CH597241A5 - Substd carboxylic acid derivs - Google Patents

Abstract

Substd carboxylic acid derivs broad spectrum antibiotics and inters

Description

  

  
 



   The present invention relates to a process for the preparation of O-substituted 7p-amino-3-cephem-3ol-4-carboxylic acid compounds of the formula
EMI1. 1
 wherein Rai is hydrogen or an amino protecting group R 1, and Rb is hydrogen or an acyl group Ac. 



  or R, and R, together represent a divalent amino protective group, R2 represents hydroxy or a radical RA2 which forms a protected carboxyl group together with the carbonyl group -C (= 0), and R3 represents an optionally substituted hydrocarbon radical or an acyl group, and salts of such compounds with salt-forming groups. 



   The enol derivatives of the present invention are enol ethers and enol esters of 3-cephem-3-ol compounds. 



   An amino protective group RA is a group which can be replaced by hydrogen, primarily an acyl group Ac, also a tri-methyl, in particular the trityl group, and an organic silyl and an organic stannyl group.  A group Ac primarily represents the acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid (incl.  Formic acid), as well as the acyl radical of a carbonic acid half derivative. 



   A divalent amino protective group formed by the radicals R'1 and Rb together is in particular the divalent acyl radical of an organic dicarboxylic acid, preferably with up to 18 carbon atoms, primarily the diacyl radical of an aliphatic or aromatic dicarboxylic acid, also the acyl radical of a, preferably substituted, z.  B. 



  containing an aromatic or heterocyclic radical, tx-aminoacetic acid, wherein the amino group via a, preferably substituted, z.  B.  two lower alkyl, such as containing methyl groups, methylene radical is connected to the nitrogen atom.  The radicals Rl and Rb together can also represent an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably with up to 18 carbon atoms. 



   A protected carboxyl group of the formula (= 0) - R2A is primarily an esterified carboxyl group, but can also represent a usually mixed anhydride group or an optionally substituted carbamoyl or hydrazinocarbonyl group. 



   The group RzÄ can be a hydroxy group etherified by an organic radical, in which the organic radical preferably contains 18 carbon atoms, which together with the -C (= O) group forms an esterified carboxyl group.  Such organic residues are e.g. B.  aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic-aliphatic radicals. 



   The group R2A can also represent an organic silyloxy radical, as well as a hydroxyl group etherified by an organometallic radical, such as a corresponding organic stannyloxy group, in particular a by 1 to 3, optionally substituted hydrocarbon radicals, preferably with up to 18 carbon atoms, such as aliphatic hydrocarbon radicals, and optionally by Halogen, such as chlorine, substituted silyloxy or stannyloxy group. 



   A radical R2 which forms a primarily mixed anhydride group with a -C (= O) group is in particular an acyloxy radical, in which axyl is the corresponding radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, such as an aliphatic, cycloaliphatic, cyclo aliphatic-aliphatic, aromatic or araliphatic carboxylic acid or a carbonic acid half derivative, such as one
Represents carbonic acid half-ester. 



   A radical RA which forms a carbamoyl group with a —C (= O) grouping is an optionally substituted amino group in which substituents are optionally substituted monovalent or divalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic aliphatic radicals with up to 18 carbon atoms and / or functional groups, such as optionally functionally modified, in particular free hydroxy, furthermore etherified or esterified hydroxy, in which the etherifying or  esterifying residues z. 

  B.  have the meanings given above and preferably contain up to 18 carbon atoms, as well as acyl radicals, preferably with up to 18 carbon atoms. 



   In a substituted hydrazinocarbonyl group of the formula C (= 0) RA2, one or both nitrogen atoms can be substituted, the substituents primarily being optionally substituted monovalent or divalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted, monovalent or divalent aliphatic, cycloaliphatic , cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms, and / or functional groups such as acyl radicals, preferably with up to 18 carbon atoms, are possible. 



   An optionally substituted hydrocarbon radical R3 is preferably a corresponding cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, but in particular an optionally substituted aliphatic hydrocarbon radical, and also a corresponding araliphatic hydrocarbon radical.  An acyl group R3 is primarily the acyl radical of an organic carboxylic acid, incl. 

 

  Formic acid, such as a cycloaliphatic, cycloaliphatic-aliphatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid, in particular the acyl radical of an aliphatic carboxylic acid, also an aromatic carboxylic acid, and a carbonic acid half derivative. 



   The general terms used in the description above and below have e.g.  B.  following meanings
An aliphatic radical, including the aliphatic radical of a corresponding organic carboxylic acid, and a corresponding ylidene radical, is an optionally substituted monovalent or divalent aliphatic hydrocarbon radical, in particular lower alkyl, and lower alkenyl or lower alkynyl, also lower alkylidene, the z.  B.  can contain up to 7, preferably up to 4 carbon atoms.  Such radicals can optionally be replaced by functional groups, e.g. 

  B.  by free, etherified or esterified hydroxy or mercapto groups such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phenylthio or phenyl-lower alkylthio, optionally substituted lower alkoxycarbonyloxy or lower alkanitroloxy, optionally substituted by oxycarbonyloxy, or lower alkanitroloxy, optionally substituted by oxycarbonyloxy, or halogen, furthermore , e.g.  B. 

  Lower alkylamino, di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino or aza-lower alkylenamino, and acylamino, such as lower alkanoylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, azido, acyl, such as lower alkanoyl or benzoyl, such as lower alkanoyl or benzoyl, optionally functionally modified, such as carboxyl or carboxyl such as lower alkoxycarbonyl, optionally substituted carbamoyl, such as N-lower alkyl or
N, N-Diniederalkylcarbamoyl, also optionally substituted ureidocarbonyl or guanidinocarbonyl, or cyano, optionally functionally modified sulfo, such as sulfamoyl or sulfo present in salt form, or optionally 0 mono- or 0,0-disubstituted phosphono, in which substituents z. 

  B.  optionally substituted lower alkyl,
Represent phenyl or phenyl-lower alkyl, where unsubstituted or O-monosubstituted phosphono can also be present in salt, such as alkali metal salt form, mono-, di- or poly-substituted. 



   A bivalent aliphatic residue, incl.  the corresponding
The remainder of a divalent aliphatic carboxylic acid is z. B. 



   Lower alkylene or lower alkenylene, which optionally, e.g.  B. 



   like an aliphatic radical indicated above, mono-, di- or polysubstituted and / or by heteroatoms, such as oxygen,
Nitrogen or sulfur can be interrupted. 



   A cycloaliphatic or cycloaliphatic aliphatic
The radical, including the cycloaliphatic or cycloaliphatic aliphatic radical in a corresponding organic carboxylic acid or a corresponding cycloaliphatic or cycloaliphatic-aliphatic ylidene radical is an optionally substituted, mono- or bivalent cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, e.g.  B. 



   mono-, bi- or polycyclic cycloalkyl or cycloalkenyl, also cycloalkylidene, or  Cycloalkyl or cycloalkenyl lower alkyl or lower alkenyl, also cycloalkyl lower alkylidene or cycloalkenyl lower alkylidene, wherein cycloalkyl and cycloalkylidene z.  B.  up to 12, such as 3-8, preferably 3-6
Ringkohelnstoffatome contains, while cycloalkenyl z.  B.  up to 12, such as 3-8, e.g. B.     5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic radical z.  B.  can contain up to 7, preferably up to 4 carbon atoms.  The above cycloaliphatic or cycloaliphatic-ali phatic radicals can, if desired, for. 

  B.  by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned, optionally substituted lower alkyl groups, or then, for.  B.  such as the aliphatic coal Wanserstnffreste mentioned above, mono-, di- or polysubstituted by functional groups. 



   An ammatic radical, including the aromatic radical of a corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon radical, e.g.  B.  a mono-, bi- or polycyclic aromatic hydrocarbon radical, in particular phenyl, as well as biphenylyl or naphthyl, which optionally, e.g.  B.  like the abovementioned aliphatic and cycloaliphatic koiale hydrogen radicals, can be mono-, di- or polysubstituted.    



   A divalent aromatic radical, e.g.  B.  an aromatic carboxylic acid, is primarily 1,2-arylene, in particular 1,2-phenylene, which optionally, z.  B.  like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, can be mono-, di- or polysubstituted. 



   An araliphatic radical, including the araliphatic radical in a corresponding carboxylic acid, also an araliphatic ylidene radical, is z.  B.  an optionally substituted araliphatic hydrocarbon radical, such as an optionally substituted, e.g.  B.  Up to three, optionally substituted mono-, bi- or polycyclic, aromatic hydrocarbon radicals containing aliphatic hydrocarbon radicals and is primarily phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl, and also phenyl-lower alkylidene, such radicals being e.g. B.  1-3 phenyl groups and optionally, z. B.  like the abovementioned aliphatic and cycloaliphatic radicals, can be mono-, di- or polysubstituted in the aromatic and / or aliphatic part. 



   Heterocyclic groups, including those in heterocyclic-aliphatic radicals, including heterocyclic or heterocyclic-aliphatic groups in corresponding carboxylic acids, are in particular monocyclic, as well as bi- or polycyclic, aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza, triaza or tetrazacyclic radicals of aromatic character, furthermore corresponding partially or fully saturated radicals, these heterocyclic radicals optionally z.  B. 



  like the above-mentioned cycloaliphatic radicals, can be mono-, di- or polysubstituted.  The aliphatic part in heterocyclic-aliphatic radicals has z.  B.  the meaning given for the corresponding cycloaliphatic-aliphatic or araliphatic radicals. 



   The acyl radical of a carbonic acid half derivative is preferably the acyl radical of a corresponding half ester, in which the organic radical of the ester group is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or a heterocyclic-aliphatic radical, primarily the acyl radical of an optionally, z.  B.  in α- or β-position, substituted lower alkyl half esters of carbonic acid, and a lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half ester of carbonic acid which is optionally substituted in the organic radical.  Acyl radicals of a carbonic acid half ester are also corresponding radicals of lower alkyl half esters of carbonic acid, in which the lower alkyl part is a heterocyclic group, e.g. 

  B.  contains one of the above-mentioned heterocyclic groups of aromatic character, both the lower alkyl radical and the heterocyclic group may optionally be substituted.  The acyl radical of a carbonic acid half derivative can also be an optionally N-substituted carbamoyl group, such as an optionally halogenated N-lower alkylcarbamoyl group. 



   An etherified hydroxyl group is primarily optionally substituted lower alkoxy, in which substituents are primarily free or functionally modified, such as etherified or esterified hydroxyl groups, in particular lower alkoxy or halogen, furthermore lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, and also heterocycoxyloxy or heterocyclyloxy, especially also optionally lower alkoxy substituted phenyl lower alkoxy. 

 

   An optionally substituted amino group is e.g.  B. 



  Amino, lower alkylamino, di-lower alkylamino, lower alkylenamino, oxane-lower alkylenamino, thian-lower alkylenamino, aza-lower alkylenamino, hydroxyamino, lower alkoxyamino, lower alkanoyloxyamino, lower alkoxycarbonylamino or lower alkanoylamino. 



   An optionally substituted hydrazino group is e.g. B. 



  Hydrazino, 2-lower alkylhydrazino, 2,2-di-lower alkylhydrazino, 2-lower alkoxycarbonylhydrazino or 2-lower alkanoylhydrazino. 



   Lower alkyl is e.g.  B.  Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. -Butyl or ter. -Butyl, and n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl, while lower alkenyl z.  B.  Vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl, lower alkynyl e.g. B.  Propargyl- or 2-butynyl, and lower alkylidene e.g. B.  Can be isopropylidene or isobutylidene. 



   Lower alkylene is e.g.  B.  1,2-ethylene, 1,2- or 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, while lower alkenylene z.  B.  1,2-ethenylene or 2-buten-1,4-ylene.  Lower alkylene interrupted by heteroatoms is e.g.  B. 



  Oxane-lower alkylene, such as 3-oxa-1,5-pentylene, thian-lower alkylene, such as 3-thia-1,5-pentylene, or aza-lower alkylene, such as 3-lower alkyl-3-aza-1,5-pentylene, e.g. B.  3-methyl-3-aza-1,5-pentylene. 



   Cycloalkyl is e.g.  B.  Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl, cycloalkenyl z. B.     Cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1, 4-cyclohexadienyl, and
Cycloalkylidene e.g.  B.  Cyclopentylidene or cyclohexylidene. 



  Cycloalkyl-lower alkyl or lower alkenyl is e.g.  B.  Cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1,1 or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, -vinyl or -alkyl, while cycloalkenyl lower alkyl or lower alkenyl e.g. 18th     1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl- or 1-, 2- or 3-cycloheptenylmethyl, -1,1- or -1,2-ethyl, -1,1- , -1,2- or -1,3-propyl, -vinyl or -allyl.  Cycloalkyl lower alkylidene is e.g.  B.  Cyclohexylmethylene, and cycloalkenyl lower alkylidene z. B.  3-cyclohexenylmethylene. 



   Naphthyl is 1- or 2-naphthyl, while biphenylyl is e.g. B.    



  Represents 4-biphenylyl. 



   Phenyl-lower alkyl or phenyl-lower alkenyl is, for.  18th     Benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl, trityl, 1- or 2-naphthylmethyl, styryl or cinnamyl, phenyl lower alkylidene z. B.     Benzylidene. 



   Heterocyclic radicals are primarily optionally substituted heterocyclic radicals of aromatic character, e.g. B.     corresponding monocyclic, monoaza-, monothia- or monooxacyclic radicals, such as pyrryl, e.g.  B.  2-pyrryl or 3-pyrryl, pyridyl, e.g.    18th 2-, 3- or 4-pyridyl, also pyndinium, thienyl, e.g. B.     2- or 3-thienyl, or furyl, e.g. B.  2-furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals such as indolyl, e.g.    18th 2- or 3-indolyl, quinolinyl, e.g.    18th 2- or 4-quinolinyl, isoquinolinyl, e.g. 18th       1-isoquinolinyl, benzofuranyl, e.g.  B.  2- or 3-benzofuranyl, or benzothienyl, e.g. 

  B.  2- or 3 benzothienyl, monocyclic diaza, triaza, tetraza, thiaza, thiadiaza or oxazacyclic radicals, such as imidazolyl, e.g.  z. B.  2 imidazolyl, pyrimidinyl, e.g.  B.  2- or 4-pyrimidinyl, triazolyl, e.g.  B.  1,2,4-triazol-3-yl, tetrazolyl, e.g.  B.  1- or 5-tetrazolyl, oxazolyl, e.g. B.  2-oxazolyl, isoxazolyl, e.g. B.  3-isoxazolyl, thiazolyl, e.g.  B.  2-thiazolyl, isothiazolyl, e.g. B.       3-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, e.g. B.    1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza, thiaza or oxazacyclic radicals such as benzimidazolyl, e.g. B.     2-benzimidazolyl, benzoxazolyl, e.g. B.  2-benzoxazolyl, or benzthiazolyl, e.g. B.  2 benzthiazolyl. 

  Corresponding partially or fully saturated radicals are, for.  B.  Tetrahydrothienyl such as 2-tetrahydrothienyl, tetrahydrofuryl such as 2-tetrahydrofuryl, or piperidyl, e.g. 18th    



  2- or 4-piperidyl.  Heterocyclic-aliphatic radicals are heterocyclic groups, in particular those containing lower alkyl or lower alkenyl.  The above-mentioned heterocyclyl radicals can, for.  B.  by optionally substituted aliphatic hydrocarbon radicals, in particular lower alkyl, such as methyl, or, for. B.     like the aliphatic hydrocarbon radicals, be substituted by functional groups. 



   Lower alkoxy is e.g.  B.  Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec. -Butyloxy, tert. -Butyloxy, n-pentyloxy or tert. -Pentyloxy.  These groups can be substituted, e.g. B.  as in halo-lower alkoxy, especially 2-halo-lower alkoxy, e.g.  B.  2,2,2-trichloro-, 2-bromo- or 2-iodoethoxy.  Lower alkenyloxy is e.g.  B.  Vinyloxy or allyloxy, lower alkylenedioxy e.g.  B.  Methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy z.  B. 



  Cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy e.g.  B.  Benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, or heterocyclyloxy or heterocyclyl-lower alkoxy z. B.  Pyridyl-lower alkoxy, such as 2-pyndylmethoxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thienyloxy. 



   Lower alkylthio is e.g.  B.  Methylthio, ethylthio or n-butylthio, lower alkenylthio z.  B.  Allylthio, and phenyl-lower alkylthio e.g. B.       Benzylthio, while mercapto groups etherified by heterocyclyl radicals or heterocyclylaliphatic radicals, in particular imidazolylthio, e.g. B.  2-imidazolylthio, thiazolylthio, e.g. B.     2-thiazolylthio, 1,2,4- or 1,3,4-thiadiazolylthio, e.g. B.  1,2,4-thiadiazol-3-ylthio or 1, 3,4-thiadiazol-2-yl-thio, or tetrazolylthio, e.g.  B.    1 are methyl 5 tetrazolylthio. 



   Esterified hydroxy groups are primarily halogen, e.g.  B.  Fluorine, chlorine, bromine or iodine, as well as lower alkanoyloxy, e.g.  B.     Acetyloxy or propionyloxy, lower alkoxycarbonyloxy, e.g. B.     Methoxycarbonyloxy, ethoxycarbonyloxy or tert.  Butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, e.g. B.  2,2,2-trichloroethoxycarbonyloxy, 2-bromoethoxycarbonyloxy or 2-iodoethoxycarbonyloxy, or phenylcarbonylmethoxycarbonyloxy, e.g. B.     Phenacyloxycarbonyloxy. 



   Lower alkoxycarbonyl is e.g.  B.  Methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert.  Butyloxycarbonyl or tert. Pentyloxycarbonyl. 



   N-lower alkyl- or N, N-di-lower alkyl-carbamoyl is e.g. B.    



  N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl or N, N-diethylcarbamoyl, while N-lower alkylsulfamoyl e.g.  B.  Represents N-methylsulfamoyl or N, N-dimethylsulfamoyl. 



   A carboxyl or sulfo present in alkali metal salt form is e.g.  B.  a carboxyl or sulfo present in sodium or potassium salt form. 



   Lower alkylamino or di-lower alkylamino is e.g.  B. 



  Methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino z.  B.  Pyrrolidino or piperidino, Oxaniederalkylenamino z.  B.  Morpholino, thiane lower alkyleneamino, e.g. B.  Thiomorpholino, and aza-lower alkylenamino e.g. B. 



  Piperazino or 4-methylpiperazino.  Acylamino particularly represents carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino z.  B.  Methoxycarbonylamino, ethoxycarbonylamino or tert. -Butyloxycarbonylamino, lower alkanoylamino, such as acetylamino or propionylamino, also for phthalimido, or optionally in salt, such as alkali metal, z. B.  Sodium or ammonium salt form, present sulfoamino. 

 

   Lower alkanoyl is e.g.  B.  Formyl, acetyl or propionyl. 



   O-lower alkyl phosphono is e.g.  B.  O-methyl- or 0-ethyl-phosphono, O, O-di-lower alkyl-phosphono z.  B.  O, O-dimethylphosphono or O, O-diethylphosphono, O-phenyl-lower alkyl-phosphono z.  B.    O-benzyl-phosphono, and 0 lower alkyl-O-phenyl-phosphono z.  B.  O-benzyl-O-methylphosphono. 



   Lower alkenyloxycarbonyl is e.g.  B.  Vinyloxycarbonyl, while cycloalkoxycarbonyl and phenylniederalkoxycarbonyl z.  B.  Adamantyloxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl or α-4-biphenylyl-α-methyl-ethoxycarbonyl represents.  Lower alkoxycarbonyl, wherein lower alkyl e.g.  B.  contains a monocyclic, monoaza-, monooxa- or monothia cyclic group, is z.  B.  Furylnideralkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl-lower alkoxycarbonyl, e.g. B. 2-thenyloxycarbonyl.    



   2-lower alkyl and 2,2-di-lower alkyl hydrazino are e.g.  B.  2-methylhydrazino or 2,2-dimethylhydrazino, 2-lower alkoxycarbonylhydrazino e.g. B.     2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert. -Butyloxycarbonylhydrazino, and lower alkanoylhydrazino e.g. B.     2-acetylhydrazino. 



   An acyl group Ac stands in particular for a naturally occurring or bio-, semi- or totally synthetically producible, preferably pharmacologically active N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem- 4-carboxylic acid compound containing acyl radical of an organic carboxylic acid or an easily cleavable acyl radical, in particular a carbonic acid half derivative. 



   An acyl radical Ac contained in a pharmacologically active N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound is primarily a group of the formula
EMI4. 1
 wherein n is 0 and Rl is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, z. 

  B.  denotes esterified or etherified hydroxy or mercapto or an optionally substituted amino group, or in which n is 1, R is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical , in which the heterocyclic radical preferably has aromatic character and / or a quaternary nitrogen atom, represents an optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or an azido group,

   and each of the radicals R11 and Rxll is hydrogen, or in which n stands for 1, Rl is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical is preferably aromatic in character has, Rii an optionally functionally modified, z. 

  B.  esterified or etherified hydroxy or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, an optionally 0-mono- or 0-disubstituted phosphono group, an azo group or a halogen atom, and Riii represents hydrogen, or in which n represents 1, each of the radicals Rl and Rii is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and Grill is hydrogen, or where n is 1, each of the radicals Rl and R11 is a functionally modified,

   preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R1t1 is hydrogen, or where n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R11 and Rlll together optionally denote an substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical connected by a double bond to the carbon atom, or in which n is 1, and R 'is an optionally substituted aliphatic, cycloaliphatic,

   cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have an aromatic character, R11 an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrogen or mean an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. 



   In the above acyl groups of the formula A, for.  B. 



  n for 0 and Rl for hydrogen or an optionally, preferably in the 1-position by amino or a, optionally in salt, z.  B.  Alkali metal salt form present sulfoamino group, substituted cycloalkyl group with 5-7 ring carbon atoms, an optionally, preferably by hydroxy, lower alkoxy, z.  B.  Methoxy, and / or halogen, e.g.  B. 



  Chlorine, substituted phenyl, naphthyl or tetrahydronaphthyl group, an optionally, e.g.  B.  by lower alkyl, e.g.  B.  Methyl, and / or phenyl, which in turn have substituents such as halogen, e.g.     Chlorine, can carry substituted heterocyclic group, such as a 4-isoyxazolyl group, or a preferably, z.  B.  by an optionally substituted one such as halogen, e.g.  B.  Chlorine, lower alkyl containing N-substituted amino group, or n for 1, Ri for a 3-amino-3-carboxypropyl radical with optionally protected amino and / or carboxy group, e.g.  B.  silylated amino or acylamino and / or silylated or esterified carboxy group, an optionally substituted, preferably by halogen, such as chlorine, optionally substituted, such as hydroxy and / or halogen, e.g.  B. 

  Chlorine, phenyloxy containing, amino and / or carboxy, substituted lower alkyl group, lower alkenyl group, optionally substituted one such as hydroxy, halogen, e.g. B.     Chlorine, and / or optionally substituted, such as hydroxy and / or halogen, e.g. B.     Phenyl group containing chlorine, containing phenyloxy, an optionally, z. B.     by lower alkyl, such as methyl, amino or aminomethyl, substituted pyridyl, pyridinium, thienyl, 1-imidazolyl or 1-tetrazolyl, an optionally substituted lower alkoxy, e.g.  B.  Methoxy group, an optionally, e.g. B.     by hydroxy and / or halogen, such as chlorine, substituted phenyloxy group, a lower alkylthio, e.g. B.  n-butylthio, or lower alkenylthio, e.g.  B.  Allylthio group, an optionally, e.g.  

  B.  by lower alkyl, such as methyl, substituted phenylthio-, 2-imidazolylthio1,2,4-triazol-3-ylthio-, 1,3,4-triazol-2-ylthio-, 1,2,4-thiadiazol-3-ylthio- , such as 5-methyl-1,2,4-thiadiazol-3-ylthio-, 1,3,4 thiadiazol-2-ylthio-, such as 5-methyl-1, 3,4-thiadiazol-2-ylthio-, or 5 -Tetrazolylthio, such as 1-methyl-5-tetrazolylthio group, a halogen, especially chlorine or bromine atom, an optionally functionally modified carboxy group, such as lower alkoxycarbonyl, e.g. B.     Methoxycarbonyl or ethoxycarbonyl, cyano or optionally, z. B.     by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl, e.g.  B. 

  Acetyl or propionyl, or benzoyl group, or an azido group, and R11 and Rlll for hydrogen, or n for 1, Rl for an optionally, z. B.     by hydroxy and / or halogen, e.g.  B.  Chlorine, substituted phenyl or thienyl group, also for a 1,4 cyclohexadienyl group, R11 for optionally substituted amino, such as lower alkoxycarbonylamino or 2-halo-lower alkoxycarbonylamino, e.g.  B.  tert. -Butyloxycarbonylamino or 2,2,2-Trichloräthoxycarbonylamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or one, optionally in salt z.  B.  Alkali metal salt form present sulfoamino group, an azido group, an optionally in salt, z. B.     Alkali metal salt form or in esterified form, e.g. 

  B.  as lower alkoxycarbonyl, e.g.  B.  Methoxycarbonyl or ethoxycarbonyl group, present carboxyl group, a cyano group, a sulfo group, an optionally functionally modified hydroxyl group, in particular acyloxy, such as formyloxy, and lower alkoxycarbonyloxy or 2-halo-lower alkoxycarbonyloxy, e.g.  B.  tert. -Butyloxycarbonyloxy or 2,2,2-trichlorocarbonyloxy, or optionally substituted lower alkoxy or phenyloxy, a 0-lower alkyl or 0, O-di-lower alkyl-phosphono group, e.g.    18th 0-methylphosphono or O, O-dimethylphosphono, or a halogen atom, e.g.  B.  Chlorine or bromine, and R111 for hydrogen, or n for 1, Rl and Rll each for halogen, e.g.  B.  Bromine, or lower alkoxycarbonyl, e.g. B. 

  Methoxycarbonyl, and Rlll for hydrogen, or n for 1, and each of the groups Rl, R11 and RIII for lower alkyl, e.g.  B.  Methyl stand. 



   Such acyl radicals Ac are z. B.     Formyl, cyclopentylcarbonyl, aminocyclopentylcarbonyl or α-amino-cyclohexylcarbonyl (with optionally substituted amino group, e.g. B.    



  optionally present in salt form sulfoamino group, or one, by a, preferably slightly, z. B.     when treating with an acidic agent such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, an acyl radical which can be split off or which can be converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as 2,2,2 trichloroethyloxycarbonyl, 2 -Bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl, phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, as well as amino group substituted by trityl), 2,6-dimethoxybenzoyl, tetrahydronaphthoyl, 2-methoxy-naphthoyl, 2-ethoxy-naphthoyl, hexyloxy-carbonyl,

   5-methyl-3-phenyl-4isoxazolylcarbonyl 3- (2-chlorophenyl) -5- methyl-44soxazolyl-carbonyl-, 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, Propionyl, butyryl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxycetyl, methylthioacetyl, butylthioacetyl, allylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl-ampionyl, 5-brimpropionyl, 5-brimpropionyl, 5-brimopropionyl, dibromoacetyl, 5-bromo-ampionyl, 5-bromoacetyl, (with if necessary, e.g. B.  as indicated, as indicated by a monoacyl or diacyl radical, e.g. B.     an optionally halogenated lower alkanoyl radical, such as acetyl or dichloroacetyl, or phthaloyl, substituted amino group and / or optionally functionally modified, e.g.  18th     in salt, such as sodium salt, or in ester, such as lower alkyl, e.g.  B. 



  Methyl or ethyl, or aryl lower alkyl, z. B.  Diphenylmethylesterform, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bismethoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, α-cyanopropionyl, azo-acetyl, -phenyl-aclylacido, 2-cyano-3,3-dimethyl-aclyyl, 2-cyano-3,3-dimethyl-aclyyl, 2-cyano-3,3-dimethyl-aclyyl, phenyl-phenyl-phenyl-phenyl, azo-acetyl, -phenyl-acetyl, azo-acetyl, phenyl-phenyl-acetyl, a-cyano-3,3-phenyl-acetyl, azidoacetyl, methoxycarbonylacetyl, methoxycarbonylacetyl, 3 chlorophenylacetyl, 4-aminomethylphenyl-acetyl, (with optionally, e.g. 

  B.  as indicated, substituted amino group), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, α-a-phenyloxypropionyl, α-a-methyl-phenyloxyphenylacetyl, α-methyl-phenyloxyphenylacetyl, α-methyl-phenyloxyphenylacetyl, α-methyl-phenyloxyphenylacetyl, α-methyl-phenyloxyphenylacetyl, α-methyl-phenyloxyphenylacetyl, a-methoxy-phenyl-phenyl, a-ethoxy-phenyl-phenyl-phenyl-a-ethoxy-phenyloxyphenylacetyl, a-methoxy-phenyloxy-phenyl, a-ethoxy-phenyl-phenyl-phenyl-a-ethoxy-phenyloxy-phenyl -Methoxy-3,4-dichloro-phenylacetyl, a-cyano-phenylacetyl, especially phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl or 3,5-dichloro-4-hydroxyphenylglycyl (where in these radicals the amino group optionally, e.g.  B.  as indicated above, may be substituted), a-hydroxyphenylacetyl (where in these radicals the hydroxyl group optionally, similar to the amino group, e.g. 

  B.  can be protected by a suitable acyl radical, in particular by formyl or an acyl radical of a carbonic acid half ester) or α-O-methyl-phosphono-phenylacetyl or α-0.0-dimethyl-phosphono-phenylacetyl, furthermore benzylthioacetyl, benzylthiopropionyl, α-carboxyphenylacetyl (with optionally, e.g.  B.  as stated above, functionally modified carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) -propionyl, 4- (3-methoxyphenyl) -butyryl, 2-pyridylacetyl, 4-aminopyridinium acetyl (optionally with, e.g. 

  B.  as stated above, substituted amino group), 2-thienylacetyl, 2-tetrayhydrothienylacetyl, α-carboxy-2-thienylacetyl or α-carboxy-3-thienylacetyl (optionally with functional, e.g. B.     as stated above, modified carboxyl group), oc-cyano-2-thienylacetyl, a-amino-2-thienylacetyl or a-amino-3-thienylacetyl (optionally with, e.g. B.     as stated above, substituted amino group), a-sulfo-phenylacetyl (optionally with, z. B.     such as the carboxyl group, functionally modified sulfo group), 3-thienylacetyl, 2 furylacetyl, 1 imidazolylacetyl, 1-tetrazolylacetyl, 3-methyl2-imidazolylthioacetyl, 1,2,4-triazol-3-ylthioacetyl,

   1,3,4-triazol-2-ylthioacetyl, 5-methyl-1, 2,4-thiadiazol-3-ylthioacetyl, 5-methyl-1,3,4-thiadiazol-2-ylthioacetyl, or 1-methyl-5-tetra - zolylthioacetyl. 



   An easily cleavable acyl radical Ac, in particular a carbonic acid half-ester, is primarily a reduction, e.g. B.     when treated with a chemical reducing agent, or by acid treatment, e.g.  B.  with trifluoroacetic acid, cleavable acyl radical of a half ester of carbonic acid, such as a lower alkoxycarbonyl radical, preferably multiply branched in the position or substituted by acylcarbonyl, in particular benzoyl radicals, or in the position by halogen atoms, e.g. B.       tert. -Butyloxycarbonyl, tert. -Pentyloxycarbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2 iodoethoxycarbonyl or a radical which can be converted into the latter, such as 2-chloro- or 2-bromoethoxycarbonyl, furthermore, preferably polycyclic, cycloalkoxycarbonyl, e.g. B. 

  Adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, primarily a-phenyl-lower alkoxycarbonyl, in which the a-position is preferably polysubstituted, e.g. B.     Diphenylmethoxycarbonyl or a-4-biphenylyl-a-methyl-ethyloxycarbonyl, or furyl-lower alkoxycarbonyl, primarily a furyl-lower alkoxycarbonyl, e.g. B.     Furfuryloxycarbonyl. 



   A divalent acyl group formed by the two radicals RA and Rb is z. B.  the acyl radical of a lower alkane or lower alkene dicarboxylic acid, such as succinyl, or an O-aryldicarboxylic acid, such as phthaloyl. 



   Another divalent radical formed by the groups Rt and Rb is z.  B.  a, especially in the 2-position, substituted, z. B.     optionally substituted phenyl or thienyl containing, and optionally in the 4-position by lower alkyl, such as methyl, mono- or disubstituted 1-oxo-3aza-1,4-butylene radical, e.g. B.  4,4-dimethyl-2-phenyl-1-oxo-3aza-1,4-butylene. 

 

   An etherified hydroxy group RA, together with the carbonyl group, forms an esterified carboxyl group, preferably easily cleavable or easily converted into another functionally modified carboxyl group, such as a carbamoyl or hydrazinocarbonyl group.  Such a group RA is e.g. B.     Lower alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy, which together with the carbonyl group forms an esterified carboxyl group which, in particular in 2 cephem compounds, can easily be converted into a free carboxyl group or into another functionally modified carboxyl group. 



   An etherified hydroxyl group Rt, which together with a -C (= O) group forms a particularly easily cleavable esterified carboxyl group, is available, for.  B.  for 2-halo-lower alkoxy, in which halogen preferably has an atomic weight of more than 19.  Such a radical, together with the = = O) group, forms a, when treated with chemical reducing agents under neutral or weakly acidic conditions, e.g.  B.  with zinc in the presence of aqueous acetic acid, easily cleavable esterified carboxyl group or an esterified carboxyl group which can be easily converted into such and is z.  B.  2,2,2-trichloroethoxy or 2-iodoethoxy, also 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter. 



   An etherified hydroxy group Rt, which, together with the = = O) grouping, also results in treatment with chemical reducing agents under neutral or weakly acidic conditions, e.g.  B.  when treating with zinc in the presence of aqueous acetic acid, further when treating with a suitable nucleophilic reagent, e.g. B.     Sodium thiophenolate, easily cleavable esterified carboxyl group, is an arylcarbonylmethoxy group, in which aryl is in particular an optionally substituted phenyl group, and preferably phenacyloxy. 



   The group Rt can also stand for an arylmethoxy group, in which aryl is in particular a monocyclic, preferably substituted aromatic hydrocarbon radical.  Such a radical, together with the = = O) group, forms an esterified carboxyl group which can be easily cleaved under neutral or acidic conditions on irradiation, preferably with ultraviolet light.  An aryl radical in such an arylmethoxy group contains, as substituents, in particular lower alkoxy, e.g.  B.  Methoxy (which are primarily in the 3-, 4- and / or 5-position in the preferred phenyl radical) and / or especially nitro (in the preferred phenyl radical preferably in the 2-position). 

  Such radicals are primarily 3 or 4-methoxybenzyloxy, 3,5-dimethoxy-benzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy.    



   An etherified hydroxy group Rt can also represent a radical which, together with the -C (= O) grouping, is a radical under acidic conditions, e.g.  B.  when treated with trifluoroacetic acid or formic acid, easily cleavable, esterified carboxyl group forms.  Such a radical is primarily a methoxy group in which methyl is substituted by optionally substituted hydrocarbon radicals, in particular aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, e.g. B.    



  Methyl, or phenyl, is polysubstituted or monosubstituted by a carbocyclic aryl group having electron-donating substituents or a heterocyclic group of aromatic character having oxygen or sulfur as a ring member, or is then a ring member in a polycycloaliphatic hydrocarbon radical or in an oxa- or thiacycloaliphatic Remainder is the ring member representing the position to the oxygen or sulfur atom. 



   Preferred polysubstituted methoxy groups of this type are e.g.    18th     tert. -Butyloxy, tert. -Pentyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or 2- (4-biphenylyl) -2propyloxy, while a methoxy group containing the above substituted aryl group or the heterocyclic group is e.g.  B.  4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or  2-Furyloxy is.  A polycycloaliphatic hydrocarbon radical in which methyl of the methoxy group is a, preferably triple, branched ring member is, for.  B.  Adamantyl, such as 1-adamantyl, and an above-mentioned oxaoder thiacycloaliphatic radical, in which methyl of the methoxy group is the ring member representing the position to the oxygen or sulfur atom, is z.  B.  2-tetrahydrofuryl, 2-tetrahydropropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulfur analogs. 



   The radical Rt can also represent an etherified hydroxyl group which, together with the -C (= O) grouping, is a hydrolytic, e.g. B.     under weakly basic or acidic conditions, forms cleavable esterified carboxyl group.  Such a radical is preferably an etherified hydroxyl group which forms an activated ester group with the -C (= O) grouping, such as nitrophenyloxy, e.g. B.     4-nitrophenyloxy or 2,4 dinitrophenyloxy, nitrophenyl-lower alkoxy, e.g.  B.  4-nitro benzyloxy, polyhalophenyloxy, e.g.  18th  2,4,6-trichlorophenyl oxy or 2,3,4,5,6-pentachlorophenyloxy, also cyanomethoxy, and acylaminomethoxy, z.  B.  Phthaliminomethoxy or succinyliminomethoxy. 



   The group Rt can also represent an etherified hydroxyl group which, together with the carboxyl group of the formula -C (= 0) - forms an esterified carboxyl group which can be cleaved under hydrogenolytic conditions, and is e.g. B.     optionally substituted α-phenyl-lower alkoxy, such as benzyloxy, 4-methoxy-benzyloxy or 4-nitrobenzyloxy. 



   The group Rt can also be a, together with the carbonyl group -C (= 0) - forming an esterified carboxyl group cleavable under physiological conditions ver etherified hydroxyl group, primarily lower alkanoyloxymethoxy, z. B.     Acetyloxymethyloxy or pivaloylmethoxy. 



   A silyloxy or stannyloxy group Rt preferably contains optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, and is primarily tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy, or tri-lower alkylstannyloxy, e.g.  B. 



  Tri-n-butylstannyloxy. 



   An acyloxy radical Rt which, together with a —C (= O) grouping, forms a, preferably hydrolytically, cleavable mixed anhydride group contains z.  B.  the acyl radical of one of the above organic carboxylic acids or carbonic acid half derivatives, and is z.  B.  Lower alkanoyloxy, e.g.  B. 



  Acetyloxy, or lower alkoxycarbonyloxy, e.g.  B.  Ethoxycarbonyloxy. 



   A radical Ru which, together with a -C (= O) grouping, forms an optionally substituted carbamoyl or hydrazinocarbonyl group is z.  B.  Amino, lower alkylamino or di-lower alkylamino, such as methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino, e.g.  B.  Pyrrolidino or piperidino, oxaniederalkylenamino, e.g.  B.  Morpholino, hydroxyamino, hydrazino, 2-lower alkylhydrazino or 2,2-di-lower alkylhydrazino, e.g.  B.  2 methylhydrazino or 2,2-dimethylhydrazino. 



   An optionally substituted aliphatic hydrocarbon radical R3 is in particular lower alkyl, such as ethyl, n-propyl and primarily methyl, furthermore tert. -Amino-lower alkyl, wherein the tert. -Amino group is separated from the oxygen atom by at least two carbon atoms, such as 2- or 3 di-lower alkylamino-lower alkyl, e.g. B.     2-dimethylaminoethyl, 2-diethylaminoethyl or 3-dimethylaminopropyl, or etherified hydroxy-lower alkyl, in which the etherified hydroxy group, especially lower alkoxy, is separated from the oxygen atom by at least two carbon atoms, such as 2 or 3-lower alkoxy-lower alkyl, e.g.  B.  2-methoxyethyl or 2-ethoxyethyl.  

  An optionally substituted araliphatic hydrocarbon radical R3 is primarily an optionally substituted phenyl lower alkyl, in particular 1-phenyl lower alkyl radical with 1-3 optionally substituted phenyl radicals, such as benzyl or diphenylmethyl, where as substituents z.  B.  esterified or etherified hydroxy, such as halogen, e.g.  B.  Fluorine, chlorine or bromine, or lower alkoxy, such as methoxy, are possible. 



   The acyl radical R3 of an aliphatic carboxylic acid is primarily optionally substituted lower alkanoyl, e.g.  B. 



  Acetyl, propionyl or pivaloyl, such radicals such.  B.  by esterified or etherified hydroxy, e.g. B.  Halogen, such as fluorine or chlorine, or lower alkoxy, e.g. B.  Methoxy or ethoxy.  The acyl radical R3 of an aromatic carboxylic acid is z.  B.  optionally substituted benzoyl, such as benzoyl, or by esterified or etherified hydroxy, e.g.  B. 



  Halogen such as fluorine or chlorine, or lower alkoxy, e.g.  B.  Methoxy or ethoxy, or lower alkyl, e.g. B.     Methyl, substituted benzoyl. 



   Salts are in particular those of compounds of the formula I having an acidic group such as a carboxy, sulfo or phosphono group, primarily metal or ammonium salts such as alkali metal and alkaline earth metal, e.g. B. 



  Sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, whereby primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for the salt formation come into question, such as lower alkylamines, e.g. B.     Triethylamine, hydroxy lower alkylamines, e.g. B.  2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g.  B.  4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, e.g. B.     1-ethylpiperidine, cycloalkylamines, e.g.  B.  Bicyclohexylamine, or benzylamines, e.g. 

  B.    N, N'-dibenzyl-ethylenediamine, also bases of the pyridine type, z * B.     Pyridine, collidine or quinoline.  Compounds of the formula I which have a basic group can also contain acid addition salts, e.g.  B.  with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g.  B. 



  Trifluoroacetic acid.  Compounds of the formula I with one acidic and one basic group can also be used in the form of an inner salt, i.e. H.  in zwitterionic form.  1 Oxides of compounds of the formula I with salt-forming groups can also form salts, as described above. 



   The new compounds of the present invention have valuable pharmacological properties or can be used as intermediates for the preparation of such.  Compounds of formula I z.  B. where Rt is an acyl radical Ac occurring in pharmacologically active N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7, B-amino-3-cephem-4-carboxylic acid compounds and Ra is hydrogen, R2 is hydroxy or one together with the carbonyl group denotes an esterified carboxyl group forming easily cleavable under physiological conditions, etherified hydroxy group Rt, and R3 has the meaning given above and in which the double bond is preferably in the 3,4-position of the cephem ring

   or salts of such compounds with salt-forming groups are against microorganisms such as gram-positive bacteria, e.g. B.     Staphylococcus aureus, (e.g.  B.  in mice at doses of about 0.001 to about 0.02 g / kg p.  O. ), and gram-negative bacteria, e.g.  B. 



  Escherichia coli (e.g. B.  in mice at doses from about 0.001 to about 0.05 g-kg p. O. ), also Klebsiella pneumoniae, Proteus vulgaris or Salmonella typhosa, in particular also against penicillin-resistant bacteria.  These new compounds can therefore accordingly, for. B.     in the form of antibiotic preparations, use. 



   Compounds of the formula I in which the double bond of the cephem ring is in the 2,3-position, or 1-oxides of compounds of the formula in which the double bond is in the 3,4 position, and in which R1, R1b, R2 and R3 are those in connection with of the formula I has given meanings, or in which the double bond of the cephem ring occupies the 3,4-position, R3 has the meaning given above, the radicals RX and Rb are hydrogen, or Rj is an amino protective group different from the above acyl radical and Rb is hydrogen, or R, and Rb together represent a divalent amino protecting group,

   and R2 represents hydroxy, or Rt and Ru have the meanings given above, R2 represents a radical Rt which, together with the —C (= O) grouping, forms a preferably easily cleavable, protected carboxyl group, and R3 represents the meanings given above are valuable intermediates that can  B.  as described below, can be converted into the above-mentioned pharmacologically active compounds. 



   The 3-cephem compounds of the formula I, in which Ra is hydrogen or preferably one, in a fermentative (i.e.  H.  naturally occurring) or bio-, semi- or totally synthetically producible, in particular pharmacologically active, such as highly active N-acyl derivative of a 6ss amino-penam- 3-carboxylic acid or 7B-amino-3-cephem- 4carboxylic acid compound or an acyl radical that can be easily cleaved off Carbonic acid half-derivative, in particular a carbonic acid half-ester, Rb stands for hydrogen, R2 for hydroxy, for optionally, e.g. B.     by optionally substituted aryloxy, e.g.  18th     4-methoxyphenyloxy, lower alkanoyloxy, e.g.  B.  Acetyloxy or pivaloyloxy, or arylcarbonyl, e.g. B.  Benzoyl, or halogen, e.g. B. 

  Chlorine, bromine or iodine, substituted lower alkoxy, such as lower alkoxy, e.g.  B. 



  Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert. -Butyloxy or tert. -Pentyloxy, bis-phenyloxymethoxy optionally substituted by lower alkoxy, e.g.  B.  Bis-4-methoxyphenyloxymethoxy, phenacyloxy, lower alkanoyloxymethoxy, e.g. B.  Acetyloxymethoxy or pivaloyloxymethoxy, or 2-halo-lower alkoxy, e.g. B.     2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, for optionally substituted phenyl-lower alkoxy, in particular 1-phenyl-lower alkoxy, such as phenylmethoxy, such radicals 1-3 optionally, e.g. B.  may contain phenyl radicals substituted by lower alkoxy, such as methoxy, nitro or phenyl, e.g. B.    



  Benzyloxy, 4-mehoxybenzyloxy, 2-biphenylyl-2-propyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxydiphenylmethoxy or trityloxy, for acyloxy, such as lower alkoxycarbonyloxy, e.g.  B.  Methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, e.g. B.     Acetyloxy, for tri-lower alkylsilyloxy, e.g. B.  Trimethylsilyloxy, or optionally, e.g. 

  B.  amino or hydrazino substituted by lower alkyl such as methyl or hydroxy, e.g. B.     Amino, lower alkyl or di-lower alkylamino such as methylamino or dimethylamino, hydrazino, 2-lower alkyl or 2,2-di-lower alkylhydrazino, e.g. B.     2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamino, and R3 is lower alkyl, e.g. B.     Methyl or ethyl, optionally substituted phenyl lower alkyl, in particular 1-phenyl lower alkyl with 1 or 2, optionally, z.  B.  by lower alkoxy, such as methoxy, substituted phenyl radicals, e.g.  B.  Benzyl or diphenylmethyl, or lower alkanoyl, e.g.  B.  Acetyl or propionyl, and optionally, e.g.  B.  by lower alkyl such as methyl, lower alkoxy, e.g. B.     Methoxy, or halogen, e.g.  B.  

  Represents fluorine or chlorine, substituted benzoyl, and the 1-oxides thereof, furthermore the corresponding 2-cephem compounds, or salts of such compounds with salt-forming groups. 



   In a 3-cephem compound of the formula I, as well as in a corresponding 2-cephem compound, furthermore in a 1-oxide of the 3-cephem compound, or in a salt of such a compound with salt-forming groups Rt is primarily hydrogen or one in fermentative (i.e.  H.    



  naturally occurring) or biosynthetically producible N acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds, such as an optionally substituted phenylacetyl or phenyloxyacetyl radical, and an optionally substituted lower alkanoyl or lower alkenoyl radical , e.g.  B.  4 hydroxyphenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl, and especially 5-amino-5-carboxyvaleryl, in which the amino and / or the carboxyl group are optionally protected and e.g. 

  B.  as acylamino or  esterified carboxyl are present, phenylacetyl or phenyloxyacetyl, or an acyl radical occurring in highly effective N-acyl derivatives of 6ss-amino-penam- 3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds, such as formyl, 2-chloroethylcarbamoyl, cyanoacetyl, 2-thienylacetyl or 1-tetrazolylacetyl, especially phenylglycyl, in which phenyl is optionally substituted by optionally protected hydroxy, such as acyloxy, e.g. B.     optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and / or halogen, e.g.  B.  Chlorine, substituted phenyl e.g. B.     Phenyl, or 3- or 4-hydroxy-, 3-chloro-4-hydroxy- or 3,5-dichloro-4-hydroxypphenyl, optionally with protected hydroxy groups, and in which the amino group is optionally substituted and e.g. 

  B.  represents an optionally present in salt form sulfoamino group or an amino group which, as substituents, is a hydrolytically cleavable trityl group or an optionally substituted carbamoyl, such as an optionally substituted ureidocarbonyl group, e.g.  B.  Ureidocarbonyl or N'-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group e.g.  B.  Guanidinocarbonyl, or a, preferably light, e.g. 

  B.  when treating with an acidic agent, such as trifluoroacetic acid, or with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, an acyl radical that can be split off or converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as 2,2,2-trichloroethyloxycarbonyl, 2 -Chlor ethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl or phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, or in which the amino group is connected to the nitrogen atom of the 7ss-amino group by a methylene group, optionally lower alkyl, such as two methyls, furthermore thienylglycyl, such as 2- Thienylglycyl (optionally with, e.g. B.     as you can read above,

   substituted amino group), or 1-aminocyclohexylcarbonyl (optionally with, e.g.  B.  as stated above, substituted amino group), also α-carboxyphenylacetyl or α-carboxy-2thienylacetyl (optionally with functionally modified, z.  B.  in salt, such as sodium salt form, or in ester, such as lower alkyl, e.g.  18th     Methyl or ethyl, or phenyl lower alkyl, e.g. B.    



  Diphenylmethylesterform, present carboxyl group), a-sulfophenylacetyl (optionally with, z.  B.  such as the carboxyl group, functionally modified sulfo group), oc-phosphono- aO-methylphosphono- or oc-0,0-dimethylphosphonophenylacetyl, or a-hydroxyphenylacetyl (optionally with a functionally modified hydroxy group, in particular with an acyloxy group, in which acyl is one, preferably light , e.g. 

  B.  when treating with an acidic agent such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, an acyl radical that can be split off or converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as 2,2,2-trichloroethoxycarbonyl, 2 -Chloräthoxycarbonyl, 2 bromoäthoxycarbonyl, 2-Jodäthoxycarbonyl, tert. -Butyloxycarbonyl or Phenacyloxycarbonyl, also means formyl), z. B.     for an acyl radical of the formula A, and Rb for hydrogen, and R2 represents hydroxy, lower alkoxy, in particular a-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, e.g. 

  B.  2,2,2-trichloroethoxy, 2-iodoethoxy or the easily convertible into this 2 chloroethoxy or 2-bromoethoxy, phenacyloxy, 1-phenyl lower alkoxy with 1-3 phenyl radicals optionally substituted by lower alkoxy or nitro z.  B.  4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxydiphenylmethoxy or trityloxy, lower alkanoyloxymethoxy, e.g.  B. 



  Acetyloxymethoxy or pivaloyloxymethoxy, lower alkoxycarbonyloxy, e.g.  B.  Ethoxycarbonyloxy, or lower alkanoyloxy, e.g. B.     Acetyloxy, and R3 is lower alkyl, e.g. B.     Methyl, 1-phenyl lower alkyl, e.g.  B.  Benzyl or diphenylmethyl, lower alkanoyl, e.g.  B.  Acetyl or propionyl, or benzoyl. 



   The invention relates primarily to 3-cephem compounds of the formula I, in which R 1 is hydrogen and R 1 is hydrogen, an acyl group of the formula
EMI8. 1
 wherein Ar is phenyl, also hydroxyphenyl, e.g.  B.  3- or 4-hydroxyphenyl, or hydroxy-chlorophenyl, e.g.  B.  3-chloro-4-hydroxyphenyl- or 3,5-dichloro-4-hydroxyphenyl, with hydroxy substituents in such radicals being replaced by acyl radicals, such as optionally halogenated lower alkoxycarbonyl radicals, e.g.  B. 



  tert. -Butyloxycarbonyl or 2,2,2-Trichloräthoxycarbonyl, can be protected, and 2-thienyl is, X is oxygen or sulfur, n is 0 or 1, and R is hydrogen or, if n is 0, optionally protected amino, such as acylamino, e.g.  B.  a-polybranched lower alkoxycarbonylamino, such as tert. -Butyloxycarbonylamino, or 2-halogen-lower alkoxycarbonylamino, z. B.     2,2,2-Trichloräthoxycarbonylamino, 2-Jodäthoxycarbonylamino or 2-Bromäthoxycarbonylamino, or 3-Guanylureido, also sulfoamino or tritylamino, optionally protected carboxy, z.  B.  esterified carboxy such as phenyl-lower alkoxycarbonyl, e.g.  B.  Diphenylmethoxycarbonyl, optionally protected sulfo, as in alkali metal, e.g.  B.  Sodium salt form, sulfo present, optionally protected hydroxy such as acyloxy e.g. 

  B.  a-polybranched lower alkoxycarbonyloxy, such as tert. -Butyloxycarbonyloxy, or 2-Halogenniederalkoxycarbonyloxy, such as 2,2,2 Trichloräthoxycarbonyloxy, 2-Jodäthoxycarbonyloxy or 2 Bromoäthoxycarbonyloxy, also formyloxy, or 0-Niederalkylphosphono or 0,0-Diiederalkylphosphono, z.  B.  0 methylphosphono or 0,0-dimethylphosphono, or a 5-amino-5-carboxy-valeryl radical, wherein the amino and / or carboxy groups are optionally protected and z. B.     as acylamino, e.g. B.     Lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, or phthaloylamino, or  as an esterified carboxy, such as phenyl-lower alkoxycarbonyl, e.g.  B.  Diphenylmethoxycarbonyl, R2 is hydroxy, lower alkoxy, especially α-polybranched lower alkoxy, e.g. 

  B.  tert. -Butyloxy, 2-halo-lower alkoxy, e.g. B.     2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally, e.g.  B.  by lower alkoxy, e.g.  B.  Methoxy, substituted diphenylmethoxy, e.g.  B.  Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, and R3 is lower alkyl, e.g. B.     Methyl, or lower alkonyl, e.g. B.     Acetyl or propionyl, also denotes the corresponding 2-cephem compounds, or salts of such compounds with salt-forming groups. 

 

   In 3-cephem compounds of the formula 1 that are particularly valuable, and also in corresponding 2-cephem compounds, Ru stands for hydrogen, for the acyl radical of the formula B, in which Ar is phenyl, X is oxygen, 110 or 1, and R is hydrogen or, when ILO represents optionally protected amino such as acylamino, e.g.  B.  a-polybranched lower alkoxy carbonylamino, such as tert. -Butyloxycarbonylamino, or 2-halo geniederalkoxycarbonylnmino, e.g. B.    2,2,2-Trichloräthoxycarb- onylamino, 2-Jodäthoxycarbonylamino, or 2-Bromoäthoxycarbonylamino, optionally protected hydroxy such as acyloxy, z. 

  B.  a-polybranched lower alkoxycarbonyloxy, such as tert.  -Butyloxycarbonyloxy, or 2-halo-lower alkoxy carbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, also formyloxy, or 0-lower alkyl or 0,0-di-lower alkyl-phosphono, z. B.       0-methylphosphono or O, O-dimethylphosphono mean, or for a 5-amino-5-carboxy-valeryl radical, for which the amino and carboxy groups are optionally protected and z.  B.  as acylamino, e.g.  B.  Lower alkanoylamino such as acetyl. 



  amino, halo-lower alkanoylamino, such as dichloroacetylamino, or phthaloylamino, or  as an esterified carboxy such as phenyl. 



  lower alkoxycarbonyl, e.g. B.  Diphenylmethoxyarbonyl, Rb is hydrogen, R2 is hydroxy, optionally halogen in the 2-position, e.g.  B.     Chlorine-, bromine- or iodine-substituted lower alkoxy, especially o-poly-branched lower alkoxy, e.g.  B.    tert. -Butyloxy, or 2-halo-lower alkoxy, e.g.  B.  2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally lower alkoxy, such as methoxy-substituted diphenylmethyloxy, e.g. B.     Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, and R3 means lower alkyl, e.g.  B.  Methyl, or lower alkanoyl, e.g.  B.  Acetyl. 



   The compounds of the formula I and salts thereof are obtained by adding a 2-cephem-3-ol compound of the formula
EMI9. 1
 or a salt thereof is isomerized by treatment with a weakly basic agent, and a compound of the formula I obtained having a salt-forming group is isolated as a salt or as a free compound. 



   In a starting material of the formula II, the carboxyl group of the formula -C (= O) -R2 in the 4-position preferably has the a-configuration. 



   In a starting material of the formula II, R2 stands for hydroxy or preferably for one with the -C (= 0) grouping an etherified hydroxyl group R2A which can be cleaved, in particular under mild conditions, and which can be cleaved under mild conditions Carboxyl protecting group Ru in a manner known per se, for. B.     as stated above, may be protected.  A group RA is e.g.  B.  in particular an optionally halogen-substituted lower alkoxy group, such as a-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, or 2-halo-lower alkoxy, wherein halogen is e.g. 

  B.     Represents chlorine, bromine or iodine, primarily 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, or an optionally substituted one, such as lower alkoxy, e.g. B.     Methoxy, or nitro-containing 1-phenyl-lower alkoxy group, such as optionally, e.g. B.  as indicated, substituted benzyloxy or diphenylmethoxy, e.g.  B.  Benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, e.g. B.  Trimethylsilyloxy. 



  In a starting material of the formula II, the radical Rz is preferably an amino protective group Rt, such as an acyl group Ac, in which any free functional groups present, e.g. B.  Amino, hydroxy, carboxyl or phosphono groups, in a manner known per se, amino groups z. B.     by acylating, tritylating, silylating or stannylating, and hydroxy, carboxy or phosphono groups, e.g. B.     by etherification or esterification, incl.  Silylating or stannylating, and R1b hydrogen. 



   So you can use 2-cephem compounds of the formula II, wherein free functional groups optionally, z. B.    



  as indicated, can be protected intermediately, it being possible for a protected carboxyl group to be formed during the reaction. 



   Suitable isomerizing agents are e.g.  B.  organic nitrogen-containing bases, especially tertiary heterocyclic bases of aromatic character, primarily bases of the pyrimidine type, such as pyridine itself, and collidines or lutidines, also quinoline, tertiary aromatic bases, e.g. B.     those of the aniline type, such as N, N-di-lower alkyl anilines, e.g.    18th     N, N-dimethylaniline or N, N-diethylaniline, or tertiary aliphatic, azacycloaliphatic or araliphatic bases, such as N, N, N-tri-lower alkylamines, e.g.  B.  N, N, N-trimethylamine, N, N-dimethyl-N-ethylamine, N, N, N-triethylamine or N, N-diisopropyl-N-ethylamine, N-lower alkyl-azacycloalkanes, e.g. B.     N-methyl-piperidine, or N-phenyl-lower-alkyl-N, N-di-lower alkyl-amines, e.g.  B. 

  N benzyl-N, N-dimethylamine, as well as mixtures thereof, such as the mixture of a base of the pyridine type and an N, N, N-tri-lower alkylamine, e.g. B.  Pyridine and tethylamine.  Furthermore, inorganic or organic salts of bases, in particular of medium to strong bases with weak acids, such as alkali metal or ammonium salts of lower alkanecarboxylic acids, eg.  B.  Sodium acetate, triethylammonium acetate or N-methyl-piperidine acetate, and other analogous bases or mixtures of such basic agents can be used. 



   The above isomerization with basic agents can, for. B.     in the presence of a derivative of a carboxylic acid suitable for forming a mixed anhydride such as a carboxylic acid anhydride or chloride, e.g. B.     with pyridine in the presence of acetic anhydride.  It is preferably carried out in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, e.g. 

  B.  chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, whereby bases used as reactants and liquid under the reaction conditions can also serve as solvents, with cooling, at room temperature or with heating, preferably in a temperature range from about -300 ° C. to about + 100 C, in an inert gas, e.g.  B.  Nitrogen atmosphere and / or in a closed vessel. 



   The 3-cephem compounds of the formula I obtainable in this way can be prepared in a manner known per se, for.  B.  by adsorption and / or crystallization, separate from any 2-cephem compounds still present. 

 

   In the 3-cephem compounds of the formula I obtainable in this way, R1, Rib and / or R2 can, as described above, be converted into other groups RX, Rb or  R2 must be transferred, whereby it must be ensured that the 3-cephem compounds are significantly more sensitive to alkaline agents than the corresponding 2-cephem compounds. 



   In the process according to the invention and in any additional measures to be carried out, if necessary, free functional groups not participating in the reaction can be present in the starting materials or in the compounds obtainable according to the process, e.g. B.  free amino groups e.g.    



  by acylation, tritylation or silylation, free hydroxyl or mercapto groups e.g.  B.  by etherification or esterification, and free carboxyl groups e.g. B.  by esterification, incl.  Silylation, temporarily protected in a manner known per se and, if desired, released in a manner known per se in each case after the reaction has taken place. 



   In a compound of the formula I obtainable according to the invention with a protected, in particular esterified, carboxyl group of the formula -C (= 0) -RA, this can be administered in a manner known per se, e.g. B.     depending on the type of group Rt, are converted into the free carboxyl group.  An esterified, e.g. B.    



  carboxyl group esterified by a lower alkyl radical, in particular methyl or ethyl, can be obtained by hydrolysis in a weakly basic medium, e.g. B.     by treatment with an aqueous solution of an alkali metal or alkaline earth metal hydroxide or carbonate, e.g.  B.  Sodium or potassium hydroxide, preferably at a pH of about 9 to 10, and optionally in the presence of a lower alkanol, can be converted into a free carboxyl group.  A carboxyl group esterified by a suitable 2 halo-lower alkyl or arylcarbonylmethyl group can e.g. B.     by treating with a chemical reducing agent such as a metal, e.g.  B. 

  Zinc, or a reducing metal salt, such as a chromium-II salt, e.g. B.     Chromium-II-chloride, usually in the presence of a hydrogen-donating agent which is able to generate nascent hydrogen together with the metal, such as an acid, primarily acetic and formic acid, or an alcohol, preferably adding water, a carboxyl group esterified by an arylcarbonylmethyl group, likewise by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, a carboxyl group esterified by a suitable arylmethyl group e.g.  B.  by irradiation, preferably with ultraviolet light, e.g. B.     below 290 my if the arylmethyl group z.  B.  one optionally in the 3, 4 and / or 5 position, e.g. 

  B.  is benzyl radical substituted by lower alkoxy and / or nitro groups, or with longer-wave ultraviolet light, e.g. B.     over 290 m, u when the arylmethyl group z. B.     a benzyl radical substituted in the 2-position by a nitro group, a by a suitably substituted methyl group, such as tert. -Butyl or diphenylmethyl, esterified
Carboxyl group e.g. 

  B.  by treating with a suitable acidic agent such as formic acid or trifluoroacetic acid, if necessary with the addition of a nucleophilic compound such as phenol or anisole, an activated esterified carboxyl group by hydrolysis, e.g. B.     by treatment with an acidic or weakly basic aqueous agent such as hydrochloric acid or aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer from pH about 7 to about 9, and a hydrogenolytically cleavable esterified carboxyl group by hydrogenolysis, e.g. B.     by treating with hydrogen in
Presence of a precious metal, e.g.  B.  Palladium catalyst, are cleaved. 



   A z.  B.  Protected by silylation or stannylation carboxyl group can in a conventional manner, for. B.     can be released by treatment with water or an alcohol. 



   Compounds of the formula I obtained can be converted into other compounds of the formula I in a manner known per se. 



   In a compound obtained, e.g.  B.  an amino protecting group Rt or    Rb, especially one that can be split off easily
Acyl group, in a manner known per se, e.g.  B.  an a-polyver branched lower alkoxycarbonyl group, such as tert. -Butyloxycarbonyl, by treating with trifluoroacetic acid and a 2-halo-lower alkoxycarbonyl group, such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxy carbonyl group by treating with a suitable redu-decent metal or corresponding metal compound, eg. B.    



  Zinc, or a chromium (II) compound, such as chloride or acetate, can advantageously be split off in the presence of a hydrogen-generating agent nascent together with the metal or the metal compound, preferably in the presence of hydrous acetic acid.  Furthermore, in a compound of the formula I obtained in which a carboxyl group of the formula -C (= o) -R2 is preferably one, e.g.  B.  by esterification, including by silylation, e.g. 

  B.  by reacting with a suitable organic halosilicon or halotin-IV compound, such as trimethylchlorosilane or tri-nbutyltin chloride, protected carboxyl group, an acyl group Rt or Rb, in which any free functional groups are optionally protected, by treatment with a Imide halide-forming agents, reacting the imide halide formed with an alcohol and cleavage of the imino ether formed, are cleaved, with a protected, e.g. B.     a carboxyl group protected by an organic silyl radical can already be released in the course of the reaction. 



   Imide halide-forming agents in which halogen is bonded to an electrophilic central atom are primarily acid halides, such as acid bromides and especially acid chlorides. 



  These are primarily acid halides of inorganic acids, especially phosphorus-containing acids, such as phosphorus oxy-, phosphorus tri- and especially phosphorus petahalides, e.g. B.     Phosphorus oxychloride, phosphorus trichloride, and primarily phosphorus pentachloride, also pyrocatechyl phosphorus trichloride, and acid halides, in particular chlorides, of sulfur-containing acids or of carboxylic acids such as thionyl chloride, phosgene or oxalyl chloride. 



   The reaction with one of the said imide halide-forming agents is preferably carried out in the presence of a suitable, in particular organic, base, primarily a tertiary amine, e.g. B.     a tertiary aliphatic mono or diamine, such as a tri-lower alkyl amine, e.g. B.     Trimethyl, triethyl or ethyl diisopropylamine, also an N, N, N ', N' tetraniederalkyl-lower alkylenediamine, e.g.  B. 

  N, N, N ', N'-tetramethyl-1,5-pentylenediamine or N, N, N', N'-tetramethyl-1,6hexyldiamine, a mono- or bicyclic mono- or diamine, such as an N- substituted, e.g. B.     N-lower alkylated, alkylene, azaalkylene or oxaalkylene amine, e.g. B.     N-methylpiperidine or N-methyl-morpholine, also 2,3,4,6,7,8-hexahydro-pyrrolo [1,2-a] pyrimidine (diazabicyclonones; DBN), or a tertiary aromatic amine, such as a di-lower alkyl aniline, e.g. B.     N, N-dimethylaniline, or primarily a tertiary heterocyclic, mono- or bicyclic base such as quinoline or isoquinoline, especially pyridine, preferably in the presence of a solvent such as an optionally halogenated, e.g. 

  B.  chlorinated, aliphatic or aromatic hydrocarbon, e.g. B.     Methylene chloride.  Approximately equimolar amounts of the imide halide-forming agent and the base can be used; but the latter can also be in excess or deficiency, e.g.  B.  in about 0.2 to about 1 fold amount or then in about one to
10-fold, in particular an approximately 3 to 5-fold excess, be present. 



   The reaction with the imide halide forming agent is preferably carried out with cooling, e.g. B.     carried out at temperatures of about -500 ° C. to about + 100 ° C., but also at higher temperatures, d.  H.  up to about 75 "C, if the stability of the starting materials and products allow an increased temperature. 

 

   The imide halide product, which is usually processed further without isolation, is, according to the process, reacted with an alcohol, preferably in the presence of one of the abovementioned bases, to form the imino ether.  Suitable alcohols are e.g. B.  aliphatic as well as araliphatic alcohols, primarily optionally substituted, such as halogenated, e.g. B.  chlorinated, or additional hydroxy groups containing lower alkanols, e.g. B.  Ethanol, n-propanol, isopropanol or n-butanol, in particular methanol, also 2,2,2-trichloroethanol, and optionally substituted phenyl-lower alkanols, such as
Benzyl alcohol.  Usually one uses, e.g.  B.  up to about 100-fold excess of the alcohol and preferably operates with cooling, e.g. 

  B.  at temperatures from about -50 "C to about 100 C. 



   The imino ether product can advantageously be subjected to cleavage without isolation.  The split of the
Imino ethers can be obtained by treating with a suitable hydroxy compound.  It is preferable to use water or an aqueous mixture of an organic one
Solvent such as an alcohol, especially a lower alkanol, e.g.  B.  Methanol.  One usually works in an acidic medium, e.g. B.     at a pH of about 1 to about 5, which, if necessary, can be achieved by adding a basic
Means such as an aqueous alkali metal hydroxide, e.g. B.    



   Sodium or potassium hydroxide, or an acid, e.g.  B.  one
Mineral acid, or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, trifluoroacetic acid or p-toluenesulfonic acid, can set. 



   The three-step process described above for cleaving an acyl group is advantageously without Iso lieren the imide halide and imino ether intermediates, usually in the presence of an organic solvent that is inert to the reactants ver, such as an optionally halogenated hydrocarbon, z. B.     Methylene chloride, and / or in an inert gas atmosphere such as a nitrogen atmosphere. 



   If the imide halide intermediate obtained by the above process is reacted with a salt, such as an alkali metal salt of a carboxylic acid, in particular a sterically hindered carboxylic acid, instead of an alcohol, a compound of the formula in which both radicals R1 and Rb are acyl groups is obtained represent. 



   In a compound of the formula I in which both radicals R01 and Rt are acyl groups, one of these groups, preferably the less sterically hindered one, e.g. B.     by hydrolysis or aminolysis, can be selectively removed. 



   In a compound of the formula I in which R = and Rb together with the nitrogen atom represent a phthalimido group, this can, for.  B.  by hydrazinolysis, d.  H.  when treating such a compound with hydrazine, are converted into the free amino group. 



   Certain acyl radicals Rt of an acylamino group in compounds obtainable according to the invention, such as.  B.  the 5 amino-5-carboxy-valeryl radical in which carboxyl, e.g.  B.  by esterification, especially by diphenylmethyl, and / or the amino group, e.g.  B.  by acylation, in particular by halo-lower alkanoyl, such as dichloroacetyl, can also be protected by treatment with a nitrosating agent such as nitrosyl chloride, with a carbocyclic arene diazonium salt such as benzene diazonium chloride, or with a positive halogen-donating agent such as an N-haloamide or imide , e.g.  B. 

  N-bromosuccinimide, preferably in a suitable solvent or solvent mixture, such as formic acid together with a nitro or cyano lower alkane and adding a hydroxyl-containing agent, such as water or a lower alkanol, e.g. B.  Methanol, or, if in the 5-amino-5-carboxy-valeryl radical Rt, the amino group is unsubstituted and the carboxy group z.  B.  is protected by esterification, and Rb is preferably an acyl radical, but can also be hydrogen, by leaving to stand in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, e.g. B. , Methylene chloride, and, if necessary, working up the free or monoacylated amino compound by methods known per se, are split off. 



   A formyl group RA can also be obtained by treatment with an acidic agent, e.g.  B.  p-toluenesulfonic or hydrochloric acid, a weakly basic agent, e.g.  B.  diluted
Ammonia, or a decarbonylating agent, e.g.  18th     Tris (triphenylphosphine) rhodium chloride, are split off. 



   A triarylmethyl such as the trityl group Rt can e.g.  B. 



   by treating with an acidic agent such as a mineral acid, e.g.  B.  Hydrochloric acid. 



   In a compound of the formula I in which R01 and Rb are hydrogen, the free amino group can be obtained by acylation methods known per se, eg. B.     by treating with carboxylic acids or reactive acid derivatives thereof such as halides, e.g. B.     Fluorides or chlorides, also pseudohalides, such as cyanocarbonyl compounds corresponding to the acids, or anhydrides (including the internal anhydrides of carboxylic acids, i.e.  H. Ketenes, or from carbamic or thiocarbamic acids, d.  H.  Isocyanates or isothiocyanates, or mixed anhydrides, such as those which z. 

  B.  with haloformic acid lower alkyl, such as chloroformic acid ethyl esters or isobutyl esters, or with trichloroacetic acid chloride are to be understood), or activated esters, as well as with substituted formimino derivatives, such as substituted N, N dimethylchloroformimino derivatives, or an N-substituted N, N- Diacylamine, such as an N, N-diacylated aniline, acylate, if necessary, in the presence of suitable condensing agents, when using acids such. B.     of carbodiimides, such as dicyclohexylcarbodiimide, when using reactive acid derivatives, e.g. B.  basic agents, such as triethylamine or pyridine, works, optionally also of salts, e.g. B.     Ammonium salts of compounds of the formula I in which R2 is a hydroxyl group can start. 



   An acyl group can also be introduced by adding a compound of the formula I in which Rf and R1 together represent a ylidene radical (which can also be added subsequently, e.g. B.  by treating a compound in which R 1 represents hydrogen with an aldehyde such as an aliphatic, aromatic or araliphatic aldehyde) stands, e.g.  B. 



     acylated by the methods indicated above, and the acylation product, preferably in a neutral or weakly acidic medium, is hydrolyzed. 



   An acyl group can also be introduced in stages.  So you can z.  B.  in a compound of formula I with a free amino group a halo-lower alkanoyl, z. B. 



     Bromoacetyl group, or e.g.  B.  by treating with a carbonic acid dihalide such as phosgene, a halocarbonyl, e.g.  B. 



  Chlorocarbonyl group, and a thus obtainable N (halo-lower alkanoyl) or  N- (halocarbonyl) -amino compound with suitable exchange reagents, such as basic compounds, e.g.  B.  Tetrazole, thio compounds, e.g.  B.  2-mercapto-1-methyl-imidazole, or metal salts, e.g.  B.  Sodium azide or  Alcohols such as lower alkanols, e.g. B.       tert. -Butanol, convert and so to substituted N-Niederalkanoly resp.  N hydroxycarbonylamino compounds arrive.  Furthermore, you can z. B.  a compound of the formula in which Ria is a glycyl group, preferably substituted in the α-position, such as phenylglycyl, and Rb is hydrogen, with an aldehyde, e.g.  B.  Formaldehyde, or a ketone such as lower alkanone, e.g.  B.  

  Acetone, and thus obtain compounds of the formula 1 in which Ru and Rb together represent a 5-oxo-1,3-diaza-cyclopentyl radical which is preferably substituted in the 4 position and optionally substituted in the 2 position. 



   In both reactants, free functional groups can be temporarily protected in a manner known per se during the acylation reaction and can be released after the acylation by methods known per se.  So you can preferably z.  B.  Amino, hydroxy, carboxyl or phosphono groups in the acyl radical during the acylation reaction, for. B.     in the form of acylamino, such as 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino or tert.  Butyloxycarbonylamino groups, from acyloxy, e.g. 

  B.  2,2,2-tri chloroethoxycarbonyloxy or 2-bromoethoxycarbonyl groups, of esterified carboxy groups, such as diphenylmethoxycarbonyl groups, or  0,0-disubstituted phosphono, such as 0,0-di-lower alkyl-phosphono, e.g. B.     0,0-dimethyl-phosphono groups, protect and subsequently, if necessary after conversion of the protective group, e.g.  B.  a 2-Bromäthoxycarbonyl- in a 2-Jodäthoxycarbonylgruppe, z.  B.  by treatment with suitable reducing agents such as zinc in the presence of aqueous acetic acid, or with trifluoroacetic acid, by hydrogenolysis or by treatment with an alkali metal halide, e.g.  B.  Sodium iodide, such protected groups, optionally partially, cleave. 



   The acylation can also be carried out by replacing an existing acyl group with another, preferably sterically hindered acyl group, e.g.  B.  by the process described above, by preparing the imide halide compound, treating it with a salt of an acid and hydrolytically splitting off one of the acyl groups present in the product thus obtainable, usually the less sterically hindered acyl group. 



   In a compound of the formula I in which R 1 and R b are hydrogen, the free amino group can also be removed by introducing a triarylmethyl group, e.g.  B.  by treatment with a reactive ester of a triarylmethanol such as trityl chloride, preferably in the presence of a basic agent such as pyridine. 



   An amino group can also be protected by introducing a silyl and stannyl group.  Such groups are introduced in a manner known per se, e.g.  B.  by treatment with a suitable silylating agent, such as a dihalodin lower alkyl silane or trinide alkyl silyl halide, e.g.  B.  Dichloro-dimethylsilane or trimethyl-silyl chloride, or an optionally N-mono-lower alkylated, N, N-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkyl-silyl) -amine, (see z.  B. 



  British patent no.  1073 530), or with a suitable stannylating agent such as a bis (tri-lower alkyl tin) oxide, e.g.  B.  Bis (tri-n-butyl-tin) oxide, a tri-lower alkyltin hydroxide, e.g.  B.  Triethyl tin hydroxide, a tri-lower alkyl-lower alkoxy-tin, tetra-lower alkoxy-tin or tetra-lower alkyl-tin compound, and a tri-lower alkyl tin halide, e.g. B.     Tri-n-butyl tin chloride (see e.g.  B.  Dutch publication 67/17107). 



   In a compound of the formula I which can be obtained according to the process and which contains a free carboxyl group of the formula = = 0) -R2, such a carboxyl group can be converted into a protected carboxyl group in a manner known per se. 



  So you get z.  B.  by treating with a suitable diazo compound, such as e.g.  B.  Diazomethane, if necessary, in the presence of a Lewis acid, such as.  B.  Boron trifluoride or by reaction with an alcohol suitable for esterification in the presence of an esterification agent such as a carbodiimide, e.g. B.     Dicyclohexylcarbodiimide and carbonyldiimidazole, furthermore with an N, N'-disubstituted 0- or  S-substituted isourea or isothiourea, in which a 0- and S-substituent e.g.  B.  Lower alkyl, especially tert. -Butyl, phenyl-lower alkyl or cycloalkyl, and N- or  N 'substituents e.g.  B. 



  Are lower alkyl, especially isopropyl, cycloalkyl or phenyl, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid, an ester.  Furthermore, acid halides, such as chlorides (produced e.g.  B.  by treatment with oxalyl chloride), activated esters (formed e.g.  B.  with N-hydroxy nitrogen compounds, such as N-hydroxy-succinimide) or mixed anhydrides (obtained e.g.  B.  with haloformic acid lower alkyl esters, such as ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride) by reaction with alcohols, optionally in the presence of a base such as pyridine, converted into an esterified carboxyl group. 



   In a compound obtained with an esterified group of the formula -C (= 0) -R2, this can be converted into another esterified carboxy group of this formula, e.g. B.    



  2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable solvent, such as acetone, in 2-iodoethoxycarbonyl. 



   Mixed anhydrides can be prepared by adding a compound of the formula I with a free carboxyl group of the formula -C (= 0) -R2, preferably a salt, in particular an alkali metal, e.g.  B.  Sodium, or ammonium, e.g.  B.  Triethylammonium salt thereof with a reactive derivative such as a halide, e.g. B.     the chloride, an acid, e.g.  B.  a lower alkyl haloformate or a lower alkanecarboxylic acid chloride. 



   In a compound obtainable according to the process with a free carboxyl group of the formula -C (= 0) -R2, this can also be converted into an optionally substituted carbamoyl or hydrazinocarbonyl group, preferably reactive, functionally modified derivatives such as the above-mentioned acid halides, generally esters, as well as reacts the above activated esters, or mixed anhydrides of the corresponding acid with ammonia or amines, including hydroxylamine, or hydrazines. 



   A carboxyl group protected by an organic silyl or stannyl group can be formed in a manner known per se, e.g.  B.  by using compounds of the formula I in which R2 is hydroxy, or salts such as alkali metal, e.g.  B. 



  Sodium salts thereof treated with a suitable silylating or stannylating agent such as any of the aforementioned silylating or stannylating agents; see e.g.  B.  British patent no.  1 073 530 or  Dutch exposition no. 



  67/17107. 



   Furthermore, modified functional substituents in groups R1A, R2b and / or R2, such as acylated amino groups, acylated hydroxy groups, esterified carboxy groups or 0,0-disubstituted phosphono groups, according to methods known per se, for.  B.  the above-described, release, or free functional substituents in groups R ,, Rb and / or R2, such as free amino, hydroxy, carboxy or phosphono groups, according to methods known per se, e.g.  B.  Acylating or  Esterify or  Substitute, modify functionally. 



   So z.  B.  an amino group by treatment with sulfur trioxide, preferably in the form of a complex with an organic base such as a tri-lower alkylamine, e.g.  B.  Tri-ethylamine, convert into a sulfoamino group. 

 

  Furthermore, the reaction mixture of an acid addition salt of a 4-guanylsemicarbazide with sodium nitrite with a compound of the formula I, wherein z. B.     the amino protective group represents a optionally substituted glycyl group, convert it and thus convert the amino group into a 3-guanylureido group.  Furthermore, you can compounds with aliphatically bonded halogen, for. B.     with an optionally substituted oc-bromo-acetyl grouping, with esters of phosphorous acid, such as tri-lower alkyl-phosphite compounds, and thus arrive at corresponding phosphono compounds. 



   Salts of compounds of the formula I can be prepared in a manner known per se.  So you can salts of compounds of formula I with acidic groups z.  B.  by treating with metal compounds such as alkali metal salts of suitable carboxylic acid, e.g.  B.  form the sodium salt of cu-ethyl-caproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.  Acid addition salts of compounds of the formula I with basic groups are obtained in a customary manner, for.  B.  by treatment with an acid or a suitable anion exchange reagent.  Internal salts of compounds of the formula I which contain a salt-forming amino group and a free carboxyl group can, for. 

  B.  by neutralizing salts such as acid addition salts to the isoelectric point, e.g. B.  with weak bases, or by treatment with liquid ion exchangers.  Salts of 1-oxides with salt-forming groups can be prepared in an analogous manner. 



   Salts can be converted into the free compounds in the usual way, metal and ammonium salts z.  B.  by treatment with suitable acids, and acid addition salts e.g.  B. 



  by treating with a suitable basic agent. 



   Mixtures of isomers obtained can be separated into the individual isomers by methods known per se, mixtures of diastereomeric isomers, for.  B.  by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation processes.  Racemates obtained can be used in the customary manner, optionally after introducing suitable salt-forming groups, eg.  B.  by forming a mixture of diastereosomeric salts with optically active salt-forming agents, separating the mixture into the diastereoisomeric salts and converting the separated salts into the free compounds, or by fractional crystallization from optically active solvents into which antipodes are separated. 



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



   So you can z. B.     the 1-oxides of compounds of the formula I which can optionally be prepared as intermediates in the isomerization of 2-cephem to 3-cephem compounds are also obtained if, starting from the 3-methylene-cepham compounds of the formula XIII described below, in the oxidation reaction to cleave the 3-methylene group in addition to the cepham-3-one compounds of the formula III also their 1-oxides are formed or the 1-oxides of the 3-methylene-cepham compounds are used in this oxidation reaction, and the 1- Oxides of compounds of the formula III can be converted into the corresponding enol derivatives, such as enol ethers and enol esters, by the method described below. 



   Such starting materials are preferably used and the reaction conditions are selected such that the compounds listed at the beginning as being particularly preferred are obtained. 



   The compounds of formula II can, for.  B.  can be prepared by making a cepham-3-one compound of the formula
EMI13. 1
 or a corresponding enol compound is converted into an enol derivative with a functionally modified hydroxyl group of the formula WR3 in the 3-position, and a compound of the formula II is isolated, and, if desired, the protected carboxyl group of the formula -C (= 0) -R2 converted into the free or into another protected carboxyl group, and / or, if desired, a compound of the formula II obtained is converted into another compound of the formula II, and / or, if desired, a compound obtained with a salt-forming group in a salt or a salt obtained is converted into the free compound or into another salt, and / or if desired,

   separating an obtained mixture of isomeric compounds into the individual isomers. 



   In the compounds of the formula III, Ri and R2A preferably have the meanings preferred in connection with the definition of the starting materials of the formula II and Rt is primarily hydrogen. 



   Cepham-3-one starting materials of the formula III can be in the keto and / or in the enol form; The starting materials of the formula III are converted from the enol form into the enol derivatives of the formula II.  It is also possible to use a mixture of a compound of the formula III and the corresponding enol from the starting material. 



   The conversion of the starting materials of the formula III into the enol derivatives is carried out in a manner known per se. 



   Enol ether, d.  H.  Compounds of the formula Hin in which R3 stands for an optionally substituted hydrocarbon radical are obtained by any process suitable for the etherification of enol groups, it being possible to use starting materials of the formula III in which R and Rb are hydrogen, but preferably Ro for a Amino protecting group Rt is.     The etherifying reagent used is preferably a diazo compound of the formula R3-N2 (nu) corresponding to the optionally substituted hydrocarbon radical R3, primarily an optionally substituted diazo lower alkane, e.g. B.  

  Diazomethane or diazoethane, also an optionally substituted phenyl-diazo lower alkane, such as a 1-phenyl diazo lower alkane, e.g. B.     Phenyldiazomethane or diphenyldiazomethane.  These reagents are used in the presence of a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclehexane, benzene or toluene, a halogenated aliphatic hydrocarbon, e.g.  B.  Methylene chloride, a lower alkanol, e.g. B.  Methanol, ethanol or tert. -Butanol, or an ether, such as a di-lower alkyl ether, e.g.  B.  Diethyl ether, or a cyclic ether, e.g.  B. 



  Tetrahydrofuran or dioxane, or a solvent mixture, and depending on the diazo reagent with cooling, at room temperature or with slight warming, further, if necessary, in a closed vessel and / or under an inert gas, e.g.  B.  Nitrogen atmosphere applied. 



   Furthermore, enol ethers of the formula II can be formed by treatment with a reactive ester of an alcohol of the formula R3OH (V) corresponding to the optionally substituted hydrocarbon radical R3.  Suitable esters are primarily those with strong inorganic or organic acids, such as mineral acids, e.g.  B.  Hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid, or strong organic sulfonic acids such as
Methanesulfonic or p-toluenesulfonic acid.  These reagents, particularly lower alkyl halides, e.g.  B. 

  Methyl iodide, or corresponding phenyl lower alkyl halides, are usually in the presence of a solvent such as an optionally halogenated, such as chlorinated aliphatic, cycloaliphati rule or aromatic hydrocarbon, eg. B.     Methylene chloride, an ether such as dioxane or tetrahydrofuran, or a lower alkanol such as methanol, or a solvent mixture, preferably using suitable condensation agents such as a silver salt, eg. B.     Silver nitrate, silver perchlorate or silver tetrafluoroborate, used as well as with cooling
Room temperature or with heating, and, if necessary, in a closed vessel and / or in an inert gas, e.g.  B. 



   Nitrogen atmosphere applied. 



   Enol ethers can also be prepared by treatment with a compound containing two or three etherified hydroxyl groups on the same carbon atom of aliphatic character;  H.  with an acetal, ketal or orthoester in the presence of an acidic agent.  So you can z.  B.  gem lower alkoxy lower alkanes, such as 2,2-dimethoxypropane, in the presence of a strong organic sulfonic acid such as p toluenesulfonic acid, and a suitable solvent such as methanol or dimethylsulfonamide, or orthoformic acid lower alkyl ester, e.g.  B.  Triethyl orthoformate, in the presence of a strong mineral acid, e.g.  B.  Sulfuric acid, or a strong organic sulfonic acid such as p-toluenesulfonic acid, and a suitable solvent such as ethanol or dioxane, use as an etherifying agent and thus arrive at compounds of the formula II in which R3 is lower alkyl, e.g. B. 

  Methyl, resp.  Ethyl stands. 



   Enol esters, d.  H.  Compounds of the formula II in which R3 is an acyl group are obtained by any process suitable for the esterification of enol groups, at least K in the starting material of the formula III being different from hydrogen, if one does not want to risk simultaneous acylation of a free amino group.  Carboxylic acids of the formula R34H (VI) corresponding to the acyl radical R3 or reactive acid derivatives thereof, such as halides, e.g.  B.  Fluorides or chlorides, also pseudohalides, such as cyanocarbonyl compounds corresponding to the carboxylic acids, or anhydrides (including the internal anhydrides of carboxylic acids, i.e.  H. 



  Ketenes, or from carbamic or thiocarbamic acids, d.  H. 



  Isocyanates or isothiocyanates, or mixed anhydrides, such as those which z.  B.  with haloformic acid lower alkyl, such as chloroformic acid ethyl esters or isobutyl esters, or with trichloroacetic acid chloride are to be understood), or activated esters, such as esters with vinylogous alcohols (d.  H. 



  Enols), e.g. B.  Esters of lower alkanecarboxylic acids with vinylogous lower alkanols (enol form of lower alkanols or lower alkanols), e.g. B.     with isopropenyl acetate, if necessary, in the presence of suitable condensing agents, when using acids such. B.     of carbodiimide compounds such as dicyclohexylcarbodiimide, or carbonyl compounds such as diimidazolylcarbonyl, when using reactive acid derivatives z.  B.  of basic agents such as tri-lower alkylamines, e.g. B.     Triethylamine, or heterocyclic bases, e.g.  B.  Pyridine, and when using esters with vinylogous alcohols in the presence of an acidic agent such as a mineral, e.g. B.     Sulfuric acid or a strong sulphonic, e.g.  B.  p-toluenesulfonic acid, works. 

  The acylation reaction can be carried out in the absence or in the presence of a solvent or solvent mixture, with cooling, at room temperature or with heating, and, if necessary, in a closed vessel and / or in an inert gas, e.g.  B. 



  Nitrogen atmosphere.  Suitable solvents are e.g.  B.  optionally substituted, in particular optionally chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as benzene or toluene, it also being possible to use suitable esterification reagents, such as acetic anhydride, as diluents. 



   In the above etherification or esterification reaction, depending on the compound of the formula III used and the reaction conditions, uniform compounds of the formula II or of the formula I, which can likewise be formed, or mixtures thereof can be obtained.  So the latter occur z.  B.  when using, e.g.  B.  compounds of the formula III contaminated by heavy metal, such as chromium-II compounds, or, if these are not isolated during their preparation from compounds of the formula VIII, when using correspondingly contaminated compounds of the formula VIII or when carrying out the reaction under basic conditions; this gives an increasing proportion of starting materials of the formula II. 

  Mixtures obtained can in a manner known per se, for. B.     using suitable separation methods, e.g. B.     through adsorption and fractional elution, incl.  Chromatography (column, paper or plate chromatography) using suitable adsorbents, such as silica gel or aluminum oxide, and eluents, further by fractional crystallization, solvent distribution, etc.  be separated. 

 

   The compounds of the formula II obtainable in this way can, analogously to the compounds of the formula I, be converted into other compounds of the formula II. 



   In the above process, as well as in any additional measures to be carried out, if necessary, free functional groups not participating in the reaction in the compounds of the formula III or in the starting materials of the formula II obtainable according to the process, similar to the conversion of 2-cephem Compounds of the formula II in 3 cephem compounds of the formula I, protected in a manner known per se and, if desired, subsequently released. 



   The compounds of formula III used in the preparation of starting materials of formula II can, for.  B. 



  be prepared by in a cephem compound of the formula
EMI14. 1
  wherein R1 preferably represents an amino protective group Rt, and wherein R2 preferably represents hydroxy, but also represents a group RA2, the acetyloxymethyl group, e.g. B.     converted into the hydroxymethyl group by hydrolysis in a weakly basic medium, such as with an aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase, such as a corresponding enzyme from Rhizobium tritolii, Rhizobium lupinii, Rhizobium japonicum or Bacillus subtilis functionally modifies free carboxyl group of the formula = 0) -R2 in a suitable manner, e.g.  B. 



  esterified by treatment with a diazo compound such as diphenyldiazomethane and the hydroxymethyl group, e.g. B.    



  by treatment with a halogenating agent such as chlorinating agents, e.g.  B.  Thionyl chloride, or iodizing agents such as N-methyl-N, N'-dicyclohexyl-carbodiimidium iodide, in a halomethyl z.  B.  Chloromethyl resp.  Converts iodomethyl group.  A chloromethyl group is either directly, e.g.  B.  by treating with a suitable chromium-II compound such as an inorganic or organic salt thereof, e.g.  B.  Chromium (II) chloride or chromium (II) acetate, in a suitable solvent such as dimethyl sulfoxide or then indirectly via the iodomethyl group (which you can e.g.  B.  by treating the chloromethyl compound with a metal iodide such as sodium iodide in a suitable solvent such as acetone), and the iodomethyl group converted to the methylene group by treatment with a suitable reducing agent such as zinc in the presence of acetic acid. 



  The methylene group in a compound of the formula
EMI15. 1
 is oxidatively degraded using the process described below; in a cepham-3-one compound obtainable in this way, in which both radicals Ria and Rb1 are hydrogen, the free amino group can be replaced by an appropriate protective group, e.g. B.  according to the procedure described above. 



   The oxidative splitting off of the methylene group in compounds of the formula VIII with the formation of an oxo group in the 3-position of the ring structure is preferably carried out with the formation of an ozonide compound by treatment with ozone.  Ozone is preferably used in the presence of a solvent such as an alcohol, e.g. B.     a lower alkanol such as methanol or ethanol, a ketone, e.g.  B.  a lower alkanone such as acetone, an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. 

  B.  a lower halogen alkane, such as methylene chloride or carbon tetrachloride, or a solvent mixture, incl.  an aqueous mixture, as well as with cooling or gentle heating, e.g. B.  at temperatures from about - 90 "C to about +40 C. 



   An ozonide formed as an intermediate is split reductively, using catalytically activated hydrogen, e.g. B.    



  Hydrogen in the presence of a heavy metal hydrogenation catalyst such as nickel, also palladium, preferably on a suitable carrier material such as calcium carbonate or coal, or chemical reducing agents such as reducing heavy metals, incl.  Heavy metal alloys or amalgams, e.g. B. 



   Zinc, in the presence of a hydrogen donor such as an acid, e.g.  B.  Acetic acid, or an alcohol, e.g.  B.  Lower alkanols, reducing inorganic salts such as alkali metal iodides, e.g. B.    



   Sodium iodide, in the presence of a hydrogen donor such as an acid, e.g.  B.  Acetic acid, or reducing organic
Compounds such as formic acid, a reducing sulfide compound, such as a di-lower alkyl sulfide, e.g. B.     Dimethyl sulfide, a reducing organic phosphorus compound, such as a Phos phine, which may contain optionally substituted aliphatic or aromatic hydrocarbon radicals as substituents, such as tri-lower alkylphosphines, e.g. B. 

  Tri-n-butylphosphine, or triarylphosphines, e.g.  18th     Triphenylphosphine, also phosphites, which optionally contain substituted aliphatic hydrocarbons as substituents, such as tri-lower alkylphosphites, usually in the form of corresponding
Alcohol adduct compounds such as trimethyl phosphite, or Phosphorigsäuretriamide, which optionally substituted aliphatic hydrocarbon radicals as substituents th contain, such as Hexaniederalkylphosphorigsäuretriamide, z.  B.    Hexamethylphosphorigsäuretriamid, the latter preferably in the
Form of a methanol adduct, or tetracyanoethylene. 

  The cleavage of the ozonide, which is usually not isolated, normally takes place under the conditions that are required for its
Manufacturing applies, d.  H.  in the presence of a suitable
Solvent or solvent mixture, as well as under
Cooling or gentle heating. 



   Depending on the type of oxidation reaction, one is obtained
Compound of formula III or the corresponding 1-oxide or a mixture of the two compounds.  One such
Mixture can in the usual way, for.  B.  through fractional
Crystallization or by chromatography (e.g.  B.  Column chromatography, thin layer chromatography), into which the individual components are separated. 



   Furthermore, a mixture of a compound of the formula III and a 1-oxide thereof obtainable according to the process can also be oxidized directly to the 1-oxide of a compound of the formula III, the above-described oxidizing agents being used for the
Production of 1-oxide compounds begins. 



   In the inventive conversion of the starting materials of the formula III to the enol derivatives of the formula II of the present invention, the starting materials need the
Formula III not to be isolated after its preparation; they can preferably be converted directly into the compounds of the formula II in the form of the crude reaction mixture after preparation from the compounds of the formula VIII. 



   The pharmacologically acceptable compounds of the present invention can e.g.  B.  be used for the production of pharmaceutical preparations which contain an effective amount of the active ingredient together or in the
Contain a mixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carrier substances which are suitable for enteral or, preferably, parenteral administration.  How to use tablets or gelatin capsules, which dilute the active ingredient together with Ver such. B.  Lactose, dextrose, sucrose, mannitol,
Sorbitol, cellulose and / or glycine, and lubricants, e.g. B.    

 

   Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g.  B. 



   Magnesium aluminum silicate, starches such as corn, wheat,
Rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and, if desired, disintegrants, e.g. B.     Strengthen,
Agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners.  Preferably, the pharmacologically active compounds of the present invention are used in the form of injectables, e.g.  B.  intravenously administrable preparations or from infusion solutions. 



  Such solutions are preferably isotonic aqueous solutions or suspensions, these e.g.  B.  from lyophilized preparations which contain the active ingredient alone or together with a carrier material, e.g.  B.  Mannitol, contained, can be prepared before use.  The pharmaceutical preparations can be sterilized and / or auxiliaries, e.g. B.    



  Contain preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts to regulate the osmotic pressure and / or buffers.  The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are made in a manner known per se, for.  B.  by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active ingredient. 



   In connection with the present description, organic radicals denoted lower contain up to 7, preferably up to 4, carbon atoms; Acyl radicals contain up to 20, preferably up to 12, carbon atoms. 



   The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius. 



   example 1
A mixture of 0.05 g of 3-methoxy-7ss-phenylacetylamino 2-cephem-4 <x -carboxylic acid diphenylmethyl ester in 0.5 ml of dimethyl sulfoxide is mixed with 5 μl of ethyl diisopropylamine and left to stand for 17 hours at room temperature.



  The mixture is diluted with toluene, with water, 2-n. Hydrochloric acid and washed with a concentrated solution of sodium chloride in water, dried over sodium sulfate and evaporated. An approximately 6: 4 mixture of 3-methoxy-7ss-phenylacetylamino-2-cephem-4lx-carboxylic acid diphenylmethyl ester and 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained Can split 50 g of silica gel.



   The 3-methoxy-7ss-phenylacetylamino-2-cephem-4-carboxylic acid diphenylmethyl ester, mp 174-177 ", after crystallization from a mixture of methylene chloride and pentane, is eluted with a 4: 1 mixture of toluene and ethyl acetate; followed of 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester with Rf-0.37 (system:

  Toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Äni0x = 258 m, u (e = 6340), Ämax = 264 my (e = 6350) and shoulder = 281 m (e = 5600); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 p, 3.02 5.62, 5.83 A 5.93 W 6.26 and 6.70, u.



   A solution of 11.82 g of the crude sodium salt of 3-hydroxymethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid (prepared by enzymatic deacetylation of the sodium salt of 3-acetyloxymethyl-7ssphenylacetylamino-3-cephem-4-carboxylic acid with the aid of a purified enzyme extract from Bacillus subtilis, strain ATCC 6633, and subsequent lyophilization of the reaction solution) in 200 ml of water is covered with 400 ml of ethyl acetate and acidified to a pH of 2 with concentrated aqueous phosphoric acid. The aqueous phase is separated off and extracted twice with 150 ml of ethyl acetate each time. The combined organic extracts are washed four times with 50 ml of water each time and dried over magnesium sulfate, then concentrated to about 400 ml.

  The solution is mixed with excess diphenyldiazomethane, left to stand for 3 hours at room temperature and then the granular crystalline precipitate is filtered off. The filtrate is concentrated to about 200 ml, cyclohexane is added while warm and, after cooling to room temperature, left to stand at about 4 "for some time.

  The precipitate is filtered off and recrystallized from a mixture of acetone and cyclohexane; the 3-hydroxymethyl-7ss-phenylacetyl amino-3-cephem-4-carboxylic acid diphenylmethyl ester obtained in this way melts at 176-176.5 "(uncorr.); [a] 2D0 = -6" +1 "(c = 1.231% in chloroform); thin-layer chromatogram (silica gel; detection with iodine vapor or ultraviolet light 22s4 m); RF = 0.42 (system: chloroform / acetone 4: 1),
Rf = 0.43 (system: toluene / acetone 2: 1), and Rf = 0.41 (system:
Methylene chloride / acetone 6: 1).



   1.03 g of 3-hydroxymethyl-7ss-phenylacetylamino are dissolved
Diphenylmethyl 3-cephem-4-carboxylate and 1.05 g of N
Methyl-N, N'-dicyclohexylcarbodiimidium iodide under one
Nitrogen atmosphere in 25 ml of absolute tetrahydrofuran and heated for one hour at 35 ". Then 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimidium iodide in 15 ml of absolute tetrahydrofuran is added and allowed during
Stand for 17 hours at room temperature under a nitrogen atmosphere. The reaction mixture is freed from the solvent on a rotary evaporator under reduced pressure. Of the
The residue is taken up in methylene chloride and filtered through a column of 50 g of silica gel (addition of 10% distilled
Water) filtered; it is washed with 4 portions of 100 ml each
Methylene chloride.

  The eluate is concentrated to a small volume and on a silica gel column (90 g; deactivated by
Addition of 10% distilled water) chromatographed. With a total of 9000 ml of a 3: 7 mixture of toluene and methylene chloride, non-polar impurities are eluted. Elution with 2
Portions of 200 ml of methylene chloride each give the 3-iodine methyl- 7ss-phenylacetylamino-3-cephem-4-carboxylic acid di phenylmethyl ester; the fractions, which are uniform according to thin-layer chromatography, are lyophilized from benzene, infrared absorption spectrum (in methylene chloride):

   characteristic
Bands at 3.00, 5.62, 5.82 p, 5.95 Ic, 6.70 p, 7.32 etc and 8.16, etc.



   The iodination reagent used above can be prepared as follows:
In a 250 ml round bottom flask with magnetic stirrer, reflux condenser and attached nitrogen balloon, 42 g of freshly distilled N, N'-dicyclohexylcarbodiimide are dissolved in 90 ml of methyl iodide under a nitrogen atmosphere at room temperature and the colorless reaction mixture is stirred for 72 hours at a bath temperature of 70 " the reaction time, the excess methyl iodide is distilled off from the now red-brown solution under reduced pressure and the viscous, red-brown residue in
150 ml of absolute toluene dissolved at 40.

  The crystal mass which spontaneously crystallizes out within a few hours is separated from the mother liquor with the aid of a glass suction filter with attached nitrogen balloon with exclusion of air, the reactor is rinsed three times with 25 ml of absolute, ice-cold toluene each time and the same toluene is used to colorless the slightly yellowish crystal mass on the glass suction filter to wash. After drying for 20 hours at 0.1 mm Hg. And room temperature, the N-methyl-N, N'-dicyclohexylcarbodiimidium iodide is obtained in the form of colorless crystals, F.

 

     111113 in the infrared absorption spectrum (in chloroform): characteristic bands at 4.72 u and 6.00 y.



   A solution of 0.400 g of 3-iodomethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester in 15 ml of 90% aqueous acetic acid is cooled to 0 in an ice bath and 2.0 g of zinc dust are added in portions with thorough stirring. After a reaction time of 30 minutes at 0, the unreacted zinc rod is filtered off using a suction filter with a diatomaceous earth layer; the filter residue is suspended several times in fresh methylene chloride and filtered again. The combined filtrates are reduced under reduced
Concentrated pressure, treated with absolute toluene and evaporated to dryness under reduced pressure.

  The residue is stirred in 50 ml of methylene chloride and 30 ml of a
0.5 molar aqueous dipotassium hydrogen phosphate solution added; the aqueous phase is separated, with two
Portions of 30 ml of methylene chloride each are extracted and discarded. The organic extracts are washed several times with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and reduced under reduced pressure
Pressure evaporated. The residue is made up on a column
22 g of silica gel (addition of 10% water) were chromatographed.



   The 3-methylene-7ss-phenylacetylamino-cepham 4cv-carboxylic acid diphenylmethyl ester is eluted with methylene chloride and
Methylene chloride, containing 2% methyl acetate, eluted and crystallized from a mixture of methylene chloride and hexane, mp 114-147; [α] 20D = -18 # 1 (c = 0.715 in chloroform); Ultraviolet absorption spectrum (in 905% strength aqueous ethanol): #max = 254 m (# = 1540) and 260 m (# = 1550); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.65, 5.74, 5.94, 6.26 y and 6.67 y.



   A solution of 1.0 g of 3-methylene-7ss-phenylacetylamino cepham-4a-carboxylic acid diphenylmethyl ester in 250 ml of methylene chloride is treated at -70 for 81/2 minutes with an oxygen-ozone mixture (0.265 mmol (ozone / minute) and 1 ml of dimethyl sulfide is added to the reaction mixture, which is stirred for 30 minutes at room temperature and for 1 ½ hours and then evaporated to dryness under reduced pressure.

  From the residue containing a mixture of 7ss-phenylacetylamino-cepham-3-one-4 # -carboxylic acid-diphenylmethyl ester and 7ss-phenylacetylamino-cepham-3-on-4 # -carboxylic acid-diphenylmethylester-1-oxide, in 50 ml of methanol were added and an excess of diazomethane (in the form of a solution in diethyl ether) was added at 0. The mixture is stirred for 15 minutes at 0 and then evaporated under reduced pressure. The residue is chromatographed on 50 g of silica gel.

  The 3-methoxy-7ss-phenylacetylamino-2-cephem-4-carboxylic acid diphenylmethyl ester is eluted with a 4: 1 mixture of toluene and ethyl acetate with Rf = 0.57 (system: toluene / ethyl acetate 1: 1); F 174-177 after crystallization from a mixture of methylene chloride and pentane; Ultraviolet absorption spectrum (in 95% strength aqueous ethanol): AmX = 258 m ', (e = 4000); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5.63, 5.74, 5.92, 6.15 and 6.66,
Example 2
The amorphous 3-methoxy-7ss is obtained in an analogous manner.



     Diphenylmethyl (D-α-tert-butyloxycarbonylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid, which can be lyophilized from dioxane, thin-layer chromatogram (silica gel; development with iodine): Rf-0.33 (System: diethyl ether); [α] 20D = 1 # 1 (c = 0.98 in chloroform); Ultraviolet
D absorption spectrum (in ethanol) #max = 264 y (e = 6300), infrared absorption spectrum (in methylene chloride):

   characteristic bands at 2.94, 5.62, 5.84, 5.88 (shoulder), 6.25 and 6.71 y; by isomerizing the corresponding 3-methoxy-7ss- (Da-tert-butyloxycarbonylamino-α-phenyl acetylamino) -2-cephem-4α-carboxylic acid diphenylmethyl ester, f.166-168 after crystallization from a mixture of methylene chloride and pentane: [ a] D = + 178 + 1 (c = 0.771 in chloroform); Thin-layer chromatogram (silica gel; developing with iodine): Rf-0.61 (system:

  Diethyl ether);
Ultraviolet absorption spectrum (in ethanol): AmaX = 257 my (e = 3550); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, u, 5.63, 5.74,
5.85 (shoulder), 5.94, 6.16, 6.64 (shoulder) and 6.72, whereby a mixture of the two compounds obtainable according to the process can be separated by chromatography on silica gel and eluting with diethyl ether; First of all starting material still present and then the desired 3-methoxy-7ss- (D-α-tert-butyloxycaronylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester is washed out.



   The starting material can be obtained as follows:
A chromatography column (diameter: 3 cm) is filled with 350 g of zinc powder, amalgamated for 10 minutes with a 0.1 molar solution of mercury (II) chloride in 0.1 N hydrochloric acid and with a lot of water and finally with a small amount Washed 1N hydrochloric acid. A solution of 55 g of green chromium III chloride hexahydrate in 55 ml of water and
11 ml of 2N sulfuric acid is poured into the reduction tube and the flow rate is regulated so that a chromium (II) chloride solution of pure blue color drips into the reaction vessel, which is kept under a nitrogen atmosphere.

  The blue chromium (II) chloride solution is then mixed with a solution of 92 g of sodium acetate in 180 ml of air-free water, the solution turning red and finely crystalline chromium (II) acetate precipitating out.



   When the precipitation is complete, the supernatant solution is removed and the chromium (II) acetate is washed twice with 250 ml of air-free water each time. A solution of 10.0 g of 3-acetyloxymethyl-7ss- (d-α-tert.-butyloxycarbonyl-amino-a-phenylacetyl-amino) -3-cephem-4-carboxylic acid is added to the moist chromium (II) acetate added to 200 ml of dimethyl sulfoxide, and the reaction mixture stirred for 15 hours under a nitrogen atmosphere at room temperature. For working up, the reaction mixture is aerated for 30 minutes and, after the addition of 1000 g of a polystyrene sulfonic acid ion exchanger in the NaForm (Dowex 50 W) and 100 ml of water, stirred for one hour. After removing the ion exchanger, the pH of the solution is 6-n. Hydrochloric acid adjusted to 2 and the aqueous phase extracted three times with 2000 ml of ethyl acetate each time.

  The organic extracts are washed once with 1000 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated.



   The crude product obtained is dissolved in 100 ml of methanol and stirred with a solution of 6 g of diphenyldiazomethane in 30 ml of benzene for 1 hour at room temperature.



  The crude product obtained after evaporation is chromatographed on 500 g of silica gel; the 3-methylene-7ss- (D-α-tert-butyloxycarbonylamino a-phenylacetyl-amino) -cepham-4α-carboxylic acid diphenylmethyl ester is eluted with a 4: 1 mixture of petroleum ether; after crystallization from a mixture of methylene dichloride and hexane, the product melts at 156-158 [α] = -50 # 1 (C = 0.713, chloroform); Ultraviolet absorption spectrum in 95% aqueous ethanol): #max = 258 (# = 990); Infrared absorption spectrum (in methylene chloride); characteristic bands at 2.94, 5.64, 5.74, 5.88 (shoulder) and 6.71.

 

   A solution of 25.7 g of 3-methylene-7fl- (Da-tert-butyloxycarbonylamino-α-phenyl-acetylamino) -cepham-4α-carbonic acid diphenylmethyl ester in 2500 ml of methylene chloride is cooled to -60 and during Treated for 110 minutes with a stream of a mixture of oxygen and ozone containing 0.45 mmol of ozone per minute. The reaction mixture is then mixed with 8 ml of dimethyl sulfide, stirred for one hour at -70 and 2 hours at room temperature and evaporated under reduced pressure.

  The residue is dissolved in 200 ml of methanol and the solution containing the 7B- (Da-tert-butyloxycarbonylamino-ar- phenyl-acetylamino) -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester is at 0 with a solution of Diazomethane in diethyl ether was added until it remained gel-colored. After stirring for 15 minutes, the mixture is evaporated under reduced pressure and the residue is chromatographed on 1100 g of silica gel. The 3-methoxy-7ss- (D-a-tert-butyloxycarbonylamino-α-phenyl-acetylamino) -2-cephem-4α-carboxylic acid diphenyl methyl ester is eluted with diethyl ether and crystallized from a mixture of methylene chloride and pentane, F.



  166-168 [α] 20 = + 178 +1 (c = @ 771 in chloroform)
D.
Thin-layer chromatogram (silica gel; developing with iodine): Rf¯0.61 (system: diethyl ether); Ultraviolet absorption spectrum (in ethanol): AmaX = 257 m (= 3550); Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 2.96, 5.63, 5.74., 5.85 (shoulder), 5.92, 6.16, 6.64 (shoulder) and 6.72 f. Further elution with diethyl ether gives the amorphous 3-methoxy-7,8- (datert-butyloxycarbonylamino-a phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, which can be lyophilized from dioxane, thin-layer chromatogram (Silica gel;
Development with iodine): Rf¯0.33 (system:

  Diethyl ether); [α] 20D = 1 | 1 (c = 0.98 in chloroform); Ultraviolet absorption spectrum (in ethanol) Ämox = 264 ', (e = 6300); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.62, 5.84, 5.88 (shoulder), 6.25 and 6.71, and the like.



   Example 3
A mixture of 8.8 g of 3-methoxy-7ss- (Da-tert-butyloxycarbonylamino-x-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, 8.6 ml of anisole and 145 ml of trifluorine acetic acid is stirred for 15 minutes at 0, then with
400 ml of pre-cooled toluene are added and the mixture is evaporated under reduced pressure. The residue is dried under high vacuum, digested with diethyl ether and filtered off. The trifluoroacetate of 3-methoxy-7ss- (D-a-phenyl-glycylamino) -3-cephem-4-carboxylic acid, which is dissolved in 20 ml of water, is thus obtained in powder form.

  You wash twice with each
25 ml of ethyl acetate and adjust the pH to about 5 with a 20% strength triethylamine solution in methanol, a colorless precipitate being formed. One stirs during one
Hour in an ice bath, then add 20 ml of acetone and leave during
Stand at about 4 for 16 hours. The colorless precipitate is filtered off, washed with acetone and diethyl ether and dried under reduced pressure. The 3-methoxy-7ss- (Da-phenyl-glycylamino) -3-cephem-4-carboxylic acid is thus obtained in the form of a microcrystalline powder as an inner salt, which is also present in the form of a hydrate, mp 174-176 (with decomposition ); [a] 20 = + 149 (c = 1.03 in 0.1-n.

  Hydrochloric acid);
D Thin-layer chromatogram (silica gel; developing with iodine): Rf¯0.36 (system: n-butanol / pyridine acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in 0.1-n.



  aqueous sodium hydrogen carbonate solution): Man = 267 (e = 6200); Infrared absorption spectrum (in mineral oil): characteristic bands a.o. at 5.72, 5.94. 6.23 and 6.60.



   The above-described 3-methoxy-7ss-D-α-phenyl-glycyl-amino) -3-cephem-4-carboxylic acid can also be obtained by isomerizing 3-methoxy-7ss (Da-phenyl-glycylamino) -2-cephem- 4a-carboxylic acid are formed; this can be obtained as follows:
A mixture of 0.063 g of 3-methoxy-7ss-zss- (Da-tert-butyloxycarbonylamino-cg-phenylacetylamino) -2-cephem-4a-carboxylic acid diphenylmethyl ester, 0.1 ml of anisole and 1.5 ml of trifluoroacetic acid is added during 15 Left to stand at 0 minutes and then evaporated under reduced pressure.



   The residue is digested with diethyl ether, filtered off and dried. The colorless and powdery trifluoroacetate of 3-methoxy-7ss- (Da-phenyl-glycylamino) -2-cephem-4a-carboxylic acid which can be obtained in this way is dissolved in 0.5 ml of water and the pH of the solution is adjusted by the dropwise addition of a 10% -igen solution of triethylamine in methanol adjusted to about 5. The mixture is stirred for one hour in an ice bath, the colorless precipitate is filtered off and dried in a high vacuum. The 3-methoxy-7ss- (D-α-phenyl-glycyl-amino) -2-cephem-4a-carboxylic acid is thus obtained as an inner salt, thin-layer chromatogram (silica gel; development with iodine):
Rf¯0.44 (system: n-butanol / pyridine: acetic acid / water 40/24: 6:30); Ultraviolet absorption spectrum (in 0.1-n.



   aqueous sodium hydrogen carbonate solution); Shoulder = 260 H-
Example 4
A mixture of 0.06 g of 3-methoxy-7ss-phenylacetylamino3-cephem-4-carboxylic acid diphenylmethyl ester and 0.05 ml of anisole and 1 ml of trifluoroacetic acid is left to stand for 5 minutes at room temperature and then evaporated under reduced pressure. The residue is taken to dryness twice with a 1: 1 mixture of chloroform and toluene and chromatographed on 5 g of silica gel (containing about 5% water).

  The amorphous 3-methoxy-7ss-phenylacetylamino3-cephem-4-carboxylic acid is eluted with methylene chloride containing 30-50% acetone and lyophilized from dioxane,
Ultraviolet absorption spectrum (in 95% aqueous ethanol): Ämax = 265 m, u (e = 5800); Infrared absorption spectrum (in methylene chloride): characteristic bands at
3.03, 5.60, 5.74, 5.92, 6.24 and 6.67.



   Example 5
A solution of 0.2 g of 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid in 10 ml of methanol is treated with a solution of diazomethane in diethyl ether at 0 'until it remains yellow and then evaporated under reduced pressure . The residue is chromatographed on silica gel.

  The methyl 3-methoxy-7ss-phenylacetylamino-3-cephem-4carboxylate is eluted with a 3: 1 mixture of toluene and ethyl acetate and recrystallized from a mixture of methylene chloride and hexane, F.171-174; [a] D20 = + 102 # 1% (c = 0.95 in chloroform); Ultraviolet absorption spectrum (in 95% strength aqueous ethanol): = 265 (# = 6250); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.62, 5.76,
5.93, 6.24 and 6.65.

 

   Example 6
In an analogous manner, with a suitable choice of starting material, 3-acetyloxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester can be obtained which, after crystallization from a mixture of acetone and diethyl ether, melts at 158-160; Ultraviolet absorption spectrum (in 95% aqueous ethanol): man = 258 m "(e = 6580) and
264 m "(e = 6550); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95, 5.59, 5.69 (shoulder), 5.78, 5.91, 6.06 (shoulder) and 6.67.



   Example 7
In an analogous manner, the following compounds can be obtained with a suitable choice of starting materials and, if necessary, after taking additional measures:
3-n-Butyloxy-7ss-phenylacetylamino-3-cephem-4-carbonic acid diphenylmethyl ester, colorless platelets with F. 168-170 after crystallization from a mixture of methylene chloride and diethyl ether, [α] 20D = +55 +1 ( c = 0.38 in chloroform);
Ultraviolet absorption spectrum (in 95% aqueous ethanol): # max = 264 (# = 7300);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at
2.98, 5.62, 5.81, 5.92, 6.25 and 6.62; 3-n-Butyloxy-7ss- (D-α-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, lyophilized from dioxane, [α] 20D = +11 +1 (c = 0.98 in chloroform); Ultraviolet absorption spectrum (in 95% strength aqueous ethanol): # max = 264 m, u (e = 6100); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88, 5.63, 5.84 (shoulder), 5.88,
6.26 and 6.71;
3-n-Butyloxy-7ss- (D-a-phenyl-glycylamino) -3-cephem
4-carboxylic acid in the form of the inner salt, F.141-142; Thin-layer chromatogram (silica gel):

  Rf¯0.21 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11); Ultraviolet absorption spectrum (in 0.1N aqueous sodium hydrogen carbonate solution): # max = 267 m (# = 7300); 3-Acthoxy-7ss- (d-α-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, as an amorphous product, thin layer chromatography (silica gel): Rf¯0.28 ( System:

  Toluene / ethyl acetate 3: 1); Ultraviolet absorption spectrum (in 95% aqueous ethenol): #max = 258 m, (e = 7000) and #max = 264 m, u (e = 6900); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5.64 ', 5.90, 6.28 and 6.73; 3-ethoxy-7ss- (D-α-phenyl-glycyclamino) -3-cephem-4-carboxylic acid, as an inner salt in the form of an amorphous product, thin-layer chromatogram (silica gel): RF-0.17 (system:

  Ethyl acetate / pyridine / acetic acid / water
62: 21: 6: 11); Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): # = 263 m (e = 5500);
3-Benzyloxy-7ss- (d-α-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, as amorphous product, thin-layer chromatogram (silica gel; development with iodine): Rf¯0 , 34 (system:

  Toluene / ethyl acetate 3: 1); [α] 20D = + 7 # 1 (c = 0.97 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max 2.58 m (3 = 6800), and 265 m (e = 6800), and shoulder = 280 m (e = 6300); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5.63, 5.88, 6.26 and 6.72;
3-Benzyloxy-7ss- (D-os-phenyl-glycylamino) -3-cephem-4 carboxylic acid, in zwitterionic form, thin-layer chromatogram (silica gel):

  Rf = 0.17 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11); Ultraviolet absorption spectrum (in 0.1 normal aqueous sodium hydrogen carbonate solution): # max = 266 m (3 = 6500); and 7ss- (5-benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, as amorphous product, thin-layer chromatogram (silica gel): Rf = 0.45 (system :

  Toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #shoulder = 258 m (e = 7450), 264 m (e = 7050) and 268 m (e = 6700); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65, 5.78, 6.03 and 6.64.



   Example 8
A solution of 0.263 g of 7ss- (5-benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 13 ml of methylene chloride is cooled to -100 and mixed with 0.132 ml of pyridine and 3, 52 ml of an 8% solution of phosphorus pentachloride in methylene chloride were added. The mixture is stirred for one hour at -, then cooled to -30, 2.2 ml of methanol, cooled to -30, is rapidly added, and stirring is continued for 30 minutes at -10 and -5. Then the reaction mixture is mixed with 6.5 ml of a 0.5 molar aqueous solution of potassium dihydrogen phosphate, stirred for 5 minutes at room temperature and the phases are separated.

  The aqueous phase is washed with methylene chloride; the combined methylene chloride phases are washed with concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in methanol and diethyl ether is added to the solution until it becomes slightly cloudy.

  The 7pp amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is thus obtained as an amorphous precipitate, thin-layer chromatogram (silica gel): Rf = 0.17 (system: ethyl acetate; development with iodine): ultraviolet absorption spectrum (in 95% - strength aqueous ethanol): lmax = 258 mfz (e = 5700); Infrared absorption spectrum (in dioxane): characteristic bands at 2.87, 5.62, 5.85 and 6.26
Example 9
A suspension of 1.65 g of 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 2 ml of anisole is mixed with 20 ml of precooled trifluoroacetic acid and stirred in an ice bath for 15 minutes. One dilutes with
100 ml of cold toluene and the reaction mixture is evaporated under reduced pressure.

  The dark brown residue is dried under high vacuum and stirred with diethyl ether; the precipitate is filtered off, washed with acetone and diethyl ether and dried. The salt of 7ss amino-3-methoxy-3-cephem-4-carboxylic acid and trifluoroacetic acid thus obtained is dissolved in 10 ml of water; the aqueous solution is washed twice with 10 ml of ethyl acetate each time, and brought to a pH of 4.5 by adding a 10% solution of triethylamine in methanol. One dilutes with
10 ml of acetone; the mixture is stirred at 0 for one hour.

  The precipitate is filtered off, with a 1: 2
Washed mixture of acetone and diethyl ether and dried in a high vacuum and gives the 7ss-amino-3-methoxy
3-cephem-4-carboxylic acid in the form of the inner salt,
Thin-layer chromatogram (silica gel): Rf¯0.16 (system: n
Butanol / acetic acid / water 67:10:23); Ultraviolet absorption spectrum (in 0.1N hydrochloric acid): #max = 261 m "(e =
5400).



   Example 10
A solution cooled to 0 of 0.257 g of Da-tert-butyloxycarbonylamino-a- (2-thienyl) acetic acid in 25 ml of methylene chloride is mixed with 0.097 ml of N-methylmorpholine and 0.129 ml of isobutyl chloroformate and for 30 minutes under one Stirred under a nitrogen atmosphere, then cooled to -100 and treated successively with 0.300 g of 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 0.085 ml of N-methylmorpholine. The reaction mixture is stirred for 30 minutes at -10 and for 30 minutes at 0, then 20 ml of water are added and the pH is adjusted to 7.9 by adding a 40% strength aqueous dipotassium hydrogen phosphate solution.

 

  The phases are separated, the aqueous solution is extracted with methylene chloride, and the combined organic solutions are washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The oily residue is purified by means of preparative layer chromatography (silica gel; system: diethyl ether; identification with ultraviolet light A = 254 m).



  The amorphous 7ss- [Da-tert-butyloxycarbonylamino-a- (2-thienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is thus obtained as the product which is uniform by thin-layer chromatography, thin-layer chromatogram (silica gel: identification with ultraviolet light A = 254 m, u): Rf¯0.34 (system: diethyl ether); [α] 20D = + 26 # 1 (c = 0.86 in chloroform); Ultraviolet absorption spectrum (in
95% aqueous ethanol): #max = = 240 m "(e = 125000) and 280 m" (e = 6000): infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.62,
5.85, 6.26 and 6.72.



   Example 11
A mixture of 0.200 g of 7ss- [Da-tert-butyloxycarbonyl-amino-a- (2-thienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 0.5 ml of anisole and 10 ml Pre-cooled trifluoroacetic acid is stirred for 15 minutes at 0, then 50 ml of cold toluene are added and the mixture is evaporated under reduced pressure. The residue is stirred with diethyl ether and the powdery precipitate is filtered off and dried. The thus obtained salt of 7ss- [Da-amino-α- (2-thienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid with trifluoroacetic acid is dissolved in about 6 ml of water, the pH value of Solution is made by adding 2-n.



  Adjusted hydrochloric acid to 1.5 and washed the aqueous solution with 20 ml of ethyl acetate and adjusted its pH to 5.0 by adding dropwise a 20% solution of triethylamine in methanol. It is diluted with 20 ml of acetone and the mixture is dissolved at 0 for 16 hours.

  The fine, colorless and microcrystalline powder is filtered off, washed with acetone and dried and gives the 7ss- [Da-amino-a- (2-thienyl) -acetylamino] -3-methoxy-3-cephem-4carboxylic acid in the form of the internal one Salt, F. 140 "(with decomposition); thin-layer chromatogram (silica gel; identification with iodine): Rf¯0.22 (system: n-butanol / acetic acid / water 67:10:23) and Rf¯0.53 (system:

  Isopropanol / formic acid / water 77: 4: 19); Ultraviolet absorption spectrum: Ämax = 235 m "(e = 11400) and 12shoulder = 272 m (# = 6100) in 0.1-n. Hydrochloric acid, and #max = 238 m" (e = 11800) and shoulder = 267 m "( e = 6500) in 0.1N aqueous sodium hydrogen carbonate solution.



   Example 12
In an analogous manner, the following compounds can be obtained in an analogous manner using the suitable starting materials, optionally after additional conversion of a product obtained:
7 ss- [D-ex-tert-butyloxycarbonylamino-x- (4-hydroxyphenyl) -acetylamino] -3-methoxy-3 -cephem-4-carboxylic acid diphenylmethyl ester, thin-layer chromatogram (silica gel; identification with iodine) : Rf¯0.35 (system:

  Toluene / ethyl acetate 1: 1); [α] 20D ¯-1 # 1 (c = 0.566 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): man = 276 m "(e = 7400);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.83, 2.96, 5.64, 5.86, 5.91 (shoulder), 623, 628, 6.65 CL and 6.72; which can be converted into the 7ss- [D-a-amino-a: - (4-hydroxyphenyl) -acetylaminol- 3-methoxy-3-cephem-4carboxylic acid as follows:
A mixture of 0.095 g of 7ss- [D-α-tert-butyloxycarbonyl-amino-α- (4-hydroxyphenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 0.25 ml of anisole and 5 ml of pre-cooled trifluoroacetic acid are stirred for 15 minutes at 0, then 50 ml of cold toluene are added and the mixture is evaporated under reduced pressure. The residue is stirred with diethyl ether and the powdery precipitate is filtered off and dried.

  The salt of 7ss- [Da-amino-n- (4-hydroxyphenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid with trifluoroacetic acid is dissolved in about 5 ml of water, the pH value the solution is made by adding 2-n. Adjusted hydrochloric acid to 1.5, and washed the aqueous solution with 20 ml of ethyl acetate and adjusted its pH by dropwise addition of a 20% solution of triethylamine in methanol to 5.0, a colorless precipitate being formed. It is diluted with 8 ml of acetone and the mixture is left to stand at 0 "for 16 hours. The precipitate is filtered off, washed with acetone and diethyl ether and dried under reduced pressure.

  The 7ss- [Dα-amino-α- (4-hydroxyphenyl) -acetylamino] -3-methoxy-3cephem-4-carboxylic acid is thus obtained in the form of the inner salt, F = 180 "(with decomposition ); Thin-layer chromatogram (silica gel; identification with iodine): Rf¯0.24 (system: n butanol / acetic acid / water 67:10:23) and Rf¯0.57 (system: isopropanol / formic acid / water 77: 4: 19 ); Ultraviolet absorption spectrum: AmaX = 228 m "(e = 12000) and 271 m" (e = 6800) in 0.1-n.

  Hydrochloric acid, and AmaX = 227 mAe (e = 10500) and shoulder = 262 m "(e = 8000) in 0.1 n. Aqueous sodium hydrogen carbonate solution; 7ss- [D-? -Tert.-butyloxycarbonylamino- ?- ( 4-isothiazolyl) - acetylamino] - 3-methoxy-3-cephem-4-carboxylic acid diphenyl 20 methyl ester, amorphous, [] D = + 260 * 10 (c = 0.65 in chloroform); thin-layer chromatogram (silica gel; identification with Iodine): Rf-0.43 (system:

  Toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Ao, ax = 250 m, u (e = 12200) and 280 m "(e = 5900); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.65 , 5.71 y (shoulder),
5.88, 6.28 and 6.73; 3 -Methoxy-7ss-methoxycarbonylacetyl-amino-3-cephem
4-carboxylic acid, thin layer chromatogram (silica gel; system: ethyl acetate / acetic acid 9: 1):

  Rf = 0.5-0.6; Ultraviolet Absorption Spectrum (in methanol): AmaX at 265 my; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66;
7ss-Bromoacetyl-amino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (solic gel; system: n-butanol /
Acetic acid / water 75: 7.5: 21): RF = 0.25-0.35; Ultraviolet absorption spectrum (in 95% aqueous ethanol): one at 264 m "; 3-methoxy-7ss-phenyloxyacetyl-amino 3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n butanol / acetic acid / water 75: 7 , 5:21):

  RF = 0.30.4; Ultraviolet absorption spectrum (in 95% aqueous ethanol): Ämax = 266 my; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66; 3-Methoxy-7ss- (2-thienyl) - acetylamino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: butanol / pyridine / acetic acid / water 38: 24: 8: 30):

  Rf = 0.5-0.6; Ultraviolet absorption spectrum (in 95% aqueous ethanol): A max at 235 and 264 mk; 7ss - (α-carboxy-α-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 40: 24: 6 : 30):
7ss-Acetoacetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 75: 5: 21): Rf = 0.3-0.4; Ultraviolet absorption spectrum (in 95% aqueous ethanol): Ämax at 238 m, u and 265 my;
7ss-cyanoacetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30):

  Rf = 0.35-0.45; Ultraviolet absorption spectrum (in 95% aqueous ethanol): one at 264 m "; infrared absorption spectrum (in mineral oil): characteristic bands at 4.32 and 5.65; 7ss- (a: cyano-propionylamino) -3-methoxy-3 -cephem-4-carboxylic acid, thin layer chromatogram (silica gel; system: n butanol / pyridine / acetic acid / water 38: 24: 8: 30):

  Rf = 0.4-0.5; Ultraviolet absorption spectrum (in 95% aqueous ethanol): # max at 265 m; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.44 and 5.66 U;
7ss - (α-cyano-α-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 75: 7.5: 21) Rf = 0.3-0.4; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max at 267 m; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.42 and 5.65;
7ss- (2-chloroethylamino-carbonylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel); Rf = 0.3-0.4 (system: n-butanol / acetic acid / water 75 / 7.5: 21);

  Ultraviolet absorption spectrum (in 0.1 molar hydrochloric acid): λ max at 266 m ";
7ss-dichloroacetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n butanol / acetic acid / water 75: 7.5: 21): Rf = 0.40; Ultraviolet absorption spectrum (in 95% aqueous ethanol): one at 264 m, u; Infrared absorption spectrum (in mineral oil): characteristic band at 5.67; 3-Methoxy-7ss - (α-sulfo-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid in the form of the disodium salt, thin-layer chromatogram (silica gel):

  Rf¯0.10-0.20 (system: n butanol / acetic acid / water 67:10:23); 3-Methoxy-7ss - (α-phenylaminocarbonyl-acctylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 67:10:23): Rf = 0 , 30; Ultraviolet absorption spectrum (in ethanol): #max at 241 m and 266 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.65;
3-Methoxy-7ss-methoxyacetylamino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system:

  Ethyl acetate / pyridine / acetic acid / water 60: 20: 6: 11): Rf = 0.30; Ultraviolet absorption spectrum (in mineral oil): characteristic band at 5.64; 3-Methoxy-7ss - (α-4-methylphenylthio-acetylamino) -3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 67:10:23): Rf = 0 .45; Ultraviolet absorption spectrum (in ethanol): Awax at 264 my; Infrared absorption spectrum (in mineral oil): characteristic band at 5.63;
7ss-Benzoylacetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n butanol / pyridine / acetic acid / water 38: 24: 8: 30):

  Rf = 0.40; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 267 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66; 7ss- (3-chloropropionylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin layer chromatogram (silica gel; system: n butanol / acetic acid / water 75: 7.5: 21): Rf = 0.30; Ultraviolet absorption spectrum (in 95% aqueous ethanol): A max at 265 m, u; Infrared absorption spectrum (in mineral oil): characteristic band at 5.65;
7ss-chloroacetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30):

  Rf = 0.50; Ultraviolet absorption spectrum (in 95% aqueous ethanol): λ max at 266 m "; infrared absorption spectrum (in mineral oil): characteristic band at 5.65;
7ss- (3-butenoyl-amino) -3-methoxy-4-cephem-4-carboxylic acid, thin layer chromatogram (silica gel; system: n butanol / pyridine / acetic acid / water 38: 24: 8: 30): Rf = 0 , 65; 3ss-methoxy-7ss- (a: -methylthio- acetylamino) - 3-methoxy3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30):

  Rf = 0.60; Ultraviolet absorption spectrum (in 95% aqueous ethanol): A max at 266 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.7;
7ss- (bis-methoxycarbonyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30): Rf = 0, 45; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): #max at 268 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.64;
7ss-dibromoacetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n
Butanol / acetic acid / water 75: 7.5: 21):

  Rf = 0.3 to 0.4; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): #max at 264 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.63, u;
3-methoxy-7ss-pivalylamino-3-cephem-4-carboxylic acid, thin layer chromatogram (silica gel):

  Rf¯0.5-0.6 (system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30); Ultraviolet absorption spectrum (in 95% aqueous ethanol): # max¯265 m; Infrared absorption spectrum (in mineral oil): characteristic Baude at 5.66; 7ss - (α-Azido-α-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf-0.4-0.5 (system: n-butanol / Pyridine / acetic acid / water 38: 24: 8: 30);

  Ultraviolet absorption spectrum (in 95% aqueous ethanol): ax 267 m ',; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.66 and 5.65; 7ss-a-0,0-dimethyl-phosphono-a-phenyl-acetylamino) - 3methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf-0.4 (system: n-butanol / acetic acid / water 67 : 10:23);

  Ultraviolet absorption spectrum (in 95% ethanol): Xmax 266 m, u; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66, u;
3-Methoxy-7ss- (5-methyl-3-phenyl-4-isoxazolyl-carbonylamino) -3-cephem-4-carboxylic acid, thin-layer chromatogram (Siilkagel):

  Rf¯0.3-0.4 (system: n-butanol / acetic acid / water 67:10:23); Infrared absorption spectrum (in mineral oil): characteristic band at 5.65;
7ss- (4-aminomethylphenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf¯0.25-0.3 (system: n-butanol / acetic acid / water 67: 10:23); Ultraviolet absorption spectrum (in 0.1 N hydrochloric acid): max 265 my; Infrared absorption spectrum (in mineral oil); characteristic band at 5.68;
7ss- (2,6-Dimethoxy-benzoylamino) -3-methoxy-3-cephem4-carboxylic acid, thin-layer chromatogram (silica gel): Rf-0.50 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30);

  Ultraviolet absorption spectrum (in 95% aqueous ethanol): λ, uax = 265 my; Infrared absorption spectrum (in mineral oil): characteristic band at 5.64; 7ss- [D-α-tert-butyloxycarbonylamino-α- (3-thienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester; Thin-layer chromatogram (silica gel): Rf¯0.3-0.4 (system: diethyl ether); Ultraviolet absorption spectrum (in 95% aqueous ethanol): man = 238 m, u and 276 mp; 7ss- [D-α-amino-α- (3-thienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid, thin layer chromatogram (silica gel):

  Rf¯0.2-0.3 (system: n-butanol / acetic acid / water 67:10:23); Ultraviolet absorption spectrum (in 0.1N hydrochloric acid): Ä ,, ax = 235 m "and 270 m, u;
7ss- [D-a-tert-butyloxycarbonylamino-a- (2-furyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester; Thin layer chromatogram (silica gel): Rf-0.35 (system:

  Diethyl ether); Ultraviolet absorption spectrum (in 95% aqueous ethanol): A max 265 m "; 7ss- [Da-amino-a- (2-furyl) -acetylamino] -3-methoxy-3cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf ¯0.25 (system: n-butanol / acetic acid / water 67:10:23);

  Ultraviolet absorption spectrum (in 0.1N hydrochloric acid): A max 265 m "; 7ss- (D-α-hydroxy-α-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, lyophilized from dioxane, Thin-layer chromatogram (silica gel): Rf-0.35 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30), ultraviolet absorption spectrum (in 95% aqueous ethanol): Amax 265 m, u; infrared absorption spectrum ( in mineral oil): characteristic band at 5.66;
7ss- (1-Amino-cyclohexyl-carbonylamino) -3-methoxy-3cephem-4-carboxylic acid, as inner salt in amorphous form, thin layer chromatogram (silica gel): Rf- 0.2-0.2S (system:

   n-butanol / acetic acid / water 67:10:23); Ultraviolet absorption spectrum (in 0.1N hydrochloric acid): A max 264 m, u; Infrared absorption spectrum (in mineral oil): characteristic band at 5.56 y;
3-methoxy-7ss- (4-pyridylthio-acetylamino) -3-cephem-4carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30): Rf = 0.25- 0.30; Infrared absorption spectrum (in mineral oil): characteristic band at 5.65; 7ss - (α-4-amino-pyridinium-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, as inner salt in amorphous form, thin-layer chromatogram (silica gel):

  Rf = 0.20-0.3 (system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30); Infrared absorption spectrum (in mineral oil): characteristic band at 5.65;
3-methoxy-7ss- (1-tetrazolyl-acetylamino) -3-cephem-4carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30): Rf = 0.35- 0.45; 3 -Methoxy-7ss- (1 -methyl-2-imidazolylthio-acetylamino) -3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30):

  Rf = 0.3-0.4; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66; 3-Methoxy-7ss- (1,2,4-triazol-3-ylthio-acetylamino) -3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 42: 24: 4 : 30): Rf = 0.3-0.4; and
7ss-Azidoacetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30): Rf = 0.40; Ultraviolet absorption spectrum (in ethanol): Aax at 264 m "; infrared absorption spectrum (in mineral oil): characteristic bands at 4.65 y and 5.64.



   Example 13
A mixture of 1.0 g of 7ss- (D-α-amino-α-phenyl-acetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid in 10 ml of acetone is mixed with 0.8 ml of triethylamine . The mixture is stirred for 24 hours at room temperature, filtered and the filtrate is then evaporated. The residue is dissolved in water, the pH is adjusted using 2-n. Hydrochloric acid adjusted to 2.5 and the precipitate then filtered and dried. The 7ss- (2,2-dimethyl-5-oxo-4-phenyl-1,3-diaza-1-cyclopentyl) -3-methoxy-3-cephem-4-carboxylic acid, which is available as a colorless product, shows in the thin-layer chromatogram (silica gel) an Rf value of 0.40 (system: n-butanol / pyridine / acetic acid / water 40/24/6/30).



   Example 14
A suspension of 0.100 g of 7ss- (D-a-amino-a-phenyl acetylamino) -3-methoxy-3-cephem-4-carboxylic acid in 5 ml of absolute methylene chloride is mixed with 0.0364 g of triethylamine and stirred for 10 minutes; most of the material goes into solution. It is cooled to - 50 and a total of 0.0652 g of the triethylamine-sulfur trioxide complex (F.89-90) is added in portions. The mixture is stirred for 5
Minutes at 0 and for two hours at 20. The solution is treated with 0.9 mmol of sodium α-ethyl hexanoate and the precipitated product is filtered off.

  After washing with methylene chloride and diethyl ether, the powdery precipitate containing the disodium salt of 3-methoxy-7ss- (D-a-sulfoamino-n-phenyl-acetylamino) - 3-cephem-4-carboxylic acid, dried under high vacuum; Thin-layer chromatogram (silica gel): Rf = 0.10 (system: n-butanol / acetic acid / water
71.5: 7.5: 21); Ultraviolet absorption spectrum (in water): #max = 267 m ".



   Example 15
A solution of 0.037 g of sodium nitrite in 0.4 ml of water is added to a cooled solution of 0.100 g of 4-guanylsemicarbazide dihydrochloride in 0.6 ml of water, while stirring, the mixture is stirred for 10 minutes at 0 and then added dropwise at 0 to one solution of 0.186 g of 7ss- (D-α-amino-α-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid in 4 ml of water, adjusted to pH 7.5 with triethylamine. The mixture is stirred for one hour at 0 ", the precipitate is filtered off, washed with water and dried.

  The crude 7ss-! D- a- (3-guanyl-ureido) -a-phenyl-acetylamino] -3-methoxy-3cephem-4-carboxylic acid is obtained in this way, which in the thin-layer chromatogram (silica gel; development with iodine vapor): Rf¯ 0.20-0.30 (system: n-butanol / acetic acid / water 67:10:23); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Ämax = 265 m e.

 

   Example 16
Dry ampoules or vials containing 0.5 g of 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid are prepared as follows: Composition (for 1 ampoule or vial) 3-methoxy-7ss-phenylacetyl- 0.5 g amino-3-cephem-4-carboxylic acid mannitol 0.05 g
A sterile aqueous solution of 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid and mannitol is subjected to freeze-drying under aseptic conditions in 5 ml. Ampoules or 5 ml vials and the ampoules or vials



  Vials sealed and checked.



   Example 17
Dry ampoules or vials containing 0.5 g of the inner salt of 3-methoxy-7, ss- (Da-phenylglycyl-amino) -3-cephem-4-carboxylic acid are prepared as follows: Composition (for 1 ampoule or vial) Inside Salt of 3-methoxy-7ss-0.5 g (Da-phenylglycyl-amino) -3-cephem-4-carboxylic acid mannitol 0.05 g
A sterile aqueous solution of the inner salt of 3-methoxy-7ss- (Da: -phenylglycyl-amino) -3-cephem-4-carboxylic acid and mannitol is freeze-drying in 5 ml. Ampoules or 5 ml. Vials under aseptic conditions subjected and the ampoules or vials sealed and checked.



   Example 18
Capsules containing 0.25 g of the inner salt of 3 methoxy-7ss- (D-α-phenyl-glycylamino) -3-cephem-4-carboxylic acid are prepared as follows; Composition (for 4000 capsules): Inner salt of 3-methoxy-7ss- 250,000 g (D-n-phenylglycyl-amino) - 3 -cephem-4-carboxylic acid corn starch 50,000 g polyvinylpyrrolidone 15,000 g magnesium stearate 5,000 g ethanol q.s.



   The inner salt of 3-Methxoy-7ss- (D-α-phenyl-glycyl-amino) -3-cephem-4-carboxylic acid and the corn starch are mixed and moistened with a solution of polyvinylpyrrolidone in 50 g of ethanol. The moist mass is pressed through a sieve with a mesh size of 3 mm and dried at 45. The dry granules are forced through a sieve with a mesh size of 1 mm and mixed with 5 g of magnesium stearate. The mixture is filled into size 0 capsules in portions of 0.320 g.



   Example 19
256.3 g of 3-methoxy-7ss- (Da-tert-butyl-oxycarbonylamino-α-phenylacetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester are mixed with a mixture of 250 ml of anisole in 1200 ml of methylene chloride and treated at 0 with 1200 ml of trifluoroacetic acid pre-cooled to 0. The mixture is left to stand at 0 for 30 minutes and the reaction mixture is diluted over the course of 15 minutes with 12,000 ml of a 1: 1 mixture of diethyl ether and petroleum ether which has been cooled to 0. The precipitated trifluoroacetic acid salt of 3-methoxy-7ss- (d-α-phenylglycylamino) -3-cephem-4-carboxylic acid is filtered off, washed with diethyl ether, dried under reduced pressure and dissolved in 1900 ml of water.

  To remove the yellowish-colored impurities, it is washed with 900 ml of ethyl acetate; the organic washing liquid is discarded and the aqueous solution (pH ,5 1.5) is adjusted to pH 4.5 with a 20% solution of triethylamine in methanol. The inner salt of 3-methoxy-7ss- (D-aphenyl-glycylamino) -3-cephem-4-carboxylic acid crystallizes out as a dihydrate in the form of colorless prisms and is filtered off after adding 1800 ml of acetone and stirring at 0 for 2 hours , F.175-177 (with decomposition); [or] 2D0 + 138 # 1 (c = 1 in 0,1-n.

  Hydrochloric acid); Ultraviolet absorption spectrum (in 0.1N aqueous sodium hydrogen carbonate solution): #max = 265 m "(e = 6500); infrared absorption spectrum (in mineral oil): bands at 2.72,, 2.87, u, 3.14, u , 3.65, 5.68, 5.90, 6.18, 6.27, 6.37, 6.56, 6.92, 7.16, 7.58, 7.74, 7.80, 8 , 12, 8.30, 8.43, 8.52, 8.65, 8.95, 9.36, 955, 9.70, 10.02, 10.38, 10.77, 11.70, 12 , 01, 12.15, 12.48, 12.60, 12.87, 13.45 and 14.30, u; microanalysis (C16H17O5N3S 2H2O; molecular weight: 399.42): calculated: C 48.11%, H. 5.30%, N 10.52% and S 8.03%; found: C 47.86%, H 5.27%, N 10.47% and S 8.00%.

 

Claims (1)

PATENT CLAIM Process for the preparation of 0-substituted 7P-amino-3-cephem-3-ol-4-carboxylic acid compounds of the formula EMI23.1 wherein Ra1 represents hydrogen or an amino protective group R1 A, and Rb represents hydrogen or an acyl group Ac, or Ra1 and Rb1 together represent a divalent amino protective group, R2 represents hydroxy or a protected carboxyl group together with the carbonyl group -C (= 0) - Rt forming radicals, and R3 stands for an optionally substituted hydrocarbon radical or an acyl group, and salts of such compounds with salt-forming groups, characterized in that a 2-cephem compound of the formula EMI23.2 or a salt thereof is isomerized by treatment with a weakly basic agent, and a compound of the formula I obtained with a salt-forming group as a salt or as a free compound is isolated. SUBCLAIMS 1. The method according to claim, characterized in that starting materials of the formula II are used in which Ra1 is an amino protective group Rt, which stands for an acyl group Ac, in which any free functional groups present may be protected, Rb1 is hydrogen, and R2 is a with - C (= O) grouping represents an etherified hydroxyl group Rt which forms an esterified carboxyl group, it being possible for any functional groups present in an esterified carboxyl group of the formula = = O) -R to be protected. 2. The method according to dependent claim 1, characterized in that Ru is an optionally substituted 1-phenyl-lower alkoxy, such as diphenylmethoxy group or an optionally halogen-substituted lower alkoxy group, such as a-polybranched lower alkoxy, z. B. tert-butyloxy, or 2-halo-lower alkoxy, such as 2,2,2-trichloroethoxy. 3. The method according to claim, characterized in that a weak organic, nitrogen-containing base, such as a tertiary heterocyclic base of aromatic character, or a tertiary aliphatic, azacycloaliphatic or araliphatic base is used as the isomerizing agent. 4. The method according to dependent claim 3, characterized in that a base of the pyridine type, such as pyridine, or a Tr-lower alkylamine, such as triethylamine or N, N-diisoropropyl N-ethylamine, used as an isomerizing agent. 5. The method according to claim, characterized in that free amino groups not participating in the reaction are intermediately protected by acylation, tritylation or silylation, free hydroxyl or mercapto groups by etherification or esterification and free carboxyl groups by esterification in a starting material. 6. The method according to claim, characterized in that in a compound obtained the protected Carboxyl group -C (= O) -RZ by solvolysis, reduction or Photolysis converted into a free carboxyl group. Process according to claim, characterized in that in a compound obtained in which Ru or Rb denotes an acyl group, a suitable acyl group e.g. split off by hydrolysis, aminolysis or hydrazinolysis and replaced by hydrogen. 8. The method according to claim, characterized in that a free amino group in a compound obtained is acylated by treatment with a carboxylic acid or a reactive derivative thereof. 9. The method according to claim or one of the subclaims 1-8, characterized in that 3-cephem compounds of the formula I according to claim, and salts of such compounds with salt-forming groups, wherein Rt one, in a fermentative or bio, half or totally synthetically producible N-acyl derivative of a 6ss-aminope nam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compound is an acyl radical, Rib stands for hydrogen, or in which R, and R1 together represent a 2- Position preferably and optionally substituted 1 in the 4-position Represent oxo-3-aza-butylene radical, R2 is hydroxy, optionally substituted lower alkoxy, acyloxy, tri-lower alkylsilyloxy, or optionally substituted amino or hydrazino, and R3 lower alkyl, optionally substituted phenyl lower alkyl, lower alkanoyl or optionally substituted Represents benzoyl. 10. The method according to claim or one of the Dependent claims 1-8, characterized in that 3-Ce phem compounds of the formula I according to the patent claim, furthermore salts of such compounds with salt-forming groups, in which Rt is a group of the formula EMI24.1 where n is 0 and Rl is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably aromatic rule, a functionally modified, z. B. esterified or etherified hydroxyl or mercapto group, or an optionally substituted amino group, or wherein n is 1, R 'hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted one heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has aromatic character and / or a quaternary nitrogen atom, an optionally functionally modified, preferably etherified or esterified, hydroxy or mercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or represents an azido group, and each of the radicals R11 and Rlll is hydrogen, or where n is 1, Rl is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably, has aromatic character, R11 a functionally modified if necessary, z. B. esterified or etherified Hydroxy or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, an optionally mono- or 0-disubstituted phosphorus group, an azido group or a halogen atom, and Rlll is hydrogen, or where n is 1 each of the radicals Rl and R is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and Rlll is hydrogen, or where n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic , denotes aromatic or araliphatic hydrocarbon radical and R11 and R together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical linked to the carbon atom by a double bond, or in which n stands for 1, and Rl an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic -aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have an aromatic character, R an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and Ril 'denotes hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical, Rbl stands for hydrogen, R2 is hydroxy, lower alkoxy, 2-halo-lower alkoxy, phenyloxy, 1-phenyl-lower alkoxy with 1-3, phenyl radicals optionally substituted by lower alkoxy or nitro, lower alkanoyloxymethoxy, lower alkoxycarbonyloxy or lower alkanoyloxy, and R3 is lower alkyl, 1-phenyl-lower alkyl, lower alkanoyl or benzoyl. Process according to patent claim or one of the dependent claims 1-8, characterized in that 3-cephem compounds of the formula I according to the patent claim or salts of compounds with salt-forming groups in which Rlb is hydrogen, pure acyl group of the formula are prepared EMI25.1 wherein Ar is phenyl, hydroxyphenyl, hydroxychlorophenyl or 2 thienyl, where in such radicals hydroxy substituents can be protected by acyl radicals, X represents oxygen or sulfur, n represents 0 or 1, and Rb represents hydrogen or, if n represents 0, optionally protected Amino, carboxy, sulfo or hydroxy, or 0-lower alkylphosphono or 0,0'-di-lower alkylphosphono, or denotes a 5-amino5-carboxy-valeryl radical in which the amino and carboxy groups are optionally protected, R2 is hydroxy, Is lower alkoxy-2-halo-lower alkoxy or optionally substituted diphenylmethoxy, and R3 is lower alkyl or lower alkanoly. 12. The method according to claim or one of the sub-claims 1-8, characterized in that 3 cephem compounds of the formula I according to claim or salts of such compounds with salt-forming groups are prepared, wherein RA1 is the acyl radical of the formula B according to sub-claim 11, wherein Ar Phenyl, X is oxygen, n is 0 or 1, and R is hydrogen, or if n is 0, optionally protected amino or hydroxy, or 0-lower alkyl- or 0, 0-di-lower alkylphosphono, or a 5-amino-5-carboxy-valeryl radical wherein the amino and carboxy groups are optionally protected, R2 is hydroxy, optionally lower alkoxy which is halogen-substituted in the 2-position or optionally lower alkoxy-substituted diphenylmethoxy, and R3 is lower alkyl or lower alkanoyl. 13. The method according to claim or one of the dependent claims 1-5, 7 and 8, characterized in that the 3-methoxy-7ss- (Da-tert-butyloxycarbonylamino-aphenylacetylamino) - 3-cephem-4-carboxylic acid diphenylmethyl ester is prepared . 14. The method according to claim or one of the dependent claims 1-8, characterized in that the 3-methoxy-7ss- (D-a-phenylglycylamino) -3-cephem-4-carboxylic acid or salts thereof are prepared. 15. The method according to claim or one of the dependent claims 1-5, 7 and 8, characterized in that the 3-methoxy-7ss-phenylacetylamino-3-cephem-4carboxylic acid diphenylmethyl ester is prepared. 16. The method according to claim or one of the dependent claims 1-8, characterized in that the 3-methoxy-7ss-phenylacetyl-amino-3-cephem-4-carboxylic acid is prepared.