptable salts of such compounds.

21. Compounds of the formula I according to claim 1 for use in the treatment of bacterial infections in the human or animal body.

22. Process for the manufacture of compounds of the formula I in which I, m, n, X, W, Y, Rt, R2, R3 and R4 have the meanings given in claim 1 and in which the carboxy groups are in free form or are esterified in physiologically cleavable form, hydrates and salts of such compounds, characterised in that a) in a compound of the formula

in which I, R1, R3 and R4 have the meanings given under formula I and the 7amino group is optionally protected by a group allowing acylation, the 7amino group is acylated by reaction with a carboxylic acid of the formula

in which m, n, X, W and Y have the meanings given under formula I and the a-aminocarboxylic acid grouping HOOC-CH(NH2)- and functional groups in the group Y are in protected form, or with a reactive functional acid derivative or a salt thereof, or b) in a compound of the formula

in which 1, m, Y, R, and R4 have the meanings given under formula I and the amino group is optionally protected by a group allowing the acylation reaction and functional groups in group Y are optionally in protected form, the amino group is acylated by reaction with a reactive functional derivative of an acid of the formula

in which n and X have the meanings given under formula I and the a-aminocarboxylic acid grouping HOOC-CH(NH2)- is in protected form, the group -X-H is acylated by reaction with a reactive functional derivative of an acid of the formula

in which 1, m, W, Y, R1, R3 and R4 have the meanings given under formula I and functional groups in the group Y are optionally in protected form, or d) a 2-cephem compound of the formula

in which m, n, X, W, Y, R1, R3 and R4 have the meanings given under formula I and the a- aminocarboxylic acid grouping HOOC-CH(NH2)- and functional groups in the group Y are in protected form, is isomerised to form the corresponding 3-cephem compound of the formula I and, if desired, a compound of the formula I obtainable according to the invention is converted into a different compound of the formula I and/or, if desired, a compound of the formula I obtainable according to the invention in which I represents 0 is converted into a compound of the formula I in which / represents 1 or 2, and/or a compound of the formula I in which / represents 1 or 2 is converted into a compound of the formula I in which / represent 0, and/or functional groups present in protected form in a compound of the formula I are converted into free functional groups, and/or a resulting salt is converted into the free compound or into a different salt, and/or a resulting free compound having a salt-forming group is converted into a salt, and/or a resulting mixture of isomeric compounds of the formula I is separated into the individual isomers.

23. Compounds of the formula

in which m, n, X, W, and Y have the meanings given in claim 1.

24. Process for the manufacture of compounds of the formula lil in which m, n, X, W and Y have the meanings given in claim 1, and in which functional groups in the group Y are optionally in protected form, characterised in that a compound of the formula V

in which n, X and W have the meanings given in claim 1 under formula I and the a-aminocarboxylic acid grouping HOOC-CH(NH2)- is in protected form, or if X-W together represent the group -CO-, alternatively a free acid or a reactive functional acid derivative or a salt thereof, is acylated with an acid of the formula

in which m and Y have the meanings given in claim 1 under formula I and in which the amino group is optionally protected by a group allowing the acylation reaction and functional groups in the group Y are protected and the carboxy group is intermediately protected, and, if desired, a resulting compound of the formula Ill is converted into a different compound of the formula Ill having correspondingly protected functional groups.

25. A process according to claim 22 substantially as hereinbefore described with reference to any one of the foregoing Examples 1 to 21.

26. Pharmaceutical preparations substantially as hereinbefore described with reference to Example 22.