NO831470L - 7BETA-ACYLAMIDO-3-CEFEM-4 CARBOXYLIC ACID COMPOUNDS, PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS AND THE USES OF THE COMPOUNDS - Google Patents

Description

The present invention relates to new 7|3-acylamido-3-cephem-4-carboxylic acid compounds, methods for their preparation, pharmaceutical preparations containing such compounds, and their use for the preparation of pharmaceutical preparations, or as pharmacologically active compounds, as well as new intermediates and method for producing them.

The present invention relates to 73-acylamido-3-cephem-4-carboxylic acid compounds of the formula

where m means an integer from 0 to 2,

hydrogen, lower alkyl, lower alkenyl, lower alkoxy,

halogen, a group of the formula -Cr^-f^'in which R_ means a free, esterified or etherified hydroxy or mercapto group, or an ammonium group, or a group of the formula -CH=CHR2, in which R ? means an ethereal mercapto group,

means carboxy or protected carboxy,

R^ means hydrogen,

Rt- means an organic residue, which is bound to the sulfonyl group by means of a carbon atom, and

Rg means a heterocyclic residue.

Stereoisomers, mixtures of these stereoisomers, hydrates and salts of compounds of formula I, process for the preparation of the compounds of formula I, pharmaceutical preparations containing compounds of formula I and use of the compounds of formula I for the preparation of pharmaceutical preparations or as pharmacology -

gically active compounds.

In the description of the present invention, the term "lower", used in the context of groups or residues, e.g. lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl, etc., that the groups or residues so designated, unless otherwise expressly defined, contain up to 7 and preferably up to 4 carbon atoms.

In formula I, m in the first line means 0. If m has the value 1, the 1-oxido group can be in the a- or (3-position. There can also be a mixture of the compounds of formula I with a 1-oxidy group in both positions.

The carbon atom in connection with the substituted amino group; with the partial formula -NSC^^Rcj is R- or S-conf igured.

There may also be a mixture of the compounds of formula I, with the substituted amino group with partial

-NHS02 in both positions.

When R 1 is lower alkyl, it contains 1-4 carbon atoms and is, for example, ethyl, propyl, butyl or especially methyl.

When R-j^ is lower alkenyl, it contains 1-4 carbon atoms, and is, for example, vinyl or allyl.

When R 1 is lower alkoxy, it contains 1-4 carbon atoms, and is, for example, ethoxy, propoxy, butoxy or especially methoxy.

When R 1 is halogen, it is fluorine, bromine, iodine or preferably chlorine.

When R 2 is esterified hydroxy or mercapto, it is a hydroxy or mercapto group, which is esterified with an aliphatic carboxylic acid, an aliphatic carboxylic acid, which is substituted-with acyl, e.g. lower alkanoyl, e.g. acetyl, carbamic acid or a substituted carbamic acid, for example lower alkanoyloxy, e.g. acetoxy, lower--alkanoyllower alkanoyloxy, e.g. acetacetoxy, or carbamoyloxy or lower alkanoylthio, e.g. acetylthio or formylthio, or carbamoylthio.

The substituents in carbamic acid are, for example, lower alkyl, e.g. methyl or ethyl, or lower alkyl substituted with halogen, e.g. chlorine, or lower alkanoyloxy, e.g. acetoxy, e.g. 2-chloroethyl or 2-acetoxyethyl.

When R 2 is hydroxy or mefcapto substituted with carbamic acid, it is, for example, methylcarbamoyloxy, ethylcarbamoyloxy, 2-chloroethylcarbamoyloxy, 2-acetoxyethylcarbamoyloxy or methylcarbamoylthio.

When R2 is an ethereal hydroxy or mercapto group, it is a hydroxy or mercapto group, which is an ethereal with an aliphatic hydrocarbon residue, for example lower alkoxy with 1-4 C atoms, e.g. methoxy or ethoxy, or lower alkylthio with 1-4 C atoms, e.g. methylthio.

When R 2 is etherether mercapto, it is preferably etherether with a heterocyclic group, which is connected to the mercapto group via a ring carbon atom, e.g. with a monocyclic heterocyclic group, which contains 1-4 nitrogen heteroatoms, and optionally in addition an oxygen or sulfur atom, or connected with a bicyclic heterocyclic group with 1-5 nitrogen heteroatoms. Such an ethereal mercapto group is called in the following "heterocyclylthio group I^" *

Heterocyclyl in a heterocyclylthio group R2 is especially aromatic, monocyclic, 5- or 6-membered diaza-, triaza, tetraaza-, tiaza-, thiadiaza, tia-, oxaza- or oxadiaza-cyclyl or is aromatic or partially saturated, bicyclic, aza-, diaza-, triaza-, tetraaza- or pentaazabicyclyl containing 5 or 6 ring atoms per ring. Substituents in the aforementioned heterocyclyl residue in a heterocyclylthio group R2 are, for example, unsubstituted lower alkyl, e.g. ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, especially methyl or substituted lower alkyl, e.g. methyl or ethyl, which is substituted with the following functional, converted functional, as well as heterocyclic groups: Hydroxy, esterified hydroxy, e.g. lower alkanoyloxy, e.g. acetoxy, or halogen, e.g. fluorine or chlorine, possibly in salt form, e.g. such as alkali metal, e.g. sodium salt, present lower alkylphosphonyl, e.g. sodium methyl- or sodium ethylphosphonyl, dilaverealkyl-phosphonyl, e.g. dimethyl- or diethylphosphonyl, carboxy, sulfo, in salt form, e.g. as an alkali metal or ammonium salt, e.g. as sodium salt, present carboxyl or sulfo, e.g. sodium carboxylate or sodium sulphonate, esterified carboxy, e.g. lower alkoxycarbonyl, e.g. methoxycarbonyl, sulfamino, in salt form, e.g. such as alkali metal, e.g. sodium salt, sulfoamino present, e.g. sodium sulfonatoamino, sulfamoyl, amino, lower alkylamino, e.g. methyl- or ethylamino, dilaverealkylamino, e.g. dimethylamido or diethylamino, acylamino, e.g. lower alkanoylamino, such as e.g. acetylamino, or lower alkanoylamino which is substituted with carboxy or halogen, e.g. chlorine, e.g. carboxyacetylamino or chloroacetylamino, as well as tetrazolyl, e.g. tetrazol-1H-5-yl.

A lower alkyl residue which is substituted with these groups is, for example: Hydroxyl lower alkyl, e.g. hydroxymethyl or 2-hydroxyethyl, acetoxy lower alkyl, e.g. acetoxymethyl or 2-acetoxyethyl, halolower alkyl, e.g. chloromethyl, 2-chloroethyl, 2,2,2-trichloroethyl or trifluoromethyl, lower-alkylphosphonoloweralkyl, e.g. ethylphosphonomethyl, dilave-alkylphosphonolaverealkyl, e.g. diethylphosphonomethyl, carboxy-lower alkyl, e.g. carboxymethyl or 2-carboxyethyl, sulpholower alkyl, e.g. sulfomethyl or 2-sulfoethyl, lower alkoxycarbonyllower alkyl, e.g. ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, sulfamoyl lower alkyl, e.g. sulfamoylmethyl or 2-sulfamoylethyl, sodium sulfonatoaminolower alkyl, e.g. sodium sulfonatoaminomethyl or 2-sodium sulfonatoaminoethyl, amino lower alkyl, e.g. aminomethyl or 2-aminoethyl, lower alkylaminolower alkyl, e.g. methylaminomethyl or 2-methylaminoethyl, diloweralkylaminoloweralkyl, e.g. dimethylaminomethyl or 2-dimethylaminoethyl, lower alkanoylaminolower alkyl, e.g. 2- acetylaminoethyl, carboxylavearalkanoylaminolavearalkyl, e.g. 3-carboxypropionylaminoethyl or 2-carboxyacetylaminoethyl, or halogen-lower anoylamino-lower alkyl, such as e.g. 3-chloropropionylaminoethyl or 2-chloroacetylaminoethyl, as well as tetrazolyl lower alkyl, e.g. tetrazol-1H-5-ylmethyl or 2-(tetrazol-1H-5-yl)-ethyl.

Lower alkenyl, such as e.g. vinyl or allyl, functional groups or modified, e.g. protected, functional groups, e.g. halogen, e.g. fluorine, chlorine or bromine, amino or substituted amino, e.g. with lower alkyl, e.g. methyl or ethyl, mono- or di-substituted amino, e.g. methylamino or dimethylamino, acylamino, e.g. lower alkanoylamino, e.g. acetylamino, or lower alkylsulfonylamino, e.g. mesylamino, or lower alkanoylamino substituted with halogen, e.g.

chlorine or carboxy, e.g. 3-chloropropionylamino or 3-carboxypropionylamino, nitro, hydroxy, lower alkoxy, e.g. methoxy or ethoxy, carboxy, esterified carboxy, e.g. lower alkoxycarbonyl, e.g. methoxycarbonyl or ethoxycarbonyl, amidated carbonyl, e.g. carbamoyl, mono- or dilave-alkylated carbamoyl, e.g. methylcarbamoyl or dimethylcarbainoyl, or cyan, as well as oxo or oxido are likewise substituents of the heterocyclyl residue in a heterocyclylthio group R2-

A heterocyclylthio group R 2 , in which heterocyclyl means aromatic, monocyclic, five-membered heterocyclyl, is preferably imidazolylthio, e.g. 2-imidazolylthio, triazolylthio or triazolylthio substituted with lower alkyl, e.g. methyl, and/or phenyl, e.g. 1H-1,2,3-triazol-5-yl-thio, 1-methyl-1H-1,2,3-triazol-4-yl-thio, 1H-1,2,4-triazol-3-ylthio, 5-methyl-1H-1,2,4-triazol-4-ylthio, 1H-1,2,4-triazol-3-ylthio, 5-methyl-1H-1,2,4-triazol-3-ylthio or 4,5-dimethyl-1,2,4-triazol-3-ylthio, tetrazolylthio, e.g. 1H-tetrazol-5-ylthio, tetrazolylthio substituted with lower alkyl, e.g. methyl or ethyl, or substituted lower alkyl, e.g. ethyl or diethylphosphonomethyl, 2-carboxyethyl, sulfomethyl, 2-sulfoethyl, 2-sodium sulfonatoethyl, 2-dimethylaminoethyl, cyanomethyl or tetrazolylmethyl, e.g. 1-methyl-1H-tetrazol-5-ylthio, 1-ethyl- or 1-diethylphosphonylmethyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio, 1-(2-carboxyethyl) —lH -tetrazol-5-ylthio, 1-sulfonethyl-1H-tetrazol-5-ylthio, 1-(2-sulfoethyl)-1H-tetrazol-5-ylthio, 1-(2-sodium sulfonatoethyl)-1H-tetrazol-5-ylthio , 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthio, 1-cyanomethyl-1H-tetrazol-5-ylthio, 1-(tetrazol-1H-5-ylmethyl)-1H-tetrazol-5-ylthio, thiazolylthio or thiazolylthio substituted with carboxy-lower alkyl, e.g. carboxymethyl, and/or lower alkyl, e.g. methyl, e.g. 2-thiazolylthio, 4-methyl-5-carboxymethylthiazol-2-ylthio or 4,5-dimethyl-2-thiazolylthio, isothiazolylthio, e.g. 3-isothiazolylthio, 4-isothiazolylthio or 5-isothiazolylthio, thiadiazolylthio or thiadiazolylthio substituted with lower alkyl, e.g. methyl, e.g. 1,2,3-thiadiazol-4-ylthio, 1,2,3-thiadiazol-5-ylthio, 1,3,4-thiadiazol-2-ylthio, 2-methyl-1,3,4-thiadiazol-5- ylthio, 1,2,4-thiadiazolyl-5-ylthio or 1,2,5-thiadiazol-3-ylthio, thiatriazolylthio, e.g. 1,2,3,4-thiatriazol-5-ylthio, oxazolylthio or oxazolylthio substituted with lower alkyl, e.g. methyl, e.g. 2- or 5-oxazolyl-

thio, or isooxazolylthio substituted with lower alkyl, e.g. methyl, e.g. 3-methyl-5-isoxazolylthio, oxadiazolylthio or oxadiazolylthio substituted with lower alkyl,

e.g. methyl, eg 1,2,4-oxadiazol-5-ylthio or 2-methyl-1,3,4-oxadiazol-5-ylthio.

A heterocyclylthio group R2, in which heterocyclyl means aromatic, monocyclic, 6-membered heterocyclyl, contains 1-3 nitrogen atoms, and is preferably 5,6-dioxotetrahydro-as-triazinylthio or 5,6-dioxotetrahydro-as-triazinylthio substituted with lower alkyl, e.g. e.g. methyl, carboxy lower alkyl, e.g. carboxymethyl or sulpholower alkyl, e.g. sulfomethyl, e.g. 1- or 2-methyl-5,6-dioxo-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-1,2,5,6-tetrahydro-as-triazin-3-ylthio, 4-carboxymethyl-5,6-dioxo- 1,4,5,6-tetrahydro-as-triazin-3-ylthio, 1- or 2-sulfomethyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio or 4-sulfomethyl-5,6-dioxo-1,4,5,6-tetrahydro-az-triazin-3-ylthio.

A heterocyclylthio group R2, where heterocyclyl means aromatic or partially saturated, bicyclic heterocyclyl containing 5 or 6 ring atoms per ring, is preferably indolylthio, indolylthio which is substituted with lower alkyl, e.g. methyl, e.g. indol-2-ylthio or N-methylindol-2-ylthio, isoindolylthio, e.g. isoindol-2-ylthio, jquinolylthio, e.g. 2-, 4- or 8-quinolylthio, benzimidazolylthio, or benzimidazolylthio, which is substituted with lower alkyl, e.g. methyl, or carboxy-lower alkyl, e.g. carboxymethyl, e.g. 1-methyl-, 1-carboxymethyl- or 1-(2-carboxyethyl)-benzimidazol-2-ylthio, benzotriazolylthio, or benzotriazolylthio which is substituted with lower alkyl, e.g. methyl, or carboxy-lower alkyl, e.g. carboxymethyl, e.g. 1-methyl- or 1-carboxymethyl-1H-benzo[d]-triazol-5-ylthio. Tetrazolepyridazinylthio or tetrazolepyridazinylthio substituted with lower alkyl, e.g. methyl or ethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, carbamoyl, lower alkylcarbamoyl, e.g. methylcarbamoyl, dilaverealkyrcarbamoyl, e.g. dimethylcarbamoyl, amino. lower alkylamino, e.g. methylamino, dilavealkylamino, e.g. dimethylamino or diethylamino, e.g. 8-methyl-, 8-ethyl-, 8-carboxy-, 8-carboxymethyl-, 8-(2-carboxyethyl)-, 8-carbamoyl-, 8-methylcarbamoyl-, 8-dimethylcarbamoyl-, 8-amino-, 8 -dimethylamino- or 8-diethylaminotetrazol-[1,5-b]pyridazin-6-ylthio.

When is an ammonium group, it is derived from an organic, tertiary, nitrogen-containing base, for example from a tertiary, aliphatic amine or preferably from a tertiary-heterocyclic, aromatic nitrogenous base, the base in question with its nitrogen atom being bound to a methylene group which is in position 3 in the cefem structure. The positive charge on the quaternary nitrogen atom

in the ammonium group is compensated, for example, by the negatively charged carboxylate group, which instead of the undissociated carboxyl group is in the 4-position in the cefem structure.

When R2 is an ammonium group, which is derived from a tertiary, aliphatic amine, it is, for example, trilower alkylammonium, e.g. trimethyl or triethylammonium.

When 1*2 is a quaternary ammonium group, which is derived from a tertiary, heterocyclic, aromatic nitrogen base, it is, for example, 1-pyrazolium or 1-pyrazolium substituted with lower alkyl, e.g. methyl or ethyl, lower alkyl,

e.g. vinyl or allyl, carboxy lower alkyl, e.g. carboxymethyl, lower alkoxycarbonyl lower alkyl, e.g. methoxycarbonylmethyl, sulpholower alkyl, e.g. sulfomethyl, amino lower alkyl, e.g. 2-aminoethyl, or diloweralkylaminoloweralkyl, e.g. 2-dimethylaminoethyl, in the 2-position, e.g. 2-methyl- or 2-ethyl-1-pyrazolium, 2-allyl- or 2-vinyl-1-pyrazolium, 2-sulfomethyl-1-pyrazolium, 2-(2-aminoethyl)-1-pyrazolium or 2-(2 -dimethylaminoethyl)-1-pyrazolium, 1-triazolium or 1-triazolium substituted in the 3-position with lower alkyl, e.g. methyl or ethyl,

carboxy lower alkyl, e.g. carboxymethyl or diloweralkylaminoloweralkyl, e.g. 2-dimethylaminoethyl, e.g. 3-methyl-1-triazolium, 3-carboxymethyl-1-triazolium or 3-(2-dimethylaminoethyl)-1-triazolium.

When R 2 is an ammonium group, which is derived from a tertiary, heterocyclic, aromatic nitrogen base, it is preferably pyridinium or pyridinium mono- or di-substituted with lower alkyl, e.g. methyl, carbamoyl, lower alkylcarbamoyl, e.g. methylcarbamoyl, hydroxy lower alkyl, e.g. hydroxymethyl, lower alkoxy lower alkyl, e.g. methoxymethyl, cyano lower alkyl, e.g. cyanomethyl, carboxy lower alkyl, e.g. carboxymethyl, sulpholower alkyl, e.g. 2-sulfoethyl, carboxyl lower alkyl, e.g. 2-carboxyvinyl, carboxylower alkylthio, e.g. carboxymethylthio, thiocarbamoyl, halogen, e.g. bromine or chlorine, carboxyl, sulfo or cyan, e.g. lower alkylpyridinium, e.g. 2-, 3-or 4-methylpyridinium, or 2-, 3- or 4-ethylpyridinium, carbamoylpyridinium, e.g. 3- or 4-carbamoylpyridinium, lower alkylcarbamoylpyridinium, e.g. 3- or 4-methylcarbamoylpyridinium, dilaverealkylcarbamoylpyridinium, e.g. 3- or 4-dimethylcarbamoylpyridinium, hydroxy-lower alkylpyridinium, e.g. 3- or 4-Hydroxymethylpyridinium, lower alkoxy and lower alkylpyridinium, e.g. 4-methoxymethylpyridinium, cyanolower alkylpyridinium, e.g. 3- cyanomethylpyridinium, carboxyl lower alkylpyridinium, e.g. 3-carboxymethylpyridinium, sulpholower alkylpyridinium, e.g. 4-(2-sulfoethylpyridinium), carboxylavereal-kenylpyridinium, e.g. 3-(2-carboxyvinyl)-pyridinium, carboxy-lower alkylthiopyridinium, e.g. 4-carboxymethyl-thiopyridinium, thiocarbamoylpyridinium, e.g. 4-thiocarbamoylpyridinium, halogen-pyridinium, e.g. 3-bromo- or 4-bromopyridinium, carboxypyridinium, e.g. 3- or 4-carboxypyridinium, sulfopyridinium, e.g. 3- or 4-sulfopyridinium, cyanopyridinium, e.g. 3-cyanopyridinium, carboxy-lower alkyl-carbamoyl-pyridinium, e.g. 3-carboxymethyl-4-carbamoylpyridinium, aminocarbamoylpyridinium, e.g. 2-amino-5-carbamoylpyridinium, carboxycarbamoylpyridinium, e.g. 3-carboxy-4-carbamoylpyridinium, cyano-halomethylpyridinium, e.g. 3-cyano-4-trifluoromethylpyridinium or amino-carboxypyridinium, e.g. 2-amino-3-carboxypyridinium.

When R 2 is an ammonium group, it is preferably pyridinium or pyridinium substituted with hydroxyl lower alkyl, e.g. hydroxymethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, halogen, e.g. chlorine or bromine, or carbamoyl, e.g. 3- or 4-hydroxymethylpyridinium, 4-carboxypyridinium, 3- or 4-carboxymethylpyridinium,

3- or 4-chloropyridinium, 3- or 4-bromopyridinium or 3- or 4-carbamoylpyridinium,

In a group with the formula -CH=CH-R2, the etherified mercaptogroup R2 has the previously mentioned meanings, e.g. heterocyclic thio. R2 preferably means 5,6-dioxotetrahydro-as-triazinylthio, which is substituted with lower alkoxy, e.g. methoxy, e.g. 4-Methoxy-5,6-dioxo-1,4,5,6-tetrahydro-az-triazin-3-ylthio.

When R^ is protected carboxyl, it is esterified with a

of the carboxyl protecting groups described below, especially esterified carboxyl which is cleavable under physiological conditions.

When R 1 is an esterified carboxyl group, which is cleavable under physiological conditions, it is primarily an acyloxyvarealoxycarbonyl group, in which acyl, e.g. the acyl group in an organic carboxylic acid, primarily means an optionally substituted lower alkane carboxylic acid, or in which acyloxymethyl forms the residue in a lactone.

When R 1 is such an esterified carboxyl group, it is preferably lower alkanoyloxy lower alkoxycarbonyl, e.g. lower alkanoyloxymethoxycarbonyl or lower alkanoyloxyethyloxycarbonyl, e.g. acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl or 2-propionyloxyethoxycarbonyl, lower alkoxycarbonyloxyvareal oxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl or tert-butoxycarbonyloxymethoxycarbonyl, amino-lower alkanoyloxy-methoxycarbonyl, especially α-amino-lower alkanoyloxymethoxycarbonyl, e.g. glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl or L-leucyloxymethoxycarbonyl, further phthalidyloxycarbonyl, e.g. 2-phthalidyloxycarbonyl, or indanyloxycarbonyl, e.g. 5-indanyloxycarbonyl.

The organic radical R^, which<*>is bound to the sulfonyl group by a carbon atom, has up to 18 carbon atoms, and is an unsubstituted or substituted, saturated or unsaturated, aliphatic, cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, an unsubstituted or substituted aromatic or aromatic -aliphatic hydrocarbon residue, or is an unsubstituted or substituted heterocyclyl or heterocyclyl-aliphatic residue.

When R, - is a saturated, aliphatic hydrocarbon residue, it is, for example, lower alkyl with 1-7, preferably 1-4, carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl or is lower alkyl which is substituted with 1, 2 or more functional or converted functional groups, for example by hydroxy, ethereal hydroxy, for example lower alkoxy, e.g. methoxy, ethoxy or tert-butyloxy, or lower alkenyloxy, e.g. vinyloxy or allyloxy, esterified hydroxy, e.g. lower alkanoyloxy, e.g. acetoxy, or halogen, e.g. chlorine, ethereal mercapto, e.g. lower alkylthio, e.g. methylthio or ethylthio, or lower alkylthio, in which lower alkyl is substituted with amino and carboxy, e.g. 2-amino-2-carboxyethylthio, or heterocyclylthio, whereby heterocyclyl as above is defined as the heterocyclyl residue in a heterocyclyl group R2, lower alkanoyl, e.g. acetyl,

aroyl, e.g. benzoyl, carboxy, esterified carboxy, e.g.

lower alkoxycarbonyl, amidated carboxy, e.g. carbamoyl, lower alkylcarbamoyl, e.g. methylcarbamoyl, diloweralkylcarbamoyl, e.g. dimethylcarbamoyl, cyano, sulfo, lower alkanesulfonyl, e.g. methanesulfonyl, sulfamoyl, lower alkyl sulfamoyl, e.g. methylsulfamoyl, dilavealkylsulfamoyl, e.g. dimethylsulfamoyl, amidino, guanidino, or amino together with one or two of the aforementioned functional groups, whereby the substituents are, if possible, in a higher than 1-position to the lower alkyl residue.

Lower alkyl is substituted with 1, 2 or more functional or converted functional groups, for example hydroxyl lower alkyl, e.g. hydroxymethyl or 2-hydroxyethyl, lower alkoxy lower alkyl, e.g. methoxymethyl, 2-methoxyethyl or 2-ethoxyethyl, lower alkenyloxy lower alkyl, e.g. 2-vinyloxyethyl, lower alkanoyloxy lower alkyl, e.g. 2-acetoxyethyl, halolower alkyl, e.g. chloromethyl, 2-chloroethyl, 3-chloropropyl, 4-chlorobutyl or 2-bromomethyl, lower alkylthiolower alkyl, e.g. 2-methylthioethyl or 2-ethylthioethyl, aminocarboxylaveraalkylthiolaveraalkyl, e.g. 2-(2-amino-2-carboxyethylthio)-ethyl, benzoyl lower alkyl, e.g. benzoylmethyl, carboxy-lower alkyl, e.g. carboxymethyl or 2-carboxyethyl, lower alkoxycarbonyl lower alkyl, e.g. ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, carbamoyl lower alkyl, e.g. carbamoylmethyl, cyanolave-•-alkyl, e.g. cyanomethyl or 1-cyano- or 2-cyanoethyl, sulpholower alkyl, e.g. sulfomethyl or 2-sulfoethyl, sulfamoyl lower alkyl, e.g. sulfamoylmethyl or 2-sulfamoylethyl, or is aminocarboxyl lower alkyl, e.g. 2-amino-2-carboxyethyl.

Lower alkyl, which is substituted with a functional or converted functional group, preferably has the partial formula:

-(CnH2n»-Nx <A)'

R

o

where n is an integer from 1 to 4, R is hydrogen, lower alkyl, sulfo, sulfo present in salt form, or an acyl group and RQ is hydrogen or lower alkyl, or in which the nitrogen is a constituent of a heterocyclic group, and R and R2 together form the alkylene, which is optionally interrupted

of nitrogen substituted by oxygen, sulphur, ^.NH

or with lower alkyl, e.g. methyl.

The group -(^nH2n^~ is a linear or branched alkylene chain and is, for example, methylene, 1,2-ethylene, 1,3-propylene, or 1,4-butylene, further 1,1-ethylene, 1,1-propylene, 1,2-propylene, 1,1-butylene or 1,1-isobutylene.

When R is lower alkyl, it has 1-7 carbon atoms, and is, for example, methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl.

When R is sulfo which is present in salt form, it is present, for example, as an alkali metal salt, e.g. sodium salt or as an ammonium salt. When R is an acyl group, it has up to 19 carbon atoms, and the acyl group is R in a carboxylic acid,

a half ester of carbonic acid, carbamic acid, a substituted carbamic acid, thiocarbamic acid, a substituted thiocarbamic acid, a sulfonic acid, the amidosulfonic acid, a substituted amidosulfonic acid or is an acylcarbamoyl or acylthiocarbamoyl group.

When R is such an acyl group, it has, for example, the partial formulas:

Ra-CO-, Ra<->0-CO-, (R<a>)R<b>N-CO-, (R<a>)R<b>N-CS-, Ra<->S02~ , (R<a>)R<b>N-SO2-, (Ra<->CO)-R<b>N-CO-, (Ra<->CO)-R<b>N-CS- or

wherein n is an integer from 1 to 4, preferably 2, k 1 or 2, Ra or R independently of each other hydrogen, an unsubstituted or substituted, saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic hydrocarbon residue, with up to 18, preferably up to 10, carbon atoms, an unsubstituted or substituted, aromatic or aromatic-aliphatic hydrocarbon residue with up to 18, preferably up to 10, carbon atoms or an unsubstituted or substituted heterocyclyl or heterocyclyl lower alkyl residue and Rchydrogen, lower alkyl, lower alkyl substituted with hydroxy, halogen , carboxy, lower alkoxy or amino, lower alkenyl, lower alkanoyl]:, lower alkanesulfonyl or sulmaoyl.

When Ra or R° is a saturated or:* unsaturated, aliphatic, cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon residue, it is for example lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl lower alkyl, cycloalkyl lower alkenyl or cycloalkenyl lower alkyl.

Substituents in such a residue Ra or R° are, for example, hydroxy, ethereal or esterified hydroxy, e.g. lower alkoxy, e.g. methoxy or ethoxy, lower alkanoyloxy, e.g. acetoxy, hydroxysulfonyloxy present in the same form or halogen, e.g. chlorine, ethereal mercapto, e.g. lower alkylthio, e.g. methylthio, carboxy, esterified carboxy, e.g. lower alkoxycarbonyl, e.g. methoxycarbonyl or ethoxycarbonyl, amidated carboxy, e.g. carbamoyl, cyano, nitro, sulfo present in salt form, amino, lower alkanoylamino, e.g. acetylamino, lower alkylamino, e.g. methyl- or ethylamino, or dilavealkylamino, e.g. dimethylamino.

When R cl or R t) is lower alkyl, they contain up to 7 carbon atoms and are e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl or n-heptyl.

When R or R is substituted lower alkyl, they are primarily substituted methyl or are ethyl or propyl, whereby the substituents are, if possible, preferably in a higher position than the 1-position in the lower alkyl residue.

When Ra or R° is substituted lower alkyl, they are, for example, hydroxyl lower alkyl, e.g. hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl, lower alkoxy lower alkyl, e.g. lower alkoxymethyl, lower alkoxyethyl or lower alkoxypropyl, e.g. methoxymethyl, 2-methoxyethyl or 3-methoxypropyl, lower alkanoyloxy lower alkyl, e.g. lower alkanoyloxymethyl, lower alkanoyloxyethyl or lower alkanoyloxypropyl, e.g. acetoxymethyl, propionyloxymethyl, 2-acetoxyethyl or 3-acetoxypropyl, halolower alkyl, e.g. halomethyl, haloethyl or halopropyl, e.g. 2-chloro- or 2-bromomethyl or 3-chloro- or 3-bromopropyl, in salt form, e.g. as an alkali metal salt, e.g. as a sodium salt, or as an ammonium salt, present hydroxysulfonyloxylaverealkyl, e.g. hydroxysulfonyloxymethyl, 2-hydroxysulfonyloxyethyl or 3-hydroxysulfonyloxypropyl, lower alkylthiolower alkyl, e.g. methylthiomethyl, 2-methylthioethyl, 2-methylthiopropyl or tert-butylthiomethyl, carboxyl lower alkyl, e.g. carboxymethyl or 2-carboxymethyl, lower alkoxycarbonyl lower alkyl, e.g. lower alkoxycarbonylmethyl or lower alkoxycarbonylethyl, e.g. methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, carbamoyl lower alkyl, e.g. carbamoylmethyl or 2-carbamoylethyl, lower alkyl carbamoyl lower alkyl, e.g. methylcarbamoylmethyl, diloweralkylcarbamoylloweralkyl, e.g. dimethylcarbamoyl-methyl, cyano lower alkyl, e.g. cyanomethyl or 2-cyanoethyl, in salt form, e.g. such as alkali metal, e.g. as a sodium salt, or as an ammonium salt, present sulpholower alkyl, e.g. sulfomethyl, 2-sulfoethyl or 3-sulfo-propyl, amino lower alkyl, e.g. aminomethyl or 2-aminoethyl, lower alkanoylaminolower alkyl, e.g. acetylaminomethyl or 2-acetylaminoethyl, lower alkylaminolower alkyl, e.g. methylaminomethyl or 2-methylaminoethyl, or dilower alkylarainolaverealkyl, e.g. dimethylaminomethyl or 2-dimethylaminoethyl.

When R cl or R t ) is lower alkenyl, they contain 2 to 7, especially 2 to 4, carbon atoms, and are e.g. vinyl, allyl or 2- or 3-butenyl. When Ra or R<b>is substituted lower alkenyl, they may be substituted with the same substituents as substituted lower alkyl.

a b

When R or R is lower alkenyl, they contain 2-7, especially 2-4 carbon atoms, and <g>~ is, for example, ethynyl, 1-propynyl or 2-propynyl.

When R a or R b is cycloalkyl, they contain 3-7 carbon atoms and are, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

When Ra or BJ° is cycloalkenyl, they contain 3-7 carbon atoms, and are, for example, cyclohexenyl, e.g. 1-cyclohexenyl, or cyclohexadienyl, e.g. 1,4-cyclohexadienyl.

When R cL or R be cycloalkyllower alkyl, they contain

4-9 carbon atoms, and is, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

When R 3. or R b is cycloalkyl lower alkenyl, they contain 4-9 carbon atoms, and are for example cyclohexylvinyl or cyclohexylallyl.

When R cl or R b is cycloalkenyl lower alkyl, contains

the 4-9 carbon atoms and are, for example, 1-cyclohekenylmethyl or 1,4-cyclohexadienylmethyl.

When R ci or R b is an aromatic or aromatic-aliphatic hydrocarbon residue, they are, for example, phenyl, phenyl lower alkyl, e.g. benzyl, 2-phenylethyl, diphenylmethyl or trityl, or phenyl lower alkenyl, e.g. 3-phenylallyl.

Phenyl, as well as phenyl lower alkyl or phenyl lower alkenyl can be substituted at the phenyl residue, for example with lower alkyl, e.g. methyl or ethyl, lower alkoxy, e.g. methoxy or halogen, e.g. fluorine or chlorine, further with nitro or amino. When R or R, a is substituted

a b

phenyl lower alkyl or phenyl lower alkenyl residue, lower alkyl may be substituted in the α position of the phenyl residue, e.g. with hydroxy, hydroxysulfonyloxy, carboxy,

sulfo or amino.

When R 3. or R b is heterocyclyl, they have up to 10 carbon atoms, and up to heteroatoms from the group nitrogen, oxygen or sulphur, and are, for example, aromatic, monocyclic, 5- or 6-membered aza-, thia-, oxa-, oxaaza -, thiaaza-, diaza-, thiadiaza-, triaza- or tetraazacyclyl. When R 61 or R b is heterocyclyl, they are, for example, pyridyl, e.g. 2- or 4-pyridyl, thienyl, e.g. 2- or 3-thienyl, furyl, e.g. 2- or 3-furyl, oxazolyl, e.g. 2-oxazolyl, thiazolyl, e.g. 2-thiazolyl, isothiazolyl, e.g. 2-or 4-isothiazolyl, pyrimidyl, e.g. 4- or 6-pyrimidyl, thiadiazolyl, e.g. 1,2,4-thiadiazolyl-3-yl, 1,2,5-thiadiazol-3-yl, or 1,2,4-thiadiazol-3-yl, triazolyl, e.g. 3-triazolyl, or tetrazolyl, e.g. 1- or 5-tetrazolyl.

6i b The substituents in the heterocyclyl residues R or R are the same as the substituents mentioned earlier for the heterocyclyl group R2 •

When Ra or R<b>is heterocyclyl, they are preferably pyridyl, e.g. 3- or 4-pyridyl, thienyl, e.g. 2- or 3-thienyl, furyl, e.g. 2- or 3-furyl, aminooxazolyl, e.g. 2-amino-4-oxazolyl, aminothiazolyl, e.g. 2-amino-4-thiazolyl, hydroxypyrimidyl, e.g. 2,6-dihydroxy-1,3-pyrimid-4-yl, aminothiadiazolyl, e.g. 5-amino-1,2,4-thiadiazolyl-3-yl, hydroxythiadiazolyl, e.g. 4-hydroxy-1,2,5-diadiazolyl-3-yl, and aminotriazolyl, e.g. 5-amino-1,2,4-triazol-3-yl.

When Ra or R is heterocyclyl lower alkyl, they are for example lower alkyl, e.g. methyl, which is substituted with

Pib

the previously mentioned heterocyclyl R or R , e.g. tetrazolyl lower alkyl, e.g. 1H-tetrazol-5-ylmethyl, or aminothiazolyl lower alkyl, e.g. 2-amino-1,3-thiazol-4-ylmethyl.

ci b

R or R is primarily hydrogen, lower alkyl,

e.g. methyl or ethyl, lower alkyl substituted by hydroxy, lower alkoxy, e.g. methoxy, halogen, e.g. fluorine, chlorine or bromine, carboxy, cyano or amino,

e.g. 1-hydroxyethyl, methoxymethyl, cyanomethyl or aminomethyl, lower alkenyl, e.g. vinyl, lower alkynyl, e.g. ethynyl, cycloalkyl, e.g. cyclopropyl, phenyl, phenyl substituted with amino or nitro, e.g. 4-aminophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, phenyl lower alkyl, e.g. benzyl, phenyl lower alkyl, in which lower alkyl is substituted in the c-position to the phenyl residue by hydroxy or amino, e.g. hydroxy- or aminobenzyl, pyridyl, e.g. 4-pyridyl, thienyl, e.g. 2-thienyl, furyl, e.g. 2-furyl, hydroxypyrimidyl, e.g. 2,6-dihydroxy-1,3-pyrimid-4-yl, hydroxythiadiazolyl, e.g. 4-hydroxy-1,2,5-thiadiazol-3-yl, tetrazolyl lower alkyl, e.g. tetrazolyl-5-ylmethyl, or aminothiazolyl lower alkyl, e.g. 2-amino-1,3-thiazol-4-ylmethyl.

When R is an acyl group, the preferred acyl group is in a carboxylic acid, for example lower alkanoyl, e.g. formyl or acetyl, lower alkanoyl substituted with hydroxy, lower alkoxy, e.g. methoxy, halogen, e.g. bromo, carboxy, cyano or amino, e.g. α-hydroxypropionyl, methoxyacetyl, bromoacetyl, carboxyacetyl, cyanoacetyl or glycyl, lower alkenoyl, e.g. acryloyl, lower alinoyl, e.g. propioloyl, cycloalkylcarbonyl, e.g. cyclopropylcarbonyl, benzoyl, 4-aminobenzoyl, 4-lower alkanoylaminobenzoyl, e.g. 4-acetylaminobenzoyl, 4-cyanobenzoyl, 4-nitrobenzoyl or 3,4-dinitrobenzoyl, pyridylcarbonyl, e.g. nicotinoyl or isonicotinoyl, furoyl, e.g. 2-furoyl, thienylcarbonyl, e.g. 2-thienylcarbonyl, hydroxypyrimidylcarbonyl, e.g. 2,6-dihydroxy-1,3-pyrimid-4-yl carbonyl, hydroxythiadiazolylcarbonyl, e.g. 4-hydroxy-1,2,5-thiadiazol-3-yl carbonyl, tetrazolyl lower alkanoyl, e.g. 2-tetrazol-5-yl acetyl or aminothiazolyl lower alkanoyl, e.g. 2-(2-amino-1,3-thiazol-4-yl)-acetyl, the acyl group of a half-ester of carbonic acid, e.g. lower alkoxy-carbonyl, e.g. methoxycarbonyl or isopropoxycarbonyl, lower alkanoyloxy substituted with carboxy and amino, e.g. 2-amino-2-carboxyethoxycarbonyl or benzonyloxycarbonyl, the acyl group of a substituted carbamic acid, for example lower alkylcarbamoyl, e.g. methylcarbamoyl or anilinocarbonyl, the acyl group of a substituted thiocarbamic acid, for example lower alkylthiocarbamoyl, e.g. methylthiocarbamoyl, the acyl group of a substituted sulphonic acid, for example lower alkanesulphonyl, e.g. methanesulfonyl, lower alkanesulfonyl substituted with halogen, e.g. fluorine, e.g. difluoromethanesulfonyl, benzenesulfonyl, 4-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl, amino-benzenesulfonyl, an acylthiocarbamoyl group, for example benzoylthiocarbamoyl or furoylthiocarbamoyl, an acylcarbamoyl group, for example benzoylcarbamoyl or furoylcarbamoyl, 2-oxo-l-imidazolidinocarbonyl, 4-lower alkyl- 2,3-dioxo-1-piperazinocarbonyl, e.g. 4-ethyl-2,3-dioxo-1-piperazinecarbonyl, and 4-lower alkylsulfonyl-1-piperazinecarbonyl, e.g. 4-methylsulfonyl-1-piperazinocarbonyl.

When R is lower alkyl, it is, for example, methyl or ethyl.

When R is lower alkyl substituted by hydroxy, halogen, carboxy, lower alkyl or amino, it is, for example, hydroxymethyl, 1- or 2-hydroxyethyl, chloroethyl, trichloroethyl, carboxymethyl, methoxymethyl, aminomethyl or 2-aminoethyl.

When R c is lower alkenyl, it is, for example, vinyl, allyl or 1-isobutenyl.

When R is lower alkanoyl, it is, for example, acetyl.

When R C is lower alkanesulfonyl, it is for example methanesulfonyl or ethanesulfonyl.

R<c> is preferably hydrogen, lower alkyl, e.g. ethyl, or lower alkanesulfonyl, e.g. methanesulfonyl.

When RQ is lower alkyl, it is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.

In a group with partial formula A, in which the nitrogen is a constituent of a heterocyclic group, R and RQ constitute the alkylene, e.g. ethylene, propylene, butylene, pentylene or hexylene, which is optionally interrupted by nitrogen substituted by oxygen, sulphur, J^NH, or by lower alkyl, e.g. methyl. Such a heterocyclic group can be substituted with one or two hydroxy or oxo groups at the carbon atom, and is, for example, 1-aziridinyl, 1-pyrrolidinyl, 1-piperidyl, 1H-2,3,4,5,6,7-hexahydroazepinyl, 4 -morpholinyl, 4-thio-morpholinyl and preferably 1-piperazinyl or 4-methyl-1-piperazinyl.

A preferred group with partial formula A is, for example, 2-aminoethyl, 2-lower alkylaminoethyl, e.g. 2-methylaminoethyl or 2-n-hexylaminoethyl, 2-dilower alkylaminoethyl, e.g. 2-dimethylaminoethyl or 2-di-n-hexylaminoethyl, 2-sulfoaminoethyl, lower alkanoylaminoethyl, e.g. 2-formylaminoethyl or 2-acetylaminoethyl, 2-lower alkyllower akanoylaminoethyl, e.g. 2-Methoxyacetylaminoethyl, 2 —-halolower alkylaminoethyl, e.g. 2-bromoacetylamino-ethyl-2-(a-hydroxypropionylamino)-ethyl, 2-glycylaminoethyl, 2- (3-amino-3-carboxypropionylami.no)-ethyl, 2- (a-hydroxy-propionylamino)-ethyl, 2- glycylaminoethyl, 2-(3-amino-3-carboxypropionylamino)-ethyl, 2-acryloylaminoethyl, 2-propioloylaminoethyl, 2-cyclopropylcarbonylaminoethyl, 2-benzoylaminoethyl, 2-(4-aminobenzoylamino)-ethyl, 2-(4-acetylaminobenzoylamino)-ethyl ethyl, 2-(4-cyanobenzoylamino)-ethyl, 2-(4-nitrobenzoylamino)-ethyl, 2-(3,4-dinitrobenzoylamino)-ethyl, 2-mandeloylaminoethyl, 2-phenylglycylaminoethyl, 2-hycotinoylaminoethyl, 2-isonicotinoylaminoethyl, 2-(2-furoyl-amino)-ethyl, 2-(2-thienylcarbonylamino)-ethyl, 2-(2,6-dihydroxy-1,3-pyrimid-4-ylcarbonylamino)-ethyl, 2-(4 -hydroxy-1,2,5-diadiazol-3-ylcarbonylamino)-ethyl, 2-(2-tetrazol-1-ylacetylamino)-ethyl, 2-[2-(2-amino-1,4-thiazol-4- yl)-acetylamino]-ethyl, 2-lower oxycarbonylaminoethyl, e.g. 2-methoxycarbonylaminoethyl or 2-isopropoxycarbonylaminoethyl, 2-(2-amino-2-carboxyethoxycarbonylamino)ethyl, 2-benzoyloxycarbonylaminoethyl, 2-lower alkylcarbamoylaminoethyl, e.g. 2-methylcarbamoylaminoethyl, 2-anilinocarbonylaminoethyl, 2-lower alkylthiocarbamoylaminoethyl, e.g. 2-methylthiocarbamoylaminoethyl, 2-lower alkanesulfonylaminoethyl, e.g. 2-methanesulfonylaminoethyl, 2-halogenomethanesulfonylaminoethyl, e.g. 2-difluoromethanesulfonylaminoethyl, 2-cyanomethanesulfonylaminoethyl, 2-benzenesulfonylaminoethyl, 2-(4-nitrogenazolesulfonylamino)-ethyl, 2-(3,4-dinitrobenzenesulfonylamino)-ethyl, 2-benzoylcarbamoylaminoethyl, 2-(2-furoylcarbamoylamino)-ethyl, 2-(2-oxo-1-imidazolidinocarbonylamino)-ethyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-ethyl and 2-(4-methylsulfonylpiperazinocarbonylamino)-ethyl.

When is an unsaturated, aliphatic hydrocarbon residue, it is, for example, lower alkenyl with 2-5 carbon atoms, e.g. vinyl or allyl.

When R^ is a saturated, cycloaliphatic hydrocarbon ring, is

the for example cycloalkyl with 3-8, especially 3-6, carbon-

atoms, e.g. cyclopropyl, cyclopentyl or cyclohexyl.

When R,, is an unsaturated, cycloaliphatic hydrocarbon residue, is

the for example cycloalkenyl with 5 or 6 carbon atoms, e.g. 1-cyclohexenyl or 1-4 cyclohexadienyl.

When Rc- is an aromatic hydrocarbon residue, it is, for example, phenyl or naphthyl, which may be substituted with the following substituents: alkyl, e.g. dodecyl or lower alkyl, e.g. methyl or ethyl, halolower alkyl, e.g. trifluoromethyl, hydroxy, ethereal hydroxy, e.g. lower alkoxy, e.g. methoxy or ethoxy,"esterified hydroxy, e.g., lower alkanoyloxy, e.g., acetoxy, or halogen, e.g., chlorine, or lower alkoxycarbonyloxy, e.g., ethoxycarbonyloxy, amino, dilower alkylamino, e.g., dimethylamino, lower alkylamino, eg methylamino, lower alkanoylamino, eg formylamino or acetylamino, dilower alkylamino-methyleneamino, eg dimethylaminomethyleneamino, hydrazino, carbazo, thiacarbamoylhydrazino, lower alkoxycarbonylamino, eg ethoxycarbonylamino, cyano, nitro, carboxyl or esterified carboxyl , eg methoxycarbonyl or ethoxycarbonyl.

When R 5 is an aromatic hydrocarbon residue, it is preferably phenyl, naphthyl, 4-alkylphenyl, e.g. 4-dodecylphenyl, 4-lower alkylphenyl, e.g. 4-methylphenyl, 3-halogeno-lower alkyl-phenyl, e.g. 3-trifluoromethylphenyl, 4-aminophenyl, 4-lower-alkanoylaminophenyl, e.g. 4-formylaminophenyl or 4-acetylaminophenyl, 4-dilaverealkylaminomethyleneaminophenyl,

e.g. 4-dimethylaminomethyleneaminophenyl, 4-hydrazinophenyl, 4-carbazophenyl, 4-thiocarbamoylhydrazino, 4-lower alkylaminophenyl, e.g. 4-ethoxycarbonylaminophenyl, 4-nitrophenyl, 4-cyanophenyl, 4-carboxyphenyl, 5-carboxy-6-hydroxy-2-naphthyl, 6-lower oxycarbonyloxy-2-naphthyl, e.g. 6-ethoxycarbonyloxy-2-naphthyl, 5- or 6-alkanoylamino-1-naphthyl, e.g. 5- or 6-acetylamino-1-naphthyl, 6-lower oxycarbonylamino-1-naphthyl, e.g. 6-ethoxy-

carbonylamino-1-naphthyl, or 4-lower alkoxycarbonyloxy-6-lower alkoxycarbonylamino-1-naphthyl, e.g. 4-ethoxy-carbonyloxy-6-ethoxycarbonylamino-1-naphthyl.

When R5 is an aromatic-aliphatic hydrocarbon residue, it is, for example, one of the aforementioned aliphatic residues, e.g. lower alkyl, e.g. methyl or ethyl, which is substituted with one of the mentioned aromatic residues, e.g. phenyl, for example benzyl or phenethyl.

When Rj- is heterocyclyl, it is for example aromatic or hydrogenated, monocyclic or benzo-fused heterocyclyl, for example monocyclic, aromatic, 5-' or 6-membered aza-, thia- or oxacyclyl, e.g. pyridyl, e.g.

2-, 3- or 4-pyridyl, thienyl, e.g. 2- or 3-thienyl, or furyl, e.g. 2- or 3-furyl, monocyclic, aromatic 5- or 6-membered diazacyclyl, e.g. imidazolyl, e.g. 2-imidazolyl or 5-imidazolyl, pyrimidyl, e.g. 4- or 5-pyrimidyl, monocyclic, aromatic, five-membered thiadiazacyclyl, e.g. thiadiazolyl, e.g. 1,3,4-thiadiazol-5-yl, monocyclic, hydrogenated, five-membered oxacyclyl, e.g. tetrahydrofuryl, e.g. 3-tetrahydrofuryl, benzofused azacyclyl, e.g. indolyl, e.g. 5-indolyl, benzofused diazacyclyl, e.g. quinoxalinyl, e.g. 7- quinoxalinyl, or indazolyl, e.g. 5-indazolyl, benzofused oxaazacyclyl, e.g. benzooxazolyl, e.g. 5-benzoxazolyl, or is benzofused thiaaza-cyclyl, e.g. benzthiazolyl, e.g. 2-, 5- or 6-benzthiazolyl.

Substituents for heterocyclyl residues R^ are, for example, oxo, hydroxy, halogen, e.g. chlorine, lower alkyl, e.g. methyl, lower alkoxycarbonyl, e.g. ethoxycarbonyl, lower alkanoylamino, e.g. acetylamino or N-lower alkylureido, e.g. N-methyl ureido.

When Rj- is substituted heterocyclyl, it is, for example, lower alkanoylamiriopyridyl, e.g. 5-acetylaminopyrid-2-yl, lower alkyl-lower alkanoyl-amino-lower oxycarbonyl-thienyl, e.g. 3-methyl-4-ethoxycarbonyl-5-acetylaminothien-2-yl, lower alkylimidazolyl, e.g. 1-methylimidazolyl-5-yl, thihydroxypyrimidyl, e.g. 2,4-dihydroxypyrimid-5-yl, lower alkanoylaminothiadiazolyl, e.g. 2-acetylamino-1,3,4-thiadiazol-5-yl, lower alkylureidothiadiazolyl, e.g. 2-methylaminocarbonylamino-1,3,4,-thiadiazol-5-yl, lower alkyl-indolyl, e.g. 2-methylindol-5-yl, dihydroxyquinoxalinyl, e.g. 2,3-dihydroxyquinoxalin-7-yl, hydroxyindazolyl, e.g. 3-hydroxyindazol-5-yl, hydroxychlorobenzoxazolyl, e.g. 27-hydroxy-6-chlorobenzOxazol-5-yl, or aminobenz-thiazolyl, e.g. 2-aminobenzthiazol-6-yl.

When Rg is heterocyclyl, it is, for example, aromatic, monocyclic, 5- or 6-membered aza-, thia-, oxa-, thiaza-, diaza-, thiadiaza-, triaza- or tetraazacyclyl, e.g. pyridyl, e.g. 3- or 4-pyridyl, thienyl, e.g. 2-or 3-thienyl, furyl, e.g. 2- or 3-furyl, thiazolyl, e.g. 2-thiazolyl, isothiazolyl, e.g. 2- or 4-isothiazolyl, pyrimidyl, e.g. 4- or 5-pyrimidyl, thiadiazolyl, e.g. 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazol-3-yl, or 1,3,4-thiadiazol-3-yl, triazolyl, e.g. 3-triazolyl, or tetrazolyl, e.g. 1- or 5-tetrazolyl.

The substituents of the heterocyclyl radical Rg are the same substituents mentioned earlier for heterocyclylthio-. the group R^..

When R 8 is heterocyclyl, it is preferably pyridyl, e.g. 3- or 4-pyridyl, thienyl, e.g. 2- or 3-thienyl, furyl, e.g. 2- or 3-furyl, aminothiazolyl, e.g. 2-amino-4-thiazolyl, hydroxypyrimidyl, e.g. 2,6-dihydroxy-1,3-pyrimid-4-yl, aminothiadiazolyl, e.g. 5-amino-1,2,4-thiadiazolyl-3-yl, hydroxythiadiazolyl, e.g. 4-hydroxy-1,2,5-thiadiazol-3-yl, or aminotriazolyl, e.g. 5-amino-1,2,4-triazol-3-yl.

When Rg is a heterocyclyl-aliphatic residue, it is for example lower alkyl, e.g. methyl, which is substituted with the previously mentioned heterocyclyl R 1 , e.g. tetrazolyl lower alkyl, e.g. tetrazol-5-ylmethyl, or aminothiazolyl lower alkyl, e.g. 2-amino-1,3-thiazol-4-ylmethyl.

The functional groups which are present in connection with formula I, in particular the carboxyl, amino, hydroxy and sulpho groups, are optionally protected by such protecting groups (conventional protecting groups),

which are commonly used in penicillin, cephalospoin and peptide chemistry.

The protection of functional groups with such protective groups, the protective groups themselves, as well as their cleavage reactions, are for example described in "Protectivé Groups in Organic Chemistry", Plenum Press, London and

New York 1973, in "Protectivé Groups in Organic Chemistry", Wiley, New York 1974, in "The Peptides", Volume I, Schrøder

and Lubke, Academic Press, London and New York 1965, as well as in "Methoden der organischen Chemie", Houben-Weyl, 4th edition, volume 15/1, Georg Thieme Verlag, Stuttgart 1974.

Such protective groups can be easily cleaved off under gentle conditions, i.e. that unwanted side reactions hardly or not at all take place, for example solvolytic, reductive, photolytic or also under physiological conditions,

A carboxyl group, e.g. the carboxyl group R^, further a

the carboxyl group present in R2, R^ and Rg is usually protected in esterified form, whereby the ester group is easily cleavable under mild conditions. A carboxyl group protected in esterified form is primarily esterified with a lower alkyl group, which is branched in the I-position of the lower alkyl group, or is substituted with suitable substituents in the 1- or 2-position of the lower alkyl group.

A protected carboxyl group, which is esterified with a lower alkyl group, which is branched in the 1-position to the lower alkyl group, is, for example, tert.-lower oxycarbonyl, e.g. tert.-butoxycarbonyl, arylmethoxycarbonyl with one or two aryl residues, wherein aryl preferably means unsubstituted or phenyl which is mono-, di- or tri-substituted with e.g. lower alkyl, e.g. tert-lower alkyl, e.g. tert-butyl, lower alkoxy, e.g. methoxy, hydroxy, halogen, e.g. chlorine, and/or nitro, for example benzyloxycarbonyl, benzyloxycarbonyl which is substituted with the aforementioned substituents, e.g. 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted with the aforementioned substituents, e.g. di-(4-methoxyphenyl)-methoxycarbonyl.

A protected carboxyl group that is esterified with a lower alkyl group, which is substituted in the 1- or 2-position to the lower alkyl group with suitable substituents, is for example 1-lower oxyllower oxycarbonyl,

e.g. methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl, 1-lower alkylthiolower oxycarbonyl, e.g. 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylethoxycarbonyl, e.g. phenazyloxycarbonyl, as well as 2-halogeno-lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl.

A carboxyl group can also be protected as an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, a lower alkylsilyloxycarbonyl group, e.g. trimethylsilyloxycarbonyl. The silicon atom in the silyloxycarbonyl group can also be substituted with two lower alkyl groups, e.g. methyl groups, and the carboxyl group or amino group of a second molecule with formula I. Compounds with such protective groups can be prepared, for example, by using dimethyldichlorosilane

as a silylating agent.

A protected carboxyl group is preferably tert-lower oxycarbonyl, e.g. tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl.

An amino group, e.g. an amino group which is present in , R^ and Rg, can e.g. be protected in the form of an easily cleavable acylamino-, arylmethylamino-, etherether mercapto-amino-, 1-acylvarealk-1-en-2-ylamino- or silylamino group.

In an easily cleavable acylamino group, acyl is, for example, the acyl group in an organic carboxylic acid with up to 10 carbon atoms, especially an unsubstituted one or one, e.g. with halogen or aryl, substituted lower alkanecarboxylic acid, or the unsubstituted or, e.g. with halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic acid half-st.er. Such an acyl group is, for example, lower alkanoyl, e.g. formyl, acetyl or propionyl, halolower alkanoyl, e.g. 2-Haloacetyl, especially 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl, benzoyl or benzoyl which is substituted with e.g. halogen, e.g. chlorine, lower alkoxy or nitro, e.g. benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl which is branched in the 1-position of the lower alkyl residue, or substituted with suitable substituents in the 1- or 2-position.

Lower alkoxycarbonyl which is branched in the 1-position in the lower alkyl residue is, for example, tert.-lower oxycarbonyl, e.g. tert-butoxycarbonyl, arylmethoxycarbonyl with 1 or 2 aryl residues, wherein aryl preferably means unsubstituted. phenyl or phenyl which is mono-, di- or tri-substituted with e.g. lower alkyl, especially tert.-lower alkyl, e.g. tert-butyl, lower alkoxy, e.g. methoxy, hydroxy, halogen, e.g. chlorine, and/or nitro, for example diphenylmethoxycarbonyl, or thi-(4-methoxy-phenyl)-methoxycarbonyl.

Lower oxycarbonyl which is substituted in the 1- or 2-position with suitable substituents is, for example, aroylmethoxycarbonyl, e.g. phenzyloxycarbonyl, 2-halogen-lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-(trisubstituted silyl)ethoxycarbonyl, in which the silyl group

is substituted with organic residues, e.g. lower alkyl, f phenyl lower alkyl or phenyl,* for example 2-trilower alkyl-silylethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or 2-(di-n-butylmethylsilyl)-ethoxycarbonyl, or 2-triphenylsilylethoxycarbonyl.

Arylmethylamino is, for example, mono-, di- or especially triphenylmethylamino. Arylmethylamino is, for example, benzyl, diphenylmethyl and especially tritylamino.

In an etherified mercaptoamino group, the etherified mercapto group is primarily arylthio, e.g. 4-nitrogenyl-thio.

In a l-aceyl lave alk-l-en-2-amino group, acyl is e.g. the acyl group in a lower alkane carboxylic acid or a carbonic acid lower alkyl half-ester. Such amino protecting groups are primarily 1-lower alkanoylprop.1-en-2-yl, e.g. 1-acetylprop-1-en-2-yl, or 1-lower oxycarbonylprop-1-en-2-yl, e.g. 1-ethoxycarbonylprop-1-en-2-yl.

A silylamino group is, for example, a lower alkylsilyl amine group, e.g. trimethylsilylamino. The silicon atom in the silylamino group can also only be substituted with two lower alkyl groups, e.g. methyl groups, and the amino group or the carboxyl group in a second molecule of formula I. Compounds with such protective groups can, for example, be prepared by using dimethyldichlorosilane as a silylating agent.

An amino group can also be protected in protonated form. As anions, primarily the anions of strong organic acids, such as halogen hydrogen acids, e.g. the chlorine or bromine anion, or of organic sulphonic acids, such as p-toluenesulphonic acid, suitable.

A protected amino group is preferably tert-butoxycarbonylamino (BOC), 4-nitrobenzyloxycarbonylamino, diphenylmethoxycarbonylamino,<*>2-halolower oxycarbonylamino, e.g. 2,2,2-trichloroethoxycarbonylamino, tritylamino and formylamino.

A hydroxy group, e.g. a hydroxy group present in R2/R and Rg can, for example, be protected with an acyl group, e.g. lower alkanoyl substituted with halogen, e.g. 2,2-dichloroacetyl, or especially with an acyl residue of a carbonic acid half-ester mentioned for protected amino groups. A preferred hydroxy protecting group is, for example, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, an organic silyl radical with the above-mentioned substituents, e.g. trimethylsilyl or dimethyl-n-butylsilyl, further an easily cleavable, etherifying group, such as tert.-lower alkyl, e.g. tert-butyl,

a 2-oxa- or a 2-thiaaliphatic or -cycloaliphatic hydrocarbon residue, for example 1-lower oxylower alkyl, or 1-lower alkylthiolower alkyl, e.g. methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thia-cycloalkyl with 5-7 ring atoms, e.g. 2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thia analogue, as well as 1-phenyl lower alkyl, e.g. benzyl or diphenylmethyl, whereby the phenyl residues can for example be substituted with halogen, e.g. chlorine, lower alkoxy, e.g. methoxy, and/or nitro.

A sulfo group, e.g. a sulf o group present in 1*2, R 5 and R 8 is preferably protected with a tert-lower alkyl group, e.g. tert-butyl, or with a silyl group, e.g. with trilower alkylsilyl. A sulfo group can, for example, be protected with carboxy protecting groups.

Salts are primarily pharmaceutically acceptable or usable non-toxic salts of compounds of formula I.

Such salts are formed, for example, by the acidic groups present in the compounds of formula I, e.g. carboxy or sulfo groups, and are primarily metal or ammonium salts, for example alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are formed with ammonia or suitable organic amines, whereby primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-di- or polyamines.y as well as heterocyclic bases, come into question for the salt formation. Such bases are, for example, lower alkylamines, e.g. triethylamine, hydroxy-lower alkylamines:, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, or tris-(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid 2-diethyldiaminoethyl ester, lower alkylene amines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. cyclohexylamine, or benzylamines, e.g. N,N'-dibenzyl-ethylenediamine, further bases of the pyridine type, e.g. pyridine, collidine or quinoline.

The basic groups present in the compounds of formula I, e.g. amino groups, can form acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. trifluoroacetic acid,

as well as with amino acids such as arginine and lysine.

Present in compounds with formula I several acidic groups, e.g. two carboxyl groups, or several basic groups, e.g. two amino groups, mono- or poly-salts can be formed. When the compounds of formula I have at least one acidic group, e.g. the carboxyl group R^ and at least one basic group, e.g. an amino group in R^ or R^, these can exist in the form of internal salts, i.e. in zwitterionic form, In connection with formula I, an acidic and a basic group can exist in the form of an internal salt and in addition acidic and/ or basic groups exist, for example, as acid addition and/or base addition salt

For isolation or purification, pharmaceutically unsuitable salts can also be used. For therapeutic use,

only pharmaceutically usable, non-toxic salts are mentioned, which are therefore preferred.

The compounds of formula I in which the functional groups are present in free form, and the carboxyl groups optionally in physiologically cleavable, esterified form, and their pharmaceutically usable, non-toxic salts, are valuable, antibiotic active substances, which can especially be used as anti-bacterial antibiotics .

For example, they are effective in vitro against gram-positive and gram-negative microorganisms, including 3-lactamase-producing strains, e.g. against bacteria such as Staphylocuccus aureus, Streptococcus pneumoniae, Streptococcus pyogenes and Neisseria gonorrhoeae in minimal concentrations of approx. 0.001 to approx. 32 yg/ml, against enterobacteria, e.g. against Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Proteus spp.- Enterobacter cloacae, Serratia marcescens, Haemophilus influenzae and Pesudomonas Aeruginosa, and against anaerobic gram-positive and gram-negative bacteria, e.g. Bacteroides fragilis or Clostridium perfringens,

in minimal concentrations of approx. 0.001 to approx. 64 ug/ml.

In vivo by subcutaneous application to mice, they are, for example, effective against systemic infections with cocci, e.g. Staphylococcus aureus, in a dose range of approx. 3 mg/kg to approx. 100 mg/kg and against systemic infections with enterobacteria, e.g. Escherichia coli, Proteus morganii or with Pesudomonas aeruginosa, in a dose range of approx. 0.1 mg/kg to approx. 100 mg/kg.

In the following experimental report, the activity of the compounds with formula I is shown using selected compounds.

Trial report.

1. Tested compounds:

For the following compounds, the antibiotic activity was tested: 1. 3-methoxy-73~ [ (2R, S) -2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3- cephem-4-carboxylic acid sodium salt (Example 16a). 2. 3-acetoxmethyl-73-[(2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 13a). 3. 7(3-[ (2R, S)-2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 14a). 4. 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73~[(2R,S)-2-(2.aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido] -3- cef em-4-carboxylic acid sodium salt (Example 15a) 5. 3-(1-carboxymethyl-1H-tetrazo1-5-ylthiomethyl)-73-[(2R,S)-2-(2-aminoethanesulfonylamino)-2- (2-Aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 18). 6. 3-(1-Sulfomethyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R ,S)-2-(2-aminoethanesulfonylamido)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 19). 7 . 73- [ (2R,S)- 2-(2-methanesulfonylaminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 21a). 8. 2-(1-methyl-1H-tetrazol- 5-ylthiomethyl)-73~[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt (Example 22a). 9.3-(4-Carbamoylpyridinomethyl) -73~[(2R,S)-2-(2-a minothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid (Example 23a). 10. 3-acetoxymethyl-73-[(2R.S)-2-(2-aminothiazol-4-yl)-2-(2-acetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 25a). 11-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 27a). 12. 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R)-2-(2-aminothiazol-4-yl)-2-formylaminoethanesulfonylamino)-acetamido)-acetamido]-3- cephem-4-carboxylic acid sodium salt (Example 28a). 13. 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73~[(2S)-2-(2-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3- cephem-4-carboxylic acid sodium salt (Example 28b). 14. 73-[(2R,S)-2-(2-(2-aminothiazol-4-ylacetamido)-ethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4- carboxylic acid sodium salt (Example 29a). 15. 7|3-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 31a). 16. 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyacetyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 34a). 17. 73-[(2R,S)-2-(2-(4-nitrobenzosulfonolamino)-ethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 38a ). 18. 73-[(2R,S)-2-(2-methylaminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid (Example 42a). 19. 73~[(2R,S)-2-(2-Methoxyethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid (Example 43a). 20. 73-[(2R,Sl-2-(2-aminothiazol-4-yl)-2-cyanomethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt (Example 44a). 21. 73-[(2R,S )—2-(2-aminothiazol-4-yl)-2-(2-methoxymalonyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 50a).

22.73~[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-bromoacetylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 51a).

23.73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(4-nitrobenzoyl-

amino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 55a). 24. 7(3-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(4-acetamido-benzosulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4- carboxylic acid sodium salt (Example 56a). 25. 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(4-ethyl-2,3-dioxopiperizin-1-ylcarbonylamino)- ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 58a). 26.73-[(2R,S)-2-(2-aminothio"zol-4-yl)-2-(2-acetylamino- ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 24a). 27. 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-butyrylamino)-ethanesulfonylamino )-acetamido]-3-cephem-4-carboxylic acid (Example 30a). 28. 73-[(2S)-2-(2-aminothiazol-4-yl)-2-(2-cyclopropylcarbonylaminoethanesulfonylamino)-acetamido] -3-Cephem-4-carboxylic acid sodium salt (Example 32a). 29. 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-propioloyl-aminoethanesulfonylamino)-acetamido] -3-cephem-4-carboxylic acid sodium salt (Example 35a). 30. 7-[(2S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt (Example or 8a). 31. 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-cyanoacetylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 33a). 32. 3-acetoxymethyl-73-[]2R,S)-2-(2-(4-nitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem- 4-carboxylic acid sodium salt (Example 39a). 33. 73-[(2R,S)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cef em-4-carboxylic acid sodium salt (example 40a). 34. 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(5-imidazolesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 65a). 35. 3-carbamoyloxymethyl-73-[]2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(4-nitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4- carboxylic acid sodium salt (Example 67a). 36. 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(4-aminobenzol-sulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt ( example 68a). 37. 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[]2R,S)-2-(2-aminothiazol-4-hl)-2-cyanomethanesulfonylaminoacetamido]-3- cephem-4- carboxylic acid sodium salt (Example 71a). 38. 3-carbamoyloxymethyl-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2:-(2-formylaminoethane sulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester ( example 72a). 39. 3-acetoxymethyl-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 73a). 40. 3-Carbamoyloxymethyl-73-[(2S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt (Example 75a). 41. 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetamido]- 3-Cephem-4-carboxylic acid sodium salt (Example 85a). 42. 3-Carbamoyloxymethyl-73-[(2S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (Example 87b). 43. 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-70-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acetylaminoethanesulfonylamino)-acetamido]- 3-cephem-4-carboxylic acid sodium salt (Example 90a). 44. 3-(1-sulfomethyl-1H-tetrazol-5-ylthiomethyl)-73~E(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4- carboxylic acid sodium salt (Example 95). 45. 3-carbamoyloxymethyl-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (example 103a). 46. 3-Carbamoyloxymethyl-73-[(2S)-2-(2-aminothiazol-4-yl)-2-(2-(4-aminobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt ( example 105a) 47. 3-acetoxymethyl-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-aminobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4- carboxylic acid sodium salt (Example 106).

II. Experimentally:

A. The antibiotic activity of the test compounds in vitro was determined by the agar dilution method of Ericsson, H.M., and Sherris, S.C., 1971, Acta Path. Microb.Scand. B, suppl. No. 217, volumes 1-90 in DST agar. The minimum concentration that was found continued to inhibit the growth of the test organisms (MIC = minimum inhibitory concentration) stated in micrograms per milliliters (µg/ml) in table i for the investigated compounds.

B. The in vivo chemotherapeutic activity against systemic infections in SPF, MF2 female mice was determined according to the method of Zak, 0. et al., 1979, Drugs Exptl. Clin. Res. 5, 4 5-5 9. The found ED^Q values in milligrams of substance per kg mouse (mg/kg) for a number of microorganisms is given for the orally (p.o.) or subcutaneously (s.c.) applied test compounds in table a. III. Test results:

Compounds of formula I in which the functional groups are protected are used as starting materials for the preparation of compounds of formula I, in which functional groups are present in free form or in physiologically cleavable form.

The present invention preferably applies to such compounds of formula I, in which functional groups are present in free form or in physiologically cleavable, protected form,

and their pharmaceutically acceptable salts, since mainly these compounds have the indicated activity, and can be used for the indicated purpose.

The invention applies in particular in connection with formula I, in which n is an integer from 0 to 2, is hydrogen, lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy or ethoxy, halogen, e.g. chlorine, or a group of the formula -Cf^-R^/wherein R2 is lower alkanoyloxy, e.g. acetoxy, carbamoyloxy, lower alkylcarbamoyloxy, aromatic, monocyclic, 5- or 6-membered heterocyclylthio, e.g. diaza-triaza-, tetraaza-, thiaza-, thiadiaza-, oxaza- or oxa-thiazacyclylthio, e.g. imidazolylthio, triazolylthio, e.g. 1H-1,2,3-triazol-5-ylthio, tetrazolylthio, e.g. 1H-tetrazol-5-ylthio, thiazolylthio, thiadiazolylthio, e.g. 1,3,4-thiadiazol-5-ylthio, oxazolylthio, oxadiazolylthio or 5,6-dioxotetrahydro-as-triazin-3-ylthio, e.g. 5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthio or 5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthio, which can . be substituted with lower alkyl, e.g. methyl, diloweralkylaminoloweralkyl, e.g. dimethylaminomethyl or 2-dimethylaminoethyl, sulpholower alkyl, e.g. sulfomethyl or sulfoethyl, carboxyl lower alkyl, e.g. carboxymethyl, amino, carboxyl lower alkylamino, e.g. 2-carboxyethylamino, carbamoyl or with tetrazolyl lower alkyl, e.g. tetrazol-1H-5-ylmethyl, or an ammonium group, e.g. 2-lower alkyl-1-pyrazolium, e.g. 2-methyl-1-pyrazolium, 2-carboxylaverealkyl-1-pyrazolium, e.g. 2-carboxymethyl-1-pyrazolium, 3-lower alkyl-1-triazolium, pyridinium, pyridinium substituted with hydroxyl lower alkyl, e.g. hydroxymethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, halogen, e.g. chlorine or bromine, or carbamoyl, e.g. 3-or 4-hydroxymethylpyridinium, 4-carboxypyridine, 3-or 4-carboxymethylpyridinium, 3- or 4-chloropyridinium, 3- or 4-bromopyridinium or 3- or 4-carbamoylpyridinium, R^ is carboxy or carboxy cleavable under physiological conditions, e.g. acyloxyvareal oxycarbonyl, e.g. lower alkanoylyloxycarbonyl, e.g. lower alkanoyloxymethoxycarbonyl, or loweralkanoyloxyethoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl or 2-propionyloxyethoxycarbonyl or lower alkoxycarbonyloxyvareal oxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl, or tert-butyloxycarbonyloxymethoxycarbonyl, is hydrogen, Rj. is lower alkyl, e.g. methyl or ethyl, hydroxy lower alkyl, e.g. hydroxymethyl or 2-hydroxyethyl, lower alkoxy lower alkyl, e.g. methoxymethyl, 2-methoxyethyl or 2-ethoxyethyl, lower alkenyloxy lower alkyl, e.g. 2-vinyloxyethyl, lower alkanoyloxy lower alkyl, e.g. 2-acetoxyethyl, halolower alkyl, e.g. chloromethyl, 2-chloroethyl, 3-chloropropyl, 4-chlorobutyl or 2-bromomethyl, lower alkylthiolower alkyl, e.g. 2-methylthioethyl or 2-ethylthioethyl, amiriocarboxylaverealkylthiolaverealkyl, e.g. 2-(2-amino-2-carboxyethylthio)-ethyl, benzoyl lower alkyl, e.g. benzoylmethyl, carboxy-lower alkyl, e.g. carboxymethyl or 2-carboxyethyl, lower alkoxycarbonyl lower alkyl, e.g. ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, carbamoyl lower alkyl, e.g. carbamoylmethyl, cyanolower alkyl, e.g. cyanomethyl or 1-cyano- or 2-cyanoethyl, sulpholower alkyl, e.g. sulfomethyl or 2-sulfoethyl, sulfamoyl lower alkyl, e.g. sulfamoylmethyl or 2-sulfamoylethyl, aminocarboxylave alkyl, e.g. 2-amino-2-carboxyethyl, or a group of partial formula A, in which the group -(CnH2n)- is ethylene or propylene, RQ is hydrogen or lower alkyl, e.g. methyl, and R is hydrogen, lower alkyl, e.g. methyl or ethyl, lower alkanoyl, e.g. formyl or acetyl, lower alkanoyl substituted with hydroxy, lower alkoxy, e.g. methoxy, halogen, e.g. bromo, carboxy, cyano or amino, e.g. α-hydroxypropionyl, methoxyacetyl, bromoacetyl, carboxyacetyl, cyanoacetyl or glycyl, lower alkenoyl, e.g. acryloyl, lavereal-quinoyl, e.g. prioloyl, cycloalkylcarbonyl, e.g. cyclopropylcarbonyl, benzoyl, 4-aminobenzoyl, 4-lower alkanoyl-aminobenzoyl, e.g. 4-acetylaminobenzoyl, 4-cyanobenzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, pyridylcarbonyl, e.g. nicotinoyl or isonicotinoyl, furoyl, e.g. 2-furoyl, thienylcarbonyl, e.g. 2-thienylcarbonyl, hydroxypyrimidylcarbonyl, e.g. 2,6-dihydroxy-1,3-pyrimid-4-ylcarbonyl, hydroxythiadiazolylcarbonyl, e.g. 4-hydroxy-1,2,5-thiadiazol-3-ylcarbonyl, tetrazolyl lower alkanoyl, e.g. 2-tetrazol-5-ylcetyl or aminothiazolyl lower alkanoyl, e.g. 2-(2-amino-1,3-thiazol-4-yl)-acetyl, the acyl group of a half-ester of carbonic acid, for example lower alkoxycarbonyl, e.g. methoxycarbonyl or isopropoxycarbonyl, lower alkanoyloxy substituted with carboxy and amino, e.g. 2-amino-2-carboxyethoxycarbonyl, or benzoyloxycarbonyl, the acyl group in a substituted carbamic acid, for example lower alkylcarbamoyl, e.g. methylcarbamoyl or anilinocarbonyl, the acyl group in a substituted thiocarbamic acid, for example lower alkylthiocarbamoyl, e.g. methylthiocarbamoyl, the acyl group in a substituted sulphonic acid, for example lower alkanesulphonyl, e.g. methanesulfonyl, benzenesulfonyl, 4-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl, aminobenzenesulfonyl, e.g. 4-aminobenzenesulfonyl, an acylcarbamoyl group, for example benzoylcarbamoyl or furoylcarbamoyl, an acylthiocarbamoyl group, for example benzoylthiocarbamoyl or furoylthiocarbamoyl, 2-oxo-1-imidazolidinocarbonyl, 4-lower alkyl-2,3-dioxo-1-piperazinocarbonyl, e.g. 4-ethyl-2,3-dioxo-1-piperazinocarbonyl, and 4-lower alkanesulfonyl-1-piperazinocarbonyl, e.g. 4-methanesulfonyl-1-piperazinocarbonyl, and Rg is pyridine, e.g. 3- or 4-pyridyl, thienyl, e.g. 2- or 3-thienyl, furyl, e.g.

2- or 3-furyl, aminothiazolyl, e.g. 2-amino-4-thiazolyl, hydroxypyrimidyl, e.g. 2,6-dihydroxy-1,3-pyrimid-4-yl, aminothiadiazolyl, e.g. 5-amino-1,2,4-thiadiazol-3-yl, hydroxythiadiazolyl, e.g. 4-hydroxy-1,2,5-thiadiazol-3-yl, or aminotriazolyl, e.g. 5-amino-1,2,4-traizol-3-yl, stereoisomers, mixtures of these stereoisomers, hydrates and pharmaceutically usable salts of such compounds,

The present invention mainly relates to compounds of formula I, in which m is 0, is hydrogen, lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, halogen,

e.g. chlorine, or a group -CH 2 -R 2 where R 2 is lower alkanoyloxy, e.g. acetoxy, carbamoyloxy, triazolylthio, e.g. 1H-1,2,3-triazol-5-ylthio, tetrazolylthio, e.g.

1H-tetrazol-5-ylthio, tetrazolylthio substituted with lower alkyl, e.g. methyl, diloweralkylaminoloweralkyl, e.g. 2-dimethylaminoethyl, sulpholower alkyl, e.g. sulfomethyl, carboxy-lower alkyl, e.g. carboxymethyl or carbamoyl, e.g. 1-methyl-1H-tetrazol-5-ylthio, 1-sulfomethyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio or 1-(2-dimethylaminoethyl)-1H-tetrazol-5- ylthio, thiadiazolylthio, e.g. 1,3,4,-thiadiazolyl-5-ylthio, thiadiazolylthio substituted with lower alkyl, e.g. methyl,

e.g. 2-methyl-1,3,4-thiadiazol-5-ylthio, 5,6-dioxotetrahydro-as-triazin-3-ylthio, which is substituted with lower alkyl, e.g. methyl, e.g. 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, pyridine or pyridinium substituted with hydroxyl lower alkyl, e.g. hydroxymethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, halogen, e.g. chlorine or bromine, or carbamoyl, e.g. 3- or 4-hydroxymethylpyridinium, 4-carboxypyridinium, 3- or 4-carboxymethylpyridinium, 3- or 4-chloropyridinium, 3- or 4-bromopyridinium or 3- or 4-carbamoylpyridinium, is carboxyl, carboxyl which is cleavable under physiological conditions, e.g. acyloxyvareal oxycarbonyl, e.g. lower alkanoylyloxycarbonyl, e.g. lower alkanoyloxymethoxycarbonyl or loweralkanoyloxyethoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl or 2-propionyloxyethoxycarbonyl, or lower alkoxycarbonyloxyvareal oxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl, or tert.-butoxycarbonyl-oxymethoxycarbonyl, R^ is hydrogen, R^ is lower alkyl, e.g. methyl or ethyl, hydroxy lower alkyl, e.g. hydroxymethyl or hydroxyethyl, lower alkoxy lower alkyl,

e.g. methoxynethyl, 2-methoxyethyl, or 2-ethoxyethyl, lower alkenyloxyveralkyl, e.g. 2-vinyloxyethyl, halolower alkyl, e.g. chloromethyl or 2-chloroethyl, lower alkylthiolower alkyl, e.g. -2-methylthioethyl or 2-ethylthioethyl, carboxyl lower alkyl, e.g. carboxymethyl or 2-carboxyethyl, carbamoyl lower alkyl, e.g. carba-

moylmethyl, cyanolower alkyl, e.g. cyanomethyl or 1-cyano- or 2-cyanoethyl, or a group of partial formula A, which means 2-aminoethyl, 2-lower alkylaminoethyl, e.g. 2-methylaminoethyl or 2-n-hexylaminoethyl, 2-dilower alkylaminoethyl, e.g. 2-dimethylaminoethyl or 2-di-n-hexylaminoethyl, 2-sulfoaminoethyl, lower alkanoylaminoethyl, e.g. 2-formylaminoethyl or 2-acetylaminoethyl, 2-lower alkyllower akanoylaminoethyl, e.g. 2-methoxyacetylaminoethyl, 2-halolower alkanoylaminoethyl, e.g. 2-bromoacetylaminoethyl, 2-(cc-hydroxypropionylamino)ethyl, 2-glycylaminoethyl, 2-(3-amino-3-carboxypropionylamino)ethyl, 2-acryloylaminoethyl, 2-propioylaminoethyl, 2-cyclopropylcarbonylaminoethyl, 2-benzoylaminoethyl, 2-(4-aminobenzoyl-amino)-ethyl, 2-(4-acetylaminobenzoylamino)-ethyl, 2-(4-cyano-benzoylamino)-ethyl, 2-(4-nitrobenzoylamino)-ethyl, 2-(3,4 -dinitrobenzoylamino)-ethyl, 2-mandeloylaminoethyl, 2-phenyl-glyclyaminoethyl, 2-nicotinoylaminoethyl, 2-isonicotinoylaminoethyl, 2-(2-furoylamino)-ethyl, 2-(2-thienylcarbonyl-amino)-ethyl, 2-(2 ,6-dihydroxy-1,3-pyrimid-4-ylcarbonyl-amino)-ethyl, 2-(4-hydroxy-1,2,5-thiadiazol-3-ylcarbonyl-amino)-ethyl, 2-(2-tetrazole -1-ylacetylamino)-ethyl, 2-[2-(2-amino-1,3-thiazol-4-yl)-acetylamino]-ethyl, 2-lower oxycarbonylaminoethyl, e.g. 2-methoxycarbonylaminoethyl or 2-isopropoxycarbonylaminoethyl, 2-(2-amino-2-carboxyethoxycarbonylamino)ethyl, 2-benzoyloxycarbonylaminoethyl, 2-lower alkylcarbamoylaminoethyl, e.g. 2-methylcarbamoylaminoethyl, 2-anilinocarbonylaminoethyl, 2-lower alkylthiocarbamoylaminoethyl, e.g. 2-methylthiocarbamoylaminoethyl, 2-lower alkanesulfonylaminoethyl, e.g. 2-methanesulfonylaminoethyl, 2-halogenomethanesulfonylaminoethyl, e.g. 2-difluoromethanesulfonylaminoethyl, 2-cyanomethanesulfonylaminoethyl, 2-benzenesulfonylaminoethyl, 2-(4-nitrobenzenesulfonylamino)-ethyl, 2-(2,4-dinitrobenzenesulfonylamino)-ethyl, 2-benzoylcarbamoylaminoethyl, 2-(2-furoylcarbamoylamino)-ethyl, 2- (2-oxo-1-imidazolidinocarbonylamino)-ethyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-ethyl and 2-(4-methanesulfonyl-1-piperazinocarbonylamino)-ethyl, and R fi is aminothiazolyl, e.g. 2-amino-4-thiazolyl, aminothiadiazolyl, e.g. 5-amino-1,2,4-thiadiazolyl-3-yl, or aminotriazolyl, e.g. 5-amino-1,2,4-triazol-3-yl, stereoisomers, mixtures of these stereoisomers, hydrates and pharmaceutically usable salts of such compounds.

The present invention primarily applies to compounds of formula I, in which m is 0, R-^ is hydrogen, lower alkoxy, e.g. methoxy, halogen, e.g. chlorine, or a group of the formula -CH2.R2, wherein R2 is lower alkanoyloxy, e.g. acetoxy, carbamoyloxy, tetrazoltio, e.g. 1H-tetrazol-5-ylthio, tetrazolylthio substituted with lower alkyl, e.g. methyl, diloweralkylaminoloweralkyl, e.g. 2-dimethylaminoethyl, sulpholower alkyl, e.g. sulfomethyl, or carboxyl lower alkyl, e.g. carboxymethyl, e.g. 1-methyl-1H-tetrazol-5-ylthio, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio, 5, 6-dioxotetrahydro-as-triazine- 3-ylthio which is substituted with lower alkyl, e.g. methyl, e.g. 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, pyridino or pyridinium which is substituted with hydroxyl lower alkyl, e.g. hydroxymethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, halogen, e.g. chlorine or bromine, or carbamoyl, e.g. 3- or 4-hydroxymethylpyridinium, 4-carboxypyridinium, 3- or 4-carboxymethylpyridinium, 3- or 4-chloropyridinium, 3- or 4-bromopyridinium, or 3- or 4-carbamoylpyridinium, R^ is carboxy, lower alkanoyloxyvarealoxycarbonyl, e.g. . lower alkanoyloxymethoxycarbonyl or loweralkanoyloxyethoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl or 2-propionyloxyethoxycarbonyl or lower alkoxycarbonyloxyvareal oxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl or tert.-butoxycarbonyloxymethoxycarbonyl, R 1 is hydrogen, R 1 - is lower alkyl, e.g. methyl or ethyl, lower alkoxy lower alkyl, e.g. methoxymethyl, 2-methoxyethyl or 2-ethoxyethyl, lower alkenyloxy lower alkyl, e.g. 2-vinyl oxyethyl, halolower alkyl, e.g. chloromethyl or 2-chloroethyl, carboxyl lower alkyl, e.g. carboxymethyl or 2-carboxyethyl, cyano lower alkyl, e.g. cyanomethyl or 1-cyano- or 2-cyanoethyl, or a group of partial formula A meaning 2-aminoethyl, 2-lower alkylaminoethyl, e.g. 2-methylaminoethyl, or 2-ethylaminoethyl, 2-dilaverealkylaminoethyl, e.g. 2-dimethylaminoethyl, 2-sulfoaminoethyl, lower alkanoylaminoethyl, e.g. 2-formylaminoethyl or 2-acetylaminoethyl, lower alkoxy lower akanoylaminoethyl, e.g. 2-methoxyacetylaminoethyl, cyanolower alkanoylaminoethyl, e.g. 2-cyanoacetylaminoethyl, lower alkanoylaminoethyl, e.g. 2-Acryloylaminoethyl, Taverealquinoylaminoethyl, e.g. 2-propionylaminoethyl, cycloalkanoylaminoethyl, e.g. 2-cyclopropanoylaminoethyl, 2-(4-hydroxy-1,2,5-diadiazol-3-ylcarbonylamino)-ethyl, 2-(2-tetrazol-5-ylacetylamino)-ethyl, 2-[2-(2-amino- 1,3-thiazol-4-yl)-acetylamino]-ethyl, 2-lower oxycarbonylaminoethyl, e.g. 2-methoxycarbonylaminoethyl, 2-lower alkanesulfonylaminoethyl, e.g. 2-methanesulfonylaminoethyl, 2-benzenesulfonylaminoethyl, 2-benzenesulfonylaminoethyl, wherein benzene is substituted with nitro or amino, e.g. 2-(4-nitrobenzenesulfonylamino)-ethyl, 2-(2,4-dinitrobenzenesulfonylamino)-ethyl, 2-(2-oxo-l-imidazolidinocarbonylamino)-ethyl, 2-(4-ethyl-2,3-dioxo-l -piperazinocarbonylamino)ethyl or 2-(4-methylsulfonyl-1-piperazinocarbonylamino)ethyl, and is aminothiazolyl, e.g. 2-aminor4-thiazolyl, stereoisomers, mixtures of these stereoisomers, hydrates and pharmaceutically usable salts of such compounds.

The invention relates quite particularly to the compounds of formula I described in the examples, their pharmaceutically usable salts, as well as the starting materials and intermediates described therein.

The invention relates above all to the pharmaceutically usable salts of the compounds of formula I listed in the test report, respectively their enantiomers.

Manufacturing Procedures:

Compounds of formula I in which the carboxyl groups exist in free form, or are esterified in a physiologically cleavable form, hydrates and salts of such compounds, which exhibit a salt-forming group, are prepared, for example, by

a) in connection with the formula

where m, R-^, R^ and R^ have the meanings mentioned below

formula I, and wherein a functional group is present

in R-^ is protected, and the 73-amino group is optionally protected by a group that allows an acylation reaction, acylate the 7(3-amino group by reaction with an acylating agent which introduces the acyl residue of a carboxylic acid with the formula

in which Rj- and R^ have the meanings mentioned under formula I, and in which a functional group present in Rj. and/or R^is in protected form, or

b) in connection with the formula

wherein m, R^, R^, R^ and Rg have the meanings mentioned under formula I, and wherein a functional group present in R^ and/or Rg is protected, and the 2-amino group is optionally protected with a group which allows the sulfonylation reaction, sulfonylates the 2-amino group by reaction with a sulfonylating agent which introduces the R^-sulfonylation residue from a sulfonylic acid with the formula in which R,- has the meaning mentioned under formula I and a functional group present in R,- is in protected form, or with a reactive, functional acid derivative or a salt thereof, or c) isomerizes a 2-cephem compound of the formula

wherein R^, R^, R^, Rcj and Rg have the meanings mentioned

in formula I, and a functional group present in R^, Rj and/or Rg, optionally present in protected form, to the corresponding 3-cephem compound of formula I and, if

desired, converts one compound of formula I obtainable according to the invention into another compound according to the definition of formula I and/or transfers a compound obtainable according to the invention of formula I, wherein m means 0, into a compound of formula I, wherein m is 1 or 2, and/or transfers a compound of formula I in which m is 1 or 2, to a compound of formula I in which m is equal to 0, and/or transfers functional groups present in a compound of formula I in protected form, in free, functional forms, and/or transfers an obtainable salt to the free compounds or in another salt, and/or transfers an obtainable free compound to a salt with a salt-forming group and/or splits an obtainable mixture of isomeric compounds of formula I in the individual isomers.

Method a) (acylation):

In a starting material of formula II, a functional group present in R, e.g. a carboxy, amino or hydroxy group, protected by a protecting group mentioned earlier, e.g. a carboxy, amino or hydroxy protection s<g>rup<pe>.

The 73-amino group in a starting material of formula II is optionally protected by a group which allows an acylation reaction. Such a group is, for example, an organic silyl group, further a ylidene group which, together with the amino groups, forms a Schiff base. An organic silyl group is e.g. such a group, which can also form a protected carboxyl group with a carboxyl group R^• It is primarily a trilower alkylsilyl group, especially trimethylsilyl. In the silylation reaction for protection of a 4-carboxyl group in a starting material of formula II, the amino group can also be silylated by using an excess of the silylating agent. A ylidene group is primarily a 1-aryl-lower alkylidene-, especially a 1-arylmethylene group, in which aryl in particular stands for a carbocyclic, primarily mono-

cyclic aryl residue, e.g. for phenyl which is optionally substituted with lower alkyl, hydroxy, lower alkoxy and/or nitro.

An acylating agent which introduces an acyl residue from a carboxylic acid of formula III is the carboxylic acid of formula III itself or a reactive, functional derivative or salt thereof.

In a starting material of formula III, a functional group present in R 1 - and/or R 8 , e.g. a carboxyl group, which should not participate in the acylation reaction,

an amino or hydroxyl group which is protected with a further mentioned protecting group, e.g. a carboxyl, amino or hydroxyl protecting group.

In a starting material of formula III, an amino group present may also be protected in ionic form, e.g. in the form of an acid addition salt, which is for example formed with a strong inorganic acid, e.g. a hydrohalic acid, e.g. hydrochloric or sulfuric acid, or with an organic acid, e.g. p-toluenesulfonic acid.

If a free acid of formula III is used for acylation, the reaction is usually carried out in the presence of suitable condensation agents such as e.g. carbodiimides, for example N,N'-diethyl-N,N'-dipropyl, N,N'-dicyclohexyl- or N-ethyl-N'-3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds , like for example. 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulphonate or 2-tert-butyl-5-methyl-1,2-oxazolium perchlorate, or a suitable acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline.

The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent, e.g. methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, optionally during cooling or heating, e.g. in a temperature range from approx. -40 to approx. +100°C, preferably from approx. -20 to approx. +50°C, and possibly under inert gas, e.g. nitrogen atmosphere.

A reactive, i.e. carboxamide function-forming, functional derivative of a carboxylic acid of formula III,

is primarily an anhydride of the carboxylic acid of formula III, preferably a mixed anhydride. A mixed anhydride is formed, for example, by condensation with another acid, e.g. an inorganic acid, e.g. a hydrohalic acid,

and is, for example, the corresponding carboxylic acid halide, e.g. the carboxylic acid chloride or bromide. A mixed anhydride is further formed by condensation with nitrogen hydrogen acid and is, for example, the carboxylic acid azide. Further organic acids suitable for the formation of the mixed anhydride are phosphorus-containing acids, e.g. phosphoric acid, diethylphosphoric acid and phosphoric acid sulphurous acids, e.g. sulfuric acid or hydrocyanic acid. A reactive, functional derivative of a carboxylic acid with formula III is also formed by condensation with an organic carboxylic acid, e.g. with a lower alkane carboxylic acid which is unsubstituted or substituted with halogen, e.g. fluorine or chlorine, e.g. pivalic acid or trifluoroacetic acid,

with a lower alkyl half-ester of carbonic acid, e.g. the ethyl or isobutyl half-ester of carbonic acid, or with an organic, e.g. aliphatic or aromatic, sulphonic acid, e.g. methanesulfonic acid or p-toluenesulfonic acid.

A reactive, functional derivative of a carboxylic acid of formula III is likewise an activated ester of the carboxylic acid of formula III, which is for example formed by condensation with a vinylogenic alcohol, i.e. with an enol, e.g. a vinylogenic lower alkenol, an iminomethyl ester halide, e.g. dimethyliminomethyl ester chloride, prepared from the carboxylic acid of formula III and e.g. The dimethyl-(1-chloroethylidene)- iminium chloride of the formula [(CH-j^N =C (Cl) CH.j] Cl , which in turn can be obtained from N,N-dimethylacetamide and phosgene or oxalyl chloride, an aryl ester,f .eg a phenyl ester substituted with halogen, eg chlorine and/or nitro, eg a petanchlorophenyl, 4-nitrophenyl or 2,3-dinitrophenyl ester, an N-heteroaromatic ester, e.g. eg N-benz-triazole ester, or an N-diazylimino ester, eg an N-succinylimino or N-phthalylimino ester.

The acylation with a reactive, functional derivative

of carboxylic acid of formula III, e.g. with a corresponding anhydride, especially an acid halide, is preferably carried out in the presence of one of the aforementioned condensation agents,

e.g. a carbodiimide, e.g. dicyclohexylcarbodiimide, or a suitable base. A suitable base is, for example, an amine, e.g. a tertiary amine, e.g. trilower alkylamine, e.g. trimethylamine, triethylamine or ethyl-di-isopropylamine, or N-N-dilaverealkylaniline, e.g. N,N-dimethylaniline, or a cyclic tertiary amine, e.g. an N-lower alkylated morpholine, e.g. N-methylmorpholine, or is, for example, a base of the pyridine type, e.g. pyridine. A suitable base is also an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate, or is oxirane, for example a 1,2-lower alkylene oxide, such as ethylene oxide or propylene oxide.

The acylation with a reactive, functional derivative

of the carboxylic acid with formula III is preferably carried out in an inert, preferably anhydrous, solvent or solvent mixture, for example in a carboxylic acid amide, e.g. formamyl, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. acetone, cyclic ether, e.g. tetrahydrofuran, an ester, e.g. acetic acid ethyl ester,

or a nitrile, e.g. acetonitrile, or in mixtures f ■

hence, possibly at lower or higher temperatures, e.g. in a temperature range from approx. -40 to approx. 100°C, 'preferred from approx. -10 to approx. 50°C, and possibly under inert gas, e.g. nitrogen atmosphere.

The acylation of a compound of formula II can also take place using a suitable reactive, functional derivative of the acid of formula III in the presence of a suitable acylase. Such acylases are known and can be produced by a number of microorganisms, e.g. of Acetobacter, such as Acetobacter aurantium, Achromobacter, such as Achromobacter aeris, Aeromonas, such as Aeromonas hydrophila, or Bacillus, such as Bacillus megaterium 400. In such an enzymatic acylation, in particular an amide, ester or thioester is used, as a lower alkyl, f .ex. methyl or ethyl ester, of the carboxylic acid of formula III

as reactive, functional derivative. Usually, such acylation is carried out in a nutrient 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 that optionally contains a buffer, e.g. . in a temperature range from approx. 2 0 to approx. 40°C, preferably approx. 37°C.

A reactive, functional derivative of an acid of formula III which is used with the acylation reaction can, if desired, be formed in situ. Thus, for example, a mixed anhydride can be prepared in situ by reacting an acid of formula III, in which functional groups are possibly protected, or a suitable salt thereof, e.g. an ammonium salt, such as is formed with an organic base,

such as pyridine or 4-methylmorpholine, or a metal salt, e.g. an alkali metal salt, e.g. sodium salt, with a suitable derivative of another acid, for example an acid halide, an unsubstituted or with halogen, e.g. chlorine substituted lower alkanecarboxylic acid, e.g. trichloroacetyl chloride, a half-ester of a carbonic acid half-halide, e.g. chloroformic acid ethyl ester, or -isobutyl ester, or with a halogen-

nid of a dilave alkyl phosphoric acid, e.g. diethyl phosphorous bromide, which can be formed by reacting triethyl phosphite with bromine. The mixed anhydride thus obtained can be used in the acylation reaction without isolation.

Method b) (sulfonyl eration):

In a starting material of formula IV, a functional group is present in R and/or Rg, e.g. a carboxyl, amino or hydroxyl group protected by a protecting group mentioned earlier, e.g. a carboxyl, amino or hydroxyl protecting group.

The 2-amino group in a starting material of formula IV is optionally protected by a group which allows a sulfonylation reaction. Such a group is, for example, an organic silyl group, e.g. a tri-lower alkylsilyl group, e.g. trimethylsilyl or a ylidene group, which together with the amino group forms a Schiff base, ot is the same group,

with h\ælken 7 the 3-amino group in the starting material with formula II is substituted, and which allows the acylation reaction according to method a).

A sulfonylating agent that introduces the R 2 -sulfony moiety

in a sulfonic acid of formula V, is the sulfonic acid of formula V itself, or a reactive, functional derivative thereof.

In a starting material of formula V, a functional group present in R^ is, e.g. a carboxyl group, an amino or hydroxyl group, or a sulfonyl group,

which should not take part in the acylation reaction, protected by means of a protecting group mentioned earlier, e.g. a carboxyl, amino, hydroxy or a sulfonyl protecting group.

In a starting material of formula V, an amino group present, as in a starting material of formula III to the amino group present, can be protected in ionic form, e.g. in the form of an acid addition salt, e.g. as hydrochloride.

If a free sulfonic acid of formula V is used in sulfonylation, the sulfonylation is usually carried out in the presence of the same condensing agents as are used in the acylation of the 73-amino group in a compound of formula II by a free carboxylic acid of formula III according to method a), f .ex. in the presence of a carbodiimide,

e.g. N,N<1->dicyclohexylcarbodiimide.

In the sulfonylation with a free sulfonic acid of formula V, the same solvents and the same reaction conditions are used as in acylation with a free carboxylic acid of formula III according to method a).

A reactive, functional derivative of a sulfonic acid of formula V, i.e. a derivative which forms a sulfonamide function, is primarily an anhydride of sulfonic acid of formula V, preferably a mixed anhydride. A mixed anhydride is formed, for example, by condensation with an inorganic acid, e.g. a halogen-hydrogen acid and is, for example, the corresponding sulphonic acid halide, e.g. the sulfonic acid chloride or bromide. Further inorganic acids suitable for the formation of the mixed anhydride are phosphorus-containing acids, e.g. phosphoric acid, diethylphosphoric acid or phosphoric acid, or sulphurous acids, e.g. sulfuric acid. A reactive, functional derivative of a sulphonic acid of formula V is also formed by condensation with an organic carboxylic acid, e.g. by an unsubstituted or with a halogen, e.g. fluorine or chlorine, substituted lower alkanecarboxylic acid, e.g. pivalic or trifluoroacetic acid, with a lower alkyl half-ester of carbonic acid, e.g. ethyl or isobutyl half-esters of carbonic acid, or with another sulphonic acid, e.g. an aliphatic or aromatic sulphonic acid, e.g. methanesulfonic acid or p-toluene-

sulfonic acid.

A reactive, functional derivative of a sulphonic acid of formula V is likewise an activated ester of the sulphonic acid of formula V. An activated ester is formed, for example, by condensation with a vinylogenic alcohol, i.e. with an enol, e.g. a vinylogenic lower alkenol, or is, for example, one with a halogen, e.g. chlorine and/or nitro substituted phenyl ester, e.g. a pentachlorophenyl, a 4-nitrophenyl or a 2,3-dinitrophenyl ester, an N-heteroaromatic ester, e.g. an N-benetriazole ester or is an N-diacyl-imino ester.g. an N-succinylimino or a phthalylimino ester.

In the sulfonylation with a reactive, functional derivative of a sulfonic acid of formula V, the same solvents and the same reagents are used as in acylation with a reactive, functional derivative of a carboxylic acid of formula III according to method a).

Method c) (isomerization):

In a 2-cephem starting material of formula VI, the optionally protected 4-carboxyl group preferably exhibits the α-configuration.

A 2-cephem compound of formula VI is isomerized as it is treated with a basic agent, and the corresponding 3-cephem compound is isolated. As a basic agent, an organic, nitrogen-containing base is used, especially a tertiary, heterocyclic base of an aromatic character, primarily a base of the pyridine type, e.g. pyridine, picoline, collidine or lutidine, further quinoline, a tertiary aromatic base, e.g. of the aniline type, e.g. an N,N-dilower alkylaniline, e.g. N,N-dimethylaniline or N,N-diethylaniline, or a tertiary aliphatic, azacycloaliphatic or araliphatic base, e.g. a tri-lower alkylamine, e.g. trimethylamine or N,N-diisopropyl-N-ethylamine, an N-lower alkyl-azacycloalkane, e.g. N-methyl-piperidine, or an N-phenyl lower alkyl-N,N-di lower alkyl amine, e.g. N-benzyl-N-dimethylamine, as well as a mixture of such basic agents, e.g. the mixture of a base of the pyridine type and a tri-lower alkylamine, e.g. pyridine and triethylamine. Furthermore, an inorganic or organic basic salt can be used, especially basic salt of a medium to strong base with a weak acid, e.g. an alkali metal or ammonium salt of a lower alkane carboxylic acid, e.g. sodium acetate, triethylammonium acetate or N-methylpiperidine acetate, as well as other analogous bases or mixtures of such basic agents.

In the isomerization of a 2-cephem compound of formula VI with a basic agent, work is preferably carried out in an anhydrous medium, in the presence or absence of a solvent,

as an optionally halogenated, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, whereby the liquid base used as isomerizing agent and under the reaction conditions can simultaneously also serve as solvent. It is possible to work during cooling or during heating, preferably in a temperature range from approx. -30°C to approx. +100°C, and possibly under inert gas, e.g. nitrogen atmosphere.

A thus obtainable 3-cephem compound of formula I

allows itself in a manner known per se, e.g. by absorption chromatography and/or crystallization, separate from any still present 2-cephalisporin starting material• with formula VI.

The isomerization of a 2-cephem compound of formula VI

to the corresponding 3-cephem compound of formula I preferably takes place, the 2-cephem compound of formula VI

in the 1 position is oxidized with a suitable oxidizing agent, and

if desired, a possibly obtainable isomeric mixture of the 1-oxides is separated, and a thus obtainable 1-oxide of the 3-cephem compound of formula I, in which m means 1, is reduced to the 3-cephem compound, in which m means 0.

Suitable oxidizing agents for oxidizing the sulfur atom in the 1-position in a 2-cephem compound of formula VI are inorganic peracids, which have a reduction potential of at least +1.5 vol, and consist of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, especially organic carboxylic acids with a dissociation constant of 10 ^ come into question. Suitable inorganic peracids are, for example, periodic and persulphuric acid. Organic peracids are, for example, percarboxylic

and persulfonic acids, which are added as a peracid or can be formed in situ using at least one equivalent of hydrogen peroxide and a carboxylic acid. For the in situ formation of peracid, a large excess of the carboxylic acid is suitably added, e.g. acetic acid, as a solvent. Suitable organic peracids are preferably permauric acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid or p-toluene-persulphonic acid.

Oxidation can likewise be carried out using hydrogen peroxide with catalytic amounts of an acid with a dissociation constant of at least 10 , whereby lower concentrations can be used, e.g. 1-2% and less,

but also larger amounts of the relevant acid. Thereby, the oxidative activity of the mixture depends primarily on the strength of the acid. Suitable mixtures are e.g. hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.

The above oxidation can be carried out in the presence of suitable acid catalysts. Thus, e.g. the oxidation with a percarboxylic acid in the presence of an acid with a dissociation constant of at least 10 ^ is catalyzed, whereby its catalytic activity depends on its acid strength. Acids that are suitable as catalysts are e.g. acetic acid, perchloric acid and trifluoroacetic acid. Usually, at least equimolar amounts of the oxidizing agent are used, preferably a small excess of approx. 10- approx. 20%, whereby a larger excess can also be used, i.e. up to 10 times the amount of the oxidizing agent or more. The oxidation is carried out under mild conditions, e.g. at temperatures from approx. -50 to approx. +100°C, preferably from approx. -10 to approx. 40°C.

The reduction of a 1-oxide of the 3-cephem compound, i.e.

a 3-cephem compound of formula I, wherein m is 0,

can be carried out in a manner known per se, by treatment with a suitable reducing agent, if necessary in the presence of an activating agent. Suitable reducing agents are, for example, tin, iron, copper or manganese cations which have a reducing effect, which can be used in the form of their salts, e.g. such as tin II chloride, acetate or formate, iron II chloride, sulphate, oxalate, or ammonium iron sulphate, copper I chloride or oxide, or manganese II chloride,

-sulphate, -acetate or -oxide, or as organic or inorganic complexes, e.g. with ethylenediaminetetraacetic acid or nitrolotriacetic acid, dithionite, iodine or iron II cyanide anions, which act reducing, which are used in the form of their inorganic or organic salts, e.g. such as alkali metal, e.g. sodium or potassium thionite, sodium or potassium iodide or sodium or potassium iron-II cyanide, hydroiodic acid, trivalent, inorganic or organic phosphorus compounds which have a reducing effect, such as phosphines, further esters, amides and halides of phosphonic, phosphine- or phosphoric acid, as well as phosphorus-sulfur compounds corresponding to these phosphorus-oxygen compounds, in which in these compounds organic residues primarily constitute aliphatic, aromatic or araliphatic residues, e.g. optionally substituted lower-

alkyl, phenyl or phenyl lower alkyl, e.g. triphenylphosphine, diphenylphosphonic acid methyl ester, diphenylchlorophosphine, phenyldichlorophosphine, benzenephosphonic acid dimethyl ester, phosphoric acid diphenyl ester, phosphoric acid trimethyl ester, phosphoric acid trimethyl ester, phosphorus trichloride, phosphorus tribromide, further phosphoric acid triphenyl ester halogen adducts, e.g. chlorine or bromine adducts, in which the phenyl radicals are optionally substituted with lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, or with halogen, e.g. chlorine, etc., halosilane compounds which at least have a hydrogen atom bound to the silicon atom which has a reducing effect, and which, in addition to halogen, such as chlorine, bromine or iodine, may also have organic residues, such as aliphatic or aromatic groups, e.g. substituted lower alkyl or phenyl, for example diphenylchlorosilane or dimethylchlorosilane,

as well as also halosilane compounds, in which all hydrogen atoms are replaced by organic residues, such as trilower alkylhalosilane, e.g. trimethylchlorosilane or trimethyliodosilane, etc., quaternary chloromethylene iminium salts, especially -chlorides or -bromides which have a reducing effect, in which the iminium groups are substituted with a divalent or two monovalent organic residues, as optionally substituted lower alkylene or lower alkyl, such as N-chloromethylene-N ,N-dimethyliminium chloride or N-chloromethylene-pyrrolidinium chloride, or complex metal hydrides, such as sodium borohydride, in the presence of suitable activating agents, such as cobalt II chloride, as well as borane dichloride.

Activating agents are used together with such reducing agents, which exhibit no or only weak Lewis acid properties. These are primarily used together with dithionite, iodine or iron II cyanide salts, and non-halogen-containing trivalent phosphorus reducing agents, and are especially organic carboxylic and sulphonic acid halides, e.g. phosgene, oxalyl chloride, acetic acid chloride or bromide, or chloroacetic acid chloride.

The reduction is preferably carried out in the presence of solvents or mixtures thereof, the choice of which is primarily determined by the solubility in the starting materials, and the choice of reducing agents, e.g. optionally substituted, e.g. halogenated or nitrated, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives, such as lower alkane carboxylic acid esters or nitriles, e.g. acetic acid ethyl ester or acetonitrile, or amides of inorganic or organic acids, e.g. dimethylformamide or hexamethylphosphoramide, ether, e.g. diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. acetone, or sulphones, especially aliphatic sulphones, e.g. dimethyl sulfone or tetramethylene sulfone, etc., together with the chemical reducing agents, these solvents preferably containing water.

Thereby, work is usually done at temperatures from approx. -2 0 to approx. +100°C, whereby when using highly reactive reducing agents or activating agents, the reaction is also carried out at lower temperatures and possibly under an inert gas atmosphere, e.g. nitrogen atmosphere.

Post-operations:

In an obtained compound of formula I, not yet protected functional groups can be protected, or present protecting groups can be exchanged for other protecting groups, e.g. by splitting off the present protecting group and introducing the desired second protecting group.

R-^conversions:

In an obtained compound of formula I, in which functional groups are possibly protected, a group R-^ can be replaced by another residue R^, or converted into another residue R^, in a manner known per se. Thus, for example, in a compound of formula I in which R^ means a group of the formula -CH2-R2 °g 1*2 f-e^s- can constitute a residue that can be replaced with mucleophilic substituents, or in a salt thereof by treatment with a mercaptan compound , e.g.

a heterocyclyl mercaptan compound, or with a thiocarboxylic acid compound, replacing such a residue R2 with an ethereal mercapto group, e.g. heterocyclyl mercapto group, respectively an esterified mercapto group R^•

A suitable residue which can be replaced by nucleophilic substituents, e.g. an ethereal mercapto group is, for example, a hydroxy group that is esterified with a lower aliphatic carboxylic acid. Such an esterified hydroxy group is especially acetyloxy and acetoacetoxy.

The reaction between such a compound of formula I and a suitable mercaptan compound, e.g. heterocyclyl mercaptan compound, can be carried out under acidic, neutral or slightly basic conditions. In acidic conditions, work is carried out in the presence of concentrated sulfuric acid, which may be diluted with an inorganic solvent, e.g. polyphosphoric acid. Under neutral or weakly basic conditions, the reaction is carried out in the presence of water and possibly an organic solvent which is miscible with water.

The basic conditions can, for example, be set by adding an inorganic base, such as an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. by adding sodium, potassium or calcium hydroxide, carbonate or bicarbonate. As organic solvents, e.g. alcohols that are miscible with water, e.g. lower alkanols, such as methanol or ethanol, ketones, e.g. lower alkanols, such as acetone, amides, e.g. lower alkanecarboxylic acid amides, e.g. dimethylformamide, or nitriles, e.g. lower alkane nitriles, e.g. acetonitrile.

In a compound of formula I in which R means a group of the formula -CH2~R2> in which R2 means free hydroxy, the free hydroxy group can be esterified with the acyl residue to an optionally N-substituted carbamic acid. The esterification of the free hydroxy group with an isocyanate compound, e.g. halo-gensulphonyl isocyanate, e.g. chlorosulfonyl isocyanate, or with a carbamic acid halide, e.g. carbamic acid chloride, leads to N-unsubstituted 3-carbamoyloxymethyl-cephalosporins of formula I. The esterification of the free hydroxy group with an N-substituted isocyanate compound, or with an N-mono- or N,N-disubstituted carbamic acid compound, f .ex. a correspondingly substituted carbamic acid halide, e.g. an N-mono- or N,N-disubstituted carbamic acid chloride, leads to N-mono- or N,N-disubstituted 3-carbamoyloxymethyl cephalosporins of formula I. It is usually worked up in the presence of a solvent or diluent, and if necessary , during cooling or heating, in a closed vessel, and possibly under inert gas, e.g. nitrogen atom sphere The compound of formula I in which R^ means a group of the formula -CH2-R2/in which R2 means free hydroxy, can be prepared from a compound of formula I,( by splitting off the acetyl residue from an acetyloxy group R2/e.g. by hydrolysis in weak basic medium, for example in an aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase, such as a corresponding enzyme from Rhizobium tritolii, Rhizobium lupinii, Thizobium japonicum or Bacillus subtilis, or a suitable citrus esterase , e.g. from Apennine shells.

Furthermore, a compound of formula I, in which R 2 means a group -CH 2 -R 2 / in which R 2 , e.g. constitutes the above-defined residue which can be replaced with nucleophilic substituents, e.g. acetyloxy or acetacetoxy, is reacted with an organic base, especially a tertiary, nitrogen-containing base, for example a tertiary, aliphatic amine, or preferably a tertiary, heterocyclic, aromatic nitrogen base, e.g. pyridine or pyrimidine with the substituents mentioned further above, under neutral or slightly acidic conditions, preferably at a pH value of approx. 6.5, in the presence of water and possibly in an organic solvent which is miscible with water. Compounds of formula I are then obtained in which R constitutes the residue with the formula -CH2-R2 °9 R2 is len9 in front of a defined ammonium group. Weakly acidic conditions can be set by adding a suitable organic or inorganic acid, for example acetic acid, hydrochloric acid, phosphoric acid or sulfuric acid. As organic solvents, for example, the aforementioned solvents which are miscible with water can be used. To increase the yield, salts, for example alkali metal salts, such as sodium and especially potassium salts, of inorganic acids, such as halogen-hydrogen acid, e.g. Hydrochloric and especially hydroiodic acid, as well as thiocyanic acid or of organic acids, such as lower alkanecarboxylic acid, e.g. acetic acid. Suitable salts are, for example, sodium iodide, potassium iodide and potassium thiocyanate. Also salts of certain anion exchangers, e.g. liquid ion exchangers in salt form, such as "Amberlite LA-1"

(liquid secondary amines with a molecular weight of 351-383, oil solutions and water-insoluble, meq./g = 2.5-2.7, e.g.

in acetate form), with acids, e.g. acetic acid, can be used for this purpose.

Acylation of the free amino group:

In an achievable connection with the formula

wherein m, R^, R^, R 4 and Rg have the meanings mentioned

under formula I, n means an integer from 1 to 4, RQ hydrogen or lower alkyl, and R hydrogen, the amino group of

in a manner known per se is substituted with a sulfo group or an acyl group that may be present in salt form.

This substitution can, for example, take place by reaction with an acylating agent, which introduces the sulf ester R or the corresponding acyl residue R. The carboxyl group R^, as well as functional groups, e.g. amino or hydroxy groups, which are present in R^ and R^, are protected by the protective groups mentioned further on.

If the amino group is substituted with the sulf ester R, the acylating agent used is, for example, a sulfur trioxide-tert.-amine complex, e.g. the sulfur trioxide-triethylamine complex.

If the amino group is substituted with the acyl group Ra-CO-, the acylating agent is used, for example the carboxylic acid Ra-Co-OH or a reactive, functional derivative thereof. A reactive, functional derivative of the carboxylic acid Ra-CO-OH is, for example, a mixed anhydride or an activated ester, which can be obtained in the manner described under method a) (acylation) by condensation of the carboxylic acid Ra-CO-OH with an inorganic acid , a carboxylic acid, with a half-ester of carbonic acid, a sulphonic acid or by condensation with a vinylogenic alcohol, etc.

If the amino group is substituted with the acyl group Ra-SO2~, the acylating agent is used, for example, the sulfonic acid Ra-SC>2-OH or a reactive, functional derivative thereof. A reactive, functional derivative of the sulfonic acid Ra<->S02-OH is, for example, a mixed anhydride or an activated ester, which can be obtained in the manner described under method b) (sulfonylation) by condensation of the sulfonic acid Ra<->S02- OH with an inorganic acid, a carboxylic acid, a half-ester of carbonic acid, another sulphonic acid or by condensation with a vinylogenic alcohol.

In the acylation of the free amino group with a free carboxylic acid of the formula Ra-CO-OH and with a free sulphonic acid of the formula R^SC^-OH, the same condensation agents are used, e.g. carbodiimides, the same solvents and the same reaction conditions as in the acylation according to method a).

In the acylation of the free amino group, with one of the reactive, functional derivatives described further on, the same solvents and the same reaction conditions are used as in the acylation with a reactive, functional derivative of a carboxylic acid of formula III according to method a).

Such a reactive, functional derivative is, for example, an anhydride, e.g. a mixed anhydride, for example a mixed anhydride with an organic acid, e.g. a hydrohalic acid, e.g. hydrogen chloride, for example the acyl chloride, or in the case of carbamic acid or thiocarbamic acid, an internal anhydride, e.g. a cyanate or thiocyanate.

If the amino group is substituted with an acyl group with the partial formulas Ra<->0-CO-, (R<a>)R<b>N-CO-, (R<a>)R<b>N-CS-, (R< a>)R<b>N-SO2~;(R -C0-)RbN-CO-, (Ra<->CO-)R<b>N-CS- or

is used as acylating agent, a reactive, functional derivative of the corresponding carbonic acid half-ester, the corresponding carbamic acid, thiocarbamic acid, amidosulfonic acid, acylcarbamic acid, acylthiocarbamic acid or a reactive, functional derivative of the carboxylic acid with

formula:

Alkylation of the amino group:

In an obtainable compound of formula (I'), in which m, R^, R^, R^ and Rg have the meanings mentioned under formula I, n means an integer from 1 to 4, Rq hydrogen and R hydrogen, optionally present in salt form sulfo or an acyl group, the amino group can be alkylated in a manner known per se with a suitable alkylating agent, for example an alkyl halide, e.g. methyl bromide, which introduces the lower alkyl residue Rqo of R.

Conversion to 1-oxide, 1-dioxide and 1-sulphide:

A compound of formula I in which m means 0 can be converted with the oxidizing agents described under method c) to the corresponding 1-oxide, in which n has the value 1.

1-oxides of formula I, which exist in the (3-configuration), can be prepared in a manner known per se according to the known method from DE-OFF document 30 13 996, and that by oxidation of a 1-sulfide with the formulas I or VI (m=0) with a percarboxylic acid, eg peracetic acid or m-chloroperbenzoic acid.

1-oxides of formula I which exist in a- or (3-configuration) can be prepared in a manner known per se, according to the known method from DE-OFF^written 3 0 13 996 and this by oxidation of a 1-sulphide with formula II,

where the 73-amino group is, for example, protected with ylidene groups, which together with the amino group form a Schiff base, with a percarboxylic acid, e.g. m-chloroperbenzoic acid, chromatographic separation of the obtained α- and 3-1-oxides of formula II and subsequent acylation with a carboxylic acid of formula III.

A compound of formula I, in which m means 0 or 1, can be converted to the corresponding 1-dioxide, in which n has the values 2, by reaction with sulfide or sulfoxide groups in oxidizing agents that transfer sulfone groups.

Such oxidizing agents are especially hydrogen peroxide, organic peracids, especially aliphatic percarboxylic acids, e.g. peracetic acid, perbenzoic acid, chloroperbenzoic acid, e.g. m-chloroperbenzoic acid, or monoperphthalic acid, oxidizing inorganic acids or their salts, e.g. nitric acid, chromic acid, potassium permanganate, or alkali metal hypochlorite, e.g. sodium hypochlorite, as well as anodic oxidation. The oxidation is preferably carried out in a suitable inert solvent, for example a halohydrocarbon, e.g. methylene chloride, chloroform or carbon tetrachloride, an alcohol, e.g. methanol or ethanol, a ketone, e.g. acetone, an ether, e.g. diethyl ether, dioxane or tetrahydrofuran, an amide, e.g. dimethylformamide,

a sulfone, e.g. dimethyl sulfone, a liquid organic carboxylic acid, e.g. acetic acid, or in water, or a mixture of these solvents, especially an aqueous mixture, e.g. aqueous acetic acid, at room temperature or during cooling or slight heating, i.e. at approx. -20 to approx.

+90°C, preferably at approx. -20 to approx. +30°C. The oxidation can also be carried out in stages, as the oxidation first takes place at a lower temperature, i.e. at approx. -2 0 to approx. 0°C to the sulfoxide step, which is optionally isolated, whereupon the sulfoxide in a second step, preferably at higher temperatures, approx. room temperature, is oxidized to the sulfone, i.e. the 1,1-dioxide of formula I.

For the processing, any excess of oxidizing agent still present can be destroyed by reduction, especially by treatment with a reducing agent, such as a thiosulphate, e.g. sodium thiosulfate.

A 1-oxide of formula I, in which m has the value 1, as well as a 1-dioxide, in which m has the value 2, can be converted to the corresponding 1-sulphide, in which m has the value 0, with the reducing agents described under method c).

Cleavage of protecting groups:

In an achievable compound of formula I, in which one or more functional groups are protected, these can e.g. protected carboxyl, amino, hydroxy and/or sulfo groups are released in a manner known per se by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis, possibly stepwise or simultaneously.

A protected carboxyl group is released in a manner known per se and depending on the nature of the protecting group in a different way, preferably by means of solvolysis or reduction.

Thus, tert.-lower oxycarbonyl or lower alkoxycarbonyl which is substituted in the 2-position with an organic silyl group or in the 1-position with lower alkoxy or lower alkylthio, or optionally substituted diphenylmethoxycarbonyl can be transferred into free carboxyl, e.g. by treatment with a suitable acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol, anisole or ethylene thioglycol. Suitable substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, can be transferred into the free carboxyl by chemical reduction, e.g.

by treatment with an alkali metal, sodium dithionite, or with a reducing metal, e.g. zinc, or metal salt, such as a chromium II salt, e.g. chromium II chloride,

usually in the presence of an agent that emits hydrogen ions,

which together with the metal or metal salt can produce nascent hydrogen, as an acid, primarily a suitable carboxylic acid, such as a lower alkane carboxylic acid which is optionally substituted, e.g. with hydroxyl, e.g. acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloro-mandelic acid, or tartaric acid, or an alcohol or thiol, whereby water is preferably added.

When treated with a reducing metal or metal salt, as described above, 2-halo lower real oxycarbonyl can also, possibly after conversion of a 2-bromo lower real oxy carbonyl group to a corresponding 2-iodo lower real oxy carbonyl group, or aroylmethoxycarbonyl be converted to free carboxyl, whereby aroyl methoxycarbonyl can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide. Substituted 2-silylethoxycarbonyl can also, by treatment with a salt of hydrofluoric acid which emits fluoride anion, such as an alkali metal fluoride, e.g. 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-lower alkyl ammonium fluoride or tri-lower alkyl aryl ammonium fluoride, e.g. tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent, such as dimethylsulfoxide or N,N-dimethylacetamide, is transferred into free carboxyl. With an organic silyl group, such as trilower alkylsilyl, e.g. trimethylsilyl, the esterified carboxyl can usually be released solvolytically, e.g.

by treatment with water, an alcohol or an acid.

A protected amino group is released in a manner known per se

and according to the nature of the protecting group in different ways, preferably by means of solvolysis or reduction. 2-halo lower oxycarbonylamino, optionally after conversion of a 2-bromo lower oxycarbonylamino group to a 2-iodo lower oxycarbonylamino group, aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can

e.g. is split by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid,

as aqueous acetic acid. " Aroylmethoxycarbonylamino can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, e.g. sodium dithionite. Optionally substituted diphenylmethoxycarbonylamino, tert.-lower oxycarbonylamino or 2-trisubstituted silylethoxycarbonylamino, can be cleaved by treatment with a suitable acid, e.g. formic or trifluoroacetic acid, optionally substituted triarylmethylamino, formylamino or 2-acetyl lower alk-1-enl-ylamino, can e.g. be cleaved by treatment with an acid, as a mineral acid, e.g. hydrochloric acid, or an organic acid, e.g. formic or trifluoroacetic acid, optionally in the presence of water, and an amino group protected with an organic silyl group can e.g. be cleaved by means of hydrolysis or alcoholysis An amino group protected with 2-haloacetyl, eg 2-chloroacetyl, can be cleaved by treatment with thiourea in the presence of a base, or with a ti olate salt, as an alkali metal thiolate, of thiourea and subsequent solvolysis, as alcoholysis or hydrolysis, of the resulting condensation product. An amino group which is protected with 2-substituted silylethoxycarbonyl can also be transferred to the free amino group by treatment with a salt of hydrofluoric acid which emits fluoride anions, as indicated above in connection with the release of a correspondingly protected carboxyl group.

Amino that is protected in the form of an azido group is released, e.g. by reduction to free amino, by treatment with zinc in the presence of an acid, such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent, such as a halogenated hydrocarbon, e.g. methylene chloride, or also in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at approx. 20-25°C, or phosphorus during cooling or heating.

A hydroxy group that is protected with a suitable acyl group, an organic silyl group or by optionally substituted 1-phenyl lower alkyl is released in the same way as a correspondingly protected amino group. A hydroxide group protected with 2,2-dichloroacetyl is released, e.g. by basic hydrolysis, while a hydroxy group etherified with tert.-lower alkyl or with a 2-oxa- or 2-thioaliphatic or -cycloaliphatic hydrocarbon residue is released by acidolysis, e.g. by treatment with a mineral acid or a strong carboxylic acid, e.g. trifluoroacetic acid.

A protected, especially esterified, sulfo group is released analogously to a protected carboxyl group.

The described cleavage reactions are carried out under conditions known per se, if necessary during cooling or heating, and optionally in an inert gas, e.g. nitrogen atmosphere.

In the presence of several protected functional groups, the protective groups are preferably selected so that more than one such group can be cleaved at the same time, for example acidolytically, as in treatment with trifluoroacetic acid or formic acid, or reductively, as in treatment with zinc and acetic acid.

Esterification of a free carboxy group:

The conversion of a free carboxy group, e.g. the free carboxy group to an esterified carboxy group, especially in a carboxy group which is cleavable under physiological conditions, takes place according to esterification methods known per se. For example, a compound of formula I is reacted in which the carboxyl group to be esterified is present in free form, and other functional groups, e.g. amino or hydroxyl groups are present in protected form, or a compound of formula I in which the carboxy group to be esterified is present in the form of a reactive, functional derivative, or a salt of a compound of formula I, with the corresponding alcohol or a reactive , functional derivative of this alcohol.

In the esterification of a compound of formula I, in which the carboxyl group to be esterified is present in free form, with the desired alcohol, the same condensation agents are used, e.g. carbodiimides, the same solvents and the same reaction conditions as in the acylation according to method a). A compound of formula I in which the carboxyl group to be esterified is in the form of a reactive, functional derivative is, for example, a mixed anhydride or an activated ester, which can be obtained in the manner described under method a) (acylation) by condensation of the carboxylic acid of formula I with an inorganic acid, a carboxylic acid, a half-ester of carbonic acid,

a sulphonic acid or by condensation with a vinylogenic alcohol.

A reactive, functional derivative of the alcohol to be esterified is primarily the ester formed by condensation with a strong, inorganic or organic acid, for example the corresponding halide, e.g. chloride, bromide or iodide, or the corresponding lower alkane-, e.g. the methanesulfonyloxy or 4-methanesulfonyloxy compound.

In the esterification of a compound of formula I, in which the carboxyl group to be esterified is in the form of a reactive, functional derivative, with the corresponding alcohol or in the esterification of a compound of formula I, in which the carboxyl group to be esterified is in free form, with a reactive, functional derivative of the corresponding alcohol, the same solvents and the same reaction conditions are used as in the acylation with a reactive, functional derivative of a

carboxylic acid with formula III according to methods a).

A compound of formula I in which the carboxyl group to be esterified is in the form of a reactive, functional derivative can also be prepared in situ analogously to the method described in method a) (acylation), and without isolation reacted with the corresponding alcohol.

Salt formation:

Salts of compounds of formula I can be prepared on i

and known manner. Thus, salts of compounds of formula I can e.g. formed by reaction between acidic groups and metal compounds, such as alkali metal salts of suitable carboxylic acids, e.g. the sodium salt of α-ethylcaproic acid or sodium carbonate, or with ammonia or a suitable organic amine, whereby stoichiometric amounts or only a small excess of the salt-forming agent are preferably used. Acid addition salts of compounds of formula I are obtained in the usual way, e.g. by treatment with an acid or a suitable anion exchange reagent. Inner salts of compounds of formula I can e.g. formed by neutralization of salts, such as acid addition salts,

at the isoelectric point, e.g. with weak bases,

or by treatment with liquid ion exchangers.

Salts can be transferred in the usual way to the free compounds, metal and ammonium salts, e.g. by treatment with suitable acids and acid addition salts, e.g. by treatment with a suitable basic agent.

In all of the above-mentioned reactions which are carried out under basic conditions, 3-cephem compounds can possibly be partially isomerised to 2-cephem compounds. An obtained 2-cephem compound or a mixture of a 2- and a 3-cephem compound can be isomerized to the desired 3-cephem compound in a manner known per se.

Mixtures of isomers can be divided in a manner known per se into the individual isomers, e.g. by fractional crystallization, chromatography, etc.

The method also includes the embodiments according to which compounds that arise as intermediates are used as starting materials, and the remaining process steps are carried out with these, or the method is interrupted at any step, furthermore the starting materials can be used in the form of derivatives or formed during the reaction.

Such starting materials are preferably used and the reaction conditions are chosen in such a way that the compounds listed above as particularly preferred are obtained.

Pharmaceutical preparations:

The pharmacologically usable compounds of formula I, their hydrates or salts can be used for the production of pharmaceutical preparations.

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

Preferably, the active substances of formula I according to the present invention are used in the form of injectables, e.g. intravenous, doseable preparations or in the form of infusion solutions. Such solutions are preferably isotonic, aqueous solutions or suspensions, such as e.g. can be prepared before the use of lyophilized preparations,

which contain the pure active substances, or the active substance together with a carrier material, e.g. mannitol.

The pharmaceutical preparations are preferably sterilized,

and may contain excipients, e.g. preservatives, stabilisers, cross-linking and/or emulsifiers, solubility mediators, salts for regulating its osmotic pressure, and/or buffer. The present pharmaceutical preparations, which can, if desired, contain additional pharmacologically valuable substances, e.g. other active substances, contains approx. 0.1-100%, especially approx. 1% to 100% of active substance f is .

The pharmaceutical preparations are produced in a manner known per se, e.g. using conventional solution or lyophilization methods.

Application:

Compounds of formula I, their hydrates or pharmaceutically acceptable salts, can be used as antibiotic active agents in the form of pharmaceutical preparations in a method for the therapeutic treatment of humans or animals, e.g. for the treatment of infections caused by gram-positive or gram-negative bacteria and cocci, e.g. in the case of enterobacteria, e.g. Escherichia coli, Klebsiella pneumoniae or Proteus spp.

Depending on the nature of the infection and the condition of the infected organism, daily doses from approx. 0.5 g to approx. 5g s.c., i.v. or i.m. for the treatment of warm-blooded (humans and animals) of approx. 70 kg weight.

Starting materials:

The starting materials used in the method for producing the compounds according to the present invention are known or, if they are new, can be produced in a manner known per se.

The starting materials with formula II, as well as corresponding compounds with protected functional groups, are known or can be prepared in a manner known per se.

The compounds of formula III, in which R,- and Rg have the meanings mentioned under formula I, and in which functional groups present in R^ and/or Rg are present in free or protected form, which have been developed especially for the preparation of the compounds of formula I, are new and likewise the subject of the present invention. These are produced, for example, as a compound with formula

in which Rg has the meanings mentioned under formula I, and a functional group present in Rg is in protected form, the 2-amino group is acylated with a sulphonic acid co'» formula

wherein Rc- has the meaning mentioned under formula I,

and a functional group present in R^ is in protected form, or with a reactive, functional acid derivative, or a salt thereof, and if desired, the protective groups present in the obtained compound are cleaved off, and/or the obtained compound of formula III is converted into another compound with formula

III.

In a compound of formula VII, a functional group present in Rg, e.g. a carboxy, amino or hydroxy group protected e.g. with a carboxyl, amino or hydroxyl protecting group. The 2-amino group in a compound of formula VII is likewise protected by a group that allows the sulfonylation reaction. Such a group is described further on in method b) (sulfonylation), for starting materials with formula IV.

In a compound of formula V, a functional group present in , e.g. a carboxyl, amino or hydroxyl group protected by a protecting group mentioned earlier, e.g. of a carboxyl, amino or hydroxyl protecting group.

The sulfonylation of a compound of formula VII with a sulfonic acid of formula V or with a reactive, functional derivative thereof takes place in an analogous manner to that described in method b) (sulfonylation).

In an obtainable compound of formula III with protected functional groups, a protective group can optionally be selectively cleaved off or a functional group which is optionally freed by the acylation reaction can be protected.

Compounds with the formulas IV and V as well as corresponding compounds with protected functional groups are known or can be prepared in a manner known per se.

2-Cefem compounds of formula VI are novel. They can be prepared analogously to the acylation method a) or analogously to the sulfonylation method b) starting from a known or in a known way per se 2-cephem compound with the formula

Also, 2-cephem compounds of formula VI can be formed

as by-products in methods a) and b), especially when working under basic conditions.

The following examples serve to illustrate the invention. The temperature is indicated in degrees Celsius. The wavelengths of the UV spectra are given in Nanometers (nm) and the e-values in parentheses. For the IR spectra, wavenumber (cm "*") is indicated.

In the examples, the following abbreviations are used:

BOC: tert-butyloxycarbonyl

Cbz: carbobenzyloxy

F: melting point

CD: thin layer chromatogram: on silica gel ready plates

SL 254 from the company Antec, Birsfelden, Switzerland

Rf 96: Rf value in the solvent system sec.-butanol-glacial acetic acid-water 67:10:23.

Example 1.

a) 3-acetoxymethyl- 7| 3-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylate acid sodium salt. 2.6 g of the 3-acetoxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4- carboxylic acid phenyl methyl ester is dissolved in a mixture of 4 ml of Cr^C^ and 0.62 ml of anisole at room temperature. Then 10 ml of CF3COOH pre-cooled to 0° are added and it is stirred without cooling for 45 minutes. After adding 750 ml of hexane-ether (2:1), stir for 5 minutes, suction off the precipitate, and wash with 100 ml of hexane-ether (1:1) mixture. The filter residue is then dissolved in 20 ml of methanol, 100 ml of water is added, the pH is adjusted to 7 by the addition of 1 N aqueous caustic soda, and it is extracted with ethyl acetate. The organic phase is washed 3 times with water. All aqueous phases are combined and evaporated in vacuo to approx. 10 ml. This solution is chromatographed on 130 g of silylated silica gel (Antec "Opti U.P.C."-12) (eluent for fractions 1-25: water, for the following fractions: water-CH^CN 95:5, fraction sizes 25 ml). The fractions containing products are combined, evaporated to approx. 10 ml volume and added to 400 ml of ethanol. The precipitated product is filtered off, washed twice each with ethanol and diethyl ester and dried. The hydrate of the title compound is obtained,

F: above 180° (during cleavage), [a]p°° = +101°±1° (0.93% in H2O); IR: 3600-2400 (wide), 1170, 1748 (shoulder), 1730 (shoulder), 1692, 1610, 1530 (Nujol); UV 253 (12100); H2O). b) 3-acetoxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 3.2 g of the 3-acetoxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminebacetamido]-3-cephem-4- carboxylic acid diphenyl methyl ester is stirred in 30 ml of absolute tetrahydrofuran and 0.37 ml of pyridine for 3 hours with 0.39 ml of methanesulfochloride at room temperature. It is then evaporated in vacuo, taken up in ethyl acetate, washed with 1 N hydrochloric acid and sodium chloride solution, neutralized with 1 N NaHCO 3 solution, washed again with sodium chloride solution, dried over Na 2 SO 3 and evaporated in vacuum. The resulting crude product is chromatographed on 200 silica gel (fraction size 50 ml, eluent: ether). By combining the product-containing fractions, the title compound is obtained; IR: 34 00, 1780, 1715 (broad), 1630, 1525 (CH 2 Cl 2 ); UV: 257 (13800; C 2 H 5 OH). c) 3- acetoxymethyl- 7+-[( 2S, R )- 2-( 2- BOC- aminothiazol-4- yl)- 2- aminoacetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

To a solution of 5.7 g of the 3-acetoxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-

(2,2,2-trichloroethoxycarbonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in 60 ml of a mixture of acetic acid-acetonitrile (1:1) is added with stirring at 0°C over the course of 10 minutes in portions 5.7 zinc dust, and is then stirred further for 3 hours at 0°. The reaction solution is then suctioned off from the zinc residue, washed with acetonitrile and evaporated in a rotary evaporator. The residue is added to water, adjusted to pH 8 with 2 N NaOH, extracted with ethyl acetate and washed neutral with NaCl solution. The crude product obtained after drying over sodium sulfate against evaporation is chromatographed on 180 g of silica gel, whereby fractions of 150 ml are taken. Eluent: ethyl acetate and ethyl acetate-methanol (9:1).

By combining and evaporating the product-containing fractions, as well as reprecipitating the evaporation residue from Cr^Cl-^-hexane, the title compound is obtained; IR: 3370, 1780, 1740-1690 (broad), 1600 (CH 2 Cl 2 ); UV: 257 (10500; C 2 OH). d) 3- acetoxymethyl- 73-[( 2R, S)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2, 2, 2- trichloroethoxycarbonylamino)- acetamido] - 3- cephem- 4- carboxylic acid diphenyl methyl ester.

4.3 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylamino)-acetic acid obtained according to example 1 e) and 4.2 g 3-acetoxymethyl-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolve in 50 ml of absolute tetrahydrofuran together with 0.8 g of hydroxybenztriazole. Then add . immediately, as well as after 1 1/2 and after 3 hours, each time 0.71 g of dicyclohexylcarbodiimide in each 60 ml of tetrahydrofuran, and stirred for a total of 6 hours at room temperature. The reaction mixture is poured into 1 liter of hexane-ether (9:1), filtered off with suction and washed with hexane. The residue is added to 1 liter of ethyl acetate and stirred. The dicyclohexylurea which is insoluble in ethyl acetate is filtered off, and the ethyl acetate solution is washed successively with saturated sodium hydrogen carbonate and common salt solutions. After drying over Na2SO4 and evaporation, the crude product is chromatographed on 200 g of silica gel (fraction size 150 ml; eluent: hexane-ether 7:3). Thereby

the title compound is obtained: IR 3390, 1780, 1725 (broad), 1690, 1635, 1528 (CH 2 Cl 2 ); UV: 259 (13330; C 1 H OH ) . e) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylamino)acetic acid. Dissolve 5 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl-2-(2,2,2-trichloroethoxycarbonylamino)-acetic acid methyl ester obtained according to example 1 f) in 50 ml of methanol. Then add 2 5 ml 1 N aqueous NaOH and it is stirred for 1/2 hour at room temperature. Then extracted with ethyl acetate and washed twice with water. Then the combined water parts are cooled to 0°, adjusted to pH 3 with 4 N hydrochloric acid, extracted with ethyl acetate , washed neutral with saturated aqueous NaCl solution, dried over Na2SO^ and evaporated.Thereby the title compound is obtained, which is processed further without characterization, IR: 3400, 3300-2750 (broad), 1725 (broad), 1540,

1500 (CH 2 Cl 2 ).

f) ( 2R, S )- 2-( 2- BOC-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylamino)- acetic acid methyl ester

8.61 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-glycine methyl ester are dissolved in a mixture of 85 ml of absolute tetrahydrofuran and 2.66 ml of pyridine. A solution of 4.4 ml of chloroformic acid-2,2,2-trichloroethyl ester in 50 ml of absolute tetrahydrofuran is then added dropwise at 5-10° and the mixture is stirred for 1 hour in an ice bath. It is then evaporated in a rotary evaporator, taken up in ethyl acetate, washed to neutral point with saturated aqueous NaHCO3 solution and with saturated NaCl solution, dried over sodium sulfate and evaporated. The crude product obtained is chromatographed on silica gel (fractions of 200 ml, eluent: Hexane-ether 1:1). After crystallization of the product-containing fractions, the title compound is obtained, IR_ 3407, 1750 (shoulder), 1737, 1726 (shoulder)l, 1540, 1502 (CH 2 Cl 2 ),

UV: 258 (8806, CH 3 OH).

Example 2■

a) 7 3-[( 2R, S )- 2-( 2- aminothiazol-4- yl)- 2- methanesulfonylaminoacetamido] - 3- cephem- 4- carboxylic acid sodium salt. 2.41 g of the 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester obtained according to example 2 b) is reacted analogously to the example la) in 6 ml CH2C12 and 2 ml anisole with 25 ml trifluoroacetic acid, worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained, F: above 200° (under cleavage), [ct]p<0>° = +117°+1<0*>(1.05% in H2O) , IR: 3600-2500, 1760, 1680. 1600. 1520 (Nujol) , UV 250 (10000, C^OH) . b) 73-[(2R,S)-2-(2-BQC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

1 g of the 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester p-toluenesulfonic acid salt obtained according to example 2 c) is reacted at 0° in 10 ml of absolute tetrahydrofuran and 0.219 ml of pyridine with 0.119 ml of methanesulfochloride analogous to example 1 b) and worked up. The resulting crude product is chromatographed on 50 g of silica gel (eluent: toluene-ethyl acetate

(9:1). and (85:15)., f rak ion size 50 ml). The product-containing fractions are combined and evaporated. The evaporation residue is reprecipitated from methylene chloride-hexane. Title compound— then obtained, [a]^°°= +11°±1° (1.07%, in CHC13), IR: 3400, 3290, 1780, 1715, 1690 (shoulder), 1630, 1530 (CH2C12), UV: 259 (14300, C 2 H 5 OH).

The starting material is produced in the following way:

c) 73-[( 2R, S )- 2-( 2- BOC-aminothiazol-4- yl)- 2- aminoacetamyldo]- 3- cephem- 4- carboxylic acid diphenyl methyl ester p- toluenesulfonic acid salt 7.21 g of the according to example 2 d) obtained 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-BOC-aminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is stirred with 3.8 g p -toluenesulfonic acid monohydrate in 100 ml of acetonitrile for 8 hours at room temperature. After precipitation with 1000 ml of ether, suction of the precipitate, washing with 500 ml of ether and drying in vacuum, the title compound is obtained, which is processed further without characterisation. d) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-BOC-aminoacetamido 1-3-cephem-4-carboxylic acid diphenyl methyl ester. 2.21 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-BOC-aminoacetic acid obtained according to example 2 e) is dissolved in 50 ml of absolute tetrahydrofuran, cooled to -20° and 0.7 56 ml of N-methylmorpholine and 0.7 28 ml of chloroformate isobutyl ester are added one after the other. It is then stirred for 3 hours at -20°, the temperature is lowered to -40°, 2.0 g of 73-amino-3-cephem-4-carboxylic acid diphenyl ester are added in solid form, stirred for 10 minutes at -40°, as well as 2 1/2 hours at 0° and then worked up as follows: The reaction mixture is taken up in ethyl acetate and washed successively with 1 N aqueous hydrochloric acid, saturated aqueous NaHCO 3 ~ solution and NaCl solution to the neutral point. The organic phase is dried over sodium sulphate, evaporated in vacuo and the crude product is chromatographed on 100 g of silica gel (eluent: toluene-ethyl acetate (95:5) and -(4:1), fraction size: 100 ml). The product-containing fractions are combined, evaporated and the evaporation residue reprecipitated from methylene chloride-ether. The title compound is obtained, Ca]^° = +11°±1° (0.86% in CHC12), IR: 3390, 1778, 1715, 1692, 1635, 1528 (CH2C12), UV: 258 (14,500, C^OH ). e) ( 2R, S).- 2-( 2- BOC- aminothioza 1 - 4- y 1) - 2- BOC- amino-acetic acid. 15 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-BOC-aminoacetic acid is stirred in a mixture of 52.5 ml of methanol and 34.5 ml of water with 105 ml of 1 N aqueous caustic soda for 1 hour at room temperature. Then extract with ethyl acetate and wash twice with 50 ml of water each time. 100 ml of dioxane and 14 g of di-t-butyl pyrocarbonate are added to the combined aqueous phases and then stirred for 3 hours at room temperature, whereby the pH is kept constant at 8 by the addition of 1 N aqueous caustic soda (titrator). Then extract with ethyl acetate and wash 3 times with water. The combined water portions are adjusted to pH 2 at 0° with 4 N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate phase is washed neutral with sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The crude product obtained is recrystallized from a methanol-methylene chloride-ether-hexane mixture. Thereby the title connection is achieved,

F: 168°, IR' 3410, 3300-2800 (broad), 1760 (shoulder), 1725, 1540, 1500 (CH 2 Cl 2 ).

Example 3.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(4-aminobenzenesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. 0.4 g of the 73-[]2R,S)-2-(2-BOC-aminothiazol-4-yl-2-(4-aminobenzenesulfonylamino)-acetamido]-3-cephem-4 obtained according to example 3 b) -carboxylic acid diphenyl methyl ester is reacted in 0.98 ml CH2C12 and 0.3 ml anisole with 3.7 ml trifluoroacetic acid analogous to example 1 a), worked up, chromatographed and reprecipitated. The titrate of the title compound is obtained, F: above 205° (under cleavage), [ a]^ °°= +102°±1° (0.78% in H 2 O), IR: 3600-2500 (broad), 1760, 1680, 1620, (shoulder), 1595, 1520 (Nujol), UV, 259 (21000, H20). b) 73-[(2-(2-BOC-aminothiazol-4-yl)-2-(4-aminobenzol-sulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester. 0.95 g of it according to example 3 c) obtainable 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(4-(2,2,2-trichloroethoxycarbonylamino)-benzenesulfonylamino)-acetamido]-3- cephem-4-carboxylic acid diphenyl methyl ester in 10 ml of acetonitrile-acetic acid (1:1) mixture with 0.87 g of zinc dust analogously to example 1 c), is worked up and chromatographed. Thereby the title compound is obtained, [a]p° = 15°±1° (0.77% in CHC13), IR: 3390, 3280, 1770, 1835, 1690, 1620, 1590, 1530 (CH2C12), UV: 262 (29800 , C2H5OH). c) 73-[( 2R, S)- 2-( 2- BOC-aminothiazol-4-yl)- 2-( 4-( 2, 2, 2-trichloroethoxycarbonylamino)- benzenesulfonylamino)-acetamido]- 3- cephem- 4-carboxylic acid diphenyl methyl ester. 3.27 g of the 73~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester-p- obtainable according to example 4 a) the toluenesulfonic acid salt is reacted at room temperature in 30 ml of absolute tetrahydrofuran and 0.72 ml of pyridine with 2.58 g of 4-(2,2,2-trichloroethoxycarbonylamino)-benzenesulfochloride analogously to example 1 b) and worked up. The resulting crude product is chromatographed on 100 g of silica gel (eluent: toluene-ethyl acetate (9:1) and (85:15), fraction size 100 ml). The product-containing fractions are combined, evaporated and reprecipitated from methylene chloride-hexane. The title compound is obtained, [a]J = +7°±1° (0.94% in CHCl 3 ), IR: 3400, 3280, 1770, 1750, 1735, 1590, 1530 (CH 2 Cl 2 ), UV: 254 (36400, C 2 OH). d) 4-(2,2,2-trichloroethoxycarbonylamino). benzene sulfochloride.

17.3 g of sulphanilic acid are suspended in 100 ml of pyridine at 0°.

15.1 ml of chloroformic acid-2,2,2-trichloroethyl ester are then added dropwise with vigorous stirring at 0° over the course of 1 hour and then stirred for 16 hours at room temperature. It is then evaporated to dryness in vacuo, the residue is then taken up several times in 1 toluene and evaporated again. Finally, the evaporation residue is dried for 60 hours in a vacuum at 50°. It is then suspended in 250 ml of absolute chloroform and heated to 40°. A total of 33.75 g of phase phosphorus pentachloride is then added in portions with stirring at 40° over the course of 1 hour and then heated for 4 hours at reflux. The cooled reaction mixture is taken up in 2.7 liters of toluene, washed 4 times with ice water, dried over sodium sulphate and evaporated. After crystallization of the crude product from CP^Cl-j-hexane, the title compound is obtained F: 90-91°, IR: 1757, 1591, 1525, 1407, 1375 (CH 2 Cl 2 ).

Example 4.

a) 73-[( 2R, S)- 2-( 2- BOC- aminothiazol-4- yl)- 2- aminoacetamido]- 3- cephem- 4- carboxylic acid diphenyl Imethyl ester- p-toluenesulfonic acid salt. 2 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-Cbz-aminoaceta- mido]-3-cephem-4-carboxylic acid diphenyl methyl ester are hydrated in 50 ml of absolute glacial acetic acid in the presence of 2 g 10% palladium/coal catalyst. After absorbing 1 equivalent of hydrogen

(the C02 released during the hydration is absorbed in aqueous KOH)

the reaction is interrupted, filtered off from the catalyst and evaporated to dryness in vacuum. The evaporation residue is taken up in ethyl acetate and washed successively with 1 N aqueous NaHCO 3 solution and with NaCl solution to the neutral point. It is then dried over sodium sulphate and evaporated. The crude amine is dissolved in 20 ml of acetonitrile, 1.0 g of p-toluenesulfonic acid monohydrate is added, and stirred for 10 minutes at room temperature. After precipitation with 500 ml of ether, suction of the precipitate, washing with 250 ml of ether and drying in vacuum, the title compound is obtained, which is identical to the toluenesulfonic acid salt which is pitched in example 2 c).

The starting material is produced in the following way:

b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2Cbz-aminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 4.4 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-Cbs-amino acid obtainable according to example 4 c) and 3.63 g of 73-amino-3-cephem- 4-carboxylic acid diphenyl methyl ester is reacted analogously to example 2 d) (1.38 ml N-methylmorpholine, 1.33 ml chloroformate isobutyl ester, 142 ml tetrahydrofuran), worked up, chromatographed (eluent: toluene-ethyl acetate (9:1 and 4:1), fraction size 300 ml) and combined. The title compound is obtained [a]p°°= +12°±1° (1.04% in CHC13), IR: 3400, 1790, 1727, 1698, 1638, 1543, 1498 (CH2C12), UV, 258 (15000, C2H5OH ). c) (2R,S)-2-(2-BOC-aminothiazor-4-yr)-2-Cbz-amino-acetic acid. 7.4 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-Cbz-aminoacetic acid methyl ester obtainable according to example 4 d) is dissolved in 270 ml of methanol. Then 60 ml of 1 N aqueous caustic soda is added and it is stirred for 3 hours at room temperature. After working up analogously to example 1 e), the title compound is obtained, IR: 3410, 3300-2800 (broad), 1760 (shoulder), 1725, 1542, 1503 (CH2C12), UV: 259 (8400, C^OH). d) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-Cbz-amino-acetic acid methyl ester.

8.61 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-glycine methyl ester are dissolved in a mixture of 85 ml of absolute tetrahydrofuran and 2.66 ml of pyridine. Then add dropwise while stirring at 0°

over 15 minutes, a solution of 4.74 ml of carbobenzoxy chloride in 50 ml of absolute dioxane and stirred for 3 hours at 0°. It is then taken up in ethyl acetate, washed to the neutral point with 1 N aqueous HCl, with 1 N aqueous NaHCO3 and with saturated aqueous NaCl solution, dried over sodium sulfate and evaporated.

The crude product obtained is chromatographed on 400 g of silica gel (fractions of 500 ml, eluent: toluene-ethyl acetate 95:5). After pooling the product-containing fractions, the title compound is obtained, IR: 3410, 1748 (shoulder), 1540, 1502, UV: 258 (8800, C₂OH).

Example 5.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-etasulfonyl-aminoacetamido]-3-cephem-4-carboxylic acid sodium salt.

1.367 g of the 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-ethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester obtainable according to example 5 b) is reacted in 3.6 ml of CP ^C^ and 1.12 ml of anisole with 13.9 ml of trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 205° (during cleavage). [a]^<0>= + H6?±1° (0.73% in H20) ,

IR: 3600, 2500 (broad), 1760, 1680, 1640 (shoulder), 1600, 1520 (Nujol) , UV: 251 (9800, ^0) . b) 73-[( 2R, S)- 2-( 2- BOC- aminothiazbl- 4- yl)- 2- ethanesulfony 1 aminoace e t amido ] - 3 - c e f em- 4 - car bok s yl sy r ed i f e r-nyl methyl ester.

3.5 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester p-toluenesulfonic acid salt are reacted in 40 ml of absolute tetrahydrofuran in presence of 1 ml of pyridine with 0.8 ml of ethane sulphochloride analogously to example 1 b), is worked up, chromatographed and reprecipitated. The title compound is achieved. = +18°±1° (0.97% in CHCl 3 ), IR. 3380, 3280, 1775, 1710, 1690 (shoulder), 1630, 1525, (CH 2 Cl 2 ), UV. 258 (14300, C 2 OH) .

Example 6.

a) 73~[( 2R, S)- 2-( 2- aminothiazol-4- yl)- 2-( 2- methyl-aminocarbonylamino- 1, 3, 4- thiadiazol- 5- ylsulfonyl-amino)- acetamido]- 3- cephem- 4- carboxylic acid sodium salt. 4.5 g of the 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methylaminocarbonylamino-1,3,4-thiadiazol- 5-ylsulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 9 ml of CH2C12 and 1.27 ml of anisole with 20 ml of trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 220° (during cleavage). [ct]p° = +71°±1° (0.93% in H 2 O), IR. 3600-2500 (broad), 1766, 1690, 1605, 1520 (Nujol), UV: 262 (14800, H20). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methylaminocarbonylamino-1,3,4-thiadiazol-5-yl-sulfonylamino)-acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester. 4.5 of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methylaminocarbonylamino-1,3,4-thiadiazol-5-ylsulfonylamino) obtainable according to example 6 c) -acetic acid and 3.3 g of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester are dissolved in 50 ml of absolute tetrahydrofuran together with 0.8 g of hydroxybenztriazole. Then add immediately, as well as after 1 1/2 and after 3 hours, each time 0.71 g of dicyclohexylcarbodiimide in each 60 ml of tetrahydrofuran bg stirring for a total of 6 hours at room temperature. The reaction mixture is poured onto 1 liter of hexane-ether (9:1) mixture, filtered off with suction and washed with hexane. The residue is added to 1 liter of ethyl acetate and stirred. The ethyl acetate-insoluble dicyclohexylurea is filtered off and the ethyl acetate solution is washed one after the other with saturated sodium bicarbonate and common salt solutions. The crude product obtained after drying and evaporation of the ethyl acetate phase is chromatographed on 200 g of silica gel (eluent: ether-ethyl acetate (1:1) and ethyl acetate, fraction size 100 ml). After combining and reprecipitating the product-containing fractions from CH2Cl2~hexane, the title compound is obtained. ^ a^ Q=+25°±1° (1.01% in CHCl 3 ), IR. 3400-2806, 1778, 1700, 1530, (CH 2 Cl 2 ), UV. 263 (21600, C 2 OH) .

Starting materials are produced in the following way:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methylamino-carbonylamino-1,3,4-thiadiazol-5-ylsulfonylamino)-acetic acid.

2.73 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-glycine is heated with 8 ml of N,0-bis-(trimethylsilyl)-acetamide in 24 ml of CH2Cl2

for 1 1/2 hours at reflux, resulting in a clear solution. It is then cooled to 0°, 0.81 ml of pyridine and 3.8 g of 2-methylaminocarbonylamino-1,3,4-thiadiazol-5-ylsulfochloride are added one after the other and then stirred for 1 hour at 0°, as well as 16 hours at room temperature. It is then taken up in ethyl acetate, washed 2 times with 1 N hydrochloric acid, as well as 4 times with saturated, aqueous NaCl solution, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting title compound is further processed without characterization (Example 6b)).

Example 7.

a) 7( 3- [ ( 2R) - 2- ( aminothiazol-4- yl)- 2- methanesulfonylaminoacetamido] - 3- cephem- 4- carboxylic acid sodium salt.

1.21 g of the 7(3-[(2R)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester obtainable according to example 7 b) is reacted in 3 ml CH2C12 and 1 ml anisole with 12 ml trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 206° (below

cleavage). IR: 3600-2500, 1766, 1680, 1600, 1520 (Nujol), UV: 250 (10500, H20). b) 73-[(2R)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester.

4.26 g of the 73-[]2R)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester obtainable according to example 7 c) is reacted with 0.81 ml of methanesulfochloride in 50 ml of absolute tetrahydrofuran and 0.56 ml of pyridine analogous to example 1 b)* (reaction duration 16 hours) and worked up. The resulting crude product is chromatographed analogously to example 2 b). Thereby the title connection is achieved. l^ Q0 = -4°±1° (0.94% in CHC13), IR: 3400, 3290, 1780, 1715, 1690 (shoulder), 1630, 1530, (CH2C12), UV: 259.

The starting material can be produced in the following way:

c) 73-[(2R)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 4 g of the 7,3-[(2R)-2-(2-BOC-aminothiazol-4-yl)-2-chloroacetylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester obtainable according to example 7 d) are stirred with 0.94 g of thiourea in a mixture of 70 ml of dioxane and 1.37 ml of acetic acid for 5 hours at room temperature and then 10 hours at 50°. Then dilute with ethyl acetate, wash once with saturated aqueous NaCHO^ solution, as well as with saturated aqueous NaCl solution to the neutral point. The crude title compound obtained after drying over Na 2 SO 4 and evaporation is further processed directly (Example 7b)). d) 73-[( 2R)- 2-( 2- BOC-aminothiazol-4- yl)- 2- chloroacetyl-aminoacetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester and 73~[( 2S)- 2-( 2- BOC- aminothiazol-4-yl)- 2- chloroacetylaminoacetamido]- 3- cephem- 4- carboxylic acid diphenyl ester.

9.6 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl-2-chloroacetylamino-acetic acid is reacted with 9.1 g of 73-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 80 ml of tetrahydrofuran analogously with example 6 b) (2.4 g of hydroxybenztriazole, three times 2.2 g of dicyclohexylcarbodiimide in each 20 ml of tetrahydrofuran)

and processed. The crude product obtained is chromatographed in 4 equal portions on each 500 g silica gel (eluent: toluene-ethyl acetate 85:15 mixture, fractions of 25 ml). Thereby, the (2R)-title compound is eluted first: [a]^ = -5°+1°

(0.81% in CHCl 3 ), IR. 3380, 3250, 1780, 1715, 1700 (shoulder), 1670, 1510 (broad) (CH 2 Cl 2 ), UV: 258 (135000, C 2 OH) .

The configuration assignment at the C-2 carbon atom to the acetic acid in the acyl side chain takes place for the (2R) and (2S) compounds due to rotational displacements and NMR comparison (CH-7) with ureidosporins, etc. e.g. H. Breuer et al., J. Antibiot. 31, 546-560 and DOS 2,924,296.

The. then eluted fractions consist of a binary mixture of the above compound with the corresponding (2S)-isomer, which can be separated further by renewed chromatography.

20°

Finally, a pure (2S) title compound is eluted. [cc]D = +42°+1° (0.82% in CHCl 3 ), IR. 3390, 3270, 1780, 1715, 1700 (shoulder), 1670 (shoulder, 1520 (broad) (CH2C12), UV: 259 (14200, C2H5OH). e) ( 2R, S )- 2-( 2- BOC- aminothiazole - 4-yl)-2-chloroacetyl-aminoacetic acid. 10 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-glyein methyl ester are dissolved in 35 ml of methanol and 23 ml of water and 70 ml of IN aqueous sodium hydroxide solution are added one after the other. Then stir for 1 hour at room temperature. It is then cooled to 0° and, within 5 minutes, 2.9 ml of chloroacetyl chloride are added dropwise, whereby the pH is kept constant at 10 by adding 2 N caustic soda (titrator). Then stir for a further 2 hours at pH 10 and 0°

(2 N NaOH-, titrator). For processing, the pH is set

to 2 with 4 N hydrochloric acid, extracted with ethyl acetate and washed 6 times with saturated aqueous NaCl solution. The crude product obtained after drying over sodium sulfate and evaporation is reprecipitated from a mixture of CH^OH-CI^C^-hexane. Thereby the title compound is obtained, which is directly further processed (Example 7 d)).

Example 8.

a) 73-[(2S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt. 2.4 g of the 73-[(2S)-2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester obtainable according to example 8 b) are reacted in 6 ml of CH2C12 and 2 ml of anisole with 25 ml of trifluoroacetic acid analogously to example 1 a), is worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 200° (during cleavage). [a]J00 = +126°±1° (0.94% in H2O). , IR: 2600-2500, 1760, 1680, 1600, 1520 (Nujol), UV: 250 (9900, H2). b) 73-[(2S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

4.48 g of the 73~[(2S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester obtainable according to example 8 c) is reacted with 0.83 ml of methanesulfonic acid chloride in 5 ml of tetrahydrofuran and 0.58 ml of pyridine analogously to example 7 b), is worked up and chromatographed.

The title compound is achieved. [a]^ 2 n° = +36°±:L o (0.89% CHC13), IR: 3400, 3290, 1780, 1715, 1690 (shoulder), 1630, 1530 (CH3C12), UV: 259 (14400 ' C^OH) .

The starting material is produced in the following way:

c) 73-[(2S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

3.89 g of the 73~t(2S)-2-(2-BOC-aminothiazol-4-yl)-2-chloroacetylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester obtainable according to example 7 d) is reacted with 0.91 g thiourea analogously to example 7 d) (70 ml dioxane + 1.34 ml acetic acid) and worked up. Thereby the crude title compound is obtained, which is directly further processed (Example 8 b)).

Example 9.

a) 73~[( 2R, S)- 2-( 2- aminothiazol-4- yl)- 2-( 2- acetylamino- 1, 3, 4thiadiazol- 5- ylsulfonylamino)- acetamido] - 3- cephem- 4- carboxylic acid sodium salt. 2 g of the 73-[(2R,S)-2-(2-BOC-aminothiazol)-4-yl)-2-(2-acetylamino-1,3,4-thiadiazole-5) obtainable according to example 9 b) -yl-sulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 5 ml CH2C12 and 0.57 ml anisole with 15 ml trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 220° (during cleavage). [a]^°°= +89°±1° (0.92" H20), IR: 3600-2500 (broad), 1760, 1690, 1600, 1520 (NUjol), UV: 263 (14800, H20). b) 73~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acetylamino-1,3,4-thiadiazol-5-ylsulfonylamino)-acetamido]-3- cephem-4-carboxylic acid diphenyl methyl ester 3 g (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acetylamino-1,3,4-thiadiazol-5-ylsulfonylamino)-acetic acid and 1.83 g of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in .

40 ml tetrahydrofuran analogous to example 6b) (0.8 g hydroxybenztriazole, 3 x 0.47 g dicyclohexylcarbodiimide in each 40 ml tetrahydrofuran), worked up, chromatographed

2qO q

and shared. The title compound is achieved. [ot] ^ = +28 +1 (0.82% in CHC13), IR: 3400-2700 (broad), 1778, 1720-1690 (broad), 1525 (CH2C12) , UV: 263 (20900, C^OH ).

Example 10.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-((1R,S)-1-cyanoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 3.18 g of the 73~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-((1R,S)-1-cyanoethanesulfonyl-amino) obtainable according to example 10 b) -acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 8' ml CH2C12 and 2.5 ml anisole with 30 ml trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained.' F: over 180° ( during cleavage), [a]^<0>= +102°±1° (0.91% in H20), IR: 3600-2400 (broad), 2255, 1760, 1680, 1640 ( shoulder), 1605, 1520 (Nujol), UV. 250 (10000, H2O). b) 73-[( 2R, S)- 2-( 2- BOC-aminothiazol-4-yl)- 2-(( 1R, S)-1- cyanoethanesulfonylamino)- acetamido]- 3- cephem- 4-carboxylic acid diphenyl methyl ester is .

3.92 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-((IR,S)-1-cyanoethanesulfonamidl)-acetic acid obtainable according to example 10 c) and 3, 3 g of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 30 ml of tetrahydrofuran analogously to example 6 b) (0.915 g of hydroxybenztriazole, 3 x 0.8 g of dicyclohexylcarbodiimide in each 7 ml of tetrahydrofuran) and worked up. After chromatography of the crude product (eluent

agent: toluene-ethyl acetate 9:1, fraction size 250 ml), union of the product-containing fractions and reprecipitation from CfLjC^-hexane, the title compound is obtained. t0^^ = +8<0>±1°

(1.02% in CHCl 3 ), IR. 3400, 330, 2250 (weak), 1780, 1720, V 1700 (shoulder), 1635, 1530 (CH2C12), UV: 258 (14200, C2H5OH).

The starting material is produced in the following way:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-((1R,S)-1-cyanoethanesulfonylamino)-acetic acid.

2.73 g of (2R,S)-2-(2-BOC-aminotaizol-4-yl)-glycine is reacted in 24 ml of CH2Cl2, with 2.3 g of 1-cyanoethanesulfochloride analogously to example 6 c) (8 ml of N, O-bis-(trimethylsilyl)acetamide, 0.81 ml pyridine) and worked up. The title compound is obtained, which is further processed without characterization.

Example 11.

a) 3-acetoxymethyl-7P-[(2R,S)-2-(5-amino-r,2,4-thiadiazol-3-yI)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylate.

A solution of 1.6 g of it according to example 11 b). obtainable 3-acetoxymethyl-7|3-[(2R,S)-2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid in 3 ml of methylene chloride and 20 ml of trifluoroacetic acid is stirred at room temperature for 30 minutes, and then evaporated in vacuo. The residue is driven off with triethyl ether. The product is dissolved in 20 ml of methanol, and adjusted to pH 7.0 with a 50% solution of sodium 2-ethyl hexanoate in methanol and ethyl acetate is added. The precipitated product is filtered off and chromatographed. The title compound is obtained with an Rf: approx. 0.60 ("Silicagel Opti" UPC 12, water-methanol 95:5), IR (NUjol) 3310, 1765, 1610, 1155.

b) 3-acetoxymethyl-7[3-[2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid. 2.3 g (6.5 mmol) of the (2R,S)-2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2-methanesulfonyl- aminoacetic acid and 0.77 ml of N-methylmorpholine are added at -5° to a stirred suspension of a Vilsmeyer reagent, which is prepared from 0.63 ml of oxalyl chloride and 0.56 ml of N,N-dimethylformamide in 25 ml of methylene chloride. The mixture is stirred for 30 minutes at 0° and then cooled to -10°. To this mixture is added dropwise a freshly prepared solution of 1.69 g (6.2 mmol) of 3-acetoxymethyl-73-amino-3-cephem-4-carboxylic acid in 20 ml of methylene chloride and 6.8 ml of N,0 -bis-(trimethylsilyl)-acetamide and stirred at 0° under nitrogen for 2 hours. The fraction solution is evaporated, diluted with ethyl acetate and extracted with dilute aqueous sodium bicarbonate solution. The aqueous extracts are adjusted to pH 2.0 with 2 N HCl and extracted with ethyl acetate. The organic phase is separated, washed with dilute aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The title connection with Rf 96copp is reached: approx. 0.45 (silica gel), IR: (Nujol), 1765, 1160.

The starting material is produced in the following way: c). (2R,S)-2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2-methanesulfonylaminoacetic acid.

A solution of 5.0 g (13.6 mmol) of the (2R,S)-2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2 obtainable according to example 11 d) -methanesulfonylaminoacetic acid methyl ester in 90 ml of 95% ethanol, 4.4 g of potassium hydroxide and 36.5 ml of water are added, and stirred for 1.5 hours at room temperature. The reaction mixture is evaporated in vacuo, the residue is dissolved. in water, the solution is adjusted to pH 8.5 with dilute hydrochloric acid, and extracted with ethyl acetate. The aqueous phase is separated, adjusted to pH 2.0 with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase is separated, washed with aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The title compound is obtained with Rf 96: approx. 0.50 (silica gel), UV: 217

(7700, ethanol).

d) (2R,S)-2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2- methanesulfonylaminoacetic acid methyl ester. A solution of 8.6 g (29.6 mmol) of the (2R,S)-2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2 obtainable according to example 11 e) -aminoacetic acid methyl ester in 30" ml of methylene chloride are added at -5° 6 ml of triethylamine and a solution of 2.8 ml of mesyl chloride in 15 ml of methylene chloride, and stirred -at 0° for 1.5 hours. The reaction mixture is evaporated in vacuo, the residue is taken up in ethyl acetate, and washed successively with dilute aqueous sodium bicarbonate solution, water, 1 N hydrochloric acid and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. After chromatography of the residue on silica gel with toluene and an increasing proportion of ethyl acetate, the title compound is obtained with Rf: 0.35 (silica gel , toluene/ethyl acetate 1:1), NMR (60 MHz, CDCl 3 ): 1.56, 2.96, 3.70, 5.65 ppm. e) ( 2R, S )- 2-( 5- BOC- amino - l, 2, 4- thiadiazol- 3- yr)- 2-am i n o e dd i k s y r e m e t y 1 e s t e r.

A suspension of 25.0 g (82.5 mmol) 2-(5-BOC-amino-1,2,4-thiadiazol-3-yl).-2-hydroxyiminoacetic acid methyl ester and 25 g of 10% palladium/charcoal catalyst in 250 ml of methanol is hydrated for 24 hours at room temperature. The reaction mixture is filtered over hyflo-supercel(S) and the filtrate is evaporated in vacuo. The title compound is obtained with an Rf value of 0.15 (silica gel)., chloroform/methanol, 95:5), NMR (60 MHz, CDCl 3 ): 1.56, 3.80, 7.07.

Example 12:

a) 73-[(2R,S)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt.

A solution of 2.3 g (3.30 mmol) of it according to example

12 b) obtainable 73~[(2R,S)-2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in 5 ml methylene chloride and 1.7 ml anisole are added analogously to example 11 a) 23 ml trifluoroacetic acid, stirred and evaporated. The residue is extracted with diethyl ether. The product is dissolved in 15 ml of methanol and adjusted to pH 7.0 with a 50% solution of sodium 2-ethyl hexanoate in methanol, and ethyl acetate is added. The precipitated product is filtered off and chromatographed ("Silicagel Opti-UPC" 12). The title compound is obtained with an Rf value of 0.70 ("Silicagel Opti-UPC" 12, water-methanol 95:5), IR (Nujol)- 3310, 1765, 1600, 1155. b) 73-[( 2R, S)-2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

A solution of 1.80 g (5.0 mmol) of 2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2-methanesulfonylaminoacetic acid and 1.83 g (5 mmol) of 73_amino-3 -cephem-4-carboxylic acid diphenylmethyl ester in 25 ml dry tetrahydrofuran is added at 0° 0.55 g 1-hydroxy-benztriazole and 1.25 g N,N'-dicyclohexylcarbodiimide in 15 ml dry tetrahydrofuran, stirred for 3.5 hours at 0° and then warmed to room temperature. After filtering the reaction mixture, the filtrate is diluted with ethyl acetate and washed successively with aqueous dilute sodium bicarbonate, hydrochloric acid and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. After expelling the residue with ether, the title compound is obtained. Rf: 0.65 (silica gel, ethyl acetate)..

Example 13.

a) 3-acetoxymethyl-73-[2R,5)-2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid. A cooled to 0° solution of 2.2 g (2.4 mmol) of the 3T-acetoxymethyl-73-[(2R, S)-2-(2-BOC-aminoethanesulfonylamino)-2- obtainable according to example 13 b) (2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester and 2.2 ml of anisole in 11 ml of absolute methylene chloride, add 11 ml of cold trifluoroacetic acid, stir for 90 minutes at 25° under a nitrogen atmosphere, and then add at 0° 100 ml of diethyl ether. The beige-coloured precipitate is filtered off, washed with a little diethyl ether and extracted after dissolving in 10 ml of water with acetic acid ethyl ester (4x5 ml). The acidic, aqueous phase cooled to 0° (pH approx. 1.8) is adjusted to pH 5 by dropwise addition of 2 N sodium hydroxide solution and 40 ml of ethanol is added. The precipitate formed is filtered off, washed with ethanol-water (3:1) and slurried for complete removal of its organic solvent for approx. 10 ml of water, and evaporated on a rotary evaporator. After drying (16 hours, 25°, 0.05 Torr) the title compound is obtained in the form of the monohydrate. F: above 210° (during decomposition): DC (Silica gel, development with nihydrin): Rf 96: approx. 0.15, [cc]p°°= +58°±1° (0.959% in 0.1 N HC1), UV: 150 (1500, 0.1 N HC1). b) 3- acetoxymethyl- 7( 3-[ ( 2R, S)- 2-( 2- BOC- aminoethanesulfonylamino-)- 2-( 2- BOC- aminothiazol- 4- yl)-acetamido]- 3- cephem- 4 - carboxylic acid diphenyl methyl ester.

To a solution cooled to 0° of 14.5 g (30 mmol) of the (2R,S)-2-(2-BOC-aminoethanesulfonylamino)-2-(2-BOC-aminothiazole-4) obtainable according to example 13 c) -yl)-acetic acid and 4.05 g (30 mmol) of 1-hydroxybenztriazole in 240 ml of absolute tetrahydrofuran are added analogously to example 12 b) a solution of 6.81 g (33 mmol) of dicyclohexylcarbodiimide in 60 ml of absolute tetrahydrofuran during about. 15 minutes and then 11.83 g (27 mmol) of 3-acetoxymethyl-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester. After a reaction time of 4 hours at room temperature, the precipitated N,N'-dicyclohexylurea is filtered off and the filtrate is evaporated on a rotary evaporator. It is processed analogously to example 12 b)

and the title compound is obtained. Rf: approx. 0.50 (silica gel, iodine, methylene chloride, acetic ester 1:1). The starting material is produced in the following way:

c) (2R,S)-2-(2-BOC-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid. To a well-stirred suspension of (2R,S)-2-(2-aminoethanesulfonylamino-2-(2-BOC-aminothiazol-4-yl)-acetic acid and 11.3 g of anhydrous sodium carbonate in 160 ml of dioxane and 80 ml of water 17.1 g of di-tert-butyl dicarbonate are added at room temperature in one go. After 2 hours, the reaction mixture cooled to 0° is acidified with 4 N hydrochloric acid to pH 2 and extracted with ethyl acetate (2 x 300 ml). The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue, which is still oily, is extracted with petroleum ether, from which the title compound can be isolated as a faint beige powder after filtration and drying. F: above 83° (under decomposition), Rf 96: about 0.65 (silica gel, UV 366). d) (2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid.

To a solution of 25.0 g (45 mmol) (2R,S)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)- acetic acid in 250 ml of acetic acid-acetonitrile 1:1 is added with vigorous stirring at 0° during 15 minutes in portions of 25 g of zinc dust. After a reaction time of 1 hour at room temperature, a further 12.5 g of zinc dust is added. After a further 3 hours, the zinc dust is filtered off from the reaction mixture and evaporated on a rotary evaporator. To remove excess acetic acid, the residue is slurried a further 2 times for approx. 50 ml of toluene, evaporated to dryness and then extracted with 250 ml of diethyl ether. The thus obtained title compound is used in the next synthesis step (Example 13 cj without further purification. Rf: 96: approx.

3.38 (Silica gel, UV 366).

e) (2R,S)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid.

A suspension of 27.3 g (0.1 mol) (2R,S)-2-amino-2-(2-BOC-aminothiazol-4-yl)-acetic acid in 273 ml of absolute methylene chloride is added under the exclusion of moisture and nitrogen atmosphere with stirring 8 0.3 ml (0.33 mol) and after 30 minutes another 10 ml of N,0-bis-(trimethylsilyl)-acetamide. After a reaction time of a total of 2 1/2 hours at 25°, the clear reaction mixture is cooled to 0°, 8.1 ml of absolute pyridine and 31.9 g (0.1 mol/ 2-(2,2,2-trichloroethoxycarbonylamino) are added -ethanesulf ochloride, dissolved in 150 ml of absolute methylene chloride. After 2.5 hours of reaction time at room temperature, the solvent is distilled off and the residue dissolved in one liter of ethyl acetate is washed with 2 x 250 ml of 1 N hydrochloric acid and 2 x 200 ml of saturated sodium chloride solution. After drying. of the organic phase with sodium sulfate and removal of the solvent on a rotary evaporator, the title compound is obtained as a pale yellow powder. Rf 96: about 0.80 (silica gel,

UV. 366).

Example 14.

a) 73-[(2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid. Analogous to example 1 a) or 13 a) is obtained by reacting 2.6 g (3.14 mmol) of the 70-[(2R,S)-2-(2-BOC-aminoethanesulfonylamino) obtainable according to example 14 b) -2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester with 13 ml of trifluoroacetic acid and 2.6 ml of anisole in 13 ml of absolute methylene chloride the title compound in the form of the hydrate. F: above 220° (during cleavage). Rf 96: approx. 0.10 (silica gel, ninhydrin), Rf: approx. 0.40 and 0.50 ("Silicagel Opti-UPC" 12, UV 366, water-acetonitrile 9:1), [a]^° =99°±1° (0.524% in 0.1 N HC1), UV . 250 (12900, 0.1N HCl). b) 73-[ 2R- S)- 2-( 2- BOC-aminoethanesulfonylamino)- 2- (2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 1 b) or 13 b) is obtained by treating 2.4 g (5 mmol) (2R,S)-2-(2-BOC-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl )-acetic acid with 1.64 g (4.5 mmol) 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.68 g 1-hydroxybenztriazole and 1.13 g (5.5 mmol) N,N1 - dicyclohexylcarbodiimide in 50 ml of tetrahydrofuran the title compound. Rf: approx. 0.60 (silica gel, UV 366, methylene chloride-ethyl acetate 1:1).

Example 15.

a). 3- (1-methyl-1H-tetrazo:1-5-ylthiomethyl).-73-[(2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido] - 3- cephem- 4- carboxylic acid.

Analogous to example 1 a) or 13 a) is obtained by treating 5.74 g (6 mmol) of the 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[( 2R,S)-2-(2-BOC-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester with 30 ml of trifluoroacetic acid and 5.7 ml anisole in 30 ml of absolute methylene chloride the title compound in the form of the dihydrate. F: above 192°

(under cleavage). Rf 96: approx. 0.13 (silica gel, ninhydrin).

[a]p° = +45°±1° (0.285% in 0.1 N hydrochloric acid). UV: 252 (14000,

in 0.1 N HCl).

b) 3-( 1- methyl- 1H- tetrazol- 5- ylthiomethyl)- 73[] 2R, S)-2-( 2- BOC- ethanesulfonylamino)- 2-( 2- BQC- aminothiazol-4- yl) - acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogously to example 1 b) or 13 b), the title compound is obtained by treating 4.8 q (10 mmol) (2R,S)-2-(2-BOC-aminoethanesulfonylamino)-(2-BOC-aminothiazol-4-yl )-acetic acid with 4.33 g (9 mmol) of 3-(1-methyl-1H-tetrazol-5-yl-thiomethyl)-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1.35 g (10 mmol) of 1-hydroxybenztriazole and 2.27 g (11 mmol) of N,N'-dicyclohexylcarbodiimide in 80 ml of tetrahydrofuran as solvent. Rf. about. 0.44 and 0.54 (silica gel UV 366, ether-ethyl acetate 1:1). The 2R, 2S diastereomer mixture can be separated chromatographically on silica gel into the 2R and 2S components.

Example 16.

a) 3- methoxy- 73~ [ ( 2R, S). - 2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

Analogous to example 1 a) or 13 a), the title compound is obtained in the form of the monohydrate by treating 6.15 g

(8.3 mmol) of the 3-methoxy-73-[(2R,S).-2-(2-BOC-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl) obtainable according to example 16 b) )-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester with 32 ml of trifluoroacetic acid and 6.2 ml of anisole in 32 ml of absolute methylene chloride. F: above 192°

(under cleavage). Rf 96: approx. 0.13 (silica gel, ninhydrin), [α]p° = +110°±1° (0.33% in 0.1 N HCl), UV. 250 (13300, i

0.1N HCl).

b) 3- methoxy- 7g-[( 2R, S)- 2-( 2- BOC- aminoethanesulfonylamino)- 2-( 2- BOC- aminothiazol-4- yl)- acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester .

Analogous to example 1 b) or 13 b), the title compound is obtained by treating 4.8 g (10 mmol) (2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl) -acetic acid with 3.94 g (9 mmol) of 3-methoxy-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1.35 g of 1-hydroxybenztriazole and 2.27 in (11 mmol) of N,N<1 ->dicyclohexylcarbodiimide in 80 ml of tetrahydrofuran as solvent. Rf: approx. 0.45 (silica gel, UV 366, methylene chloride-ethyl acetate 1:1).

Example 17.

a) 3- methoxy- 7| 3-[(2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

To a solution of 1.01 g (1.2 mmol) of the 3-methoxy-73-[(2R,S)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-obtainable according to example 17 b)- ethanesulfonylamino)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-thiazol-4-yl-acetamido]-3-cephem-4-carboxylic acid in 15 ml of acetic acid-acetonitrile 1:1, is added with vigorous stirring at room temperature 1.2 6 g of zinc dust and after 1 hour a further 0.63 g of zinc dust. After a further 2 hours it is evaporated in a rotary evaporator. The residue dissolved in 10 ml of water, extracted with ethyl acetate

(2 x 5 ml) and the aqueous phase is adjusted to pH 5 with

1 N sodium hydroxide solution. The precipitate formed is filtered off and dried. The title compound thus obtained is identical to the product obtained according to example 16 a). b) 3- methoxy- 7g-[( 2R, S)- 2-( 2-( 2, 2, 2- trichloroethoxycarbonylamino)- ethanesulfonylamino)- 2- ( 2-( 2 , 2 , 2-trichloroethoxycarbonylamino)- thiazole- 4-yl)-acetamido]-3-cephem-4-carboxylic acid.

A solution of 1.41 g (1.4 mmol) of that according to Example 17

c) obtainable 3-methoxy-73-[(2R,S)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-thiazole -4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in 7 ml of methylene chloride is added to 7 ml of trifluoroacetic acid and evaporated after 2 hours in a rotary evaporator. The residue is taken up to remove excess trifluoroacetic acid twice in toluene (20 ml) and evaporated. The title compound thus obtained can be used in the next reaction step without further purification. Rf 96: approx. 0.36 (silica gel, UV 366).

The starting material is produced in the following way:

c) 3- methoxy- 7[ 3- [ ( 2R, S) - 2 - ( 2 - ( 2 , 2 , 2- trichloroethoxy-carbonylamino)- ethanesulfonylamino)- 2-( 2-( 2, 2, 2- trichloroethoxycarbonylamino)-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

A solution of 1.26 g (2.0 mmol of the (2R,S) obtainable according to example 17 d). -2-(2-(2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-thiazol-4-yl)-acetic acid and 0.714 g (1, 8 mmol) 3-methoxy-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 20 ml of absolute tetrahydrofuran in the presence of 0.27 g of 1-hydroxy-benztriazole and 0.45 N,N<1->dicyclohexylcarbodiimide is stirred for 3 .5 hours at room temperature. The N,N'-dicyclohexylurea formed is filtered off and the filtrate is evaporated. The residue dissolved in 60 ml of ethyl acetate is then washed with 20 ml each of ice water, 1 N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solution. After drying the organic phase with sodium sulphate and removing the solvent on a rotary evaporator, the residue is purified on silica gel with methylene chloride/ethyl acetate 1:1 as eluent, from which the title compound is obtained as an amorphous powder. Rf: approx. 0.46 (silica gel, UV 366, methylene chloride-ethyl acetate 1:1). d) (2R,S)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-thiazol-4-yl)-acetic acid.

A suspension of 1.74 g (5 mmol) of (2R,S)-2-amino-2-(2-(2,2,2-' trichloroethoxycarbonylamino)-thiazol-4-yl)-acetic acid in 17 ml of absolute methylene chloride 2.45 ml of N,O-bis-(trimethylsilyl)-acetamide are added while stirring, humidity is kept in a fume hood and nitrogen atmosphere. 0.4 ml of absolute pyridine and 1.42 g (5 mmol) of 2-(2,2,2-trichloroethoxycarbonylamino)-ethanesulfochloride are then added to the reaction mixture cooled to 0°. The reaction mixture is stirred for a further 1 1/2 hours at 0° and 4 hours at room temperature, then diluted with ethyl acetate (60 ml) and washed with 1 N hydrochloric acid and saturated sodium chloride solution. After drying the organic phase over sodium sulfate and removing the solvent on a rotary evaporator, the crude product is purified on silica gel with ethyl acetate as eluent, from which the title compound is obtained as a beige, amorphous powder. Rf 96: approx. 0.75 (silica gel, UV 366) .

The compounds obtained in examples 13 a), 13 b), 14 a), 14 b), 15 a) and 15 b) can also be obtained according to the one in example

17 a) to 17 d) described procedure.

Example 18.

3-( 1- carboxymethyl- 1H- tetrazol- 5- ylthiomethyl)- 7 3-[ 2R, S)- 2-( 2- aminoethanesulfonylamino)- 2-( 2- aminothiazol- 4- yl)- acetamido]- 3- cephem-4-carboxylic acid sodium salt.

A slurry of 1.07 g (2 mmol) of 3-acetoxymethyl-73-[(2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem -4-carboxylic acid and 0.64 g (4 mmol) of 1-carboxymethyl-5-mercapto-1H-tetrazole in 6 ml of water are adjusted to pH 7 by adding 1 N caustic soda. The clear solution is then stirred under nitrogen for 4 hours at 65°, cooled and introduced into 300 ml of ethanol. The precipitate formed is filtered off, dissolved in water and purified on 25 g of silylated silica gel (Antec "Opti-UPC" 12) with water as eluent. After combining the thin-layer chromatographically uniform fractions, the solvent is distilled off on a rotary evaporator. The residue is dried in high vacuum, from which the title compound is obtained in the form of the hydrate. F: above 150° (during cleavage). Rf: approx. 0.63 (silica gel "Opti-UPC" 12, UV 366, acetonitrile-water 1:9), UV. 251 (15000 in 0.1 N HCl).

Example 19.

3-( 1- sulfomethyl- 1H- tetrazol- 5- ylthiomethyl)- 73-[( 2R, S)-2-( 2- aminoethanesulfonylamino)- 2-( 2- aminothiazol- 4- yl)-acetamido]- 3- cephem- 4- carboxylic acid sodium salt.

Analogous to example 18, the title compound is obtained in the form of the dihydrate starting from 1.07 g (2 mmol) of 3-acetoxymethyl-73-[(2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-aminothiazole-4- yl)-acetamido]-3-cephem-4-carboxylic acid and 1.02 g (4 mmol) 1-sulfomethyl-5-mercapto-1H-tetrazole sodium salt in 6 ml of water.

F: above 180° (during cleavage). Rf: approx. 0.20 (silica gel "Antec UPC" 12, UV, 366, water), UV: 252 (14900, 0.1 N HCl).

Example 20.

3-[ 1-( 2- dimethylaminoethyl)- 1H- tetrazol- 5- ylthiomethyl]-73-[( 2R, S)- 2-( 2- aminoethanesulfonylamino)- 2-( 2- aminothiazol- 4- yl)- acetamido ]- 3- cephem- 4- carboxylic acid.

Analogous to example 18, the title compound is obtained starting from 1.07 g (2 mmol) of 3-acetoxymethyl-73-[(2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)- acetamido]-3-cephem-4-carboxylic acid and 0.69 g (4 mmol) of 1-N,N-dimethylaminoethyl-5-mercapto-1H-tetrazole in 6 ml of water. Rf: approx.

0.18 (silica gel Antec "Opti-UPC" 12, UV 366, acetonitrile-water 2:8).

Example 21.

a) 73~ [ ( 2R, S)- 2 - ( 2- methanesulfonylaminoethanesulfonylamino) - 2-( 2- aminothiazol-4- yl)- acetamido]- 3- cephem-4- carboxylic acid tr. ium salt.

A solution of 1.13 g (1.4 mmol) of that according to Example 21

b) obtainable 73-[(2R,S)-2-(2-methanesulfonylaminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester and 1,1 ml of anisole in 5.5 ml of absolute methylene chloride, 5.5 ml of trifluoroacetic acid is added, stirred for 1 hour at room temperature under exclusion of moisture, and then 60 ml of cold diethyl ether are added at 0°. The beige precipitate is filtered off, washed with diethyl ether, adjusted to pH 7 after dissolving in 20 ml of water with 1 N sodium hydroxide solution and extracted with 3 x 10 ml of ethyl acetate. The aqueous phase is concentrated to approx. 5 ml, and purified on silated silica gel (Antec "Opti-UPC" 12) with water as eluent. The thin-layer chromatographically uniform fractions are purified, evaporated on a rotary evaporator and dried in high vacuum, from which the title compound is obtained in the form of the dihydrate. F: above 185° (during cleavage). Rf 96:

about. 0.30 (silica gel, UV 366), UV: 250 (10300, water).

b) 73-[(2R,S)-2-(2-methanesulfonylaminoethanesulfonyl-amino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

To a solution of 4.0 g (5.5 mmol) of it according to example

21 c) obtainable 73~[(2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester in 60 ml of absolute methylene chloride 0.4 8 ml of absolute pyridine and then 0.5 ml of methane sulphochloride are added while stirring and exclusion of moisture. After 4 hours, the reaction mixture is diluted with 300 ml of ethyl acetate

and washed with 3 x 50 ml saturated sodium chloride solution, dried over sodium sulphate and evaporated on a rotary evaporator. The residue is purified on silica gel (40 times the amount) with methylene chloride/ethyl acetate 1:1 as eluent, from which the title compound is obtained as a colourless, amorphous powder.

Rf: approx. 0.28 (silica gel, UV 366, methylene chloride-ethyl acetate 1:1).

The starting material is produced in the following way:

c) 73-[] 2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester.

To a solution cooled to 0° of 5.25 g (5.8 mmol) of the 73~ prepared according to example 21 d) [ (2R, S)-2-(2-(2 , 2 , 2-trichloroethoxycarbonylamino) -ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester in 50 ml of acetic acid/acetonitrile (1:1), while stirring, add 5.25 g of zinc dust in portions. After 1 hour of reaction time at room temperature, a further 5 g of zinc dust is added. After a total of 5 hours of reaction time, the reaction mixture is diluted with 200 ml of ethyl acetate, filtered off from the zinc dust and washed with cold, saturated, aqueous sodium bicarbonate and sodium chloride solution. After drying with sodium sulfate and removing the solvent on a rotary evaporator, the title compound is obtained, which can be used in the next reaction step without further purification. Rf: approx. 0.58 (silica gel, UV 366). d) 7ft-[( 2R, S)- 2-( 2-( 2, 2, 2- trichloroethoxycarbonylamino)- ethanesulfonylamino)- 2-( 2- BOC- aminothiazol-4- yl)- acetamido]- 3- cephem- 4-carboxylic acid diphenyl methyl ester.

A solution of 11.12 g (20 mmol) of the (2R,S)-2-(2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazole-4) prepared according to example 21 e) -yl)-acetic acid and 7.4 g (20 mmol) of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 200 ml of absolute tetrahydrofuran in the presence of 2.7 g of 1-hydroxybenztriazole and 4.54 g of dicyclohexylcarbodiimide are stirred for 3 hours at room temperature. The dicyclohexylurea formed is then filtered off and the filtrate is evaporated. The residue which is dissolved in ethyl acetate (300 ml) is washed with 1 N hydrochloric acid, saturated sodium bicarbonate and sodium chloride solution. After drying the organic phase with sodium sulfate, the solvent is removed in a rotary evaporator and the precipitated crude product is purified on silica gel (40 times the amount) with methylene chloride/ethyl acetate (1:1) as eluent, from which the title compound is obtained as an amorphous powder. DC (silica gel, identification UV: Rf. approx. 0.65 (methylene chloride/ethyl acetate 1:1). e) 73-[( 2R, S)- 2-( 2- aminoethanesulfonylamino)- 2-( 2-BOC-aminothiazor - 4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

A solution of 0.828 g (1 mmol) 73-[ (2R,S)-2-(2-BOC-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem- 4-carboxylic acid diphenyl methyl ester in 10 ml of absolute methylene chloride is added with stirring at room temperature 0.38 g of p-toluenesulfonic acid monohydrate. After 5 hours, the reaction mixture is diluted with diethyl ether (30 ml) and washed with saturated sodium bicarbonate and sodium chloride solution. The organic phase is dried (sodium sulfate) and evaporated on a rotary evaporator. The title compound thus obtained is identical to the product obtained

according to example 21 c).

Example 22.

a) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73~[(2R,S)-2- (2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt. 3.5 g of the 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73~[(2R,S)-2-(2-BOC-aminothiazol-4-yl) obtainable according to example 22 d) -2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester in 7.5 ml CH2Cl2 and 2.45 ml anisole is reacted with 28 ml trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 165° (during cleavage) . [a]p° = -9°±1° (0.80% in H20). IR: 3700-2500 (broad), 1762, 1685, 1603, 1521 (Nujol). UV: 260 (13600, H20) . b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt. 2.18 g of the 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R)-2-(2-BOC-aminothiazol-4-yl)-2 obtainable according to example 22 e) -methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 4.5 ml CH2C12 and 1.52 ml anisole with 17.4 ml trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 168° (during cleavage). [α]p° = -22°±1° (0.96% in H 2 O) fIR. 3700-2500 (broad), 1762, 1685, 1602, 1521 (Nujol). UV: 260 (3500, H20). c) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R)-2- (2-Aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt.

2.42 g of the 3-(1-methyl-

1H-tetrazol-5-ylthiomethyl)-73-[(2S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 5 ml of CE^C^ and 1.69 ml of anisole with 19.3 ml of trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 168° (during cleavage).

[<x]p° =+8°±l+ (0.85% in H 2 O) . IR: 3700-2500 (broad), 1762, 1685, 1603, 1521 (NUjol), UV: 260 (13700, H2). d) 3-( 1- methyl- 1H- tetrazol- 5- ylthiomethyl)- 73~[( 2R, S)-2- ( 2- BOC- aminothiazol- 4- yrV- 2- methanesulfonylaminoacetamido]- 3- cephem- 4 - carboxylic acid diphenyl methyl ester.

3 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetic acid obtainable according to example 22 f) is reacted with 3.5 g of 3-(1-methyl-1H-tetrazol- 5-ylthiomethyl)-73-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 40 ml of tetrahydrofuran analogously to example 6b) (0.76 g of hydroxy-benztriazole, three times 0.7 g of dicyclohexylcarbodiimide in each 5 ml of tetrahydrofuran), is worked up, and chromatographed. The title compound is obtained: [ct]j^ = -99°±1°

(0.75% in CHCH3). IR: 3400, 3300, 1780, 1720, 1695 (shoulder), 1600 (weak), 1525 (CH2C12). UV: 260 (16000, EtOH).

e) 3-( 1- methyl- 1H- tetrazol- 5- ylthiomethyl)- 73-[( 2R)- 2-( 2- BOC- aminothiazol- 4- yl)- e- methanesulfonylaminoacetamido] - 3- cephem- 4- carboxylic acid diphenyl methyl ester

and

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73~[(2S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

The binary mixture of the two title compounds obtained according to example 22 d) is chromatographed on 300 g of silica gel

(stage column, eluent: toluene-ethyl acetate 4:1, 7:3 and

1:1 mixture). Thereby, the title compound is first eluted with the 2R configuration (as regards the configuration assignment, cf. example 7 d). [α]^° = -126°±1° (0.75% in CHCl 3 ). IR: 3400, 3300, 1780, 1720, 1695 (shoulder), 1600 (weak), 1525, (CH 2 Cl 2 ). UV. 260 (16100, EtOH).

The following fractions consist of a binary mixture of the (2R) and (2S) title compound. Finally, the single (2S) title compound is eluted. [α]^ = -86 ±1° (0.93% in CHCl 3 ). IR: 3400, 3300, 1780, 1720, 1695 (shoulder), 1600 (weak), 1525 (CH2C12). UV: 260 (16200, EtOH).

The starting material is produced in the following way:

f) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonyl-aminoacetic acid.

5 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-glycine is reacted in

45 ml CH2C12 with 2.14 ml mesyl chloride analogous to example

6 c) (15 ml N,0-bis-(trimethylsilyl)-acetamide, 1.45 ml pyridine) and worked up. The title compound is obtained which is further processed according to example 22 d) without characterization.

Example 2 3.

3-( 4- carbamoylpyridiniummethyl). - 73- [ (2R, S) - 2 - ( 2-' aminothiazol-4- yl) - 2- methanesulfonylaminoacetamido] - 3- cephem- 4- carboxylic acid.

2.81 g 3-acetoxymethyl-73~[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt (preparation see example 1 a), 0 .95 g of isonicotinamine, 8.6 g of sodium iodide and 0.94 g of trichloroacetic acid are heated in 5.75 ml of water for 1 1/2 hours at 70°. It is then cooled and introduced into 1 liter of ethanol. The precipitate that is thereby filtered off, washed with ether and dried. It is then dissolved in a little water and the water phase is extracted with 175 ml of liquid each time

ion exchanger, LA 1 (HOAC-Form), hexane and ethyl acetate (2x). The aqueous phase is then adjusted to pH 6.8 with 1 N NaOH and evaporated in vacuo. The pH is then adjusted to 2.2 with 1 N hydrochloric acid and chromatographed on 100 g of silylated silica gel ("Antec Opti-UPC" 12), water-acetonitrile (95:5). The product-containing fractions are combined, evaporated to approx. 5 ml volume and introduced into 400 ml of ethanol. The precipitated product is filtered off, washed with ethanol and diethyl ether, and dried. The hydrate of the title compound is obtained. F: above 160° (during cleavage). [a]£ = -3°±1° (0.78% in H 2 O). IR: 2700-2500 (broad), 1779, 1688, 1610, 1568, 1522 (Nujol), UV. 260 (13600, H 2 O).

Example 24.

a) 7(3-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acetyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 1.7 g of the 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acetylaminoethanesulfonyl-amino)-acetamido]-3-cephem-4- Carboxylic acid diphenyl methyl ester is reacted in 4 ml of CH2C12 and 1.28 ml of anisole with 15 ml of trifluoroacetic acid analogously to example 1 a), worked up and reprecipitated. The title compound is achieved. F: above 200° (during cleavage) . [<x]p° = +98°±1° (0.84% in H 2 O) . IR. 3700-2600 (broad), 1760, 1650 (broad), 1600, 1521, (Nujol), UV: 251 (10200), 312 (1100, H20). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester.

2.21 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acetylaminoethanesulfonyl-amino)-acetic acid which can be prepared according to example 24 c) is reacted with 1.9 g 73 -amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 20 ml of tetrahydrofuran

analogous to example 6b) (0.53 g of hydroxybenztriazole,

three times 0.4 6 g dicyclohexylcarbodiimide in each time 4 ml tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. [a]^° = +23°±1° (0.80% in CHCl3). IR: 3400, 3300, 1781, 1720, 1675, 1529 (CH 2 Cl 2 ). UV. 258 (13600, EtOH).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazole-4-yD-2-(2-acetylaminoethanesulfonylamino)-acetic acid.

6.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid is reacted in 24 ml of CH2Cl2 with 0.71 ml of acetyl chloride analogously to example 6 c) ( 10 ml N,0-bis-(trimethylsilyl)-acetamide, 0.81 ml pyridine) and worked up. The title compound is obtained, which without characterization is further processed according to example 24 b).

Example 25.

a) 3-acetoxymethyl-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 1.32 g of the 3-acetoxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl1-2-(2-acetyl-aminoethanesulfonylamino)-acetamido]- 3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 3.2 ml CH2C12 and 1 ml anisole with 12 ml trifluoroacetic acid analogously to example 1 a), worked up and reprecipitated. The hydrate of the title compound is obtained. F: above 160° (during cleavage). [g]^ = +61°±1° (0.79% in H20), IR: 3700-2500 (broad), 1762, 1680 (shoulder), 1605, 1624 (Nujol), UV: 258 (12700, EtOH ). b) 3- acetoxymethyl- 7 3-[ 82R, S)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2- acetylaminoethanesulfonylamino)- acetamido] - 3- cephem- 4- carboxylic acid diphenyl methyl ester.

1.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acetylaminoethane-sulfonylamino)-acetic acid (preparation see ex. 24 c)) is reacted with 1.46 g 3-acetoxymethyl-73-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 16 ml of tetrahydrofuran analogous to example 6b) (0.4 g of hydroxybenztriazole, three times 0.35 g of dicyclohexylcarbodiimide in each time 3 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. [a]p° = +6°±1° (0.71% in CHCl3). IR: 3400, 3300, 1787, 1725, 1695, 1677, 1540 cm<-1>(CH 2 Cl 2 ), UV: 258 (14900, EtOH).

Example 26.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-benzoyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 1.46 g of the 73~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-benzoylaminoethanesulfonyl-amino)-acetamido]-3- obtainable according to example 26 b) cephem-4-carboxylic acid diphenyl methyl ester is reacted in 3.2 ml CH2C12 and 0.1 ml anisole with 12 ml trifluoroacetic acid analogously to example 1 a), worked up and reprecipitated. The hydrate of the title compound is obtained. F: above 185° (during cleavage). [<x]p° = +79°±1° (0.91% in H 2 O) . IR: 3700-2500, 1760, 1680 (shoulder), 1640, 1600, 1577, 1525, (Nujol), UV: 230 (17300,H20). b) 73-C(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-benzoyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

2.39 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-benzoylaminoethanesulfonylamino)-

acetic acid is reacted with 2 g of 73-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 20 ml of tetrahydrofuran analogously to example 6b) (0.56 g of hydroxybenztriazole, 3 times 0.4 9 g of dicyclohexylcarbodiimide in each time 4 ml of tetrahydrofuran), worked up and chromatographed. The title compound is achieved.

[a]p° = +20°±1° (1.01% in CHCl 3 ), IR. 3400, 3300, 1785, 1720, 1665, 1602, 1520 (CH 2 Cl 2 ), UV: 255 (11500, EtOH).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-benzoyl-aminoethanolsulfonylamino)-acetic acid.

6.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid is reacted in 24 ml of tetrahydrofuran with 1.16 ml of benzoyl chloride analogously to example 6 c ) (10 ml N,0-bis-(trimethylsilyl)-acetamide, 0.81 ml pyridine) and worked up. The title compound is obtained, which without characterization is further processed.

Example 27.

..a) 70-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 1.9 of the 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3-cephem-4 obtainable according to example 27 b) -carboxylic acid diphenyl methyl ester is reacted in 10 ml CH2Cl2 and 0.57 ml anisole trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 215° (during cleavage). [a]^<0>= +101°±1° (1.22% in H2O). IR: 3700-2500 (broad), 1760, 1670, 1600, 1520 (Nujol), UV: 252 (9900), (200, H20). b) 73-[( 2R, S)- 2-( 2- BOC-aminothiazol-4-yl)- 2-( 2- formyl-aminoethanesulfonylamino)- acetamido]- 3- c' ephem- 4- carboxylic acid diphenyl methyl ester .

2.3 g of the (2R,S).2.(2-BOC-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetic acid obtainable according to example 27 c) is reacted with 2.0 g of 73-amino -3-cephem-4-carboxylic acid diphenyl methyl ester in 30 ml of tetrahydrofuran analogous to example 6b) (0.5 g of hydroxybenztriazole, 3 times 0.4 g of dicyclohexylcarbodiimide each time in 6 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved.

[a]^° = +18°±1° (0.99% in CHCl3). IR. 3400, 3300, 1790. 1727, 1690, 1600, 1542 (Nujol). UV: 260 (13400, EtOH).

The starting material is produced in the following way:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-formylamino-ethanesulfonylamino)-acetic acid.

6.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid is reacted in 25 ml of tetrahydrofuran with 1.35 ml of the mixed anhydride of acetic and formic acid prepared from acetic anhydride and formic acid, see G. Buchi et al., JACS 93, 2492 (1971), analogous to example 6 c)

(10 ml N,O-bis-(trimethylsilyl)-acetamide, 0.81 ml pyridine).

and processed. The title compound is obtained which is further processed without characterization.

Example 28.

a) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R)-2- (2-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonyl-amino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

1.17 g of the 3-(1-methyl-1H-tetrazol-5-ylthiomethyl-73-[(2R)-2-(2-BOC-aminothiazol-4-yl)-

2-(2-Formylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 5.5 ml CH C~ m C14~ m and 0.2 9 ml anisole with 8.2 ml trifluoroacetic acid analogously to example 1 a), are worked up and combined. The hydrate of the title compound is obtained. F: above 165° (during cleavage).

[a]p° = -12°±1° (1.00% in H2O). IR. 3700-2600 (wide), 1760, 1675, 1605, 1520 (Nujol). UV: 259 (13200, H 2 O) .

b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-70-[(2S)-2- (2-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonyl-amino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 1.1 g of the 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-70-[(2$)-2-(2-BOC-aminothiazol-4-yl)- 2-(2-Formylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 5.5 ml CH2C12 and 0.29 ml anisole with 8.2 ml trifluoroacetic acid analogously to example 1 a), worked up and reprecipitated. The hydrate of the title compound is obtained. F: above 165° (during cleavage). [a]^ = +7°±1° (1.09% in H2O). IR: 2700-2600, 1762. .1672, 1605, 1524 (Nujol). UV. 259 (13500, H20).

c) 3-(1-methyl-1K-tetrazol-5-ylthiomethyl)-70-[(2R)-2-(2-BOC-aminothiazol-4-yl)-2-(2-formylaminoethan-

sulf onylamino) - acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

and

3-( 1- methyl- 1H- tetrazol- 5- ylthiomethyl)- 70-[( 2S)-2-( 2- BOC-aminothiazol-4- yl)- 2-(2-formylamihoethanesulfonylamino)- acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

3 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-formylaminoethane-sulfonylamino)-acetic acid (preparation according to example 27

c) react with 2.77 g of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 60 ml

tetrahydrofuran analogously to example 6b) (0.65 g of hydroxybenztriazole, 3 times 0.52 g of dicyclohexylcarbodiimide in each time 7 ml of tetrahydrofuran) and worked up. The crude product obtained is chromatographed on 300 g silica gel (step column)

(eluent: toluene-ethyl acetate 4:1, 2:1 and 1:1 mixture and ethyl acetate). Thereby, the title compound is first eluted with the 2R configuration.

20°

(As for the configuration, see example 7 d) ; ^a^D = -83°±1° (0.85% in CHCl 3 ). IR_<*>3400, 3300, 1788, 1691,

1605, 1542 (CH 2 Cl 2 ). UV: 260 (16800, EtOH).

The follower reactions consist of a binary mixture of the above (2R) compound and the (2S) isomer.

From the last fractions, the title compound with the 2S configuration ion is obtained; [ct]^° = -84°±„1° (0.95% in CHCl 3 ), IR: 3400, 3300, 1789, 1722, 1691, 1605, 1542 (CH 2 Cl 2 ). UV: 260 (17000, EtOH).

Example 29.

a) 73-[( 2R, S )- 2-( 2-( 2-aminothiazol-4'- ylacetamido)-ethanesulfonylamino)- 2-( 2-aminothiazol-4- yl)-acetamido]-3-cephem-4 -carboxylic acid sodium salt.

A solution of 3.9 g (4 mmol) 73-[(2R,S)-2-(2-(2-BOC-aminothiazol-4-ylacetamido)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4 -yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester and 3.9 ml of anisole in 20 ml of methylene chloride are added to 20 ml of trifluoroacetic acid, stirred for 1 hour at 25° under a nitrogen atmosphere and then added at 0° to 300 ml of diethyl ether . The beige precipitate is filtered off, washed with a little diethyl ether and adjusted to pH 7 after dissolving in 30 ml of water with 2 N hydroxide solution. After extraction with ethyl acetate, the aqueous phase is purified on silylated silica gel (Opti-UPC^) with <3 water as eluent. The title compound is obtained in the form of the dihydrate. F: over 170°

(fission). Rf 0.38 (silica "Opti-UPC", H,O-CH.,CN, 8:2). [a]p = +89 ±1° (H2O, c = 0.152%), UV (H2<D) : 251

(e = 15,550) . b) 73-[( 2R, S)- 2-( 2-( 2- BOC-aminothiazol-4-yracetamido)-ethanesulfonylamino)- 2-( 2- BOC- aminothiazol-4- yl)-acetamido]- 3- cephem-4-carboxylic acid diphenyl methyl ester.

To a solution of 2.48 g (4 mmol) of it according to example

29 c) obtainable (2R,S)-2-(2-(2-BOC-aminothiazol-4-ylaceta-mido)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid and 0, 54 g (4 mmol) of 1-hydroxybenztriazole in 40 ml of absolute tetrahydrofuran is added with stirring at room temperature to a solution of 0.91 g (4.4 mmol) of N,N'-dicyclohexylcarbodiimide in 10 ml of absolute tetrahydrofuran and after approx. 10 minutes 1.46 g (4 mmol) 7'-amino-3-cephem-4-carboxylic acid diphenyl methyl ester. After a reaction time of 4 hours, the precipitated N,N'^-dicyclohexylurea is filtered off and the filtrate is evaporated on a rotary evaporator. The residue, which is dissolved in 400 ml of ethyl acetate, is washed twice with 50 ml each of 1 N hydrochloric acid and saturated sodium chloride solution.

The crude product obtained after drying over sodium sulfate

and removal of the solvent on a rotary evaporator, purified on 160 g of silica gel with methylene chloride-ethyl acetate

(1:1) as eluent. The title compound is achieved.

Rf (silica gel, development with iodine): 0.33 CHCl3/CH2OH/CH3COOH 75:22:3).

Preparation of the starting material:

c) (2R,R)-2-(2-(2-BOC-aminothiazol-4-ylacetamido)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid.

To a solution of 3.87 g (15 mmol) 2-BOC-aminothiazol-4-yl-acetic acid and 2.03 g (15 mmol) 1-hydroxybenztriazole, add 3.4 g (16.5 mmol) while stirring at room temperature N,N'-Dicyclohexylcarbodiimide. After a reaction time of 15 minutes, 5.71 g (15 mmol) of (2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid are added to the obtained suspension. After a reaction time of 4 hours, the N,N'-dicyclohexylurea obtained is filtered off and the filtrate is evaporated on a rotary evaporator. The residue, which is dissolved in 500 ml of ethyl acetate, is washed 3 times with each of 1 N hydrochloric acid and saturated sodium chloride solution. The crude product obtained after drying over sodium sulfate and removal of the solvent on a rotary evaporator is purified on 400 g of silica gel with methylene chloride - ethyl acetate 1:2 as eluent, from which the title compound is obtained as an amorphous powder.

Example 30.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-butyryl-amino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. Analogous to example 2 9 a), the title compound is obtained as 1,5-hydrate by reaction of 3.1 g (3.9 mmol) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl) -2-(2-butyrylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 3.1 ml of anisole with 15 ml of trifluoroacetic acid in 15 ml of absolute methylene chloride. F: above 17 0° (decomposition). Rf 96: approx. 0.43: ta]^° = +86°±1° (h20, C = 0.872%). UV (H2O). 250 (e= 10700). b) 73-[( 2R, S)- 2-( 2- BOC- aminotiazoT- 4- yT)- 2-( 2-butyrylamino)- ethanesulfonylamino)- acetamodi]- 3-c e f em- 4- - kar bok syl acid diphenyl methyl ester .

Analogous to example 2 9 b), the title compound is obtained by reaction of 3.4 g (7.5 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-butyrylamino)- ethanesulfonylamino)-acetic acid with

2.75 g (7.5 mmol) of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1.01 g of 1-hydroxybenztriazole and 1.7 g of N,N'-dicyclohexylcarbodiimide in 80 ml of tetrahydrofuran. Rf (silica gel): 0.45 (ethyl acetate).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(-2-butyryl-amino)-ethanesulfonylamino)-acetic acid.

A suspension of 3.80 g (10 mmol) of (2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid in 90 ml of absolute tetrahydrofuran is added with stirring, moisture exclusion and nitrogen atmosphere 10 ml of N,O-bis-(trimethylsilyl)-acetamide. After 1 hour's reaction time at 65°, the reaction mixture is cooled to 0°, 0.88 ml of pyridine and 1.14 ml of butyric acid chloride, dissolved in 10 ml of tetrahydrofuran, are added and stirred for a further 15 hours at room temperature. After removal of the solvent, the residue is taken up in ethyl acetate and washed 4 times with 50 ml each of 0.5 N hydrochloric acid and saturated sodium chloride solution. After drying over sodium sulfate, the solvent is removed on a rotary evaporator, from which the title compound is obtained, which without further purification can be used in the next reaction step.

Example 31.

a) 7 3-[( 2R, S)- 2-( 2-aminothiazol-4- yl)- 2-( 2- acryloyl-aminoethane sulfonylamino)- acetamido]- 3- cef em- 4-carboxylic acid sodium salt.

1.84 g of the drug obtained according to example 31 b) 7'-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonyl-amino)-acetamido)-3- Cepheme-4-carboxylic acid diphenyl methyl ester is reacted in 4.14 ml of CE^C^ and 1.34 ml of anisole with 15.5 ml of trifluoroacetic acid analogously to example 1 a), worked up,

chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 190° (during cleavage). IR: 3700-2600 (broad), 1760, 1660, 1600, 1522 (Nujol); UV: 255 (10000, H2O). b) 7( 3- [ ( 2R, S) - 2 - ( 2- BOC- aminothiazol-4-yl) - 2- ( 2-acryloylaminoethanesulfonylamino)- acetamido]- 3—

cephem-4-carboxylic acid diphenyl methyl ester.

2.88 g according to example 31 c) obtainable (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetic acid, is reacted with 2.2 g of 7(3- amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 20 ml of tetrahydrofuran analogous to example 6 b) (0.66 g of hydroxybenztriazole, 3 times 0.58 g of dicyclohexylcarbodiimide in each time 5 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved.

[a]^° = +26°±1° (1.01% in CHC13): IR: 3400, 2200, 1778, 1715, 1675, 1605 (shoulder), 1515 (CH2C12); UV: 257 (3400, EtOH).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetic acid.

6.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid is reacted in 24 ml of tetrahydrofuran with 0.81 ml of acrylic acid chloride analogously to example 6c) ( 10 ml N,0-bis-(trimethylsilyl)-acetamide; 0.81 ml pyridine) and worked up. The title compound is obtained as without characterization \eideref orarbeids.

Example 32.

a) 73-[( 2S)- 2-( 2-aminothiazol-4- yl)- 2-( 2- cyclopropyl- carbonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

I, 4 g of the 7(3-[ (2S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-cyclopropylcarbonylaminoethanesulfonylamino)-acetamido]-2 obtainable according to example 32 c) -cephem-4-carboxylic acid diphenyl methyl ester is reacted in 7k4 ml CH2C12 and 0.4 ml anisole with II, 2 trifluoroacetic acid analogously to example 1 a), worked up and precipitated. The hydrate of the title compound is obtained.

F: cleavage from 200°. [ o.]^ 0 = +107°±1° (0.85% in H20) ;

IR: 3700-2600, 1769, 1670 (shoulder), 1645, 1600, 1530 (Nujol); UV: 255 (11000; H20). b) 73-[(2R)-2-(2-aminothiazol-4-yl)-2-(2-cyclopropyl-carbonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 1 g of the 73~ obtainable according to example 32 c) [(2R)-2-(2-BOC-aminothiazol-4-yl)-2-(2-cyclopropylcarbonylaminoethanesulfonylamino)-acetamido]-3-cephem-4- Carboxylic acid diphenyl methyl ester is reacted in 5.3 ml of CH2C12 and 0.28 ml of anisole with 8 ml of trifluoroacetic acid analogously to example 1 a), worked up and repeated. The hydrate of the title compound is obtained. F: cleavage from 200°. [a]^° = +77°±1° (0.56% in H 2 O);

IR: 3700-25000 (broad), 1760, 1670 (shoulder), 1645, 1600, 1525 (Nujol); UV 255 (9600), 315 (600; H2O).

c) 7 3-[(2R)-2-(2-BOC-aminothiazol-4-yI)-2-(2-cyclopropylcarbonylaminoethanesulfonylamino). acetamido]-3- cephem- 4- carboxylic acid diphenyl methyl ester

and

73-[(2S)-2-(2-BOG-aminothiazor-4-yr)-2-(2-cycloXo-propylcarbonylamino ethane sulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

2.4 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-cyclopropylcarbonylaminoethanesulfonylamino)-acetic acid obtainable according to example 32 d) is reacted with 1.93 g 73 ~amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 30 ml of tetrahydro-

furan analogous to example 6b) (0.54 g hydroxybenztriazole, 3 times 0.4 6 g dicyclohexylcarbodiimide in each time 4 ml tetrahydrofuran) and worked up. The crude product obtained is chromatographed on 300 g of silica gel (step column) (eluent: toluene-ethyl acetate 2:1). Thereby, the title compound with the (2R) configuration is first eluted. numberD 2 0°=<+>2°±1°

(0.95% in CH 2 Cl 2 ); IR: 3300, 1791, 1730, 1700, 1670, 1640, 1602, 1540 (CH 2 Cl 2 ); UV: 258 (12500, EtOH).

The follower reactions consist of a binary mixture of the (2R) and (2S) title compounds.

Finally, the (2S)-title compound [a]£ = +38°±1° is obtained

(0.85% in H 2 O); IR: 3400, 3300, 1792, 1739, 1704, 1670, 1640, 1602, 1540 (CH 2 Cl 2 ); UV: 257 (11900; EtOH).

Preparation of the starting material:

d) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-cyclopropylcarbonylaminoethanesulfonylamino)-acetic acid.

6.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid is reacted analogously to example 6 cl in 24 ml of tetrahydrofuran with 0.875 ml of cyclopropanecarboxylic acid chloride ( 16 ml of N,0-bis-(trimethylsilyl)-acetamide, 0.81 ml of pyridine and work up The title compound is obtained which is further worked up without characterization.

Example 3 3.

a)/ 7g-[ ( 2R, S) - 2- ( 2- aminothiazol-4- yl) - 2- ( 2- cyanoacetyl-a- irclnoetane sul f onylamino) - acetamido] - 3- cef em- 4 -

carboxylic acid sodium salt.

Analogous to example 2 9 a) is obtained by reacting 2.23 g (2.8 mmol) of the 73-[]2R,S)-2-(2-BOC-aminothiazol-4-yl) obtainable according to example 33 b) )-2-(2-cyanoacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 2.2 ml of anisole with 11 ml of trifluoroacetic acid the title compound in the form of the dihydrate. F: above 168°

(under cleavage). Rf (silica gel Cpti-UPCj^): ca* C.35 (H 2 O) . b) 7( 3— [ ( 2R, S)-2-( 2- BOC-amir. othiazol-4- yl)- 2-( 2-cyanacetylaminoethanesulfonylamino)- acetamido]-3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogously to example 2 9 b), the title compound is obtained as an amorphous powder by reacting "2.91 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-cyanoacetylaminoethanesulfonylamino)-acetic acid with 2.38 g of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.88 g of 1-hydroxybenztriazole and 1.48 g of N,N'-dicyclohexylcarbodiimide in 60 ml of absolute tetrahydrofuran Rf (silica gel): approx. 0.18 (methylene chloride/ethyl acetate 1:1).

Preparation of starting materials:

c) (2R)S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-cyanoacetyl-aminoethanesulfonylamino)-acetic acid.

A suspension of 3.8 g (10 mmol) of (2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid in 100 ml of absolute tetrahydrofuran is added with stirring, moisture exclusion and nitrogen atmosphere 10 ml of N,I-bis(trimethylsilyl)-acetamide. After 1 hour's reaction time at 65°, the reaction mixture is cooled to 0°, 0.96 ml of pyridine and 1.0 ml of cyanoacetic acid chloride are added and then stirred for 3 hours at room temperature. After removal of the solvent, the residue is taken up in ethyl acetate and washed 4 times each with 0.5 N hydrochloric acid and saturated sodium chloride solution. After drying; over sodium sulfate, the solvent is removed on a rotary evaporator. The title compound is obtained, which is used without purification in the next reaction step.

Example 34.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxy-acetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 3 g of the 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonylamino)-acetamido]-3-cephem- 4-carboxylic acid diphenyl methyl ester is reacted in 8 ml of CH2C12 and 0.9 ml of anisole with 15 ml of trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained.

F: cleavage above 150°. [a]^° .= +93°±1° (1.22% in H 2 O) . IR: 3700-2600 (broad), 1760, 1665, 1600, 1525 (Nujol), UV: 252 (9600, H20). b) 73~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxy-acetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

3.6 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonylamino)-acetic acid obtainable according to example 36 c) is reacted with 2.9 g of 73-amino-3 -cephem-4-carboxylic acid diphenylmethyl ester in 40 ml of tetrahydrofuran analogous to example 6 b) (1 g of hydroxybenztriazole, 3 times 0.53 g of dicyclohexylcarbodiimide in each time 7 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved.

[a]p° = +19°±1° (1.16% in CHC13), IR: 3400, 3300, 1790, 1728, 1692, 1640 (shoulder), 1600, 1530 (CH2C12), UV: 260 (14000 , EtOH).

The starting material is prepared in the following way: c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxy-acetylaminoethanesulfonylamino)-acetic acid.

6.7 g (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfo-

nylamino)-acetic acid is reacted in 25 ml of tetrahydrofuran with 0.92 ml of methoxyacetyl chloride analogously to example 6 c) (10 ml of N,0-bis-(trimethylsilyl)-acetamide, 0.81 ml of pyridine) and worked up. The title compound is obtained, which is further processed without characterization.

Example 35.

a) 73-(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-propioioyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

1.3 g of 7|3-[.(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-propioloyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diph enyl methyl ester is reacted in 7 ml of CH2C12 and 0.37 ml of anisole with 10.6 ml of trifluoroacetic acid analogously to example 1 a), worked up and reprecipitated. The hydrate of the title compound is obtained.

F: cleavage from 220°. [a]^0 = +91°±1° (1.00% in H20), IR: 3700-2700 (broad), 2120, 1760, 1675 (shoulder), 1645, 1600, 1522 (Nujol), UV: 249 (9700), 314 (700, H 2 O). b) 73~[(2R,S)-2-(2-BQC-aminothiazol-4-yl)-2-(2-prop-pioloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

3.1 g of the 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3-cephem- 4-carboxylic acid diphenyl methyl ester is reacted with 0.258 ml propiolic acid in 45 ml tetrahydrofuran analogously to example 6b) (0.56 g hydroxybenztriazole, 3 times 0.29 g dicyclohexylcarbodiimide in each time 5 ml tetrahydrofuran), worked up and chromatographed. The title compound is achieved. IR: 3400, 3300, 2120, 1790, 1726, 1700 (shoulder), 1668,

1603, 1540 (CH 2 Cl 2 ), UV: 258 (13800, EtOH).

Preparation of the starting material:

c) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

12.9 g of the 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino) obtainable according to example 35 d) -acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is stirred with 14 g of zinc dust in 150 ml of acetonitrile-acetic acid 1:1 mixture for 3 hours at 0°. The zinc residue is then filtered off, washed with acetonitrile and evaporated in vacuo to dryness. The evaporation residue is taken up in 0.5 liters of ethyl acetate-water 1:1 mixture, adjusted to pH 8 with 1 N sodium hydroxide solution, diluted with a little ethyl acetate and washed neutral with saturated, aqueous sodium chloride solution. It is then dried over sodium sulphate, evaporated in vacuo and the crude product is precipitated from CH„C1„-ether-hexane once. The title compound is achieved.

2 no o o

[a]^ = +2<9>±<1> (1.09% in CHC13). IR: 3450-2600 (broad), 1770, 1715, 1690 (shoulder), 1640, 1532 (CH 2 Cl 2 ), UV: 258 (11800, EtOH). d) 7 3-[( 2R, S)- 2-( 2- BOC-aminothiazol-4- yl)- 2-( 2-( 2, 2, 2-trichloroethoxycarbonylamino)- ethanesulfonylamino)-acetamido]- 3- cephem - 4- carboxylic acid diphenyl methyl ester.

11.8 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-X2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino)-acetic acid is reacted with 7.05 g of 73~ amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 100 ml of tetrahydrofuran. analogous to example 6b) (1.95 g hydroxybenztriazole, 3 times 1.7 g dicyclohexylcarbodiimide in each time 20 ml tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. [g]^ = ^14°±1°

(0.90% in CHCl 3 ), IR. 3400, 3300, 1781, 1720, 1700 (shoulder), 1635, 1520 (CH 2 Cl 2 ), UV: 258 (13600, EtOH).

Example 36.

a) 7B-[( 2R, S)- 2-( 2-(( 2R)- 2- amino- 2- carboxyethoxy-carbonylamino)- ethanesulfonylamino)- 2-( 2- aminothiazol-4- yl)- acetamido]- 3- cephem- 4- carboxylic acid sodium salt.

Analogous to example 29 a), the title compound is obtained in the form of the dihydrate by reaction of 1.5 g (1.35 mmol) 7p-[(2R,S)-2-(2-((2R)-2-BOC-amino- 2-diphenylmethoxycarbonylethoxycarbonyl-amino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cef em-4-carboxylic acid Hiphenyl methyl ester with 1.5 ml of anisole and 7.5 ml of trifluoroacetic acid in 7, 5-ml methylene chloride. above 151°. Rf (silica gel "Opti-UPC, ": approx. 0.75 (water/acetonitrile 9:1), [a.]* 2 D° = +68 n +1 n(0.659% in 0.1 N HC1, UV (in 0.1 N HCl), 252 (e= 12900). b) 73- [ ( 2R, S).- 2- ( 2- ( ( 2R) - 2- BOC- amino- 2- diphenylmethoxy-carbonylethoxycarbonylamino) - ethanesulfonylamino)-2-(2-BOC-aminothiazol-e-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogously to example 2 9 b), the title compound is obtained as a yellowish powder by reaction of 1.56 g (2 mmol) (2R,S)-2-(2-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonyl- amino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid with 0.73 g (2 mmol) 73-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in the presence of 0.27 g 1 -hydroxybenztriazole and 0.45 g of N,N<1->dicyclohexylcarbodiimide in 30 ml of tetrahydrofuran. Rf: approx. 0.63 (methylene chloride/ethyl acetate 1:1).

Preparation of the starting material:

c) ( 2R, S)- 2-( 2-(( 2R)- 2- BOC-amino- 2- diphenylmethoxy-carbonylethoxycarbonylamino)- ethanesulfonylamino)- 2-( 2 - BOC- aminotiazo 1 - 4 - y 1) - acetic acid.

A suspension of 1.9 g (5 mmol) of (2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid in 60 ml of absolute tetrahydrofuran is added with stirring, moisture exclusion and nitrogen atmosphere 5.0 ml of N,0-bis(trimethylsilyl) ■ acetamide. After 1 hour of reaction time at 60°, the reaction mixture is cooled to room temperature, 0.4 ml of pyridine and 2.17 g of (2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonyl chloride are added and then stirred for 2 hours. After removal of the solvent, the residue is taken up in 250 ml of ethyl acetate and washed 3 times each with 0.1 N hydrochloric acid and saturated sodium chloride solution. After drying over sodium sulfate, the solvent is removed in a rotary evaporator and the residue is purified on silica gel with methylene chloride-ethyl acetate 1:1 as eluent, from which the title compound is obtained as an amorphous powder.

Rf (silica gel): approx. 0.58 :(chloroform/methanol/glacial vinegar 75:22: 3) .

Example 37.

a) 7| 3-[(2R,S)-2-(2-aminothiazol-4-yr)-2-(2-ethoxycarbonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 2 9 a) the title compound is obtained as

1.5 hydrate by reaction of 4.2 g (5.25 mmol) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-ethoxycarbonylaminoethanesulfonylamino)- acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester with 4.2 ml of anisole and 20 ml of trifluoroacetic acid in 20 ml of methylene chloride. F: above 168° (during cleavage).

[a]^° = +95°±1° (1.02% in water), UV: (water): 251 (e=10500). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(ethoxy-carbonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 29 b), the title compound is obtained as amorphous powder by treating 3.8 g (8.4 mmol) (2R,S)-2-(2-ethoxycarbonylaminoethanesulfonylamino)-2-(2-BOC-amino thiazole-4- yl)-acetic acid with 3.08 g (8.4 mmol) of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1.13 g of 1-hyd->..roxybenztriazole and 1.90 g of N,N' -dicyclohexylcarbodiimide.

Rf (silica gel): approx. 0.58 (ethyl acetate).

Preparation of the starting material:

c) (2R,S)-2-(2-ethoxycarbonylaminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid.

A suspension of 3.8 g (10 mmol) of (2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazor-4-yl)-acetic acid in 90 ml of absolute tetrahydrofuran is added with stirring, moisture exclusion and nitrogen atmosphere 10 ml of N,O-bis(trimethylsilyl)-acetamide. After 1 hour's reaction time at 65°, the reaction mixture is cooled to 0°, 0.90 ml of pyridine and 1.05 ml of ethyl chloroformate are added and then stirred for 4 hours at room temperature. After removal of the solvent, the residue is taken up in ethyl acetate and washed 4 times with each of 0.5 N hydrochloric acid and saturated chloride solution. After drying over sodium sulfate, the solvent is removed in a rotary evaporator. The title compound is obtained which can be used in the next reaction step without further purification.

Example 38.

a) 73-[( 2R' S)- 2-( 2-( 4- nitrobenzenesulfonylamino)-ethanesulfonylamino)- 2-( 2- aminothiazol-4- yl)- acetamido ] - 3- c e fem- 4- carboxylic acid sodium salt.

Analogous to example 29 a), the 1,5 hydrate of the title compound is obtained as a yellowish powder by reaction of 2.0 g (2.19 mmol) 73-[(2R,S)-2-(2-(4-nitrobenzenesulfonylamino)-ethanesulfonylamino) ) -2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 2.0 ml of anisole and 10 ml of trifluoroacetic acid in 10 ml of methylene chloride. F: above 175° (cleavage). [a]^0 = +79°±1° (0.066% in water), UV:

(water): 257 (e=19200, Rf 96 (silica gel): approx. 0.50.

b) 7&~[( 2R,S)- 2-( 2-( 4- nitrobenzenesulfonylamino)-ethanesulfonylamino)- 2-( 2- BOC- aminothiazol-4- yl)-acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogous to example 29 b), the title compound is obtained as amorphous powder by treating 3.4 g (6.0 mmol) (2R,S)-2-(2-(4-nitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2-aminothiazole -4-yl)-acetic acid with 2.2 g (6.0 mmol) of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.81 g of 1-hydroxy benztriazole and 1.36 g of N,N'- dicyclohexylcarbodiimide in 60

ml of tetrahydrofuran. Rf (silica gel): approx. 0.50 (methylene chloride/ ethyl acetate 1:1).

Preparation of the starting material:

c) (2R,S)-2-(2-(4-nitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetic acid.

A suspension of 7.61 g (20 mmol) of (2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid in 200 ml of absolute tetrahydrofuran is added with stirring, moisture exclusion and nitrogen atmosphere, 20 ml of N,6-bis(trimethylsilyl)-acetamide. After 1 hour at 65°, the reaction mixture is cooled to 0°, 2.4 ml of pyridine and 6.65 g of 4-nitrobenzene sulfochloride are added and then stirred for 4 hours at room temperature. After removal of the solvent, the residue is taken up in 250 ml of ethyl acetate and washed 4 times each time with 0.5 N hydrochloric acid and saturated sodium chloride solution. After drying over sodium sulfate, the solvent is evaporated on a rotary evaporator. The crude product is chromatographed on 350 g of silica gel with a methylene chloride-ethyl acetate (4:1) mixture as eluent. The title compound is obtained as amorphous powder.

Example 39.

a) 3-acetoxymethyl-7 3-[(2R,S)-2- (2- (4-nitrobenz'ene-sulfonylamino)-ethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido ]- 3- cephem- 4- carboxylic acid sodium salt.

Analogous to example 29 a), the title compound is obtained as a pale yellow powder by reacting 6.8 g (6.9 mmol) of 3-acetoxymethyl-7(3-[ (2R,S)-2-(2-(4-nitrobenzene sulf onylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester in 6.8 mo anisole with 6.8 ml trifluoroacetic acid in 68 ml methylene chloride. F: over 155° (under decomposition). Rf (silica gel "Opti-UPC12": approx. 0.23 (water/acetonitrile 4:1). [a]^° = +2°+l° (0.858%' in water), UV (in water): 258 (£=23300). b) 3- acetoxymethyl- 7| 3-[ ( 2R, S)- 2-( 2-( 4- niltrobenzenesulfonylamino)- ethanesulfonylamino)- 2-( 2 - BOC- aminothiazol - 4 - yl) - acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogously to example 2 9 b), the title compound is obtained as a pale yellow powder by treating 10.18 g (18 mmol) (2R,S)-2-(2-(4-nitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2-aminothiazole- 4-yl)-acetic acid with 7.9 g (18 mmol) of -3-acetoxy-methyl-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 2.4 3 g of 1-hydroxybenztyrazole and 4.1 g N,N'-dicyclohexylcarbodiimide in 150 ml of tetrahydrofuran. Rf (silica gel): approx. 0.53 (methylene chloride/ethyl acetate 1:1).

Example 40.

a) 73-[(2R,S)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 29 a) is obtained in the hydrate of the title compound as a yellowish powder with the reaction of 2.0 g (2.1 mmol) 7(3-[ (2R,S)-2-(2-(2,4-dinitro benzenesulf onylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 2.0 ml of anisole and 10 ml of trifluoroacetic acid in 10 ml of methylene chloride. F: above 150° (decomposition". [a]p<0>= +78°±1° (0.59% in water, Rf: approx.

0.30 (silica gel "Opti-UPC"12, cnnn-acetonitrile 4:1), UV. 245 (31500 in water). b) 73-[( 2R, S)- 2-( 2-( 2, 4- dinitrobenzenesulfonylamino)-ethanesulfonylamino)- 2 -( 2-( 2- BOC- aminothiazol-4- yl)-acetamido]- 3 - c e f em- 4-carboxyl acid in phenyl methyl ester.

Analogously to example 29 b), the title compound is obtained as a pale yellow, amorphous powder by treating 2.0 g (3.3 mmol)

(2R,S)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid with 2.0 g of 3-acetoxymethyl-73-amino- 3-cephem-4-carboxylic acid diphenylmethyl ester in the presence of 0.44 g of 1-hydroxybenztriazole and 0.74 g of N,N<1->dicyclohexylcarbodiimide in 40 ml of tetrahydrofuran.

Rf (silica gel): approx. 0.48 (methylene chloride/ethyl acetate 1:1).

Preparation of the starting material:

c) (2R,S)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid.

A suspension of 3.80 g (10 mmol) of (2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid in 100 ml of absolute tetrahydrofuran is added with stirring, moisture exclusion and nitrogen atmosphere 10 ml of N,O-bis(trimethylsilyl)-acetamide. After a reaction time of 1 hour at 65°, the reaction mixture is cooled to 0°, 1.2 ml of pyridine and 4.0 g of 2,4-dinitrobenzene sulphochloride are added and they are stirred for 4 hours at room temperature. After removal of the solvent, the residue is taken up in 250 ml of ethyl acetate and washed 4 times each time with 0.5 N hydrochloric acid and saturated sodium chloride solution. After drying over sodium sulfate, the solvent is removed

a rotary evaporator. The crude product is purified on 250 g of silica gel with methylene chloride-ethyl acetate (4:1) mixture as eluent. The title compound is obtained as amorphous powder.

Example 41.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yr)-2-(2-cyanomethanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 0.5 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-cyanomethanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 2 ml CH2Cl2 and 0.2 ml anisole with 5 ml trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: cleavage from 220°. IR: u.a. 2374, 1755 (Nujol), UV: 251 (9700), 320 (650, H20). b) 73-[( 2R, S)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2- cyan-methane sulfony laminoethane sulfonyl amino)- ac et amido]-3- cephem- 4- carboxylic acid diphenyl methyl ester.

2.2 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-cyanomethanesulfonyl amino)-ethanesulfonylamino)-acetic acid is reacted with 0.6 g of 73-amino-3-cephem -4-carboxylic acid diphenylmethyl ester in 25 ml tetrahydrofuran analogously to example 6b) (0.6 g hydroxybenztriazole, 3 times 0.3 g dicyclohexylcarbodiimide in each time 5 ml tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. IR: 3400, 3300, 2775, 1779, 1710, 1660, 1520 (CH 2 Cl 2 ), UV: 259 (3200, EtOH).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-cyanomethanesulfonylaminoethanesulfonylamino)-acetic acid.

6.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfo-ylamino)-acetic acid is reacted in 25 ml of tetrahydrofuran with 1.5 ml of cyanomethylsulfochloride analogously to example 6 c) (10 ml N,0-bis(trimethylsilyl)-acetamide, 0.81 ml pyridine) and worked up. The title compound is obtained, which without characterization is further processed.

Example 42.

a) 7 3-[(2R,S)-2-(2-methylaminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

3.4 g of the 73-[(2R,S)-2-(2-methylaminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido)-3-cephem- 4-carboxylic acid diphenyl methyl ester is dissolved in 10 ml of methylene chloride, 1.3 ml of anisole and 62 ml of trifluoroacetic acid are successively added to the solution, and then stirred under the exclusion of atmospheric moisture for 1 hour at room temperature.

From the initially clear solution, a voluminous precipitate precipitates. The suspension is then poured onto an ice-cold mixture of petroleum ether (600 ml) and diethyl ether (300 ml), the precipitated trifluoroacetate is suctioned off, washed with petroleum ether and dried in high vacuum at room temperature. The crude trifluoroacetate salt is then dissolved in 20 ml of ethanol-water (1:1) mixture, the solution is cooled to +5°, and adjusted to a pH value of 5.0 by dropwise addition of 2N sodium hydroxide solution while stirring and cooling.

The solution is then poured into 600 ml of ethanol, and evaporated on a rotary evaporator at 50° to approx. 100 ml volume. This operation is repeated twice, each time adding 300 ml of ethanol, whereby the amorphous product precipitates out. It is suctioned off and washed successively with ethanol, a mixture of ethanol-diethyl ether and diethyl ether. The hydrate of the title compound is obtained. F: cleavage from 190°. [alp<0>= +91°±1° (1.138% in 0.1 N HCl). IR: 3320 (wide), 3195, 3120, 1775 (shoulder), 1765, 1690 (shoulder), 1680 (shoulder' 1670, 1640 (shoulder), 1615 (wide), 1520,

1380, 1350, 1150, 1120 (shoulder), (in Nujol).

Rf (silica gel): 0.23 (n-butanol-pyridine-acetic-water 42:24:4:30). b) 73-[(2R,S)-2-(2-methylaminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

A solution of 5.7 g of 73-[(2R,S)-2-(2-(N-methyl-2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl )-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester in 100 ml of acetonitrile-acetic acid (1:1) mixture is added with stirring to 3.2 g of zinc dust and stirred vigorously for 3 hours at room

(R)

temperature. The suspension is then filtered through Celite v<->~, the filter residue is washed once more with acetonitrile and the filtrate is evaporated on a rotary evaporator at 45° to approx. 20 ml volume. The solution is diluted with ethyl acetate, and washed successively with water and 1 N sodium hydrogen carbonate solution (pH 8) several times, dried over sodium sulfate and evaporated on a rotary evaporator at 4 5°. The crude product is purified by chromatography on 25 times the quantity of silica gel. Eluent: methylene chloride-methanol-(97:3). Thereby the title compound is obtained as a foam. Rf (silica gel): approx. 0.45 (methylene chloride/methanol 9:1). IR: 3280 (wide), 1785, 1720, 1690 (shoulder), 1635, 1545, 1380 (shoulder), 1370, 1330, 1185,

1145 (Nujol).

c) 7 3-[( 2R, S )- 2 -( 2 -( N- methyl- 2, 2, 2- trichloroethoxycarbonylamino )- ethanesulfonylamino)- 2-( 2- BOC- amlnothiazol-4- yl)- acetamido] - 3- cephem- 4- carboxylic acid diphenyl methyl ester.

A solution of 4.50 g of (2R,S)-2-[2-(N-methyl-2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino]-2-(2-BOC-aminothiazol-4-yl)- acetic acid, 2.58 g of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester and 0.65 g of 1-hydroxy-benztriazole in 52 ml of tetrahydrofuran are cooled to +2°, a solution of 0.82 g of N,N<1 ->dicyclohexylcarbodiimide in 7 ml of tetrahydrofuran is added dropwise over 10 minutes and the reaction mixture is stirred in an ice bath. After 3 hours, a new solution of 0.82 g of N,N'-dicyclohexylcarbodiimide in 7 ml of tetrahydrofuran is added dropwise to the reaction mixture. After stirring for a total of 6 hours at 0°, the suspension is filtered off with suction, the residue is washed with ethyl acetate, the filtrate is diluted with ethyl acetate, washed several times with 1 N sodium bicarbonate solution and water, dried over sodium sulfate and evaporated on a rotary evaporator at 4 5°. The crude product is purified by chromatography on a 20-fold amount of silica gel. Eluent: methylene chloride with 2-5% methyl acetate. The title compound is obtained as a foam. DC (silica gel, identification: UV 366). Rf = approx. 0.60 (double stain-diastomer mixture-toluene-ethyl acetate-1:1). IR: 3280 (wide), 1790, 1725, 1690 (shoulder), 1640, 1565 (shoulder), 1550, 1380, 1335, 1190, 1155 (Nujol).

Preparation of the starting material:

d) (2R,S)-2-[2-(N-methyl-2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino]-2-(2-BOC-aminothiazol-4-yl)-acetic acid.

A suspension of 5.0 g of (2R,S)-2-amino-2-(2-BOC-aminothiazol-4-yl)-acetic acid in 80 ml of acetonitrile-methylene chloride 1:1 mixture is added to 18.5 ml of N ,0-bis-'(trimethylsilyl)-acetamide and stirred under exclusion of moisture at room temperature, whereby the acid dissolves slowly. After stirring for 1 hour, the clear solution is cooled to 0°, and 4.0 ml of absolute pyridine is added. A solution of 9.0 g of 2-(N-methyl-2,2,2-trichloroethoxycarbonylamino)-ethanesulfonyl chloride in 20 ml of methylene chloride is added dropwise with stirring and cooling during 30 minutes, and the reaction mixture is stirred for 1.5 hours at room temperature . The suspension is then diluted with ethyl acetate, evaporated somewhat, washed twice each time with 30 ml of 1 N hydrochloric acid (pH approx. 2), and twice with soda solution, dried over sodium sulfate and evaporated on a rotary evaporator at 50°. The crude product is purified by chromatography on a 20-fold amount of silica gel. Eluent: methylene chloride with 10-30% methyl acetate. The title compound is obtained as a foam. DC (silica gel, identification: UV 366 nm). Rf= 0.48 (methylene chloride-methanol-4:1).

IR: 3200 (broad), 1715 (broad), 1680 (shoulder), 1540, 1370, 1324, 1185, 1145 (in methylene chloride). e) 2-(N-methyl-2,2,2-trichloroethoxycarbonylamino)-ethanesulfochloride.

A suspension of 50 g of 2-methylaminoethanesulfonic acid (prepared according to the prescription of B.Josephsch, Biochemische Zeitschrift, Berlin, 265, 448 (1933) - CA 28: 7909 (1934) in 1400 ml of pyridine is cooled to +10°. 50 ml of chloroformic acid- 2,2,2-trichloroethyl ester is added dropwise over the course of 40 minutes with vigorous stirring and cooling between +10 and +15°, and the mixture is stirred for 18 hours at room temperature.

the tion through Celite ^and the residue is washed with pyridine. The filtrate is evaporated on a rotary evaporator at 55°, the oily residue is added to toluene several times, whereby the pyridinium salt of 2-(N-methyl-2,2,2-trichloroethoxycarbonylamino)-ethanesulfonic acid precipitates crystalline. This is mixed with petroleum ether, suctioned off and washed with petroleum ether. F: 77-85°

(under cleavage).

A solution of 76 g of 2-(N-methyl-2,2,2-trichloroethoxycarbonylamino)-ethanesulfonic acid-pyridinium salt in 380 ml of chloroform is added with vigorous stirring over the course of 30 minutes at room temperature in portions to 38 g of phosphorus pentachloride, whereby the temperature rises to 35 -4 0° during chlorine hydrogen evolution.

The reaction mixture is then heated for 3 hours at reflux, the solution is cooled to +5°, diluted with 200 ml of benzene, washed with 150 ml of ice-cold water, dried over sodium sulfate and evaporated on a rotary evaporator at 55°. The remaining, semi-solid mass is mixed with 300 ml of diethyl ether,

the precipitated crystals (by-product) are suctioned off, and the rest is

kes with a little diethyl ether. The filtrate is evaporated on a rotary evaporator at 55°. The oily 2-(N-methyl-2,2,2-trichloroethoxycarbonylamino)-ethanesulfonyl chloride remains. IR: 1715, 1620 (shoulder), 1370, 1180, 1160 (in methylene chloride).

Example 43.

a) 73-[(2R,S)-2-(2-Methoxyethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid. Analogous to example 42 a), the hydrate of the title compound is obtained by treating 1.8 g of 73_[(2R,S)-2-(2-methoxyethane-sulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido ]-3-cephem-4-carboxylic acid diphenyl methyl ester (prepared according to example 4 2 b) with 50 ml of trifluoroacetic acid and 0.8 ml of anisole o 2 0^ in 5 ml of methylene chloride. F: over 180 (fission). ta3D = +96°±1° (1.955% in H20), IR: 3320 (broad), 3210, 1775 (shoulder), 1765 (broad), 1705 (shoulder), 1680, 1605, 1520, 1375, 1365, 1160 , 1145 (in Nujol), DC (silica gel, identification: UV 366 nm): Rf = 0.39 (n-butanol-pyridine-glacial acetic-water-42:24:4:30). b) 73-[(2R,S)-2-(2-Methoxyethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

By reacting 3.0 g of (2R,S)-2-(2-methoxyethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid with 2.6 g of 73-amino-3-cephem-4 -carboxylic acid diphenyl methyl ester in the presence of 0.55 g of 1-hydroxybenzotriazole and 1.54 g of N,N<1->dicyclohexylcarbodiimide in 45 ml of tetrahydrofuran, the title compound is obtained. The crude product is purified on a 20 times larger quantity of silica gel. Eluent: methylene chloride-methyl acetate-(9:1).

DC (silica gel, identification: UV 366 nm): Rf = 0.58 (double spot diastereomer mixture system: toluene-chloroform-ethyl acetate-ethanol-32:32:32:5).

Preparation of the starting material:

c) ( 2R, S )- 2-( 2- methoxyethanesulfonylamino)- 2-( 2- BOC- aminothiazol-4-yl-acetic acid. A solution of 5.4 g of (2R,S)-2-(2-methoxyethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid methyl ester in 45 ml of methanol is added to 11 ml of 2 N sodium hydroxide solution and stirred at room temperature . After a reaction time of 2.5 hours, a further 6 ml of 2 N sodium hydroxide solution is added. After a total of 5 hours of reaction time, the pH value of the clear solution is adjusted to 7.5<*> by dropwise addition of 1 N hydrochloric acid and the largest part of the methanol is evaporated on a rotary evaporator at 50°. The aqueous solution is then cooled to 0°, covered with ethyl acetate, acidified with stirring by adding 20% aqueous citric acid (pH 2.5-3.0) and extracted twice with ethyl acetate. The organic extracts are combined, washed twice with a little soda solution, dried over sodium sulphate and evaporated on a rotary evaporator at 50°. The crude product is purified by chromatography on a 20 times greater amount of silica gel. Eluent: methylene chloride with 30-40% methyl acetate. Thereby the title compound is obtained as a yellow foam. DC (silica gel, identification: UV 366 bm), Rf = 0.47 (n-butanol-glacial acetic-water 67:10:23), IR: 3320 (broad), 3300 (shoulder), 2950, 1770 (shoulder), 1730, 1570 (shoulder), 1550, 1390, 1370, 1140, 1110 (in methylene chloride) d) ( 2R, S )- 2-( 2- methoxyethanesulfonylamino)- 2-( 2- BOC-amino thiazol-4-yl) - acetic acid methyl ester.

A solution of 5.0 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-glycine methyl ester in 40 ml of dioxane and 10 ml of N-methylmorpholine is cooled to +2°. A solution of 30 ml of 2-methoxyethanesulfonyl chloride (prepared according to the prescription of A.S. Matlack, J.org.Chem. 23, 729 (1958)) in 20 ml of dioxane is added dropwise during 20 minutes with stirring and cooling, and the reaction mixture is stirred in 2.5 hours at room temperature. The suspension is evaporated to half the volume on a rotary evaporator at 50°, diluted with ethyl acetate, with water, 20%-id aqueous citric acid (pEK3) and washed 3 more times with some water, and dried over sodium sulf at. After evaporation of the solvent on a rotary evaporator at 50°, the title compound remains as a yellow foam. DC (silica gel: identification<1>UV 366 nm): Rf = 0.54 (toluene-chloroform-ethyl acetate-ethanol-32: 32:32:5) IR: 3390, 3260, 1740 (shoulder), 1720, 1535, 1370, 1330, 1185 (shoulder), 1125 (in methylene chloride).

Example 44.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-cyanomethane-sulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt.

4.3 g of 73-t(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-cyanomethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester are reacted in 20 ml of CH2C12 and 1.4 ,1 anisole with 15 ml of trifluoroacetic acid analogously to example 1 a), is worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained.

F: above 230° (decomposition). [a]^° = +99°±1° (0.90% in H2O).

IR: 3700 to 2500, 2260, 1755, 1675, 1600, 1520 (Nujol),

UV: 250 (9200), 320 (700, H20). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-cyano-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester.

3.9 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-cyanomethanesulfonyl-amino acetic acid and 3.8 g of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 45 ml of tetrahydrofuran analogously to example 6b) (1.35 g of hydroxybenztriazole, 3 times 0.66 g of dicyclohexylcarbodiimide in each time 8 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved.

[a]^° = +14°±1° (0.92% in CHC13), IR: 3400, 3300, 2260

(weak), 1780, 1720, 1700, 1635, 1530 (CH2C12), UV: 259

(14000, EtOH).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-cyanomethanesulfonylaminoacetic acid.

3.4 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetic acid is reacted in 30 ml of CH2Cl2 with 2.6 g of cyanomethylsulfochloride analogously to example 6 c) (10 ml of N,0-bis -(trimethylsilyl)-acetamide, 1.0 ml pyridine) and worked up. The title compound is obtained, which without characterization is further processed.

Example 45.

a) 73-[( 2R, S)- 2-( 2- aminothiazol-4-yl)- 2-( 2-(( 3R)- 3-amino- 3- carboxypropionylamino)- ethanesulfonylamino)-acetamido]- 3- cephem-4-carboxylic acid sodium salt.

3.1 g 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-((3R)-3-BOC-amino-3-t.-butoxycarbonylpropionylamino) -ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 7.5 ml of CH2C12 and 5 ml of anisole with 60 ml of trifluoroacetic acid analogously to example 1 a), worked up and reprecipitated. The hydrate of the title compound is obtained. F: above 210°

(fission). [a]^° = +89°±1° (0.84% in H2O). IR: 3700 to 2500 (broad), 1760, 1640, 1600, 1520 (Nujol), UV: 252

(9200), 316 (660, H 2 O). b) 73-[( 2R, S)- 2-( 2- BOC-aminothiazol-4-yl)- 2-( 2-(( 3R)-3- BOC- amino- 3- t.- butoxycarbonylpropionylamino)-ethanesulfonylamino )- acetamido]- 3- cephem- 4- carboxylic acid sodium salt.

0.5 g 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester (preparation see example 35 c)) is converted with 0.22 g

(3R)-3-BOC-amino-3-t.butoxycarbonylpropionic acid in 2.5 ml of tetrahydrofuran analogously to example 6b) (70 ml of hydroxy-benztriazole, 3 times 60 mg of dicyclohexylcarbodiimide in each time 0.5 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. [α]p0 = +32°±1° (0.96% in CHCl 3 ), IR: 3400, 3280, 1780. 1705, 1675, 1530 (CH 2 Cl 2 ), UV: 257 (14000, EtOH).

Example 46.

a) 7 3-[( 2R, S)- 2-( 2- aminothiazol-4- yl)- 2-( 2- pivaloyl-aminoethanesulfonylamino)- acetamido] - 3- cef em- 4 -

carboxylic acid sodium salt.

1.62 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-pivalol-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 3.6 ml CH2C12 and 1.13 ml anisole with 13.5 ml trifluoroacetic acid analogously to example 1 a), are worked up and reprecipitated. The hydrate of the title compound is obtained. F: above 144° (decomposition). [a]^<0>= +92°±1° (0.69% in H2O). IR: 3700 to 2700 (broad), 1755, 1675 (shoulder) 1657, 1616, 1522 (Nujol), UV 250 (9700, H20). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-pivaloulaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

2.06 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(.2-pivaloylamino-ethanesulfonylamino)-acetic acid is reacted with 1.6 g of 73-amino-3-cephem- 4-carboxylic acid diphenylmethyl ester in 17 ml of tetrahydrofuran analogous to example 6b) (0.45 g of hydroxybenztriazole, 3 times 0.39 g of dicyclohexylcarbodiimide in each time 3.4 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. = +20°±1° (0.69% in CHC13) , IR: 3450 , 3400, 3280, 1780. 1715, 1695, 1650, 1520 cm"<1>(CH2C12),

UV: 258 (14000, EtOH).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-pivaloyl-aminoethanesulfonylamino)-acetic acid.

8.5 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid is reacted in 30 ml of tetrahydrofuran with 1.56 ml of pivalic acid chloride analogously to example 6 c) (12.5 mg N,0-bis-(trimethylsilyl)-acetamide, 1.03 ml pyridine) and worked up. The title compound is obtained, which without characterization is further processed.

Example 47.

a) 73-[( 2R, S)- 2-( 2- aminothiazol-4-yl)- 2-( 2-(( 2R)- 2-amino- 2- phenylacetamido)- ethanesulfonylamino)- acetamido] - 3- cephem-4-carboxylic acid. 2.1 g 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-((2R)-2-BOC-amino2-phenylacetamido)-ethanesulfonylamino)-acetamido ]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 10 ml CH2Cl2 and 0.57 ml anisole with 15 ml trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 24 0° (during cleavage). [a]^° = +57°±1° (0.97% in H20), IR: 3700 to 2500 (broad), 1760, 1670, 1600, 1522 (Nujol), UV: 251 (9200), 320 ( 1000, H 2 O). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-((2R)-2-BOC-amino-2-2-phenylacetamido)-ethanesulfonylamino )-adetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester. 1 g 73-[(2R,S)-2-)2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester (preparation see example 35 c) ) is reacted with 0.34 g of N-BOC-(D)-phenylglycine in 15 ml of tetrahydrofuran analogously to example 6 b) (0.18 g of hydroxybenztriazole, 3 times 0.09 g of dicyclohexylcarbodiimide in each time 2 ml of tetrahydrofuran), worked up and chromatographed. The title compound is achieved.

[ct]p = -3 ±1° (0.99% in CHCl3). IR: 3400, 3300, 1790 , 1725, 1680, 1639, 1600, 1541 cm"<1>(CH 2 Cl 2 ). UV: 250 (13100, EtOH).

Example 48.

a) 7&-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2-aminoacetamido)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. 1.9 g 73-[(2R,S)-2-)2-BOC-aminothiazol-4-yl)-2-(2-(2-BOC-aminoacetamido)-ethanesulfonylamino)-acetamido]-3-cephem- 4-carboxylic acid diphenyl methyl ester is reacted in 10 ml CH2C12 and 0.57 ml anisole with 15 ml trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: over 2 30° (cleavage). [a]^0 = +78°±1° (0.92% in HCOOH), IR: 3700 to 2500, 1765, 1685, 1654, 1611, 1542, 1529cm-1 (Nujol), UV: 252 (9500) , 318 (300, H 2 O). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(2-BOC-aminoacetamido)-ethanesulfonylamino)-acetamido]-3-ce fem-4 - vessel book sewn in feny1me ty1e ster.

3.1 g 73-[(2R,S)-2-(2-BQC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester (preparation see example 35 c) react with 0.74 g of N.BOC-glycine in 45 ml of tetrahydrofuran analogously to example 6b) (0.56 g of hydroxybenztriazole, 3 times 0.2 9 g

dicyclohexylcarbodiimide in each time 6 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved.

[a]p° = +24°±1° (1.00% in CHC13), UR: 3400, 3300, 1790, 1725, 1690, 1640, 1542cm~<1>(CH2Cl2), UV: 259 (14000, EtOH).

Example 49.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyalyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 1.7 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyalyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 8 ml CH2CL2 and 0.43 ml anisole with 12 ml trifluoroacetic acid analogous to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F:* above 200° (during cleavage) . [a]J° = +73°+1° (0.89% in H 2 O), IR: 3700 to 2600 (broad), 1760, 1685, 1600, 1525 (Nujol). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyalylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

3.2 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyalylamino-ethanesulfonylamino)-acetic acid is reacted with 2.48 g of 73-amino-3-cephem-4 -carboxylic acid diphenylmethyl ester in 26.2 ml of tetrahydrofuran analogous to example 6b) (0.69 g of hydroxybenztriazole, 3 times 0.6 g of dicyclohexylcarbodiimide in each time 5.2 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. [oOq = +17°±1 (0.84% in CHCl 3 ).

IR: 3400, 3300, 1788, 1725, 1705, 1637, 1602, 1540 (CH 2 Cl 2 ), UV: 250 (9200, EtOH).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyalyl-aminoethanesulfonylamino)-acetic acid. 6.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid is reacted in 24 ml of tetrahydrofuran with 0.92 ml of oxalic acid monomethyl ester chloride analogously to example 6 c) (16 ml of N,0-bis-(trimethylsilyl)-acetamide, 0.81 ml of pyridine) and worked up. The title compound is obtained, which is further processed without characterization.

Example 50.

a) 7 B - [ ( 2R, S) - 2 - ( 2 - aminothiazol - 4 - yl) -2 - ( 2 - me toc cy-malonylaminoethanesulfonylamino)- acetamido]- 3- cephem-4- carboxylic acid sodium alt. 2.817 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxy-malonylaminoethanesulfonylamino)*-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 6 ml of CH2C12 and 1.92 ml of anisole with 22 ml of trifluoroacetic acid analogous to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 165° (during cleavage). [a]D = +94°±1° (0.75% in H20), IR: 3700 to 2600 (broad), 1765, 1665, 1606, 1525, 1525 (Nujol), UV: 252 (9800, H2) . b) 7B-[( 2R, S)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2- methoxy-malonylaminoethanesulfonylamino)- acetamido]- 3- cephem-4- carboxylic acid diphenyl methyl ester. 4.18 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxymalonyl-aminoethanesulfonylamino)-acetic acid is reacted with 2.9 g of 73-amino-3-cephem-4 -carboxylic acid diphenylmethyl ester in 25 ml of tetrahydrofuran analogous to example 6b) (0.87 g of hydroxybenztriazole, 3 times 0.76 g of dicyclohexylcarbodiimide in each time 5 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. [a]^° = +23°±1° (0.82% in CHCl3). IR: 3400, 3300, 1778, 1710, 1696, 1520 (CH 2 Cl 2 ), UV: 257 (14400, EtOH).

Production of the starting material.

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxy-malonylaminoethanesulfonylamino)-acetic acid.

6.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonyl amino)-acetic acid is reacted in 24 ml of tetrahydrofuran with 1.07 ml of malonic acid monomethyl ester chloride analogously to example 6 c ) (10

ml of N,0-bis-(trimethylsilyl)-acetamide, 0.81 ml of pyridine) and worked up. The title compound is obtained, which is further processed without characterization.

Example 51.

a) 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-bromoacetyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium sa. Lt. 1.5 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-bromoacetyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 8 ml of CH2C12 and 0.4 ml of anisole with 12 ml of trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 220° (during cleavage). IR: i.a. 1770 (New Year). UV: 253 (11100, H 2 O). b) 7 3 ~[( 2 R, S)- 2-( 2- BOC-aminot ia zol- 4- y1)- 2 -( 2- bromo-acetylaminoethanesulfonylamino)- acetamido]- 3- cephem-4- carboxylated i phenylmethyl st is. 3.3 g of (2R,S)-2-(2-BOC-amino.thiazol-4-yl)-2-(2-bromoacetylamino-ethanesulfonylamino)-acetic acid is reacted with 2.38 g of 73-amino-3-cephem -4-carboxylic acid diphenylmethyl ester in 25 ml of tetrahydrofuran analogous to example 6b) (0.66 g of hydroxybenztriazole, 3 times 0.76 g of dicyclohexylcarbodiimide in each time 5 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. IR: 3400, 3300, 1790, 1735, 1682, 1630, 1535 cm<-1>(CH 2 Cl 2 ), UV: 256 (14500, EtOH).

Preparation of the starting material: c)( 2RyS)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2- bromoacetyl- aminoethanesulfonylamino)- acetic acid.

6.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-iminoethanesulfonylamino)-acetic acid is reacted in 24 ml of tetrahydrofuran with 0.82 ml of bromoacetic acid bromide analogously to example 6c ) (16 ml N,0-bis-(trimethylsilyl-acetamide, 0.81 ml pyridine) and worked up. The title compound is obtained, which is further worked up without characterization.

Example ' 52.

73-[( 2R , S )- 2-( 2- aminothiazol-4-yl)- 2 -( 2-( 2 -( i -thy 1 -1H -tetra sol -5 -ylthio) -acetamido) - e t an su 1 f o -hylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

1.5 g of the 70-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-bromoacetylaminoethanesulfonylamino-ethanesulfonylamino)-acetamido]-3-cephem- 4-carboxylic acid sodium salt is added to 30 ml of water with 245 mg of 1-methyl-1H-mercapto-tetrazole sodium salt and stirred for 3 hours at room temperature, whereby the pH is kept constant at pH 7 by the addition of 1 N caustic soda. It is then evaporated in a vacuum, chromatographed and reprecipitated according to example 1 a). The hydrate of the title compound is obtained. F: above 172° (during cleavage). IR: 3700 to 2700 (broad), 1760, 1650, 1600, 1530cm<-1>(Nujol). UV: 252 (8900, H20)

Example'' 53 .

a) 73-(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxy-succinylaminoethanesulfonylamino)-acetamido]-3-cephem-'; 4 - vessel bo xy l sy r e - n a t r lum s a l t.

1.5 g 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxysucciniyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxyl -

acid diphenyl methyl ester is reacted in 4 ml CH2C12 and 0.4 3 ml anisole with 10 ml trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 210 o (decomposition). 2 0^= +89°±1°

(0.97% in CHC13), IR: 3650 to 2700 (broad), 1765, 1730, 1650, 1600, 1525 (NUjol), UV: 252 (9700), 310 (600, H20).

b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxy-succinylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 4.2 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxysuccinyl-aminoethanesulfonylamino)-acetic acid is reacted with 3.1 g of 73-amino-3-cephem -4-carboxylic acid diphenylmethyl ester in 45 ml of tetrahydrofuran analogous to example 6 b) (1.1 g of hydroxybenztriazole, 3 times 0.58 g of dicyclohexylcarbodiimide in each time 6.6 ml of tetrahydrofuran), is worked up and chromatographed. The title connection opnos. [<x]^° = +16°±1° (1.00% in CHCl 3 ), IR: 3400, 3300, 1790, 1730, 1680, 1630,.1543 (CH 2 Cl 3 ). UV: 255 (12700, EtOH).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxy-succinylaminoethanesulfonylamino)-acetic acid.

6.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid is reacted in 25 ml of tetrahydrofuran with 1.22 ml of succinic acid monomethyl ester chloride analogously to example 6 c)

(10 ml N,0-bis-(trimethylsilyl)-acetamide, 0.81 ml pyridine) and worked up. The title compound is obtained, which is further processed without characterization.

Example 54.

a) 73~[ ( 2R, S) - 2-( 2- aminothiazol-4 - yl) - 2-( 2- hydroxy-malonylaminoethane sulfonylamino)- acetamido]- 3-

cephem-4-carboxylic acid disodium salt.

3.3 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-t.-butoxy-malonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 6.7 ml of CE^Cl^ and 2.15 ml of anisole with 25 ml of trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 200° (during cleavage).

[<x]p° = +93°±1° (0.76% in H 2 O), IR: 3700 to 2600 (broad), 1762, 1645, 1595, 1525, (Nujol). UV: 253 (1600), 214 (200, H 2 O) . b) 7 p-[( 2 R , S )- 2 -( 2- BOC- aminot iazo l- 4- yl )- 2 -( 2 - t.-butoxymalonylaminoethane sulfonylamino)- acetamido]-3-ce'f em-4-carboxylic acid dif enylme tyl ester . 6 g 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester (preparation see example 35 c)), reacted with 1.5 g of malonic acid mono-t-butyl ester in 25 ml of tetrahydrofuran analogously to example 6b) (0.93 g of hydroxybenztriazole, 3 times 0.82 g of dicyclohexylcarbodiimide in each time 5 ml of tetrahydrofuran), worked up and chromatographed. The title compound is achieved.

[a]p° = +25°±1° (0.79% in CHC13), IR: 3400, 1785, 1720, 1675, 1635, 1602, 1535cm~<1>(CH2C12), UV: 258 (13700, EtOH).

Example 55.

a) 73~[( 2R, ff )- 2-( 2-aminothiazol-4-yl)- 2 -( 2 -( 4- nitro-benzoylamino)- ethanesulfonylamino)- acetamido]- 3-cephem- 4- carboxylic acid sodium salt.

2.6 g 73~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(4-nitrobenzo-oylamino)-ethanesulfonylamino)-acetamido]-3-cephem- 4-carboxylic acid diphenyl methyl ester is reacted in 6 ml of CH2C12 and 0.76 ml of anisole with 10 ml of trifluoroacetic acid analogously to example 1 a), oppar-

beedes, chromatographed and reprecipitated. The hydrate of the title for-o 2 0^ bond is obtained. F: above 220 (during cleavage). ^ a^ Q = /79°±1° (1.18% in H 2 O). IR: 3650 to 2600 (broad), 1765, 1670, 1650, 1598, 1525 (Nujol), UV: 259 (18700, H20). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(4-nitrobenzoylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(4-nitrobenzoyl-amino)-ethanesulfonylamino)-acetic acid is reacted with 3.6 g of 73~amino-3 -cef em-4-carboxylic acid phenyl methyl ester in 60 ml of tetrahydrofuran analogously to example 6b) (1.3 g of hydroxybenztriazole, 3 times 0.66 g of dicyclohexylcarbodiimide in each time 6.6 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. [a]^° = +14°+1° (0.95% in CHCl 3 ). IR: 3400, 3300, 1787, 1725, 1692, 1670, 1650, 1600, 1530 (CH 2 Cl 2 ). UV: 259 (23200, EtOH).

Preparation of the starting material:

c) (2R,S)-g-(2-BOC-aminotaizol-4-yl)-2-(2-(4-nitro-benzoylamino)-ethanesulfonylamino)-acetic acid.

6.7 g of (2R, S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid is reacted in 25 ml of tetrahydrofuran with 3.7 g of p-nitrobenzoyl chloride analogously to example 6c) (10 ml N,0-bis-(trimnylsilyl)-acetamide, 0.81 ml pyridine) and worked up. The title compound is obtained, which is further processed without characterization.

Example 56.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(4-acetamidobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 29 a), the title compound is obtained as 2,5-hydrate by reaction of 1.4 g (1.5 mmol) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)- 2-(2-(4-acetamidobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1.4 ml of anisole and 7 ml of trifluoroacetic acid in 7 ml of methylene chloride. F: above 185° (during cleavage). Rf: approx. 0.45 (silica gel "Opti-UPC 12", water-acetonitrile 4:1).

UV: 256 (28700, water). b) 7B-[( 2R, S)- 2-( 2- BOC-aminothiazol-4- yl)- 2-( 2-( 4- acetamidobenzenesulfonylamino)- ethanesulfonylamino)-acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester . Analogous to example 2 9 b), the title compound is obtained as a pale yellow, amorphous powder by treating 1.44 g (2.5 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-( 2-(4-acetamidobenzene-sulfonylamino)-ethanesulfonylamino)-acetic acid with 0.92 g (2.5 mmol) of 73-amino3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.34 g of 1-hydroxybenztriazole and 0.57 g N,N'-dicyclohexylcarbodiimide in 27 ml of tetrahydrofuran. Rf: approx. 0.10 (silica gel, methylene chloride-ethyl acetate 1:1).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(4-acetamidobenzenesulfonylamino)-ethanesulfonylamino)-acetic acid.

A suspension of 3.8 g (10 mmol) of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid in 100 ml of absolute tetrahydrofuran is added with stirring, moisture exclusion and nitrogen atmosphere 10 ml of N,O-bis(trimethylsilyl)-acetamide. After a reaction time of 1 hour at 65°, the reaction mixture is cooled to 0°, 0.88 ml of pyridine and 2.65 g of 4-acetamidobenzene sulphochloride are added and then stirred for 20 hours at room temperature. After removal of the solvent, the residue is taken up in 300 ml of ethyl acetate and washed 3 times each with 0.1 N hydrochloric acid and saturated aqueous sodium chloride solution. After drying over sodium sulfate, the solvent is removed on a rotary evaporator, and the residue is purified on silica gel with ethyl acetate-methanol 4:1 as eluent, from which the title compound is obtained as an amorphous powder. DC (silica gel) Rf: approx. 0.23 (chloroform-methanol-glacial acetic acid 75:23:3).

Example 57.

a) 7[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-isopropane-sulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 0.4 g of 73-[(2R,SI-2-(2-BOC-aminothiazol-4-yl)-2-(2-isopropanesulfonylaminoethanesulfonylamino)-acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 0, 84 ml of CH2C12 and 0.27 ml of anisole with 3.13 ml of trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 175° (under cleavage), IR: 3700 to 2700 (broad), 1762, 1680, 1602, 1520 (Nujol), UV: 250 (9800), 310 (1100, H20). b) 7P-[(2R,S)-2-(2-BOC.aminothiazol-4-yl)-2-(2-isopropanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 3.2 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-isopropanesulfonylaminoethanesulfonylamino)-acetic acid is reacted with 2 g of 73-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 15 ml of tetrahydrofuran analogous to example 6b) (0.6 g of hydroxybenztriazole, 3 times 0.52 g of dicyclohexylcarbodiimide in each time 4 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. IR: 3405, 3290, 1781, 1720, 1678, 1520 (CH 2 Cl 2 ), UV: 259 (13800, EtOH).

Preparation of the starting materials:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-isopropane-.i sulfonylaminoethanesulfonylamino)-acetic acid.

8.3 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid is reacted in 30 ml of CH2Cl2 with 2.66 g of isopropane sulfochloride analogously to example 6 c) ( 10 ml N,0-bis-(trimethylsilyl)-acetamide, 1.01 ml pyridine) and worked up. The title compound is obtained, which is further processed without characterization.

Example 58. a). - acetamido]- 3- cephem- 4- carboxylic acid sodium salt.

Analogous to example 29 a), the title compound is obtained as a dihydrate by reaction of 2.0 g (2.23 mmol) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2 -(4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 2.0 ml of anisole with 10 ml of trifluoroacetic acid in 10 ml of methylene chloride. F: above 170° (during cleavage). DC (silica gel-"Opti UPC12"): Rf: approx. 0.31 (water-acetonitrile 8:2). [a]^° = +83°±1° (1.303% in H 2 O), UV: 240 (14600, H 2 O). b) 73-[( 2R, S )- 2-( 2- BOC- aminothiazol-4-yl)- 2-( 2-( 4-ethyl- 2, 3- dioxopiperazin-1- ylcarbonylamino)-ethanesulfonylamino)- acetamido ]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogous to example 29 b), the title compound is obtained as a yellowish powder by treating 2.20 g (4 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(4- ethyl-2,3-dioxopiperazin-l-ylcarbonylamino)-ethanesulfonylamino)-acetic acid with 1.46 g of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.54 g of 1-hydroxybenztriazole and 0.91 g N,N'-dicyclohexylcarbodiimide in 40 ml of tetrahydrofuran. DC (silica gel): Rf: approx. 0.10 (ethyl acetate).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino)-ethanesulfonylamino)-acetic acid.

A suspension of 3.8 g (10 mmol) of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid in 50 ml of absolute tetrahydrofuran is added with stirring, moisture exclusion and nitrogen atmosphere 5 ml N,0-bis(trimethylsilyl)-acetamide. After 1 hour's reaction time at 65°, the reaction mixture is cooled to room temperature, 2 ml of pyridine and 5.12 g of 4-ethyl-2,3-dioxo-piperazin-1-ylcarbonyl chloride are added and then stirred for 5 hours. After removal of the solvent, the residue is taken up in 250 ml of ethyl acetate and washed 3 times with each of 1 N hydrochloric acid and saturated aqueous sodium chloride solution. After drying over sodium sulfate, the solvent is removed on a rotary evaporator, from which the title compound is obtained as an amorphous powder. DC (silica gel). Rf: approx. 0.18 (chloroform-methanol-glacial vinegar 75:22:3).

Example 59.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-isopropane-sulfonylaminoacetamido]-3-cef em-4-carboxylic acid sodium salt.

0.89 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-isopropane-sulfonylaminoacetamido]-2-dephen-4-carboxylic acid diphenyl methyl ester is reacted in 2.15 ml of CH2C12 and 0.69 ml of anisole with 8 ml of trifluoroacetic acid analogously to example 1 a), are worked up and reprecipitated. The hydrate of the title compound is obtained. F: above 220° (during cleavage). [oi]q<0>= +95°±1° (0.19% in H 2 O) .

IR: 3700 to 2600 (broad), 1760, 1680, 1605, 1522 (Nujol).

UV: 250 (10000), 310 (1500, H20). b) 7g-[(2R,S)-2-(2-BOC-aminothiazol)-4-yl)-2-isopropanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester.

2.99 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-isopropanesulfonyl-aminoacetic acid are reacted with 2.4 g of 73-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 18 ml tetrahydrofuran analogous to example 6b) (0.72 g hydroxybenztriazole, 3 times 0.62 g dicyclohexylcarbodiimide in each time 5 ml tetrahydrofuran), is worked up and chromatographed. The title compound is achieved.

[a]p° = +16°±1° (0.83% in CHCl 3 ), IR: 3400, 3300, 1780, 1715, 1675, 1522 (CH 2 Cl 2 ). UV: 258 (14200, EtOH).

Production of the starting material.

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-isopropanesulfonylaminoacetic acid.

3.4 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetic acid is reacted in 30 ml of CH2C12 with 2.66 g of isopropane sulfochloride analogously to example 6 c) (10 ml of N,0- bis-(trimethylsilyl)-acetamide, 1.01 ml pyridine) and worked up. The title compound is obtained, which is further processed without characterization.

Example 60.

a) 7j3-[(2R,S)-2-(2-aminothiazol-4-yl)-2-n-octylsulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 29 a, the title compound is obtained in the form of the dihydrate by reaction of 3.03 g (3.8 mmol) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-n .octylsulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 3 ml

anisole and 15 ml of trifluoroacetic acid in 15 ml of methylene chloride^

F: above 172° (during cleavage) . Rf 96: approx. 0.55, [a]^ = +81°±1° (1.042% in ethanol-water 1:1). UV: 252 (9100 in ethanol-water 1:1). b) 7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-n.octyl-sulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogously to example 29 b), the title compound is obtained as a yellowish powder by treating 2.25 g (5 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-n.octylsulfonylaminoacetic acid with 1 .83 g (5 mmol) of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.68 g of 1-hydroxybenztriazole and 1.14 g of N,N'-dicyclohexylcarbodiimide in 50 ml of tetrahydrofuran.

Rf: approx. 0.61 (silica gel, methylene chloride-ethyl acetate 1:1).

Preparation of the starting material:

c) ( 2R, S)- 2-( 2- BOC-aminothiazol-4- yl)- 2- n. octylsulfonylaminoacetic acid♦

A suspension of 2.73 g (10 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetic acid 8 30 ml absolute tetrahydrofuran is added under stirring, moisture exclusion and nitrogen atmosphere 8 ml N, O-bis(trimethylsilyl)-acetamide. After a reaction time of 1 hour at 60°, the reaction mixture is cooled to room temperature, 0.8 ml of pyridine and 1.96 ml of 1-octane sulfochloride are added and then stirred for 16 hours. After removal of the solvent, the residue is taken up in 250 ml of ethyl acetate and washed 3 times with each of 0.5 N hydrochloric acid and saturated aqueous sodium chloride solution. After drying over sodium sulfate, the solvent is removed on a rotary evaporator, and the residue is purified on silica gel with chloroform-ethyl acetate 4:1 as eluent, from which the title compound is obtained as an amorphous powder.

Rf = approx. 0.58 (silica gel, chloroform-methanol-glacial acetic acid 75:22:3).

Example 61.

a) 7 3-[(2R,S)-2-(2-aminothiazol-4-yl)-2-p-toluenesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt.

1.88 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-p-toluenesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 4.4 ml of CH2C12 and 1.4 ml of anisole with 15 ml of trifluoroacetic acid analogously to example 1 a), are worked up and reprecipitated. The hydrate of the title compound is obtained. F: above 213°

(under cleavage). fct]^<0>= +96°±1° (0.91% in H 2 O) . IR:

3650 to 2700 (broad), 1755, 1657, 1609, 1518 (Nujol). UV: 230 (19000, H20). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-p-toluene-sulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

2.44 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-p-toluenesulfonyl-aminoacetic acid are reacted with 1.8 g of 70-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 20 ml of tetrahydrofuran analogous to example 6b) (0.52 g of hydroxybenztriazole, 3 times 0.46 g of dicyclohexylcarbodiimide in each time 4 ml of tetrahydrofuran), is worked up and chromatographed. 73-[(2R,S)-2-(2-OBC-aminothiazol-4-yl)-2-(p-toluenesulfonylamino)-acetamido]-3-cefgm-4-carboxylic acid diphenyl methyl ester is obtained.

[a]p° = +1°±1° (0.86% in CHC13). IR: 3400, 3390, 1782, 1729, 1700, 1645, 1600, 1530 (CH 2 Cl 2 ). UV: 259 (13000, EtOH).

Production of the starting material.

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-p-toluenesulfonylamino-acetic acid.

2.73 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetic acid is reacted in 24 ml of tetrahydrofuran with 2.1 g of p-toluenesulfochloro-

ride analogously to example 6c) (10 ml N,0-bis-(trimethylsilyl)-acetamide, 0.81 ml pyridine) and work up. The title compound is obtained, which is further processed without characterization.

Example 62.

a) 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-p-nitrobenzene-sulfonylamino-acetamido]-3-cephem-4-carboxylic acid sodium salt. Analogous to example 29 a), the title compound is obtained in the form of the monohydrate by reaction "of 1.61 g (2.0 mmol) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2 -p-nitrobenzenesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 3.5 ml of anisole with 8 ml of trifluoroacetic acid in 8 ml of methvlene chloride. F: above 188° (under decomposition). Rf 96: 0.43, [ a]^ ° = ±11°±1<0>(0.268% in water), UV. 258 (18900, water). b) 7( 3-[ ( 2R, S)- 2-( 2- BOC- aminothiazole - 4- yl) - 2- pT- nitro-benzenesulfonylaminoacetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogous to example 20 b), the title compound is obtained by treating 2.29 g (5 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-p-nitrobenzenesulfonylaminoacetic acid with 1.83 g (5 mmol) 73~2-mino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.68 g of 1-hydroxybenztriazole and 1.15 g of N,N<1->dicyclohexylcarbodiimide in 30 ml of tetrahydrofuran. From: approx. 0.83 (methylene chloride-ethyl acetate 1:1).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-p-nitrobenzenesulfonylaminoacetic acid.

A suspension of 2.73 g (10 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetic acid in 27 ml of absolute methylene chloride is added under stirring, moisture exclusion and nitrogen atmosphere 8 ml of N ,O-bis(trimethylsilyl)-acetamide. After 1 hour's reaction time at 60°, the reaction mixture is cooled to room temperature, 0.81 ml of pyridine and 2.21 g of p-nitrobenzene sulfochloride are added and then stirred for 5 hours. After removal of the solvent, the residue is taken up in 250 ml of ethyl acetate and washed 3 times with each of 1.0 N hydrochloric acid and saturated aqueous sodium chloride solution. After drying over sodium sulfate, the solvent is removed on a rotary evaporator, and the residue is purified on silica gel with methylene chloride-ethyl acetate 1:1 as eluent, from which the title compound is obtained as an amorphous powder.

Rf 96: approx. 0.65.

Example 63.

a) 73-[] 2R,S)-2-(2-aminothiazol-4-yl)-2-(4-acetamido-benzenesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 29 a), the title compound is obtained in the form of the dihydrate by reaction of 4.0 g (4.9 mmol) 73~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2- (4-acetamidobenzenesulfonylamino) ■ acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 4 ml of anisole with 20 ml of trifluoroacetic acid in 20 ml of methylene chloride. F: above 191° (during cleavage). Rf: approx. 0.33 (silica gel "Opti-UPC12", water-acetonitrile 9:1), [α]^° = +91 ±1° (0.982% in water). UV: 260 (27200, water). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(4-acetamidobenzenesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogously to example 2 9 b), the title compound is obtained as a beige powder by treating 2.35 g (5 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(4-acetamidobenzenesulfonylamino) )-acetic acid with 1.83 g (5 mmol) of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.675 g of 1-hydroxybenz triazole and 1.15 g of N,N<1->dicyclohexylcarbodiimide in 25 ml of tetrahydrofuran. Rf: approx. 0.40 (silica gel, ethyl acetate).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(4-acetamido-benzenesulfonylamino)-acetic acid.

A suspension of 2.73 g (10 mmol) of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetic acid in 30 ml of absolute tetrahydrofuran is added under stirring, exclusion of moisture and nitrogen atmosphere 8 ml of N, O-bis(trimethylgyl)-acetamide. After 1 hour's reaction time at 60°, the reaction mixture is cooled to room temperature, 0.8 ml of pyridine and 2.34 g of 4-acetamino-benzene sulphochloride are added and then stirred for 4 hours. After removal of the solvent, the residue is taken up in 250 ml of ethyl acetate and washed 3 times with each of 1 N hydrochloric acid and saturated aqueous sodium chloride solution. After drying over sodium sulfate, the solvent is removed on a rotary evaporator, and the title compound is obtained as an amorphous powder. Rf 96: approx. 0.68.

Example 64.

a) 7β-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-amino-naphth-1-ylsulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 1.57 g of 7B-[82R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminonaphth-1-ylsulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 3.4 ml of CH2C12 and 1.07 ml of anisole with 12.5 ml of trifluoroacetic acid analogously to example 1 a), are worked up and reprecipitated. The hydrate of the title compound is obtained. F: above 215° (during cleavage). = +90°±1° (0.078% in H20), IR: 3650 to 2700 (broad), 1762, 1680, 1628, 1605, 1555, 1520 (Nujol), UV: 243 (44800), 347 (3900, H20 ). b) 73-[( 2R, S)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2- amino-naphth- 1- yl- sulfonylamino)- acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

2.71 g 73~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-naphth-1-ylsulfonylamino)-acetamido ] -3-cephem-4-carboxylic acid diphenyl methyl ester is reacted with 2.4 g of zinc dust in 30 ml of acetonitrile-glacial acetic acid 1:1 mixture analogously to example 37 c) and worked up. After chromatographic purification of the crude product on 100 g of silica gel (eluent: toluene-ethyl acetate 1:1 mixture), the title compound is obtained. [cc]q° = -5°±1° (0.70% in CHCl 3 ), IR: 3500, 3395, 3300, 1785, 1720, 1700, 1628, 1600, 1535, 1508 (CH 2 Cl 2 ). UV: 245

(57800), 350 (4300, EtOH). c) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-naphth-1-ylsulfonyl-amino)-acetamido ]- 3- cephem- 4- carboxylic acid diphenyl methyl ester .

7.41 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetamido] 3-cephem-4-carboxylic acid diphenyl methyl ester and 7.41 g of 2-(2,2, 2-trichloroethoxycarbonylamino)-naphthyl-1-sulfochloride is stirred in 75 ml of tetrahydrofuran and 0.963 ml of pyridine for 6 hours at room temperature. It is then taken up in ethyl acetate, washed with 1 N hydrochloric acid and saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated. After chromatographic purification of the crude product on 250 g of silica gel (eluent: toluene-ethyl acetate 9:1 mixture), the title compound is obtained. [a]^ = -5°±1°

(1.00% in CHC13). IR. 3400, 3300, 1785, 1750, 1724, 1700, 1620, 1605 (CH 2 Cl 2 ). UV: 249 (58800), 325 (4400, EtOH).

Preparation of the starting material:

d) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

7.52 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-chloroacetyl-aminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester (preparation see example 7 d) is reacted with 1.76 g of thiourea analogous to example 7 c) (125 ml dioxane, 2.58 ml acetic acid) and worked up. The title compound is obtained, which is further processed without characterization.

Example 65.

a) 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(5-imidazol-sulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 1.6 g of 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(5-imidazolesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 10 ml of CH2C12 and 0.56 ml of anisole with 15 ml of trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 230° (during cleavage). fa]^ = +83°±1° (1.01% in H2O). IR: 3700 to 2600 (broad), 1760 (broad), 1680, 1640, 1600, 1520 (Nujol), UV: 250 (9200, H20) . b) 7 3-[( 2R , S )- 2-(2-Aminotiazo1-4-yl)- 2-(5-imidazbl-sulfonylamino)-acetamido]-3-cephem-4-carboxylic acid e-diphenyl methyl ester•

2.9 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetamido]■ 3-cephem-4-carboxylic acid diphenyl methyl ester (preparation see example 64d) and 0.8 g 5-imidazole sulfochloride is reacted in 30

ml of tetrahydrofuran and 0.55 ml of N-methylmorpholine analogously to example 64 c), are worked up and chromatographed. The title compound is achieved. [<x]D = -6°±1° (0.077% in CHCl3). IR: 3450 to 2700 (broad), 1785, 1725, 1700 (shoulder), 1640 (shoulder), 1602, 1545 (CH2C12). UV: 258 (14100, EtOH).

Example 66. a) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7&-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(4- nitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 2 9 a), the dihydrate of the title compound is obtained by reaction of 3.7 g (3.6 mmol) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R,S)-2 -(2-BOC-amino-thiazol-4-yl)-2-(2-(4-nitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 3.7 ml of anisole with 18, 5 ml of trifluoroacetic acid in 18.5 ml of methylene chloride. F: above 160° (during cleavage).

Rf: approx. 0.10 (silica gel "Opti-UPC-, ~", water-acetonitrile 4:1), [cx]p = 22°±1° (0.595% in water). UV: 259 (25000 in water). b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(4-nitrobenzenesulf onylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogously to example 2 9 b), the title compound is obtained as a yellowish powder by treating 3.1 g (5.5 mmol) (2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(4 -nitrobenzenesulfonylamino)-ethanesulfonylamino)-acetic acid with 2.72 g (5.5 mmol) of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1-hydroxytriazole and 1.25 g of N,N'-dicyclohexylcarbodiimide in 50 ml of tetrahydrofuran. Rf: approx. 0.43 (silica gel, methylene chloride-ethyl acetate 1:1) .

Example 67.

a) 3- carbamoyloxymethyl- 73-[( 2R, S)- 2-( 2- aminothiazol-4- yl)- 2-( 2-( 4- nitrobenzenesulfonylamino)- ethanesulfonylamino)- acetamido]- 3- cephem- 4- carboxylic acid sodium salt.

Analogous to example 2 9 a), the title compound is obtained as a pale yellow powder in the form of the dihydrate by reacting 1.58 g (1.6 mmol) of 3-carbamoyloxymethyl-73-[(2R,S)-2-(2-BOC -aminothiazol-4-yl)-2-(2-(4-nitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1.7 ml of anisole with 8 ml of trifluoroacetic acid in 8 ml of methylene chloride. F: above 112° (during cleavage).

Rf: approx. 0.18 silica gel "Opti-UPC , ", water-acetonitrile 4:1), [a]^ = +45 ±1° (0.766% in water), UV: 256 (23700, in water). b) 3- carbamoyloxymethyl- 73-[( 2R, S)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2-( 4- nitrobenzenesulfonylamino)-ethanesulfonylamino)- acetamido]- 3- cephem- 4-carboxylic acid diphenyl methyl ester.

Analogous to example 29 b), the title compound is obtained as a pale yellow, amorphous powder by treating 4.52 g (8.0 mmol)

(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(4-nitrobenzenesulfonyl-amino)-ethanesulfonylamino)-acetic acid with 3.51 g (8 mmol) of 3-carbamoyloxymethyl- 7(3-amino-3-cef em-4 -car bok syl acid dif enyl methyl ester in the presence of 1.08 g of 1-hydroxybenztriazole and 1.81

g of N,N'-dicyclohexylcarbodiimide in 80 ml of tetrahydrofuran.

Rf.: approx. 0.33 (silica gel, methylene chloride-ethyl acetate 1:1).

Example 68.

a) 7( 3- [ ( 2R, S) - 2- ( 2- aminotlazol-4- yr), - 2-( 2- ( 4- amino-benzenesulfonylamino)- ethanesulfonylamino)- acetamido]-3- cephem- 4 - carboxylic acid sodium salt.

Analogous to example 29 a) is obtained by reaction of 0.77 g (2 mmol) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(4-amino -benzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1.8 ml of anisole with 9 ml of trifluoroacetic acid in 9 ml of methylene chloride the title compound as a yellowish powder in the form of the trihydrate. F: above 170° (during cleavage). M^<0>= +72°±1° (0.743% in

water), UV: 257 (24200, in water).

Preparation of the starting material:

b) 7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(4-aminobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

A solution of 1.83 g (2 mmol) of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(4-nitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido] -3-cephem-4-carboxylic acid diphenyl methyl ester in 40 ml acetic acid ethyl ester is hydrated in the presence of 0.85 g of 10% palladium/charcoal catalyst at normal pressure and room temperature. It is filtered off, washed with ethyl acetate, the filtrate is evaporated and the title compound is obtained as a yellowish powder. Rf: approx. 0.31 (silica gel, methylene chloride-ethyl acetate 1:1) .

Example 69.

a) 3-carbamoyloxymethyl-73-[(2R,S)-2-(2-amino t ia zo1-4-yl)-2- me t an sulfonylamiiro ac e t amido ]- 3 - ce fem- 4-carboxylic acid sodium salt . 3.9 g of 3-carbamoyloxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester are reacted in 8.9 ml of CH2C12 and 2.97 ml of anisole with 33.4 ml of trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 160° (during cleavage). [a]^° = +62°±1° (1.20% in H2<D) . IR: 3650 to 2500 (broad), 1760, 1695, 1605, 1520cm~<1>. UV: 255 (12500 in H20). b) 3-carbamoyloxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 2.5 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylamino-acetic acid (preparation see example 22 c) is reacted with 2.59 g of 3-carbamoyloc synretyl-73-amino -3-cephem-4-carboxylic acid diphenylmethyl ester in 33 ml of tetrahydrofuran analogous to example 6 b) (0.63 g of hydroxybenztriazole, 3 times 0.58 g of dicyclohexylcarbodiimide in each time 4 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. [a] 2 0 = -9°±1° (0.97% in CHC13). IR: 3500, 3400, 3270, 1770, 1700, 1680 (shoulder), 1560, 151Scm<-1>(CH 2 Cl 2 ). UV: 257 (16200, EtOH).

Example 70.

a) 3-( 1- methyl- 1H- tetrazol- 5- ylthiomethyl)- 73-[( 2R, S)— 2-( 2- amino- thiazol- 4- yl)- 2- methanesulfonylaminoacetamido] - 3- cephem- 4- carboxylic acid pivaloyloxymethyl ester hydrochloride. 1.65 g of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73~[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem- 4-carboxylic acid sodium salt (preparation see example 22 a)), and 0.735 ml of iodomethylpivalate are stirred in 16.5 ml of dimethylformamide for 30 minutes at 0°. Then 10 ml of phosphate buffer of pH 8 is added and the mixture is stirred for a further 5 minutes at 0°. The mixture is then taken up in 25 ml of acetic acetate, washed twice with saturated aqueous sodium chloride solution and dried over sodium sulfate. Then 4.5 ml of 0.7 N HC1 in CH2C12 are filtered off and added. The resulting amorphous precipitate is separated by decantation, washed 3 times with hexane and dried at room temperature in a vacuum. Then triturate with ether, filter off from ether and dry again. The title connection ice is achieved. F: above 110° (during cleavage). [alD 2 0^ = -21°±1° (1.07% in DMSO). IR: 3600 to 2400 (broad), 1782, 1750, 1695, 1628, 1545cm<_1>(Nujol). UV: 258 (1200, CH 3 OH).

Example 71.

a) 3-( 1- methyl- 1H- tetrazol- 5- ylthiomethyl)- 7B-[( 2R, S)-2-( 2- aminothiazol- 4- yl)- 2- cyanomethanesulfonylamino-acetamido] - 3- cephem- 4- carboxylic acid sodium salt. 2.5 g 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7|3-[ (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-cyanomethanesulfonylaminoacetamido]-3- cephem-4-carboxylic acid diphenyl methyl ester is reacted in 5 ml of CH2CI2 and 0.7 ml of anisole with 10 ml of trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 210° (during cleavage). [a]p° = -9°±1° (0.91% in H20). IR: 3650 to 2500 (broad), 2260, 1760, 1685, 1605, 1520 (Nujol). UV: 257 (13600 in H 2 O) . b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R,S)-2- (2-BOC-aminothiazol-4-yl)-2-cyanomethanesulfonyl-aminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 2.6 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-cyanomethanesulfonyl-amino-acetic acid (preparation see example 44 c) is reacted with 3.3 g of 3-(1-methyl- 1H-tetrazol-5-ylthiomethyl)-73-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 30 ml tetrahydrofuran analogously to example 6b) (0.9 g hydroxybenztriazole, 3 times 0.4 3 g dicyclohexylcarbodiimide in each time 6.6 ml tetrahydrofuran), worked up and chromatographed. The title compound is achieved. [a]p° = -85°±1° (0.97% in CHCl3).

IR: 3400, 3300, 2260, 1785, 1722, 1700 (shoulder), 1625,

1540 (CH 2 Cl 2 ). UV: 258 (15800, EtOH).

Example 72.

a) 3-carbamoyloxymethyl-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

2.2 g of 3-carbamoyloxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 4 ml of CH2C12 and 0.636 ml of anisole with 10 ml of trifluoroacetic acid analogously to example 1 a), is worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 190° (during cleavage). [a]p° = /53°±lo (1.03% in H 2 O). IR: 3650 to 2500 (broad), 1760, 1670, 1605, 1520cm<-1>(Nujol). UV: 257

(13300), H 2 O). b) 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3-cephem-carboxylic acid diphenyl methyl ester.

2.3 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-formylamino-ethanesulfonylamino)-acetic acid (preparation see example 27 c) is reacted with 2.4 g of 3-carbamoyloxymethyl -73-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 30 ml of tetrahydrofuran analogous to example 6b) (0.5 g of hydroxybenztriazole, 3 times 1.2 g of dicyclohexylcarbodiimide in each time 10 ml of tetrahydrofuran), is concentrated and chromatographed. The title compound is achieved. [a]^<0>= (1.01% in CHCl3). IR: i.a. 1785cm<-1>(CH 2 Cl 2 ). UV: 258 (14400, EtOH).

Example 73.

a) 3-acetoxymethyl-73-[82R,S)-2-(2-aminothiazol-4-yl-2-(2-formylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

2.7 g of 3-acetoxymethyl-73-[(2R,S)-2-)2-BOC-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 14 ml CH2C12 and 0.73 ml anisole with 21 ml trifluoroacetic acid analogously to example 1 a), is worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 165° (below

cleavage). [ct]^ = +77°±1 (0.85% in H 2 O) . IR: 3650 to 2500 (broad), 1760, 1725 (shoulder), 1670, 1605, 1520 (Nujol), UV: 256 (12000, H20). b) 3-acetoxymethyl-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

2.3 g (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-formylamino-ethanesulfonylamino)-acetic acid (preparation see example 27

c) react with 2.1 g of 3-acetoxymethyl-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 30 ml of tetrahydrofuran

analogous to example 6b) (0.5 g hydroxybenztriazole, 3 times 0.4 g dicyclohexylcarbodiimide in each time 6 ml tetrahydrofuran), is worked up and chromatographed. Title connection— the ice is achieved. [a]£° = +56°±1° (1.28% in CHC13). IR: 3300, 1780, 1720, 1680, 1550 (Nujol). UV: 257 (15600, EtOH).

Example 74.

73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formyl-aminoethanesulfonylamino')-acetamido]-3-cef'em-4-carboxylic acid pivaloyloxymethyl ester hydrochloride. 1 g 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt and 0.5 ml iodomethylpivalate reacted in 10 ml of dimethylformamide analogously to example 70 and worked up. The title compound is achieved. [a]p° = +63°±1° (0.95% in CMSO). IR: 3650 to 2400 (broad), 1780, 1750, 1670 (broad), 1630, 1540, (Nujol), UV: 258 (11500, CH-jOH) .

Example 75.

a) 3-carbamoyoxymethyl-73-[(2S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt. 1.65 g of 3-carbamoyloxymethyl-73-[(2S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 4.9 ml of CH2C12 and 1 .6 ml of anisole with 18 ml of trifluoroacetic acid analogous to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 17 0° (during cleavage). [a]p° = +83°+l° (0.95% in H 2 O). IR: 3650 to 2500 (broad), 1760 , 1695, 1605, 1520 (Nujol). UV: 255 (12600, HjO) . b) 3-carbamoyloxymethyl-7S-[(2R)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt.

1.65 g of 3-carbamoyloxymethyl-73-[(2R)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 4.9 ml of CH-jCl ,, and 1.6 ml of anisole with 18 ml of trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 175° (during cleavage).

[a]p° = +48°±1° (0.96% in H 2 O). IR: 3650 to 2500 (broad), 1760, 1695, 1605, 1520 (Nujol). UV: 255 (12400, H20) .

c) 3- carbamoyloxymethyl- 73-[( 2S)- 2-( 2- BOC- aminothiazol-4- yl)- 2- methanesulfonylaminoacetamido]- 3- cephem-4- carboxylic acid diphenyl methyl ester

and

3- Carbamoyloxymethyl- 73-[( 2R )- 2-( 2- BOC-aminothiazol' 4- yl)- 2- methanesulfonylaminoacetamido]- 3- cephem- 4-carboxylic acid diphenyl methyl ester.

2.5 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methanesulfonyl-aminoacetic acid (preparation see example 22 c)) is reacted with 2.59 g of 3-carbamoyloxymethyl-73-amino -3-cephem-4-carboxylic acid diphenylmethyl ester in 33 ml tetrahydrofuran analogous to example 6b) (0.63 g hydroxybenztriazole, 3 times 0.58 g dicyclohexylcarbodiimide in each time 4 ml tetrahydrofuran) and worked up. The precipitated crude product is chromatographed on 300 g

silica gel.i (step column) [eluent: toluene-ethyl acetate 2:1 and 1:1 mixture]. Thereby, the title compound with 2R configuration is first eluted. (As for the configuration device, compare example 7 d) ). f**]^~-5°<+>l°

(1.08% in CHC13). IR: 3520, 3410, 3280, 1795, 1725, 1700 (shoulder), 1582, 1540 (CH 2 Cl 2 ). UV: 259 (15200 in C 2 OH).

Higher fractions consist of a binary mixture of the above (2R) compound with the (2S) isomer.

From the last fraction, the title compound is obtained with the 2S configuration. [a]^° = -7°±1° (0.99% in CHClg). IR: 3520, 3410, 3290, 1780, 1725 1695 (shoulder), 1582, 1540 (CH 2 Cl 2 ). UV: 258 (16400, EtOH).

Example 76.

a) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyethanesulfonyl-amino)-acetamido] - 3- cephem- 4- carboxylic acid sodium salt 4 g 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)- 2-(2-Methoxyethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is dissolved in 7 ml of methylene chloride. The solution is added in order to 1.5 ml of anisole and 70 ml of trifluoroacetic acid and stirred under exclusion of moisture for 1 hour at room temperature. From the original clear solution, a voluminous precipitate is precipitated. The suspension is then poured onto an ice-cold mixture of 100 ml petroleum ether and 300 ml diethyl ether, the precipitated trifluoroacetate is filtered off with suction, washed with petroleum ether and dried in high vacuum at room temperature. The crude trifluoroacetate salt is then dissolved in 30 ml acetonitrile-water- mixture, the solution is cooled to +5° and adjusted to a pH value of 5.8 by adding 1 N caustic soda dropwise while stirring and cooling. Then the solution is poured into 600 ml of ethanol and evaporated on a rotary evaporator at 50° to approx. 100 ml volume. This precaution is repeated twice, each time adding 300 ml of ethanol, whereby the amorphous product precipitates out. It is suctioned off and washed successively with ethanol, a mixture of ethanol-diethyl ether and diethyl ether. The hydrate of the title compound is obtained. Melting point from 146° during cleavage. [a^D° = -7°±1°

(2.039% in o.l N NaHCO 3 ). IR: 3310 (broad). 3200, 1785 (shoulder), 1765 (wide), 1685, 1610 (wide), 1525, 1375,

1350, 1175, 1145 (in Nujol). Rf.: Approx. 0.44 (silica gel,

UV 366 n-butanol-pyridine-glacial vinegar-water-42:24:4:30).

b) 3-( 1- methyl- 1H- tetrazol- 5- ylthiomethyl)- 7( 3-[ ( 2R, S)- 2-( 2- BOC- aminothiazol- 4- yl)- 2-( 2- methoxyethanesulfo- nylamino)- acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogous to example 42 c), the title compound is obtained by reacting 3.0 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-acetic acid (preparation see example 43 d) with 3-(1-methyl- 1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.50 g of 1-hydroxy-benzotriazole and 1.60 g (2 x 0.80 g) of N,N<1->dicyclohexylcarbodiimide in a 50 ml mixture of dioxane-tetrahydrofuran-(1:1). The raw product is cleaned on

a 20 times larger amount of silica gel. Eluent: methylene chloride with 10 to 20% methyl acetate. Rf: approx. 0.52 (silica gel, UV 33 6, double spot diastomer mixture, chloroform-ethyl acetate-ethanol 42.5:42.5:5).

Example 77.

a) 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methyl-carbamoylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 76 a), the title compound is obtained by reacting 3.4 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methylcarbamoylaminoethanesulfonylamino).acetamido]-3 - 4-carboxylic acid diphenyl methyl ester with 60 ml of trifluoroacetic acid in 5 ml of methylene chloride and 1.2 ml of anisole, and subsequent treatment of the trifluoroacetate salt with 1 N caustic soda. The amorphous product melts above 178° during cleavage. t0^^ = +83°±1° (2.039% in 0.1 N NaHCO 3 ). IR: 3320 (wide), 3190 (wide), 1760 (wide), 1645, 1600, 1565, 1520, 1375, 1365, 1165 (shoulder), 1140 (in Nujol). Rf: 0.33 (silica gel, UV: 366, n-butanol-pyridine-glacial acetic acid-water 42:24:4:30). b) 7(3-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methylcarbamoylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 24 a), the title compound is obtained by reacting 3.0 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methylcarbamoyl-aminoethanesulfonylamino)-acetic acid with 2.5 0 g of 7B-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1.60 g (2 x 0.80 g) of N,N<1->dicyclohexylcarbodiimide in 50 ml of tetrahydrofuran. The crude product is purified on a 25 times greater quantity of silica gel. Eluent: methylene chloride-methyl acetate-(1:1). F: above 140° (during cleavage). Rf: 0.15 (silica gel, UV 366, double spot diastereomer mixture chloroform-ethyl acetate-ethanol 42.5:42.5:5).

Preparation of the starting material:

c) ( 2 R , S ) - 2 - ( 2 - BOC - amino thiaz o 1 - 4 - yl ) - 2 - ( 2 - methyl Icarba - moylaminoethanesulfonylamino) - acetic acid.

A solution of 3.8 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2- methylcarbamoylaminoethanesulfonylamino)-acetic acid methyl ester in 15 ml of methanol and 10 ml of water is added to 18 ml of 1 N sodium hydroxide and the reaction mixture is stirred for 4 hours at 30°. The resulting acid is then isolated analogously to example 43 d). After evaporation of the solvent, the title compound remains as a foam. F: 93-96° (during cleavage).

d) ( 2R, S )- 2-( 2- BOC- aminothiazol- 4- yl)- 2-( 2- methylcar- bamoylaminoethanesulfonylamino)- acetic acid methyl ester. To a solution of 4.70 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid methyl ester in 40 ml of tetrahydrofuran is added dropwise while stirring for 30 minutes a solution of 0.80 g of methyl isocyanate in 8 ml of tetrahydrofuran. The reaction mixture is then stirred for 4 hours at +2°, and 1 hour at room temperature. The solution is then evaporated to dryness on a rotary evaporator at 50° and the crude product is purified on a 20 times greater amount of silica gel. Eluent: methylene chloride with 55 to 70% methyl acetate. The title compound is obtained as a foam. F: above 70° (during cleavage). Rf: approx. 0.07 (silica gel, UV 336, toluene, chloroform, ethyl acetate 1:1:1) .

Example 78.

a) 73-[(2R,S)-2-(2-amiriophiazol-4-yl)-2-(2-anilino-formamideethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogously to example 76 a), the title compound is obtained by reacting 2.70 g of 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-anilinoformamidetansulfonylamino)-acetamido]-3 -cephem-4-carboxylic acid diphenyl methyl ester with 50 ml of trifluoroacetic acid in 1.0 ml of anisole and 5 ml of methylene chloride, and subsequent treatment of the trifluoroacetate salt with 1 N caustic soda.

The amorphous product melts above 210° during decomposition.

IR: 3360, 3305, 3270, 3180 (wide), 1785 (shoulder), 1760, 1650, 1640, 1590, 1560, 1535, 1510, 1375, 1365, 1145, 113

(in Nujol). Rf: 96: approx. 0.29.

b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-anilinoformamidoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 42 c), the title compound is obtained by reacting 2.8 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-anilinoformamideethanesulfonylamino)-acetic acid with 2.10 g of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1.20 g (2 x 0.60 g) of N,N<1->dicyclohexylcarbodiimide in 50 ml of tetrahydrofuran. The crude product is purified on a 20 times larger amount of silica gel. Eluent: Methylene chloride with 15 to 25% methyl acetate. F: above 128-131° during cleavage. Rf: approx.

0.43 (silica gel, UV: 366, double stain, diastereomer mixture, toluene-chloroform-ethyl acetate 1:1:1 + 5% ethanol).

Preparation of the starting material:

°) ( 2R, S )- 2-( 2- BOC- aminothiazol- 4- yl)- 2-( 2- anilino- formamide ethanesulfonylamino)-acetic acid. Analogously to example 43 d), the title compound is obtained by reacting 2.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-anilinoformamideethanesulfonylamino)-acetic acid methyl ester in 25 ml of methanol with 6 ml of 2 N caustic soda and stirring for 4 hours at 40°. Rf 96: approx. 0.69. d) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-anilino-formamideethanesulfonylamino)-acetic acid methyl ester.

A solution of 4.54 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetic acid methyl ester in 30 ml of tetrahydrofuran is reacted with 1.60 ml of phenyl isocyanate in 20 ml of tetrahydrofuran analogously to example 77 d), the reaction mixture is evaporated to dryness on a rotary evaporator at 50°, and the crude product is purified on a 15 times larger quantity of silica gel. Eluent: Methylene chloride with 15 to 25% methyl acetate. The title compound is obtained as a foam. Rf: 0.24 (silica gel,

UV 366, toluene-chloroform-ethyl acetate-1:1:1 +3% ethanol).

Example 79.

a) 3-(1-methyl-1H-tetrazol-5-ylthiomethl)-7g-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methylcarbamoylamino-ethanesulfonylamino)- acetamido]- 3- cephem- 4- carboxylic acid sodium salt.

Analogous to example 43 a), the title compound is obtained by reacting 3.6 g of 3-(l-meth<y>l-lH-tetrazol-5-<y>ltiomet<y>l)-7B-[(2R,S) -2-(2-BOC-aminothiazol-4-yl)-2-(2-methylcarbamoylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester with 45 ml of trifluoroacetic acid in 2.10 ml of anisole and 5 ml of methylene chloride and subsequent treatment of trifluoroacetate salts with 1 N caustic soda. F: above 16 0° during cleavage.

[a]^'° = -34+1° (2.207% in dimethyl sulfoxide). Rf: 0.35 (silica gel, UV 366, n-butanol-pyridine-glacial acetic acid-water 42:24:4: 30. b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-[( 2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methylcarbamoyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogously to example 42 c), the title compound is obtained by reacting 2.20 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-BOC-methylaminoethanesulfonylamino)-acetic acid with 1.8 g of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.27 g of 1-hydroxytriazole and 0.90 g (2 x 0.45 g) of N,N'-dicyclohexylcarbodiimide in 45 ml of tetrahydrofuran. The crude product is purified on a 40 times larger amount of silica gel. Eluent: methylene chloride-methyl acetate (85:15). Rf: approx. 0.48 (silica gel, UV 366, double stain, diastereomer mixture, toluene-ethyl acetate 1:1).

Preparation of the starting material:

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-BOC-methylaminoethanesulfonylamino)-acetic acid.

9.5 g (2R,S)-2-[2-N-methyl-2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino]-2-(2-BOC-aminothiazol-4-yl)-acetic acid

(preparation example 42 d)), is treated in 100 ml of acetonitrile-glacial acetic acid 1:1 with 12.0 g (9.5 g - 2.5 g) of zinc dust. Processing analogously to example 13 d). A solution of the crude product is poured onto n-hexane, whereby the amorphous (2R,S)-2-(2-N-methylamino-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid precipitates. Rf: approx. 0.13 (silica gel, UV 366, chloroform-methanol-glacial vinegar-water 45:12:1:2) 45 g* of this acid is reacted in 60 ml of dioxane and 30 ml of water with 6.4 ml of di-tert-butyl -dicarbonate in the presence of 4.3 g of sodium carbonate analogously to example 13 c). After mixing the crude product with petroleum ether, the amorphous title compound is obtained. Rf: approx. 0.58 (silica gel,

UV 366, chloroform-methanol-glacial vinegar-water 45:12:1:2).

Example 80.

a) 73~[( 2R, S)- 2-( 2- aminothiazol-4- yr)- 2-( 2- n- butyl-aminoethanesulfonylamino)- acetamido]- 3- cephem- 4-

i ka r bo k s y 1 s y r é.

Analogous to example 76 a), the title compound is obtained by reacting 7(3-[ (2R, S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-n-butylaminoethanesulfonylamino)-acetamido]-3 -cephem-4-carboxylic acid diphenyl methyl ester with 50 ml of trifluoroacetic acid in 1.0

ml of anisole and 5 ml of methylene chloride and subsequent treatment of the trifluoroacetate salt with 1 N caustic soda. The amorphous product melts at 166-173° during cleavage. IR: 3310 (wide) 3190, 1785 (shoulder), 1765 (wide), 1680, 1600 (wide), 1520, 1355 (wide), 1175 (shoulder), 1150 (in Nujol). Rf: approx. 0.38 (silica gel, UV 366, n-butanol-pyridine-glacial acetic acid-water 42:24:4:30). b) 73-[(2R,S)-2-(2-BOC-aminothia2Ol-4-yl)-2-(2-BOC-n-butylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 43 c), the title compound is obtained by reacting 2.3 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-BOC-n-butylaminoethanesulfonylamino)-acetic acid with 1 .5 g of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.98 g (2 x 0.49 g), in dicyclohexylcarbodiimide in 50 ml of tetrahydrofuran. The crude product is purified on a 25 times greater quantity of silica gel. Eluent: methylene chloride with 7

to 10% methyl acetate. Rf: approx..0.45 (silica gel, UV 366, toluene-ethyl acetate 2:1).

Production of the starting material.

c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-BOC-n-butylaminoethanesulfonylamino)-acetic acid.

7.1 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(N-butyl-2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino)-acetic acid is treated in 80 ml of glacial acetic acid acetonitrile (1:1) with 14.0 g

(10.0 g and 4.0 g) zinc dust. The reaction mixture is worked up analogously to example 13 d). By mixing the crude product with diethyl ether, the amorphous (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-n.butyl-aminoethanesulfonylaminoacetic acid is obtained. Rf 96: approx. 0.42 (silica gel, UV 366). 8.9 g of this acid is dissolved in 80 ml of dioxane and reacted in 20 ml of water with 4.7 ml of di-tert-butyl dicarbonate in the presence of 2.5 g of sodium carbonate analogously to example 13 c). The crude product is purified on a 20 times larger amount of silica gel. Eluent: methylene chloride with 10

to 30% methyl acetate. The title compound is achieved. Rf 96:

0.45 (silica gel, UV 366).

d) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(N-butyl-2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino)-acetic acid.

The reaction of the trimethylsilyl ester of 10 g of (2R,S)-2-amino-2-(2-BOC-aminothiazol-4-yl)-acetic acid with 20 g of oily 2-(N-n-butyl-2,2,2-trichloroethoxycarbonylamino) -ethanesulfonyl chloride (prepared according to example 42 e) takes place analogously to example 4 2 d). The crude product is purified on a 20 times larger amount of silica gel. Eluent: methylene chloride with 10 to 30% methyl acetate. The title compound is achieved. Rf 96: 0.64 (silica gel, UV 366).

Example 81.

a) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyacetylamino-ethanesulfonylaminep)- acetamido]-3-cephem-4-carboxylic acid sodium salt. 3.5 g of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)- 2-(2-Methoxyacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 60 ml of CH2C12 and 0.9 ml of anisole with 10 ml of trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: cleavage above 205°. [ct]p° = -2°±1° (0.93% in H 2 O) . IR: 3650-2500 (wide), 1763, 1665, 1600, 1520 (Nujol). UV: 258 (12500, H20) . b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyacetyl-aminoethanesulfonylamino) - acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

5.5 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonyl-amino)-acetic acid obtainable according to example 36 c) is reacted with 6.0 g of 3 -(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 55 ml tetrahydrofuran analogous to example 6 b)

(.1.6 g of hydroxybenztriazole, 3 times 0.83 g of dicyclohexyl-

carbodiimide in each time 5 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. E^q0= -73°±1°

(0.88% in CHCl 3 ), IR: 3400 (broad), 1787, 1720, 1683, 1538 (CH 2 Cl 2 ). UV: 260 (16800, EtOH).

Example 82.

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-

2-(2-Aminothiazol-4-yl)-2-(2-Methoxyacetylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride.

0.5 g 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7&-[]2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonylamino)-acetamido ]-3-cephem-4-carboxylic acid sodium salt (preparation see example 81 a)) and 0.19 ml of iodomethyl pivalate are reacted in 5 ml of dimethylformamide analogously to example 70 a), worked up and transferred into hydrochloride. The title compound is achieved. F: above 150° (during cleavage). [α]^° = -18°±1° (1.03% in DMSO).

IR: 3660-2300 (broad), 1780, 1748, 1690 (shoulder), 1660-1620 (broad), 1540 (Nujol). UV: 260 (12000, CH 3 OH).

Example 83.

a) 3-(1-methyl-1H-tetrazol-5-ylthiométhyT)-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-benzoylaminoethanesulfonylamino)-acetamido ]- 3- cephem- 4- carboxylic acid sodium salt. 6 g of the 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2, which can be prepared according to example 83 b) -(2-benzoylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 10 ml CH2CL2 and 1.5 ml anisole with 15 ml trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 2 05° (during cleavage). [a]^° = +25±1° (1.02% in H20). IR: 3660-2500 (wide), 1760, 1680 (shoulder), 1630 (shoulder), 1600, 1578, 1522 (Nujol). UV: 230 (20000), 260 (shoulder, H20). b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R,S)-2-(2-BQC-aminothiazol-4-yl)-2-(2-benzoylaminoethane-sulfonylamino) - acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 8 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-benzoylaminoethanesulfonylamino)-acetic acid obtainable according to example 26 c) is reacted with 7.4 g of 3-(1- methyl-1H-tetrazol-5-ylthiomethyl)-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 80 ml of tetrahydrofuran analogous to example 6b) (0.2 g of hydroxy-benztriazole, 3 times 1 g of dicyclohexylcarbodiimide in each time 8, 3 ml of tetrahydrofuran, work up and chromatograph. The title compound is obtained. [a]<2>° = -67°±1° (1.00% in CHCl3). IR: 3400, 3300 (broad), 1788, 1722, 1698 (shoulder ), 1663, 1601, 1579, 1538 (CH 2 Cl 2 ). UV: 259 (15800, CH 2 Cl 3 ).

Example 84.

3-( 1- methyl- 1H- tetrazol- 5- ylthiomethyl)- 73-[( 2R, S)-2-( 2- aminothiazol-4- yl)- 2-( 2- benzoylaminoethanesulfonylamino)- acetamido]- 3- cephem- 4- carboxylic acid-piva1oyloc syrnethyl st is hydrochlor id.

0.8 g 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73~[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-benzoylaminoethanesulfonylamino)-acetamido ]-3-cephem-4-carboxylic acid sodium salt (preparation see example 83 a) and 0.3 ml of iodomethylpivalate are reacted in 8 ml of dimethylformamide analogously to example 70 a), worked up and transferred into the hydrochloride. The title compound is achieved.

F: above 195° (during cleavage). ta]^° = -12°±1° (0.69% in DMCO). IR: 3660-2500 (broad), 1782, 1750, 1692, 1630, 1600 (shoulder), 1577 1535 (Nujol), UV: 220 (21000), 258 (13700, CH30H).

Example 85.

a) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73~[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylaminoethane-sulfonylamino)- acetamido]-3-cephem-4-carboxylic acid sodium salt.

2.13 g of the 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7 3-[(2R,S)-2-(2-BOC-aminothiazol-4-yl) obtainable according to example 85 b) )-2-(2-acryloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 4.1 ml CH2Cl2 and 1.35 ml anisole with 15.5 ml trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated . The hydrate of the title compound is obtained. F: above 157° (during cleavage). [a]p0 = 0° (0.75% in H20) .

IR: 3660-2500, 1763, 1690 (shoulder), 1660, 1625 (shoulder), 1600, 1550 (shoulder), 1525 (Nujol). UV: 255 (13500, H20) . b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acryloylamino-ethanesulfonylamino) - acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester. 2.88 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetic acid obtainable according to example 31 c) is reacted with 2.9 g of 3-( 1-methyl-1H-tetrazol-5-ylthiomethyl)-7 3-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 30 ml of tetrahydrofuran analogous to example 6 b) (0.66 g of hydroxybenztriazole, 3 times 0.58 g of dicyclohexylcarbodiimide in each time 4 ml of tetrahydrofuran), is worked up and 20^ o is chromatographed. The title compound is achieved. [Q]D ="66 ±1° (0.98% in CHC13), IR: 3390, 3290, 1775, 1710 1690 (shoulder), 1670 (shoulder), 1620, 1600 (shoulder), 1515 (CH2C12), UV: 260 (16000, EtOH).

Example 86.

3- Carbamoyloxymethyl- 7B-[( 2R, S )- 2-( 2- aminothiazol-4-yl)- 2- methanesulfonylaminoacetamido]- 3- cephem- 4-carboxylic acid pivalouloxyrnetyl ester hydrochloride.

1.815 g of 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt (preparation see example 69 a) and 0.9 ml of iodomethylpivalate is reacted in 18.15 ml of dimethylformamide analogously to example 70 a), worked up and transferred into the hydrochloride. The title connection is achieved. • F: above 123° (during cleavage). [α]D = +30±1° (0.81% in DMSO). IR: 3600-2300 (wide), 1780, 1745, 1700, 1630, 1545 (Nujol). UV: 260 (11800, CH 3 OH).

Example 87.

a) 3-carbamoyloxymethyl-7B-[(2R)-2-(2-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 2.62 g of the 3-carbamoyloxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)^-^-acryloylaminoethanesulfonylamino)-acetamido] obtainable according to example 87 c) -3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 5.4 ml of CH2C12 and 1.76 ml of anisole with 20 ml of trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 155° (during cleavage). [ctjp<0>= +40°±1° (0.85% in H 2 O) . IR: 3660.2500 (broad), 1760, 1700, 1658, 1605, 1522 (Nujol). UV: 253 (12800, H 2 O). b) 3-carbamoyloxymethyl-73-[(2S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 3.45 g of the 3-carbamoyloxymethyl-7 3-[(2S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acryloyl-aminoethanesulfonylamino)-acetamido]-3-cephem- 4-carboxylic acid diphenylmethyl ester is reacted in 7 ml of CH2C12 and 2.3 ml of anisole with 26 ml of trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 160° (during decomposition). [a]p ° = +69°±1° (0.92% in HjO). IR: 3660-2500 (broad), 1762, 1700 (shoulder), 1600, 1605, 1522 (Nujol). UV: 253 (13800, H20) c) 3- carbamoyloxymethyl- 73-[( 2R)- 2-( 2- BOC-aminothiazol-4- yl)- 2-( 2- acryloylaminoethanesulfonylamino)-acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester. 3- carbamoyloxymethyl -7 3-[(2S)-2-(2-BOC-aminothiazol-4-yl-2-(2-acryloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester r. 9.93 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetic acid obtainable according to example 31 c) is reacted with 8.95 g of 3-carbamoyloxymethyl -7 3-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 70 ml tetrahydrofuran analogous to example 6b) (2.28 g hydroxybenztriazole, 3 times 2.0 g dicyclohexylcarbodiimide in each time 10 ml tetrahydrofuran) and worked up. The crude product obtained is chromatographed on 700 g of silica gel [eluent: toluene-ethyl acetate 7:3, 3:2, 1:1 and 1:2 mixture. Thereby, the title compound is first eluted with the 2R configuration (as regards the configuration assignment, cf. example 7 d).

[a]p° = -5°±1 (0.75% in CHClg). IR: 3520, 3420, 3300, 3200, (shoulder). 1775, 1712, 1670 (shoulder), 1620, 1580, 1520 (CH 2 Cl 2 ). UV: 259 (16000, EtOH).

The following fractions consist of a binary mixture of the above-mentioned (2R) compound with the (2S) isomer.

From the last fractions, the title compound with the 2S configuration is obtained. [a]^° = +4°±1° (0.91% in CHCl3). IR: 3550, 3429, 330, 3200 (shoulder), 1778, 1715, 1700 (shoulder), 1670 (shoulder), 1620 (shoulder), 1600, 1580, 1522 (CH2C12). UV: 259 (16200, EtOH).

Example 88.

3- carbamoyloxymethyl- 7B-[( 2R)- 2-( 2- aminothiazol-4- yl)- 2-( 2- acryloylaminoethanesulfonylamino)- acetamido] - 3- cephem- 4- carboxylic acid pivaloyloxymethyl ester hydrochloride. *

0.54 g of 3-carbamoyloxymethyl-7B-[(2R)-2-(2-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (preparation see example 87 a) and 0.23 ml of iodomethylpivalate are reacted in 5.4 ml of dimethylformamide analogously to example 70 a), worked up and transferred into the hydrochloride. The title compound is achieved. F: above 13 0°

(under cleavage). IR: 3660-2400 (broad), 1780, 1748, 1700, 1660, 1627, 1545 (Nujol). UV: 259 (11000, CH 3 OH).

Example 89.

3- carbamoyloxymethyl- 73-[( 2S)- 2-( 2- aminothiazol-4-yl)- 2-( 2- acryloylaminoethanesulfonylamino)- acetamido] - 3- cephem- 4- carboxylic acid pivaloyloxymethyl ester hydrochloride id.

0.67 g of 3-carbamoyloxymethyl-73-[(2S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonyloxyamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt (preparation see example 87 b)) and 0.29 ml of iodomethyl pivalate are reacted in 6.7 ml of dimethylformamide analogously to example 70 a), worked up and transferred into the hydrochloride. The title compound is achieved. F: above 125°

(under cleavage). IR: 3660-2400 (broad), 1780, 1748, 1700, 1660, 1627, 1545 (Nujol), UV: 259 (11000, CH3OH).

Example 89.

3- carbamoyloxymethyl- 7B-[( 2S)- 2-( 2- aminothiazol-4- yl)- 2-( 2- acryloylaminoethanesulfonylamino)- acetamido] - 3- cephem- 4- carboxylic acid pivaloyloxymethyl ester hydrochloride.

0.67 g of 3-carbamoyloxymethyl-7(3-[ (2S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonyloxyamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt, (preparation see example 87 b) and 0.29 ml of iodomethylpivalate is reacted in 6.7 ml of dimethylformamide analogously to example 70 a), the hydrochloride is worked up and transferred. The title compound is achieved. F: above 125° (during cleavage). IR: 3660-2400 (broad), 1780, 1748, 1700, 1660, 1627, 1545 (Nujol), UV: 259 (110000, CH3OH).

Example 90.

a) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acetylaminoethanesulfonylamino)-acetamido ]- 3- cephem- 4- carboxylic acid sodium salt.

3.5 g of the 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R)S)-2-(2-BOC-aminothiazol-4-yl) which can be prepared according to example 90 b) -2-(2-acetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 6 ml of CH 2 Cl 2 and 0.9 ml of anisole with 10 ml of trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 180° (during cleavage). [a]^<0>= -2°±1° (0.81% in H20). IR: 3660-2500 (wide). 1765, 1690-1600 (broad), 1522 (Nujol). UV: 260 (13200, H20).

b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acetylaminoethane-sulfonylamino) - acetamido]- 3- cephem- 4- carboxyl-

diphenyl methyl ester.

4.7 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-acetylaminoethanesulfonylamino)-acetic acid, which can be prepared according to example 24 c) are reacted with 4.5 g of 3-(l -methyl-1H-tetrazol-5-ylthiomethyl)-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 50 ml tetrahydrofuran analogously to example 6b) (1.2 g hydroxybenztriazole, 3 times 0.6 g dicyclohexylcarbodiimide in each time 5 ml tetrahydrofuran), worked up and chromatographed. The title compound is achieved. = -76°+l° (1.47%

in CHC13), IR: 3420 (shoulder), 3398, 3300 (broad), 1789,

1722, 1676, 1543 (CH 2 Cl 2 ). UV: 260 (16600, EtOH).

Example 91.

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7 3-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acetylaminoethanesulfonylamino)-acetamido] - 3- cephem- 4- carboxylic acid pivaloyloxy methyl ester hydrochloride.

0.5 g 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acetylaminoethanesulfonylamino)-acetamido ] -3-cephem-4-carboxylic acid sodium salt, (preparation see example 90 a) and 0.2 ml of iodomethylpivalate is reacted in 5 ml of dimethylformamide analogously to example 70 a), worked up and transferred into the hydrochloride. The title compound is achieved.

F: above 180° (during cleavage). [a]^<0>= -20°±1° (1.08% in DMSO). IR: 3660-2500 (wide), 1785, 1750, 1694, 1630,

1545 (Nujol). UV: 260 (12800, CH 3 OH).

Example 92.

a) 3-carbamoyloxymethyl-73-[(2R)-2-(2-aminothiazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

1.1 g of the according to example 92 c (preparable 3-carba-

Moyloxymethyl-73-[(2R)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 5 ml of CP^Cl,, and 0.3 ml of anisole with 10 ml of trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: over 190° (below

A aO

cleavage). [a]p = +49°±1° (0.84% in H2O). IR: 3660-2500 (broad), 1762, 1670, 1610, 1525 (Nujol). UV: 255 (12200,

H2O). b) 3-carbamoyloxymethyl-73-[(2S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

1.7 g of the 3-carbamoyloxymethyl-7B-[]2S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxy-acetylaminoethanesulfonylamino)-acetamido], which can be prepared according to example 92 c) -3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 5 ml of CH2C12 and 0.47 ml of aniso] with 10 ml of trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 190° (during cleavage).

[a]p° = +6°±1° (0.99% in H20). IR: 3660-2500 (broad), 1762, 1705 (shoulder), 1670, 1605, 1525 (Nujol). UV 255 (12800, H20).

c) 3- carbamoyloxymethyl- 73-[( 2R)- 2-( 2- BOC-aminothiazol-4- yl)- 2-( 2- methoxyacetylaminoethanesulfonyl-amino)- acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester

and

3- caffamoyloxymethyl- 73-[( 2S)- 2-( 2- BOC-aminothiazol-4-yl)- 2-( 2- methoxyacetylaminoethanesulfonyl-amino)- acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

6.7 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonyl-) obtainable according to example 4 c)

amino)-acetic acid is reacted with 6 g of 3-carbamoyloxymethyl-73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 70 ml of tetrahydrofuran analogous to example 6b), (1.8 g of hydroxybenztriazole, 3 times 0.93 g of dicyclohexylcarbodiimide in each time 6.6 ml tetrahydrofuran) and worked up. The crude product obtained is chromatographed on 400 g of silica gel [eluent: toluene-acetic acid 4:1, 1:1 and 1:2 mixture and ethyl acetate]. Thereby, the title compound is first eluted with the 2R configuration (for configuration assignment cf. example 7 d).

[a]^° = +20°±1° (0.25% in CHCl3). IR: 3530, 3415 (broad), 1787, 1728, 1690, 1583, 1542 (CH 2 Cl 2 , UV: 259 (16600, EtOH).

The following fractions consist of a binary mixture of the above-mentioned (2R) compound and the (2S) isomer.

From the last fractions, the title compound is obtained with 2S-

f\r\ O

the configuration. fa]^ = +7°±1° (0.92% in CHCl 3 ). IR:

3525, 3418, 3290 (broad), 1785, 1728, 1685, 1584, 1542 (CH 2 Cl 2 ). UV: 259 (16000, EtOH).

Example 93.

a) 3-acetoxymethyl-73-[(2R,S)-2-(2-aminothiazbT-4-yl)-2-(2- propioloyraminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

10.0 g of the 3-acetoxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-propioloyl-aminoethanesulfonylamino)-acetamido obtainable according to example 93 b) ]-3-cephem-4-carboxylic acid. diphenylmethyl ester is reacted in 15 ml CH2C12 and 2.82 ml anisole with 20 ml trifluoroacetic acid analogously to example 1 a), worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. [01]^° = +155°±1° (1.08% in H20) .

IR: 2660-2500 (broad), 2110, 1758, 1680 (shoulder), 1650-1610 (broad), 1520 (Nujol). UV: 250 (16000, H20) . b) 3-acetoxymethyl-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-propioloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 15 g of the 3-acetoxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3- obtainable according to example 83 c) Cepheme-4-carboxylic acid diphenylmethyl ester is reacted with 1.15 ml propiolic acid in 200 ml tetrahydrofuran analogously to example 6b) (2.5 g hydroxybenztriazole, 3 times 1.3 g dicyclohexylcarbodiimide in each time 20 ml tetrahydrofuran), worked up<*>and chromatographed. The title compound is achieved. IR: 3400, 3300, 2120, 1790, 1726,

1700 (shoulder), 1668, 1603, 1540 (CH2CH2). UV: 258 (13500, EtOH).

Preparation of the starting material:

c) 3-acetoxymethyl-73~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 5.5 g of the 3-acetoxymethyl-73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(2,2,2) obtainable according to example 83 d) -trichloroethoxycarbonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted with 5.5 g of zinc dust in 60 ml of acetonitrile-ethyl acetate 1:1 mixture analogously to example 35 c) and worked up. The title compound is obtained. [a]p = +67°±1 (0.78% in CHCl-j). IR: 3320 (shoulder), 3270, 1785, 1740 (shoulder), 1725, 1680 (shoulder), 1626, 1550 (Nujol). UV: 257 12400 (EtOH). d) 3- acetoxymethyl- 7 3-[( 2R, S)- 2-( 2- BOC-aminothiazol-4-yl)- 2-( 2-( 2, 2, 2- trichloroethoxycarbonylamino)-ethanesulfonylamino)- acetamido] - 3- cephem- 4- carboxylic acid diphenyl methyl ester.

4.6 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(2,2,2-trichloroethoxycarbonylamino)-ethanesulfonylamino)-acetic acid obtainable according to example 13 e) reacted with 3.29 g of 3-acetoxymethyl-73-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 40 ml of tetrahydrofuran analogous to example 6b) (0.76 g of hydroxybenztriazole, 3 times 0.67 g of dicyclohexylcarbodiimide in each time 4 ml tetrahydrofuran), worked up and chromatographed. The title compound is achieved. t0^^ = ^°

(0.79% in CHC13). IR: 3420 (shoulder), 3400, 3290, 1787, 1740 (shoulder), 1730, 1700 (shoulder), 1605 (weak), 1541, 1525 (shoulder), 1498 (Nujol). UV: 257 (15300, EtOH).

Example 94.

73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4- carboxyl pivaloyloxymethyl ester hydrochloride.

1.78 g 73~[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonyl-acetamido]-3-cephem-4-carboxylic acid sodium salt (preparation see example 2 a) and 1.027 ml iodomethyl pivalate is reacted in 17.8 ml of dimethylformamide analogously to example 70 a), the hydrochloride is worked up and transferred. The title bond is obtained. F: above 140° (during cleavage). [a]p° =• +70°±1°

(0.88% in DMSO) . IR: 3660-2300 .(broad)., 1780, 1750, 1695, 1630, 1540 (Nujol). UV: 256 (11000, CH 3 OH).

Example 95.

3-(1-sulfomethyl-1H-tetrazol-5-ylthiomethyl)-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid disodium salt.

Analogous to example 18, the hydrate of the title compound is obtained starting from 1.26 g of 3-acetoxymethyl-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4- kar carboxylic acid sodium salt, (preparation see example 1 a) and 1.33 g of 1-sulfomethyl-5-mercapto-1H-tetrazole sodium salt in 4.2 ml of water. F: above 180° (during cleavage). [a]^=+9°±1° (0.77% in H20). IR: 3660-2500 (wide), 1760, 1682, 1605, 1550 (shoulder), 1522 (Nujol). UV: 260 (14800, H20).

Example 96.

3-( 4- carbamoylpyridiniummethyl)- 7B-[( 2R, S)- 2-( 2-aminothiazol-4- yl)- 2-( 2- formylaminoethanesulfonyl-amino)- acetamido]- 3- cephem- 4- carboxylic acid.

3.3 g 3-acetoxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt, (preparation see example 73 a),

1.0 g of isonicotinamide, 9.1 g of sodium iodide and 1.0 g of trichloroacetic acid are reacted in 6.1 ml of water analogously to example 23, worked up, chromatographed and reprecipitated. The title compound is achieved. F: above 175° (during cleavage). IR: 2700-2500 (broad), 1778, 1720 (shoulder), 1688, 1610, 1570, 1520 (Nujol). UV: 260 (13000, H20).

Example 97.

a) 3-carbamoyloxymethyl-73-[(2R)-2-(2-aminothiazol-4- yl)- 2- ethanesulfonylaminoacetamido]- 3- cephem- 4- carboxylic acid sodium salt. 1.8 g of 3-carbamoyloxymethyl-73-[(2R)-2-(2-BOC-aminothiazol-4-yl)-2-ethanesulfonylamino acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester obtainable according to example 97 c) is reacted in 3.75 ml of CH2Cl2 and 1.32 ml of anisole with 15 ml of trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The title compound is achieved. F: above 170° (during cleavage). [a]^° = +44°±1° (0.98% in H 2 O). IR: 3660-2500 (wide). 1761, 1697, 1605, 1521 (Nujol). UV: 258 (12400, H 2 O) . b) 3-carbamoyloxymethyl-7P-[(2S)-2-(aminothiazol-4-yl)-2-ethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt. 2.07 g of 3-carbamoyloxymethyl-73-[(2S)-2-(2-BOC-aminothiazol-4-yl)-2-ethanesulfonylamino-acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester obtainable according to example 97 c) is reacted in 4.3 ml CH2C12 and 1.52 ml anisole with 17.25 ml trifluoroacetic acid analogously to example 1 a), is worked up, chromatographed and reprecipitated. The title compound is achieved. F: above 170° (during cleavage). [a]p° = +78°±1° (1.06% in H2O). IR: 3660-2500 (wide), 1760, 1700, 1605, 1520 (Nujol). UV: 255 (12700, H 2 O). c) 3-carbamoyloxymethyl-7B-[(2R)-2-(2-BOC-aminothiazol-4-yl)-2-ethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

and

•> 3- carbamoyloxymethyl- 7B-[( 2S)- 2-( 2- BOC-aminothiazol-4-yl)- 2- ethanesulfonylaminoacetamido]- 3- cephem- 4-carboxylic acid diphenyl methyl ester. 3 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-ethanesulfonylaminoacetic acid obtainable according to example 97 d) is reacted with 3 g of 3-carbamoyloxy-methyl-7B-amino-3-cephem -4-carboxylic acid diphenylmethyl ester in 40 ml tetrahydrofuran analogous to example 6 b), /.73 g hydroxybenztriazole, 3 times 0.67 g dicyclohexylcarbodiimide in each time 4 ml tetrahydrofuran)

and processed. The precipitated crude product is chromatographed on

450 g silica gel [stage column, eluent: toluene-ethyl>-acetate 3:2, 1:1 and 1:2 mixture]. Thereby, the title compound is first eluted with the 2R configuration (for configuration assignment cf. ex. 7 d). [α]D = -26°±1 (0.79% in CHCl 3 ). IR: 3530, 3420, 3300, 1778, 1715, 1698 (shoulder), 1582, 1530 (CH 2 Cl 2 ). UV: 260 (15800, EtOH).

The following fractions consist of a mixture of the (2R) and (2S) title compounds. To osist, the uniform 2S title compound is eluted. [α]^ = -12°+1° (0.83% in CHCl 3 ). IR: 3530, 3420, 3300, 1775, 1715, 1695 (shoulder), 1582, 1530 (CH 2 Cl 2 ). UV: 260 (16000, EtOH).

The starting material is produced in the following way:

d) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-ethanesulfonyl-aminoacetic acid. 3 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetic acid is reacted in 30 ml of CH2Cl2 with 1.82 ml of ethanesulfochloride analogous to example 6 c), (1.05 ml of N,0 -bis-(trimethylsilyl)-acetamide, 1.043 ml of pyridine) and worked up. The title compound is obtained, which is further processed without characterization.

Example 98.

a) 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 21 a), the title compound is obtained starting from 8.07 g (10 mmol/ 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido ]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 40 ml of absolute methylene chloride, with 8 ml of anisole and 40 ml of trifluoroacetic acid, which is identical to that of Example 21. F: above 175° (under decomposition). UV: 253 ( 10500), water. [a]^0 = +95°±1° ]0.880% in water). b) 73-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

A solution of 9.17 g (20 mmol) of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino-acetic acid prepared according to example 98 c) and 7.3 g (20 mmol) of 73-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in 200 ml of absolute tetrahydrofuran in the presence of 2.7 g of 1-hydroxybenztriazole and 4.54 g of dicyclohexylcarbodiimide is stirred for 16 hours at room temperature. It is then filtered off mixed dicyclohexylurea and the filtrate is evaporated. The residue, which is dissolved in 600 ml of ethyl acetate, is washed with 0.5 N hydrochloric acid and sodium chloride solution. After drying the organic phase with sodium sulfate, the solvent is removed in a rotary evaporator and the precipitated crude product is purified on silica gel (a 30

times the amount) with methylene chloride/ethyl acetate (1:1)

as eluent, from which the title compound is obtained as amorphous powder. DC (silica gel, identification UV 366). Rf. about. 0.25 (methylene chloride/ethyl acetate 1:1). c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetic acid.

To a suspension of 22.92 g (60 mmol) of the (2R,S)-2-(2-aminoethnasulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid obtainable according to example 13 d) in 480 ml of absolute tetrahydrofuran are added while stirring, and moisture exclusion at room temperature 60 ml of N,0-bis-(trimethylsilyl)-acetamide. The reaction mixture is stirred for 1 hour at 65°, cooled to

0° and 7.1 ml of absolute pyridine and 7 ml of methane sulphochloride are added. After a reaction time of 2 hours, a further 2.4 ml of pyridine and 2.3 ml of methane sulphochloride are added to the reaction mixture heated to room temperature. After a further 16 hours of reaction time, the solvent is removed on a rotary evaporator, the residue is dissolved in ethyl acetate and washed 3 times each time with cold IN hydrochloric acid and saturated sodium chloride solution. The organic phase dried over sodium sulfate is freed from solvent on a rotary evaporator, from which the title compound is obtained as a beige, amorphous powder,

which can be used in the next synthesis step without further purification. Rf 96: 0.48 (silica gel, UV 366).

Example 99.

7B-[( 2R, 2)- 2-( 2- aminothiazol-4- yl)- 2-( 2- methanesulfonylaminoethanesulfonylamino)- acetamido]- 3- cephem- 4- carboxylic acid pivaloyloxy methyl ester hydrochloride.

600 mg of 7 B - [(2R,S)-2-(2-methanesulfonylaminoethanesulfonyl-amino)-acetamido]-3-cephem-4-carboxylic acid pivalate is stirred in 6 ml of dimethylformamide for 30 minutes at 0°C. Then 10 ml of phosphate buffer of pH 87 is added and it is stirred for a further 5 minutes at 0°C. It is then taken up in 25 ml of ethyl acetate, washed twice with rnette tea, aqueous sodium chloride solution and dried over sodium sulphate. It is then filtered off, and 1.6 ml of 0.7 N hydrochloric acid in methylene chloride is added. The resulting amorphous precipitate is separated by decantation, washed 3 times with hexane and dried at room temperature in a vacuum. Then triturate with ether, filter from the ether and dry again. The title compound is obtained, which still contains 0.5 g of dimethylformamide. F: above 100°C (during decomposition). +60°±1° (0.810% in DMSO) . UV: 255

(103 00, CH 3 OH).

Example 100.

a) 3-acetoxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-dephen-4-carboxylic acid sodium salt.

Analogous to example 21 a), the title compound is obtained in the form

of the 1,5-hydrate starting from 7.03 g (8 mmol) according to example 100 b) prepared 3-acetoxymethyl-78-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2 -(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 35 ml of methylene chloride, in the presence of 7 ml of anisole with 35 ml of trifluoroacetic acid. F: above 115°C (during decomposition). Rf: (silica gel, UV 366). [a] 2 0 u= 0 +48±

1° (0.825% in water). UV: 255 (11900, water). b) 3-acetoxymethyl-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 98 b), the title compound is obtained as amorphous powder starting from 9.17 g (20 mmol) according to example 98 c) prepared (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-( 2-methanesulfonylaminoethanesulfonylamino)-acetic acid, dissolved in 200 ml of absolute tetrahydrofuran, in the presence of 2.7 g of 1-hydroxybenztriazole and 4.54 g of dicyclohexylcarbodiimide with 8.77 g (20 mmol) of 3-acetoxymethyl-7B-amino-3-cephem -4-carboxylic acid diphenyl methyl ester. Rf: 0.58 (silica gel, UV: 366, ethyl acetate).

Example 101.

3- acetoxymethyl- 7 B - [ ( 2R, S)- 2-( 2- aminothiazol-4-yl)- 2-( 2- methanesulfonylaminoethanesulfonylamino)-acetamido ] - 3- cephem- 4- carboxylic acid pivaloyloxymethyl ester hydrochloride.

1.9g (3 mmol) 3-acetoxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt and 0.78 ml of iodomethyl pivalate are reacted in 19 ml of dimethylformamide analogously to example 99 and worked up, from which the title compound is obtained, which contains 0.5 equivalents of dimethylformamide. F: 20°

above 95° (during cleavage). = +24±1° (1.07% in DMSO).

UV: 260 (12100 in methanol).

Example 102.

a) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylamino-ethanesulfonylamino)- acetamido] - 3- cephem- 4- carboxyl-acid sodium salt.

Analogously to example 21 a), the title compound is obtained in the form of the dihydrate starting from 7.15 g (7.5 mmol) of the 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B prepared according to example 102 b) - [(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 37 ml of methylene chloride, in the presence of 7 .2 ml of anisole with 37 ml of trifluoroacetic acid F: above 123° (under decomposition). Rf: 0.25 (silica gel, UV 266. [a]^ = -4°±1° (0.802% in water). UV: 260 (13450, water). b) 3 - ( l- methyl- lH- tetrazoJL - 5- ylthiomethyl) - 7B-[ ( 2R, S) - 2- (2-bOC-aminothiazol-4-yl)-2-(2-methanesulfonylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester.

analogously to example 98 b), the title compound is obtained as an amorphous powder starting from 9.17 g (20 mmol) of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2 prepared according to example 98 c) -(2-methanesulfonylaminoethanesulfonylamino)-acetic acid,

dissolved in 200 ml of absolute tetrahydrofuran, in the presence of 2.7 g of 1-hydroxybenztriazole and 4.54 g of dicyclohexylcarbodiimide with 19.1 g (20 mmol) of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7 3 -amino-3-cephem-4-carboxylic acid diphenyl methyl ester. Rf: 0.50 (silica gel, UV: 366, ethyl acetate).

Example 103.

a) 3 carbamoyloxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 21 a), the title compound is obtained in the form of the dihydrate starting from 1.05 g (1.2 mmol) of the 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2- BOC-aminothiazol-4-yl)-2-(2-methanesulfonyl-aminoethanesulf onylamino)-acetamido j-3-cephem-4-carboxylic acid di phenyl methyl ester, dissolved in 6 ml of methylene chloride, in the presence of 1 ml of anisole with 6 ml of trif luoacetic acid. F: above 108°

(during cleavage". Rf: 96: 0, 22 (silica gel. UV: 366).

[a]^ ? fl °= +44°±1° (1.105% in water). UV: 255 (12600, water). b) 3-carbamoyloxymethyl-7B-[(2R)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 21 a), the title compound is obtained in the form of the 1.5 hydrate starting from 2.51 g (2.85 mmol) of the 3-carbamoyloxymethyl-7B-[(2R)-2-(2) prepared according to example 103 d) -BOC-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 14 ml of methylene chloride, in the presence of 2.5 ml of anisole with 14 ml of trifluoroacetic acid . Q:

above 105° (during decomposition). Rf 96: 0.22 (silica gel,

UV 366). = +35° + l° (0.884% in water). UV: 255 (2000, water). c) 3-carbamoyloxymethyl-7B-[(2R,S)-2-(aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-4-carboxylic acid sodium salt

Analogous to example 21 a), the title compound is obtained in the form of the dihydrate starting from 3.96 g (4.5 mmol) of the 3-carbamoyloxymethyl-7b~[(2S)-2-(2-BOC-) prepared according to example 103 d) aminothiazol-4-yl)-2-(2-methanesulfonylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester dissolved in 22.5 ml of methylene chloride, in the presence of 4 ml of anisole with 22.5 ml of trifluoroacetic acid. F: above 122°

(under cleavage). Rf 96: 0.22 (silica gel, UV 366).

[a]^ = +59°+l° (0.958% in water). UV: 255 (13400, water). d) 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester).

3- carbamoyloxymethyl- 7 g-[( 2R)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2- methanesulfonylaminoethanesulfonylamino)-acetamido ]- 3- cephem- 4- carboxylic acid diphenyl methyl ester and

3- carbamoyoxymethyl- 7 p-[( 2S)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2- methanesulfonylaminoethanesulfonylamino)-acetamido |- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogous to example 98 d), the title compound is obtained as a 2R,S-diastereomer mixture" starting from 9.17 g (20 mmol) of the (2R,S)-2-(2-BOC-aminothiazole-4-) prepared according to example 98 c) yl)-2-(2-methanesulfonylamino)-ethanesulfonylaminoacetic styrene, dissolved in 200 ml of absolute tetrahydrofuran, in the presence of 2.7 g of 1-hydroxybenztriazole and 4.53 g of dicyclohexylcarbodiimide with 8.8 g (20 mmol) of 3-carbamoyloxymethyl-1- 7 B-amino-3-cephem-4-carboxylic acid diphenyl methyl ester The crude product is chromatographed on silica gel (1000 g) with methylene chloride-ethyl acetate 1:1, and ethyl acetate as eluent, from which the title compound with 2R configuration, (Rf: 0.48, silica gel, ethyl acetate), 2R,S configuration and 2S configuration (Rf: 0.43 silica gel, ethyl acetate) are isolated as amorphous powder (for configuration assignment compare example 7 d).

Example 104.

a) 3- carbamoyloxymethyl- 7 B-[( 2S)- 2-( 2- aminothiazol-4-yl)- 2-( 2-( 4- nitrobenzenesulfonylamino)- ethanesulfonylamino) - acetamido]- 3- cephem- 4- carboxylic acid sodium salt .

In addition to example 67 and in analogy to example 29 a), the title compound was obtained as a yellowish powder in the form of the dihydrate by reacting 0.85 g (0.86 mmol) of 3-carbamoyloxymethyl-7B-[(2S)-2-(2 -BOC-aminothiazol-4-yl)-2-(2-(4-nitro-benzenesulfonylamino)-ethanesulfonylamino)-acetamido -3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.85 ml of anisole with 5 ml of trifluoroacetic acid in 5 ml methylene chloride. F: above 155° (during cleavage). Rf: approx. 0.45 (silica gel "Opti-UPC" 12, water-acetonitrile 4:1). [a]D = +5 +1° (0.673 in water). UV: 258 (23200 , in water) . b) 3- carbamoyloxymethyl- 7 g-[( 2R)- 2-( 2- aminothiazol-4-yl)- 2-( 2-( 4- nitrobenzenesulfonylamino)- ethanesulfonylamino )- acetamido]- 3- cephem- 4- carboxylic acid sodium salt . As a supplement to example 67 and in analogy to example 29 a), the title compound is obtained as a pale yellow powder in the form of the dihydrate by reaction of 0.8 g (0.81 mmol) 3-carbamoyloxymethyl-7 g- [ ( 2R)-2- ( 2-BOC-aminothiazol-4-yl)-2-(2-(4-nitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cef em-4-carboxylic acid diphenyl methyl ester in the presence of 0.8 ml of anisole with 4 ml of trifluoroacetic acid in 4 ml methylene chloride. F: above 112° (during cleavage). Rf: approx. 0.45 20 ° (silica gel "Opti-UPC" 12, water-acetonitrile 4:1). [a] Q = +36°+l° (0.515% in water). UV: 256 (21900 in water). c) 3- carbamoyloxymethyl- 7 3-[( 2R)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2-( 4- nitrobenzenesulfonylamino)- ethanesulfonylamino )- acetamido]- 3- cephem- 4 - carboxylic acid diphenyl methyl ester.

and

3- Carbamoyloxymethyl- 7g-[( 2S)- 2-( 2- BQC- aminothiazol-4- yl)- 2-( 2-( 4- nitrobenzenesulfonylamino)- ethanesulfonylamino) - acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogously to example b), the crude product is obtained as a 2R,S-diastereomeric mixture by treating 4.52 g (8.0 mmol) of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2 -(2-(4-nitrobenzenesulfonylamino)-acetic acid with 3.51 g (8 mmol) of 3-carbamoyloxymethyl-76-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1.08 g of 1-hydroxybenztriazole and 1.81 g dicyclohexylcarbodiimide in 80 ml of tetrahydrofuran. The crude product is chromatographed on silica gel (300 g) with methylene chloride-ethyl acetate 7:3 as eluent, and from the first fractions the title compound with 2R configuration (Rf: 0.38) is eluted and from the subsequent fractions the title compound 2S configuration.

(Rf: 0.33, silica gel, methylene chloride/ethyl acetate 1:1).

Example 105.

a) 3- carbamoyloxymethyl- 7 B-[( 2S)- 2-( 2- aminothiazol- 4-y1)- 2-( 2-( 4- aminobenzenesulfonylamino)- ethanesulfonylamino)- acetamido]- 3- cephem- 4- carboxylic acid sodium salt . Analogously to example 29 a), the title compound is obtained as a yellowish powder in the form of the dihydrate by reacting 3.06 g (3.2 mmol) of the 3-carbamoyloxymethyl-78-[(2S)-2-( 2-BOC-aminothiazol-4-yl)-2-(2-(4-aminobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 15 ml of anisole with 3 ml of trifluoroacetic acid in 15 ml of methylene chloride. F: above 150° 8under decomposition).[a] 2 0 0= +52+1° (1.03% in water). UV: 258 (28500 in water). b) 3- carbamoyloxymethyl- 7 3-[( 2R) — 2-( 2- aminothiazol-4-yl)- 2-( 2-( 4- aminobenzenesulfonylamino)- ethanesulfonylamino) - acetamido]- 3- cephem- 4- carboxylic acid sodium salt .

Analogous to example 29 a), the title compound is obtained as a yellowish powder in the form of the dihydrate by reacting 2.6 g (2.7 mmol) of the 3-carbamoyloxymethyl-7e-[(2R)-2-( 2-BOC-aminothiazol-4-yl)-2-(2-(4-aminobenzenesulfonylamino)-ethanesulfonylamino)-acetamido -3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 2.6 ml of anisole with 13 ml of trifluoroacetic acid in 13 ml methylene chloride. F: above 150° (during cleavage), [a] 2 0°= +38°±1°

(1.03% in water). UV: 258 (28900, in water).

c) 3- carbamoyloxynethyl- 7 B-[ ( 2S)- 2-( 2- boc- aminothiazol-4- yl)- 2-( 2-( 4- aminobenzenesulfonylamino)- ethanesulfonylamino )- acetamido- 3- cephem- 4- carboxylic acid diphenyl methyl ester. A solution of 3.5 g (3.55 mmol) of the 3-, arbamoyloxymethyl-7B-[ (2S)-2-(2-BOC-aminothiazol-4-yl)-2-( 2-(4-nitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester in 70 ml of ethyl acetate is hydrated in the presence of 1.7 g of 10% palladium/charcoal catalyst at normal pressure and room temperature. It is filtered off and washed with ethyl acetate, the filtrate is evaporated and the title compound is obtained as a yellow powder. Rf: 0.44 (silica gel, UV: 266, ethyl acetate). d) 3- carbamoyloxynethyl- 7 B-[( 2R)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2-( 4- aminobenzenesulfonylamino)- ethanesulfonylamino)- acetamido]- 3- cephem- 4 - carboxylic acid diphenyl methyl ester.

A solution of 2.96 g 83 mmol) of the 3-carbamoyloxynethyl-7 i -[(2R)-2-(2-BOC-aminothiazol-4-yl9-2-(2-(4) obtained according to example 104 c) -nitrobenzenesulfonylamino (9-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in 600 ml of ethyl acetate is hydrated in the presence of 1.5 g of 10% palladium/charcoal catalyst at normal pressure and room temperature. After absorption of 3 equivalents of hydrogen gas, filtered off the catalyst and washed with ethyl acetate. The filtrate is evaporated, from which the title compound is obtained. Rf: 0.46 (silica gel,

UV 366, ethyl acetate?.

Example 106.

a) 3- acetoxymethyl- 7B-[ ( 2R, S)- 2-( 2- aminothiazol-4- yl)- 2-( 2-( 4- aminobenzenesulfonylamino)- ethanesulfonylamino)-acetamido]_- 3- cef em- 4- kar bok syl sy r ena tr ium salt.

Analogous to example 29 a), the title compound is obtained as a yellowish powder in the form of the 1,5-hydrate by reacting 3.75 g (2.9 mmol) of 3-acetoxynretyl-7 B-[ (2R,S)-2-(2 -BOC-aminothiazol-4-yl)-2-(2-(4-aminobenzenesulfonylamino)-ethanesulfonylamino )-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 3.8 ml of anisole with 19 ml of trifluoroacetic acid in 19 ml methylene chloride. F: above 152° (during cleavage). = +48°±1° (0.869% in water). UV: 258 (28500 in water). b) 3- acetoxymethyl- 7B-[( 2R, S)- 2-( 2- BOC- aminothiazol- 4-yl)- 2-( 2-( 4- aminobenzenesulfonylamino)- ethanesulfonylamino)- acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

A solution of 7.5 g (7.6 mmol) of the 3-acetoxymethyl-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-obtained according to example 39 b) (2-(4-Nitrobenzenesulfonylamino)-ethanesulfonylamino-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in 40 ml of ethyl acetate is hydrated in the presence of 3.5% palladium/charcoal catalyst at normal pressure and room temperature. After absorption of 3 equivalents hydrogen gas, the catalyst is filtered off and washed with ethyl acetate. The solvent is removed on a rotary evaporator, from which the title compound is obtained. Rf:

0.58 (silica gel, UV: 366, ethyl acetate).

Example 107.

a) 3-( 1- methyl- 1H- tetrazol- 5- ylthiomethyl)- 7B-[( 2R, S)-2-( 2-( 2, 4- dinitrobenzenesulfonylamino)- ethanesulfonylamino )- 2-( 2- aminothiazol- 4-yl)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 29 a), the title compound is obtained as a yellowish powder by reaction of 5.6 g (5.15 mmol) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7 8-[ (2R,S)- 2-(2-2,4-dinitro-benzenesulfonylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido-3-cephem-4-carboxylic acid diphenylmethyl ester in the presence of 5.6 ml of anisole and 20 ml of trifluoroacetic acid in 28 ml of methylene chloride. b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl-70-[(2R,S)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2- BOC-aminothiazole) - 4-y1)-acetamido1-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogously to example 29 b), the title compound is obtained as a pale yellow, amorphous powder by treating 6.1 g (10 mmol)

of the (2R,S)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-ethyl acetate obtained according to example 40 c) with 4.94 g 3-(1-Methyl-1H-tetrazol-5-ylthiomethyl)-7-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 1.35 g of 1-hydroxybenztriazole and 2.26 g of dicyclohexylcarbodiimide in 120 ml of tetrahydrofuran (reaction time : 16 hours at room temperature). Rf: 0.70 (silica gel, UV: 366, ethyl acetate).

Example 108.

a) 3- carbamoyloxymethyl- 7 8-[( 2R, S)- 2-( 2-( 2, 4- dinitro-benzenesulfonylamino)- ethanesulfonylamino)- 2-( 2- aminothiazol-4- yl)- acetamido]- 3- cephem- 4- carboxylic acid sodium salt.

Analogously to example 29 a), the dihydrate of the title compound is obtained as a yellowish powder by reacting 7.0 g (6.78 mmol) of 3-carbamoyloxymethyl)-70-[(2R,S)-2-(2-(2,4- dinitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 7.0 ml of anisole and 35 ml of tri-

fluoroacetic acid in 3 5 ml of methylene chloride. [aj = +40 +1°

(0.977% in water). Rf: 0.10 (Silica gel "Opti-UPC" 12, water), uv: 250 (2300O in water). b) 3-carbamoyloxymethyl-78-[(2R,S)-2-(2-(2,4-dinitro-benzenesulfonylamino)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido] - 3- cephem- 4- carboxyl-acid diphenyl methyl ester.

Analogously to example 29 b), the title compound is obtained as a pale yellow, amorphous powder by treating 9.17 g (15 mmol)

of the (2R,S)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-2-(2-30C-aminothiazol-4-yl)-acetic acid obtained according to example 40 b) with 6.6 g carbamoyloxymethyl-76-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 2.03 g of 1-hydroxybenztriazole and 33.4 g of dicyclohexylcarbodiimide in 200 ml of tetrahydrofuran (reaction time 16 hours at room temperature). DC (silica gel, identification UV 266).

RF 0.25 (methylene chloride/ethyl acetate 1:1).

Example 109.

a) 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-<-2,4-dinitro-benzenesulfonylamino)-acetamido]-3-cephem-4-carboxyl acid sodium salt. Analogous to example 29 a), the title compound is obtained in the form of the dihydrate by reaction of 5.02 g (5.9 mmol) 7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2- (2,4-dinitrobenzenesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 5 ml of anisole with 25 ml of trifluoroacetic acid in 25 ml of methyl-2 0°

linoleic chloride. F: above 150° (during cleavage).[a] = +24°+l°

(0.362% in water). UV: 246 (19800, water). Rf.: 0.33 ("silica gel OPTI-UPC 12, water/acetonitrile 4:1).

b) 7e-[( 2R, S)- 2-( 2- BOC-aminothiazol-4- yl)- 2-( 2, 4-dinitrobenzenesulfonyl)- aminoacetamido]- 3- cephem- 4-

carboxylic acid diphenyl methyl ester.

Analogous to example 29 b), the title compound is obtained by treating 10.06 g (20 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2,4-dinitrobenzenesulfonylamino)-acetic acid with 7.33 g (20 mmol) of 78-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 2.7 g of 1-hydroxybenztriazole and 4.54

g N,N<1->cyclohexylcarbodiimide in 200 ml tetrahydrofuran (reaction time 16 hours at room temperature). Rf: 0.70 (methylene chloride/ethyl acetate 1:1).

Preparation of the starting material:

c) (2r,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2,4-dinitro-benzenesulfonylaminoacetic acid).

A suspension of 40.95 g (0.15 mol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-aminoacetic acid in 500 ml absolute tetrahydrofuran is added under stirring, moisture exclusion and nitrogen atmosphere 109 ml N,O-bis(trimethylsilyl)-acetamide. After a reaction time of 1 hour at 60°, the reaction mixture is cooled to 0°, 13 ml of pyridine and 48 g (0.18 mol) of 2,4-dinitrobenzene sulphochloride are added and then stirred for 16 hours at room temperature. After removal of the solvent, the residue is taken up in 1500 ml of ethyl acetate and washed 3 times with 1.0N hydrochloric acid and saturated aqueous sodium chloride solution. After drying over sodium sulfate, the solvent is removed on a rotary evaporator. The residue is slurried in ether and filtered, from which the title compound is obtained as an amorphous powder. Rf: 0.35 (silica gel, UV 366, chloroform/methanol/acetic acid 75:22:13).

Example 110. a) 3-carbamoyloxymethyl-78-[(2S)-2-(2-aminothiazol-4-yl)-2-(2,4-dinitrobenzenesulfonylamino)-acetamido]-33-cephem-4-carboxylic acid sodium salt.

Analogously to example 29 a), the title compound is obtained in the form of the dihydrate by reacting 2.78 g (3 mmol) of 3-carbamoyloxymethyl-7ø-[(2S)-2-(2-BOC-aminothiazol-4-y1)-2- (2,4-Di-nitrobenzenesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 2.8 ml of anisole with 14 ml of trifluoroacetic acid in 14 ml of methylene chloride. F: above 131°

(under cleavage). Rf 96: 0.38 (silica gel, UV 366).

[a]£ 2 0°- +88°±1' (0.497% in water). UV: 250 (22300, water).

b) 3- carbamoyloxymethyl- 7B- [( 2R9- 2-( 2- BOC- aminothiazol-4-yl)- 2-( 2, 4- dinitrobenzenesulfonylamino)- acetamido]-3- cephem- 4- carboxylic acid sodium salt. Analogous to' example 29 a) the title compound is obtained in the form of the dihydrate by reacting 3.51 g (2.8 mmol) of 3-carbamoyloxymethyl-7B-[(2R)-2-82-bOC-aminothiazol-4-yl)-2-( 2,4-dinitrobenzenesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester in the presence of 3.5 ml of anisole with 17.5 ml of trifluoroacetic acid in 17.5 ml of methylene chloride. F: above 130° (during cleavage). Rf 96: approx. 0.30 (silica gel, UV 266). [a]* 2 f) °= -36°+l° (0.556% in water). UV: 250 (21800, water). c) 3- carbamoyloxymethyl- 7 B-[( 2R)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2-( 2, 4- dinitrobenzenesulfonylamino)- ethanesulfonylamino )- acetamido]- 3- cephem-4-carboxylic acid diphenyl methyl ester.

and

3- carbamoyloxymethyl- 7 B-[( 2S)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2-( 2, 4- dinitrobenzenesulfonylamino)- ethanesulfonylamino) - acetamido]- 3- cephem- 4 - carboxylic acid diphenyl methyl ester.

Analogous to example 29 b), the crude product is obtained as a 2R,S-diastereomer mixture by treating 10.06 g (20 mmol)

of the (2R,S)-2-(2-BOC-aminothiazol-4-yly-2-(2-(2,4-dinitrobenzenesulfonylamino)-

ethanesulfonylamino)-acetic acid with 8.79 g (20 mmol) of 3-carbamoyloxymethyl-76-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in the presence of 2.7 g of 1-hydroxybenztriazole and 4.54 g of dicyclohexylcarbodiimide in 80 ml of tetrahydrofuran (reaction time 16 hours at room temperature). The crude product is chromatographed on silica gel (1000 g) with toluene/ethyl acetate 4:1 as eluent and in the first fractions the title compound is eluted with the 2R configuration (Rf: 0.63) and the last fractions the title compound with the 2S configuration (Rf: 0.15 , silica gel, methylene chloride/ethyl acetate 1:1).

Example 111.

a) 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-O2-difluoromethanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 21 a), the title compound is obtained in the form of the 1,5-hydrate starting from 1.85 g (2.2 mmol) 7ø-[(2R,S)-2-(2-BOC-aminothiazol-4-yl) - 2-(,2-difluoromethanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 10 ml of methylene chloride, in the presence of 1.85 ml of anisole with 10 ml of trifluoroacetic acid. F: over 170°

(under cleavage). Rf 96. 0.38 (silica gel, UV 366).

20°

[ci]q = +98° + l° (0.890% in water). Uv: 250 (10600, water).

b) 7ø-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-difluoro-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 98 b), the title compound is obtained as amorphous powder starting from 2.47 g (5 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-difluoromethanesulfonylaminoethane-sulfonylamino )-acetic acid, dissolved in 60 ml of absolute tetrahydrofuran, in the presence of 0.68 g of 1-hydroxybenztriazole and 1.13 g of dicyclohexylcarbodiimide with 1.83 g (5 mmol) of 7ø-amino-3-cephem-4-carboxylic acid diphenyl methyl ester. Rf: 0.73 (silica gel, UV 366, ethyl acetate). c) (2R,S)-2-(2-BOC aminothiol-4-yl)-2-(2-difluoro-methanesulfonylaminoethanesulfonylamino)-acetic acid.

Analogous to example 98 c), the title compound is obtained after esterification of 11.41 g (30 mmol) of (2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid with 30 ml N,O-bis-(trimethylsilyl)-acetamido in 150 ml of tetrahydrofuran after reaction with 5.87 g of difluoromethanesulfochloride in the presence of 3.1 ml of pyridine, which can still be purified on silica gel (300 g) with methylene chloride-ethyl acetate as eluent. Rf 96: 0.71 (silica gel, UV 366).

Example 112.

a) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-difluoromethanesulfonyl-aminoethanesulfonylamino)- acetamido-3-cephem-4-carboxylic acid sodium salt. Analogous to example 21 a), the title compound is obtained in the form of the dihydrate starting from 2.6 g (2.68 mmol) 3-(1-methyl-1H-5-ylthiomethyl)-7B-[(2R,S)-2- (2-BOC-aminothiazol-4-yl)-2-(2-difluoromethanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 13 ml of methylene chloride, in the presence of 2.6 ml of anisole and 13 ml of trifluoroacetic acid. F: above 150° (during cleavage). Rf 96: (sili-0 0 o kagel, UV 366).[a]^ = -4°±1° (0.984% in water). UV 258 (14400, water). b) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(difluoromethane- sulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 98 b), the title compound is obtained as amorphous powder starting from 2.47 g (5 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-difluoromethanesulfonylaminoethanesulfonylamino) -acetic acid, dissolved in 60 ml of absolute tetrahydrofuran, in the presence of 0.68 g of 1-hydroxybenztriazole and 1.13 g of dicyclohexylcarbodiimide with 2.47 g (5 mmol) of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl) -7 6-amino-3-cephem-4-carboxylic acid diphenyl methyl ester . Rf: 0.65 (silica gel, UV 366, ethyl acetate).

Example 113.

a) 3-carbamoyloxymethyl-78-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-difluoromethanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 21 a), the title compound is obtained in the form of the 1,8-hydrate starting from 1.5 g (1.64 mmol) 3-carbamoyloxymethyl)-78-[(2R,S)-2-(2-BOC-aminothiazole) -4-yl)-2-(2-difluoromethanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 7.5 ml of methylene chloride, in the presence of 1.5 ml of anisole with 7.5 ml of trifluoroacetic acid. F: above 145° (during cleavage). Rf 96: 0.34 (silica gel, UV 366). [ a] £u = +50°±1° (0.921% in water). UV 256 (13000, water). b) 3- carbamoyloxymethyl)- 7 8-[( 2R, S)- 2-( 2- BQC- aminothiazol-4- yl)- 2-( 2- difluoromethanesulfonylaminoethanesulfonylamino)- acetamido]- 3- cephem- 4 - carboxylic acid diphenyl methyl ester.

Analogously to example 98 b), the title compound is obtained as amorphous powder starting from 1.7 g (3.44 mmol) (2R,S)-2-82-BOC-aminothiazol-4-yl)-2-(2-difluoromethanesulfonylaminoethane-sulf onylamino)-acetic acid, dissolved in 40 ml of absolute tetrahydrofuran, in the presence of 0.47 g of 1-hydroxybenztriazole and 0.78 g of dicyclohexylcarbodiimide with 1.51 g (3.44 mmol) of 3-carbamoyloxymethyl-7-8-amino-3- cephem-4-carboxylic acid diphenyl methyl ester. Rf: 0.51 (silica gel, uV 366, ethyl acetate).

Example 114.

a) 76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-difluoromethane-sulfonylamino-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 21 a), the title compound is obtained in the form of the 2,5-hydrate starting from 3.5 g (4.76 mmol) 7B-[(2R,3)-2-(2-BOC-aminothiazol-4-y1) -2-difluoromethanesulfonylamino-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 17.5 ml of methylene chloride, in the presence of 3.5 ml of anisole with 17.5 ml of trifluoroacetic acid. F:_ above 161° (during cleavage). Rf 96. 0.30 (silica gel, uv 366). [a] ^ = +106°+1° (0.746% in water). UV 252 (10500, water). b) 7B-[( 2R, S)- 2-( 2- B0C-aminothiazol-4- yl)- 2- difluoro-methanesulfonylaminoacetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogous to example 98 b), the title compound is obtained as amorphous powder starting from 1.94 g (5 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-difluoromethanesulfonylaminoacetic acid, dissolved in 40 ml of absolute tetrahydrofuran, in the presence of 0.68 g of 1-hydroxybenztriazole and 1.13 g of dicyclohexylcarbodiimide with 1.89 g of 7B-amino-3-cephem-4-carboxylic acid diphenyl methyl ester. Rf: 0.58 (silica gel, UV 366, ethyl acetate). c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-difluoromethanesulfonylaminoacetic acid.

Analogously to example 98 c), the title compound is obtained after esterification of 13.65 g (50 mmol) of (2R,S)-2-amino-2-(2-BOC-aminothiazol-4-yl)-acetic acid with 40 ml of N,O -bis(trimethyl)-acetamide in 200 ml of tetrahydrofuran and after reaction with 9.03 g of difluoromethanesulfochloride in the presence of 4.8 ml of pyridine which can still be purified on silica gel, (420 g) with methylene chloride/ethyl acetate as eluent. Rf 96: 0.61 (silica-

gel, UV 366).

Example 115.

a) 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-difluoromethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 21 a) the title compound i is obtained

form of the dihydrate starting from 6.47 g (8.0 mmol) of 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-difluoromethanesulfonylaminoacetamido]-3-cephem -4-carboxyl-acid diphenyl methyl ester, dissolved in 32.5 ml of methylene chloride,

in the presence of 6.5 ml of anisole with 32.5 ml of trifluoroacetic acid.

F: above 142° (during cleavage). Rf 96: 0.28 (silica gel,

UV 366). [a] ^ = +57°+l° (1.152% in water). UV 257

(13000, water). b) 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-BQC-aminothiazol-4-yl)-2-difluoromethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 98 b), the title compound is obtained as an amorphous powder starting from 4.65 g (12 mmol) of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2 obtained according to example 114 c) -difluoromethanesulfonylaminoacetic acid, dissolved in 95 ml of absolute tetrahydrofuran, in the presence of 1.62 g of 1-hydroxybenztriazole and 2.72 g of dicyclohexylcarbodiimide with 5.3 g of 3-carbamoyloxy 1-7 ø-amino-3-cephem-4-carboxylic acid diphenyl methyl ester. Rf: 0.58 (silica gel, UV 366, ethyl acetate).

Example 116.

a) 7B-[(2R,S)-2-(2-aminothiazoly1-4-y1-2-(2-pyrid-3-ylsulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 21 a), the title compound is obtained in the form of the 1,5-hydrate starting from 4.0 g (4.5 mmol) 7ø-[(2R,S)-2-(2-BOC-aminothiazol-4-yl) -2-(2-pyrid-3-ylsulfonylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 20 ml of methylene chloride in the presence of 3.3 ml of anisole with 20 ml of trifluoroacetic acid. F: above 164°

(under cleavage). Rf 96: 0.30 (silica gel, UV 366).

Pf<io>

!"a£ = +80°±1° (0.779% in water). UV 254 (12300, water). b) 76 - i ( 2R, S)- 2-( 2- BOC-aminothiazol-4- yl) - 2-(2-pyrid-3-ylsulfonylaminoethanesulfonylamino)-acetamido]-3-cef em-4-carboxyl acid-di f phenyl methyl ester.

Analogous to example 98 b), the title compound is obtained as an amorphous powder starting from 4.7 g (9 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-pyrid-3- ylsulfonylaminoethanesulfonylaminoacetic acid, dissolved in 90 ml of absolute tetrahydrofuran, in the presence of 1.22 g of 1-hydroxybenztriazole and 2.10 g of dicyclohexylcarbodiimide with 3.5 g (9 mmol) of 7?-amino-3-cephem-4-carboxylic acid diphenylmethyl ester, TReaction time 5 hours). Rf: 0.45 (silica gel, uv 366, methylene chloride/ethyl acetate 1:1). c) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-pyrid-3-ylsulfonylaminoethanesulfonylamino)-acetic acid.

Analogously to example 98 c), the title compound is obtained after esterification of 7.61 g (20 mmol) of (2R,S)-2-(2-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid with 16 ml of N,O-bis-(trimethylsilyl)-acetamide in 60 ml of tetrahydrofuran and after reaction with 5.14 g of 3-pyridine sulfochloride hydrochloride in the presence of 4.9 ml of N-methylmorpholine. Rf :96: 0.40 )silica gel, UV 366).

Example 117.

a) 7 - (2R, S)-2-(2-minothiazol-4-yl)-2-pyrid-3-ylsulfo-

Example 117.

a) 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-pyrid-3-ylsuifonylamino-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogously to example 21 a), the title compound is obtained in the form of the hydrate starting from 3.43 g (4.5 mmol) 70-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-pyride -3-ylsulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 20 ml of methylene chloride, in the presence of 3.3 ml of anisole and 20 ml of trifluoroacetic acid. F: above 179° (during decomposition). Rf 96: 0.35 (silica gel, UV 366). [a] ^ = +94°±1° (0.929% in water). UV 254 (11800, water). b) 7ø-[(2R,S)-2-'(2-BOC-aminothiazol-4-yl)-2-pyrid-3-ylsulfonylamino-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester.

Analogous to example 98 b) the title compound is obtained as an amorphous powder starting from 2.9 g (7 mmol) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-pyrid-3-ylsulfonylaminoacetic acid, dissolved in 70 ml of absolute tetrahydrofuran, in the presence of 0.95 g of 1-hydroxybenztriazole and 1.6 g of dicyclohexylcarbodiimide with 2.6 g of 7ø-amino-3-cephem-4-carboxylic acid diphenyl methyl ester.

Rf. 0.38 (silica gel, UV 366, methylene chloride/ethyl acetate 1:1). c) (2R,S)-2-(2^BOC-aminothiazol-4-yl)-2-pyrid-3-ylsulfonylamino-acetic acid.

Analogous to example 98 c), the title compound is obtained after esterification of 2.73 (10 mmol) of ?2R,S)-2-amino-2-(2-BOC-aminothiazol-4-yl)-acetic acid with N,O-bis( trimethylsilyl)-acetamide in 30 ml of tetrahydrofuran and after reaction with 2.57 g of 3-pyridine sulfochloride hydrochloride in the presence of 1.6 ml of N-methylmorpholine. Rf 96: 0.49 (silica gel, UV 266).

Example 118.

a) 3- acetoxymethyl- 7 g- [( 2R, S)- 2-( 2-( 2- aminothiazol-4-ylacetamido)- ethanesulfonylamino)- 2-( 2- aminothiazol-4-yl)- acetamido ]- 3 - cephem-4-carboxylic acid sodium salt.

Analogously to example 29 a), the title compound is obtained in the form of the dihydrate starting from 1.04 g (1 mmol) 3-acetoxymethyl-7ø-[(2R,S)-2-(2-(2-BOC-aminothiazol-4-ylacetamido) )-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 5 ml of methylene chloride, in the presence of 1 ml of anisole with 5 ml of trifluoroacetic acid. F: above 150° (during cleavage). Rf: 0.25 (silica gel "Opti UPC" 12, UV 366, water/acetonitrile 4:1), [ a] * 2 fl °=+57°+l° (1.183% in water). UV 254 (18500, water). b) 3- acetoxymethyl- 7 g-[( 2R)- 2-( 2-( 2- aminothiazol-4-ylacetamido)- ethanesulfonylamino)- 2-( 2- aminothiazol-4- y1)- acetamido] 3- cephem- 4-carboxylic acid sodium salt.

Analogous to example 29 a), the title compound is obtained in the form of the dihydrate starting from 1.60 g (1.54 mmol) 3-acetoxymethyl-7 g-[(2R)-2-(2-(2-BOC-aminothiazol-4- ylacetamido)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester dissolved in 8 ml of methylene chloride, in the presence of 1.6 ml of anisole with 8 ml of trifluoroacetic acid. F: above 151° (during cleavage). Rf: 0.25 (silica gel "Opti UPC" 12, UV 366, water/acetonitrile 4:1).

20 °

= +39°±1° (1.111% in water). UV 254 (17700, water). c) 3- acetoxymethyl- 7g-[( 2S)- 2-( 2-( 2- aminothiazol-4-ylacetamido)- ethanesulfonylamino)- 2-( 2- aminothiazol-4- yl)- acetamido]- 3- cephem- 4-carboxylic acid sodium salt.

Analogous to example 29 a), the title compound is obtained in the form of the dihydrate starting from 1.90 g (1.83 mmol) 3-acetoxymethyl-7ø-[(2S)-2-(2-(2-BOC-aminothiazol-4-ylacetamido) -ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 9.5 ml of methylene chloride, in the presence of 1.9 ml of anisole with 9.5 ml trifluoroacetic acid. F: above 150° (during cleavage). Rf: 0.25 (silica gel,

200

"Opti UPC" 12, UV 366, water/acetonitrile 4:1). [a] ^ = +61°±1° (1.473% in water). UV 254 (18800, water). d) 3- acetoxymethyl- 7B-[( 2R, S)- 2- 82-( 2- BOC- aminothiazol-4- ylacetamido)- ethanesulfonylamino)- 2-( 2- BQC- aminothiazol-4- yl)- acetamido] - 3- cephem- 4- carboxylic acid diphenyl methyl ester,

3- acetoxynethyl- 7B - [ ( 2R) - 2 - ( 2 - ( 2- BQC- aminothiazol- 4-ylacetamido)- ethanesulfonylamino)- 2-( 2- BOC- aminothiazol- 4- yl)- acetamido j- 3- cephem- 4- carboxylic acid diphenyl methyl ester and

3- acetoxymethyl- 7B-[( 2S)- 2-( 2-( 2- BOC- aminothiazol- 4-ylacetamido)- ethanesulfonylamino)- 2-( 2- BOC- aminothiazol- 4- yl)- acetamido]- 3- cephem-4-carboxylic acid diphenyl methyl ester.

Analogously to example 29 b), the title compound is obtained as a 2R,S diastereomer mixture starting from 3.5 g (5.7 mmol) of the (2R,S)-2-(2-(2-BOC-) obtained according to example 29 c) aminothiazol-4-ylacetamido)-ethanesulfonylamino)-2-(2-B0C-aminothiazol-4-yl)-acetic acid, dissolved in 60 ml of tetrahydrofuran, in the presence of 0.77 g of 1-hydroxybenztriazole and 1.29 g of dicyclohexylcarbodiimide with 2 .5 g (5.7 mmol) 3-acetoxymethyl-7B-amino-3-cephem-4-carboxylic acid diphenyl methyl ester (reaction time 16 hours at room temperature). The crude product is chromatographed on silica gel (280 g) with methylene chloride/ethyl acetate 1:1 as eluent, and in the first fractions the title compound is eluted with 2R configuration (Rf: 0.58, silica gel, ethyl acetate), in the following fractions the title compound is eluted with 2R,S -configuration and in the last fractions the title compound with the 2S configurations (Rf: 0.48, silica gel, ethyl acetate).

Oak sample 119.

a) 3- carbamoyloxymethyl- 7 B-[( 2R9- 2-( 2-( 2- aminothiazol-4- ylacetamido)- ethanesulfonylamino)- 2-( 2- aminothiazol-4- yl)- acetamido]- 3- cephem- 4- carboxylic acid sodium salt.

Analogous to example 29 a), the title compound is obtained in the form of the dihydrate starting from 4.17 g (4 mmol) of 3-carbamoyloxymethyl-7B-[(2R)-2-(2-(2-BOC-aminothiazol-4-ylacetamido)- ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 20 ml of methylene chloride, in the presence of 4 ml of anisole with 20 ml of trifluoroacetic acid. F: above 155° (during cleavage). Rf: 0.20 (silica gel "Opti UPC" 12, UV 366, water/acetonitrile 4:1), [a]^ ? fl o= +34°±1° (1.341% in water). UV 256 (18500, water). b) 3- carbamoyloxymethyl- 7B-[( 2S)- 2-( 2-( 2- aminothiazol-4- ylacetamido)- ethanesulfonylamino)- 2-( 2- aminothiazol-4- yl) acetamido]- 3- cephem- 4 - carboxylic acid sodium salt.

Analogous to example 29 a), the title compound is obtained in the form of the 2,5-hydrate starting from 4.17 g (4 mmol) of 3-carbamoyloxymethyl-7B-[(2S)-2-(2-(2-BOC-aminothiazole- 4-ylacetamido)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 20 ml of methylene chloride, in the presence of 4 ml of anisole with 20 ml of trifluoroacetic acid. F: above 160° (during cleavage). Rf. 0.18 (silica gel "Opti UPC" 12, UV 366, water/acetonitrile 4.1).

9 n °

[ol]q = +57°±1° (0.884% in water). UV 257 (18500, water). c) 3- carbamoyloxymethyl- 78 -[ ( 2R )- 2-( 2-( 2- BOG-aminothiazol-4- ylacetamido)- ethanesulfonylamino)- 2-( 2- BOC- aminothiazol-4- yl )- acetamido]- 3-Cephem-4-Carboxy1-acid diphenyl methyl ester.

and

3- carbamoyloxymethyl- 78-[( 2S )- 2-( 2-( 2- BOC- aminothiazol-4 - ylacetamido ) - ethanesulfonylamino)- 2-( 2- BOC-aminothiazol - 4 - yl )- acetamido]- 3- cephem-4-carboxyl-acid phenyl methyl ester.

Analogous to example 29 b), the title compound is obtained as a 2R,S diastereomer mixture starting from 7.44 g (12 mmol)

of the (2R,S)-2-(2-(2-BOC-aminothiazol-4-ylacetamido)-ethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid obtained according to example 29 c), dissolved in 120 ml of tetrahydrofuran, in the presence of 1.62 g of 1-hydroxybenztriazole and 2.72 g of dicyclohexylcarbodiimide with 5.27 g (12 mmol) of 3-carbamoyloxymethyl-7-8-amino-3-cephem-4-carboxylic acid diphenyl methyl ester (reaction time 16 hours at room temperature). The crude product is chromatographed on silica gel (700 g) with methylene chloride/ethyl acetate 1:1 as eluent, from which the title compounds with 2R configuration (Rf: 0.33, silica gel, ethyl acetate), respectively the 2R configuration (Rf: 0.25, silica gel, ethyl acetate ) is isolated as an amorphous powder.

Example 120.

a) 3-carbamoyloxymethyl-78-[(2R)-2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

Analogous to example 13 aj, the title compound is obtained in the form of the 1,5-hydrate starting from 3.6 g (4 mmol) of 3-carbamoyloxymethyl-7 8-[(2R)-2-(2-BOC-aminoethanesulfonylamino)-2-( 2-BOC-aminothiazol-4-yl-acetamido j-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 16 ml of absolute methylene chloride, in the presence of 3.2 ml of anisole and 16 ml of trifluoroacetic acid F: above 140°

(under cleavage). Rf.0.75 (silica gel "Opti UPC" 12, water/acetonitrile 4:1). UV: 254 (13800, 0.1 NHC1). b) 3-carbamoyloxymethyl-7B-[(25)-2-(2-aminoethanesulfonylamino)-2-(2-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid.

Analogous to example 13 a), the title compound is obtained in the form of the 1,5-hydrate starting from 4.96 g (5.5 mmol) 3-carbamoyloxymethyl-7B-[(2S)-2-(2-BOC-aminoethanesulfonylamino)- 2-(2-BOC-aminothiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester, dissolved in 22 ml of absolute methylene chloride,

in the presence of 4.4 ml of anisole and 22 ml of trifluoroacetic acid.

F: above 142° (during cleavage). Rf: 0.75 (silica gel "Opti UPC" 12, water/acetonitrile 4.1). UV 254 (13600, 0.1 N HCl).

c) 3- carbamoyloxymethyl- 78-[( 2R)- 2-( 2- BOC- aminoethanesulfonylamino )- 2-( 2- BOC- aminothiazol-4- yl)- acetamido ]- 3- cephem- 4- carboxylic acid diphenyl methyl ester and

3- carbamoyloxymethyl- 7 8-[( 2S)- 2-( 2- B0e- aminoethanesulfonylamino)- 2-( 2- BOC- aminothiazol-4- yl)- acetamido ]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogous to example 13 b), the crude product is obtained as a 2R,S diastereomer mixture by treating 9.6 g (20 mmol)

(2R,S)-2-(2-BOC-aminoethanesulfonylamino)-2-(2-BOC-aminothiazol-4-yl)-acetic acid with 8.79 g (20 mmol) of 3-carbamoyl-oxyrnethy1-7 8-amino -3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 2.7 g of 1-hydroxybenztriazole and 4.54 g of dicyclohexylcarbodiimide in 200 ml of tetrahydrofuran. The crude product is chromatographed on silica gel (1000 g) with methylene chloride/ethyl acetate 7:3 and 1:1 respectively as elution

agent, from which the title compounds with 2R configuration (Rf: 0.65) and 25 configuration (Rf: 0.55, silica gel, diethyl ether/ethyl acetate 1:1) are obtained.

Example 121.

a) 76-[(2R,S)-2-82-aminothiazol-4-yl)-2-(2-phenylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. Analogous to example 76 a), the title compound is obtained by reacting 1.9 g of 76-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-phenylaminoethanesulfonylamino)-acetamido]-3 -cephem-4-carboxylic acid diphenyl methyl ester with 40 ml of trifluoroacetic acid in 1.0 ml of anisole and 4 ml of methylene chloride, and subsequent treatment of the trifluoroacetate salt with 1 N sodium hydroxide solution. F: from 176° (during cleavage). IR: 3320 (wide), 3200 , 1775 (shoulder), 1760, 1745 (shoulder), 1680, 1645, 1600, 1375, 1325 (shoulder), 1145 (in Nujol). Rf: approx. 0.74 (silica gel, UV 366, n-butanol-pyridine-glacial acetic acid-water 42.24:4:30). b) 76-[( 2R, 2)- 2-( 2- BOC-aminothiazol-4-] 1)- 2-( 2- phenyl-aminoethanesulfonylamino)- acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

6.0 g 76-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-phenyl-2-trichloroethoxycarbonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester, prepared analogously to example 42 c)-e), treated in 60 ml of acetonitrile-ethyl acetate (1:1) with 20 g (2 x 10 g) zinc dust, worked up analogously to example 13 d), whereby the title compound is obtained as a foam. Rf: approx. 0.43 (silica gel, UV 366, double stains, diastereomer mixture, toluene-chloroform-ethyl acetate 1:1:1 +

1% ethanol).

Example 122.

a) 78-[( 2R, S )- 2-( 2-aminothiazol-4-yl)- 2-( 2-( 2- furoyl)-ureido)- ethanesulfonylamino)- acetamido]- 3- cephem- 4-carboxylic acid sodium salt .

Analogous to example 76 a), the title compound is obtained by reacting 1.9 g of 76-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(3-(2-furoyl)-ureido -ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester with 50 ml of trifluoroacetic acid in 0.40 ml of anisole and 5 ml of methylene chloride, and subsequent treatment of the trifluoroacetate with 1 N caustic soda.

F: from 196° during cleavage. IR: 3310 (wide), 3200, 1765 (wide), 1690 (wide), 1600 (wide), 1375, 1365, 1340 (shoulder), 1175, 1150 (in Nujol). Rf: approx. 0.38 (silica gel,

UV 366, n-butanol-pyridine-glacial acetic acid-water 42:24:4:30).

b) 78-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(3-(2-furoyl)'-urei do)-ethanesulfonylamino)-acetamido]-

3- cephem- 4- carboxylic acid diphenyl methyl ester.

A solution of 3.50 g of 78-[(2R,S)-2-(2-BQC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester in 100 ml of ethyl acetate is prepared, cooled to +3°, a solution of 0.85 g of 2-furoyl isocyanate in 50 ml of ethyl acetate is added dropwise while stirring and cooling over the course of 1 hour and the reaction mixture is then stirred for 5 hours in an ice bath. The ethyl acetate solution is then washed with water, dried over sodium sulphate, evaporated at 50° on a rotary evaporator and the crude product is purified by chromatography on a 60 times larger quantity of silica gel. Eluent: methylene chloride with 25 - 40% methyl acetate. The title compound is obtained as a foam. Rf: approx. 0.27 (silica gel,

UV 366, double stain, diastereomer mixture, toluene-chloroform-ethyl acetate 1:1:1 + 5% ethanol.

Example 123.

a) 7b- f ( 2R, S)- 2-(' 2- aminothiazol-4- yl)- 2-( 2-( 3- ethoxy-carbonylureido)- ethanesulfonylamino)- acetamido]- 3-cephem- 4- carboxylic acid sodium salt .

Analogous to example 76 a), the title compound is obtained by reacting 1.29 g of 7b~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(3-ethoxycarbonylureido)-ethanesulfonylamino )-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester with 50 ml of trifluoroacetic acid in 0.40 ml of anisole and 5 ml of methylene chloride and subsequent treatment of the trifluoroacetate salt with 1 N caustic soda. F: from 232° during cleavage. IR: 3320 (broad), 3200, 1775 (shoulder), 1760 (broad), 1730, 1690 (broad), 1640, 1605, 1375, 1365, 1175 (shoulder), 1145 (in Nujol). Rf: approx. 0.42 (silica gel, UV 366, n-butanol-pyridine-glacial acetic acid-water 42:24:4:30). b) 78-f(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-(3-ethoxycarbonylureido)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 122 b), the title compound is obtained by reacting 3.40 g of 7b~[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3 -cephem-4-carboxylic acid diphenyl methyl ester with 2.5 ml of ethoxycarbonyl isocyanate in 150 ml (100 ml and 50 ml) of ethyl acetate. The crude product is purified by chromatography on a 20 times greater amount of silica gel. Eluent: methylene chloride with 15-25% methyl acetate. Rf: approx. 0.16 (silica gel, UV 366, double stain, diastereomer mixture. toluene-chloroform-ethyl acetate, 1:1:1 + 3% ethanol).

Example 124.

a) 7b-f(2R,S)-2-(2-aminothiazol-4-yl)-2(2-(3-benzenesulfonylureido)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 76 a), the title compound is obtained by reacting 1.5 g of 7b-[(2R,S)-2-C>2-BOC-aminothiazol-4-yl)-2-(2-(3-benzenesulfonylureido)- ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester with 50 ml of trifluoroacetic acid in 0.4 ml of anisole and 5 ml of methylene chloride and subsequent treatment of the trifluoroacetate salt with 1 N caustic soda. F: from 200° during cleavage. IR: 3320 (broad), 3200, 1785, 1760, 1685, 1640 (shoulder), 1600 (broad), 1375, 1365, 1350 (shoulder), 1165 (shoulder), 1135 (in Nujol), Rf: approx. 0.37 (silica gel, UV 366, n-butanol-pyridine-glacial acetic acid-water 42:24:4:30). b) 7B-[( 2R, S)- 2-( 2- BOC- aminothiazol-4- yl)- 2-( 2-( 3-benzenesulfonylureido)- ethanesulfonylamino)- acetamido^- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogous to example 122 b), the title compound is obtained by reacting 3.50 g of 78-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3 -cephem-4-carboxylic acid diphenyl methyl ester with 1.10 g of benzenesulfonyl isocyanate in 120 ml of ethyl acetate (100 ml and 20 ml). The crude product is purified by chromatography on a 20 times greater amount of silica gel. Eluent: methylene chloride with 20 to 30% methyl acetate. Rf: approx. 0.14 (silica gel, UV 366, double stain, diastereomer mixture, toluene-chloroform-ethyl acetate 1:1:1 + 3% ethanol).

Example 125.

a) 3-carbamoyloxymethyl-7-8-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 76 a), the title compound is obtained by reacting 6 g of 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyethanesulfonylamino)-acetamido] -3-cephem-4-carboxylic acid diphenyl methyl ester with 100 ml of trifluoroacetic acid in 2.5 ml of anisole and 10 ml of methylene chloride and subsequent treatment of the trifluoroacetate salt with 1 N caustic soda. F: from 148° during cleavage. IR: 3320 (wide), 3200, 1785 (shoulder), 1760, 1700 8wide), 1605 (wide),

1380, 1330, 1145, 1115 cm"<1>(in Nujol), Rf: 0.37 (silica gel, UV 366, n-butanol-pyridine-glacial acetic acid-water 42:24:4:30). b) 3- carbamoyloxymethyl- 7 g-[ (2R, S)- 2-( 2- BOC-aminothiazol-4- yl)- 2-( 2- methoxyethanesulfonylamino)-acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogously to example 42 c), the title compound is obtained by reacting 4.30 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-methoxyethanesulfonylamino)-acetic acid with 4.0 g of 3 -carbamoyloxymethyl-7B-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 2.40 g (2 x 1.20 g) of N,N'-dicyclohexylcarbodiimide in a total of 110 ml of tetrahydrofuran. The crude product is purified chromatographically on a 25-fold so

large amount of silica gel. Eluent. methylene chloride with 25 to 45% methyl acetate. Rf: approx. 0.33 (silica gel, UV 366, double stain, diastereomer mixture, toluene-ethanol 9:1).

Example 12 6.

7B-[(2r,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxy-ethanesulfonylamino)-acetamido]-3- carbamoyloxymethyl-3- cephem-4- carboxyl-acid pivaloyloxy-methyl ester hydrochloride.

1.90 g of 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt and 0, 90 g of iodomethyl pivalate are reacted in 12 ml of N,N-dimethylformamide analogously to example 70 a) and worked up. Rf: from 112° during cleavage. Rf: 0.36 (silica gel "Opti UPC" 12, UV 366, acetonitrile-water 1:1).

Example 127..

a) 3-carbamoyloxymethyl-7-6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogously to example 76 a), the title compound is obtained by reacting 3.1 g of 3-carbamoyloxymethyl-78-[( 2R, S )-2-( 2-BOC-aminothiazol-4-yl)-2-(2-BOC-methylaminoethanesulfonylamino )-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester with 46 ml of trifluoroacetic acid in 1.10 ml of anisole and 7.5 ml of methylene chloride and subsequent treatment of the trifluoroacetate salt with 1 N caustic soda. F: from 180° during cleavage. IR: 3330 (broad), 3190 (broad), 1785 (shoulder), 1765, 1695 (broad), 1610 (broad), 1375, 1365, 1325, 1155, 1130 (shoulder), (in Nujol). Rf: approx. 0.24 (silica gel, UV 366, n-butanol-pyridine-glacial acetic acid-water 42:24:4:30). b) 3- carbamoyloxymethyl- 7B^[ ( 2R, S)- 2-( 2- BQC-aminothiazol-4- yl)- 2-( 2- BOC- methylaminoethanesulfonylamino)-acetamido]- 3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogous to example 42 c), the title compound is obtained by reacting 2.0 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-OBC-methylaminoethanesulfonylamino)-acetic acid, (see preparation example 79 c)) and 2.0 g of 3-carbamoyloxymethyl-78-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.37 g of 1-hydroxy-benztriazole and 1.30 g (0.70 and 0.60 g ) N,N'-dicyclohexylcarbodiimide in 90 ml of tetrahydrofuran. The crude product is purified by chromatography on a 40 times greater amount of silica gel. Eluent: Methylene chloride-methyl acetate-(7:3). Rf: approx. 0.32 (silica gel, UV 366, double stain, diastereomer mixture, toluene-ethyl acetate 1:1) .

Example 128.

a) 7 g - [(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-sulfoamino-ethanesulfonyl-amino)-acetamido]-3-cephem-4-carboxylic acid disodium salt.

Analogous to example 76 a), the title compound is obtained by reacting 3.1 g of 7g-[(2R,S)-2-(2-BOC-aminothiazol-4-yl) 2-(2-sulfoaminoethanesulfonylamino)-acetamido]-3- cephem-4-carboxylic acid diphenyl methyl ester with 40 ml of trifluoroacetic

acid in 1.25 ml of anisole and 6 ml of methylene chloride and subsequent treatment of the trifluoroacetate salt with 1 N caustic soda.

F: from 205° during cleavage. IR: 3420 (wide), 3340 (shoulder), 3200 (wide), 1780 (shoulder), 1755, 1680, 1635, (shoulder), 1600, 1360, 1325 (shoulder), 1180, 1145 (in Nujol). Rf: approx. 1.18 (silica gel, UV 366, n-butanol-pyridine-glacial acetic acid-water 42:24:4:30). b) 7g-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-sulfo-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

A solution of 5.0 7ø-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-amino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester in 40 ml methylene chloride is cooled to +2°, 2.7 ml N-methylmorpholine is added, 33.6 ml chlorosulfonic acid trimethylsilyl ester is added dropwise while stirring and cooling over the course of 5 minutes and the reaction mixture is stirred for 4

hours at room temperature. The suspension is then diluted with ethyl acetate, the methylene chloride is sucked off at 50° on a rotary evaporator, the ethyl acetate solution is washed successively with a 20° citric acid solution, and water. (2x). The organic phase is dried over sodium sulphate, filtered and evaporated at 50° on a rotary evaporator. The crude product is purified by chromatography on a 30 times larger amount of silica gel. Eluent: Chloroform-methanol-32% aqueous acetic acid 15:4:1. The title compound is obtained as a foam.

Rf: approx. 0.36 (silica gel, uv 366, chloroform-methanol-32%, aqueous acetic acid 15:4:1).

Example 129.

a) 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(vinylsulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 76 a), the title compound is obtained by reacting 1.9 g of 7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(vinylsulfonylamino)-acetamido J-3-cephem -4-carboxylic acid diphenylmethyl ester with 60 ml trifluoroacetic acid in 0.70 ml anisole and 5 ml methylene chloride and subsequent treatment of the trifluoroacetate salt with 1 N caustic soda. F: from 210° during cleavage. IR: 3300 (wide), 3190 (wide), 1775 (shoulder), 1755 (wide), 1680, 1640 (shoulder), 1600 (wide), 1375, 1365, 1150, 1120 (shoulder), (in Nujol). Rf: approx. 0.27 ("silica gel "Opti UPC" 12, UV 366, acetonitrile with 5% water). b) . 7B-[( 2R, S)- 2-( 2- BOC- aminothiazol- 4- yl)- 2- (2-vinyl-sulfonylamino)-acetamido)-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 42 c), the title compound is obtained by reacting 1.50 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(vinylsulfonylamino)-acetic acid and 1.50 g of 7-amino -3-cephem-4-carboxylic acid in the presence of 1.0 g (2 x 0.50 g) of N,N<1->dicyclohexylcarbodiimide in a mixture of 20 ml of tetrahydrofuran and 10 ml of N,N-dimethylformamide. The crude product is purified by chromatography on a 20-fold amount of silica gel, eluent: methylene chloride with 5% methyl acetate, and the title compound is obtained as a foam. Rf: approx. 0.7 (silica gel, UV 366, double stains, diastereomer mixture, toluene-chloroform-ethyl acetate 1:1:1 + 3% ethanol).

c) (211, S)-2-(2-BOC-aminothiazol-4-yl)-2-(vinylsulfonylamino)-acetic acid. 40 g of (2R,S)-2-(2-BOC-aminotaizol-4-yl)-2-(vinylsulfonyl-amino)-acetic acid ethyl ester are dissolved in 350 ml of ethanol, added dropwise with stirring and slight cooling during 20 minutes to 350 ml of 2 N caustic soda and the reaction mixture is stirred at room temperature. After a reaction time of 2 hours, a further 100 ml of 2 N caustic soda is added dropwise to the clear, dark-orange colored solution. After a reaction time of a total of 5 hours at room temperature, the pH of the mixture is adjusted to 7.5 with 10% hydrochloric acid, the largest part of the ethanol is distilled off at 50° on a rotary evaporator, and the aqueous solution is extracted with diethyl ether. The aqueous phase is then separated, covered with ethyl acetate, cooled in an ice bath, acidified while stirring and cooling by adding 20% phosphoric acid (pH 2.0) dropwise and extracted twice with ethyl acetate. The organic phases are combined, washed twice with water, dried over sodium sulphate, filtered and evaporated on a rotary evaporator at 50°. The oily residue solidifies by mixing with a mixture of methylene chloride-petroleum ether (1:1). F: 119-122°. Rf: approx. 0.64 (silica gel,' UV 366, n-butanol-glacial acetic acid-water 67:10:23). d) (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(vinylsulfonylamino)-acetic acid ethyl ester.

A solution of 50 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-glycine ethyl ester in 400 ml of dioxane and 45 ml of N-methylmorpholine is cooled to +10° and added dropwise with vigorous stirring and cooling during of 30 minutes a solution of 40 g of 2-bromoethanesulfonyl chloride, prepared according to the prescription of C.S: Marcel et al., J. Am. Chem. Soc., 49, 1833 (1927),

in 100 ml of dioxane. The reaction mixture is stirred for 5 hours at room temperature. The largest part of the solvent is then evaporated on a rotary evaporator at 50° and it

the remaining suspension is diluted with ethyl acetate, washed successively with 20% citric acid solution, water, 1 N sodium bicarbonate solution and water (3x). The organic phase is dried over sodium sulphate, filtered and evaporated on a rotary evaporator at 50°. The crude product is purified by chromatography on a 10-fold amount of silica gel, and the title compound is obtained as a foam. Rf: approx. 0.46 (silica gel, UV 366, toluene-ethyl acetate 1:1).

Example 130.,

a) 3-carbamoyloxymethyl-7e-[(2R,S)-2-82-aminothiazol-4-y1)-2-(vinylsulfonylamino)-acetamido j-3-cephem-4-carboxylic acid sodium salt. Analogous to example 76 a), the title compound is obtained by reacting 1.8 g of 3-carbamoyloxymethyl-7S-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(vinylsulfonylamino)-acetamido] -3-cephem-4-carboxylic acid diphenyl methyl ester with 40 ml of trifluoroacetic acid in 1.0 ml of anisole and 4 ml of methylene chloride and subsequent treatment of the trifluoroacetate salt with 1 N caustic soda. F: from 168° during cleavage. IR: 3330 (broad), 3190, 1785 (shoulder), 1760, 1700 (broad), 1610 (broad), 1620, 1375, 1365 (weak), 1325, 1150, 1120 (in Nujol). Rf: approx. 0.24 (silica gel, UV 366, n-butanol-pyridine-glacial acetic acid-water 42:24:4:30). b) 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(vinylsulfonylamino)-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

Analogous to example 42 c), the title compound is obtained by reacting 1.30 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(vinylsulfonylamino)-acetic acid (preparation see example 129 c)) and 1.70 g of 3-carbamoyloxymethyl-7B-amino-3-cephem-4-carboxylic acid diphenyl methyl ester in the presence of 0.90 g (0.50 and 0.40 g) of N,N'-dicyclohexylcarbodiimide in a total of 40 ml of tetrahydrofuran. The crude product is purified by chromatography on a 25 times greater amount of silica gel, eluent methylene chloride with 15-20% methyl acetate, and the title compound is obtained as a foam. Rf: approx. 0.18 (silica gel, uV 366, double cover, diastereomer mixture, toluene-chloroform-ethyl acetate 1:1:1 +3% ethanol).

Example 131.

a) 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7 6-[(2R,S)-2- (2-aminothiazol-4-yl)-2-(2-methylaminoethanesulfonyl-amino)-acetamido]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride.

A suspension of 2.20 g of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl-7 8 -[ (2R,S)-2-(2-BOC-methylaminoethanesulfonylamino-acetamido]-3-cephem-4- pivaloyloxymethyl carboxylic acid in 0.9 ml of anisole and 5 ml of methylene chloride is added to 40 ml of trifluoroacetic acid, the reaction mixture is stirred under exclusion of atmospheric moisture for 4 5 minutes at room temperature, and then poured onto an ice-cold mixture of 800 ml of petroleum ether and 200 ml of diethyl ether. It is filtered off, washed with a mixture of petroleum ether-diethyl ether and dried under high vacuum at room temperature. The trifluoroacetate salt is dissolved in about 300 ml of ethyl acetate, and the solution is washed successively with 1 N sodium bicarbonate solution (2 x 60 ml) and soda solution. The organic phase is dried over sodium sulfate, filtered, excess hydrogen chloride in methylene chloride is added and evaporated on a rotary evaporator at 20-30° to approx. 50 ml. The precipitated title compound is filtered off with suction, washed with ethyl acetate and diethyl ether, and dried at room temperature under high vacuum. F: from 110° with decomposition. IR: 3 180 (broad), 1785 (shoulder), 1775, 1750, 1690, 1625, 1375, 1365 (shoulder), 1335, 1150, 1115 (in Nujol) Rf. about. 0.28 ("Silica gel Opti UPC" 12, UV 366, acetonitrile-water 4:1). b) 3 - ( 1- methyl- III- tetrazol- 5- yltiomethyl) - 78-[ ( 2R, S)- 2- (2-BOC-aminothiazol-4-yl)-2-(2-BOC-methylaminoethane-sulfonylamino)-acetamido]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester.

Analogously to example 42 c), the crude product is obtained by adding 2.60 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-BOC-methyl-aminoethanesulfonylamino)-acetic acid, ( preparation see example 79 c)), and 1.90 g of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid pivaloyloxymethyl ester in the presence of 0.32 g of 1-hydroxy-benztriazole and 1 .90 g (2 x 0.95 g) of N,N'-dicyclohexylcarbodiimide in a total of 70 ml of tetrahydrofuran. The crude product is purified by chromatography on a 45 times greater amount of silica gel, eluent: methylene chloride-methyl acetate (4:1), and the title compound is obtained as a foam. Rf: approx. 0.26 (silica gel, UV 366, double stain, diastereomer mixture, toluene-ethyl acetate 1:1).

Example 132.

a) 78-[(2R,S)-2-(2-aminothiazol-4-yl)-2-2-dimethylamino-sulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

Analogous to example 76 a), the title compound is obtained by reacting 2.20 g of 78-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-(2-dimethylaminosulfonylaminoethanesulfonylamino)-acetamido]-3 - cephem-4-carboxylic acid diphenyl methyl ester with 40 ml of trifluoroacetic acid in 0.9 ml of anisole and 4 ml of methylene chloride and subsequent treatment of the trifluoroacetate salt with 1 N caustic soda. F: from 183° during cleavage. Rf: approx. 0.63 (silica gel,

UV 366, n-butanol-pyridine-glacial acetic acid-water 42:24:4:30).

b) 7 3-[( 2R, S)- 2-( 2- BOC-aminothiazol-4- y1- 2-( 2- dimethyl-aminosulfonylaminoethanesulfoylamino)- acetamido]-3- cephem- 4- carboxylic acid diphenyl methyl ester.

Analogous to example 128 b), the title compound is obtained by reacting 4.0 g of 76-[(2R,S)-2-2-(2-BOC-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido] -3-cephem-4-carboxylic acid diphenyl methyl ester with 1.80 ml of N,N-dimethylamidosulfonic acid chloride in a mixture of 100 ml of dioxane and 2 ml of N-methylmorpholine. The crude product is purified by chromatography on a 30 times larger amount of silica gel. Eluent: methylene chloride with 15% methyl acetate. Rf. about. 0.64 (silica gel, UV 366, double stain, diastereomer mixture, toluene-ethyl acetate 1:2).

Example 133.

a) 3-( 2, 5- dihydro- 6- hydroxy- 2- methyl- 5- oxo- as-triazin- 3- ylthiomethyl)- 7b-[( 2R, S)- 2-( 2- aminothiazol-4- yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid disodium salt. 1.5 g 3-(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-ylthiomethyl)-7B-[(2R,S)-2-(2-chloroacetamidotriazole -4-yl)-2-methanesulfonylaminoacetamido -3-cephem-4-carboxylic acid sodium salt, (preparation see example 133 b), is stirred under a nitrogen atmosphere with 0.7 g of thiourea in 15 ml of water for 8 hours at room temperature, whereby the pH of the reaction mixture is maintained constant at pH 6.8 by addition of 0.1 N aqueous sodium hydroxide using a titrator. Then extract with ethyl acetate and wash twice afterwards with water. The combined aqueous phases are evaporated in vacuo and chromatographed on 150 g "Opti UPC" 12 silica gel. The product-containing fractions that are eluted with H20-CH3CN9:1 mixture are combined, evaporated and the hydrate of the title compound is precipitated by the addition of ethanol, filtered off with suction and dried. IR: 3700-2500 (wide), 1765, 1685, 1640 (shoulder), 1600, 1550 (shoulder), 1500 (Nujol). b) 3-( 2, 5- dihydro- 6- hydroxy- 2- methyl- 5- oxo- as-triazin- 3- ylthiomethyl)- 7B-[( 2R, S)- 2-( 2- chloroaceta- midothiazole - 4-yl)-2-methanesulfonylamino-acetamidoJ-3-cephem-4-carboxylic acid disodium salt.

200 mg of (2R,S)-2-(2-chloroacetamidothiazol-4-yl)-2-methanesulfonyl-aminoacetic acid in 1.82 ml of methylene chloride is added to 0.102 ml of triethylamine. Then cool to 0°, add 128 mg of phosphorus pentachloride and stir for 5 minutes at 0°, and 20 minutes at room temperature. It is then evaporated in vacuo, extracted twice with hexane and then dissolved in 1.8 ml of tetrahydrofuran.

The precipitated triethylamine hydrochloride is then filtered off. The solution obtained, which contains (2R,3)-2-(2-chloroacetamido-thiazol-4-yl)-2-methanesulfonylaminoacetic acid chloride, is used directly for the subsequent acylation. 150 mg of 3-(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-ylthiomethyl)-7B-amino-3-cephem-4-carboxylic acid is heated with 0.4 ml of N ,0-bis-(trimethylsilyl)-acetamide in 1.5 ml of tetrahydrofuran for 1 hour at reflux. Then cool to 20°, add 0.033 ml of pyridine and the acid chloride solution obtained according to the above-mentioned regulation, and stir for 3 hours at room temperature. Then 2 ml of water are added, the pH is adjusted to 7 with 1 N sodium hydroxide and evaporated in vacuo to dryness. Then chromatograph in water on 20 g "Opti UPC" 12 silica gel. The product-containing fractions that have been eluted with water are combined, evaporated and the hydrate of the title compound is precipitated by the addition of ethanol, filtered off with suction and dried. IR: 3700-2500 (wide), 1760, 1685, 1640 (shoulder), 1600, 1550 (shoulder), 1500 (Nujol).

Example 134.

a)_ 3-carbamoyloxymethyl 1-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt.

1.2 g of the 3-carba-

Moyloxymethyl-7e-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methoxycarbonylimethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 2 ml of CR^C^ and 0.38 ml anisole with 2.5 ml of trifluoroacetic acid analogously to example 1 a), is worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. IR: 3650-2500 (wide), 1775 (shoulder), 1744, 1677, 1604, 1520 (Nujol),

uV: 253 (10200, H 2 O). b) 3-carbamoyloxymethyl-7b-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methoxycarbonylmethanesulfonylamino-acetamido]-3-cefem-4J-carboxylic acid diphenylmethyl ester.

10.2 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methoxycarbonylmethanesulfonylamino-acetic acid obtainable according to example 134 c) is reacted with 10.9 g of 3-carbamoyloxymethyl-7B_amino- 3-cephem-4-carboxylic acid diphenyl methyl ester in 100 ml of tetrahydrofuran analogous to example 6b) (3.3 g of hydroxy-benztriazole, three times 1.73 g of dicyclohexylcarbodiimide in each time 6.66 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. IR: 3400, 3300, 1787, 1740, 1725, 1695, 1630, 1504, 1495 (Nujol).

c) ( 2R, S )- 2-( 2- BOC- aminothiazol- 4- yl)- 2- methoxycarbonylmethanesulfonylamino- acetic acid-

6.8 g of (2R,S)-2-(2-BOC-aminothiazol-4-yl)-glycine is reacted in 60 1 of tetrahydrofuran with 5.2 g of methoxycarbonylmethanesulfo-chloride analogously to example 6 c) (20 ml of N,O -bis-(trimethylsilyl)-acetamide, 2 ml pyridine) and worked up. The title compound is obtained, which without characterization is further processed according to example 134 b).

Example 135.

7B-[( 2R;S )- 2-( 2- aminothiazol-4- yl)- 2- pivaloyl-oxymethoxycarbonylmethanesulfonylaminoacetamidoJ-3- cephem- 4- carboxylsylpivaloyloxymethyl ester hydrochloride.

1.3 g of 73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-carboxymethanesulfonylamino-acetamido]-3-cephem-4-carboxylic acid disodium salt, (preparation see example 137) and 1 .3 ml of iodomethylpivalate are reacted in 13 ml of dimethylformamide analogously to example 70 a), worked up and transferred into the hydrochloride. The title compound is achieved. F: above 160° (during cleavage), [a] 2 0°= +29°+l°

(0.92% in DMSO). IR: 3650-2300"ibred), 1785 (shoulder, 1755, 1695, 1650 (shoulder), 1630, 1530 (Nujol). UV: 260 (9000, CH3OH).

Example 136.

7b-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride.

1.0 g of 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methoxycarbonyl-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt, (preparation see example 138' a) and 0.52 ml of iodomethylpivalate is reacted in 10 ml of dimethylformamide analogously to example 70 a), worked up and transferred into the hydrochloride. The title compound is achieved. F: above 95° (during cleavage).

[a]p°°= +56°+1° (0.99% in DMSO). IR. 3660-2300 (wide), 1785, 1747, 1695, 1630 1540 (Nujol). UV: 255 (9500, CH-1OH).

Example 13 7.

7s-[(2R,S)-2-(2-aminothiazol-4-yl)-2-carboxy-methanesulfonylaminoacetamido]-3-cephem-4-carboxyl-acid disodium salt.

2.7 g [(2R,S)-2-(2-aminothiazol-4-yl)-2-methoxycarbonyl-

methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt, (preparation see example 138 a)), is stirred in 135 ml of water with 135 ml of 0.1 N aqueous sodium hydroxide for 20 minutes at room temperature. The pH is then adjusted to 7 with 2 N hydrochloric acid, evaporated in a vacuum and chromatographed as described in example 1 a). The hydrate of the title compound is obtained.

F: above 220° (during cleavage). (aJ^ = +61°±1° (1.13%

inH2O). IR: 3700-2500 (broad), 1780 (shoulder), 1760, 1670 (shoulder), 1630-1565 (broad), 1520 (Nujol). UV: 253 (7000, H 2 O) .

Example 138.

a) 78-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt. 12 g of the 7B-[(2R,s)-2-(2-BOC-aminothiazol-4-yl)-2-methoxycarbonylmethanesulfonyl-aminoacetamido ]-3-cephem-4-carboxylic acid diphenylmethyl ester, which can be prepared according to example 138 b), are reacted in 20 ml CH2Cl2 and 3.8 ml anisole with 25 ml trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained.. F: above 190° (under decomposition). [a]D 2 0°=+98°+1° (0.99% in H 2 O). IR: 3650-2500 Cbred), 1775 (shoulder), 1745, 1678, 1605, 1520 (Nujol). UV: 252 (9800, H 2 O). b) 7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methoxy-carbonylmethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 10.2 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methoxycarbonylmethanesulfonyl-amino-acetic acid obtainable according to example 134 c) is reacted with 7.3 g of 7B-amino-3 -cephem-4-carboxylic acid diphenylmethyl ester in 100 ml of tetrahydrofuran analogous to example 6 b), (3.3 g of hydroxybenztriazole, 3 times 1.73 g of dicyclohexylcarbodiimide in each time 6.66 ml of tetrahydrofuran), is worked up and chromatographed. The title compound is obtained, [aj ^ 2 0°= +16°±1° (1.10% in EtOH). IR: 3400,3300, 1789, 1740 (shoulder), 1725, 1696, 1635, 1542, 1497 (CH 2 Cl 2 ). UV: 258 (14200, EtOH).

Example 139.

a) 3-carbamoyloxymethyl-7B-[(2R,S)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid sodium salt. 2.2 g (2.9 mmol) 3-carbamoyloxymethyl-7B-[(2R,S)-2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2- methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester is reacted in 4.4 ml CH2C12 and 1.5 ml anisole with 21 ml trifluoroacetic acid analogously to example 12 a), worked up, chromatographed and lyophilized. The title compound with an Rf value of 0.55 is obtained (silica gel "Opti UPC" 12, water:acetonitrile 6:1). IR (Nujol): characteristic absorption bands at 3310, 1755, 1617, 1158. b) 3- carbamoyloxymethyl- 7B-[( 2R, S)- 2-( 5- BOC- amino-1, 2, 4- thiadiazole- 3- yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester.

1.8 g 5.0 mmol) (2R,S)-2-(5-BOC-amino-1,2,4-thiadiazol-3-yl)-2-methanesulfonylaminoacetic acid and 2.2 g (5.0 mmol ) 3-carbamoyloxymethyl-7B-amino-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted in 40 ml tetrahydrofuran analogously to example 12 b), (0.55 g hydroxybenztriazole), 1.25 g N,N<*->dicyclohexylcarbodiimide, are worked up and combined

from ether. The title compound is achieved. Rf value: 0.50 (silica gel, ethyl acetate). IR: (Nujol): characteristic absorption bands at 1765 and 1160.

Example 14 0.

In an analogous manner to that in examples 1-139, the following compounds can be prepared: 3-methyl-7B-[(2R,SJ-2-82-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]- 3-cef em-4-carboxylic acid . IR: i.a. 1765 (Nujol). UV: 250 814100, 0.1 N HCl).

3-Chloro-7 S -[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1766 (Nujol). UV: 251 (15200, 0.1N HCl).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7 6-[(2R,S)-2-(2-aminothiazole-4 -yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1762 (Nujol). UV: 240 (18600), 270 (22100, 0.1 N HCl).

3- pyridinium methyl-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido j-3-cephem-4-carboxylate, IR: i.a. . 1761 (Nujol). UV: 249 (1400, 0.1N HCl).

3z-(4-Carbamoylpyridiniummethyl)-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylate. IK: i.a. 1764 (Nujol). UV: 250 814800, 0.1 N HCl).

3-methyl-76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid: IR: b. a. 1770, 1748, 1730, 1692, 1610, 1530 (Nujol). UV: 2533 (12500, H2O).

3-Methoxy-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 252 (13300, H20)

3-Chloro-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 253 814400, H20).

3-(1-Carboxyl-1-1II-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-Aminothiazol-4-<y>1)-2-(2-methanesulfonylaminoethanesulfonyl- amino)-acetamido]-3-cef em-4-carboxylic acid . IR: i.a. 1765 (Nujol). UV: 252 (12900, H 2 O).

3-(1-sulfomethyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonyl-amino)-acetamido ] - 3-cef em-4-carboxylic acid . IR: i.a. 1768 (Nujol). UV: 251 (13000, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4- yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid, IR: i.a. 1768 (Nujol). UV: 241 (19000), 271 (22500, H20).

3-Pyridinium methyl 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylate. IR: i.a. 1765 (Nujol). UV: 252 (14800, H 2 O) .

3-(4-Carbamoylpyridiniummethyl)-7B-[(2R,S)-2-12-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylate. IR: i.a. 1769 (Nujol). UV: 251 (15000, H 2 O).

3-Methyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonyl-1-amino-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1768 (Nujol). UV: 252 814400, H20).

3-Methoxy<y->7 B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylamino-acetamido]-3-cephem-4-carboxylic acid. IR: i.a.

1770 (Nujol). UV: 250 (15000, H20).

3-Chloro-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonyl-1-amino-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1771 (Nujol). UV: 251 (14100, H 2 O).

3-(i-carboxymethyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (New Year). UV: 252 (14900, H 2 O).

3-Pyridinium methyl 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylate. IR: i.a. 1769 (Nujol). UV: 251 (15200, H 2 O).

3-Methyl-7B-[(2R,S)-2-(2-Aminothiazol-4-yl)-2-ethanesulfonyl-1-amino-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 251 (14200, H 2 O).

3-Methoxy-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-ethanesulfonylamino-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 251 (13900, HjO).

3-Chloro-7B-[(2R,S)-2-(2-aminothiazol-4-yl).-2-ethanesulfony 1-amino-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1771 (Nujol). UV: 252 (15000, HjO).

3-acetoxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-ethanesulfonylaminoacetamido]-3-cef em-4-carboxylic acid. IR: i.a. 1669 (Nujol). UV: 253 (14000, H 2 O).

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-r[(2R,S)-2-(2-aminothiazol-4-yl)-2-ethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid . IR: i.a. 1770 (Nujol). UV: 251 (14200, H 2 O) .

3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-ethanesulfonylaminoacetamido]-3-cephem-

4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 250 (14500, H20). 3 - (1-sulfomethyl-1H-tetrazol-5-ylthiomethyl)-7(3-[ ( 2R,S)-2-(2-aminothiazol-4-yl)-2-ethanesulfonylaminoacetamido]-3-cephem-4 -carboxylic acid. IR: i.a. 1768 (Nujol). UV: 251 (14700, H20). 3-[i-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl]-7 p -

[(2R,S)-2-(2-aminothiazol-4-yl)-2-ethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1768 (Nujol). UV: 252 (13900, H 2 O).

3-(2-Methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazine-3-yl1-thiomethyl)-7 ø-[(2R,s)-2-(2-aminothiazole -4-yl)-2-ethanesulfonylaminoacetamido]-3-cephem-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 240 (18000), 270 (22000, H20).

3-Pyridinium methyl-7 3~[(2R,S)-2-(2-aminothiazol-4-yl)-2-ethanesulfonylaminoacetamido]-3-cephem-4-carboxylate. IR: i.a. 1766 (Nujol). UV: 251 (14000, H 2 O).

3-(4-carbamoylpyridinium methyl)-7 ø-[(2R,S)-2-(2-aminothiazol-4-yl)-2-ethanesulfonylaminoacetamido]-3-cephem-4-carboxylate, IR: i.a. 1770 (Nujol). UV: 253 (15200, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7β-[(2R,S)-2-(2-aminothiazol-4- yl)-2-(2-acetyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1768 (Nujol). UV: 240 (18300), 270 (21900).

3-me ty 1-7 ø-[ ( 2R, S ). - 2-(2-aminothiazol-4-yl)-2-(2-formylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid.

IR: i.a. 1770 (Nujol). UV: 252 (14800, H 2 O).

3-Methoxy-7-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid.

IR: i.a. 1771 (Nujol). UV: 252 (14900, H 2 O).

3-Chloro-7b-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid.

IR: i.a. 1769 (Nujol). UV: 253 (14700, H 2 O).

3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl)-7 8-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3 -cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 252 (15500, H 2 O).

3-(1-sulfomethyl-1H-tetrazol-5-ylthiomethyl)-7g-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)-acetamido]-3 -cephem-4-carboxylic acid. IR: i.a. 1771 (Nujol). UV: 253 15300, H20).

3-[(1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl]-7 g-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylaminoethanesul- phenylamino)-acetamido]-3-cephem-4-carboxylic acid IR: ia 1769 (Nujol) UV: 252 (15400, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7g-[(2R,S)-2-(2-aminothiazol-4- yl)-2-(2-formyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 240 (17900). 270 (21800, H20).

3-methyl-7 g-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2-aminothiazol-4-ylacetylamino)-ethanesulfonylamino)-acetamido-3-cephem- 4-carboxylic acid. IR: 1768 (Nujol). UV: 249 (13200, H 2 O).

3-chloro-7g-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2-aminothiazol-4-ylacetylamino)-ethanesulfonylamino)-acetamido-3-cephem-4 -carboxylic acid. IR: i.a. 1770 (Nujol). UV: 249 (14100, H 2 O).

3-methoxy-7 - (2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2-

aminothiazol-4-ylacetylamino)-ethnasulfonylamino)-acetamido-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 249 (14200, H 2 O).

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2-aminothiazol-4- ylacetylamino)-ethanesulfonylamino)-acetamide q-3-cephem-4-carboxylic acid. IR: i.a. 1771 (Nujol). UV: 249 (15200, H 2 O).

3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl)-7b~[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2-aminothiazol-4-ylacetylamino) )-ethanesulfonylamino)-acetamido;-3*-cef em-4-carboxylic acid.

IR: i.a. 1768 (Nujol). UV: 251 (14700, H2<D).

3-(1-sulfurnethyl-1H-tetrazol-5-ylthiomethyl)-76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2-aminothiazol-4-ylacetylamino) )-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1767 (Nujol). UV: 251 (14900, H 2 O).

3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl]-7 q-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2- aminothiazol-4-ylacetyl-amino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1771 (Nujol). UV: 252 (15100, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7β-[(2R,S)-2-(2-aminothiazol-4- yl)-2-(2-(2-aminothiazol-4-ylacetylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1768 (Nujol). UV: 240

(19100), 270 (22500, H 2 O).

3-pyridiniummethyl-7 6- [ (2R, §9>-2- ( 2-aminothiazol-4-yl) - 2- ( 2-(2-aminothiazol-4-ylacety1amino)-ethanesulfonylamino)-acetamido ] -3- cef em-4-carboxylate IR: i.a. 1768 (Nujol) UV: 251 (14400, H20).

3-(4-carbamoylpyridiniummethyl-7s-(2R,S)-2-'(2-aminothiazol-4-yl)-2-(2-(2-aminothiazol-4-ylacetylamino)-ethanesulfonylamino)-

acetamido]-3-cephem-4-carboxylate. IR: i.a. 1767 (Nujol). UV: 251 (14600, H 2 O).

3-Methyl-7s-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-p.nitrobenzenesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1767 (Nujol). UV: 251 (14900, H 2 O) .

3-Methoxy-7s-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-p.nitro-benzenesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 251 (14800, H 2 O).

3-Chloro-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-p.nitrobenzenesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 252 (15200, H 2 O) .

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7β-[(2R,S)-2-(2-aminothiazol-4- yl)-2-(2-p-nitrobenzenesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 240

(18500). 270 (22000, H 2 O).

3-Pyridinium methyl 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-p.nitrobenzenesulfonylaminoethanesulfonylamino)racetamido]-3-cephem-4-carboxylate. IR: 1769 (Nujol). UV: 252 (14800, H 2 O).

3-(4-Carbamoylpyridiniummethyl)-7β-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-p.nitrobenzenesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylate. IR: i.a. 1771 (Nujol). UV: 251 (14700, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7b-](2R,S)-2-(2-aminothiazol-4- yl)-2-(2-butyryl-aminoethanesulfonylamino)-acetamido]-3-cef em-4-carboxylic acid.

IR: i.a. 1770 (Nujol). UV: 241 (17900). 271 (22500, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7 B-[ (2R,S)-2-(2-aminothiazol-4 -yl)-2-ethoxycarbonyl aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 240 (18000). 270 (22100, H 2 O).

3-Methyl-76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 251 (14000, H2O).

3-Methoxy-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769. (Nujol) . UV: 251 (14100, H 2 O).

3-Chloro-7e-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 252 (15000.H20).

3-Acetoxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1771 (Nujol). UV: 251 (15100, H 2 O).

3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyethanesulfonylamino)-acetamido] -3- cef em-4-carboxylic acid . IR: i.a. 1769 (Nujol). UV: 250 (14700, H20).

3-(1-sulfomethyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-2 (2-aminothiazol-4-yl)-2-(2-methoxyethanesulfonylamino)-acetamido 1-3 -cephem-4-carboxylic acid. IR: i.a. 1771 (Nujol).

UV: 251 (15100, H20)

3-f(1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl1-78-f(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyethanesulfonyl-amino) -acetamido 1 -3-cef em-4-carboxylic acid IR: i.a. 1770

(Nujol). UV. 252 (14800, H20).

3-(Methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-4-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl) -2-(2-Methoxyethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769 CNujol). UV: 241 (17700), 272 (21800, H20).

3-Pyridinium methyl-76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(.2-methoxyethanesulfonylamino)-acetamido]-3-cephem-4-carboxylate. IR: i.a. 1771 (Nujol). UV: 250 (15000, H20).

3-(4-Carbamoylpyridiniummethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyethanesulfonylamino)-acetamido]-3-cephem-4-carboxylate. IR: i.a. 1771 (Nujol). 252 (14800, H20).

3-Methyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-cyanomethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: i.a. 2260, 1770 (Nujol). UV: 250 (9400, H20).

3-Methoxy-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-cyanomethanesulfonylaminoacetamido]-3-cef em-4-carboxylic acid . IR: i.a. 2260, 1769 (Nujol). UV. 251 (10100, H20).

3-Chloro-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-cyanomethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: i.a. 2260, 1771 (Nujol). uv: 250 (9900, H20).

3-acetoxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-cyano-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: i.a. 2260 (Nujol). UV: 250 (9700, H20).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7-[(2R,S)-2-(2-aminothiazol-4- yl)-2-cyanometansulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: 2260, 1771 (Nujol). UV: 240 (19000), 270 (22000, H20) .

3-k arbamoyloxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-

(2-Aminothiazol-4-yl)-2-cyanomethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: i.a. 2260, 1770 (Nujol).

UV. 251 (9000, H 2 O).

3-Pyridinium methyl 7 8-[(2R,S)-2-(2-aminothiazol-4-yl)-2-cyano-methanesulfonylaminoacetamido]-3-cephem-4-carboxylate. IR: i.a. 2260, 1769 (Nujol). UV: 250 (10000, H20).

3-(4-Carbamoylpyridiniummethyl)-76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-cyanomethanesulfonylaminoacetamido j-3-cephem-4-carboxylate. IR: i.a. 2260, 1771 (Nujol). UV: 250 (9800 H20).

3-Methyl-76-[(2R,S)-2-(2-acryloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV. 250 (14800, H20).

3-Methoxy-7-6(2R-S)-2-(2-aminothiazol-4-yl)-2-(2-acryloyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 251 (14900, H 2 O).

3-Chloro-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylamino-ethanesulfonylamino).acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1771 (Nujol). UV* 252 (13800, H2O).

3-acetoxymethyl-76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 251 (13300, H2C).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-76-[(2R,S)-2-(2-acryloylaminoethanesulfonyl-amino) -acetamido]-3-cephem-4-carboxylic acid. IR: i.a.

1769 (Nujol).

3-pyridiniummethyl-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetamido]3-cephem-4-

carboxylate. IR: i.a. 1770 (Nujol). UV: 251 (14000, M20).

3-(4-Carbamoylpiperidiniummethyl)-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylate. IR: i.a. 1768 (Nujol).

UV: 249 (16200, H 2 O).

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-cyclopropylcarbonylaminoethanesulfonyl-amino)-acetamido] -3-cephem-4-carboxylic acid. IR: i.a.

1769 (Nujol). UV: 255 (14200, H2O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7 6-[(2R,S)-2-(2-aminothiazol-4 -yl)-2-(2-cyclopropylcarbonylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770, UV: 241 (13000), 271 (22000, H 2 O).

3-Carbamoyloxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-cyclopropylcarbonylaminoethanesulfonylamino)-acetamido j-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 251 (14200, H 2 O).

3-Methyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-cyanoacetyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 251 (14200, H 2 O).

3-Methoxy-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-cyano-acetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 252 (14100, H 2 O).

3-Chloro-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-cyanoacetyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1771 (Nujol). UV: 252 (15100, H 2 O).

3-acetoxymethyl-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-cyanoacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-

yl)-2-(2-cyanoacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 253 (14800, H 2 O).

3-(1-methyl)-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-cyanoacetylaminoethanesulfonylamino)-acetamido]-3 -cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 253 (14400, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-yl-thiometh<y>1)-7 6-[(2R,S)-2- (2-Aminothiazol-4-yl)-2-(2-cyano-acetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 241 (19000), 272 (21000, H20).

3-Carbamoyloxymethyl-76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-cyanoacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 251 (11000, H 2 O).

3-Pyridinium methyl 76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-cyanoacetylamioneethanesulfonylamino)-acetamido]-3-cephem-4-carboxylate. IR: i.a. 1776 (Nujol). UV: 250 (12100, H20).

3-(4-Carbamoylpyridinium methyl)-76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-cyanoacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylate. IR: i.a. 1771 (Nujol). UV: 253 (16100, H 2 O).

3-Methyl-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxy-acetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 251 (14200, H 2 O).

3-Methoxy-78-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxy-acetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 250 (14300, H20).

3-Chloro-7s-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyacetylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1771 (Nujol). UV: 251 (13900, H 2 O).

3-Acetoxynethyl1-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 251 (14800, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4- yl)-2-(2-methoxyacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1771 (Nujol). UV: 240 (17700), 270 (20900, H20).

3- Pyridinium methyl 7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylate. IR: i.a. 1770 (Nujol). UV: 251 (14800, H 2 O) .

3-(4-carbamoylpyridinium methyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylate. IR: i.a. 1771 (Nujol) UV: 251 (14800, H20).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4- yl)-2-(2-propiolyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 2120, 1760 (Nujol). UV: 241 (17300), 271

(22400, H 2 O).

3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-propioloylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid.. IR: i.a. . 2120, 1764 (Nujol). UV: 249 (9900, H 2 O).

3-methyl-7s-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methylamino-

ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid.

IR: i.a. 1768 (Nujol). UV: 249 (11100, H 2 O).

3-Methoxy-7β-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1767 (-Nujol). UV: 248 (12100, H 2 O).

3-Chloro-7-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methylamino-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid.

IR: i.a. 1768 (Nujol). UV: 249 (12400, H 2 O).

3-Acetoxymethyl-7b-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1765 (Nujol). UV: 249 (14200, H2<D) .

3-(1-carboxymethyl-1H-tetrazol-5-ylthiomethyl)-7b-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methylaminoethanesulfonylamino)-acetamido]-3- cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 251 (14200, H 2 O).

3-(1-sulfomethyl-1H-tetrazol-5-ylthiomethyl)-7s-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methylaminoethanesulfonylamino)-acetamido]-3- cef em-4-carboxylic acid . IR: i.a. 1770 (Nujol).

UV: 249 (9900, H 2 O).

3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl]-7 b-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methylaminoethanesulfonylamino )-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1769 (Nujol). UV: 248 (10300, H20)

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazole-4 -yl)-2-(2-methyl-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 240 (17700), 271 (21900, H20).

3-pyridiniummethyl-7s_[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methylaminoethanesulfonylamino)-acetamido]-3-cephem-4-car-

boxylate. IR: i.a. 1770 (Nujol). UV: 249 (14000, H 2 O).

3-(4-Carbamoylpyridiniummethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methylaminoethanesulfonylamino)-acetamido J-3-cephem-4-carboxylate. IR: i.a. 1769 (Nujol). UV: 250 (14300, H20).

3-methyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2,4-di-nitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem -4-carboxylic acid. IR: i.a. 1768 (Nujol). UV:

251 814100, H20). 3-methoxy-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4- carboxylic acid. IR: i.a. 1765 (Nujol). UV: 251 (13800, H 2 O).

3-chloro-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2,4-dinitro-benzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem -4- carboxylic acid. IR: i.a. 1765 (Nujol). UV: 249 (13900, H 2 O).

3-acetoxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cef em-4 -carboxylic acid. IR: i.a. 1765 (Nujol).

UV: 251 (14600, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4- yl)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1768 (Nujol). UV: 241 (16900). 270 (20100,H20).

3-pyridiniummethyl-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cef em- 4-carboxylate. IR: i.a. 1768 (Nujol).

UV: 250 (14900, H20). 3 -(4-carbamoylpyridiniummethyl)-7 8 -[ (2R,S)-2 -(2-aminothiazol-4-yl)-2-(2-(2,4-dinitrobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]-3 -cephem-4-carboxylate. IR: i.a. 1768 (Nujol). UV: 250 (15200, lj20) .

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-78-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2-cyanomethanesulfonylamino)-ethanesulfonylamino )-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1768 (Nujol). UV: 251 (14300, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7 6-[(2R,S)-2-(2-aminoptiazol-4 -yl)-2-(2-(2-cyano-methanesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV 240 (19000, H20) .

3-carbamoyloxymethyl-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(2-cyanomethanesulfonylamino)-ethanesulfonylamino)-acetamido]-3-cef em-4- carboxylic acid. IR: i.a. 1768 (Nujol).

UV: 249 (14800, H 2 O).

3-methyl-7 8-[(2R,S)-2-(2-aminothiazol-4-yl)-2-vinylsulfonyl-amino-acetamido]-3-cephem-4-carboxylic acid. IR: 1768 (Nujol) UV: 251 (14200, H20).

3-Methoxy-7-6(2R,S)-2-(2-aminothiazol-4-yl)-2-vinylsulfonylamino-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1768 (Nujol). UV: 250 (14900, H20).

3-Chloro-7 8-[(2R,S)-2-C2-aminothiazol-4-yl)-2-vinylsulfonyl-1-amino-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1767 (Nujol). UV: 251 (13900, H 2 O).

3-acetoxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-vinylsulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1768 (Nujol). UV: 252 (14100, H 2 O) .

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7S-[(2R,S)-2-(2-aminothiazol-4-yl)-2-vinylsulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1768 (Nujol). UV: 251

(14400, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-as-triazin-3-ylthiomethyl)-7s-[(2R,S)-2-(2-aminothiazol-4- yl)-2-vinylsulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1768 (Nujol). UV: 241 (18900), 280 (22200, H20).

3-carbamoyloxymethyl-7 B - [(2R,S)-2-(2-aminothiazol-4-yl)-2- vi ny ls ul f onylaminoacetamido ]«- 3-cef em-4-carboxylic acid .

IR: i.a. 1765 (Nujol). UV: 251 (14000, H 2 O).

3- Pyridiniummethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-vinylsulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1766 (Nujol). UV: 252 (14100, H 2 O).

3-(4-Carbamoylpyridiniummethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-vinylsulfonylaminoacetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1767 (Nujol). UV: 251 (15000, H 2 O).

3-methyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(3-pyridyl-sulfonylamino)-ethanesulfonylamino)-acetamido]- 3-cephem-4- carboxylic acid. IR: i.a. 1770 (Nujol). UV: 251 (13800, H 2 O).

3- methoxy-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(3-pyridylsulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4- carboxylic acid. IR: i.a. 1769 (Nujol). UV: 252 (14100, H 2 O).

3-chloro-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(3-pyridyl-sulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4- carboxylic acid. IR: i.a. 1770 (Nujol). UV 251 (13800, H20).

3- Acetoxymethyl-7β-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(3-pyridylsulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 250 (14800, H20).

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(3-pyridylsulfonylamino)-ethanesulfonylamino) -acetamido ] -3-cef em-4-carboxylic acid . IR: i.a. 1769 (Nujol). UV: 251 (15100, H 2 O).

3-(2-methyl-5,6-dioxo-1,2,5,6-tetrahydo-as-triazin-3-ylthiomethyl)-7β-[(2R,S)-2-(2-aminothiazol-4- yl)-2-(2-(3-pyridylsulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1768 (Nujol). UV: 241 (18900). 270 (21500, H 2 O).

3-carbamoyloxymethyl-7 8 - [ ( 2R , S ) - 2-(.2-aminothiazol-4-yl) - 2-(2-(3-pyridylsulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4- carboxylic acid. IR: i.a. 1768 (Nujol). UV: 251 (13800, H 2 O).

3-(4-carbamoylpyridiniummethyl)-7 ø-[(2R,3)-2-(2-aminothiazol-4-yl)-2-(2-(3-pyridylsulfonylamino)-ethanesulfonylamino)-acetamido]-3-cephem -4-carboxylic acid. IR: 1768 (Nujol).

UV: 251 (13800, H 2 O).

3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7?-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methylcarbamoylaminoethanesulfonyl-amino)-acetamido]- 3-cephem-4-carboxylic acid. IR: i.a.

1770 (Nujol). UV: 251 (15200, H 2 O).

7ø-[(2R,S)-2-(2-Dimethylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR: i.a. 1770 (Nujol). UV: 251(14000, H 2 O).

3-carbamoyloxymethyl-7[delta]-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acetylmethylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. IR. blue. 1770 (Nujol). UV: 252 (14300,

II20).

3-Carbamoyloxymethyl-73-[(2R,S)-2-(2-aminothiazol-4-yl)-2-vinylsulfonylaminoacetamido]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester.

7 3-[ (2R,S)-2-32-aminothiazol-4-yl)-2-(2-dimethylaminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 7 3-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-guanidinoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid. 7 3-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-ureidoethanesulfonyl-amino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 7 3-[(2R,S)-2-(2-thioureidoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt. 7 3-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(N-(methoxycarbonyl-iminomethoxycarbonylamino)-methylamino)-ethanesulfonylamino)-acetamido]-3-cephem-4 -carboxylic acid sodium salt. 7 3-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(4-pyridyl)-ethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt.

as well as the R and S derivatives, the salts, e.g. the sodium salt, and the esters cleavable under physiological conditions, e.g. pivaloyloxymethyl, 2-propionyloxyethyl, ethoxycarbonyloxyethyl or tert-butyloxycarbonyloxymethyl ester.

Example 141.

Dry ampoules or medicine bottles containing 0.5 g of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7S-[(2R,S)-2-(2-aminothiazol-4-yl J -2-(2 -aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt is prepared as follows: 3-(1-methyl-1H-tetrazol-5-ylthiomethyl-7B-[(2R,S)-2-(2-aminoethanesulfonylamino) -acetamido]-3-cephem-4-carboxylic acid sodium salt 0.5 g Mannitol 0.05 g A sterile, aqueous solution of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7e-[(2R,S)- 2-(2-Aminothiazol-4-yl)-2-(2-aminoethanesulfonylamino)-acetamido]-3-cephem-4-carboxylic acid sodium salt is enclosed in 5 ml" ampoules or medicine bottles under aseptic conditions and tested.

similarly, the compounds mentioned in the other examples can be filled into dry ampoules or medicine bottles.

Example 142.

7b-[(2R,S)-2-(2-aminothiazol-4-yl)-2- pivaloyl-oxymethoxycarbonylmethanesulfonylaminoacetamido j-3-cephem-4- carboxylic acid pivaloyloxynrethyl ester.

1.3 g 7 B -[(2R,S)-2-(aminothiazol-4-yl)-2-carboxymethanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid disodium salt.

(preparation see example 137) and 1.3 ml of iodomethylpivalate is reacted in 13 ml of dimethylformamide and 5 ml of methanol analogously to example 70 a), worked up and transferred into the hydrochloride. The title compound is achieved. F: above 160° (during cleavage), [ a] £ = +29°±1° (0.92% in DMSO). IR: 3650-2400 (wide), 1785 (shoulder), 1755, 1695, 1650 (shoulder), 1630, 1530 (Nujol). UV: 260 (9000, CH 3 OH).

Example 143.

a) 3- carbamoyloxymethyl- 7 B-[ ( 2R, S)- 2-( 2- aminothiazol-4- yl)- 2- methoxycarbonylmethanesulfonylaminoacet-

amido] - 3- cef em- 4- carboxylic acid sodium salt.

3.4 g of the 3-carbamoyloxymethyl-7b-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methoxycarbonylimethanesulfonylaminoacetamido]-3-cephem, which can be prepared according to example 143 b) 4-carboxylic acid diphenyl methyl ester is reacted in 6 ml of CH2C12

and 0.98 ml of anisole with 10 ml of trifluoroacetic acid analogously to example 1 a), are worked up, chromatographed and reprecipitated. The hydrate of the title compound is obtained. F: above 210°

(under cleavage). [a]* 2 0°= 158°+1° (0.89% in H 2 O). IR: 3650-2500 (wide), 1750, 1710 (shoulder), 1677, 1610, 1520 (Nujol). UV: 258 (12800, II~,0)._

b) 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methoxycarbonylmethanesulfonylamino-acetamido]-3-cephem-4-carboxylic acid diphenyl methyl ester. 10.2 g of the (2R,S)-2-(2-BOC-aminothiazol-4-yl)-2-methoxycarbonylmethanesulfonylamino-acetic acid obtainable according to example 134 c) is reacted with 10.9 g of 3-carbamoyloxymethyl-78- amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 100 ml tetrahydrofuran analogous to example 6 b), (3.3 g hydroxy-benztriazole, 3 times 1.74 g dicyclohexylcarbodiimide in each time 6.66 ml tetrahydrofuran), is worked up and chromatographed. The title compound is achieved. ^ a^ D 2 0°~ 0<o>±l° (0.94% in CHCl 3 ). IR: 3225, 3420, 3400 (shoulder), 3300, 1787, 1730, 1700 (shoulder), 1581, 1542 (CH 2 Cl 2 ). UV: 259 (15400, CHC13).

Example 144.

3-( 1, 2, 3- triazol-5- ylthiomethyl)- 7B-[( 2R, S)- 2-( 2-aminothiazol-4- yl)- 2-( 2- methanesulfonylamino)-ethanesulfonylamino- acetamido]- 3- cephem- 4- carboxylic acid sodium salt.

A slurry of 1.52 g (2.4 mmol) of 3-acetoxymethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylamino)-ethanesulfonylaminoacetamido]- 3-cephem-4-carboxylic acid sodium salt and 0.590 g (4.8 mmol) of 5-mercapto-1,2,3-triazole in 7 ml of water are adjusted to pH 7, stirred for 5 hours at 70°, then cooled to 0° and is added to 300ml of ethanol. The precipitate formed is filtered off, dissolved in 10 ml of water and purified on 25 g of silylated silica gel (Antec "Opti UPC" 12) with water as eluent, from which the title compound is obtained in the form of the dihydrate. Temp. from 131° (during cleavage). Rf: approx. 0.75 (silica gel "Opti UPC" 12,

UV 366, acetonitrile-water 1:4).-

Claims (1)

1. Process for the preparation of 76-acylamido-3-cephem-4-carboxylic acid compounds with the formula: where m is an integer from 0 to 2, hydrogen, lower alkyl, lower alkenyl, lower alkoxy, halogen, a group of the formula -CI-^^' where ^2 is a free, esterified or etherified hydroxy or mercapto group or an ammonium group, or a group of the formula -CH=CHR2 , where R2' is an etherified mercapto group, R^ carboxy or protected carboxy, R^ hydrogen, R, - an organic residue which is bound to the sulfonyl group with a carbon atom, and Rg a heterocyclic residue, stereoisomers, mixtures of these stereoisomers, hydrates and salts of compounds of formula I, characterized by ata) in a compound of the formula in which m, R^ , R^ and R^ have the meanings mentioned under formula I, and in which a functional group present in R^ is protected, and the 7B~ amino group is optionally protected by a group that allows an acylation reaction, is acylated The 7e-amino group by reaction with an acylating agent, which introduces an acyl residue of a carboxylic acid with the formula in which R^ and Rg have the meanings mentioned under formula I, and in which a gfunctional group present in R^ and/or Rg is present in protected form, orb) in a connection with the formula in which m, R-^, R^ , R^ and Rg have the meanings mentioned under formula I, and in which a functional group present in R^ and/or Rg is protected, and the 2-amino group is optionally protected by a group that allows the sulfonylation reaction, the 2-amino group is sulfonylated by reaction with a sulfonylating agent which introduces an R 2 -sulfonylation residue of a sulfonic acid with the formula where Rj. has the meaning mentioned under formula I, and a functional group present in R5 is in protected form, or with a reactive, functional acid derivative or a salt thereof, or c) a 2-cephem compound of the formula in which R-j^ R^ , R^ , R1- and Rg have the meanings mentioned under formula I, and a functional group present in R-^ , R^ and/or Rg is possibly present in a protected form, isomerized to the corresponding 3- cefem compound of formula I and, if desired, converts a compound of formula I obtainable according to the invention into another compound according to the definition of formula I, and/or transfers a compound of formula I obtainable according to the invention, wherein m means 0, into a compound of formula I, in which m means 1 or 2, and/or transfers a compound of formula I, in which m means 1 or 2, to a compound of formula 1, in which m means 0, and/or transfers in protected form present functional groups in a compound of formula I to free functional groups, and/or transfers an obtainable salt to the free compound or to another salt, and/or transfers an obtainable free compound with a salt-forming group to a salt and/or separates a achievable mix g of isomeric compounds of formula I in the individual isomers. 2. Process according to claim 1 for the production of compounds of formula I, wherein m means an integer from 0 to 2, R^ hydrogen, lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy or ethoxy, halogen, e.g. chlorine, or a group of the formula -CH2 -R2 / in which R2 is lower alkanoyloxy, e.g. acetoxy, carbamoyloxy, lower alkylcarbamoyloxy, aromatic, monocyclic, 5- or 6-membered heterocyclylthio, e.g. diaza-, triaza-, tetraaza-, thiaza-thiadiaza-, oxaza or oxadiazacyclyl-thio, e.g. imidazolylthio, triazolylthio, e.g. 1H-1,2,3-triazol-5-ylthio, tetrazolylthio, e.g. 1H-tetrasol-5-ylthio, thiazolylthio, thiadiazolylthio, e.g. 1,3,4-thiadiazol-5-ylthio, oxazolylthio, oxadiazolylthio or 5,6-dioxotetrahydro-as-traizin-3-ylthio, e.g. 5,6-dioxo,1,2,5,6-tetrahydro-as-triazin-3-ylthio or 5,6-dioxo-1,4,5,6-tetrahydro-as-triazin-3-ylthio which can be substituted with lower alkyl, e.g. methyl, diloweralkylaminoloweralkyl, e.g. dimethylaminomethyl or 2-dimethylaminoethyl, sulfolavereal alkyl, e.g. sulfomethyl or sulfoethyl, carboxyl lower alkyl, e.g. carboxymethyl, amino, carboxyl lower alkylamino, e.g. 2-carboxyethylamino, carbamoyl or with tetrazolyl lower alkyl, e.g. tetrazol-1H-5-ylmethyl, or an ammonium group, e.g. 2-lower alkyl 1-1-pyrazolium, e.g. 2-methyl-1-pyrazolium, 2-carboxylavealkyl-1-pyrazolium, e.g. 2-carboxymethyl-1-pyrazolium, 3-lower alkyl-1-triazolium, e.g. 3-methyl-1-triazolium, pyridinium, pyridinium substituted with hydroxyl lower alkyl, e.g. hydroxymethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, halogen, e.g. chlorine or bromine, or carbamoyl, e.g. 3- or 4-hydroxymethylpyridinium, 4-carboxypyridinium, 3- or 4-carboxymethylpyridinium, 3- or 4-chloropyridinium, 3- or 4-bromopyridinium or 3- or 4-carbamoylpyridinium, R 1 is carboxy or, under physiological conditions, cleavable carboxy, e.g. acyloxyvareal oxycarbonyl, e.g. lower alkanoylyloxycarbonyl, e.g. lower alkanoyloxymethoxycarbonyl or loweralkanoyloxyethoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl or 2-propionyloxyethoxycarbonyl or lower alkoxycarbonyloxyvareal oxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl or tert-butyloxycarbonyloxymethoxycarbonyl1, R^ is hydrogen, R^ is lower alkyl, e.g. methyl or ethyl, hydroxy lower alkyl, e.g. hydroxymethyl or 2-hydroxyethyl, lower alkoxy lower alkyl, e.g. methoxymethyl, 2-methoxyethyl or 2-ethoxyethyl, lower alkenyloxy lower alkyl, e.g. 2-vinyloxyethyl, lower alkanoyloxy lower alkyl, e.g. 2-acetoxyethyl, halolower alkyl, e.g. chloromethyl, 2-chloroethyl, 3-chloropropyl, 4-chlorobutyl or 2-bromomethyl, lower alkylthiolower alkyl, e.g. 2- methylthioethyl or 2-ethylthioethyl, aminocarboxylaveraalkylthiolaveraalkyl, e.g. 2-(2-amino-2-carboxyethylthio)-ethyl, benzoyl lower alkyl, e.g. benzoylmethyl, carboxy-lower alkyl, e.g. carboxymethyl or 2-carboxyethyl, lower alkoxycarbonyl lower alkyl, e.g. ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, carbamoyl lower alkyl, e.g. carbamoylmethyl, cyanolower alkyl, e.g. cyanomethyl or 1-cyano- or 2-cyanoethyl, sulpholower alkyl, e.g. sulfomethyl or 2-sulfoethyl, sulfamoyl lower alkyl, e.g. sulfamoylmethyl or 2-sulfamoylethyl, aminocarboxylave alkyl, e.g. 2-amino-2-carboxyethyl or a group of partial formula A, where the group -(^n H2n ^ means ethylene or propylene, Rq is hydrogen or lower alkyl, e.g. methyl, and R hydrogen, lower alkyl, e.g. methyl or ethyl, lower alkanoyl, e.g. formyl or acetyl, lower alkanoyl substituted with hydroxy, lower alkoxy, e.g. methoxy, halogen, e.g. bromo, carboxy, cyano or amino, e.g. -hydroxypropionyl, methoxyacetyl, bromoacetyl, carboxyacetyl, cyanoacetyl or glycyl, lower alkenoyl, e.g. acryloyl, lower alkynyl, e.g. propiolyl, cycloalkylcarbonyl, e.g. cyclopropylcarbonyl, benzoyl, 4-aminobenzoyl, 4-lower alkanoyl-aminobenzoyl, e.g. 4-acetylaminobenzoyl, 4-cyanobenzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, pyridylcarbonyl, e.g. nicotinoyl or isonicotinoyl, furoyl, e.g. 2-furoyl, thienylcarbonyl, e.g. 2-thienylcarbonyl, hydroxypyrimidylcarbonyl, e.g. 2,6-dihydroxy-1,3-pyrimid-4-ylcarbonyl, hydroxythiadiazolylcarbonyl, e.g. 4-hydroxy-1,2,5-thiadiazol-3-ylcarbonyl, tetrazolyl lower alkanoyl, e.g. 2-tetrazol-5-ylcetyl or aminothiazolyl lower alkanoyl, e.g. 2-(2-amino-1,3-thiazol-4-yl)-acetyl, the acyl group in a half-ester of carbonic acid, for example lower alkoxycarbonyl, e.g. methoxycarbonyl or isopropoxycarbonyl, lower alkanoyloxy substituted with carboxy and amino, e.g. 2-amino-2-carboxyethoxycarbonyl, or benzoyloxycarbonyl, the acyl group in a substituted carbamic acid, for example lower alkylcarbamoyl, e.g. methylcarbamoyl or anilinocarbonyl, the acyl group in a substituted thiocarbamic acid, eg lower alkylthiocarbamoyl, e.g. methylthiocarbamoyl, the acyl group in a substituted sulphonic acid, for example lower alkanesulphony1, e.g. methanesulfonyl, benzenesulfonyl, 4-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl, aminobenzenesulfonyl, e.g. 4-aminobenzenesulfonyl, an acylcarbamoyl group, for example benzoylcarbamoyl or furoylcarbamoyl, an acylthiocarbamoyl group, for example benzoylthiocarbamoyl or furoylthiocarbamoyl, 2-oxo-l-imidazolidinocarbonyl, 4-lower alkyl-2,3-dioxo-l-piperazinocarbonyl, e.g. 4-ethyl-2,3-dioxo-1-piperazinocarbonyl, and 4-lower alkanesulfonyl-1-piperazinocarbonyl, e.g. 4-methanesulfonyl-1-piperazinocarbonyl, and R 1 is pyridyl, e.g. 3- or 4-pyridyl, thienyl, e.g. 2- or 3-thienyl, furyl, e.g. 2- or 3-furyl, aminothiazolyl, e.g. 2-amino-4-thiazolyl, hydroxypyrimidyl, e.g. 2,6-dihydroxy-1,3-pyrimid-4-yl, aminothiadiazolyl, e.g. 5-amino-1,2,4-thia diazol-3-yl, hydroxythiadiazolyl, e.g. 4-hydroxy-1,2,5-thiadiazol-3-yl, or aminotriazolyl, e.g. 5-amino-1,2,4-triazol-3-yl, stereoisomers, mixtures of these stereoisomers, hydrates and pharmaceutically usable salts of such compounds, characterized in that the precautions mentioned in claim 1 are carried out. 3. Process according to claim 1 for the preparation of compounds of formula I, in which m is equal to 0, R 1 is hydrogen, lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, halogen, e.g. chlorine, or a group -CH2 R2 , in which R_ means lower alkanoyloxy, e.g. acetoxy, carbamoyloxy, triazolylthio, .eg. 1H-1,2,3-triazol-5-ylthio, tetrazolylthio, e.g. 1H-tetrazol-5-ylthio, tetrazolylthio substituted with lower alkyl, e.g. methyl, diloweralkylaminoloweralkyl, e.g. 2-dimethylaminoethyl, sulpholower alkyl, e.g. sulfomethyl, carboxy-lower alkyl, e.g. carboxymethyl, or with carbamoyl, e.g. 1-methyl-1H-tetrazol-5-yl-thio, 1-sulfomethyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio or 1-(2-dimethylaminoethyl)-1H-tetrazol- 5-ylthio, thiadiazolylthio, e.g. 1,3,4-thiadiazol-5-ylthio, thiadiazolylthio substituted with lower alkyl, e.g. methyl, e.g. 2-methyl-1,3,4-thiadaizol-5-ylthio, 5,6-dioxotetrahydro-as-triazin-3-ylthio which is substituted with lower alkyl, e.g. methyl, e.g. 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 with hydroxyl lower alkyl, e.g. hydroxymethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, halogen, e.g. chlorine or bromine, or carbamoyl, e.g. 3-or 4-hydroxymethylpyridinium, 4-carboxypyridinium, 3- or 4-carboxymethylpyridinium, 3- or 4-chloropyridinium, 3- or 4-bromopyridinium, or 3- or 4-carbamoylpyridinium, R, is carboxyl, or under physiological conditions cleavable carboxyl, e.g. acyloxyvareal oxycarbonyl, e.g. lower alkanoylyloxycarbonyl, e.g. lower alkanoyloxyethoxycarbonyl or loweralkanoyloxyethoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl or 2-propionyloxyethoxycarbonyl, or lower alkoxycarbonyloxyvareal oxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl or tert.-butoxycarbonyloxyethoxycarbonyl, R^ is hydrogen, R^ is lower alkyl, e.g. methyl or ethyl, hydroxy lower alkyl, e.g. hydroxymethyl or hydroxyethyl, lower alkoxy lower alkyl, e.g. methoxymethyl, 2-methoxyethyl or 2-ethoxyethyl, lower alkenyloxy lower alkyl, e.g. 2-vinyloxyethyl, halolower alkyl, e.g. chloromethyl or 2-chloroethyl, lower alkylthiolower alkyl, e.g. 2-methylthioethyl or 2-ethylthioethyl, carboxy lower alkyl, e.g. carboxymethyl or 2-carboxyethyl, carbamoyl lower alkyl, e.g. carbamoylmethyl, cyanolower alkyl, e.g. cyanomethyl or 1-cyano- or 2-cyanoethyl, or a group of partial formula A, which means 2-aminoethyl, 2-lower alkylaminoethyl, e.g. 2-methylaminoethyl or 2-n-hexylaminoethyl, 2-dilower alkylaminoethyl, e.g. 2-dimethylaminoethyl or 2-di-n-hexylaminoethyl, 2-sulfoaminoethyl, lower alkanoylaminoethyl, e.g. 2-formylaminoethyl or 2-acetylaminoethyl, 2-lower alkyllower akanoylaminoethyl, e.g. 2-methoxyacetylaminoethyl, 2-halolower alkanoylaminoethyl, e.g. 2-bromoacetylamino-ethyl, 2-(-hydroxypropionylamino)-ethyl, 2-glycylaminoethyl, 2-(3-amino-3-carboxypropionylamino)-ethyl, 2-acryloylaminoethyl1, 2-propioloylaminoethyl, 2-cyclopropylcarbonylaminoethane, 2 -benzoylaminoethyl, 2-(4-aminobenzoylamino)-ethyl, 2-(4-acetylaminobenzoylamino)-ethyl, 2-(4-cyanobenzoyl-amino)-ethyl, 2-(4-nitrobenzoylamino)-ethyl, 2-(3, 4-dinitro-benzoylamino)-ethyl, 2-mandeloylaminoethyl, 2-phenylglycylaminoethyl, 2-nicotinoylaminoethyl, 2-isonicotinoylaminoethyl, 2-(2-furoylamino)-ethyl, 2-(2-thienylcarbonylamino)-ethyl, 2-(2, 6-dihydroxy-1,3-pyrimid-4-ylcarbonylamino)-ethyl, 2-(4-hydroxy-1,2,5-thiadiazo1-3-ylcarbonylamino)-ethyl, 2-(2-tetrazol-1-ylacetylamino) -ethyl, 2-[2-(2-amino)-1,3-thiazol-4-yl)-acetylaminoj-ethyl, 2-acryloylaminoethyl, 2-propioloylaminoethyl, 2-cyclopropylcarbonylaminoethyl, 2-benzoylaminoethyl, 2-(4- aminobenzoylamino)-ethyl, 2-(4-ethylaminobenzoylamino)-ethyl, 2-(4-cyanobenzoylamino)-ethyl, 2-(4-nitrobenzoylamino)-ethyl, 2-(3,4-dinitrobenzoylamino)-ethyl, 2-mandeloylamino ethyl, 2-phenylglycylaminoethyl, 2-nicotinoylaminoethyl, 2-isonicotinoylaminoethyl, 2-(2-furoyl-amino)-ethyl, 2-(2-thienylcarbonylamino)-ethyl, 2-(2,6-dihydroxy-1,3-pyrimide) -4-ylcarbonylamino)-ethyl, 2 - (4 - hydroxy-1,2,5-thiadiazol-3-ylcarbonylamino)-ethyl, 2 - (2-tetrazol-1-ylacetylamino)-ethyl, 2-[-(2 -amino-1,3-thiazol-4-yl)acetylamino]-ethyl, 2-lower oxycarbonylaminoethyl, e.g. 2-methoxycarbonylaminoethyl or 2-isopropoxycarbonylaminoethyl, 2-(2-amino-2-carboxyethoxycarbonylamino)ethyl, 2-benzoyloxycarbonylaminoethyl, 2-lower alkylcarbamoylaminoethyl, e.g. 2-methylcarbamoylaminoethyl, 2-anilinocarbonylaminoethyl, 2-lower alkylthiocarbamoylaminoethyl, e.g. 2-methylthiocarbamoylaminoethyl, 2-lower alkanesulfonylaminoethyl, e.g. 2-methanesulfonylaminoethyl, 2-halogenomethanesulfonylaminoethyl, e.g. 2-difluoromethanesulfonylaminoethyl, 2-cyanorethanesulfonylaminoethyl, 2-benzenesulfonylaminoethyl, 2-(4-nitrobenzenesulfonylamino)-ethyl, 2-(2,4-dinitro-benzenesulfonylaminoethyl), 2-benzoylcarbamoylaminoethyl, 2-(2-furoylcarbamoylamino)-ethyl, 2-(2-oxo-1-imidazolidino-carbonylamino(-ethyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-ethyl and 2-(4-methanesulfonyl-1-piperazinocarbonylamino) )-ethyl and R, is aminothiazolyl, eg 2-amino-4-thiazolyl, aminothiadiazolyl, eg 5-amino-1,2,4-thiadiazolyl-3-yl, or aminotriazolyl, eg 5-amino-1,2,4-triazol-3-yl, steroisomers, mixtures of these steroisomers, hydrates and pharmaceutically usable salts of such compounds, characterized in that the precautions mentioned in claim 1 are carried out. 4. Process according to claim 1 for the preparation of compounds of formula I, in which m is equal to 0, R 1 is hydrogen, lower alkoxy, e.g. methoxy, halogen, e.g. chlorine, or a group of the formula -CH2-R2-/ ^where R2 is lower alkanoyloxy, e.g. acetoxy, carbamoyloxy, tetrazolylthio, e.g. II-tetrazol-5-ylthio, tetrazolylthio substituted with lower alkyl, e.g. methyl, diloweralkylaminoloweralkyl, e.g. 2-dimethylaminoethyl, sulpholower alkyl, e.g. sulfomethyl or carboxy-lower alkyl, e.g. carboxymethyl, e.g. 1-methyl-1H-tetrazol-5-ylthio, 1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthio, 1-sulfomethyl-1H-tetrazol-5- ylthio or 1-carboxymethyl-1H-tetrazol-5-ylthio, 5,6-dioxotetrahydro-as-triazin-3-ylthio substituted with lower alkyl, e.g. methyl, e.g. 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 with hydroxyl lower alkyl, e.g. hydroxymethyl, carboxy, carboxy-lower alkyl, e.g. carboxymethyl, halogen, e.g. chlorine or bromine, or carbamoyl, e.g. 3- or 4-hydroxymethylpyridinium, 4-carboxypyridinium, 3- or 4-carboxymethylpyridinium, 3- or 4-chloropyridinium, 3- or 4-bromopyridinium, or 3- or 4-carbamoylpyridinium, R 1 is carboxy, lower alkanoyloxylavereal oxycarbonyl, e.g. lower alkanoyloxymethoxycarbonyl or loweralkanoyloxyethoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl or 2-propionyloxyethoxycarbonyl or lower alkoxycarbonyloxyvareal oxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl or tert.-butoxycarbonyloxymethoxycarbonyl, R. is hydrogen, R.sub.3 is lower alkyl, e.g. methyl or ethyl, lower alkoxy lower alkyl, e.g. methoxymethyl, 2-methoxyethyl or 2-ethoxyethyl, lower alkenyloxy lower alkyl, e.g. 2-vinyloxyethyl, halolower alkyl, e.g. chloromethyl or 2-chloroethyl, carboxyl lower alkyl, e.g. carboxymethyl or 2-carboxyethyl, cyano lower alkyl, e.g. cyanomethyl or 1-cyano- or 2-cyanoethyl, or a group of partial formula A, which means 2-aminos to, 2-lower alkylaminoethyl, e.g. 2-methylaminoethyl or 2-ethylaminoethyl, 2-dilower alkylaminoethyl, e.g. 2-dimethylaminoethyl, 2-sulfoaminoethyl, lower alkanoylaminoethyl, e.g. 2-formylaminoethyl or 2-acetylaminoethyl, lower alkoxy lower alkanoylaminoethyl e.g. 2-methoxyacetylaminoethyl, cyanolower alkanoylaminoethyl, e.g. 2-cyanoacetylaminoethyl, lower alkenoylaminoethyl, e.g. 2-acryloylaminoethyl, lower alkinoylaminoethyl, e.g. 2-propionylaminoethyl, 2-lower oxycarbonylaminoethyl, e.g. 2-methoxycarbonylaminoethyl, 2-lower alkanesulfonylaminoethyl, e.g. 2-methanesulfonylaminoethyl, 2-benzenesulfonylaminoethyl, 2-benzenesulfonylaminoethyl, in which benzene is substituted by nitro or amino, e.g. 2-(4-nitrobenzenesulfonylamino)-ethyl, 2-(2,4-dinitrobenzenesulfonylamino)-ethyl, 2- (2-oxo-1-imidazolidinocarbonylamino)-ethyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-ethyl, or 2-(4-methylsulfonyl-1-piperazino-carbonylamino)-ethyl, and Rg is aminothiazolyl, e.g. 2-amino-4-thiazolyl, stereoisomers, mixtures of these stereoisomers, hydrates and pharmaceutically usable salts of such compounds, characterized in that the precautions mentioned in claim 1 are carried out. 5v Process for the preparation of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7b-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylaminoethanesulfonylamino)- acetamido]-3-cephem-4-carboxylic acid, according to claim 1. 6. Process for the preparation of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylamino-acetamido]- 3-cephem-4-carboxylic acid according to claim 1. 7. Process for the production of 3-(4-carbamoylpyridiniummethyl)-76-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cephem-4-carboxylic acid, according to requirement 1. 8. Process for the preparation of 3-acetoxymethyl-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylaminoethane-sulfonylamino)-acetamido]-3-cephem- 4-carboxylic acid according to claim 1. 9. Process for the preparation of 3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-cyanomethanesulfonylaminoacetamido]-3 -cephem-4-carboxylic acid, according to claim 1. 10. Process for the production of 3-carbamoyloxymethyl-7B-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-formylamino-ethanesulfonylamino)-acetamido]-3-cephem-4 -carboxylic acid, according to claim 1. 11. Process for the production of 3-carbamoyloxymethyl-7 8-[(2R,S)-2-(2-aminothiazol-4-yl)-2-methanesulfonyl-aminoacetamide]-3-cephem-4-carboxylic acid, according to claim 1 . 12. Process for the production of 3-carbamoyloxy methyl-7 6-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-(4-nitrobenzenesulfonylamino)-ethnasulfonylamino)-acetamido]-3-cephem-4-carboxylic acid, according to claim 1. 13. Process for the production of 3-carbamoyloxymethyl-7B-[(2R,S)-2-2-(2-aminothiazol-4-yl)-2-(2-methanesulfonylaminoethanesulfonylamino)-acetamido]-3-cephem-4 -carboxylic acid, according to claim 1. 14. Process for the production of 3-carbamoyloxymethyl-7s-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-acryloylamino-ethanesulfony 1 amino )-acetamido]-3-cephem -4-carboxylic acid, according to claim 1. 15. Process for the preparation of 3-carbamoyl-oxynethyl 1-7 8-[(2R,S)-2-(2-aminothiazol-4-yl)-2-(2-aminobenzenesulfonylamino)-ethanesulfonylamino)-acetamido]- 3-cephem-4-carboxylic acid, according to claim 1. 16. Process for the production of 3-carbamoyloxymethyl-7 8 -[(2S)-2-(2-aminotriazol-4-yl)-2-(2-methoxyacetylaminoethanesulfonylamino)-acetamido]-3-cephem- 4-carboxylic acid, according to claim 1. 17. Process for the preparation of 3-acetoxymethyl-7B-[ (2S)-2-(2-(2-aminothiazol-4-ylacetamido)-ethanesulfonylamino )-2-(2-aminothiazol-4-yl)-acetamido]- 3-cephem-4-carboxylic acid, according to claim 1. 18. Process for the preparation of 3-carbamoyl-oxynethyl 1-7B-[(2S)-2-(2-(2-aminothiazol-4-ylacetamido)-ethanesulfonylamino)-2-(2-aminothiazol-4-yl)acetamido ]-3-cephem-4-carboxylic acid, according to claim 1. 19. Process for the production of 3-carbamoyloxymethyl-7 8-[(2S)-2-(2-aminothiazol-4-yl)-2-ethanesulfonyl-1-aminoacetamido]-3-cephem-4-carboxylic acid, according to claim 1. 20. Process for the preparation of 3-(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-ylthiomethyl)-7 B-[(2R,S)-2-(2 -aminothiazol-4-yl)-2-methanesulfonylaminoacetamido]-3-cef em-4-carboxylic acid, according to claim 1. 21. Process for the production of pharmaceutical preparations, characterized in that 78-acylamido-3-cephem-4-carboxylic acid compounds of formula I, stereoisomers, mixtures of these stereoisomers, hydrates and salts are produced using the method according to claim 1, and these mixed with a pharmaceutical carrier material. 22. Process for the production of pharmaceutical preparations, characterized in that an active substance of formula I, as well as stereoisomers, mixtures of these stereoisomers, hydrates and salts thereof, are processed with a pharmaceutical carrier material. 23. Process for the preparation of compounds of formula III, where R', - and Rg have the meanings mentioned in claim 1 under formula I, and in which a functional group present in R,, and Rg is present in free or protected form, characterized by that in a connection with formula in which Rg has the meanings mentioned under formula I, and a functional group present in Rg is present in protected form <1>, the 2-amino group is acylated with a sulphonic acid with the formula wherein R,, has the meaning mentioned under formula I, and a functional group present in Rj is present in protected form, or with a reactive, functional acid derivative or a salt thereof, and if desired, the protective groups present are cleaved off in an obtainable compound ' else, and/or an obtainable compound of formula III is converted into another compound of formula III.