CA1178270A - Aminohydroxyphenyl compounds, processes for their manufacture, pharmaceutical preparations containing these compounds, and the use of these compounds - Google Patents

Abstract

4-13033/+

Aminohydroxyphenyl compounds, processes for their manu-facture, pharmaceutical preparations containing these compounds, and the use of these compounds.

Abstract Novel 7.beta.-[D-2-amino-2-(aminohydroxyphenyl)-acetylamino]-ceph-3-em-4-carboxylic acid compounds of the formula in which R represents hydrogen or an acyl group, R0 represents hydrogen or lower alkyl, R1 represents hydrogen or a group of the partial formula (R)(Ro)N-, R2 represents carboxyl or protected carboxyl, and R3 represents hydrogen, halogen having an atomic number of up to 35 or lower alkoxy, are manufactured. Intermediates are also included.
The novel compounds have valuable antibiotic properties and are effective against both gram-positive and gram-negative micro-organisms and have a low toxi-city. They may therefore be used for the treatment of corresponding infections.

Description

~-13033/+

~minohydroxyphenyl compounds, processes Eor their manu-facture, pharmaceutical preparations containing these compounds, and the use of these compounds.

The present invention relates to novel 7~-1D-2-amino-

2-(aminohydroxyphenyl)-acetylamino]-ceph 3-em-~-carboxylic acid compounds of the formula tR)(Ro)~ O ~)n OH ~ ~ R3 (I) O
: R~

~k -2- ~7~

in which the index n represents O or 1, R represents hydrogen or an acyl group, Ro represents hydrogen or lower alkyl, Rl represents hydrogen or a group of the partial formula tR)~Ro)N~, R2 represents carboxyl or protected carboxyl, and R3 represents hydrogen, halo~en having an atomic number of up to 35 or lower alkoxy, and hydrates and salts of compounds of the formula I, processes for the manufacture of compounds of the formula I, pharmaceutical preparations containing compounds of the formula I, and the use of these compounds for the manu~act-ure of pharmaceutical preparations or as pharmacologically active compounds.
In the above formula, the index n represents especially 0. If n has the value 1 the corresponding 1-oxide compound is in the a- or ~-form.
In the present description, the term "lower" used in connection with definitions of substituents or compounds indicates that the corresponding substituents or compounds contain up to 7, preferably up to 4, carbon atoms, unless ~ expressly defined otherwise.
; The general definitions used hereinbefore and herein-after preferably have the following meanings within the framework of the present description:
An acyl group R has up to 19 carbon atoms and is the acyl group R of a carboxylic acid, a carbonic acid semi-ester, carbamic acid, a substituted carbamic acid, thio-carbamic acid, a substituted thiocarbamic acid, a sulphonic acid, amidosulphonic acid or a substituted amidosulphonic acid.
Such acyl groups R have, for example, the formulae:
R -CO-, Ra_O_co_, R~RaN_CO_, RaRaN-cs-~ Ra-S~2-orRaRaN-S~ ~' in which Ra represents hydrogen or an optionally ~L~7B~ f3 substituted hydrocarbon radical and two radicals ~a in an acyl group may, within the scope oE their meanings, be the same or different.
~ n optionally substituted hydrocarbon radical Ra in an acyl group R has up to 18 carbon atoms and is, for example, a lower aliphatic, cycloaliphat:ic, cycloaliphatic-aliphatic, aromatic or araliphatic radical which may be substituted, for example, by lower alkyl, lower alkoxy, halogen, nitro, oxo, hydroxy, optionally functionally modi-fied carboxy, amino or lower alkylated amino, or a corres-ponding protected functional group.
A lower aliphatic radical Ra is, for example, lower alkyl, especially having from 1 to 6, preferably from 1 to 4, carbon atoms, for example methyl, ethyl, propyl or buty.l., or lower al~enyl, especially having from 2 to 5 carbon atoms, for example vinyl, propenyl or butenyl.
A cycloaliphatic radical Ra is cycloalkyl h;lving Erom 3 to 8, especially f:(.m 3 to 6, carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
A cycloaliphatic-aliphatic radical Ra is one of the mentioned aliphatic radicals that is substituted by one of the mentioned cycloallphatic radicals, for example cyclo-propylmethyl or ethyl or cyclohexylmethyl or -ethyl.
.~n aromatic radical Ra is especially phenyl or napthyl.
An araliphatic radical Ra is one of the mentioned aliphatic radicals that is substituted by from one to three of the mentioned aromatic radicals, for example benzyl, phenethyl, diphenylmethyl or trityl.
Preferred substituted hydrocarbon radicals Ra are, for example, halo-lower alkyl, for example 2-fluoro-, 2-chloro-, 2-bromo- and 2-iodoethyl, oxo-lower alkyl, for example acetonyl, optionally protected, for example acylated, hydroxy-lower alkyl, for example 2-hydroxyethyl and acetoxyethyl, optionally esterified carboxy-lower al'~yl, for example 2-carboxymethyl and 2-ethoxycarbonylmethyl, ~.~L7~

amino- and mono- or di-lower alkylamino-lower alkyl, for example 2-aminoethyl, 2-methylaminoethyl, 2-dimethylamino-ethyl, and acylamino-lower alkyl, for example 2-acetami~o-ethyl, lower alkylphenyl, for example tolyl and ~ylyl, lower alkoxyphenyl, for example methoxyphenyl, halo-phenyl, for example fluoro- or chlorophenyl, hydroxyphenyl, nitrophenyl, carboxyph~nyl and aminophenyl, wherein in each case the sub-stituents may be in the o-, m- or ~-position of the phenyl nucleus, and phenacetyl.
Preferred acyl groups R are, for example, lower alkanoyl, such as formyl, acetyl or propionyl; halo-lower alkanoyl, such as 2-haloacetyl, especially 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl;
benzoyl optionally subs~ituted, ~or example, by halog~n, lower alkoxy or nitro, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl; lower alkoxycarbonyl branched in the l-position of the lower al`~yl radical or suitably substituted in the 1- or 2-position, especially tert.-lower alkoxycarbonyl, for example tert.-butoxycar-bonyl; arylmethoxycarbonyl having one or two aryl radicals that are phenyl radicals optionally mono- or poly-substitu-ted, for example, by lower alkyl, especially tert.-lower alkyl, such as tert.-butyl, lower alkoxy, such as ~ethoxy, hydroxy, halogen, for example chlorine, and/or nitro: such as optionally substituted benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, or optionally substitute~ diphenyl-methoxycarbonyl, for example benzhydryloxycarbonyl or di-(4-methoxyphenyl)-~ethoxycarbonyl; aroylmethoxycarbonyl, in which the aroyl group is preferably benzoyl optionally sub-stitute~, for example, by halo3en, such as bromine, for example phenacyloxycarbonyl; 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2 chloroethoxycar-bonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl;
carbamoyl; ~-lower alkylcarbamoyl, for example ~-methylcarb-amoyl; N,N-di-lower alkylcarbamoyl, for example N,N-dimethylcarbamoyl; thiocarbamoyl; N-lower alkyltnio-IJ~ f ~

carbamoyl, foe example ~-methylthiocarbamoyl; N,N-di-lower alkylthiocarbamoyl, for example N,N-dimethylthiocarbamoyl;
lower alkylsulphonyl, for exa~ple methylsulphonyl or ethylsulphonyl, arylsulphonyl, for example phenylsul~honyl or tolylsulphonyl; sulpha~oyl; N-lower alkylsulphamoyl, Eor example N-methylsulphamoyl; or N,~-di-lower alkylsulphamoyl, for example N,N-dimethylsulphamoyl.
Ro as lower alkyl is, for example, methyl, ethyl, n-propyl, n-butyl, tert.-butyl, and n-pentyl, n-hexyl or n-heptyl~
If Rl represents a partial formula (R~Ro)~~, the two groups of the partial formula (R)~Ro)N- may, within the scope of their meanings, be the sa~e or different. Pre-ferably, one group takes up the 3-position (meta), the other group the 5-position (meta) and the hydroxy group takes up the 4-position (~ ) on the phenyl rin~.
R2 in the meaning of "protected carboxyl" is protec-ted carboxyl that can be readily spli~ or carboxyl that can be split under physiological conditions, and is esterified by the groups described below.
R3 as halogen having an atomic number of up to 35 represents fluorine or bromine but especially chlorine.
R3 as lower alkoxy is, for example, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert.-butoxy, and n-pentyl-oxy, n-hexyloxy, n-heptyloxy, or especially methoxy.
The functional groups in the compounds of the formula I, especially the 4-carboxyl, the D-2-amino and the hydroxy group on the phenyl ring, are optionally protected by pro-tecting groups that are used in penicillin, cephalosporin and peptide chemistry.
Such protecting groups can ~e split off readily, that is to say without undesired side-reactions t~ing place, for example by solvolysis, reduction, photolysis or alterna-tively under physiological conditions.
Such protecting groups and the manner in which they are split off are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, Lon~on, New YoLk, 1973, in "The Peptides", vol. I, Schr'oder and Lubke, Academic Press, London, New York, 196~, and in "~lethoden ~er organischen Cnemie", Houben-Weyl, 4th edition, vol. 15/1, Georg Thieme Verlag, Stuttgart 1974.
Thus, carboxyl groups, for example the carboxyl group R2, are usually protected in esterified form, such ester groupings being readily split under mild conditions. Carb-oxyl groups Qrotected in this manner contain as esterifying groups especially lower alkyl groups branched in the 1-pO5 i tion or suitably substituted in the 1- or 2-position.
Preferred carboxyl groups in esterified form are, inter alia, tert.-lower alkoxycarbonyl, for example tert.-butoxy-carbonyl; arylmethoxycarbonyl having one or two aryl radicals that are phenyl radicals optionally mono- or poly-substituted, for example, by lower alkyl, such ag tert.-lowe~ alkyl, ~or example tert.-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, for example chlorine, and/or nitro: such as benzyloxycarbonyl optionally substituted, for example as indicated above, for example 4-nitrobenzyloxy-carbonyl or 4-methoxybenzyloxycarbonyl, or diphenylmethoxy-carbonyl optionally substituted, for example as indicated above, for example diphenylmethoxycarbonyl or di-(4-methoxy-phenyl)-methoxycarbonyl; l-lower alkoxy-lower alkoxy-carbonyl, such as methoxymethoxycarbonyl, l-methoxyetlloxy-carbonyl or l-ethoxymethoxycarbonyl; l-lower alkylthio-lower alkoxycarbonyl, such as l-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl; aroylmethoxycarbonyl, in which the aroyl group is benzoyl optionally substituted, for example, by halogen, such as bromine, for example phenacyloxycar-bonyl; 2-halo-lower alkoxycarbonyl, for example 2,2,2-tri-chloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxy-carbonyl or 2-iodoethoxycarbonyl; or 2-(tri-substituted silyl)-ethoxycarbonyl, in which each of the subs~ituents represents, independently of one another, an aliphatic, araliphatic, cycloaliphatic or aro.matic hydrocarbon r~dical having, for example, up to 1~ carbon atoms and being option-ally su~stituted, for example, by lower alkyl, lower alkoxy, aryl, haloyen and/or nitro, such as corresponding option~lly substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl: for example 2-tri-lower alkylsilylethoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycar-bonyl, such as 2-triphenylsilylethoxycarbonyl.
~ urther protected carboxyl groups in esterified form are corresponding silyloxycarbonyl groups, especially organic silyloxycarbonyl groups, or corresponding stannyl-oxycarbonyl groups. In these, the silicon or tin atom contains as substituent preferably lower alkyl, especially methyl, but also lower alkoxy, for example metho~y, and/or halogen, for example chlorine. Suitable 5ilyl or stannyl protectin~ groups are especially tri-lower alkylsilyl, espe-cially trimethylsilyl, also dimethyl-tert.-butyl-silyl, lower alkoxy-lower alkyl-halo-silyl, for example methoxy-methyl chloro-silyl, or di-lower alkyl-halo-silyl, for example dimethyl-chloro-silyl, or correspo~dingly substitu-ted stannyl compounds, for example tri-n-butylstannyl.
Preferred protected carboxyl groups are tert.-lower alkoxycarbonyl, such as tert.-butoxycarbonyl, and especially benzyloxycarbonyl optionally substituted, for example as mentioned above, such as 4-nitrobenzyloxycarbonyl, and di-~henyl~ethoxycarbonyl.
An esterified carboxyl group that can be split under physiological conditions is especially an acyloxymethoxy-carbonyl group wherein acyl represents, for example, the radical of an organic carboxylic acid, especially of an optionally substituted lower alkanecarboxylic acid, or r~herein acyloxymethyl forms the radical of a lactone, or alternatively l-lower alkoxycarbonyloxy-lower alkoxycar-bonyl, wherein lower alkyl is methyl, propyl, butyl or especially ethyl. Such groups are lower alkanoyloxy-methoxycarbonyl, for example acetoxymethoxycarbonyl or ~L~7~'~7~3 pivaloyloxymethoxycarbonyl, amino-lower alkanoyloxy;nethoxy-carbonyl, especially a-amino-lower alkanoyloxymethoxy-carbonyl, for example glycyloxymethoxycarbonyl, L-valyloxy-met~oxycarbonyl, L-leucyloxymethoxycarbonyl, phthalidyloxy-carbonyl, for example 2-phthalidyloxycarbonyl, 4-crotono-lactonyl or ~-butyrolacton-4-yl, indanyloxycarbonyl, for exa~ple 5-indanyloxycarbonyl, or l-ethoxycarbonyloxyethoxy-carbonyl.
A protected D-2-amino group may, for example, be in the form of a readily splittable acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-l-enylamino, silylamino or stannylamino group or in the form of an azido group.
In a corresponding acylamino group, acyl is, for example, the acyl radical of an organic carboxylic aci~
having, for example, up to 1~ carbon atoms, especially of an alkanecarboxylic acid optionally substituted, for example, by halogen or aryl, or o~ a benzoic acid optionally sub-stituted, for example, by halogen, lower alkoxy or nitro, or of a carbonic acid semi-ester. Such acyl groups are, for example, lower alkanQyl, such as formyl, acetyl, or propionyl; halo-lower alkanoyl, such as 2-haloacetyl, espe-cially 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro or 2,2,2-trichloroacetyl benzoyl optionally substituted, for example, by halogen, lower alkoxy or nitro, for example benzoyl, 4-chloro-, 4-methQxy- or 4-nitrobenzoyl; lower alkoxycarbonyl branched in the l-position of the lower alkyl radical or suitably substituted in the 1- or 2-position, especially tert.-lower alkoxycarbonyl, for example tert.-butoxycarbonyl; arylmethoxycarbonyl having one or two aryl radicals that are preferably phenyl optionally mono- or poly-substituted, for example, by lower alkyl, especially tert.-lower alkyl, such as tert.-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, for example chlorine, and/or nitro: such as optionally substituted benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, or optionally substitute~

g ~L71~

diphenylmethoxycarbonyl, for example benzhydryloxycar~onyl or di-(4-m~thoxyphenyl)-methoxycarbonyl; aroylmethoxycar-bonyl, in which the aroyl group is preferably benzoyl optionally substituted, for example, by halogen, such as bromine, for example phenacyloxycarbonyl; 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodo-ethoxycarbonyl; or 2-~tri-substituted silyl)-e~hoxycarbonyl, in which each of the substituents represents, independently of one another, an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical having, for exa~ple, up to 1~
carbon atoms and being optionally substituted, for example, by lower alkyl, lower alkoxy, aryl, halogen or nitro, such as corresponding optionally substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl: for example 2-tri-lower alkylsilyleth~xycarbonyl, such as 2-trimethylsilylethoxy--carbonyl or 2-(di-n-butyl-methyl-silyl~-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilyl-ethoxycarbonyl.
Further acyl radicals coming into consideration as amino-protecting groups are corresponding radicals of organic phosphoric, phosphonic or phosphinic acids, such as di-lower alkylphosphoryl, for example dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphos-phoryl, dicycloalkylphosphonyl, for example dicyclohexyl-phosphoryl, optionally substituted diphenylphosphory:L, for example diphenylphosphoryl, diphenyl-lower alkylphosphoryl optionally substituted, for example, by nitro, for example dibenzylphosphoryl or di-4-nitrobenzylphosphoryl, optionally substituted phenoxyphenylphosphonyl, for example phenoxy-phenylphosphonyl, di-lower alkylphosphinyl, ~or example diethylphosphinyl, or optionally substituted diphenylphos-phinyl, for example diphenylphosphinyl.
In an arylmethylamino group that is a mono-, di-or especially tri-arylmethylamino group, the aryl radicals are especially optionally substituted phenyl eadicals. ~u_h -10- ~ ~7~'~J~

groups are, ~or example, benzyl-, diphenylmethyl- and especially tritylamino.
An etherified mercapto group in an amlno group pro-tected by such a radical is especially arylthio or aryl-lower alkylthio in which aryl is especially pher.yl option-ally substituted, for example, by lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro. A corresponding amino-protectin~ group is, for example, 4-nitrophenylthio.
In a l-acyl-lower alk-l-en-2-yl radical that may be used as an amino-protecting group, acyl is, for example, the corresponding radical of a lower alkanecarboxylic acid, of a benzoic acid optionally substituted, for example, by lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen~ such as chlorine, and/or nitro, or especially of a carbonic ac:id semiester, such as a carbonic acid lower alkyl semiester~ Corresponding protecting groups are especially l-lower alk~lnoylprop-l-en-2-yl~ or example l-acetylprop-l-en-2-yl, or l-lower alkoxycarbonylprop-1-en-2-yl, for example l-ethoxycarbonylprop-l-~n-2-yl.
A silyl- or stannylamino group is an organ~c silyl- or stannylamino group in which the silicon or tin atom prefer-ably contains as substituent lower alkyl, especially methyl, but also lower alkoxy, for example methoxy, and/or halogen, for example chlorine. Corresponding silyl or stannyl groups are especially tri-lower alkylsilyl, especially trimethyl-silyl, but also dimethyl-tert.-butyl-silyl, lower alkoxy-lower alkyl-halo-silyl, for example methoxy-methyl-chloro-silyl or di-lower alkyl-halo~silyl, for example dimethyl-chloro-silyl, or correspondingly substituted stannylt for example tri-n-butylstannyl.
An amino group may also be protec~ed in protonated form; as anions there come into consideration especially those of strong inorganic acids, such as hydrohalic acids, for example the chlorine or bromine anion, or of organic sulphonic acids, such as p-toluenesulphonic acid.

.,.~

,~J,'~3 Preferred amino-protecting groll~s are acyl ra~icals of carbonic acid semiesters, especially tert.-butoxycarbonyl, or benzyloxycarbonyl optionally substituted, for example as indicated, for example 4-nitrobenæyloxycarbonyl, or di-phenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, or trityl or formyl.
Hydroxy-protecting groups are, for example, acyl radicals, such as lower alkanoyl optionally substituted, for example, by halogen, such as 2,2-dichloroacetyl, or especially the acyl radicals of carbonic acid semiesters mentioned in connection with a protected amino group, espe-cially 2,2,2-trichloroethoxycarbonyl, or organic silyl or stannyl radicals, also etherifying groups that are readily split off, such as tert.-lower alkyl, for example tert.-butyl, 2-halo-lower alkyl, for example 2,2,2-trichloro-, 2-chloxo-, 2 bromo- or 2-iodoethyl, 2-oxa- or 2--thia-aliphatic or -cycloaliphatic hydrocarbon radicals, espe-cially l-lower alkoxy-lower alkyl or l-lower alkylthio-lower alkyl, for example methoxymethyl, l~-methoxyethyl, 1-ethoxyethyl, l-methylthiomethyl, l-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thiacycloalkyl having from 5 to 7 ring atoms, for example 2-tetrahydrofuryl or 2-tetra-hydropyranyl or corresponding thia analogues, and also optionally substituted l-phenyl-lower alkyl, such as option-ally substituted benzyl or diphenylmethyl, there coming into consideration as substituents of the phenyl radicals, for example, halogen, such as chlorine, lower alkoxy, such as methoxy, and/or nitro.
Salts of compoun~s of the formula I according to the invention are especially pharmaceutically acceptable non-toxic salts, such as those of compounds of the formula I
having acid groups, for example having a free carboxyl or sulpho group. Such salts are especially metal or ammonium salts, such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, an~ also ammonium salt; lormed with ammoni~ or suitable ~'7~ 3 organic amines, wherein especially aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines and also heterocyclic bases come into consideration for the salt formation, for example lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example 4-aminob~nzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, or example l-ethylpiperidine, cycloal~ylamines, for example dicyclohexylamine, or ben~ylamines, for example N,N'-dibenzylethylenediamine, also bases of the pyridine type, for example pyridine, collidine or quinoline. Compoun~s oE the formula I having a basic group can form acid addition salts, for example with inorganic acids, such ~s hydrochloric acid, sulphuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, for example trifluoroacetic acid, and also with amino acids, such as arginine and lysine. If several acid or basic groups are present, mono- or poly-salts may be formed. Compounds of the formula I having a free acid group, for example the 4-carboxyl group, and a free basic group, for example the D-2-amino group, may also be in the form of internal salts, i.e. in zwitterion form, or one part of the ~olecule may be in the form of an internal salt and another may be in the form of a normal salt.
It is also possible to use pharmaceutically unaccept-able salts for the isolation or purification of compounds of the formula I. Only pharmaceutically aceptable non-toxic salts are used therapeutically and these are therefore pre-ferred.
~ he novel compounds of the formula I, in which the functional groups are either in free form or the 4-carboxyl group is optionally in an esterified form that can be split under physiological conditions, and their pharmaceutically acceptable non-toxic salts having valuable pharmacological .

~L~7 !3Z~7a) properties.
~ hus, compounds of the Eormula I in free form or in the form of their salts are effective ln vitro against gram-positive and gram-negative cocci, for example Staphylococcus aureus, Stre3tococcus pyogenes or Neisseria spp., in con-centrations of from approximately O.l to approximately 32 ~g/ml, against gram-negative bacteria, for example enterobacteria, for example Escherichia coli, Klebsiella pneumoniae or Proteus s~p., or against Haemophilus _ influe_zae in concentrations of from 0.5 to approximately o4 ~g/ml.
In vivo, when administered perorally or subcutaneously to mice, compounds (I) are effective against systemic infec-tions caused by gram-positive cocci, for example S~aphylococcus aureus, in a dosage range of from approxi-mately 1.5 to approximately 30 mg~kg and againqt systemic infections caused by gram-negative bacteria, for example Escher~chla coli, Proteus mlrabilis or Rlebsiella ~ in dosage range of rom approximately 1.4 to approxlmately 100 mg/kg, and have a low level of toxicity.

~est evaluation I. Tested_compounds ~ he antibiotic activity of the following compounds was tested:
1. 7~-[D-2-amino-~-(3-methylsulphonylamino-4-hydroxy-phenyl)-acetylamino~-3-methoxyceph-3-em-4-carboxylic acid (Example la)).
2. 7~-[D-2-amino-2-~3-methylsulphonylamino-4-hydroxy-phenyl)-acetylamino]-ceph-3-em-4-carboxylic acid (Example 2a)).

3. 7~-[D-2-amino-2-(3-methylsulphonylamino-4-hydroxy-phenyl)-acetylamino]-3-chloroceph-3-em-4-carboxylic acid (Example 3a)).

4. 7~-[D-2-amino-2-(3-ethylsulphonylamino-4-hydroxy-~.7~2~13 --lg--phenyl)-acetylamino] ceph-3-em-4-carboxylic acid (Example 9a))-

5. 7~-[D-2-amino~2-(3-et~ylsulphonylamino-4-hy~loxy-phenyl)-acetylamino]-3-chloroce~h-3-em-4-carboxylic acid ~Example lOa)).

6. 7~-[D-2-amino-2-~3-ethylsulphonylamino-4-hydroxy-phenyl) acetylamino~-3-methoxyceph-3-em-4-carboxylic acid (Example lla)).

II. Methodol~

A. The antibiotic activity of the test compounds in vitro was established by the agar dilution method according to Ericsson, H.~., and Sherris, S.C., 1971, Acta Path.
Microb. Sc~nd. Section ~, Suppl. No. 217, vol. 1-90, in DST
agar. The minimum concentrations still inhibiting growth o~
the test organisms (MIC = minimum inhibiting concentra-tions) are given in micrograms per millilitre (~g/ml) for the tested compounds in Table 1.
B. The chemotherapeutic activity ln vivo against systemic infections in female SPF, MF2 mice was established accord-ing to the method of 2ak, 00, et al~, 1979, Drugs Exptl.
Clin. Res. 5, 45.59. The ED50 values found in milligrams substance per kilogram mouse (mg/kg) against a number of micro-organisms are indicated in Table 2 for the test com-pounds administered orally (p.o.) or subcutaneously (s.c.).

~8J2 III. Results Tabl _ ~antibiotic activity in vitro) _ . _ . . _~

micro organisms MIC [~g/ml]
__ _ _ _ Tested compounds _ . 1 2 ~ 4 _ S 6 Streptococcus pyro~enes Aronson 0.1 4 O.S 1 0.5 O.S
~ei~9eria men_nqitidis 1 8 0.5 4 0.1 0.1 Escherichia coli DC20.5 4 0.5 4 2 2 Klebsiella Pneumoniae . ~ _ _ _ _ 2 4 1 4 1 16 ..~

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The novel compound~ of the formula I can therefore be used accordingly, for example in the ~orm of anti-biotically active preparations, for the treatment of infections caused by gram-positive or gram-negakive bacteria.
Compounds of the formula I in which the functional groups are protected are used as intermediate~ for the manufacture of compounds of the formula I in which the functional groups are in fr~e form.
The invention relates preferably to those compounds of the formula I in which functional group~ are in free form or in which the 4-carbox~l group is protected in a form that can be s~lit u~der physiological cond:itions and to the pharmaceutically acceptable 5alt9 thereof, since it i9 primarily these oompounds that have the specified activity and can be used ~or the purpo~e indica~
ted.
Prominence should be ~iven to compounds of the formula I in which the index n represents 0, R represents hydrogen or an acyl group, for example lower alkanoyl, halo-lower alkanoyl; benzoyl optionally ~ub~tituted by halogen, lower alkoxy or nitro, tert.-lower alkoxycarbonyl; arylmethoxycarbonyl having one or two aryl radical~ that are phenyl radicals optionally mono- or polysubstituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or nitro;
aroylmethoxycarbonyl in which the aroyl group is benzoyl optionally substituted by halogen: 2-halo-lower al~oxycar~onyl, carbamoyl, N-lower alkylcarbamoyl, ~ di-lower alkyl-carbamoyl; thiocarbamoyl; N-lower alXylthiocarbamoyl ~,~-di-lower alkyl-thiocarbamoyl, lower alkylsulphonyl;

aryl~ulphonyl, ~ulphamoyl, ~-lower alkyl~ulphamoyl, or ~,~-di-lower al~yl~ulpha~oyl, ~0 repre~nt~ hydrogen or low~r alkyl, Rl repr~e~t~ hydro~en or a group o the partial ~ormula (R)(Ro)~7-, in which R
and ~0 hav~ the m~aning~ yiven above, R~ repre~entJ carboxyl or lower alka~oyl-m~thoxycarbonyl, ~nd R3 represent~ hydrog2n, fluorine, chlorine, ~romine, methoxy, ethoxy, i~opropoxy or t~rt.-butoxy, and hydrate~ and ~alt~ o~ ~ompound3 (I), e~pecially pharmaceutically acceptable ~alts of compounds of the formula I.
Special pro~inence ~hould b~ givon to compounds of the fonnula I in which the ind~x n repr~sent~ O, R repre~ents hydrogen; lower alkanoyl ha~ing up to 4 c~rbon atom~, ~or example ~oxmyl, acetyl or propionyl, halo~lower alkanoyl having up to 4 carbon ato~, ~or ~xample 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-tri~luoro- or 2,2,2-trichloroac~tyl, benzoyl optionally ~ub~tituted by halog~n, low~r alXoxy, for example methoxy, or nitro, for example 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitro~enzoyl:
tert.-lowor alXoxycarbonyl, for example tert.-butoxycarbonyl, ~enzyloxycarbonyl optionally sub~tituted by nitro, for example benzyloxycarbonyl or 4-nitro-ben7.yloxycar~onyl, diphenyl~ethoxy-carbonyl optionally ~ub3tituted by lower alkoxy, for ~xample methoxy, for example bsnzhydryloxycarbonyl or bi~-.., (4-methoxyphenyl~-methoxycarbonyl;
phe~acyloxycarbonyl, 2-halo-lower alkoxy-carbonyl having up to 4 carbon atoms, for exa~ple 2,2,2-trichloro-, 2-chloro-, 2-bromo- or 2 iodoeth~xycarbonyl, carba-moyl; N-lower alkyLcarbamoyl, ~or example ~-methylcarbamoyl, N,~-di-lower alkyl-carbamoyl, for oxample ~,X-dimethyl-carbamoyl: thiocarba~oyl, ~-lower alkyl-thiocarbamoyl, ~or example ~-methylthio-carbamoyl, ~ i-lower alkylthiocarbamoyl, for exa~ple ~ dimethylthiocarba~loyl:
low~r alkyl~ulphonyl, for example m~hyl-~ulphonyl or eth~l~ulpho~yl, aryI~ulphonyl, ~or example phenyl~ulphonyl or tolyl-~ulphonyl, ~ulphamoyl, ~-lower alkyl-aulphamoyl, ~or example ~-methyl3~1phamoyl, or ~ lower alkyl~ulphamoyl, for example N,~-dimethylsulphamoyl, Ro repre~ent~ hydrogen or lower alkyl, for example methyl or ethyl, Rl represents hydrogen or a group o~ the partial formula ~R)~Ro)~~, in which R and Ro have th~ meanings yiven above, R2 represent~ carboxyl, and R3 represent~ hydrog~n, chlorine or methoxy, and hydrate~ and salt of compound~ (I), especially pharma-ceutically acceptable salts of compound~ of the formula I.
The invention relate~ especially to compouncl3 of the formula I in which the index n represents 0, R represent~ hydrogen, lower alkanoyl having up to 4 carbon atoms, for exampl~
acetyl, lower alkylsulphonyl having up to 4 carbon atom~, for example ~ethyl-~ulphonyl or ethylsulphonyl, ~7~

Ro represent~ hydrogen, Rl represents hydrogen or a group o~ the partial formula (R)(Ro)~~ in which R
and Ro have the meanings given above, R2 r~preJents carboxyl, an~
R3 represents hydrogen, chlorine or rnethoxy, and salt~ o~ ~uch com~ounds, esp~cially pharmaceuti~ally acceptable ~alts of co~pounds o~ the formula I.
The invention relates more especially to co~pound~
o the formula I in which the index n represents 0, repre~ent~ hydrog2n, lower alkanoyl having up to 4 carbon atoms, for example ac~tyl, lower alkyl~ulphonyl havi~g up to 4 carbon atoms, ~or example methyljulphonyl or ethylsulphonyl, Ro r~pre~ents hydrogen, Rl repr~sent~ hydrogen or a group of the partial ~ormula (R)~Ro~N- ~n w~ich R and Ro have the maanings given above, R2 repre~ent~ carboxyl, and R3 represents hydrogen, chlorine or methoxy, and in which the two group~ of the partial formula ~)(Ro)~~ take up the 3 and 5-position (meta) and the hydroxy group taXes up the 4-position ~ ) on the phenyl ring, and hydrate~ and salts of such compounds, especially pharmaceutically acceptable ~alt~ of compound~ of the formula I.
Of all the compounds to which the invention relates, special mention should be made of the compound~ of the formula I described in the Examples and also of the salts, especially the pharmaceutically acceptable salts, of such compounds having salt-forming groups.
The compounds of the formula I of the present invention are obtained according to processes Xnown er _.

7~3 Compounds of the ormula I and hydrates and salts of such compounds that have a salt-forming group are manufactured, for example by a) in a compound of the ~ormula (~)n H / S
i=N I_R3 ~II) 0~ \ ~

in which the index n represents O or 1 and the 7~-amino group i~ optionally protected by a group allowing acylation, and R~ and R3 have the meanings given under formula I, acylating the 7~-amino group by reaction with an acylating agent that introduces the acyl radical of a carboxylic acid of the formula (R)(Ro)N

CH~C-OH (III), ~ .=~ ~ ~ 2 in which R, Ro and R1 have the meanings given under formula I and in which the hydroxy group on the phenyl ring and/or the amino group(~) are optionally in protected form and other functional group~ pre~ent are optionally protected, or b) i30merising a 2-cephem compound of the formula (R)(~o)~
o S
~ C~ = < \~ (IV), in which R, Ro, Rl, R2 and R3 under ~ormula I and in which the hydroxy group on the phenyl ring and/or the amino group~s) are optionaLly in protected ~orm and other ~unctional group~ present are optionally prot~cted, or c) in a compound of the ormula ~2 ~)n o S' . ~ ~ . _ C~ N _ . / \.
OH Rl ~ 2 ~ R3 (V), i ,.

~i7B'~7~

in which the index n reprosent~ 0 or 1 and Rl represents nitro or the radical Rl which has the meanings given under ormula I, R~ and R3 have the meanings given under formula I and in which the hyd:roxy group on the phenyl ring and/or the amino group(s) are optionally in protected form and other function,al yroups present are sptiona}ly protected, reducing t'he nitro group(s) on the phenyl ring by reaction with an agent that converts nitro group~ into amino groups, and, if de~ired, in a resulting rompound converting a free amino group of the partial formula (R)(Ro)N- in which ~ and Ro represent hydrogen into a substituted amino group and/or, i de~ired, converting a resulting compound in which n repre~enta 0 into a compound in which n represents 1 and/or convertiny a re~ulting com-pound ln which n represent~ 1 into a compound in which n r~present~ 0 and/or convertin~ functional group~
pre3ent in protected form in a r~sulting co~pound into the free functional group and/or co~verting a resulting salt into the free compound or into a different salt and/or converting a resulting compound having a salt-forming group into a ~alt and/or separating a resulting mixture of isomeri~ compounds into the individual isomers.

Proces~ a~ (Acylation):
In ~he ~tartinq'material of the formula II, the 4-carboxyl group may be protected prefera~ly in e~terified form, for example as described above, especially in the form of a ~ilyl e~ter, 3uch as a trimethylsilyl ester, whi~h is generally formed immediately before the acylation reaction by treatment with a correspon~ing silylating agent, for example trimethylchlorosilane or N,o-bis-(trimethylsilyl)-acetamide. The carboxylic acid starting material of the-formula II may, however, al~o be used in salt form, for example in ammonium salt form, such as ~7~13 in the form of a triethylammonium ~alt, or in protected form, which can be obtained by rea~ting the carboxylic acid starting material II with a suitabLe organic phosphorus halide compound, ~uch a~ with a lower alXyl-or lower alkoxypho~phoru~ dihalide, such as methyl-phosphoru~ dichloride, ethylpho~phoru~ dibromide or methoxxpho~phoru~ dichloride. Starting materials of the formula II in which the ~-amino group i~ protected by a group allowing the acylation reaction are protected, for sxample, by a ~ilyl radical, such as one of the ~ilyl xadical~ mentioned a~ove.
Other group~ by which the 7~-amino group may be protecte~ in reactive form are tha carbonyl group - ~ C=O~- and optionally l-~ubstituted l-halo- or l-alXoxy-mathylen~ group~. In such methylene group~, haloqen i3 bromine or especially chlorine and al~oxy i8 especially optionally ~ubstituted lowar alkoxy, ~uch as ethoxy, propoxy, butoxy or pr~ferably m~thoxy. The optionally pre3ent other ~ub~tituent in the l-po~ition o~ ~uch a methylene group i9 any organic radical that i9 ~terically hindered only slightly, ~or exampl~ optionally ~ub~tituted lower alkyl, 3uch as methyl, 4-amino-4-carboxybutyl, in which the amino group and the car~oxy group may be protected, be~zyl, phenoxymethyl, thienylmethyl or alternatively furylm~thyl, ~uch a~ 2-thienyl- or 2-~urylmethyl.
In an acyl radical of an acid of the formula III, the D-2-amino group is optionally protected by customary amino-protecting groups or alternatively in ionic form, i.e. the ~tarting material of the formula III having the D- -amino group may alternatively be used in the form of an acid addition 3alt, preferably with a strong inorganic acid, such a~ a hydrohalic acid, far example hydrochloric acid, or the D-2-amino group is optionally protected in ma~ked form, for example in the form of an azido group.

8~7~1~
- ~5 -In a ~tarting material of the formula III, the hydrogen Ro in ~ub~tituted amino groups of the partial formula (R)(Ro)M~ in which R repre~ents an acyl group and Ro represents hydrog~n is optionally replaced by a further acyl group.
The hydroxy group on the phenyl ring i~ optionally protected by one of the customary hydroxy-protecting groups mentioned a~ove.
Free amino group~ Am present on the phenyl ring are optionally protected ~y the customary amino-protecting gr~up described above.
Acylating agents introducing the acyl radical of ~ carboxylic acid of the formula III are, for ex~nple, the carboxylic acid itself or it~ reactlve functional derivatives .
If there is u~ed ~or acylation a carboxylic acid of the fonmula III, in w~ich functional group~ present, apart ~rom the 4-carboxyl group participatin~ in the reaction, may be protected, the reaction i~ normally carried out in the pre~ence of ~uitable conden~ation agent-~, s~ch as carbodiimides, for example ~ diethyl-, N,N'-dipropyl-, N,~'-dicyclohexyl- or ~-ethyl-~' 3-dimethylaminopropylcarbodiimide, suitable carbonyl compound3, for example carbonyldiimidazole, or 1,2-oxazolium compound~, such a~ 2-ethyl-5-phenyl-1,2-oxazolium 3'-~ulphonate or 2-tert.-butyl-5-methyl-1,2-oxazolium perchlorate, or a ~uitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline~
The co~den~ation reaction is preferably carried out in an anhydrou~ reaction medium, prefera~ly in the pre~ence of a solvent or diluent, for example methylene chloride, dimethylformamide, acetonitrile or tetrahydro-furan, if desired or neces~ary w~ile cooling or heating, for exa~ple in a temperature range of ~rom approximately -40C to approximately +100C, preerably from approximatel~

. .

~ 3 7~'~J'7''~

-20C to approximately i50C and/or in an inert gas atmosphere, for exampla a nitrogen atmosphere.
A reactive ~unctional derivative of a carboxylic acid of th~ form~la III, in which functional group~
pre3ent, apart from the carboxyl group participating in the reaction, may be protected, i~ especially an anhydride of ~uch an acid, including and preferably a mixed anbydride. Mixed anhydrides are, for example, tho~e with inorganic acids, such as hydrohalic acids, i.~. the corre~ponding acid halides, for example chlorides or bromides, al~o with hydrazoic acid~ i.e4 the corresponding acid azide~, with a phosphoru~-containing acid, for example pho3phoric acid, diethyl-phosphoric acid or phosphorousacid, or with a sulphur-containing acid, for example ~ulphuric acid, or with hydrocyanic acid. Other mixed anhydrides are, ~or example, ~ho~e with ~rganic carboxylic acids, ~uch a3 with lower al~anecarboxylic acids optionally su~titute~, for example, by halogen, ~uch as fluorine or chlorine, for example pivali~ acid or trichloroacetic acid, or with ~emiester~, e~pecially lower alkyl semiasters of carbonic acid, such a~ the ethyl or isobutyl semiester of carbonic acid, or with organic, especially aliphatic or aromatic, ~u~phonic acids, for example ~-toluenesulphonic acid.
Other derivatives, suitable for reaction with the amino group, of an acid o~ the formula III, in which functional groups present, apart from the carboxyl group participating in the reaction, may be protected, are activated esters, such as esters with vinylogous alcohols, i.e. with enol~, such as vinylogous lower alkenols, or intinomethyl ester halides, such a~ dimethyliminomethyl ester chloride, manufactured from the carboxylic acid of the form~la III and, for example, dimethyl~ chloro-ethylidene)-iminium chloride of the formula ~CH3~2 ~=C(Cl)CH3Cl~ which can be obtained, for example, from N,~-dimethylacetamide and phosgene, aryl esters, for example phenyl e~ters substituted, for example, by halogen, such a~ chlorine, and/or nit.ro, for example 4-nitrophenyl, 2,3-dinitrophenyl or pentachlorophe~yl e~ter, N-heteroaromatic esters, such as ~-benztriazole e~ter~, for example l-benztriazole ester, or M-diacylimino esters, ~uch as N-succinylimino or ~-phthalylimino e~ter~
The acylation wîth a reactive functional derivative Q~ an acid of the ormula III, such as a corre~ponding anhydride, especially an acid halide, is pre~erably carried out in the presence o~ an acid-binding agent, ~or example an organic ha~e, such a~
a~ organic amine, for exa~ple a tertiary amina, such a~ tri-lower alkyl~mine, for example trimethylamine, triethylamine or ethyldiisopropylamine, or N,N di-lower alkylanillne, for exa~ple ~,N-dimethylaniline, or a cyclic tertiary amine, such a~ an ~-lower alkylated morpholine, such as ~-methylmorp~oline, or a base of the pyridi~e type, ~or example pyridine, an inorganic base, ~or example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for example ~odium, potas~ium or calcium hydroxide, car~onate or bicarbonate, or an oxirane, for example a 1,2-lower al~ylene oxide, such as ethylene oxide or propylene oxide.
The above acylations are prPferably carried out in an inert, preferably anhydrou3, 301Yent or solvent mixture, for example in a carboxylic acid amide, such a~ a formamide, for example dimethylfonmamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ~cetone, for example acetone, an ester, for example e~hyl acetate, or a nitrile, for example acetonitrile, or a mixture -- 2~ --thereof, i nece~ary or de~irPd at reduced or elevated temperature, for example in a temperature ran~e of from approximately -40C to approximately ~100C, preferably from approximately -10C to approximately +50C, and/or in an inert ~as atmo~phere, for exampl~ a nitrogen atmo3phere.
The acylation can al~o be carr:ied out by u~ing a ~uitable derivative of the acid of the formula III
in the pre~ence of a suitable acylase. Such acylases are know~ and can be formed by a num~er of micro-organism~, for example by P~udomona~ E~L_ um ATCC 17 808 or by numerou~ other acylating ~trains, ~uch a~ xanthomona~, acetobacter, for example ~5~5~ E ~Y~
achromobacter, for example aS~5~2~ E ~ B~ æ ~hea ~, ~9~ urea, ~2a5~ 3~nati9, ocardia g~s~ b~ or bacillus, for example B~acil:Lu~
~ oO. In an enzymatic acylation of thi~ type thare are u~ed as corresponding derivatives especially ~mide~, e~ters or thioester~, such as lower alkyl e~ters, for example methyl or ethyl ester, of the carboxylic acid o~ the formula III. Acylation of thi~ type i5 generally carried out in a nutrient medium containing the corres-ponding micro-organism, in a filtrate of the culture broth or, optionally after isolation of the acylase, including after adsorption on a carrier, in an aqueous medium optionally containing a buffer, for example in a temperature ran~e of from approximately ~20C to approxima ely ~0C, preferably at approximately 37C.
A reactive functional derivative of an acid of the formula III used in the acylation reaction may, if de3ired, be formed in itu. ~hus, for example, a mixed anhydride can be manufactured by reacting an acid of the formula III, optionally having appropriately protected functional groups, or a ~uitable salt thereof, for example an ammonium salt, which i9 formed, for example, with an organic base, such as pyridine or 4-methyl-morpholine, or a metal salt, for example an alkali metal salt, with a suitable acid derivative, ~uch as a corresponding acid halide of an optionally substituted lower alkanecarboxylic acid, for example trichloroacetyl chloride, with an e~ter of a carbonic acid semihalide, for exampLe chloroformic acid ethyl ester or isobuty}
ester, or wi~h a halide of a di-lower alXylphosphoric acid, for example diethyl phosphoro~romidate, which can be formed by reacting triethyl phosphite with bromine, and the mixed anhydride so obtained is used without isolation in the acylation reaction.
If a racemic mixture of a ~taxting material of the fonmula III i~ u~ed in the acylation, a racemi.c mixture of a compound of the formula I i9 obtainecl.
This can be su~seqùently separated into the desir~d D- and L- configuration antipodes by the cu~tomary method3 de3cribed in the literature or the separation o~ racemic mixtures. The D~configuration antipodes o~
a star~ing material of the formula III are, howe~er preferably used in the acylation~

Process-b~ g~U~ ~E~ee):
In a 2-cephem starting material of the formula IV, the optionally protected carboxyl group R2 in the 4-position i~ preferably in the a-configuration.
2-cephem compounds of the formula IV can be iso-merised ~y treatm0nt with a weakly basic agent and i~olating the corresponding 3-cephem compound. Suitable isomerising agents are, for example, organic nitrogen-containing bases, especially tertiary heterocyclic bases of aromatic character, especially bases of the pyridine type, such as pyridine itself, and picolines, collidines or lutidines, also quinoline, tertiary aromatic bases, for example those of the aniline type, such as N,~-di-lower alkylanilines, for example ~ dimethylaniline or `7~

N,~-diethylaniline, or tertiary aliphatic, azacyclo-aliphatic or araliphatic ba~es, such as ~,~,N-tri-lower alXylamine~, for example ~,N,~-trimethylamine or ~
diisopropyl-N-ethylamine, ~-lowex alkylazacycloalkane~, for example ~-methylpipexidine, or ~--phenyl-lower alXyl-~,~-di-lower alkylamines, for e~ample N-benzyl-N,M-dimethylamine, and mixtures of such basic agents, such a~ the mixture of a base of the pyridine type and an ~,N,~-tri-lower alkylamine, for example pyridine and triet~ylamine. Furthermore, inorganic or organic 9alt8 of bases, especially of medium-~trength to strong bases with weak acids, such a5 ~lkali metal salt~ or ammonium salts of lower al~anecarboxylic acids, for example sodium acetate, triethylammonium acetate or ~-methylpiperidine acetate, and other analogou3 b,asas or mixtures o~ such basic agents can al~o be u~ed.
~ ha i~meri~atio~ of 2-cephem campound~ o the formula IV with basic agents is preferably carried out in an anhydro~-~ medium, in the presence or absence of a 901vent, such a~ an optionally halogenated, for example chlorinated, aliphatic, cycloaliphatic or aromatic hydrocar~on, or a solvent mixture, it being possible for the ba~es u~ed as reagents w~ich are liquid under the reaction conditions to sexve, at the same time, a~ ~olvents, optionally while cooling or while heating, preferably in a temperature range of from approximately -30C to approximately ~100C, in an inert gas atmosphere, for example a nitrogen atmosphere, and/or in a closed vessel .
The 3-cephem compound~ of the formula I obtainable in this ~anner can be separated from the 2-cephem compounds which may ~till be present in a manner known se, for example by adsorption and/or crystallisation.
The isomerisation of 2-cephem compounds of the formula IV to form the corresponding 3-cephem com~ounds ~ ~;lL 7~ r ~3 is preferably carried out by oxidising these ~n the l-position, if desired, separating the isomeric mixture~
o~ the l-oxides formed, and reducing the l-oxides of the correspondin~ 3-cephem compounds obtained in thi~ manner.
There come into consideration as suitable oxidi~ing agents for the oxidation in the l-po~ition of 2-cephem compounds of the formula IV, inorganic peracid~ that have a reduction potential of at least +1.5 volts and comprise non-metallic elements, organic peracids or mixtures consi~ting o hydrogen peroxide and acids, especially organic carboxylic acid~, having a dissociation constant of at leas~ 1~ 5. Suitable inorganic peracid~ are periodic acid and persulphuric acid. Organic peracids are corre~ponding percarboxylic and per~ulphonic acids which are added as ~uch or may be formed in itu~by u~ing at least one equivalant of hydrog~n peroxide and a carboxylic acid. In thi~ ca~e, it iA expedient to u~e a large Qxce~s o~ the carboxylic acid i, for ex~mple, acetic acid i3 used as solvent. Su~table peracids are, for example, performic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3-~hloroperbenzoic acid, monoperpht~alic acid or ~-tolueneper~3ulphonic acid.
~ he oxidation can likewi~e be effected usin~
hydrogen peroxide with catalytic quantitie~ af an acid having a dissociation conqtant of at l~ast lO 5, it being pos3ible to use low concentration~, for example 1-2 % and below, or alternatively relatively large amounts of the acid. In this case, the effectivenes~
of the mixture depends primarily on the strength of the acid. Suitable mixture~ are, for example, those of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.
The foregoing oxidation may be carried out in the pres~nce of ~uitable catalysts. ThU5, for example, the oxidation with percar~oxylic a~ids can be catalysed by the presence of an acid having a dissocation con-stant of at least 10 5, the effectivenes~ of this acid being dependent on its strength~ Acid~ ~uitable as catalyst~ are, for example, acetic acid, perchloric acid and trifluoroacetic acid. Usually, at 1east equi-molar amounts of the oxidi~ing agent, and prefera~ly a ~light excess of from approximately 10 % to approxi-mately 20 %, are u~ed, it alternatively being possibl0 to u~e relatively large excesses, i.e. up to 10 times the amount or more of the oxidising agent. The oxida-tion is carried out under mild conditions, for example at temperatures of from approximately -50C to approxi-mately ~100C, pre~erably ~rom approximately -10C to approximately +40C.
The reduction o~ the l-oxide~ o 3-cephem compounds ~an be carried out .in a manner Xnown ~ se ~y tre3tment with a reducing agent, if nece~ary in tha presence of an activating agent. There come into onsideration as reducin~ agents, for exampleo catalytically activated hydxoge~, thexe being used noble metal catalysts that contain, for example, palladium, platinum or rhodium and whic~ axe aptionally employed together with a suitable carrier material, ~uch as carbon or barium sulphate, reducing tin, iron, copper or manganese ca~ions, which are used in the form of corresponding compo~mds or complexes of an inorganic or organic kind, for example, in the form of tin(II~ chloride, fluoride, acetate or formate, iron(II) chloride, sulphate, oxalate or succinate, copper(I~ chloride, benzoate or oxide, or manganese~II) chloride, sulphate, acetate or oxide, or in the form of complexe~, for example with ethylene-diaminetetraacetic acid or nitrolotriacetic acid, reducing dithionite, iodide or iron(II) cyanide ~nion~, which are u~ed in the form of corresponding inorganic or organic salt~, such a~ alkali metal dithionite, iodide or iron(II) cyanide, for example ~odium or potassium dithionite, sodium or pota~3iurn iodide or 30dium or pota~sium iron(II) cyanide, or in the form of the corresponding acid~, such as hydriodic acid, reducing trivalent inorganic or organic phosphoru~ compounds, such as phosp~ines, also esters, amicles and halides of phosphinou3, phosphorous or phosphonous acid, and also phosphoru~-sulphur compounds corresponding to the~e phosphorus-oxygen compounds, in which organic radicals are especially aliphatic, aromatic or araliphatic radicals, for example optionally sub~tituted lower alkyl, phenyl or phenyl-lower alXyl group~, such as, for example, tri-ph~nylphosphine, tri-n~butylphosphine, diphenylpho~phinous acid methyl ester, diphenylchlorophosphine, phenyldichloFo-pho3phine, benzenephosphonous acid dimethyl ester, ~utanepho~phonous aci~ methyl ester, phosphorous ~cid triphenyl ester, phosphorou~ acid trimethyl e~ter, phosphoru~ trichloride, pho~phorus tribromide, etc., reducing halosilane compounds that have at least one hydrogen atom bonded to the ~ilicon atom and which may contain, apart ~rom halogen, such as chlorine, bromine or iodine, al~o organic radicals, such as aliphatic or aromatic groups, for example optionally 3ubstituted lower alkyl or phenyl groups, such as chlorosilane, bromo-silane, di~; or trichlorosilane, di- or tribromosilane, diphenylchlorosilane, or dimethylchlorosilane, or alternatively halo~ilane compound~ in which a}l the hydrogen atoms are replaced by organic radical~, such as a tri-lower alkylhalo~ilane, for example trimethyl~
chloro~ilane or trimethyliodosilane, or cyclic sulphur-containing silane~, such as 1,3-dithia-2,4-disilacyclo-butanes or 1,3,5-trithia-2,4,6-trisilacyclohexanes, of which the silicon atoms are substituted by hydrocarbon radicals, such as especially lower al~yl radicals, for example 2,2,4,4-tetramethyl-1,3-dithia-2,4-di~ilacyclo-- 3~ -butane or 2,2,4,4,6,6-hexamethyL-1,3,5-trithia-2,4,6-trisilacyclohexane, etc., reducing quaternary chloro-methyleneiminium salts, especially chlorides or bromides, in which the iminium group is substituted by one bivalent or two monovalent organic radicals, such as optionally substituted lower alkylene or lower alkyl groups, such as ~-chloromethylene-~,~-diethyliminium chloride or ~-chloromethylenepyrrolidinium chloride, and complex metal hydrides, such as sodium ~orohydride, in the presence of suitable activating agents, ~uch as cobalt(II) chloride, and also borane dichloride.
As activating agents which are used togethe:r with those of the above-mentioned reducing agant~ that do not them~elves have the properties of Lewis acids, i.e.
especially together with the dithionite, iodide or iron(II~ cyanide reducing agents and the triv~lent phosphorus reducing agents that do not contain halogen, or ar.e u~ed in the catalytic reduction, there may be mentioned especially organic carboxylic and ~ulphonic acid halide~, but alqo sulphur, pho~phorus or silicon halide.~ having a second order hydrolysis con~tant which is the same as or greater than that of benzoyl chloride, fo~ example phosgene, oxalyl chloride, acetyl chloride or ~romide, chloroacetic acid chloride, pivaloyl chloride, 4-methoxybenzoyl chloride, 4-cyanoben20yl chloride, ~-toluanesulphonyl chloride, methanesulphonyl chloride, thionyl chloride, pho~phorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichloro-phosphine, benzenephosphonous acid dichloride, dimethyl-chlorosilane or trichlorosilane, also ~uitable acid anhydrides, such as trifluoroacetic acid anhydride, or cyclic sultones, such as ethanesultone, propanesultone, 1,3-butanesultone or 1,3 hexanesultone.
The reduction is carried out preferably in the presence of solvents or mixtures thereof, the choice of which is determined primarily ~y the solu~ility of 2~

the starting material~ and by the chosen reducing agent, thu~, for exa~ple, lower alkanecarboxylic acids or esters thereof, such a~ acetic acid and ethyl acetate, in the ca~e of catalytic reduction, and, for example, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, optionally substituted by halogen or nitro, for example benzene, methylene chloride, chloroform or nitromethane, suitable acid derivative~, such as lower alkanecar~oxylic acid esters or nitriles, for example ethyl acetate or acetonitrile, or amide~ Gf inorganic or organic acids, for exampla dimethylformamide or hexamethylphosphoramide, ethers, for example diethyl ether, tetrahydrofuran or dioxan, Xetone~, for example acetone, or sulphones, especially aliphatic ~u~phones, for example dimethyl~ulphone or tetramethylene~ulE~hone, etc., together with the chemical reducing agent~, the~e solvents preferably containing no ~ater. The reaction is usually carried out at temperature~ of from approxi-mately -20C to approximately 100C, it being possible, when u~ing very reactive activating agents, to carry out the reaction at lower temperatures.
If a racemic mixture of a starting material of the formula IV is used in the isomerisation, a racemic mixture of a compound of the formula I i5 obtainad.
This can be subsequently separated into the desired D- and L-~on~iguration antipodes by the customary methods de~cribed in the literature for the separation of racemic mixtures.
The D-configuration antipodes of a starting material of the formula IV are, however, preferably used in the isomerisation.
Process c? (Red~ t tro qr~Q~l In a compound of the formula V in which the D-2 amino group, tha hydroxy group on the phanyl ring and the 4-carboxyl group are optionally in prote~ted form, , the aromatic nitro yroup(s) on the phenyl ring i~(are) reduced by reaction with a suitable agent that converts nitro groups into amino groups.
Suitable agents that convert ni.tro groups on the phenyl ring into amino group~ are cu~tomary reducing agents which are u~ed optionally in the presence of a catalyst and/or a suitable carrier material.
As customary reducing agents there come into consideration especially: catalytically activated hydxogen, there being used as hydrogenation catalysts, for example, noble metals, for example palladium, platinum or rhodium, the~e being used optionally with a suitable carrier material, ~uch a~ carbon, barium sulphate or carbonate or calci~n carbonate, reducing tin~II) or iron~II) cations which are used preferably in the form of their chlorides, the latter al~o in the form of their sulphates, reducing dithionite or sulphite anions which are used as inorganic salts, for example with alkali metal cations, in the form of alXali metal ~alt~, ~or example ~odium dithionite or sodium sulphite, or alkali metal hydrogen calts, for example sodium bisulphite, non-noble metals, for example iron, tin, zinc or aluminium which are used optionally in the presence of their corresponding metal salt~ or with other neutral salt~, for example calcium, magnesium, potassium or sodil~n chloride, al80 sulphides, for example hydrogen sulphide, di- or polysulphides, for example sodium disulphide or sodium polysulphide, alkali metal sulphide or alXali metal bisulphide, for example sodium sulphide or sodium bisulphide, ammonium sulphide or ammonium polysulphide, hydro~en-yielding agent~, for example sub~tituted or un~ubstituted hydrazine, for example phenylhydrazine which iq used optionaLly in the form of it~ acid addition ~alt, or molecular hydrogen which i released by electrolytic reduction at the cathode.

The reduction with catalytically activated hydrogen i5 carried out at normal pressure or moderately elevated pressure up to approximately 5 atmospheres gauge.
The reduction with zinc, aluminium, tin or tin(II) ions generally take~ place in acidic solution, for example in a hydrochloric acid solution. If iron(II) cations are used as the reducing agent, the operation i~ generally carried out under slightly basic conditions.
In that cas , any soluble iron(II) salt, for example iron(II) sulphate, i9 added to the reaction mixture whereupon the reducing iron(II) hydroxide precipitates out. The reduction with elementary iron, which may be added, for example, in the form of iron powder, generally takes place under slightly acidic conditions, for example under hydrochloric acid condition~,or under neutral conditions. In the latter case, salts, for example iron(II) chloride, lron(II) sulphate, iron(III) chloride, calcium ch}oride, magnesium chloride, potas~ium chloride or sodium chloride, are also added for the purpose o activation.
The reductions with dithionite anion are normally carried out with dithionite anions in a neutral or sligh~ly alkaline medium which i~ produced, for example, by adding tertiary aromatic bases, for example pyridine.
The reduction3 with .sulphite anions take place in a slightiy acidic medium, for example in an ace ic acid medium, or in a neutral medium.
The reduction with 3ulphides may be carried out in a slightly acidic medium, for axample in an acetic acid medium, or in a neutral or slightly basic aqueous medium which is produced during the reduction with hydrogen sulphide in the presence of ammonia or or tertiary aromatic bases, for example pyridine. Sodium sulphide or sodium polysulphide are freshly manufactured before the xeduction is carried out by introducing the equivalent quantity of sulphur into a sodium sulphide solution. Sodium bisulphide is produced by introducing hydrogen sulphide into a ~odium sulphide solution.
A~monium sulphide or a~nonium pol~sulphide is advanta-geously produced in situ by introducing hydrogen ~ulphide i~to an ammoniacalaqueous reaction solution and optionally adding elementary sulphur.
The reduction with hydrogen-yielding agentq, for example hydrazi~es, is accelerated by the above~mentioned hydrogenation catalysts, for example Raney nickel, palladium-carbon or platinum. The electrolytic reduction of ~he nitro groups to form the amine requires a high eLectrode potential and is carried out using cathodes made of metaLs with a high overvoltage, such as lead, tin, nickel, copper or zinc. The electrolysis is generally carried out in a sulphuric acid or hydrochloric acid ~olution.
The above-mentioned reducing agent~ are u~d in equimolar quantity or prefera~ly in excess. The addition of an excess of reducing agent i9 intended to prevent the formation of undesired intermediates, for example nitro~o compounds or hydroxylamines.
The reduction is prsferably carried out in the pre~ence of solvents or mixtures thereof, the c~oice of which is determined primarily by the solubility of the starting materials, the reducing agent chosen and the ability to bind the reaction water formed during the reduction, thus, for example, lower alkanols, for example methanol or ethanol, lower alXyl ethers of ~lycol~, for example ethylene glycol monomethyl ether or -ethyl ether, }ower alkanecarboxylic acids or esters thereof, such as acetic acid and ethyl acetate, i~ the case of catalytic reduction, and, for example, aliphatic, cyclo-aliphatic, aromatic or araliphatic hydrocarbons optional-ly substituted by halogen or ~itro, for example benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives, such as lower alkanecarboxylic acid esters or nitriles, for example ethyl acetate or acetonitrile, or amides of inorganic or organic acids, for example dimethylformamide or hexamethylphosphoric acid triamide, ethars, for example diethyl ether, tetrahydrofuran or dioxan, ketones, for example acetone, or sulphones, especially aliphatic ~ulphone~, for example dimethylsulphone or tetramethylene~u:Lphone etc.
In order to increase the solubility especially of the salt-like reduciny agentsin the xeaction mixture, water is added to that mixture as required. The operation is usually carried out at temperatures of from approxi-mately -20C to approximately 100C and when using very reactive activating agents the reaction may also be carried out at lower temperatures.
If ~ racemic mixture of a starting material of the formula V i5 used in the reduction of the nitro ~roup(s), a racemlc mixture of a compound of the Eormula I
is obtained~ This can be ~ubsequently separated into the D- and L-coniguration antipodes by the customary methods described in the literature for the separation of racemic mixtures. The D configuration antipodes of a starting material of the formula V arepreferably used in the reduction.

- ~o -

9~E~E~eratiens_ In a compound of the formula I, the sub~titue~t~
(R)(Ro)~ 1 and R2 ma~, withln the scope o~ their mean.ings and in any ~eque~ce, be conNerted into dif~eren~
substituents (R)(Ro)N , R1 and R20 ~hus, a free ami~o group of the partial formula (R)(Ro)N~ in which R and Ro repre~ent hydrogen may be converted into an acylamino group o~ the partial ~ormula (R)(Ro)~ in which R
represent~ an acyl group and Ro represents hydrogen or lower alkyl. ~ free carbo~yl group may be est~rl~ied or an esteri~ied carboxyl group R2 may be converted into a ~ree carbo~gl group. Protecti~ group~ optionally pre~ent i~ a compou~d o~ tha ~ormula I, ~or exampl~ a D~2-amino-protecting group or a hydroxy-protect~ng group, ara ~plit off. ~hes~ ~3ub~eque~t operatlon~ are carried out in a manner k~own ~E ~e, ~or example a~ foll~3:

II, in a resulting compouIld OI the ~ormula I~
R and Ro repre~ent h~drogen and/or the sub~tituent R
represents a group of the partial formula (~)(Ro)~~
in which R ar~d Ro likewi~e rspresen~ hydrogen, the iree amlno group~s) on the phenyl ring may be sub~tituted 1~ a manner k~own E~ ~e b~ an ac~l group ~ or a lower al~yl radical Ro~
This subst~tution ca~ ba carried out, for examplQ, by acylat~ng ~ith a ~uitable acylati~g agen~ tha~ i~troduces the oorre~po~di~g acyl radical R.
The amino group(s) on the phenyl ring is(are) optionally i~ reactive ~orm i.e. in a form allowi~g acylation and protected, ~or e~ample, by the customary silyl radicals de~cribed above. ~he hydro~y group on the phenyl r~ng is optionally protected by o~e of the customary hydro~y-protecting groups de~cribed above and the D-2-amino group is optionally protected by one of the cu~tomary amino-protect~g groups described above.

B~

I~ the amino group(s) is~are) sub~tituted by a~
acyl radical Ra-aO-, there i9 used as acylating agen~, for e~ample~ the correspondin~ carboxylic acid or a reactive der~vative thereo-~, especially a~ anhydride, including a mi3ed or internal anhyaride o~ ~uch a~ acid.
~ixed anhydrides o~ carboxyllc acids ar9 ~ ~or exampl~, those with hydrohalic acids, i.e. the corresponding carboxyl~c acld hal~de~, especially chloriae~, also with hydroc~anic acid~ or those with s~itable carbonic acld ~emi-deri~ati~es, ~uch as corresponding ~emiesters, for e ample the mi~ed anhydrides ~ormed with a halo~ormic acid lower alkyl ester~ such as chloro~ormic ac d ethyl ester or isobutyl ester, or with lower ~lkanecarbo~y:lic acid~ optionall~ ~ubRtituted, ~or e~ample 9 by halogen, such as chlorine, such as the mixed anhydrides formed with piYaloyl chloride or trichloroacetyl chloride. Inte.rnal anhydrides are, ~or example, tho~e o~ organio carboxrlia acids, i.e. ~eten~ uch as ketene or diketene1 or thos~
of oarbamia or ~hiocarbamic ac~d, i.e. isocyanates or isothlo~ganate~. ~urbhe~ reacti~e derivativs~ o~ or~an~c oar~o~ylio acids tha~ oan be used a~ acylating agent~
are activated esters, such a~ suitably substitutea phe~l esters, ~or esample pentachlorophenyl or 4-nitrophenyl ester.
If the am~o group(~) on the phenyl r~ng in a compou~d o~ the ~ormula I i~(are) substituted by an acyl radical Ra-S02-, there i~ used as acylating agPn~, ~or egample~ the corre~po~ding sulphonic acid or a reactive derivativa thereof, especially an an~dride thereo~, includ~ng and pr~erably a miged anhydride. ~ed anhydrides of sulphonic acid~ are, for example, those ~ith inorganic ac~ds, especially with hydrohalic ac~ds, i~e. the corres-ponding sulphonic acid halides, ~or example the sulphonic acid chlor~de or bromid0.
Other sulphonic acidderivatives suitable ~or ~ 78;~

substitu~ing the amino group(~) on the phan~l rlng are acti~ated esters o~ the lo~er alkylsulphonic acid~, such as ester~ with vinylogous alcohols (i.e. e~ol~ uch aæ
vinglogous lower alkenol~, or aryl esters, ~uch as phenyl e3ters pre~erably ~ub~titu~ed, ior ~xample, by nitro or halogen, ~uch as chlorine, for e~ample penta-chlorophenyl ester, 4 ~itrophengl e~ter or 2,4-dlnltro-phenyl e~ter, heteroaromatic e ters, ~uch a~ benztriazole e~ter~, or diacylimino e~ters~ such a~ ~uccinylimino or phthalylimi~o ester, II the ami~o group(s) on the phe~yl ring i~(are) substituted by a~ ac~rl radioal R hav~ng the meaning Ra~
O-CO-, RaRa~ or ~aRa~-S02-, there i~ used as acylati a~ent a reaoti~e deri~rat~e o:E the correspondlng ¢a~bonic acid 3emiester, the corre~pondi~g carbamio acid, thio-carbamic aeid or am~do~ulphonio acid. Su¢h reac~ive derlvatives are, ~or exampl~ dr~de~, mixed anhydride~, ior e:s~ample with irlorganic acids, such as hydro~a:li¢ aoid~
or, ~n the oa~e oY the ~arbamic ac~d or thiocarbamic aoid, illte~al anhydride~, for e~ampla the cyanate9 or thiocyanates .
~ he ac~lation reactions may, if necessary, be carried ou~ in the presence of ~uitable conden~atio~ agents, when u~ing ~ree carbo~ylic acids or sulphonic acids, ~or e~ample in the presence o~ carbadi m~de~9 ~or e~ample N,~'-diethyl~ diprop~ ,N'-diisopropyl , ~,N'-dicyolohe~yl~ or N-eth~ 3-dimethylami~opropyl-carbodiimide, ~uitable ¢arbonyl compound~9 ~or e~mple carbonyldiimidazole, or isoxa~ollnium ~alts, ~or e~ampls ~-sth~1~5~phenyliso~azolin~um 31-sulphonate and ~-tert.-butyl-5-methyliso~azolinium perchlorate, or a ~uitable ac~lamino compound, ~or example 2-ethoxy-1-etho~ycarbonyl-1,2-dihydroquinol~ne. Such conden~ation reactions are pre~erably carried out in an anhydrous reaction medium~
~or e~ample in methylene chloride, dimethylformamide or t'~

- ~3 -acetonitrile.
~ he acylation reaction with a sulphonic acid oorresponding to the radic~l R or with a reactive deriva-tive thereof ~ay also be c~rried out in the presence o~
an acid-binding agent, for example an organic base9 ~uch as an organic amine~ for example a tertiary amine t such as tri-lower alkylamine, ~or example trie~h~lamine, N,~-di-lower alkylaniline, for exa~ple ~,~-dimethylaniline, or a base of the pyridine type; for example pyridi~e, an inorganic base, for egample an alkali meta} or alkali~e earth metal hydro~ide, carbonate or bicarbonate, for e~ample sodium, potassium or cslcium h~dro~de, carbonate or bi-carbonate, or an oxirane, ~or e~ample a lower 1,2-alkylene o~ide, such ~ ~hylene o~ide or 1,2-propylene oxide.
~ he acylation reaction~ may be carr~ed out in the absence or presence of a solvent or sol~e~t mixture, ~hile ~ooling, at room temperature or while heating, and9 if ~eces~ary, ~n a closed vessel and/or in an inert gas atmosphere, for e~ample a nitrogen atmo~phere~ Suitable solvents are those mentioned above or, for e~ample, optionally substituted, especially optionall~ chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, such a~ benzene a~d toluene, it being possible to use suitable esterifying reagents, such as acetic anhydride, also as diluents.

~Ikylation of the amino group~s) o~ the phen~l ring:
Ifç 1~ a resulti~g compound of the formula I, R and Ro represent hydrogen and/or the substituent R1 represents a group oD the partial formula (R)(Ro~N- in which R and Ro likewise represent hydrogen9 the free amino group(~) on the phenyl ring may be alkylated by a suitable alk~lating agent that introduces the lower alkyl radical Ro, ~or e~ample an alkyl halide, ~uch as methyl bromide, to form the Ro ( lower alkyl)-substituted amino group(s).

J

Such RO-~ub~tituted amino group(s) may be ~ub~equently sub~tituted i~ the manner de cribed abo~e by an acylati~g agent introducing the acyl radical Ro In thi~ manner, compo~ds of the formula I are obtained in which the group o~ the partial formula (R)(Ro)~-is substituted by a lower alk~l radical a~d b~ acyl a~d in which Rl 19 hydro~en or a group of the partial ~ormula (R)(Ro)~~ ~ub~bituted by lower alkyl and acyl.
~ uch compounds can al90 be ma~ufactured preferably b~ substit~ lng ~he ami~o group(s) on the pheny~ ring by an acyl radical R corre~ponding to the mean~ng~ giYen abo~e and then metallat~ng ~he 30 obtained ~econdary amino group(~) on the phsnyl ring ~dith a suitable metallat-ing reagent ~ollo~ed by a reactive compound correspondin~
to the radical Ro~
Suitable metallat~ng reagents are, ~or example, lithiwm dii~opropylamiae or butyllithium. A reactiYe compound corre~ponding to the radical Ro i9, fox e~ample, a compound o~ the formula ~0-X in which X i~ a lluoleo-~ugal l~avlng group, ~or e~ample a halogen atom, for e~ample chlor~e, bromine or iodi~, or a ~ulp~onylo~y group, for exam~le me~ylo~ or tosylo~.

~ compound of the formula I i~ which the index n represents 0 can be conYerted by the oxidising agent~
describ0d under proces~ b) into the corre~pondlng 1~oxide in whic~ the ~ndex n ha3 the value 1.
A 1-oxide of the formula I in which the inde2 n ha~
the value 1 can be converted by the reducing agents desoribed under process b) into the corresponding 1-sulphide in which the index _ ~as the value 0.

Esterification_f a ~35 ~ S~Y~L
~ he con~ersion of a free carboxyl group, especially a corresponding group R2, in a compoun~ of the ~ormulaI

7~3~f'~

into an estsrified carbo2yl group, especially into an esterifled carboxyl group that can be split under phy~iological condltio~, is a~Pected according to e~terification methods kr~own per se, for e:~:ample by reacting a compound OI tl~e formula I ~ w}~ch oth~r, optio~ re~ent ~unctional group~ ar~ optiox~lly i~ protected for~n9 or a rea~titre Iu~ctio~al carbogg der~vatlve9 irlclud:~g a ~alt, thereof, with a correspond~ a}cohol or a reactive Lunctlorlal dsri~ative thereo~.
The e~teriIica~ioll of the Iree carbo~l grouE
wi:th the des~red alcohol i~ carrled ou~ in tha prese~ce of a su~table co:~densatio~ agent. Customary conden~ation a~e~s are, ~r example, oarbodiimido~, ~or e~ample ~,N'-diethyl~ dipropg~ , ~,N'~dicyolohexyl-or ~-ethyl-N' (3-dimebh~laminopropyl)-carbodiimide, ~ultablo carbonyl compounds, ~or example c~rbon~ldi lm~dazol~5 or ~2-oxazolium ~ompou~d~, ~or ~xample 2-ethyl-5-phenyl-1,2-o~azolium 3' sulphonate and 2~t~rt.--but~l-5-methyliso~azol~um perchlorate, or a ~u~table acylamino oompound, ior e~mpls 2-ethoxy-1-etho~y-carbonyl-1,2-dlhydroqulnoline. ~he co~den~at~n reaction i~ pre~erably carried ou~ ~n an anhydrou~ react~on medium, preierabl~ ~n the pre~ence o~ a solvan~ or d~luent, ~or e~ample methylerle chloride, dimethyl~o~mamlde, ~cetoni-trile or tetrah~dro~uran, ~d, i~ necessary, whlle cooling or heating and/or in an inert gas atmosphere.
Suitable react~ve functional derivatives o~
the carbo~yl compounds o~ the ~o~mula I to be esteri~ied are, ~or e~ample, anhydrides, especially m~xed anhyclrldes, and acti~ated esters.
Mixed anhydrides are~ ~or e~ample, ~ho~e with inorganic acids7 ~uch a~ h~droh~lic acids, i~e. the correspo~ding acid hal~des, ~or e~ample chloride~ or bromide~, also hydrazoic ac~d, i.e. ~he corresponding a~id azides, a~ well as phosphorus-coD~aining acld3, J
-- ~6 --for example pho~phoric acid, diethylphosphoric acid or phosphorous acid, or sulphur-contai~ing acid~ îor e~ample sulphuric acid, or hydrocya~ic acid. Further migad anhydrides are, f or c~mple, those ~ith orga~ic carboxylic acid~, such as with low~alkanecarbo,~lic acids optio~ally subs~ituted, for e~:ample, by halogen, such as fluor~ne or chlorlne, for e~ample pivalic acid or trichloroacetic acid9 or with semie~ter~, e~peciall~ lower aIkyl ~emie~ter~ of carbonic acid, such as the ethyl or i~obutyl semiester o~ carbonic acidg or ~ith organ~c, e~pecially aliphatic or aromatic, ~ulp~onic acid~, for example p-toluenesulphonic acid.
~ otivated e~ter~ ~uitable ~or reaction ~ith the alcohol ~re, ~or e~ample9 ester~ with vinylo~ou~
alcohols (i.e. enols)~ such as vinglo~ou~ lo~er alkenol~, or iminomethyl ester halides~ such as dimethyli~:Lnometh~l s~ter chloride, manu~actured from the free carbo~lic aoid and dimethyl-chloromethglidene-iminium chloride o~ the ~ormula [(~3) ~ ~C~Cl~ ~ Cl ~ , or ~yl e9ter9~ ~uch a~ pe~achlorophen~l, 4~nitrophenyl or 2,~-di~itrophenyl e~ter, heteroaromatic e~ters, ~uch as be~2tria201e e~ter~, for e~ample 1-ben~triazole ester, or diacylimi~o e3ter~, 3uch as 3ucc~nylimino or phthalylimino e~ter.
~ he esteri~ication with such an acid derivative, ~uoh a~ an anhydride, especially with an aeid halide, is preferably carried out in the pre3ence of an acid-binding agent, for example an organic base, ~uch as an organic amine~ for example a tertiary amine, 3uch a~
a tri-lower alkylamin~, for example trimethylamlne~
~rlethylamine or ethyldii30propylamine, or an ~ di-lower alkylaniline, for example N,N-dimethylaniline, or a cyclic tertiary amine, ~uch a~ an ~-lower alkylated morpholine, ~uch as ~-methylmorpholine, or a ba~e of ~7;~
- ~7 -the pyridine type, f or exampl~ pyridina, a~ inorganic base, ~or e~ample an alkali metal or alkal.lne earth metal hydra~ide, carbo~ate or bicarbonate, for example ~odium,pota~ium or calcium hydro~ide, carbonate or b~carbonate, or an oxirane, for example a 1 72 -lower alk~lene oxide, ~uch a~ eth~lene oæide or propylene oxide .
A reacti~e, ~unc~io~al derivati~e of the esterifyi~g alcohol is especially a corre~ponding ester, pre~erably with a ~trong lnorganic or organic acid, and i~ ~pecial~y a corr~sporLding halide 9 ~or ~Xampl8 chloride~ brom~de or iodida, or a corresponding lower aIkylsulphonylo~y or aryl~ulphon~lo~y compound, such a~ methyl~ulphonyloxy or 4-meth~lphcnyl~ulpho~1-oxy ~
S~ch a reactive e~ter of an alcohol can bereacted with the ~ree oarbo~yl compound of the ~ormula I or with a salt, euch a~ an alkali metal or ammonium ~alt thereo~, the reaction pre~erably being carried out 1~ ~he ~re~ence of an acid-bi~dlng age~t when usi~g tha ~ree acid~
~ h~ abo~e e3tert~$catio~ reac~ion~ are carried ou~ in an inert, usually anhydrou~, ~olvent or 901vent mi2ture, for e2ample ln a carbo2ylic acid amide, ~uch as a ~or~amide, ~or e~ample dimethylformamide, a halogenated hydrocarbon, ~or e~ample methylene chloride, carbo~ tetrachloride or chlorobenzene, a ~etone, for e~ample aceto~e, an ester, ~or example ethyl acetate, or a nltrile, for example acetonitrile, or mi~tures thereo~, if necessary while cooling or heating~ for e~ample in a temperature range of ~rom appro~imately -40C to appro~imately +100C, pre~erably at from approxi~ately -10C to appro~imately +40C andJor in an inert gas atmospherey ~or egample a nitrogen atmo~phere~
~ urthermor6, the acid derivati~e may, i~ desired, b~ formed ln qitu. For example, a mi2ed anhydride i~
obtained by treating the carbo~ylic acld compound ha~i~g appropriately protected ~ ctional groups, or a ~uitable ~alt thereof, such as an a~onium ~alt, ~or e~mpl~ with an organic amine, such as piperidine or 4-methylmorpholine, or a metal 3altp fo:r example an a}~ali metal salt, with a suitable acid derivative, such as the correspo~ding acid halide o~ an optio~ally substituted lower alkanecarbo2ylic acid, for example trichloroacetyl chloride9 with a ~emie~ter oP a carbo~ic acid 3emiha1ide, for example chloro~o~2ic acid ethyl ~ter or i~obutyl ester, or with a hal$de of a di-lower alkylphosphoric acid t ~or e~ample diethgl pho3phorobromidate, a~d the mi~ced a~hydride 90 obtalned i9 u~ed withou~ isolatio~.

Splitti~ of~ o~ ~rot~:
In a resulting compound of the formula I ~ whlch one or more ~u~ctional ~roup3 are protected, these, X~r example protected carboxyl, aml~o, hydro~y and/or ~ulpho groups, can be ~roed, ~n a ma~er ~now~ per se, by means of solvolysi~, especially hydrolysis, alcoholy~i~
or acidoly~i~, or by means of reduct~on, especially hydroge~oly~is or chemical reductlon, optionally ~tep-wi~e or ~imultaneously.
~ hus, tert3-lo~er alkoxycarbon~l~ or lower alkogy-carbonyl substituted in the 2-po3ition by an organic ~ilyl group or in the 1-position by lower alkoxy or lower alkylthio, or optionally substituted diphenyl-metho2ycarbonyl can be con~erted into frea carbo~yl, for e~ample, by treatment with a ~uitable acid9 such as formic acid or trifluoroaoetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole.
Optionally 3ubstituted benzylo~ycarbonyl can be freed, ~or e~ample, by means of hydrogenoly~i~, i.e. by treatment ~7i~

~Aith hyarogen in the pre~ence of a metallic hydrogenation cataly~t, such a~ a palladium catalyst. Furthermore, ~uitably ~ubstituted benzyloxycarbonyl, ~uch aY 4-nitro-benzyloxycarbonyl, can be converted into free carboæyl also bg chemical reduction, for e~ample b~ treatment with an alkali metal dithionite, for example 90dium dithionite, or with a reducing metal, for example zinc, or metal salt~ such a~ a chromium(II) salt~ for example chromium(II) chloride, usually i~ the presence of a hydrogen-yielding agent which, together with the metal, is capable o~
produc~ng nascent hgdrogen, s~ch as an acid, especially a 3uitable carboxylic acid, æuch as a lower alkane-aarboxglic acld optio~ally ~ub~tituted, ~or eæample, by hydroxy, ~or example acetic ~cid, I ormic acid, glyoolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic aoid or tartaric ac~d, or an alcohol or thlol, water preforably bei~g added. ~y treatment with a xeduc~n~ ~etal or metal ~alt a~ de~cribed above it 13 also po3~1ble to co~vert 2-hala-low~r alkoxy-carbo~yl t optionally a~ter con~erting a 2-brvmo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alko~ycarbonyl group, or aroylmetho~ycarbonyl in~o ~ree ~arbo~yl, it being possible to split aroylm~thogy-oarbonyl li~ewi~e by treatment with a nucleophilic, pre~erably salt-formi~g, reage~t, ~uch as SQdiUm thio-phenolate or sodium iodide~ ~ubstltut~d 2-silyletho~y-carbonyl can also be oo~erted into ~ree carboxyl by treatme~t with a salt o~ hydro~luoric acld which yields the ~luoride anion, such as an alkali metal fluoride, ~or e~ample ~odium or potassium Yluoride, in the presence o~ a macrocycl~c polyether ("Crown ether"), or with a ~luoride of an organic quaternary base, such as tetra-lower alkylammonium fluorida or tri-lower alkyl-aryl-ammonium ~luoride, ~or sxample tetraethylammonium ~luorlde or tetrabutylammonium ~luoride, in the presenoe o~ an aprotic ~olvent, ~uch as dimethyl sulphoxid~ or ~
dimethylacetamide. ~ carbo~yl group esteri~ied by an organic silyl or stannyl groupt ~uch as tri-lower alkyl-~ilyl or tri-lower alkyl~tannyl, for example trimethyl-silyl, can be ~reed i~ the u~ua~ manner by sol~oly~
~or exampl~ by treatment with water, an alcohol or an acid.
~ protected amino group ls ~reed in a manner known ~ e and, depending on the type o~ protecting group, in di~ferent ~ay~, pre~erably b~ means o~ solvolys~s or reduction. 2-halo-lower alko~ycarbonylamino, optionally a~ter conve~lng a 2-bromo-lower alkoæycarbonglamino group ~nto a 2-iodo-lower alko~ycarbonylamino group, aroylmotho~ycarbonylami~o or 4-nitrobe~zyloxycarbonyl-amino can be ~pli-t, ~or e~ample, by treatment with a ~uitable chemical reducing age~t, ~uch a~ c, in the pre~encc o~ a ~uitable carbox~lic acid, ~uch ag aq~leou~
acetic acid. Aroylmethoxyaarbonylamino can also be split by -treatment with a nucleophilic, pre~erabl~ salt-forming, reagent, such a~ ~odium thiophenolate, and 4-nitrobenzyl-o~ycarbonylami~o al~o by treatment with a~ alkall metal dithio~ite, for e~ample ~odium dithionite~ Optionally ~ub~titutad diphenylmetho~ycarbonylamino, tert.-lower alko~ycarbo~ylamino or 2-tri-~ubstituted silyletho~y-carbonylamino can be freed by treatment with a ~uitable acid, for e~ample formic or tri~luoroacetic acid, optionQlly sub~tituted benzyloxycarbonylamino, for exampls b~ means o~ hydrogenolysi~, i.e. by treatment with hydrogen in the presence of a suitablo hydroge~ation catalyst, such as a palladium catalyst, optionally sub-~tituted triarylmethylamino, formylamino or 2-acyl-lower alk-1-anylamino, for example by treatment with an acid, ~uch as a mineral acid, for e~ample hydrochloric acid, or an organic acid, for egample formic, acetic or tri-fluoroacetic acid, optionally in the presence of water, ~17~3~ i 11 _ 51 -and an amino group protected by an organic silyl or qtannyl group, for example by means of hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl, ~or e~ample 2-chloroacetyl, can ~e ~reed ~y treatment with thiourea in the presence o~ a base, or with a thio-late salt, such as an alkali metal thiolate, of thio~ea, and by subsequent solvoly~ij, such as alcoholysis or hydrolysis, of the resulting condensation product. ~n amino group protected by 2-substituted silyletho3ycar-bonyl can also be converted into tke free amino group by treatment with a salt o~ hydro~luoric acid which yields fluoride anions, as stated above in connection with -the free~ng of a corre~pondingly protected carboxyl group.
pho~phoramido, phosphonamido or pho~phinamido group can be converted into the ~ree amino group, ~or example by treatment with a phosphorus-co~tainin~ acid, such as a pho~phoric, phosphonic or pho~phin~ a¢id, ~or example orthophosphoric acid or polyphosphoric ~cid, a~ acid ester thereof~ for e2ample monomethyl, monoethyl, dimethyl or diethyl phosphate, or monom~thylphosphonic acld, or an anhydride thereof, ~uch a~ phosphoru~ pento~ide.
~ n amino gro~p masked in the ~orm o~ an azido group is converted into the free amino group, ~or example by reduction, ~or e~ample by cata}~tic hydrogenation with hydrogen in the presence o~ a hydrogenatio~
catalyst, such as platinum o~ide, palladium or Raney nickel, or alterna~ively by treatment with zinc in the presence o~ an acid, such as acetic acid~ Catalytic hydrogenation i~ pre~erably carried out in an inert solvent, such as a ~alogenated hydrocarbon, ~or example methylene chloride, or alternatively in water or a mi~ture of water and an organic solvent, such as an alcohol or dioxan, at from approximately 20C to 25C, c alternatively while cooling or heatingO

~7~

~ hydro~y group protected by a suitable acyl grOUp9 an organic ~ilyl or 3ta~nyl group or by optionally sub stituted 1~pheny1-lower alkyl i~ ~reed in the same manner a~ a correspondingly protected ami~o g:roup~ ~ hydroxy group protected by 2,2-dichloroacetyl i9 freed, for exampl~, by ba~ic hydrolysis, whil~t a hydroxy ~roup etheri-~ied tert.-lower al~yl or by a 2-o~a- or 2-thla-aliphatic or a 2-oæa- or 2-thiacycloaliphatic hydrocarbo~ radical is freed by acidolysis, ~or e~ampie by treatment with a mineral acid or a strong carboxylic acid, ~or example tri~luoroacetic acid. A 2-halo-lo~ler alkyl group i~
split off by reduction,.
A protected, especially e~teri~ied, sulpho group i~ ~reed analogou~ly to a protected carbo~yl group9 ~ he de~cribed ~pl~tting reaction~ are aarr~ ~3d out under condltions known ~ e, if nece~ary while cooling or heating, in a clo~3ed ve~sel and/or i~ an inert ga9 atmo~phere, for example a nitrogen atmosphere.
~ he reductive splltting methods ~nown ~ se ~or 2-halo-lower alko~ycarbonyl and 2-halo-lower alkoxy groups may advantageou~ly be carri~d out under especially mild condition~ in the presence of a catalytic quantity o~ a transition metal oomplex of a corrin or porph~n compound, it bei~g pos~ible to ~plit even groups that are normally di~ficult to split, for example 2-chloroetho~y-carbonyl a~d 2-c~loroetho:~ groups.
~ i!ransition metal complege~ of corrin and porph~n compounds which are u~ed as catalyst3 for reductivs splitting are derived from transition metal3 tha~ appear i~ more than one ~alency stage, ~uch a~ copper, palladium~
rhodium and especially cobalt. Pre~erred catalysts are model compounds for the ~ynthe~is of vitamin B12, for e~ample derivative~ that are dsrived from the 2,2,393, 7,7,8,8,12,12,13,13,17,17,18,18-hexadecamethyl-10j20-diazahe~ahydroporphin cobalt(III) cation and especially vitami~ of the ~t2 group including, e~pecially, cyano-cobalamin, aquocobalamin and hydroxycobalamin, and their derivati~e~ and decompo~ition product3, such a~ cobyrinic aoid and the e~ters thereof, corphyrinic acid, corph~nic acid, cobamic acid and cobamide. The ~uantlty o~ the catalyst i~ generally from appro~imately 0.1 to appro~imately 0~001, pre~erably ~rom appro.~imately 0.03 to appro~imately 0.003, molar equivalent, ba~ed o~ th~ component to be reduced, but in a favourable experimental arrangement, ~or e~ample in an optimi~ed electro-reductio~, the qua~tity may be ~ar belcw the lowe~t limit~
~ he reduction i3 carried out in a manner known e by conventional method~i~ the pre~encs of a proton ~ource. Any inorganic and crganic acld~ a~d ousto~lry protic ~olvents may be used a~ the proton ~ol~ce; acid~
are advantageou~ly u~ed in a bu~fered form or a~ sa.lts, the pE ~alue belng preIerably between approximately 4.0 and 9.5, e~pecially betwe~ approximatel~ 5.5 a~d 7.5 and above all in the region o~ the neutral point.
A reduction method th~t recommends itsel~ as one of the most gentle methods i~ cathodic electroreduction under con~entional condltions, such a~ u~ing a mercury cathode or some other cathode that may generally be used in electroreductio~, ~uch as a carbon cathode~ in the pre~ence of customary au~iliary electrolytes, such as ammonium and/or alkali metal ~alts, especlally lithium salt~, o~ ~trong inorganic acids, such as, especially, halides and perchloratss, pre~arably those that are di~tingui~hed by a good solubilit~ in the aqueous-organic medium used. ~he sol~ents used9 apart ~rom water, are conventional water-mi~cible organic ~olvents, for e~ample low~r alkanols, such a3 methanol, ethanol and i30prop~1 alcohol, or di~ethylformamide 7 and similar l~rer aliphat$c amides, also nitriles, such as acetonitrile, ether~, such ~L1,7~; t`,,~3 as diethyl ether, 1,2-dimethoxy- and 1,2-diethoxyethan~
and cyclic ethers of the tetrahydro~uran type, ketones, such as acetone, carbonate~, such a~ dimethyl and dieth~l carbonate, a~d ~ulpho~ldes, ~uch a~, especially, dimethyl sulphoxide. ~he tern~ rature of the electroreduction may be varied with~n a wide ran~e, i.e. from approximately -20C up to the boiling temperature of the reaction mixture; it i~ pref~rably at room temperature or belo~
~ ~urther suitable ~ariant o~ the reductive spl~tting i9 reductio~ with a metal, especially with ~in¢ or alternatively with magne~ium. If neces~ary, the customary ~igorou~ cond~tions may be applied, for e~ample ~ro~ima-tel~ 90~O aqueou3 acetic acid as the medium and/or ele~ated temperature up to the boiling poi~t o~ the mi.~ture with a corre~pondingly 3hortened reaction timeO ~he operation i9 7 ho~ever, pre~erably carried out under as mild condition~
a~ po~ible, ~or e~ample i~ the abo~e-mentioned pre~erred pH range i~ the re~ion o~ the neutral point and at temperature~ o~ from appro~imately 0 to approximately 40a, pre~erably at appro2imately from 10 ~o 25C; the operation is generally carried out with a~ approximately

10-~old molar exces3 of the metal, pre~rably zi~c in the ~orm o~ zinc du~t which i9 ad~a~tageously activated immediately be~ore ~he reaction i~ a co~ventional manner, ~or example by stirring with dilute hydrochloric acid and carefully washing until nau~ral. In order to obtain the de~ired buf~er e~fect, ammonium salts of hydrohalic acids may advantageously be used, especially tho~e to be found in the p~rticular group of the formula I to be split of~. The reduction is carried out in the above-men~ioned organ~c solvents or mi~ture~ thereof; protic solvent~ are pre~erred. It is also possible to use other conventional variants o~ the reduction process; an e~ample i~ reduction ~ith metal cations in low valency stages, for example with chromium(II~ salts, uch as c:hromium(II) chloride or acetate, al~o reduction with comple~ metal h~drides, for e~ample with ~odium boro-hydride and related lower alko~y sodium borohydride~
and lower alko~ylithium borohydride~, and also catalytic hydrogenation, for example using a palladium catalyst.
When ~everal protected functional groups are prese~t, the protecting gIoups ar~ pre.~erabl~ ~o chosen thst more than one ~uch group can be 9plit off ~imul-taneously, ~or example by acidelysis, ~uch a~ b~ treat-ment with tri~luoroacetic acid or formic acid, or by re~uct~on; æuch a~ by treatment with zinc and acetic acid, or with hydrogsn a~d a hydrogenation cataly~t, ~uch a~ a palladium-carbon catalyst.

~a~
Salt~ o~ compound~ of the formula I haYin~ ~c~lt-~orml~g group~ ca~ be manu~actured in a manner ~nowu E~ se. ~hu~, ~alt~ o~ compounds of the formu~ I ha~ing acid group~ can be formed, ~or e~ample, by treatment with metal compounds, ~uch a~ all~sli metal salt~ of ~uitable orga~ic carbo~ylia acids, ~or example the sodium salt of a-ethylcaproic acid, or with inorganlc alkali metal or alkaline eart~ metal salts, for ~xample sodium bicarbonate9 or with am~onia or a suitable organic ~ine, preferably stoichiometric quantities or only a small e~ae~s of the salt-~orming agent being used. ~cid addition ~alts o~
compound~ o~ the formula I are obtained in the u~ual manner, ~or e~ample bg trea~ment with an acid or a .quit-able anion e~change reagent. Internal ~alts of compound~
of the formula I that contain, for example, a free carb-o~yl group can be formsd, ~or e~ample, by ~eutralising salt~, such as acid addition salt~, to the isoelectric point, for e~ample ~ith weak bases, or by treatment with liquid ion exchangers.
Salts can be con~erted in the usual manner into the free compounds; metal and ammonium salts can be ~17~

converted, for e~a~ple, by treatment with sui~able aclds and acid additio.n salts, for e~ample, by treatment with a suitable basic agent.
~ he l-o~ide o~ -the formula I in which the index n ha~ the value 1 may b~ u~ed in the ~-- or ~-~orm or in the ~orm o~ a mi~:ture OI the two isomers i~ the sub~equent reactions de~cribed aboveO
~ he methods de~cribed in the literature, for e~mple ~ractio~al cry~talli~ation, c~romatography, etc., are suitable for separating racemie migtures The process also includes th~ e embodimer.ts according to which compounds ~ormed a~ lntermediate~
are u~ed aq starting material~ and the remaining proces3 steps are carrled out with the~e, or the process i~
discontinued at an~ stage; in addition., starting mat;erials ~ay be u~ed in the ~orm o~ derivative~ or may be formed during the reaction.
Pre~erabl~, the ~tartin~ materials and the reactio~ co~ditions are 50 chosen that the compound~
mentioned above as being especially pre~erred are o~tainedO

~ e ~tarting materials used in the process ~or th~ manu~acture o~ the compound~ of the pre~ent invention are k~own or, i~ novel, can be manu~actured in a manner known ~er se.
The ~tarting compounds of the type of ~he formula II a~d al~o oorresponding compounds hav~ng protected ~unctional group3 are k~own.
~ hs following compounds of the formula III a~d proce~se~ ~or the manufacture thereof are known ~rom Germa~l Offenlegungs3chrift 2,4~2,190 or can be ma~ufactured in a l~anner kno~m Per se: R, Ro and Rl repre~ent hydrogen, R repre~e~ts an acyl radic~l o~ the ~ormula Ra-S02- , in which Ra represents lower alkyl, Ro represents hydrogen y~'v or lower alkyl and R1 represe~ts hgdro~en; R represent~
an acyl radical ~ the formula RaRaN-CO-, R~R~N-C~- or R ~aN-~02- , In which in each ca~e one radical ~a represents lower alkyl and the other radical Ra represents hydrogen, and R1 represent h~drogen.
Compounds of the formula III in which R repre~ent~
an acyl radical of the formula Ra-O-CO- in which ~a has the meanings g~ven abo~e or comp~und~ of the ~ormula III
in which R repre~ents a~ acyl radical of the formula ~ CO~, RaRaN-C~ or R~Ra~-S02- in which ~n each case both radicals Ra represen~ optionally ~ub~tituted h~dro-carbon radicals or both radicals Ra repre~ent hydroge~, can be mant~aotured analogously ~ prooess a~, for e~cample~
by acyla~ing a compound of the formula III in which R, R~ and R1 represe~t h~droge~ w~th the acyl radical R of a correspondingly substitut~d carbonio ac~d semie~ter, o~ a correspondin~l~ sub~tituted carbami~ acid, ~hio-carbamio acid or amidosulpho~ic acid, or a reaative derivati~e o~ ~uch aoids, ~or e~ample an acid anhydride, such a~ an acid chloride.
aompounds o~ the formula III in which R represe~t~
an acyl group having the meanings glven above and R~ repre-~ents hydroga~ and Rl represents a group of -the partial formula (R)(Ro)N~ in which R rapre~ent~ a~ acyl gro~lp and Ro represents hydrogen, can be manufactured analogously to proces~ a) by acylating ~ree amino groups of a corres-ponding compou~d of the formula III with the acyl radical of a correspondingly substituted carbo~ylic acid or sulphonic acid, of a carbonic acid semiester, a carbamic acid, ~hiocarbamic acid or amidosulphonic acid, or a reactive derivative of such acids, ~or e~ample an acid anhydride, such as an acid chloride.
Compound~ oi the formula III in which R and Ro represent hydrogen and R1 represents a group o~ the partial iormula (R)~Ro)N~ in which R and Ro likewise represent ~ ~7~

hydrogan9 can be manufactured by reducing the correspond-i~g dinitrohydroxyphenyl-D-2-aminoacet$c acid~, for e~ample 3,5-dinitro-4-hydroxyphe~yl-~-2-aminoaaetic acid, with Raney nickel or one o~ the abo~e-mentioncd reducing agents that co~vert nitro groups into amino groups, ~or example with palladium-carbon.
In compound~ o~ the formula III in which R and Ro repre~ent hydrogen and R1 represents hydroger, or a group of the partial formula (R~(Ro)~~ having the meanings given abo~e for R a~d Ro~ tke amino group(s) on the phenyl ring can be al~ylated in a manner known E~E se by ~ ~uit-able alkylating agent that introduce~, for example, a lower alkyl radical Ro~ ~or e~ample an aI~yl halide, ~uch as methyl bromide.
Such alk~lated amino group(8) on the phenyl ring may be ~ub~equently ~ub~tituted in the manner de~crihed above by a~ acylating agent that introduces the acyl rad~oal R.
Oompound~ of the formula III are thus obtained in which R repre ents an acyl group, Ro represents a lower alkyl radical and R1 represents hydrogen or a group of the partial ~ormula (R)(Ro~N~ in which ~ likewise repre-sen~s an acyl group a~d Ro represent3 a lower alkyl radical.
~ hch compounds can be manufactured pre~erably by substituting the amino group(s) on the phenyl ring b~
an acyl radial R corresponding to the meaning~ give~ abo~e and then metallating the resulting secondar~ amino group(s) on the phenyl ring with a ~uitable metallatinb~ reagent followed by a reacti~e compound corresponding to the radical Ro~
Suitable metallating reagents are, for e~ample, lithium diisopropylamide or but~llithium. ~ reactive compound corresponding to the radical Ro is, for e~ample, -- 5~ --a compound of the formula Ro~'~ in ~rhich ~ i~ a nueleo-fugal leaving group, ~or e~ample a halogen atom, ~or examplQ chlorine, brominQ or iodine, or a sulphonyloxy group, for e~ample mesylo~y or tosylo~y.
I~ the ca~e o~ the acylation and alkyla~ion reaction~ of the amino group(~) on the phenyl ri~g, tha hydroxy group on t~e phenyl ring is opt~onally protected by the eu~toma~y hydroæy-~roteeting group9 deseribed above and the D-2-amino group is optionally proteeted by the eu~tomary amino-proteeting groups de~eribed abova~
Compounds of the formula III ha~e a chiralitg ee~tre on the earbon atom in the 2 or a-position of the aeetyl radical.
For ths above acylation proee~s according to a) for the manu~aeture of compound~ o~ the ~ormula I, compound~
of the formula III are pre~erably us~d in which the amino group that i~ in the 2- or a-position o~ the acyl radical, ha~ the D-eo~iguxatio~. Sueh compound~ ean be obtainod, ~or example, by ~eparatin~ raeemle mixtures o~ eompound~
cf the ~ormula III into the des.ired D-eonflguration antipodes. ~ ~umber of conventional methods described in li~erature, especially those u~ed ~or splitting racemic a-amino acid~q, m~y be used.
Starting materials of the formula IV may be ~ormed, ~nter alia, a~ a by-product in the manu~acture of compounds o~ the type of the formula I, ~or example when tb~se are ~ormed under basic conditions. ~he~ need not be in pure form but may be u~ed, ~or sxample, in admixtuxe ~ith corresponding compounds of the formula I.
~ he invention relate3 also to compounds of the formula ~ 1~ which Rl represents hydrogen, nitro or a group of t~e partial ~ormula (R)(Ro)N~, i~ which represents hydrogen ox an acyl group and Ro represents h~drogen or lower alkyl, R2 represents carbo~yl or protectad ~7~ 3 carboxyl and R~ represents hydrogen, halogen having an atomic number of up to ~5 or lower alko~y, and hydrates and salts of compou~ds of the formula V and processes for the manu~acture thereo~. Compounds o~
the formula V are manu~actured, for example, by, in a compound o~ the formula ()n H H ~
~2N_ _ ~,S~. (II) O
~2 in which the index ~ repre~ent~ 0 or 1 and the 7~-amino group i~ optionally protected by a group allowi~g acylation~ a~d R2 a~d R~ ha~e the mea~ings gi~en under formula ~, acylating the 7~-amlno group by reaction with an acylating agent that introduces the acyl radical of a carbo~ylic acid of the formula C~--C~ 0~ ~YI) ~ '~- R' ~ 2 in which the hydro~y group on the phenyl ring and/or the D-2-amino group are optionally in protected form a~d in which other fu~ctional groups present are optionally protected, and5 if desired, converting a resulting compound in which the index n represent~ 1 into a compound in which the inde~ n repre~ents O and/or, if 7~
~ 61 -desired, oonverting ~unctional groups pre~ent in protected form in a re~ulting compound into free functional group~
and/or conNerting a re~ulting salt into the free compound or into a ~ifferent ~alt and/or ~onverting a resulti~g ~ree compound that ~3~ a ~alt-~orming group into a salt and/or separating a resulting miæture o~ isomeric compounds into the individual isomers.
~ he novel compounds of the ~or~ula 7 in which the ~unctional groups are either in free form or the 4-carboxyl ~roup is optionally in an esterified ~orm that can be ~plit under physiological conditions, a~d their pharmaceutically acceptable non-toxic ~alt~ have valuable pharma¢ological pr~perties~
~ hu~, oompound~ of the ~ormula V in ~ree ~orm or in the form of their sal~s are effective ~n v~tro aga~n.
~ram-po~iti~e and gram-negative cocci, ~or example ~taPhyloQoccus aureu~, Streptococcus E~s~ or _isseria ., ln conoentration~ o~ from approxlmately 0.1 to a~p~o~imatel~ 32 ~g/ml and against gram-negat~ve bacteria, for example en~erobacteria, ~or example ~3cherichia col~, Eleb~iel~a E~ 9~ Salmonella t~phimurium, Proteu~
., in concentration~ o~ from approgimateiy 2 to appro2imately 64 ~g/ml, and a~ainst anaerobes~ for example Chlostridium E~ e~, in a concentration of approxi~
mately ~ g/ml.
In ~i~o, in the case of peroral administration to mice, compounds of the formula Y are e~fecti~e again3t sy~temic infection3 caused by gram-positive cocci J ~or example StaPhylococ_us aureus, and against gram negati~e bacteria, for e~ample E3cherichia coli or Elebsiella pneumoniae, in a do3age range o~ ~rom appro~imately 7 to ap~proximately 18 mg/kg, and ha~e a low toxicity.
In compounds of the ~ormula Y, R, Ro~ ~ and R~
have the pre~erred meanings given above under formula I.

_ 62 -~ he functional groups present in compounds of the formula V, e~pecially the 4-carbo~yl, the D-2 amino and the h~droxy group on the phenyl ringJ are optionally protected by the protecting groups given above under formula I.
Salts o~ compound~ o~ the formula V are the ~alt~ given abo~e under formula I~
Compounds of the fonmula V have a chirality centre at the carbon atom in the 2- or -position of the acetyl radical. ~or the manu~acture of compoc~ds o~ the ~ormula there are u~ed ~n ~he acylation pr~ferably compounds of the ~ormula III in which the ~mino group in the 2-po~ition of the acetyl radical ha~ ~he D-configuration.
~he~a compound~ can ~e obtalned, for e~a~ple, by ~eparating racemic mixture~ o~ compound~ o~ the formula VI by means of the con~entional method~
~ he acylation proce3s i~ carried out analogou~ly to the processe~ described above l~der a).
Carbo~yl~c acids o~ the formula ~I in which ~1 repre3ents nitro or hydrogen are known from German Of~enlegungs~chrift 2,444,762.
Compound~ of the formula VI in which R1 represents a group of the partial formula (R)(Ro)~~ in which ~
r~presents an ac~l group havi~g the meanlngs given abovs and ~0 repre~ent~ hydrogen, can be obtained, ~or e~a~ple, by acylating a carboxylic acid of the ~ormula VI in which R1 repre~ents a group o~ the partial ~ormula (R)(Ro)~~ in which R and Ro represent hydrogen~ with the acyl radical of a cQrrespondingly ~ub~tituted carboxylic acid or sulphonic acid, o~ a carbonic acid semiester, carbamic acid, thiocar~amic acid or amido~ulphonic acid, or a reactive derivative of such acid~, for examp1e an acid anh~dride, ~uch as an acid chloride. Compound~ o~ the formula VI in which R1 represents a group of the partial ~ormula (R~(Ro)~- i~ which R represents an acyl group ~ 7~
_ 63 -ha~ing the meanings given above and Ro represents lower alkyl, can be obtained, ~or example, by alkylating a free amino group on the phenyl ring b~ a suitable alkylatlng agent that introduce~ the radical ~0, ~or e~ample an alkyl halide, optionally i~ the presence of ba3e~, such a8 pyri-dine, to ~orm the seco~dary amlno group and then acylating.
~ he present invention rela-tes al~o to no~el s-tarting compounds, and i~termediates and processes for the manu~actura thereof, The no~el compounds of the formulae I and V
of the pre3snt invention can be used, for e~ample, for the manufacture of pharmaceutical pre~arations that contain an ef~ective quantity of the active ~ubstance together or i~ admixture with inorganic or organic, ~olid or liquid, pharmaceutically acceptable carriers that are suitable for enteral or parenteral administration.
~hus~ tabl~t~ or gelat~n capsules are u~ed that contain the active ~ubstance to~ether with dilue~ts, ~or example lactose, de~trose~ sucrose, man~itol, sorbltol, cellulose and~or gl~cine, and lubricants; ~or e~ample silica, talc, stearic acid or salts thereo~ t such as magne~ium or calcium ~tearate, and/or polyethylene ~lycol; tablets also contain binders~ for example magnesium aluminium silicate, ~tarches, ~uch as ma~æe~ wheat, rice or arrowroot starch~ gelatin~
tragacanth, methylcellulose, sodium carbo~ymethylcellulose and/or polyv1nylpyrrolidone and, if desired~ disinte-grating agents, ~or egample starches, agar, alginic acid or a salt ther~of, such a~ sodium alginate,and/or ef~erves-cing m~turss, or adsorbents,dyestuffs, ~1avouring sub~tances and ~weeteners. It i9 also possible to use the novel pharmacologically active compounds in the ~orm of injectable, for example intravenously administrable) preparations or in the ~orm of in~usion solutions. Such solu~ions are pre~erably isotonic aqueous solutions or suspensions , ~ 3 it being po_sible to manu~acture these before use, ~or example ~rcm lyophili~qed preparations that contain the active substance alone or together ~ith a carriar, for example mannitol. The pharmaceutlcal preparations may be sterilised and/or co~tain adjunct~, for e~ample pre~erva tives, stabili~ers, wettin~ agent~ and/or emulsifiers, solubiliser~, salt~ for regula~ing the osmotic pres~ure and/or buffers. The pre~ent ~harmaceutical prepQration~, which may, l~ de~ired, contain other pharmacologically valuable ~qubstances, are manufactured in a manner known e, for e~ample by means of conventional mi~ing, granulati~g, dragée-making, dissolYing or lyophilising proccsse~, and contai~ ~rom appro~imately 001% bo lO~o~
e~peciall~ ~rom appro~imately 1~o to apuroximately 5~/0, a~d in the ca~e of lyophilisates up to 100%~ o~ the active substance.
aompound~ o~ the formulae I and IV, e~pecially tho3e in which R2 repre~ent~ an e~terified carboxyl ~roup that oan be split under phy~iological condib~ons, for example pi~aloylox~metho~ycarbonyl, can also be ad-mini3tered orally, ~or example in the form of capsule~.
~he~e contain the active ~ub~tance, optionally together with suitable carriers, in the form of a granulate and i~ doses of from approximate~y 0.2 g to approximately 0.5 g per do~age un~t.
Dependi~g on the type ¢ in~eation and the condi tion of the ln~ected organism, daily do~es of from 0.5 g to 5 g 3.c~ or p~o. are used for the trsatment o~
warm-blooded animals weighing appro~imately 70 kg.

~L:a'7~Z'.`i~

The following Examples serve to illustrate the invention. Temperatures are given in degrees Centigrade.

Example 1 a) 18 ml of cold trifluoroacetic acid are added to a solution cooled to 0 of 3.5 g (4.7 n~ole) of 7~-[D~2-tert.-butoxycarbonylamino-2~(3-methylsulphonylamino-4-hydroxyphenyl)-acetylamino 3 -3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl ester and 3.5 ml of ani~ole in 18 ml of absolute methylene chloride, the mixture is stirred at 0 for 45 minutes under a nitrogen atmos~hers and then, at 0, 100 ml of diethyl ether are added. The b~ige precipitate i~ filtered o, wa~hed with a smalll quantity o~ diethyl ether and dried und~r reduced pressura.
The requlting t~ifluoroace~ia acid ~alt o~ 7~-CD-2-amino-2-(3-methylsulphonylaml~o-4-hydro~y~hanyl) -acetylamino] -3-methoxyceph-3-em-4-carboxylic acid i~ dissolved in 20 ml of ice water and extracted with ethyl acetate (5 x 10 ml ).
The acidic aqueou~ phase (pH 2) i~ adjusted to pH 4.5 by the dropwi~e addition of 2~ qodium hydroxide solution and, at 0, ethanol ~100 ml) i9 added. The precipitate ~ormed i~ filtered off, washed with ~0 ml of water/ethanol 1-4, taken up in approximately 10 ml of water in order to remove the organic solvent and concentrated in a rotary evaporator. After drying, ~16 hours, room temperature, 0.05 torr), 7~-[D-2-amino-2-(3-methylsulphonylamino~-hydroxyphenyl)-acetylamino]-3-methoxyceph-3-em-~-carboxylic acid is ob~ained in the form of a monohydrate.
Melting point: from 150 (with decomposition~;
~LC (silica gel, developing with ninhydrin): R~ 0.46 (system: secO-butanol/acetic acid/water 67:10:23), W spectrum (in 0.1N aqueous hydrochloric acid~: 278 nm ( F = 7700), ~7~

~]D = ~144 + 1 (in 0.1~ aqueou~ hydrochloric acid, c - 1.34~ ~0).
The ~tarting material may be obtained as ollows:
b) To a solution cooled to -15 of S.26 g t14.6 mmole) of D~2-tert.-butoxycarbonylamino-2-(3-methyl-sulphonylamino-4-hydrox~phenyl)-acetic acid and 1.6 ml of ~-methylmorpholine in 100 ml of absolute tetrahydro-furan there are added, under a nitrogen atmo~phere, 1.9 ml of chloroformic acid isobutyl ester and, after one ~our, 6.3 g (14.6 mmole) of 7~-amino-3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl ester hydrochloride and 1.6 ml of N-methylmorphQline. After stirring at room temperature for 3 hour~, the reaction mixture is diluted with ethyl acetate, wa~hed twice with ice water and twice with saturated sodium chloride solution, dried over ~odium sulphate and ~reed of solvent in a rotary e~aporator.
The residue i~ purified on ~ilica gel using diethyl ether~ethyl acetate 1:1 as eluant, yielding 7~-tD-2-tert.-butoxycarbanylamino-2-~3-methyl2~ulphonylamino-4-hydroxy phenyl)-acetylamino~-3-methoxyceph~3~em-4-carboxylic acid diphenylmethyl ester in the form of a colourless amorphous powder.
TLC (silica gel, identification with iodine) R ~ .26 tdiethyl ether/ethyl acetate 1 Exam~e 2 a) In a manner analogous to Example la), 7~-[D~2-a~ino-2-(3-methylsulphonylamino 4-hydroxyphenyl~-acetylamino~-ceph-3-em-4-carboxylic acid is obtained in the form of a 1.5 hydrate by treating 2.13 g ~3 mmole) of 7~D-2-tert.-butoxycarbonylamino-2-(3-methylsul-phonylamino-4-hydroxyphenyl)-acetylamino~-ceph-3-em-4-carboxylic acid diphenylmethyl e~ter with 10 ml of tri-fluoroacetic acid and 2 ml of anisole in 10 ml of absolute methylene chloride.

Melting point: from 20Q with decomposition, TLC (~ilica ~el, developing with ninhydrin): R ~ .1g (system: sec.-butanol/acetic ac.id/water 67:10:23), W spectrum (in o~lN a~ueous hydrochloric acid: 232 nm ( F = 11600), ~70 nm (~houlder):
Ca~D = + 122 ~ 1 to.lN a~ueou3 hydrochloric acid, c = l.353 %).
The starting material may be obtained as follow~:
b) In a manner analogous to Example 1b)l 7~-[D-2-tert.-butoxycar~onylamino-2-~3-methylsulphonylamino-4-hydroxyphenyl)-acetylamino]-ceph-3-em~4-carboxylic acid diphenylmethyl ester i~ obtained by treating a mixed anhydride, obtained from 3.6 g (lo.o mmole) of D-2-tertO-butoxycarbonylamino-2-~3-methylsulphonylamino-4-hydroxy-phenyl)-acetic acid and 1.3 ml of chloroformic acid isobutyl ester in the presence of 1.1 ml of N-methyl-morpholine and 100 ml of absolute tetrahydrofuran at -15, with 3.66 g (10 mmole) of 7~-aminoceph -3-em-4-carboxylic acid diphenylmethyl ester according to the proces~ described in Example 1b).
~LC (~ilica gel, identification with iodine): Rf~0.48 (ethyl acetate).

~) In a manner analogous to Example 1a), 7~-[D-2-amino-2-(3-methylsulphonylamino-4-hydroxyphenyl)--acetylamino~-3-chloroceph-3-em-4-carboxylic acid is obtained in the form of a monohydrate by treating 2.3 g (3.1 mmole) of 7~-[D-2-tert~-buto~carbonylamino-2-(~-methylsulphonylamino-4-hydroxyphenyl)-acety1amino]-3-chloroceph-3-em 4-carboxylic.acid diphenylmethyl ester with 11 ml of trifluoroacetic acid and 2.3 ml of anisole in 11 ml of absolute methylene chloride according to the process described.

Z Lr O

_ 68 -Melting point: from 172 with decomposition TLC (3ilica gel, developing with ninhydrin~: R~-0.16 (system: sec.-butanol/acetic acidJwater 67:10:23) W spectrum (in 0.1N aqueous hydrochloric acid):
235 nm (~houlder), 270 n~ (~ a 8600 );
C~]D = ~9~ ~ 1 ~0.1~ aqueous hydr~chloric acid, c = ~.313 %~.
The starting material may be obtained as follows:
b) In a manner analogous to Example 1b), 7~ 2-tert.-butoxycarbonylamino-2-(3-methylsulphonylamlno-4-hydroxyphenyl)-methylamino]-3 chloroceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained by treating a mixed anhydride, obtainPd from 3.0 g ~8.3 mmole) of D-2-~ert.-butoxycarbonylamino-2-~3-m2thylsulphonylamino-4-hydroxyphenyl3 -acetic acid and 1.'l ml of chlo~of~rmic acid isobutyl ester in the presence o~ 0.32 ml of N-methylmorpholine and 100 ml of absolute tetrahydrofuran at -15, with 3.33 g ~8.3 mmole~ of 7~-amino-3-chloro-ceph-3 em-4-carboxylic acid diphenylmethyl ester according to the proces~ de~cribed in Example 1b).
TLC (silica gel, identification with iodine): R~0~38 (toluene/ethyl acetate 1:1).

a) 20 ml of cold trifluoroacetic acid are added to a ~o}ution c~oled to 0 of 3.8 g (5.75 mmole) of 7~
~D-2-tert.-butoxycarbonylamino -2-(3-amino-4-hydroxyphenyl)-acetylamino-3-methoxyceph-3-em-4-carkoxylic acid diphenyl-methyl ester and 3.8 ml of ani30le in 20 ml of absolute methylene chloride, the mixture is stirred at 0 for 45 minutes under a nitrogen atmosphere and then 200 ml of petroleum ether/diethyl ether 1-1 are added. The beige precipitate i~ filtered off, wa~hed with a $mall quantity of diethyl ether, then dissol~ed in 40 ml of ice water and extracted with ethyl acetate (4 x 20 ml). The a~ueous ~:~7~J~7~

_ 69 -phase (pH~2) is adjusted to pH 5 wnth ~N sodium hydroxide qolution, concentrated to approximately half it~ volume under reduced pre~ure and, at 0, ethanol (80 ml) i5 added dropwi~e. The re~ulting crude product, 7~-[D-2-amino-2-(3-amino-4-hydroxyphenyl)-acetylamino]-3-methoxyceph-3 em-4-carboxylic acid,i~ purified on Amberlite XAD- ~u~ing water/i~oprop~no.l ~8:12 as eluant.
Melting point: from 150 with decompo~ition.
TLC (~ilica gel, developing with ninhydrin)0 R ~ .13 (sec.-butanol/acetic acid/water 67:10:23).
The starting material may be prepared a~ follow~:
b) A solution of 8 g (11.6 mmole) of 7~-~D-2-tert.-butQxycarbonylamino -2-(3-nitro-4-hydroxyphenyl~-ac~tylaminoJ-3-m~thoxyceph-3-em-4-carboxylic acid d.iphenyl-m~thyl aster in ethyl acetate (150 ml) i~ hydrogenaited in the pre~ence of 2 g of palladium c æ bon (10 ~) a5 c,~taly9t~
After the theoretical quantity (778 ml) of hydrogen ha~
been absorbed, the reaction m~cture i~ filtered over Celite~)and ~reed of solvent under reduced pres~sure. Ihe reqidue i9 then purified on silica gel u~ing ethyl acetate a-~ eluant, yielding 7~-[D-2-tert.-butoxycarbonyl-amino-2-(3-amino-4-hydroxyphenyl)-ace~ylamino]-3-methoxy~
ceph-3-em 4-carboxylic acid diphenylmethyl ester in the form of an amorphou~ heige powder.
TLC ~silica gel, d~veloping with iodine): R~-o.35 ~ethyl acetate).
C) To a ~olution cooled to -15 of 10.9 g (35 r~mole) of D-2-tert.-butoxycarbonylamino-2-(3-nitro-4-hydroxy-phenyl~-acetic acid and 3.9 ml of ~-methylmorpholine in 350 ml of absolute methylene chloride ~here are added, under a nitro~en atmosphere, 4.6 ml o~ chloroformic acid i~obutyl ester and later 15.15 g (35 mmole) of 7~-amino-3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl ester hydrochloride and 3.9 ml of N-methylmorpholine. After stirring at room ~emperature for 3 hours, the reaction h ~``

_ 70 -mixture is diluted with ethyl acetate, washed twice wi th ice water and ~wice with saturated sodium chloride solution, dried over sodium sulphate and freed of solvent in a rotary e~aporator. The residue i~ purified on ~ilica gel using diethyl ether/ethyl acetate 3:1 as eluant, yielding 7Q-[D-2-tert~-bu~oxycarbonylamino~2-(3-nitro-4-hydroxyphenyl)-acetylamino~3-methoxyceph-3-em-4-carbcxylic acid diphenylmethyl ester in the form o a colourless amorphous powder.
T~C ~ilica gel, identification with iodine): R~Oo 65 (diethyl ether~ethyl acetate 1:1).
d) ~hile stirring, a su~pension cooled to 0 of 30 g (0.14 mole~ o~ D-2-amino-2-(3-nitro-4-hydroxyphenyl)-acetic acid in 140 ml of water is adju~ted to pH 7 with 2N sodium hydroxide solution, then diluted with 280 ml o~ dioxan, and 15 g (0.14 mole) of sodium carb~nate and 33.8 g (0.15 mole) o dl-ter~.-butyldicarbona~e are added.
~fter a reaction period of 3 hour~ at room temperaturQ, the reaction mixture, cooled again to 0, i9 adjusted to pH 7 wnth 4N hydrochloric a~id and freed of the 901vent S
in a rotary e~apvrator. The oily residue i~ taken up in 1~ sodium bicarbonate solution (200 ml3 and extracted with diethyl ether (4 x 100 ml)~ The aqueous pha~e i9 then adiusted to pH 2 with 4~ hydrochloric acid a~d extracted with ethyl acetate (4x 1 50 ml ) . The combined organic pha~es are dried over sodium sulphate and freed of ~olvent under xeduced pressure, yielding D-2-tert.-butoxycarbonylamino-2-(3-nitro-4-hydroxyphenyl)-acetic acid.
TLC: (~ilica gel, indentification with ninhydrin3:
Rf-0.73 (sec.-butanol/acetic acid/water 67:10;23).
e) While stirring, 33.4 g (0.2 mo~e) of D-2-amino-2-(4-hydroxyphenyl)-acetic acid are added, in portions, to 40 % nitric acid (86 ml) cooled to 0. After 3 hours ~7~

_ 71 -at room temperature, the reaction mixture, cooled again to 0, is diluted with 40 ml of ice water and adjusted to pH 3.5 with 2~ sodium hydroxide solution (250 ml).
The resulting precipi~ate is then fil~ered off, washed with a small quantity of ice water and dried in a high ~acuum to constant weight. D-2-amino-2-~3-nitro-4-hydroxyphenyl~-acetic acid is obtained in the ~nm of a yellow powder which can ke used in the next reaction step without further purification.
TLC (~ilica yel, identification with ninhydrin): Rf~0.38 (sec.-~utanol/acetic acid/water 67:10:23).

In a manner analogous to Example 4a), 7~-[D-2-~mino-2-(3-nitro-4-hydroxyphenyl)-acetylamino]-3-metboxyceph~3~em-4-carboxylic acid is obtained by treating 3.4S g t5.0 mmole) o~ 7~-[~-2-tert. butoxycarbonylamino-2-t3-nitro-4-hydroxyphenyl)-acetylamino]-3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl e~ter with 17 ml of tri~luoroacetic acid and 3.5 ml o~ anisole in 17 ml of absolute methylene chloride.
Melting point: fro~ 160 with decomposition:
TLC (silica gel, developing with ninhydrin): R ~ ~31 (n-butanol/acetic acid/water 45:45:10~:
W (0.1N ~aHC03 solution~: 216 nm ( = 17100), 268 nm (~ = 7200), 343 nm (~ = 2280).

~mBa~

a~ 5 ml of cold trifluoroacetic acid are added to a solution cooled to 0 of 0~95 g (1.4 mmole) of 7~-ED-2-tert.-butoxycarbonylamino-2-(3,5-diamino-4-hydroxyphenyl)~acetylamino 3 3-methoxyceph-3-em-4-car~oxylic acid diphenylmethyl ester and 1.0 ml of anisole in 5 ml of absolute methylene chloride, and the mLXtUre i3 stirred at 0 under a nitrogen atmosphere for 45 minutas, and then 100 ml of diethyl ether are added. The beige precipitate is filterecl off, washed with a small q~lantity o~ diethyl ether, then poured into 10 ml of ice water and extracted with ethyl acetate (4 x 10 ml). The aqueous phase (pH~~) is adjusted to pH 5 with 1~ sodium hydroxide solution and then, at 0, 50 ml of isopropanol are addea dropwi~e. The resulting crude product, 7~-[D-2-amino-2-(3,5-diamino-4-hydroxyphenyl)-acetylamino]-3-mRthoxyceph-3-em 4-carhoxylic acid~is puriied on Amkerlite XAD-2 using water/isopropanol 88:12 as eluant.
TLC (silica gell developi~g with ninhydrin): Rf~0.05 (sec.-butanol/acetic acid/water 67:10:~3), W spectrum (in o.1N aqueous hydrochloric acid):
250 nm (~houlder), 270 nm ~7800).
The starting material may be prepared as ~ollow~:
b) A solution of 2.S g t3~ mmole) o 7~-[~-2-tert.-bu~oxycarbonylamino-2-(3,5-dinitro-4-hydroxyphenyl)-acetylamino]-3-methoxyceph-3-em-4-carboxylic acid di-phenylmethyl ester in ethyl acetate (50 ml) i~ hydrogenated in the presence of 2 g of palladium-carbon ~10 %) as catalyst. After the theoretical quantity of hydrogen has been absorbed, the reaction mixture is filtered over Celite and freed of solvent under reduced pressure. The residue is then purified on ~ilica gel using ethyl acetate as elua~t, yielding 7~-[D-2-tert.-butoxycarbonylamino-2-(3,5~diamino~4 hydroxyphenyl~-acetylamino]-3-methoxyceph-3~em-4-carboxylic acid diphenylmethyl ester in the form of an amorphous brown powder.
TLC (silica gel, developing with iodine): Rf~o.1o (ethyl acetate~.
c) To a solution cooled to -15 of 7.14 g (20 mmole) of D-2-tert~-butoxycarbonylamino-2-~3,5-dinitro-4-hydroxyphenyl)-acetic acid and 2.2 ml of ~-methylmorpholine in 200 ~1 o~ absolute methylene chloride there are added, _ 73 -under a nitrogen atmosphere, 2.6 ml of chloro~ormic acid isobutyl ester and, after one hour, 8.66 ~ (20 mmole) of 7~-~mino-3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl ester hydrochloride and 2.2 ml of ~-methyLmor~holine. Ater 3 hours at room temperature, the reaction mixture is diluted with ethyl acetate, washed twice with ice water and twice with ~aturated sodium chloride solution, dried over ~odium sulphate and freed of solvent in a rotary evaporator. The residue i~ purified on 3ilica gel using ethyl acetate a~ eluant, yielding 7~-~D-2-tertO-butoxycarbonylamino-2-(3,5-dinitro-4-hydroxyphenyl)-acetylamino]-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester in the form ofan amorphous yellow powder.
TLC (silica gel, identification with i~dine): R~Oa25 (ethyl acetate).
d) ~t 0~5~ ~6 ml O~ nitric acid are added dropwise, while 3tirring, to a 3u~pension o~ 33.44 g ~0.2 mole) of D-2-amino-2-(4-hydroxyphenyl)-acatic acid in 56 ml of concentrated sulphuric acid. After a reaction period of 2 hour~ at 20-25, the reaction mixture is diluted with 160 ml of ice water, adjusted to pH 7 with 2N sodium hydroxide solution and concentrated to approximately 200 ml under reduced pressure. After the addition of 400 ml o~ dioxan and 21.2 g of sodium carbonate, 48 g of di-tert.-butyl dicarbonate are added. After 3 hour~, the reaction mixture iY concentrated in order to remove ~he organic solvent, diluted again with water ~200 ml) and extracted with diethyl ether (2 x 200 ml). The aqueous phase is then adjustad to pH 2 with 4N hydro-chloric acid and extracted with ethyl acetate (4 x 200 ml).
Ater dryin~ the combined organic phases over sodium sulphate, the solvent is removed in a rotary evaporator.

The resulting D-2-tert.-butoxycarbonylamino-2-(3,5-dinitro-4-hydroxyphenyl)-acetic acid is a pale yellow crystallisate.
Melting point: 96-98:
TLC (silica gel, identification with iodine):
Rf-0.68 (~ec.-butanol/acetic acid/water 67~10:23).

Example 7 15 ml of cold trifluoroacetic acid are added to a solution cooled to 0 of 2.94 g ~4 mmole) of 7~-~D-2-tert.-butoxycarbonylamino-2~(3,5-dinitro-4-hydroxy-phenyl)-acetylamino]-3-methoxyceph-3~em-4-carboxylic- acid diphenylmethyl ester (Example 6c)) and 3 ml of anisole in 15 ml of absolute methylene chloride, stirred at 0 under a nitrogen atmosphere ~or 4S minutes and then 150 ml of diethyl ether are added. The resulting yellow precipitate is ~iltered off, washed with a small quant~ty o~ diethyl ether, then taken up in 20 ml of ice water.
The aqueous phase i~ adjusted to pH 4.5 with 2N sodium hydroxide solution, isopropanol (80 ml) is added drop-wise thereto and the mixture is stirred for approximately 30 minutes. After filtration, in order to remove the organic solvent, the 7~-[D-2-amino-2-~3,4-dinitro-4-hydroxyphenyl~-acetylamino]-3-metho~yceph-3 em-4-carboxylic acid. i3 suspended twice in a ~mall quantity of water and concentrated to dryness under reduced pressure.
TLC (silica gel, identification with ninhydrin):
R ~ .15 (sec.-butanol/acetic acid/water 67:10:23) [a3D = +1~5 f 1 (in 0.1~ aqueous hydrochloric acid, c = 0.17g %).

~7~

_ 75 -~m~2~

In a manner analogous to Example 6a~, 7~-~D 2-amino-2-(3,4-diamino-~-hydroxyphenyl)-acetyl~mino]
ceph-3-em-4-carboxylic acid i~ obtained b~ treating 1.7 g (2.6 mmole) of 7~-~D-2-tert.-butoxycarbonyl-~mino-2-(3,5-diamino 1-hydroxyphenyl)-acetylamino]-ceph-3-em-4-carb~xylic acid diphenylmethyl ester with 107 ml of an~ole and 8~5 ml o~ tri~luoroacetic acid in 8.5 ml of absolute methylene chloride according to the process described.
Melting p~int- ~rom 190 (decomposition), TLC (silica gel, identifica~ion with ninhydrin):
Rf~0.05 (sec.-butanol/acetic acid/water 67:10:23):
~a~D - ~14~ ~ ~ (in o~1~ aqueou~ hydrochloric acid, c = 0.181 %).

~,2a~

a) In a mannar analogous to Example 1a), 7~-~D-2 amino-2-(3-ethylsulphonylamlno-4-hydroxyphenyl)-acetylamino]-ceph-3-em-4-carboxylic acid is obtained in the form of a dihydrate ~y treating 2 g (2.77 mmole) o~
7~-[D-2-tert.-butoxycarbonylamino-2-(3-e~hylsulphonyl-amino-4-hydroxyphenyl)-acetylamino]-ceph-3-em-4-carboxylic acid diphenylmRthyl ester with 10 ml of trifluoroacetic acid and 2 ml of anisole in 10 ml of absolute methylene chloride.
Melting point: from 181 with decomposition.
The ~tarting material may be prepared as follows:
b) 3.664 g (10 mmole) of 7~-aminoceph -3-em-4-carboxyli~ acid diphenylmethyl ester and 3.743 g (10 mmole) of D-2-tert.-butoxycarkonylamino-2-(3-ethylsulphonylamino-4-hydroxyphenyl)-acetic acid are added to 80 ml of ~7~

tetrahydrofuran and the mixture is cooled to 0 5~
2.063 g ~10 mmole) of N,N'-dicyclohexylcarbodiimide dissolved in 20 ml of tetrahydrofuran are added drop-wise to the yellow solution~ The mixture is stirred for 1 hour at 0-5 and for 3 hours at room temperatureO
The yellow suspension i9 iltered with suction and washed with THF. The solvent i9 removed at 30 in vacuo, yielding a yellow foamy residue to which 500 ml of ethyl acetate are added~ The organic phase is then washe~ 4 times using 60 ml of ice water each time and shaken once with 50 ml of saturated sodium chloride ~olution. The ethyl acetate pha~e is dried over sodium sulpha~e and filtered. The solver~t is removed at 30 in vacuo, yielding 7~-~D-2-tert.-butoxycar~onylamino-2-(3rethyl~ulphonylamino-4-hydroxyphenyl)-acetylamino]-ceph~3-em-4-carboxylic acid diphenylme~hyl ester in ~he orm of a yellow foam~ residue.
c) 2.823 g t10 mmole) of D-2-tert.-butoxycarbonyl-a~ino-2-(3-amino-4-hydroxyphenyl)-acetic acid are added to 56 ml of mRthylane chloride. 5064 ml to.o2 mole) of 87 % strength ~,0 bis-~trimethylsilyl~-acetamide are added dropwi~e thereto over a period of 10 minutes and the mixture is qtirred at room temperature for ~ hour.
1~61 ml (0.02 mole) of pyridine are then addedand the mixture is cooled to 0-5~. 1.89 ml (0~02 mole) of ethane sulphochloride are added and the mixture is maintained at 0~ for ~ hour and then, after heating, at room temperature for 2 hour ~ The solvent is eva~orated off, ethyl acetate i~ added to the reAidue and the mixture is then washed twice with dilute hydrochloric acid solution. The ethyl acetate pha~e is extracted several times with dilute 5 ~ strength s~dium bicarbonate solution.
The aqueous phases are combined and adjusted to pH~ with approximately-25 ml of 2~ hydrochloric acid~ The product ~3L7~

that is thus precipitated out i5 extracted several times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. D-2-tert.-butoxycarbonylamino-2-(3-ethylsulphonylamino-4-hydroxyphenyl)-acetic acid is obtained in the form of a pinkish-beige foam.
TLC (silica gel, identification with iodine):
Rf 0078 (sec.-butanol/acetic acid/water 67:10:23).
Example 10 a) ~n a manner analogous to Ex~mple la), 7~-~D-2-amino-2-(3-ethylsulphonylamino-4-hydroxyphenyl)-ac~tylamino]-3-chloroceph-3-em-4-carboxylic acid is obtained in the form o~ a 1.5 hydrate by treating 3.4 g (4.5 mmole) of 7~-CD-2-tert.-butoxycarbonylamino-2-(3-ethylsulphonyl2mino-4-hydroxyphenyl)-acetylamino]-3-chloroceph-3-em-4-carboxylic acid diphenylmethyl ester with 17 ml of trifluoroacetic acid and 3~4 ml of anisole in 17 ml of absolute methylene chloride according to the proces~ described.
Melting point: from 165 with decompo~ition.
TLC (silica gel, developing with ninhydrin):
R~0.34 ~ystem : sec.-butanol/acetic acid/
water 67:10:23), ~]D = +95 ~ 1 (O,lN aqueous hydrochloric acid, c = 1.163 %).
b) In a manner analogous to Example ~b), 7~-~D-2-tert.-butoxycarbonylamino-2-~3-ethylsulphonyl~mino-4-hydroxyphenyl)-acetylamino~-3-chloroceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained from 3.74 g (10 mmole) of D-2-tert.-butoxycarbonylamino-2~
~3-ethylsulphonylamino-4-hydroxyphenyl~-acetic acid and 4.0 g (10 mmole) of 7~-amino-3-chloroceph-3-em-4-carbo~ylic acid diphenylmethyl ester in the presence of 2.06 g (10 mmole) of ~,~'-dicyclohe:~ylcarbodiimide in tetrahydrofuran according to the process described.

~,2a~

a) In a manner analogous to Example ~a), 7~-~D-2-amino-2-(3-ethylsulphonylamino-~-hydroxyphenyl)-acetylamino~-3-methoxyceph-3-em-4-car~oxylic acid is obkained in the form of a monohydrate by treating 2074 g (3.6 mmole) of 7~D-2-~er~-butoxycarhonylamino-2-(3-ethylsulphonylamino-4-hydroxyphenyl~-acetylamino]-3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl ester with 14 ml of trifluoroacetic acid and 2.7 ml o~ anisole in 14 ml o absolute methylene ch~oride according ~o the process described.
MRlting point: from 190~ with decompo~ition, TLC ~silica gel, developing with ninhydrin: R~Vo.32 (system: ec.-butanol/acetic acid/water 67:10:23);
W ~pactrum (in 0.1N aqueou~ hydrochloric acid):
279 1~111 ( = 825Q ), ~]D = +138 + 1 (0.1N aqueous hydrochloric acid, c = 0.967 %).
b) In a manner analoyous to Example 9b), 7~-~D-2-tert.-butoxycarbonylamino-2.-(3-ethylsulphonylamino-4-hydroxyphenyl) acetylamino}3-methoxyceph-3-em-4-carboxylic acid diphenylme~hyl ester is obtained from 2~28 g (6.1 mmole) of D-2-tert.-butoxycarbonylamino-2-(3-ethylsulphonylamino-4-hydroxyphenyl)acetic acid and 2.12 g (6.1 mmole) of 7~-amino-3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl ester in the presence of 1.26 g (6.1 mmole~ of N,N'-dicyclohexylcarkcdiimide in tetrahydr~furan according to the pr~cess decribed.

TLC ( ~;ilica gel, identification with iodi.ne):
R~O. 34 ~ diethyl ether/ethyl acetate 1:1 ) .

~e~

a) In a m~nner analogous to Examp~.e la ), 7~-~D-2 amino- 2- ~ 3-acetylamino-4-hydrox~henyL )-acetylamino]-3-methoxyceph-3-em-4-~ar~oxylic acid is o~tained in the form of a monohydrate by treating 1. 32 g ( 1. 88 mmole) of 7~-~D-2-tert.-butoxycarbonylamino-2-(3-acetylamino-4-hydroxyphenyl)-acetylamino]-3-methoxyceph -3~em-4-carboxylic acid diphenylmethyl ester with 6.60 ml of trifluoroacetic acid and 1.32 ml of ani~ole in 6.60 ml of a~solute methylene chloride.
~elting point: from 149 with decomposition:
TLC (sili~a gel, identification with ninhydrin):
0~22 (~ec.-butan~l/acatia acid~water 67:10:23~, ~]D w ~156 + 1 (O~lN aqueous hydrochloric acid, c = O.90C~ %).
The ~tarting material may ~e prepared as follows:
b) 2.38 g (5.5 mmole) of the hydrochloride of 7~
amino 3-methoxyceph-3-em-4-carboxylic acid diphenyl-methyl e~ter, la78 g (5.5 mmole) of D~2-tert.-butoxy-carbonylamino-2-(3-acetylamino-4-hydroxyphenyl)-acetic acid and 0.64 ml (5.5 mmole) of 2,6-lutidine are ad~ed to 80 ml of tetrahydrofuran and the mixture is cooled to 0. 1.13 g (5.5 mmole) of ~,~'-dicyclohexylcarbodiimide di~solved in 10 ml of tetrahydrofuran are added dropwise to the white suspen~ion. The mixture is stirred at room temperature for 1 hour. The beige suspension is filter2d with ~uction and washed with THF. The solvent is removed at 30 in vacuo, yielding a yellow foamy residue to which 250 ml of ethyl acetate are added. The mixture is then shaken ~everal times with 25 ml of 5 % ~trength sodium bicarbonate solution and ~uffer so}ution ~pH = 2.06).

'Z~
- ~o -The ethyl acetate pha e is washed several times with saturated sodium chloride solution, dried over sodium sulphate and filtered off. The solvent is removed at 30~ ~n vacuo, yielding 7~-~D-2-tert.-butoxycarbonylamino-2-(3-acetylamino-4-hydroxyphenyl)-acetylamino~-3-methoxyceph-3-em-4-carboxylic acid d:iphenylmethyl ester.
TLC (silica gel, identiication with iodine):
Rf 0.39 (ethyl acetate).
c~ 4.23 g ~15 mmole) of D-2-tert.-butoxycarbonyl-amino-2~(3-amino-4-hydroxyphenyl)-acetic acid are added to 85 ml of methylene chloride. 7.35 ml (30 mmole) of 87 % strength N,O-bis-(trimethylsilyl)-acetamide are added dropwice thereto and the mixture i~ stirred at room temperature for ~ hour. 2.42 ml ~30 mmol~) of pyridine are then added and the dark yellow solution is cooled to 0-5. 2.13 ml (30 mmo~e) of acetyl chloride are added thereto and the mixture i~ maintained at 0 for ~ hour and then, a~ter heatin~, at room temperature for 2 hours. The solvent i~ evaporated off, ethyl ac~tatc i9 added to the residue and the mixture is wa~hed twice with dilute hydrochloric acid solution. The organic phase is extracted several times with 5 % strength sodium bicarbonate ~olution. The aqueous phases are combined and adjusted to p~2 with approximately 30 ml of 2~
hydrochloric acid~ Ethyl acetate is added to the aqueous phase. The organic pha~e is then washed with saturated sodium chloride solution, dried with sodium sulphate and concentrated. D-2-tert.--butoxycarbonylamino 2-~3-acetyl-amino-4-hydroxyphenyl)-acetic acid is obtained in the form of a yellow powder.
TLC (silica gel, identification with iodine):
R~o~ 75 (sec.-butanol/acetic acidJwater-67:10:23).

~ ~ 7 Examole .13 a) 20 ml of cold txi~luoroacetic acid are added to a solution cooled to 0 of 4.1 g (4.9 mmole) of 7~-[D-2-tert.-butoxycar~onylamino- 2- ~ 3, 5-bis- (methylsulphonyl-amino)-4-hydroxyphenyl)-acetylamino~-ceph-3-em-4-carboxylic acid diphenylmethyl ester and 4.1 ml of anisole in 20 ml of absolute methylene chloride, the mixture is stirred at 0 under a nitrogen atmo~phere for 1 hour and then,at 0~, 300 ml of diethyl ether are added thereto.
The beige-coloured precipita~e is filtered off, washed with a small quantity of diethyl ether and dried under reduced pre~sure. The re~ulting acetic acid ~alt o 7~- rD- 2-tert.-butoxycarbonylamino-2-(3,5-bi~-(methyl-~ulphonylamino)-4-hydroxyphenyl)-acetylamino~-ceph-3-em-4-carboxylic acid is di~solved in 30 ml of acet:ic acid and extracted with 4 x 15 ml of ethyl acetate. ~le acidic aqueous phase (approximat~ly pH 2) i~ adju~ted to p~ 4.8 by the dropwise addition of 2~ sodium hy~roxide ~olution, concentrated to approximately 20 ml i~ a rotary evaporator a~d, at 0, 60 ml o~ iqopropanol are added. The precipitate formed i9 filtered of and wa~hed with 20 ml of isopropanol/water (1:4) and 20 ml of isopropanol. The crude product i~ then purified by column chromatography (silica gel: Opti-UPC12 by Antec) using water/acetonitrile (19:1) as eluant, and, after the removal of the solvent and drying, (16 hours at room temperature and 0.05 torr), 7~-~D-2-amino-2-~3,5-bis-(methyl~ulphonylamino)-4-hydroxyph2nyl)-acetylamino]-3-metho~yceph-3-em-4-carboxylic acid is obtained in the form of a dihydrate.
Melting point: from 150 (with decomposition):
$LC (~ilica gel, developing with ninhydrin) R~: approximately 0.18 (system: sec.-butanol/acetic acid~water 67:10:23), ~7~2~

W ~pectrum (in O.lN aqueous hydrochloric acid):
281 nm (E = 8120), ~a]D ~ +107 - 1 - ( in 0. lN aqueou~ hydrochloric acid, c = 1~054 %).
The 3tarting material may be obtained a~ follow~:
b) A solution of 2.476 g ~12 mmole) of ~
dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran is added dropwise to a suspension cooled to 0-5 of 4. 76 g (12 mmole~ of 7~-amino-3-methoxyceph-3-em-4-car~oxylic acid diphenylmethyl ester and 5.44 ~ (12 mMole) of D-2-tert~-butoxycarbonylamino-2-~3,5~bis-lmethylsulphonyl-amino)-4-hydroxyphenyl}-acetic acid in 50 ml of tetra-hydrofuran. After a reaction period of l hour at 0-5 and 3 hours at room temperature, the precipitate formed is filtered off from the ~,N'-dicyclohexylurea and waqhed with a small ~uantity of tetrahydro~uran. After removing th~ ~olvent, the yellow residue is dis~olved in 500 ~l of ethyl acetate, and washed 4 times with 50 ml of 5 % strength sodium bicarbonate solution (pH = 2) and 4 times with ~aturated sodium ~hloride solution.
After drying the organic phase over ~odium sulphate and removing the solvent in a rotary evaporator, the crude product i8 purified by column chromatography (silica gel) using diethyl ether/ethyl acetate (2:1) as eluant, yielding 7~-[D-2-tert.-butoxycarbonylamino-2-(3,5-bis-(methylsulphonylamino)-4-hydroxyphenyl)-acetylamino~-3-methoxyceph-3-em-4-carboxylic acid diphenylmethyl eqter .
TLC (silica gel, identification with iodine):
Rf-0.28 (ethyl acetate).
c) 6.7 ml (27.3 mmole)-of ~,0-bis-(trimethylsilyl)-acetamide are added, with the exclusion of moisture and while stirring, to a solution of 5.4 g (18.2 mmole) of D-2-tert.-butoxycarbonylamino-2-(3,5-diamino-4-hydroxy-phenyl)-acetic acid in lO0 ml of abso}ute methylene chloride and the mixture i9 allowed to react for 1 hour~
After the addition of 4.4 ml of pyridine and 4.24 ml (54.6 mmole) of methane ~ulphochloricle to the solution cooled to 0, the reaction mixture i~ stirred for 30 minutes at 0 and for 3 hours at room temperature. The reaction mixture is then diluted with 2~0 ml of ethyl acetate and washed 3 time~ with 30 ml of ice water and 3 times wit~ saturated sodium chloride solution.
~he organic phase i~ dried over sodil~m ~ulphate and freed of solvent in a rotary ~vaporator. The crude product is purified by col~mn chromato~raphy ~ silica gel) using diethyl eth~r/ethyl acetate 9 :1 a~ eluant, yielding D-2-tert.-butoxycarbonylamino-2-~3,5-bi 9-~(methylsulphonylamino-4-hydroxyphenyl)~acetic acid in the form of an amorphous yellow powder.
TLC (silica gel, identification with ninhydrin), R~ 0.~8 (~ec.-butanol/acetic acid/water 67:10:23~, ~a]D ~ 83 ~ 1 ~ab301ute ethanol, c - 0.60 %).
d) A solution of 11.5 g (32.2 ~mole~ of D-2-tert~
butoxycarbonylamino-2-(3,$-dinitro-4-hydroxyphenyl)-acetic acid in 200 ml of methanol i3 hydrogenated in the pre3ence o~ 1.5 g of palladium-carbon (10 %) as catalyst.
After the theoretical quantity of hydrogen has been ab~or~ed, the reaction mixture is filtered over Celite and freed of solvent in a rotary evaporator, yielding D 2-tart .-butoxycarbonylamino-2 (3,5-diami~o-4-hydroxyphenyl~-acetic acid which i~ used in reaction tep C) without further purification.
TLC (silica gel, identification with ninhydrin):
Rf 0.50 (sec.-butanol/acetic acid/water 67:10:23).

Exam~le 14 a) In a manner analogous to Example 13a), 7~-[D-2-amino-2-~3,5-bis-methylsulphonylamino-4-hydroxyphenyl)--- 84 ~

acetylamino]-ceph-3-em-4-carboxylic acid is obtained in the form o~ a dihydrate by treating 2.3 g (2.~7 mmole) of 7~-[D 2-tert.-butoxycarbonylamino-2-(3,5-bis-(methylsulphonylamino-4~hydroxyphe~1yl)~acetylamino]-ceph-3-em-4-carboxylic acid diphenylmethyl ester with

11.5 ml of trifluoroacetic acid and 2.3 ml of anisole in 11.5 ml of absolute methylene chloride.
Melting point: from 150 (with decomposition).
~LC ~silica gel, identification with ninhydrin) Rf 0~13 (sec.-butanol/acetic acid~water 67:10:23), ~]D = +91 + 1 (001N aqueous hydrochloric acid, c = 0.89 %).
The starting matexial may ~e obtained as follows:
b) In a manner analogous to Example 13b), 7~-~D-2-tert.-butoxycarbonylamino-2-(3,5-bis-(methyl~ulphonyl-amino)-4-hydroxyphenyl)-acetylamino]-ceph-3-em-4-carboxylic acid diphenylmethyl ester i~ obtained from 4.532g~10 mmolo) o D-2-~ert.-b~toxycarbonylamino-2-(3,5 bi3-(methylsulphonylamino)~4-hydroxyphenyl 3 -acetic acid and 3.654 g (10 mmole) of 7~-aminoceph-3-em-4-carboxylic acid dip~enylmethyl ester in the presence of 30063 g (10 mmole) of ~ dicyclohexylcarbodiimide in tetra-hydrofuran according to the process described.

a) In a manner analogous to Example 13a), 7~- CD 2 amino-2-(3,5-bis-(methylsulphonylamino)-4-hydroxyphenyl)-acetylamino]-3-chloroceph-3-em-4-carboxylic acid is obtained in the form of a dihydrate by treating 4.47 g (5.35 mmole) of 7~-[D-2-tert.-butoxycarbonylamino-2-(3,5-bis-(methylsulphonylamino)-4-hydroxyphenyl)-acetylamino]-3-chloroceph~3-em-4-carboxylic acid diphenyl-methyl ester with 20 ml of trifluoroacetic acid ard 4 ml .

7~

of anisole in 20 ml of absolute methylene chloride according to the process described.
Melting point: from 150 with decomposition;
TLC (silica gel, developing with ninhydrin) R~0.23 (system: sec.-butanol/acetic acid/water 67:~0:23), W spectrum (in 0.1~ aqueous hydrochloric acid):
270 nm ~ - 7600), L~D = +62 ~ ~ (0.1N aqueous hydrochloric acid, c = O.g80 %).
b~ In a manner analogous to Example 13b), 7~-[D-2~tert.-butoxycarbonylamino-2-(3,5-bis-~methylsulphonyl-amino-4-hydroxyphenyl)-acetylamino~-3-chloroceph-3-~m-4-carboxylic acid diphenylmethyl ester is o~tained from 4.53 g (10 mmole) o~ D-2-tert.-butoxycarbonylamino-2`~
C3,5-bis-(methyl~lphonylamino)-4-hydroxyphenyl]-ac~tic acid and 4.0 g (10 mmole~ of 7~-amino-3-chloroceph-3iem-4-carboxylic acid diphenylmethyl ester in the presence of 2.06 g (10 mmole) of N,N'-dicyclohexylcarbodiimide in tetrahydrofuran a~cording to the process described.
TLC (silica gel, identi~ica ion with iodine):
Rf 0.43 (diethyl ether/~thyl acetate Example 16 While ~tirring and checking the pH value, a suspension of 4.75 g of 7~-[D-2-amino-2-(3-methyl-sulphonylamino-4-hydroxyphenyl)-acetylamino]-3-methoxyceph -3-em 4-carkoxylic acid in 50 ml of water and 2 ml of alcohol i~ slowly made into a solution at a pH
value o~ 1PSS than 7.6 with a total of approximately 5 ml of 2N sodium hydroxide solutionO The solution is freed of the small quantity of residual sub~tances by filtxation and, after lyophilising, yields 4.9 g of the sodium ~alt o 7~-[D-2-amino-2-(3-methylsulphonyl-amino-4-hydroxyphenyl)-acetylamino]-3-methoxyceph-3-em-4-carboxylic acid.
W ~pectrum in OolN HCl: 278 nm ( = 7600);
TLC: Rf 0.46.

~a~

In a manner analogous to Example 16 it i~ possiblP
to prepare:
the sodium ~alt of 7~-~D-2-amino-2-~3-methylsulphonyl-amino-4-hydroxyphenyl) acetylamino]-3-chloroceph-3-em-4-carboxylic acid, W spectrum in O.lN HCl: 235 nm ~shoulder3, 270 ~n (c = 85~0), TLC: R ~ 0.16:
the sodium salt of 7~-~D-2-amino-2-(3-methylsulphonyl-amino-4-hydroxyphenyl)-acetylamin~]-ceph-3-em-4-carbaxylic acid, W ~pectr~m in 0.1~ HCl: 235 nm ~ = 11400), TLC: Rf 0.19:
the sodium salt o~ 7~-~D-2-amino-2-(3-amino 4-hydroxy-phenyl)-acetylamino]-3-methoxycep~-3-em-4-carboxylic acid:
the ~odium salt of 7~-~D-2-amino-2-(3,5-diami~o-4-hydroxyphenyl)-acetylamino]-3-methoxyceph-3-em-4-carboxylic acid, W ~pectrum in O.lN HCl: 270 nm S = 7600), T~C: Rf 0.05;
TLC: silica gel, developing with ninhydrin, system:
sec.-butanol/acetic acid/water 67:10:23.

Exam~le 18 The ollowing compounds may be p:repared analogously to Examples 1 to 16:
7~-CD-2-amino-2-(3,5-bis-(ethylsulphonylamino) 1-hydroxyphenyl)-acetylamino]-ceph-3-em-4-carboxylic acid, W spectrum in O.lN HC1: 209 nm (~ = 3900), 272 nm (shoulder), TLC: Rf-0.13 7~-[D-2-amino-2-(3,5-bi~-(ethylsulphonylamino)~4-hydroxyphenyl)~acPtylamino]-3-methoxyceph-3-em-4~
carbo~ylic acid, W ~pectrum in 0.1~ HC1:281 nm (~ = 8100), TLC: Rf~0.18 7~-~D-2-amino-2-(3,5-bis-(athyl~ulphonylamino)-4-hydroxy-~henyl)-acetylamins]-3-chloroceph-3-em-4-carb~ylic acid, W spectrum in O~N ~C~: 21~ nm ~ = 37000), 270 Nm ~ =
7500) :
7~-[D-2-amino-2-(3-acetylamino 4-hydroxyphenyl)-acetyl-amino~-ceph-3-em-4-carboxylic acid, W spectrum in 0.1N HC~: 275 nm (~ = 6900), 7~-[D2-amino-2-[3-formylamino-4-hydroxyphenyl~
acetylamin~]-3-methoxyceph-3-em-4-carboxylic acid, W ~pectrum in o.1N HC1: 279 nm ~ = 7600):
7~-[D-2-amino-2-(3-formylamino-4-hydroxyphenyl)~acetyl-amino]-3-chloroceph-3 em-4-carboxylic acid, W spectrum in 0.1~ HC1: 270 nm (~ = 8100), 7~-~D-2-amino-2-t3-formylamino-4-hydroxyphenyl~-acetyl-amino]-ceph-3-em 4-carboxylic acid, W spectr~m in 0.1N HC1: 232 nm (~ = 11500), 270 nm (shou~der), r ~ 88 --7~-~D-2-amino-2-~3-(3-methylureido)-4-hydroxyphenyl]-acetylamino~-3-methoxyceph-3-em-4-carboxylic acid, W spectrum in O.lN HCl: 244 nm (~ - 8500~ 275 nm (shoulder);
7~D-2-amino-2-~3-(3-methylureido)-4-hydroxyphenyl~-acetylamino]-3-chloroceph-3-em-4-carboxylic acid;
7~D-2-amino-2-~3-(3-methylthioureido)-4-hydroxyphenyl3-acetylamino}-ceph-3-em-4-carboxylic acid, 7~-~D-2-amino-2-~3-(3-methylthioureido)-4-hydroxyphenyl]-acetylamino]-3-methoxyceph-3-em-4-car~oxylic acid, 7~-~D-2-amino-2-~3-(3-methylthioureido)-4-hydroxyphenyl]-acetylamino]-3-chloroceph-3-em-4-carboxylic acid and salts thereof, for example the sodium salt~, TLC: thin-layer chromatography on silica gel prepared plates, sy~tem: sec.-butanol/acetic acid/water 67:10:23.

Ex~me~

~ ry ampoule~ or phials containing 0.5 g of the internal salt of 7~-~D~2-amino-2-~3-methyl~ulphonyl~mino-4-hydroxyphenyl)-acetylamino]-3 methoxyceph-3-em-4-carboxylic acid are prepared as follows:
Com~osition (for 1 ampoule or phial~
internal salt of 7~-~D-2-amino-2-(3-methylsulphonylamino-4-hydroxyphenyl)-acetylamino~-3-methoxy_ ceph-3-em-4-carboxylic acid 0.5 g mannitol ~.05 g A sterile aqueous solution of the internal salt of 7~-~D-2-amino-2-(3-methylsulphonylamino-4-hydroxy-phenyl)-acetylamino]-3-methoxyceph-3-em-4-carboxylic acid and the mannitol in 5 ml ampoules or 5 ml phials i5 freeze dried under aseptic conditions and the ampoules or phials are sealed and tested.

89 _ ~L'7~

Example 20 Cap~ules containing 0.~5 g of the internal ~alt of 7~-~D-2-amino-2-~3-methylsulphonylamino-4-hydroxy-phenyl)-acetylamino]-3-methoxyceph-3 em-4-carboxylic acid are prepared as follows:
om~osition (for 1000 cap~ules) internal salt of 7~-[D-2-~mino~
2-(3-methylsulphonylamino-4-hydroxyphenyl)-acetylamino]-3-methoxyceph-3-em-4-carboxylic acid 250.000 g maize starch 50.000 g polyvinylpyrrolidona 15.000 g magnesium stearate 5.000 g ethanol ~. 8 .
The internal salt of 7~-[D-2-amino-2-(3-methyl-sulphonylamino-4-hydroxyphenyl)-acetylamino]-3~
methoxyceph-3-em-4-car~oxylic acid and the maize ~tarch are mixed together and moi~tened with a aolution of the polyvinylpyrrolidone in 50 g o ethanol. The moist ma~s is pressed through a sieve having a mesh width of 3 mm and dried at 45. The dry granulate is ~orced through a sieve having a mesh width of 1 mm and mixed with 5 g of magne~ium stearate. The mixture i~ introduced in 0.320 ~ portions into size 0 dry-filled capsule~.

Claims (14)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Process for the manufacture of compounds of the formula ( I ) in which the index n represents 0 or 1, R represents hydrogen or an acyl group, R0 represents hydrogen or lower alkyl, R1 represents hydrogen or a group of the partial formula (R)(R0)N-, R2 represents carboxyl or protected carboxyl, and R3 represents hydrogen, halogen having an atomic number of up to 35 or lower alkoxy, and hydrates and salts of compounds of the formula 1, characterized in that a) in a compound of the formula (II) in which the index n represents 0 or 1 and the 7.beta.-amino group is optionally protected by a group allowing acyla-tion, and R2 and R3 have the meanings given under formula I, the 7.beta.-amino group is acylated by reaction with an acylating agent that introduces the acyl radical of a carboxylic acid of the formula (III), in which R, R0 and R1 have the meanings given under formula I and in which the hydroxy group on the phenyl ring and/or the amino group(s) are optionally in protec-ted form and other functional groups present are optionally protected, or b) a 2-cephem compound of the formula ( IV ), in which R, R0, R1, R2 and R3 have the meanings given under formula I and in which the hydroxy group on the phenyl ring and/or the amino group(s) are optionally in protected form and other functional groups present are optionally protected, is isomerised by treatment with a weakly basic agent or by oxidising in the 1-position and reducing the 1-oxide of the 3-cephem compound or c) in a compound of the formula ( V ), in which the index n represents 0 or 1 and R1 represents nitro or the radical R1 which has the meanings given under formula I, R2 and R3 have the meanings given under formula I and in which the hydroxy group on the phenyl ring and/or the amino group(s) are optionally in protected form and other functional groups present are optionally protected, The nitro group(s) on the phenyl ring is(are) reduced by reaction with a customary reducing agent that converts nitro groups into amino groups, in the presence of a solvent and when a compound is required wherein R is an acyl group, the free amino group on the phenyl ring wherein R and R0 is hydrogen is acylated with an acylating agent that introduces the acyl group R, and/or, when a compound is required, wherein one or more carboxyl groups are present in esterified form that can be split under physiological conditions, esterifying in a compound obtained the free carboxyl group or a functional derivative thereof, by treating with a corres-ponding alcohol, or, by reactinq a salt of the carboxyl group with a reactive functional derivative of this alcohol, and/or, when a pure isomer is required, separating a mixture of isomers obtained into the individual isomers, and/or, when a salt is required, converting a free compound obtained into a salt or a salt obtained into a different salt, and/or, when a free compound is required, converting a salt obtained into the free com-pound.

2. Process for the manufacture of compounds of the formula I according to claim 1, in which the index n represents 0, R represents hydrogen or lower alkanoyl, halo-lower alkanoyl;
benzoyl, benzoyl substituted by haloqen, lower alkoxy or nitro; tert.-lower alkoxycarbonyl, arylmethoxycarbonyl having one or two phenyl radicals or phenyl radicals mono- or polysubstituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or nitro;
aroylmethoxycarbonyl, in which the aroyl group is benzoyl or benzoyl substituted by halogen, 2-halo-lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, thio-carbamoyl, N-lower alkylthiocarbamoyl;
N,N-di-lower alkylthiocarbamoyl. lower alkylsulphonyl, arylsulphonyl, sulpha-moyl, N-lower alkylsulphamoyl; or N,N-di-lower alkylsulphamoyl, R0 represents hydrogen or lower alkyl, R1 represents hydrogen or a group of the partial formula (R)(R0)N-, in which R
and R0 have the meanings given above, R2 represents carboxyl or lower alkanoyl-methoxycaxbonyl, and R3 represents hydrogen, fluorine, chlorine, bromine, methoxy, ethoxy, isopropoxy or tert.-butoxy, and hydrates and pharmaceutically acceptable salts of compounds of the formula I.

3. Process for the manufacture of compounds of the formula I according to claim 2, in which the index n represents 0, R represents hydrogen; formyl, acetyl or propionyl; 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl; tert.-butoxycarbonyl; benzyl-oxycarbonyl, 4-nitrobenzyloxycarbonyl;
benzhydryloxycarbonyl or bis-(4-methoxy-phenyl)-methoxycarbonyl; phenacyloxy-carbonyl; 2,2,2-trichloro-, 2-chloro-, 2-bromo- or 2-iodoethoxycarbonyl; carba-moyl; N-methylcarbamoyl; N,N-dimethyl-carbamoyl; thiocarbamoyl; N-methylthio-carbamoyl; N,N-dimethylthiocarbamoyl;
methylsulphonyl or ethylsulphonyl; phenyl-sulphonyl or tolylsulphonyl; sulphamoyl;
N-methylsulphamoyl; N,N-dimethylsulphamoyl, R0 represents hydrogen, methyl or ethyl, R1 represents hydrogen or a group of the partial formula (R)(R0)N-, in which R and R0 have the meanings given above.
R2 represents carboxyl, and R3 represents hydrogen, chlorine or methoxy, and hydrates and pharmaceutically acceptable salts of such compounds of the formula I.

4. Process for the manufacture of compounds of the formula I according to claim 3, in which the index n represents 0, R represents hydrogen, acetyl, methyl-sulfonyl or ethylsulphonyl, R0 represents hydrogen, R1 represents hydrogen or a group of the partial formula (R)(Ro)N- in which R and R0 have the meanings given above, R2 represents carboxyl, and R3 represents hydrogen, chlorine or methoxy, and pharmaceutically acceptable salts of compounds of the formula I.

5. Process for the manufacture of compounds of the formula I according to claim 4, in which the index n represents 0, R represents hydrogen, acetyl, methyl-sulphonyl or ethylsulphonyl, R0 represents hydrogen, R1 represents hydrogen or a group of the partial formula (R)(Ro)N- in which R
and R0 have the meanings given above, R2 represents carboxyl, and represents hydrogen, chlorine or methoxy, and in which the two groups of the partial formula (R)(R0)N- take up the 3- and 5-positions (meta) and the hydroxy group takes up the 4-position (para) on the phenyl ring, and pharmaceutically acceptable salts of such compounds of the formula I.

6. Process for the manufacture of 7.beta.-[D-2-amino-2-(3-methylsulphonylamino-4-hydroxyphenyl)-acetylamino]-3-methoxyceph-3-em-4-carboxylic acid, according toclaim 5, characterised in that the 7.beta.-amino-3-methoxy-ceph-3-em-4-carboxylic acid wherein 4-carboxy is protected, is acyl-ated with D-2-amino-2-(3-methylsulfonylamino-4-hydroxy-phenyl)-acetic acid, wherein D-2-amino is protected, and the protected functional groups are converted into the free functional group.

7. Process for the manufacture of 7.beta.-[D 2-amino-2-(3-methylsulphonylamino-4-hydroxyphenyl)-acetylamino]-ceph-3-em-4-carboxylic acid, according to claim 5, characterised in that the 7.beta.-amino-ceph-3-em-4-carboxylic acid wherein 4-carboxy is protected, is acylated with D-2-amino-2-(3-methylsulfonylamino-4-hydroxyphenyl)-acetic acid wherein D-2-amino is protected, and the protected functional groups are converted into the free functional groups.

8. Process for the manufacture of 7.beta.[D-2-amino-2-(3-methylsulphonylamino 4-hydroxyphenyl)-acetylamino]-3-chloro-ceph-3-em-4-carboxylic acid, according to clalm 5, charac-terised in that the 7.beta.-amino-3-chloro-ceph-3-em-4-carb ic acid wherein 4-carboxy is protected, is acylated with D-2-amino-2-(3-methylsulfonylamino-4-hydroxyphenyl)-acetic acid, wherein D-2-amino is protected, and the protected functional groups are converted into the free functional groups.

9. Process for the manufacture of 7.beta.-[D-2-amino-2-(3-amino-4-hydroxyphenyl)-acetylamino]-3-methoxyceph-3-em-4-carbox-ylic acid, according to claim 5, characterised in that 7.beta.-[D-2-amino-2-(3-nitro-4-hydroxyphenyl)-acetylamino]-3-methoxy-ceph-3-em-4-carboxylic acid wherein D-2-amino and 4-carboxy are protected is reduced by hydrogen in the pres-ence of a catalyst and the protected functional groups converted into the free functional groups.

10. Process for the manufacture of 7.beta.-[D-2-amino-2-(3-eth-ylsulphonylamino-4-hydroxyphenyl)-acetylamino]-ceph-3-em-4-carboxylic acid, according to claim 5, characterised in that the 7.beta.-amino-3-cephem-4-carboxylic acid wherein 4-carboxy is protected, is acylated with D-2-amino-2-(3-ethylsulfonylamino-4-hydroxyphenyl)-acetic acid, wherein D-2-amino is protected, and the protected functional groups are converted into the free functional groups.

11. Process for the manufacture of 7.beta.-[D-2-amino-2-(3-eth-ylsulphonylamino-4-hydroxyphenyl)-acetylamino]-3-methoxy-ceph-3-em-4-carboxylic acid, according to claim 5, characterised in that the 7.beta.-amino-3-methoxy-ceph-3-em-4-carboxylic acid wherein 4-carboxy-is protected, is acylated with D-2-amino-2-(3-ethylsulfonylamino-4-hydroxyphenyl)-acetic acid, wherein D-2-amino is protected, and the pro-tected functional groups are converted into the free func-tional groups.

12. Process for the manufacture of 7.beta.-[D-2-amino-2-(3-eth-ylsulphonylamino-4-hydroxyphenyl)-acetylamino]-3-chloro-ceph-3-em-4-carboxylic acid, according to claim 5, characterised in that the 7.beta.-amino-3-chloro-ceph-3-em-4-carboxylic acid wherein 4-carboxy is protected, is acylated with D-2-amino-2-(3-ethylsulfonylamino-4-hydroxyphenyl)-acetic acid, wherein D-2-amino is protected, and the pro-tected functional groups are converted into the free func-tional groups.

13. Process for the manufacture of 7.beta.-[D-2-amino-2-(3-ace-tylamino-4-hydroxyphenyl)-acetylamino]-3-methoxyceph-3-em-4-carboxylic acid, according to claim 5, characterised in that the 7.beta.-amino-3-methoxy-ceph-3-em-4-carboxylic acid where-in 4-carboxy is protected, is acylated with D-2-amino-2-(3-acetylamino-4-hydroxy-phenyl)-acetic acid, wherein D-2-amino is protected, and the protected functional groups are converted into the free functional groups.

14. Compounds of the formula (I) in which the index n represents 0 or 1, R represents hydrogen or an acyl group, R0 represents hydrogen or lower alkyl, R1 represents hydrogen or a group of the partial formula (R)(R0)N-, R2 represents carboxyl or protected carboxyl, and R3 represents hydrogen, halogen having an atomic number of up to 35 or lower alkoxy, and hydrates and salts of compounds of the formula I , whenever prepared according to claim 1 or an obvious chemical equivalent thereof.