CH579090A5 - 7-Amino-3-methylene-cephams prepn. - by reducing 7-amino-3-acyloxymethyl-3-cephems, used as inters for antibiotic cephalosporins - Google Patents

Abstract

Cpds. of formula (I) (where R is a second bond between the attached C atom and posn. E, with only a single bond between posn. 3 and 4; R1 is H or an amino-protecting gp.; R2 is H or an acyl; or R1 and R2 together represent a divalent amino-protecting gp.; and R3 is OH, or together with the carbonyl gp. forms a protected carboxyl residue), their 1-oxides and salts, are prepd. by reducing cpds. (II) (I; R is acyloxy; and R3 is as before or R+R3 is -O-), or their oxides or salts with a metal (amalgam) having a normal potential of -2.4 to -0.40 volt (pref. Al) at pH 1-8 in the presence of water. (I) and their l-oxides and salts are inters. for antibiotic cephalosporins, and are readily isomerizable to 7-amino-3-methyl-3-cephems.

Description

  

  
 



   The invention relates to a process for the preparation of 7, B-amino-3-methylene-cepham-4-carboxylic acid compounds de; formula
EMI1. 1
 where Rla represents hydrogen or an amino protective group R1A, Rlb represents hydrogen or an acyl group Ac, or Rla and Rjb together represent a divalent amino protective group, and R2 represents hydroxy or a carboxyl group which forms a protected carboxyl group together with the carbonyl group -C (= O) - Radical R2A is, and salts of such compounds with salt-forming groups. 



   The compounds of the formula I which can be prepared according to the invention or their salts can be used as intermediates for the preparation of antibiotically active cephalosporan compounds. 



   In compounds of the formula I, the optionally protected carboxyl group of the formula -C (= o) -R2 preferably has the os configuration. 



   An amino protective group R1A is a group which can be replaced by hydrogen, primarily an acyl group Ac, furthermore a triarylmethyl, 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 together by the radicals Rla and Rlb 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, furthermore the acyl radical of a, preferably substituted in a position, z. B.  an aromatic or heterocyclic radical containing cc-aminoacetic acid, wherein the amino group via a, preferably substituted, z. B.  two lower alkyl, such as methyl groups containing methylene radical is connected to the nitrogen atom. 

  The radicals Rla and Rlb 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 -C (= O) - R2A is primarily an esterified carboxyl group, but can also represent a usually mixed anhydride group or an optionally substituted carbamoyl or hydrazino-carbonyl group. 



   The group R2A can be a hydroxyl group which is etherified by an organic radical, in which the organic radical preferably contains up to 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 hydroxy group esterified by an organometallic radical, such as a corresponding organic stannyloxy group, in particular a hydrocarbon radical optionally substituted by 1 to 3, 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 R2A which forms a primarily mixed anhydride group with a -C (= O) group is in particular an acyloxy radical in which acyl is the corresponding radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, such as an aliphatic, cycloaliphatic, cycloaliphatic -aliphatic, aromatic or araliphatic carboxylic acid or a carbonic acid half-derivative, such as a carbonic acid half-ester. 



   A radical R2A which forms a carbamoyl group with a -C (= O) group 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 bivalent 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 ones 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 (= O) -R2A, one or both nitrogen atoms can be substituted, the substituents primarily being optionally substituted monovalent or bivalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted, monovalent or bivalent 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. 



   The general terms used in the description above and below have e.g. B.  the 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 hydroxyl 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 alkoxycarbonyloxy or lower alkanoyloxy, optionally substituted by oxo- or halo Amino, e.g. B.    Lower alkylamino, di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino or aza-loweralkylenamino, and acylamino, such as lower alkanoylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, azido, acyl, such as lower alkanoyl or benzoyl,

   optionally functionally modified carboxyl, such as carboxyl present in salt form, esterified carboxyl, such as lower alkoxycarbonyl, optionally substituted carbamoyl, such as N-lower alkyl- or N, N-di-lower alkylcarbamoyl, also optionally substituted ureidocarbonyl or guanidino carbonyl, or cyano, optionally functionally modified sulfo, such as sulfamoyl or sulfo present in salt form, or optionally O-mono- or O, O-disubstituted Phos phono, wherein substituents z.  B.  optionally substituted
Represent lower alkyl, phenyl or phenyl lower alkyl, unsubstituted or 0-monosubstituted phosphono also in
Salt, such as alkali metal salt form, can be mono-, di or polysubstituted. 



   A bivalent aliphatic residue, incl.  the corresponding
The remainder of a divalent aliphatic carboxylic acid is z. B.  Never deralkylen or lower alkenylen, which optionally, z.  B.  such as an aliphatic radical specified above, mono-, di- or poly-substituted and / or by heteroatoms, such as oxygen,
Nitrogen or sulfur can be interrupted. 



   A cycloaliphatic or cycloaliphatic-aliphatic
Remainder, including the cycloaliphatic or cycloaliphatic aliphatic radical in a corresponding organic carboxylic acid or a corresponding cycloaliphatic or cy cloaliphatic-aliphatic ylidene radical in an optionally substituted, mono- or bivalent cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, z.  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, in which cycloalkyl and
Cycloalkylidene e.g.  B.  contains up to 12, such as 3-8, preferably 3-6 ring carbon atoms, 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 aliphatic radicals can, if desired, e.g.  B.  by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned, optionally substituted lower alkyl groups, or then, for. B.  like the abovementioned aliphatic hydrocarbon radicals, mono-, di- or polysubstituted by functional groups. 



   An aromatic 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, especially phenyl, and biphenylyl or naphthyl, which may optionally, for. B.  like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, can be mono-, di- or polysubstituted. 



   A divalent aromatic radical, e.g. B.  an aromatic one
Carboxylic acid, is primarily 1,2-arylene, especially 1,2
Phenylene, optionally, e.g.  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, and also 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 the ss or p-position, substituted lower alkyl half esters of carbonic acid, as well as 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.  one of the abovementioned heterocyclic groups of aromatic character, it being possible for both the lower alkyl radical and the heterocyclic group to be optionally 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 hydroxy 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, also lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, and also heterocyclyloxy or, in particular, heterocyclyloxy optionally 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 tert. -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-ethylene or 2-buten-1P-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, cycloalkyl is e.g. B.  Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl, Cv- - cloalkenyl 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 cycloheptyl-methyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, -vinyl or -allyl , while Cycloalkenyi-lower alkyl or lower alkenyl z.  B.  1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl- or 1-, 2- or 3-cycloheptenyl-methyl, -1,1- or -1,2-ethyl, -1, Represents 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. B.  Benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl, trityl, styryl or cinnamyl, naphthyl-lower alkyl z.  B.  1- or 2-naphthylmethyl, and phenyl lower alkylidene e.g.  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, e.g. B.  2-, 3- or 4-pyridyl, also pyridinium, 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. B.  2- or 3-indolyl, quinolinyl, e.g. B.  2- or 4-quinolinyl, isoquinolinyl, e.g. B.  l-isoquinolinyl, benzofuranyl, e.g. B.  2 or 3-benzofuranyl, or benzothienyl, e.g. B.  2- or 3-benzothienyl, monocyclic diaza, triaza, tetraza, oxaza-, thiaza or thiadiazacyclic radicals, such as imidazolyl, e.g. 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- or 4-isoxazolyl, thiazolyl, e.g. B.  2-thiazolyl, isothiazolyl, e.g. B.  3- or 4-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, oxaza- or thiazacyclic radicals, such as benzimidazolyl, e.g. B. 



  2-benzimidazolyl, benzoxazolyl, e.g. B.  2-benzoxazolyl, or benzthiazolyl, e.g. B.  2-benzothiazolyl.  Corresponding partially or fully saturated radicals are, for. B.  Tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, or piperidyl, e.g. B.  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-chloro-, 2-bromo- or 2-iodoethoxy.    Lower alkenyloxy is e.g. B.  Vinyloxy or allyloxy, lower alkylenedioxy e.g.  B.  Methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy, e.g. B.  Cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy, e.g. B.    3enzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, or heterocyclyloxy or heterocyclyl-lower alkoxy z. B. 

  Pyridyl-lower alkoxy, such as 2-pyridylmethoxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxv.    



     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 pyridylthio, e.g. B.  4-pyridylthio, 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-ylthio, or tetrazolylthio, e.g. B.    Are 1-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 arylcarbonylmethoxycarbonyloxy, 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 is especially carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino, e.g. 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, propionyl or pivaloyl.    O-lower alkyl phosphono is e.g. B.  O-methyl- or O-ethyl-phosphono, O, O-di-lower alkyl-phosphono, e.g. B. 



  O, O-dimethylphosphono or O, O-diethylphosphono, O-phenyl-lower alkyl-phosphono, e.g. B.  O-benzyl-phosphono, and O-lower alkyl-O-phenyl-lower alkyl-phosphono, e.g. B.  O-benzyl-O-methyl-phosphono. 

 

     Lower alkenyloxycarbonyl is e.g. B.  Vinyloxycarbonyl, while cycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl, e.g. B.  Adamantyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or o ,, - 4-diphenylyl-a-methyl-ethoxycarbonyl represents.  Lower alkoxycarbonyl, wherein lower alkyl e.g. B.  contains a monocyclic, monoazza, monooxa- or monothiacyclic group, is z. B.  Furyl-lower alkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl-lower alkoxycarbonyl, such as 2-phenyloxycarbonyl. 



   2-lower alkyl and 2,2-di-lower alkyl hydrazino is e.g. B. 



  2-methylhydrazino or 2,2-dimethylhydrazino, 2-lower alkoxycarbonylhydrazino z. 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 an N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4 which is naturally occurring or which can be bio-, semi- or totally synthetically producible, preferably pharmacologically active -carboxylic acid compound containing acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, or an easily cleavable acyl radical, in particular a carbonic acid semi-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, Rt 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, 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 RII and RflT is hydrogen, or in which n is 1, RI 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 has aromatic character, RII an optionally functionally modified, z. B. 

   esterified or etherified hydroxy or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl or sulfo group, an optionally O-mono- or O-disubstituted phosphono group, an azido group or a halogen atom, and RIII is hydrogen, or in which n is 1, each of the radicals RI and RlI is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and RIII is hydrogen, or where n is 1, RI is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic -aliphatic,

   denotes aromatic or araliphatic hydrocarbon radical and RII and R111 together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical connected to the carbon atom by a double bond, or in which n stands for 1, and RI 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 aromatic character, RII an optionally substituted aliphatic, cycloaliphatic,

   cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and RIII is hydrogen or 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 RI for hydrogen or an optionally, preferably in the 1-position by optionally protected amino, such as amino, acylamino, in which acyl is primarily the acyl radical of a carbonic acid half ester, such as a lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl radical, or one, 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, acyloxy, in which acyl is primarily the acyl radical of a carbonic acid half-ester, such as a lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl radical, 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 has substituents such as halogen, e.g. B.  Chlorine, may carry substituted heterocyclic group, such as a 4-isoxazolyl group, or a preferably, z. B.  by an optionally substituted one such as halogen, e.g. B. 

  Chlorine, containing lower alkyl radical N-substituted amino group, or n for 1, Rl for an optionally, preferably by halogen, such as chlorine, by optionally substituted, such as hydroxy, acyloxy, in which acyl has the meaning given above, and / or halogen, e.g. B.  Chlorine, phenyloxy containing, or optionally protected amino and / or carboxy substituted lower alkyl group, e.g. B.  for a 3-amino-3-carboxy-propyl radical with optionally protected amino and / or carboxy group, e.g. B.    silylated amino or acylamino, such as lower alkanoylamino or halo-lower alkanoylamino group, and / or silylated or esterified carboxy group, for a lower alkenyl group, for an optionally substituted, such as optionally acylated hydroxy and / or halogen, e.g. B. 

  Chlorine, also optionally protected, such as acylated amino-lower alkyl, such as aminomethyl, or optionally substituted, such as optionally acylated hydroxy and / or halogen, e.g. B.  Phenyl group containing chlorine, containing phenyloxy, an optionally, e.g. B.  by lower alkyl, such as methyl, or optionally protected, such as acylated amino or aminomethyl, substituted pyridyl, pyridinium, thienyl, 1-imidazolyl or 1-tetrazolyl group, an optionally substituted lower alkoxy, e.g. B.  Methoxy group, an optionally, e.g. B.  by optionally acylated 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-imidazolylthio-, 1,2,4-triazol-3 1,2,4-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 carboxyl group, such as lower alkoxycarbonyl, e.g. B. 

  Methoxycarbonyl or ethoxycarbonyl, cyano or optionally, e.g. 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 RII and RITT for hydrogen, or n for 1, RI for an optionally, z. B.  by optionally acylated hydroxy and / or halogen, e.g. B. 

  Chlorine, substituted phenyl, furyl, thienyl or 4-isothiazolyl group, also for a 1,4-cyclohexadienyl group, RII for optionally protected or substituted amino, e.g. B.  acylated acylamino, such as lower alkoxycarbonylamino, 2-halo-lower alkoxycarbonylamino or phenyl-lower alkoxycarbonylamino, e.g. B.  tert. -Butyloxycarbonylamino, 2,2,2-Trichloräthoxycarbonylamino or Diphenylmethyloxycarbonylamino, Tritylamino, 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, carboxyl group present, a cyano group, a sulfo group, an optionally functionally modified hydroxyl group, in particular acyloxy, such as formyloxy, and also lower alkoxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy or phenyl-lower alkoxycarbonyloxy, e.g. B.  tert. -Butyloxycarbonyloxy, 2,2,2-trichlorocarbonyloxy or diphenylmethoxycarbonyloxy, or optionally substituted lower alkoxy or phenyloxy, an O-lower alkyl or O, O-di-lower alkyl-phosphono group, e.g. B.       O-methyl-phosphono or O, O-dimethylphosphono, or a halogen atom, e.g. B. 

  Chlorine or bromine, and Rm for hydrogen, or n for 1, RI and R11 each for halogen, e.g. B.  Bromine, or lower alkoxycarbonyl, e.g. B.  Methoxycarbonyl, and RIII for hydrogen, or n for 1, RI for an optionally, z. B.  by optionally acylated hydroxy and / or halogen, e.g. B.    



  Chlorine, substituted phenyl, Ftuyl, thienyl or 4-Isothiazolylgruppe, also for a 1-4-Cyclohexadienylgruppe, Rrr for optionally, z. B.  aminomethyl protected as indicated above, and RIII for hydrogen, or n for 1 and each of the groups RI, RII and R'TI for lower alkyl, e.g. B.  Methyl stand. 



   Such acyl radicals Ac are z. B.  Formyl, cyclopentylcarbonyl, a-aminocyclopentylcarbonyl or -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, cleavable or an acyl radical that can be converted into such, 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 groups substituted by trityl), 2,6-dimethoxybenzoyl, tetrahydronaphthoyl, 2-methoxy-naphthoyl, 2-ethoxy-naphthoyl, hexahydroxy-carbonyl, benzyloxycarbonyl Methyl-3-phenyl-4-isoxazolylcarbonyl, 3- (2-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-,

   3 - (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, butylthioacetyl , Allylthioacetyl, methylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3 chloropropionyl, 3-bromopropionyl, aminoacetyl or 5-amino-5-carboxy-valeryl (with optionally, e.g. B.  as indicated, as indicated by a monoacyl or diacyl radical, e.g. B.  an optionally halogenated Niederalkanoyfrest such as acetyl or dichloroacetyl, or phthaloyl, substituted amino group and / or optionally functionally modified, z. B.  in salt, such as sodium salt or.  in ester, such as lower alkyl, e.g. B.  Methyl or ethyl, or aryl lower alkyl, e.g. B. 

  Diphenylmethylesterform, present carboxyl group), azidoacetyl, carboxy acetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bismethoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, z-cyano-propionyl, 2-cyano-3,3-dimethyl-acrylacido, 2-cyano-3,3-dimethyl-acrylacido -phenylacetyl, 3-chlorophenylacetyl, 4-aminomethylphenyl-acetyl (with optionally, e.g. B. 

   as indicated, substituted amino group), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, z-phenyloxyphenylacetyl, phenyloxyphenylacetyl, a-phenyloxyphenylacetyl, a-methoxyphenyl-acetyl, c'-methoxyphenyl-acetyl, a-phenyloxyphenylacetyl, a-methoxyphenyl-acetyl, c'-methoxyphenyl-ethoxy-3-phenoxy-, a-methoxy-phenyl-ethoxy-3-phenoxy- cc-cyano-phenylacetyl, especially phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl, 3,5-dichloro-4-hydroxyphenylglycyl, z-aminomethylnx-phenylacetyl or a-hydroxyphenylacetyl, where in these radicals an existing amino group if necessary, for. B. 

   as stated above, may be substituted and / or an existing, aliphatic and / or phenolically bonded hydroxyl group, if appropriate, analogously 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 oc-O-methyl-phosphono-phenylacetyl or aO, O-dimethyl-phosphono-phenylacetyl, also benzylthioacetyl, benzylthiopropionyl, a-carboxyphenylacetyl ( with optionally, z. 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, 3-thienylacetyl, 2-tetrahydrothienylacetyl, 2-furylacetyl, l-imidazolylacetyl, l-tetrazolyl-acetyl, α-carboxy-2-thienylacetyl or x-carboxy-3-thienyl- acetyl (optionally with functional, e.g. B.  as stated above, modified carboxyl group), x-cyano-2-thienyl-acetyl, a-amino-a- (2-thienyl) -acetyl, a-amino-x- (2-furyl) -acetyl or x- Amino-x- (4-isothiazolyl) acetyl (optionally with, e.g. B.  as stated above, substituted amino group), a-sulfophenylacetyl (optionally with, e.g. B. 

   such as the carboxyl group, functionally modified sulfo group), 3-methyl-2-imidazolyl-thioacetyl, 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-tetrazolylthioacetyl. 



   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 group which is multiply branched and / or aromatically substituted on the carbon atom in a position to the oxy group, or a methoxycarbonyl group substituted by aryl carbonyl, in particular benzoyl radicals, or a lower alkoxycarbonyl radical substituted in the p position by halogen atoms , e.g. B.  

   tert. -Butyloxycarbonyl, tert. -Phenyloxycarbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a radical which can be converted into the latter, such as 2-chloro- or 2-bromo ethoxycarbonyl, furthermore, preferably polycyclic, cycloalkoxycarbonyl, e.g. B.  Adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, such as 4-methoxyphenylmethoxycarbonyl, primarily a-phenyl-lower alkoxycarbonyl, in which the a-position is preferably polysubstituted, e.g. B.  Diphenylmethoxycarbonyl or a4-biphenyl-x-methyl-ethyloxycarbonyl, or furyl-lower alkoxy carbonyl, primarily cc-furyl-lower alkoxycarbonyl, e.g.  B. 



  Furfuryloxycarbonyl. 



   A divalent acyl group formed by the two radicals R1A and R1b is z. B.  the acyl radical of a lower alkane or lower alkene dicarboxylic acid, such as succinyl, or an o-arylenedicarboxylic acid, such as phthaloyl. 



   Another divalent radical formed by the groups R1A and Rlb 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 l-oxo -3-aza-1,4-butylene radical, e.g. B.    4,4-dimethyl-2-phenyl-1-oxo-3-aza-1,4-butylene.    



   An etherified hydroxy group R2A 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 R2A is e.g. B.     Lower alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy, which together with the carbonyl grouping 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 hydroxy group R2A, which together with a -C (= O) group forms a particularly easily cleavable esterified carboxyl group, is available, for.  B.  for 2-habgen-lower alkoxy, in which halogen preferably has an atomic weight of more than 19.  Such a radical, together with the -C (= 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-iodine ethoxy, also 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter. 



   An etherified hydroxy group R2A, which together with the -C (= O) group, also when treated 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 R2A 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 -C (= 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-dimethoxybenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitrobenzyloxy. 



   An etherified hydroxy group R2A can also represent a radical which, together with the -C (= O) grouping, is an acidic group, 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 The remainder denotes the ring member representing the cc position to the oxygen or sulfur atom. 



   Preferred polysubstituted methoxy groups of this type are tert. Lower alkoxy, e.g. B.  tert. -Butyloxy or tert. Pentyloxy, optionally substituted diphenylmethoxy, e.g. B.  Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, furthermore 2- (4-biphenylyl) -2-propyloxy, while a methoxy group containing the above substituted aryl group or the heterocyclic group is e.g. B.  one. a-Lower alkoxyphenyl-lower alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or  Furfuryloxy, as is 2-furfuryloxy.  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 oxa- or thiacycloaliphatic radical, in which methyl of the methoxy group is the ring member representing the z-position to the oxygen or sulfur atom, is z. B.  2-oxa- or 2-thio-lower alkylene or lower alkenylene with 5-7 ring atoms, such as 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulfur analogs. 



   The radical R2A 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, cleavable esterified carboxyl group forms.  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-nitrobenzyloxy, polyhalophenyloxy, e.g. B.  2,4,6-trichlorophenyloxy or 2,3,4,5,6-pentachlorophenyloxy, also cyanomethoxy, and acylaminomethoxy, e.g. B.  Phthaliminomethoxy or succinyliminomethoxy. 



   The group R2A can also represent an etherified hydroxyl group which, together with the carboxyl group of the formula -C (= O) - forms an esterified carboxyl group which can be cleaved under hydrogenolytic conditions, and is e.g. B.  optionally, e.g. B.  C-phenyl-lower alkoxy substituted by lower alkoxy or nitro, such as 3enzyloxy, 4-methoxy-benzyloxy or 4-nitrobenzyloxy. 



   The group R2A can also form an etherified hydroxyl group which, together with the carbonyl group -C (= 0) - forms an esterified carboxyl group which can be cleaved under physiological conditions, primarily lower alkanoyloxymethoxy, e.g. B.  Acetyloxymethyloxy or pivaloyloxymethoxy. 

 

   A silyloxy or stannyloxy group R2A 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 R2A, 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 R2A 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, for example.  Pyrrolidino or piperidino, oxaniederalkylenamino, e.g. B.  Morpholino, hydroxyamino, hydrazino, 2-mederalkylhydrazino or 2,2-dimethylhydrazino. 



   Salts are in particular those of compounds of formula 1 with an acidic grouping 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, with 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-Aminob enzo esäure-2-diethylamino ethyl ester, lower alkyleneamines, z. B.    l-ethyl piperidine, cycloalkylamines, e.g. B.  Bicyclohexylamine, or benzylamines, e.g. B. 



     N, N'-dibenzyl-ethylenediamine, also bases of the pyridine type, e.g. 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 formula 1 with one acidic and one basic group can also be used in the form of internal salts, i.e. H.  in zwitterionic form. 



   Particularly noteworthy are those salts of compounds of the formula 1 with an acidic group which are derived from the cations used in the preparation according to the invention or which are formed during the reaction. 



   Some compounds falling under the formula I, as well as salts thereof, and processes for their preparation are already known.  Such compounds can be prepared by adding a 7-amino- or 7-acylamino-3-acetoxymethyl-3-cephem-4-carboxylic acid according to the Dutch laid-open specification no.  71. / 16873 with a chromium-II-compound or a 3-thio-substituted 7-amino- or 7-acylamino-3-thiomethyl-3-cephem-4-carboxylic acid compound according to German Offenlegungsschrift No.  2209 020 reduced by means of molecular hydrogen in the presence of a metallic hydrogenation catalyst or with nascent hydrogen.  However, both methods are not completely satisfactory from a technical point of view, provided that only moderate yields are obtained. 

  As a result of longer reaction times or through the use of elevated temperatures, 7-amino- or 7-acylamino-3-methyl-3-cephem-4-carboxylic acid derivatives and in some cases also the corresponding 3-methyl-2- cephem derivatives, which must be removed from the reaction mixture by chromatography.  In the process according to the Dutch laid-open specification, the formation of chromium complexes also has an unfavorable effect on the yield.  A further disadvantage of the method according to the German Offenlegungsschrift is that the preparation of the thio-substituted starting materials from the natural, easily accessible 3-acetoxymethyl-3-cephem-4-carboxylic acid derivatives means an additional synthesis. 



   The publications mentioned above show that the 7-amino-3-methylencepham-4-carboxylic acid compounds of the formula I themselves have little or no antibiotic properties, whereas they easily become the valuable 7p-amino. 3-methyl-3. cephem. 4th carboxylic acid.    



  compounds can be isomerized.  Such 3-methyl compounds, e.g. B.  the cephalexin [7,8- (D-c, -aminophenyl-acetamido) -desacetoxy-cephalosporanic acid] have excellent antibiotic properties even when administered orally and can therefore be used to treat various bacterial infections in humans and animals. 



   Compounds of the formula I can also be used as intermediates for the preparation of valuable 3-oxo-cepham and 3-hydroxy and 3-substituted-hydroxy-3-cephem compounds.  Of these, the compounds of the formula are particularly valuable
EMI7. 1
 in which R1a, Rlb and R2 are as defined above, and R3 is an optionally substituted hydrocarbon radical or an acyl group, and which contain a double bond in the 2,3- or in the 3,4-position, and 1-oxides of compounds of the formula II, in which the double bond is in the 3,4-position.  or salts of such compounds with salt-forming groups. 



   The enol derivatives of the formula II are ethers and esters of 2-cephem-3-ol and 3-cephem-3-ol compounds. 



   In 2-cephem compounds of the formula II with a double bond in the 2,3-position, the optionally protected carboxyl group of the formula -C (= O) -R2 preferably has the s configuration. 



   An optionally substituted hydrocarbon radical Rs 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 RT 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. 



   An optionally substituted aliphatic hydrocarbon radical R3 is in particular lower alkyl with up to 7, preferably up to 4 carbon atoms, such as ethyl, n-propyl, isopropyl or n-butyl and primarily methyl, furthermore lower alkenyl, e.g. B.  Allyl, tert. -Aminoniederalkyl, 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-Dimethylaminoäthyl, 2-Di äthylaminoäthyl or 3-Dimethylaminopropyl, or etherified hydroxy-lower alkyl, in which the etherified hydroxy group, in particular 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 Rs is primarily an optionally substituted phenyl-lower alkyl, in particular 1-phenyl-deralkyl 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 chromium, or lower alkoxy, such as methoxy, can be used. 



   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, such as halogen, e.g. B. 



  Fluorine or chlorine, or lower alkoxy, e.g. B.  Methoxy or ethoxy, may be substituted.  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 such as methoxy or ethoxy, or lower alkyl, e.g. B. 



  Methyl, substituted benzoyl. 



   The compounds of the formula II have valuable pharmacological properties or can be used as intermediates for the preparation of such.  Compounds of formula II, wherein z. B.  Rla for an acyl radical Ac occurring in pharmacologically active N-acyl derivatives of 6,8-aminopenam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds and Rlb for hydrogen, or in which Rla and Rlb together one in the 2-position preferably, for. B.  by an aromatic or heterocyclic radical, and preferably in the 4-position, e.g. B. 



  1-oxo-3-aza-1,4-butylene radical substituted by 2 lower alkyl, such as methyl, R2 is hydroxy or an etherified hydroxy group R2A which forms an esterified carboxyl group easily cleavable under physiological conditions together with the carbonyl group, and R3 is the above has given meaning, 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 II in which the double bond of the cephem ring is in the 2,3-position, or 1-oxides of compounds of the formula II in which the double bond is in the 3,4-position and in which Rla, Rlb, R2 and R3 have the im Relation to the formula I have 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 Rla and Rlb are hydrogen, or R1a is an amino protective group different from the above acyl radical and Rlb is hydrogen mean, or Rla and R1b together represent a divalent amino protective group different from the abovementioned divalent radicals,

   and R2 represents hydroxy, or Rla and Rlb have the meanings given above, R2 represents a radical R2a which, together with the -C (= O) grouping, forms a preferably easily cleavable, protected carboxyl group, and R3 has the meanings given above has, are valuable intermediates, which in a simple manner, z. B.  as described below, can be converted into the above-mentioned pharmacologically active compounds. 



   The compounds of the formula I in which Rla is hydrogen or preferably one in a fermentative (i.e. H.  naturally occurring) or bio-, semi- or totally synthetically producible, especially pharmacologically active, such as highly active N-acyl derivative of a 6P-amino-penam-3-carboxylic acid or 7P-amino-3-cephem-4-carboxylic acid compound or an acyl radical easily cleavable acyl radical of a carbonic acid half-derivative, in particular a carbonic acid half-ester, Rlb represents hydrogen, or in which Rla and Rlb together preferably have a 2-position, e.g. B.  by an aromatic or heterocyclic radical, and preferably in the 4-position, e.g. B. 

   represented by 2 lower alkyl, such as methyl, substituted 1-oxo-3-aza-1,4-butylene radical, and R2 for hydroxy, for optionally, z. B.  by optionally substituted aryloxy, such as lower alkoxyphenyloxy, e.g. B.    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, or optionally substituted aryl, such as phenyl, - lower alkoxyphenyl, nitrophenyl or diphenyl-substituted lower alkoxy, such as lower alkoxy, e.g. B.  Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert. -Butyloxy or tert. -Pentyloxy, bis-phenyloxy-methoxy optionally substituted by lower alkoxy, e.g. B.  Bis-4-methoxyphenyloxy-methoxy, phenacyloxy, lower alkanoyloxymethoxy, e.g. B. 



  Acetyloxymethoxy or pivaloyloxymethoxy, 2-halo-lower alkoxy, e.g. B.  2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromo ethoxy or 2-iodoethoxy, 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-methoxy-benzyloxy, 2-biphenylyl-2-propyloxy, 4-nitro-benzyloxy, 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 or pivaloyloxy, 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, e.g. B.  2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamino, and salts of such compounds with salt-forming groups. 



   Primarily, in a compound of the formula I, or in a salt of such a compound with salt-forming groups, Rla is hydrogen or a fermentative (i.e. H.  naturally occurring) or biosynthetically producible N-acyl derivatives of 6p-amino-penam-3-carboxylic acid or 7M, B-amino-3-cephem-4-carboxylic acid compounds containing acyl radical, such as an optionally, z. B.  by hydroxy, substituted phenylacetyl or phenyloxyacetyl radical, also an optionally, z. B.  by lower alkylthio, or lower alkenylthio, and optionally substituted, such as acylated amino and / or functionally modified, such as esterified carboxyl, substituted lower alkanoyl or lower alkenoyl radical, e.g. B.  

   4-Hydroxy-phenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl, and in particular 5-amino -5-carboxy-valeryl, in which the amino and / or the carboxyl groups 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 6P-amino-penam-3-carboxylic acid or 7p-amino-3-cephem-4-carboxylic acid compounds, such as formyl, haloethylcarbamoyl, z. B.  2-chloroethylcarbamoyl, cyanoacetyl, phenylacetyl, thienylacetyl, e.g. B.  2-thienylacetyl, or tetrazolylacetyl, e.g. B.  l-tetrazolylacetyl, especially phenylglycyl, wherein phenyl optionally, e.g. B. 



  by optionally protected hydroxy, such as acyloxy, e.g. B. 



  optionally halogen-substituted lower alkoxycarbonyl oxy or lower alkanoyloxy, and / or by 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-hydroxyphenyl (optionally with a protected, such as acylated hydroxy group), and in which the amino group is optionally substituted and z.  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, cleavable or convertible into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as one of the above, e.g. B.  optionally halogen or benzoyl-substituted lower alkyloxycarbonyl radicals, e.g. B.  2,2,2 -Trichloräthyloxycarbonyl, 2-Chloräthoxycarbonyl, 2-bromo ethoxycarbonyl, 2-Jodäthoxycarbonyl, tert. -Butyloxycarbonyl or phenacyloxycarbonyl, or a carbonic acid half-amide such as carbamoyl or N-methylcarbamoyl, furthermore a-thienylglycyl, such as a-2- or a-3-thienylglycyl, a-furylglycyl, such as?

  -2-furylglycyl, α-isothiazolylglycyl such as α-4-isothiazolylglycyl, 1-amino-cyclohexylcarbonyl or aminopyridinium, e.g. B.  4-aminopyridinium (optionally with, e.g. B. 



  as indicated above, substituted amino group), furthermore z-carboxy-phenylacetyl or α-carboxy-2-thienylacetyl (optionally with a functionally modified, e.g. B.  in salt, such as sodium salt form, or in ester, such as lower alkyl, e.g. B. 



  Methyl or ethyl, or phenyl lower alkyl, e.g. B.     Diphenylmethylesterform, present carboxyl group), -Sulfo- -phenylacetyl (optionally with, z. B.  such as the carboxyl group, functionally modified sulfo group), α-phosphono-, @ -O-methylphosphono or oO, O-dimethyl-phosphono-phenylacetyl, or, sc-hydroxyphenylacetyl (optionally with functionally modified hydroxyl group, in particular with an acyloxy group, wherein acyl has a, preferably slightly, 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, cleavable or convertible into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as one of the above, e.g. B.  lower alkoxycarbonyl radical optionally substituted by halogen or benzoyl, e.g. B.  2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl or Phenacyloxycarbonyl, also means formyl), or pyridylthioacetyl, z. B.  4-pyridylthioacetyl, e.g. B, for an acyl radical of the formula A, and Rlb for hydrogen, or Rla and Rlb together for one, in the 2-position, preferably optionally by protected hydroxy, such as acyloxy, z, B. 

   optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and / or by 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-hydroxyphenyl (optionally with a protected, such as acylated hydroxy group) substituted 1-oxo-3-aza-1 , 4-butylene radical which optionally contains x2 lower alkyl, such as methyl, in the 4-position, and R2 represents hydroxy, lower alkoxy, in particular α-polybranched lower alkoxy, e.g. B.  tert. -Butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, z. B. 



  2,2,2-trichloroethoxy, 2-iodoethoxy or the easily convertible 2-chloroethoxy or 2-bromoethoxy, phenacyl oxy, 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'-dimethoxy-diphenylmethoxy or trityloxy, lower alkanoyloxymethoxy, e.g. B.     Acetyloxymethoxy or pivaloyloxymethoxy, lower alkoxycarbonyloxy, e.g. B.  Ethoxycarbonyloxy, or lower alkanoyloxy, e.g. B.     Acetyloxy. 



   The invention relates primarily in particular to compounds of the formula I in which R1b is hydrogen and Rla is hydrogen, cyanoacetyl, an acyl group of the formula
EMI9. 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, as well as thienyl, z. B.  2- or 3-thienyl, also pyridyl, e.g. B.  4-pyridyl, aminopyridinium, e.g. B.  4-aminopyridinium, furyl, e.g. B.     2-furyl, isothiazolyl, e.g. B.  4-isothiazolyl, or tetrazolyl, e.g. B.  1-tetrazolyl, X is oxygen or sulfur, n is 0 or 1, and R is hydrogen or, when n is 0, optionally protected amino such as acylamino, e.g. B.  c-polybranched lower alkoxycarbonylamino, such as tert. -Butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g. 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.    tc-polybranched lower alkoxycarbonyloxy, such as tert. -Butyloxycarbonyloxy, or 2-Halogenniederalkoxycarbonyloxy, such as 2,2,2-Trichloräthoxycarbonyloxy, 2-Jod äthoxycarbonyloxy or 2-Bromäthoxycarbonyloxy, also formyloxy, or O-Niederalkylphosphono or O, O-Diiederalkylphosphono, z. B.  O-methyl-phosphono or O, O-dimethylphosphono, or a 5-amino-5-carboxy-valeryl radical, in which 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 5 5-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 salts of such compounds with salt-forming groups. 

 

   In compounds of the formula I to be designated as particularly valuable, Rla is hydrogen, for the acyl radical of the formula B, in which Ar is phenyl, X is oxygen, n is 0 or 1, and R is hydrogen or, if n is 0, optionally protected amino, such as acylamino , z, B, oc-polybranched lower alkoxycarbonylamino, such as tert. -Butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g. B. 

   2,2,2-trichloroethoxycarbonylamino, 2-Jodäthoxycarbonylamino or 2-Bromäthoxycarbonylamino, optionally protected hydroxy such as acyloxy, z. B.     -Polybranched lower alkoxycarbonyloxy, such as tert. -Butyloxycarbonyloxy, or 2-halogen lower alkoxycarbonyloxy, such as 2,2,2-Trichloräthoxycarbonyloxy, 2-Jodäthoxycarbonyloxy or 2-Bromäthoxycarbonyloxy, also formyloxy, or O-lower alkyl or O, O-di-lower alkylphosphono, z. B.  O-methylphosphono or 0,0-dimethyl-phosphono, mean, or for a 5-amino-5-carboxy-valeryl radical, wherein the amino and 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, Rlb is hydrogen and R2 is hydroxy, optionally halogen in the 2-position, e.g. B.  Chlorine, bromine or iodine substituted lower alkoxy, in particular x-polybranched 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'-dimethoxydiphenylmethoxy. 



   Particularly valuable individual compounds which can be prepared according to the invention are 3-methylene-7v- (D-cc-tert, -butyloxycarbonylamino-phenylacetylamino) -cepham-4x-carboxylic acid and 3-methylene-7p- (phenylacetylamino) -cepham-4 - carboxylic acid, and salts and esters thereof, e.g. B.  the diphenyl methyl esters. 



   The novel process according to the invention for the preparation of 7p-amino-3-methylenceepham-4-carboxylic acid compounds of the formula I and their salts is characterized in that a 7p-amino-3-acetoxymethyl-3-cephem-4 ° carboxylic acid compound is used formula
EMI10. 1
 wherein Rla, R1b and R2 have the meaning given above or a salt of this compound with a metal which has a normal potential of -2.4 to -0.40 volts, or an amalgam thereof, at a pH of 1 to 8, reduced in the presence of water and, if desired, a compound of the formula I obtained converted into another compound of the formula I, and / or if desired,

   a compound obtained with a salt-forming group is converted into a salt or a salt obtained is converted into the free compound or into another salt, and / or, if desired, a mixture of isomers obtained is separated into the individual isomers. 



   Examples of metals with a normal potential of -2.4 to -0.40 volts are magnesium, manganese, zinc, iron, chromium, cadmium and, in particular, aluminum.  They are used in coarse or preferably fine-grained form.  The metals can also, preferably, be used as amalgams or in superficially amalgamated form.  Processes for producing such amalgamated metals are known.  A preferred reducing agent is amalgamated aluminum, which by treating aluminum grit z, B.     with 0.5 percent mercury (II) chloride solution is obtained. 



   The reaction according to the invention is carried out within a pH range from 1 to 8, preferably 2-7.  Optimal results are obtained in a range from pH 5 to 6. 



  The pH value can be adjusted to the desired value with organic or inorganic acids and kept constant during the reduction by continuously adding further amounts of acid.  Suitable organic acids are, in particular, acids which are water-soluble or which are soluble in the solvent mixture used, such as lower aliphatic carboxylic acids, e.g. B.  lower alkanecarboxylic acids such as formic, acetic, propionic, butyric or valeric acid, or lower aliphatic sulfonic acids such as methane, ethanoic or propanesulfonic acid, aromatic carboxylic acids such as benzoic acid, aromatic sulfonic acids such as benzenesulfonic acid, aliphatic poly-, such as dicarboxylic acids, such as lower alkanoic or alkanedicarboxylic acids, e.g. B. 

  Oxalic, maleic, malonic or succinic acid, aromatic polycarboxylic acids, such as trimellitic or trimesic acid, or corresponding polysulfonic acids, such as o-benzenedisulfonic acid or the like.  The acids mentioned can carry substituents, including in particular halogen, such as fluorine or chlorine, or lower alkyl, lower alkoxy, hydroxy or amino groups.  Examples of such acids are the chloroacetic, trifluoroacetic, p-toluenesulphone, p-methoxyphenyl acetic, tartaric, tartaric, citric and the known amino acids, the amino group of which can optionally be substituted, e.g. B, ethylenediaminetetraacetic acid. 



   Inorganic acids which can be used for the reaction are mainly mineral acids, such as hydrohalic acids, e.g. B, fluorine or hydrochloric acid, halogenated oxygen acids, such as perchloric acid, acids derived from sulfur, such as hydrogen sulfide and sulfuric acid, and acids derived from phosphorus, such as phosphoric acid or metaphosphoric acid. 



   Some of these acids are not only used to adjust the pH value, but also, as will be explained in more detail below, to complexly bind the metal cations formed during the reaction or to precipitate them out of the solution,
Of the acids mentioned, for example, hydrogen fluoride with aluminum 3+ cations, oxalic acid with aluminum + 3, zinc + 2 and chromium + 3 cations, tartaric acid with magnesium 2+ cations, citric acid with chromium 3+ cations, and metaphosphoric acid with magnesium 2 + - and ethylene amine tetraacetic acid to enter into soluble complexes with aluminum + 3-, magnesium + 2-, manganese + 2-, zinc + 1- chromium, iron and cadmium + 2-cations due to favorable complex formation constants. 



   Hydrogen sulfide, for example, is able to precipitate manganese + 2-, zinc + 2-, iron and cadmium + 1-ions and phosphoric acid magnesium + 2- and iron + 1-ions from aqueous solutions. 



   The reaction according to the invention is optionally carried out in the presence of reagents which increase the reducing power of the metals or amalgams.  These include, in particular, those reagents which remove the metal cations formed during the reaction from the redox equilibrium.  Such reagents are in particular chemical compounds that either bind the metal cations in complex form or precipitate out of the reaction solution.  Suitable complexing agents are the anions of the complexing acids already mentioned.    Accordingly, instead of these acids, their soluble salts can also be used, the cations of these salts having to be different from those formed during the reaction.  

  Accordingly, preferred salts are in particular corresponding alkali salts, such as lithium, sodium or potassium salts, or ammonium or substituted ammonium salts, such as mono-, di- or tetra-lower alkyl, e.g. B.  methyl, ethyl or propylammonium salts and the like.  Of course, when using such salts, the desired pH must be set by adding another acid. 



   The reaction according to the invention is carried out in water, if appropriate with the addition of one or more organic solvents.  Organic solvents which are inert under the reaction conditions can be used as such, such as lower aliphatic or aromatic, optionally N-mono- or N, N-disubstituted, for example lower-alkyl-substituted amides, e.g. B.  Diethylformamide or, preferably, dimethylformamide, lower dialkyl sulfoxides, e.g. B.  Dimethyl sulfoxide, lower alkanols, e.g. B. 



  Methanol or ethanol, water-soluble ethers such as cyclic ethers, e.g. B.  Tetrahydrofuran or dioxane, lower ketones, e.g. B.  Acetone, or lower nitriles, e.g. B.  Acetonitrile.  When using a solvent or solvent mixture, this contains at least 10 to 20% water. 



   Antifoams can be added to the reaction mixture to prevent foaming.  For example, lower carboxylic acid esters, e.g. B.  Ethyl acetate to prevent foaming. 



   The reaction temperature and reaction time essentially depend on the nature of the starting material of the formula III used, the metal or metal amalgam used, the solvent and the pH.  The temperature can be between about 0 "to 100" and is preferably between about 250 and 50 ".     The reaction time varies from a few minutes to a few hours.  In general, the reaction is complete after about 72 to 1 hour. 



   Under the conditions mentioned, especially the optimal conditions, practically no isomerization products, in particular no 3-methyl-3-cephem compounds, are obtained. 



   Starting materials of the formula III are known or can be prepared by known methods. 



   In a starting material of the formula III, the radical R1a preferably denotes an amino protective group R1A, 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.  Silylation or stannylation, can be protected, R1b hydrogen and R2 in particular hydroxyl, as well as one with the -C (= O) group an etherified hydroxyl group R2A which can be cleaved under mild conditions and which can be cleaved, in particular under mild conditions, with any functional groups present in a carboxyl protecting group R2A in a manner known per se, e.g. B.  as stated above, may be protected.  A group R2A is e.g. B.  in particular an optionally halogen-substituted lower alkoxy group, such as cc-polybranched lower alkoxy, e.g. B.  tert. -Butyloxy, or 2-halo-lower alkoxy, wherein halogen z. 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. 



   Preferred starting materials of the formula III are those in which R1a is an acyl group Ac which represents a 6-aminopenam-3-carboxylic acid or a 6-amino-penam-3-carboxylic acid or in a bio-, semi-synthetic or totally synthetically producible, preferably pharmacologically active, N-acyl derivative 7-amino-3-cephem-4-carboxylic acid compound containing acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, or an easily cleavable acyl radical, in particular a carbonic acid half-derivative, RTb is hydrogen and R2 is a hydroxyl group or a salt of such a compound . 



   Preferred salts of the starting materials of the formula III, in which R2 is hydroxy, are the metal, such as alkali metal, in particular the sodium or potassium salts, as well as the ammonium salts of ammonia or suitable organic amines, in particular of lower alkylamines, such as triethylamine, and hydroxy-lower alkylamines, such as 2-hydroxyethylamine, or the inner salts. 



   Starting materials of the formula III or their salts can be used as crude products or, preferably, in pure form.  The cleaning can be done by customary methods, e.g. B.  be carried out by chromatography or via suitable derivatives.  For example, a starting material of the formula III, in which R2 is hydroxy, can be converted into one of the abovementioned salts, e.g. B.  the sodium or 2-hydroxyethylamine salt, from which it can then be recovered in purified form or converted into another salt. 



   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. B.  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, inkyl.  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 (= O) -RB, this can be carried out in a manner known per se, e.g. B.  depending on the type of group R2A, can be 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, i. 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 an 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 m when 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 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, optionally 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 of pH about 7 to about 9, and a hydrogenolytically cleavable esterified carboxyl group by hydrogenolysis, e.g. B.  by treating with hydrogen in the presence of a noble 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 protective group RlA or    Rlb, in particular an easily cleavable acyl group, in a manner known per se, for. B.  a z-poly-branched lower alkoxycarbonyl or phenyl lower alkoxycarbonyl group, such as tert. -Butyloxycarbonyl- or p-methoxyphenylmethoxycarbonyl, by treatment with trifluoroacetic acid and a 2-halo-lower alkoxycarbonyl group, such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treatment with a suitable reducing metal or corresponding metal compound, e.g. 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 metal compound, preferably in the presence of acetic acid containing water.  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 halogen-tin-IV compound, such as trimethylchlorosilane or tri-n-butyltin chloride, protected carboxyl group, an acyl group R1A or Rlb, in which any free functional groups that may be present are optionally protected, by treatment with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleavage of the imino ether formed, with a protected, z. B.  a carboxyl group protected by an organic silyl radical can be released during 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 pentahalides, 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 usually 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 ethyldiisopropylamine, 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-1,6-hexylenediamine, 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.    NWMethyl- piperidine or N-methyl-morpholine, also 2,3,4,6,7,8-hexa hydro-pyrrolo [1,2-cGlpyrimidin (diazabicyclononen; 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.  be present in about 0.2 to about 1 times the amount or then in about to 10 times, in particular about 3 to 5 times, excess. 



   The reaction with the imide halide forming agent is preferably carried out with cooling, e.g. B.  carried out at temperatures of about -50 "C to about + 10 C, but also at higher temperatures, d. H.  z. B.  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 and araliphatic alcohols, primarily optionally substituted, such as halogenated, e.g. B. 



  chlorinated, or additional hydroxyl-containing lower alkanols, e.g. B.  Ethanol, propanol or butanol, especially methanol, also 2-halo-lower alkanols, e.g. B.  2,2,2 trichloroethanol or 2-bromoethanol, 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 -500C to about 10 C.    



   The imino ether product can advantageously be subjected to cleavage without isolation.  The cleavage of the imino ether can be achieved by treatment with a suitable hydroxy compound, preferably by means of hydrolysis.  It is preferable to use water or an aqueous mixture of an organic 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 obtained by adding a basic agent such as an aqueous alkali metal hydroxide, e.g. B.  Sodium or potassium hydroxide, or an acid, e.g. B.  a mineral acid, or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, trifluoroacetic acid or p-toluene sulfonic acid. 

 

   The three-step process for cleaving an acyl group described above is advantageously carried out without isolating the imide halide and imino ether intermediates, usually in the presence of an organic solvent which is inert towards the reactants, such as an optionally halogenated hydrocarbon, e.g. B.  Methylene chloride, and / or in an inert gas atmosphere such as a nitrogen atmosphere. 



   If the intermediate imide halide product obtainable by the above process is reacted with a salt, such as an alkali metal salt of a carboxylic acid, especially a sterically hindered carboxylic acid, instead of an alcohol, a compound of the formula I is obtained in which both radicals Rla and R1b are acyl groups .   



   In a compound of formula I ,.  wherein both radicals; R1a and Rlb represent 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 R1A and Rlb 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 RlA of an acylamino group in compounds obtainable according to the invention, such as. B.  the 5-amino-5-carboxy-valeryl radical.     wherein carboxyl, e.g. B.  by esterification, especially by diphenylmethyl, and / or the amino group, e.g. B.  by acylation, in particular by halo-lower alkanol, 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-releasing agent such as an N-halogen amide 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 treating the reaction product with a hydroxyl-containing agent such as water or a lower alkanol, e.g. B.  Methanol, or, if the amino group in the 5-amino -5-carboxy-valeryl radical R1A is unsubstituted and the carboxy group z. B.  is protected by esterification, and Rlb is preferably an acyl radical, but can also mean hydrogen, by standing in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, for example.  Methylene chloride and, if necessary, working up the free or monoacylated amino compound by methods known per se, are split off. 



   A formyl group R1A 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.  dilute ammonia, or a decarbonylating agent, e.g. B.  Tris - (triphenylphosphine) rhodium chloride, are split off. 



   A triarylmethyl, such as the trityl group R1A, 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 Rla and Rlb 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 that are 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, and with substituted formimino derivatives, such as substituted N, N-dimethylchloroformimino derivatives, or an N-substituted one 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 such. 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 R1a and Rlb together represent a ylidene radical (which can also be added subsequently, e.g. B.  by treating a compound in which R1a and R1b are hydrogen with an aldehyde such as an aliphatic, aromatic or araliphatic aldehyde), e.g. B.  acylated by the methods given above, and the acylation product, preferably in a neutral or weakly acidic medium, 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 so 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, implement and so to substituted N-Niederalkanoylbzw.    N-hydroxycarbonylamino compounds arrive.  Furthermore, you can z. B.  a compound of the formula I in which R1a is a glycyl group, preferably substituted in the -position, such as phenylglycyl, and R1b 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 I in which R1A and R1b together with the nitrogen atom 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 those mentioned above, e.g. B.  2,2,2-Trichloräthoxycarbonylamino-, 2 Bromoäthoxycarbonylamino- or tert. -Butyloxycarbonylamino groups, from acyloxy, such as those mentioned above, e.g. B.  2,2,2 Trichloräthoxycarbonyloxy- or 2-Bromäthoxycarbonylgruppen, of esterified carboxy, such as those mentioned above, e.g. B. 



  Diphenylmethoxycarbonyl groups, or  O, O-disubstituted phosphono such as those mentioned above, e.g. B.  O, O-di-lower alkylphosphono-, 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.  partially, split. 

 

   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 R1a and R1b 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 tri lower 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 e.g. B.  British patent no.  1 073 530), 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 alkyl tin hydroxide, e.g. B. 

  Triethyl tin hydroxide, one
Tri-lower alkyl-lower alkoxy-tin, tetra-lower alkoxy-tin or tetra-lower alkyl-tin compound, and a tri-never deralkyl-tin halide, eg. B.  Tri-n-butyl tin chloride (see e.g. B.  Dutch interpretation 67/11107).    



   In a compound of the
Formula I, which contains a free carboxyl group of the formula -C (= O) - R2, can be converted into a protected carboxyl group in a manner known per se.  So he holds z. B.  by treating with a suitable diazo compound such as a diazo lower alkane, e.g. B.  Diazomethane or diazobutane, or a phenyldiazo lower alkane, e.g.  B. 



   Diphenyldiazomethane, if necessary, in the presence of a
Lewis acid, such as. B.  Boron trifluoride, or by reacting with an alcohol suitable for esterification in the presence of a
Esterifying agent such as a carbodiimide, e.g. B.  Dicyclo hexylcarbodiimide and carbonyldimidazole, also with a
N. N'-disubstituted O 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.  Lower alkyl, especially isopropyl, cycloalkyl or phenyl, or 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, and a strong organic sulfonic acid, an ester. 

  Furthermore, acid halides, such as chlorides (produced e.g. B.  by treating with oxalyl chloride), activated
Ester (formed e.g. B.  with N-hydroxy nitrogen compounds, such as N-hydroxy-succinimide) or mixed anhydrides (he keep z. B.  with haloformic acid lower alkyl esters, such as
Ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides such as trichloro acetic acid chloride) by reacting with alcohols, if appropriate in the presence of a base such as pyridine, in an esterified one
Carboxyl group are converted. 



   In a compound obtained with an esterified
Grouping of the formula -C (= O) -R2, this can be converted into another esterified carboxy group of this formula, eg. B.  2-Chloräthoxycarbonyl or 2-Bromäthoxycar bonyl by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable solvent, such as acetone, in 2-Jodäthoxycarbonyl. 



   Mixed anhydrides can be prepared by adding a compound of the formula I with a free carboxyl group of the formula -C (= O) -R ,, preferably a salt, in particular a special 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, one
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 (= O) -R2, this can also be converted into an optionally substituted carbamoyl or hydrozinocarbonyl group, preferably reactive, functionally modified derivatives, such as the above-mentioned acid halides, generally esters , as well as 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 one 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, R1b and / or R2, such as substituted amino groups, acylated hydroxy groups, esterified carboxy groups or O, O-disubstituted phosphono groups, according to methods known per se, for. B.  the above-described, release, or free functional substituents in groups R1A, R1b 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.  Triethylamine, 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 R1A represents an optionally substituted glycyl group, convert 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 -bromo-acetyl group, with esters of phosphorous acid, such as tri-lower alkyl-phosphite compounds, and thus arrive at the 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 acids, e.g. B.  the sodium salt of a-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 additoin salts of compounds of the formula I with basic groups are obtained in the 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 diastereoisomeric 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. 



   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. 



   In the above-described conversions of compounds of the formula I or their salts into other compounds of the formula I or their salts, care must be taken that such conversions take place in a neutral or acidic environment, as under basic conditions the 3-exo-methylene group, Rearrangement of the double bond into the 3- and especially the 2-position of the cepham ring, can be isomerized to a 3-methyl group. 



   The production of the mentioned valuable 3-oxo-cepham-, as well as 3-hydroxy- and 3-subst. Hydroxy-3-cephem compounds, in particular of compounds of the formula II, can be carried out using the compounds of the formula I as follows:
A compound of the formula I obtained according to the invention in which R2 is a hydroxyl group or a salt thereof is converted into a compound of the formula by one of the processes described
EMI15. 1
 converted by the process described below oxidatively into a cepham-3-one compound of the formula
EMI15. 2
 or a corresponding enol with a double bond in 2,3 or 3,4-position, or a 1-oxide of such a compound. 



   The oxidative splitting off of the methylene group in compounds of the formula Ia with formation of an oxo group in the 3-position of the ring structure can be carried out in various ways. 



   Preferably it is done to form an oxonide intermediate 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 a nickel or palladium catalyst, 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 DlWiederalkyl- sulfide, z. B. 

  Dimethyl sulfide, a reducing organic phosphorus compound, such as a phosphine, 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. B.    Triphenylthosphine, furthermore phosphites which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphites, usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphorous acid triamides which optionally contain substituted aliphatic hydrocarbon radicals as substituents, such as hexan lower alkyl phosphorous acid triamides. 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 used for its production, i.e. H.  in the presence of a suitable solvent or solvent mixture, as well as with cooling or slight heating. 



   Depending on the type of oxidation reaction, a compound of the formula IV or the corresponding 1-oxide or a mixture of the two compounds is obtained.  Such a mixture can be separated into the compound of the formula IV and the corresponding 1-oxide, or it can be oxidized to give uniform 1-oxide of a compound of the formula IV. 



   A mixture of a compound of the formula IV with the corresponding 1-oxide can be prepared in a conventional manner, e.g. B.  by fractional crystallization or by chromatography 3 (e.g. B.  Column chromatography, thin layer chromatography), <separated into the individual components.



   In the conversion of the starting materials of the formula IV to the enol derivatives of the formula II of the present invention, the starting materials of the formula IV do not need to be isolated after their 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 Ia.



   The compounds of the formula II are obtained by converting a cepham-3-one compound of the formula IV or a corresponding enol with a double bond in the 2,3 or 3,4 position, or a 1-oxide of such a compound, into an enol derivative with a functionally modified hydroxyl group of the formula -O-R3 in the 3-position, and, if desired, in a compound of the formula II obtained, the protected carboxyl group of the formula -C (= O) -R2A into the free or into another protected one Carboxyl group converted, and / or, if desired, a compound of the formula II obtained in another compound of the formula II, and / or, if desired, a compound obtained with a salt-forming group in a salt or a obtained compound
Converts salt into the free compound or into another salt,

   and / or, if desired, a mixture of isomers obtained separating into the individual isomers.



   Cepham-3-one starting materials of the formula IV can be in the keto and / or in the enol form, with the ring double bond in 2,3, but preferably in
3,4 position can be. Usually, the starting materials of the formula IV are converted from the enol form into the enol derivatives of the formula II. Furthermore, e.g. also a
Use a mixture of a compound of the formula IV and the corresponding l-oxide as the starting material and obtain the mixture of a compound of the formula II and the corresponding l-oxide as the product.



   The conversion of the starting materials of the formula IV into the enol derivatives can be carried out in a manner known per se.



   Enol ether, i.e. Compounds of the formula II in which R3 is an optionally substituted hydrocarbon radical are obtained by any method suitable for etherifying enol groups, it being possible to use starting materials of the formula IV in which Rga and Rlb are
Are hydrogen, but in which Rla is preferably a
Amino protecting group R1A is. The etherifying reagent used is preferably a diazo compound of the formula R3-N2 (V) corresponding to the optionally substituted hydrocarbon radical Ra, primarily an optionally substituted diazo lower alkane, e.g.

  Diazomethane, diazoethane or diazobutane, furthermore an optionally substituted phenyl-diazo-lower alkane, such as a 1-phenyldiazo-lower alkane, e.g.



   Phenyldiazomethane or diphenyldiazomethane. These reagents are in the presence of a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane,
Benzene or toluene, a halogenated aliphatic hydrocarbon, e.g. Methylene chloride, a lower alkanol, e.g.



   Methanol, ethanol or tert-butanol, or an ether such as a di-lower alkyl ether, e.g. Diethyl ether, or a cyclic ether, e.g. Tetrahydrofuran or dioxane, or one
Solvent mixture, and depending on the diazo reagent under
Cooling, at room temperature or with slight warming, further, if necessary, in a closed vessel and / or under an inert gas, e.g. Nitrogen atmosphere applied.



   Enol esters, i.e. Compounds of the formula II in which R3 is an acyl group are obtained by any method suitable for the control of enol groups, where at least one of the groups Rla and Rlb in the starting material of the formula IV is different from hydrogen, unless a simultaneous acylation of a free one is used Amino group wants to risk. So preferably use the
Acyl radical R3 corresponding carboxylic acids of the formula R3-OH (VI) or reactive acid derivatives thereof, such as halides, e.g. 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.

  Ketenes, or from cargamic or thiocarbamic acids, i.e. Isocyanates or isothiocyanates, or mixed anhydrides such as those found e.g. 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 (i.e. enols), e.g. Esters of lower alkanoic acids with vinylogous lower alkanols, e.g.



  Acetic acid isopropenyl ester, whereby, if necessary, in the presence of suitable condensing agents, when using acids e.g. of carbodimide compounds, such as dicyclohexylcarbodiimide, or carbonyl compounds, such as diimidazolylcarbonyl, when using reactive acid derivatives e.g. basic agents such as tri-lower alkylamines, e.g. Triethylamine, or heterocyclic bases, e.g.



  Pyridine, and when using esters with vinylogous alcohols in the presence of an acidic agent such as a mineral, e.g. Sulfuric acid or a strong sulphonic, e.g. 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. Nitrogen atmosphere. Suitable solvents are e.g. 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.



   A mixture of a compound of the formula II and the corresponding 1-oxide obtainable according to the process can be separated with the aid of suitable separation methods, e.g. by 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. Furthermore, a mixture of a compound of the formula II and the corresponding l-oxide can either be oxidized directly to the 1-oxide or reduced to a 3-cephem compound of the formula II. These oxidation and reduction steps are described below in connection with the isomerization of a 2-cephem to the corresponding 3-cephem compound using a 1-oxide as intermediates.



   Obtained cephem compounds of the formula II in which the double bond is in the 2,3 or 3,4 position can be converted into 1-oxides of the corresponding 3-cephem compounds by oxidation with suitable oxidizing agents, such as those described below. The 1-oxides obtained from 3-cephem compounds of the formula II in which the double bond is in the 3,4-position can be reduced by reduction with suitable reducing agents, e.g. reduce the described, to the corresponding 3-cephem compounds of the formula II. In these reactions, care must be taken to ensure that, if necessary, free functional groups are protected and, if desired, are subsequently released again.

 

   Obtained cephem compounds can be isomerized. Thus obtained 2-cephem compounds of the formula II, in which the double bond is in the 2,3-position, can be converted into the corresponding 3-cephem compounds of the formula II, in which the double bond is in the 3,4-position, by converting a 2- Cephem compound of the formula II, wherein free functional groups optionally, for example as indicated, may be temporarily protected, isomerized. You can e.g. Use 2-cephem compounds of the formula II in which the group of the formula -C (= O) -R2 represents a free or protected carboxyl group, it being possible for a protected carboxyl group to also be formed during the reaction.



   For example, a 2-cephem compound of the formula II can be isomerized by treating it with a weakly basic agent and isolating the corresponding 3-cephem compound of the formula II from an optionally obtained equilibrium mixture of the 2- and 3-cephem compounds.



  Suitable isomerizing agents are e.g. organic nitrogen-containing bases, in particular tertiary heterocyclic bases of aromatic character, primarily bases of the pyridine type, such as pyridine itself, as well as collidines or lutidines, also quinoline, tertiary aromatic bases, e.g. those of the aniline type such as N, N-di-lower alkyl anilines, e.g. N, N-dimethylaniline or N, N-diethylaniline, or tertiary aliphatic, azacycloaliphatic or araliphatic bases, such as N, N, N tri-lower alkylamines, e.g. 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.

  N-methyl-piperidine, or N-phenyl-lower alkyl-N, N-di-lower alkyl-amines, e.g., N-benzyl-N, N-dimethylamine, and mixtures thereof, such as the mixture of a base of the pyridine type and an N, N, N-tri-lower alkylamine, e.g. Pyridine and triethylamine.



  Furthermore, inorganic or organic salts of bases, in particular of moderately strong to strong bases with weak acids, such as alkali metal or ammonium salts of lower alkanecarboxylic acids, e.g. 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 e.g.



  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. with pyridine in the presence of acetic anhydride. It is preferable to work in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, e.g. 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 of about -30 "C to about + 100 C, in an inert gas, e.g. nitrogen atmosphere, and / or in a closed vessel.



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



   The isomerization of 2-cephem compounds of the formula II can also be carried out by oxidizing them in the 1-position, if desired, separating an available isomer mixture of the 1-oxides from 3-cephem compounds of the formula II, and the 1- Oxides of the corresponding 3-cephem compounds reduced.



   Suitable oxidizing agents for the 1-position oxidation of 2-cephem compounds are inorganic peracids which have a reduction potential of at least +1.5 volts and consist of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, especially organic carboxylic acids, with a dissociation constant of at least 10-5.



  Suitable inorganic peracids are periodic and persulfuric acid. Organic peracids are corresponding percarbonic and persulfonic acids which can be added as such or formed in situ by using at least one equivalent of hydrogen peroxide and a carboxylic acid.



   It is advisable to use a large excess of the carboxylic acid if e.g. Acetic acid is used as a solvent. Suitable peracids are e.g. Performic acid, peracetic acid, trifluoroacetic acid, permaleic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid.



   The oxidation can also be carried out using hydrogen peroxide with catalytic amounts of an acid with a dissociation constant of at least 10-5, using low concentrations, e.g. 1-2% and less, but also larger amounts of acid can be used. The effectiveness of the mixture depends primarily on the strength of the acid. Suitable mixtures are e.g. those of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.



   The above oxidation can be carried out in the presence of suitable catalysts. E.g. the oxidation with percarboxylic acid can be catalyzed by the presence of an acid with a dissociation constant of at least 10-1, the effectiveness of which depends on its strength. Acids suitable as catalysts are e.g. Acetic acid, perchloric acid and trifluoroacetic acid. Usually at least equimolar amounts of the oxidizing agent are used, preferably a small excess of about 10% to about 20%, larger excesses also being used, i.e. up to 10 times the amount of the oxidizing agent or above, can use.

  The oxidation is carried out under mild conditions, e.g. at temperatures from about -500C to about +100 "C, preferably from about -100C to about +40" C.



   The oxidation of 2-cephem compounds to the 1-oxides of the corresponding 3-cephem compounds can also be achieved by treatment with ozone, furthermore with organic hypohalite compounds such as lower alkyl hypochlorites, e.g.



  tert-butyl hypochlorite, which is obtained in the presence of inert solvents, such as optionally halogenated hydrocarbons, e.g. Methylene chloride, and used at temperatures from about -100C to about +30 "C, with periodate compounds such as alkali metal periodates, e.g.

  Potassium periodate, which is preferably used in an aqueous medium at a pH of about 6 and at temperatures of about -100C to about +30 "C, with iodobenzene dichloride, which is used in an aqueous medium, preferably in the presence of an organic base, e.g. Pyridine, and with cooling, for example at temperatures from about -20 "C to about 0, or with any other oxidizing agent which is suitable for converting a thio group into a sulfoxide group.



   In the 1-oxides of 3-cephem compounds of the formula II obtainable in this way, in particular in those compounds in which Rla, R1b and R2 have the preferred meanings given above, the groups Rla, Rlb and / or R2 can be converted into one another within the given framework , split off or introduced. A mixture of isomeric and 8-1-oxides can e.g. chromatographically, be separated.

 

   The reduction of the 1-oxides of Ceph-3-em compounds of the formula II can be carried out in a manner known per se by treatment with a reducing agent, if necessary in the presence of an activating agent. Possible reducing agents are: catalytically activated hydrogen, using noble metal catalysts which contain palladium, platinum or rhodium and which are optionally used together with a suitable carrier material such as carbon or barium sulfate;

   reducing tin, iron, copper or manganese cations, which are in the form of corresponding compounds or complexes of an inorganic or organic nature, e.g. as tin (II) chloride, fluoride, acetate or formate, iron (II) chloride, sulfate, oxalate or succinate, copper (I) chloride, benzoate or oxide, or manganese (II) chloride, sulfate, acetate or oxide, or as complexes, e.g. with ethylenediaminetetraacetic acid or nitrolotriacetic acid, can be used; reducing dithionite, iodine or iron (II) cyanide anions, which in the form of corresponding inorganic or organic salts, such as alkali metal, e.g.

  Sodium or potassium dithionite, sodium or potassium iodide or iron (II) cyanide, or in the form of the corresponding acids, such as hydriodic acid, can be used; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, also esters, amides and halides of phosphinous, phosphonous or phosphorous acid, as well as phosphorus-sulfur compounds corresponding to these phosphorus-oxygen compounds, in which organic residues are primarily aliphatic, aromatic or araliphatic residues, e.g. optionally substituted lower alkyl, phenyl or phenyl lower alkyl groups, e.g.

  Triphenylphosphine, tri-n-butylphosphine, methyl diphenylphosphinate, diphenylchlorophosphine, phenyldichlorophosphine, dimethyl benzene phosphonate, methyl butanephosphonate, triphenyl phosphate, trimethyl phosphate, phosphorus trichloride, phosphorus trichloride, etc .; reducing halosilvanic compounds which have at least one hydrogen atom bonded to the silicon atom and which, in addition to halogen such as chlorine, bromine or iodine, also contain organic radicals such as aliphatic or aromatic groups, e.g. may have optionally substituted lower alkyl or phenyl groups, such as chlorosilane, bromosilane, di- or trichlorosilane, di- or tribromosilane, diphenylchlorosilane, dimethylchlorosilane, etc .;

   reducing quaternary chloromethylene iminic acid, in particular chlorides or bromides, in which the iminium group is substituted by one divalent or two monovalent organic radicals, such as optionally substituted lower alkylene or lower alkyl groups, such as N-chloromethylene -N, N-diethyliminium chloride or N-chloromethylene pyrrolidinium chloride; and complex metal hydrides such as sodium borohydride in the presence of suitable activating agents such as cobalt-II chloride.



   As activating agents used together with those of the above reducing agents which themselves do not have Lewis acid properties, i. which are primarily used together with the dithionite, iodine or iron -lt-cyanide and the non-halogen-containing trivalent phosphorus reducing agents or in the catalytic reduction are, in particular, organic carboxylic and sulfonic acid halides, and also sulfur and phosphorus - Or silicon halides with the same or greater hydrolysis constant of the second order than benzoyl chloride, e.g.

  Phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride; Pivalic acid chloride, 4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulphonic acid chloride, methanesulphonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenephosphonous acid chloride, or, furthermore, benzolphosphonous anhydride, or, furthermore, suitable fluorophosphoric acid, such as trihydric acid anhydric acid, such as trihydric acid fluorine, trihydric acid, such as trihydric acid, such as trihydrofluorine, trihydric acid, such as trihydrofluorine, trihydric acid, such as trihydrofluoric acid, such as tri-anhydric acid, such as tri-anhydride, tri-anhydric acid, such as 1,3-propane sultone, 1,4-butane sultone or 1,3-hexane sultone.



   The reduction is preferably carried out in the presence of solvents or mixtures thereof, the selection of which is primarily determined by the solubility of the starting materials and the choice of reducing agent, e.g.



  Lower alkanoic acids or esters thereof, such as acetic acid and ethyl acetate, in the catalytic reduction, and e.g. optionally substituted, such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. Benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives such as lower alkanecarboxylic acid esters or nitriles, e.g. Ethyl acetate or acetonitrile, or amides of inorganic or organic acids, e.g. Dimethylformamide or hexamethylphosphoramide, ethers, e.g. Diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. Acetone, or sulfones, especially aliphatic sulfones, e.g. Dimethyl sulfone or tetramethylene sulfone, etc., together with the chemical reducing agents, these solvents preferably not containing water.

  The process is usually carried out at temperatures of about −200 ° C. to about 100 ° C., it being possible to carry out the reaction at lower temperatures when using very reactive activating agents.



   In the 3-cephem compounds of the formula II obtainable in this way, Rla, R, b and / or R2 can, as described, be converted into other groups R1a, Rlb or R2, it being necessary to ensure that the 3-cephem compounds are essential to basic agents are more sensitive than the corresponding 2-cephem compounds.



   The pharmacologically usable compounds obtainable from the compounds of the formula I which can be prepared according to the invention can e.g. can be used for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for enteral or, preferably, parenteral administration. Thus, tablets or gelatine capsules are used which contain the active ingredient together with diluents, e.g. Lacose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g.

  Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, colorants, flavorings and sweeteners. The pharmacologically active compounds are preferably used in the form of injectables, e.g. intravenously administrable preparations or from infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these e.g. from lyophilized preparations which contain the active substance alone or together with a carrier material, e.g. Mannitol, contained, can be prepared before use.

  The pharmaceutical preparations can be sterilized and / or auxiliary materials, e.g. 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, can contain further pharmacologically valuable substances, are made in a manner known per se, e.g. by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain from about 0.10 / 0 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 designated lower contain, unless expressly defined, 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 I.
A solution of 3.3 g of about 90 percent (5.6 mmol) 7ss- (D-0c-tert-butyloxycarbonylamino-5c-phenylacetylamino) - -cephalosporanic acid sodium salt in 80 ml of 0.5-m. aqueous potassium phosphate buffer (pH 7) and 8 ml of dimethylformamide is adjusted to pH 6.0 with concentrated phosphoric acid.



  The aluminum amalgam obtained from 3.3 g of aluminum grit is added and the mixture is stirred for 30 minutes at 45 and pH 6.0 (kept constant by adding phosphoric acid).



  It is diluted with 100 ml of ice, covered with a layer of cold ethyl acetate and adjusted to pH 2.0 with concentrated phosphoric acid. After saturation with common salt, the organic layer is separated off and extracted twice with ethyl acetate. The extracts, washed with saturated sodium chloride solution and dried over sodium sulphate, give 3.55 g of a greenish foam on evaporation, which is crystallized in 9 ml of ethyl acetate. It is slowly diluted with 15 ml of ethyl acetate-hexane 2: 3, filtered after standing for 2 hours at -5 and the 3-methylene-7P- (Da-tert.-butyloxycarbo-nylamino-α-phenylacetylamino) -cepham-4α is obtained. -carboxylic acid, F: 196-7 (corr.); La1.20 = +35 + 1 (C = 1.0; 5-n. Sodium bicarbonate).

  IR spectrum (Nujol): 2.98; 5.67; 5.74; 5.92; 6.01; 6.55; 6.62; 7.50; 8.01; 8.32; 8.56; 9.51; 10.77; 11.36; 11.82 s, m. Thin-layer chromatogram on silica gel: Rf = 0.58 (system 52 / n-butanol-glacial acetic acid-water 75: 7.5: 21) and Rf = 0.35 (system 100j ethyl acetate-pyridine-glacial acetic acid-water 60: 20: 6: 11 ).



   The 7ss- (D-α-tert-butyloxycarbonylamino-α-phenylacetylamino) -cephalosporanic acid sodium salt used as starting material is prepared by adding 50 g according to J.L.



  Spencer et al., Journal of Medicinal Chemistry 9, 746 (1966) obtained crude 7p. (D. tert .. butyloxycarbonylamino. Phe.



  nylacetylamino) -cephalosporanic acid is dissolved in 170 ml of dioxane, diluted with 170 ml of ethyl acetate and slowly mixed with 50 ml of a 50 percent solution of sodium a-ethyl hexanoate in methanol while cooling. The filtered salt is washed with dioxane / ethyl acetate 2: 1 and pure ethyl acetate and digested with 11 ether, then with 200 ml of ethanol.



   That used; Aluminum is amalgamated as follows: 3.3 g of aluminum grit are swirled in 100 ml of 5% sodium hydroxide solution for 30 seconds and, after decanting, washed 3 times with 300 ml of water each time. The metal is then treated for 3 minutes with 130 ml of 0.5 percent mercury (II) chloride solution and washed 3 times with 300 ml of water each time. The whole procedure is repeated once and the amalgam is finally washed 3 times with tetrahydrofuran. Approx. 15 ml of ethyl acetate are used to transfer the amalgam into the reaction vessel.



   Example 2
30 g (53 mmol) of pure 7ss (-D- α-tert-butyloxycarbonyl-aminophenylacetylamino) -cephalosporanic acid ethanolamine salt are dissolved according to example 1 in 750 ml of 0.5-m. Potassium phosphate buffer (pH 7) and 75 ml of dimethylformamide with the amalgam prepared from 50 g of aluminum as in Example 1, stirred for 30 minutes at 45 and pH 5.5. Analog processing gives crystalline 3-methylene-7ss- (D-α-tert-butyloxycarbonylamino-phenylacetylamino) -cephamic-4c-carboxylic acid.



   The ethanolamine salt used as the starting material is obtained as follows: A solution of 30 g of 7p- (Dc-tert-butyloxycarbonylamino-phenylacetylamino) -cephalosporanic acid in 150 ml of methanol is mixed at 0 with a solution of 3.6 ml of ethanolamine in 30 ml of methanol added and the deposited salt filtered off after 30 minutes.



   Example 3
202 g (0.4 mol) of crystalline 7P- (D -a-tert-butyloxycarbonylamino-phenylacetylamino) -cephalosporanic acid, m.p. 1301320 (corr.) Are placed in a 10 l reaction vessel -in 4.51 0.5- m. aqueous potassium phosphate buffer (pH 7) and 450 ml of dimethylformamide largely dissolved with stirring. The pH is adjusted to 6.0 by adding concentrated phosphoric acid and the amalgam obtained from 200 g of aluminum grit (preparation see below) is added. 0.5 l of ethyl acetate is added and the temperature of the mixture is allowed to rise to 40 within 10 minutes with self-heating, without cooling. The temperature is brought to 46 for a further 10 minutes by occasional cooling with the ice bath and is kept constant there.

  After 15 minutes at 460, the mixture is cooled to 29 (acetone-dry ice bath) within 10 minutes and the mixture is poured onto 3 kg of ice and 5 l of ice-cold ethyl acetate. It is acidified to pH 2 with concentrated phosphoric acid while stirring and saturated with common salt. After the phases have separated, the aqueous phase is extracted twice with cold ethyl acetate each time.



   The organic phases are washed once with 4 liters of cold, saturated sodium chloride solution, dried over magnesium sulfate and concentrated to about 11 in vacuo. The starting crystallization of the product is completed by standing in the refrigerator for 3 hours. Filtration and drying give crystalline 3-methylene-7ss- (D-α-tert-butyloxycarbonylamino-phenylacetylamino) -4a-carboxylic acid.



   That used; The amalgam is prepared as follows: 200 g of aluminum grits are poured over with 21 5 percent aqueous sodium hydroxide solution and etched for 40 seconds while swirling. It is decanted and washed twice with water. The residue is treated with 2 liters of 0.5 percent aqueous mercury (II) chloride solution for 3 minutes while swirling around, decafed and shaken again for 3 minutes with a further 21 sublimate solution. After decanting and washing 3 times with water, the amalgam is used immediately as a reducing agent.



   Example 4
In a manner analogous to that described in Example 1, 3-methylene-7p-phenylacetylamino) -cepham-4c-carboxylic acid can be obtained starting from the sodium salt of 7x-phenylacetylamino) - -cephalosporanic acid.



   Example 5
A solution of 8 g of 3-methylene-7ss- (D-α-tert.butyloxycarbonylamino-, sc-phenylacetylamino) -cepham-4K-carboxylic acid in 100 ml of methanol is mixed with a solution of 6 g of diphenyldiazomethane in 30 ml of benzene stirred for 1 hour at room temperature.

  The crude product obtained after evaporation is chromatographed on 500 g of silica gel. The 3-methylene-70- (D-CC-tert-butyloxycarbonylamino-a-phenylacetyl-amino) -cepham-4α-carboxylic acid diphenylmethyl ester is treated with a 4: 1 mixture of petroleum ether eluted diethyl ether; after crystallization from a mixture of methylene dichloride and hexane, the product melts at 156-158; [α] D = -50 + 1 (C = 0.713, chloroform); Ultraviolet absorption spectrum in 95% aqueous ethanol): A.mnX 258 y (E = 990);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 i, 5.64 pt, 5.74, 5.88 (shoulder) and 6.71!
Example 6
In a manner analogous to that described in Example 3, starting from 3-methylene-7ss - (α-phenylacetylamino) -cepham--4α-carboxylic acid, 3-methylene-7ss - (α-phenylacetylamino-cepham-4α ; -carboxylic acid diphenylmethyl ester are obtained.



  F. 144-147 (methylene chloride-hexane); [α] 20 D = 18 + 1 (c = 0.715 in chloroform); Ultraviolet absorption spectrum (in 95% 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! Y, 6.26, and 6.67.



   Example 7
A solution, cooled to 15, of 2.0 g of 3-methylene-7ss - (α-phenylacetylamino) -cepham-4α-carboxylic acid diphenylmethyl ester in 80 ml of absolute methylene chloride is mixed with 3.2 ml of absolute pyridine and 32 ml of an 8 % solution of phosphorus pentachloride in methylene chloride and stirred for one hour under a nitrogen atmosphere at a temperature between 10 and 5. The reaction mixture is then cooled to 25, mixed with 25 ml of absolute methanol and stirred for one hour at 10, then for 1.5 hours at room temperature.

  80 ml of a 0.5 molar aqueous solution of potassium dihydrogen phosphate are then added, the pH is adjusted to 2 with 20% aqueous phosphoric acid and the mixture is stirred at room temperature for 30 minutes.



   The organic phase is separated off; the aqueous phase is extracted twice with 150 ml of methylene chloride each time and the organic solutions are combined, dried over sodium sulfate and evaporated. The oily residue is taken up in 25 ml of ethyl acetate and, at 0, a solution of 1.14 g of 4-methylphenylsulfonic acid monohydrate in 25 ml of ethyl acetate is added. A voluminous precipitate separates out, which is filtered off, washed with cold ethyl acetate and diethyl ether, dried and recrystallized from a mixture of methylene chloride and diethyl ether.

  The 4-methylphenylsulphonate of 7ss-amino-3-methylene-cepham-4α-carboxylic acid diphenylmethyl ester, mp 153-155; is thus obtained in the form of colorless needles; [α] D = -14 + 1 (c = 0.97 in methanol); Ultraviolet absorption spectrum (in ethanol): #max = 257 (# = 1500); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.5, 5.60, 5.73, 8.50, 9.68 and 9.92.



   Example 8
A solution, cooled to 70, of 5.0 g of 3-methylene -7ss- (D-α-tert-butyloxycarbonylamino-α-phenylacetylamino) -cepham-4α-carboxylic acid diphenylmethyl ester is added with vigorous stirring for 1 hour Oxygen-ozone stream containing 0.21 mmol ozone / min. initiated. After a further 10 minutes, 3 ml of dimethyl sulfide are added to the reaction mixture, the mixture is stirred for one hour at 65 and for 2 hours at room temperature and then evaporated under reduced pressure.

  The crude product, which contains the 7ss- (D-α-tert-butyloxycarbonylamino-α-phenylacetyl-amino) -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester, in 150 ml of methanol is at 0 with an excess Amount of a solution of diazomethane in diethyl ether is added and the mixture is stirred for 15 minutes and then evaporated.



  A yellowish foam is obtained which is chromatographed on 200 g of silica gel. The amorphous 3-methoxy-7ss- (Da-tert-butyloxycarbonylamino-a-phenyl-acetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester is eluted with a 3: 1 mixture of toluene and ethyl acetate, thin-layer chromatogram ( Silica gel):

  Rf = 0.22 (system: toluene / ethyl acetate 3: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.60, 5.85, 6.23 to and 6.70 l
Example 9
In an analogous manner, starting from 3-methylene-7ss- (la-phenylacetylamino) -cepham-4a-carboxylic acid diphenylmethyl ester, the amorphous 7ss - (α-phenylacetylamino) -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester [ Thin layer chromatography (silica gel): Rf ¯ 0.47 (system:

  Toluene / acetone / methanol / acetic acid 80: 10: 5: 5); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95, 5.61, 5.77, 5.85, 5.95, 6.21 and the like. 6.87; the compound shows a positive iron (III) chloride reaction, which suggests the presence of the enol form] and from this the 3-methoxy-7ss - (α-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained, Ultraviolet absorption spectrum (in ethanol): #max = 264 (# = 1300); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.63, 5.83, 5.94, 6.26 and 6.68.



   Example 10
A mixture of 2.44 g of 3-methoxy-7ss- (D-α-tert-butyl-oxy-carbonylamino-α-phenylacetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester, 2.1 ml Anisole and 41 ml of trifluoroacetic acid are left to stand for 5 minutes at room temperature and then evaporated. The residue is taken up in 200 ml of a 3: 1 mixture of toluene and chloroform, evaporated and dried in a high vacuum.



  The brown residue is digested several times with diethyl ether, suction filtered and dried. The light blue powdery trifluoroacetate of 3-methoxy-7ss- (D-α-phenyl-glycyl-amino) -3-cephem-4-carboxylic acid obtained is dissolved in 5 ml of methanol, 5 ml of diethyl ether and 0.5 ml of water and the pH of the solution is adjusted to about 4 by adding dropwise a 3% solution of triethylamine in diethyl ether; a fluffy, brownish precipitate separates out.



  The precipitation is completed by further addition of diethyl ether, the precipitate is filtered off and reprecipitated three times from a mixture of methanol and dithyl ether.



  The amorphous inner salt of 3-methoxy-7ss- (D-α-phenyl-glycyl-amino) -3-cephem-4-carboxylic acid - shows an Rf value of about 0.14 in a thin-layer chromatogram (silica gel) - (system : Ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10).



   Example 11
A mixture of 0.06 g of 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, 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 together 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 - (α - -phenylacetylamino) -3-cephem-4-carboxylic acid is eluted with methylene chloride containing 30-50% acetone and lyophilized from dioxane, ultraviolet absorption spectrum (in 95% aqueous ethanol): # max = 265, (# 5800); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 5.66, 5.90, 6.24 and 6.50; [α] D20 = +110 # 1 (C = 0.740); Dioxane).

 

   Example 12
A solution of 21.8 g (80 mmol) of 7ss-aminocephalosporanic acid in 900 ml of 0.5-m. Phosphate buffer (pH 7) and 100 ml of dimethylformamide are mixed with 40 g of aluminum amalgam. The mixture is stirred at pH 6.0 and 45 for 1 hour. After cooling, the reaction mixture is washed with cold ethyl acetate and the aqueous phase is filtered through Celite. The filtrate, which is set to pH 3.5, is evaporated in vacuo and the residue is taken up in 200 ml of methanol-water 7: 3. The filtered off portion (27.5 g) contains not only the product but also considerable amounts of inorganic salts.

  By shaking with 150 ml of water, standing at 0 for 3 hours and filtering, the 7ss-amino-3-methylene-cepham-4α-carboxylic acid is obtained as a virtually colorless powder. Thin-layer chroma on silica gel: Rf (system 52 / n-butanol-glacial acetic acid-water 75: 75: 21) = 0.20, Rf (system 100 / ethyl acetate-pyridine-glacial acetic acid-water 60: 20: 6:11) = 0 , 13, Rf (system 200 / n butanol-carbon tetrachloride-methanol-formic acid-water 30: 40: 20: 5: 5) = 0.34.



   Example 13 7ss-Amino-3-methylene-cepham-4α-carboxylic acid benzyl-dryl ester (Example 7) is cleaved in trifluoroacetic acid solution for 5 minutes at 20 to give the free acid. Evaporation, taking up in toluene and evaporation again gives 7ss-amino-3-methylene-cepham-4α-carboxylic acid.



   Example 14
A solution of 2.5 g of N-tert-butyloxycarbonyl-D- - -phenylglycine in 30 ml of tetrahydrofuran and 1.4 ml of triethylamine is mixed with 1.3 ml of isobutyl chloroformate at 10 and stirred at 10 for 20 minutes. To do this, you quickly pour one; ice-cold solution of 2.1 g of 7p-amino.3.me thylen-cepham.4-carboxylic acid in 40 ml of 0.5-m. Dipotassium hydrogen phosphate solution. The mixture is stirred for 34 hours at 0 and 1/2 hour at 25, the tetrahydrofuran is evaporated and the aqueous phase is washed with ether.

  Extraction at pH 2.0 with ethyl acetate and crystallization from ethyl acetate-hexane gives the 3-methylene-7ss- (D-α-tert-butyloxycarbonylamino-α-phenylacetylamino) -cepham-4α-carboxylic acid.



   Example 15
A solution of 0.50 g of the 4-methylphenylsulfonate of 7ss-amino-cepham-3-one-4i-carboxylic acid diphenylmethyl ester, which is mainly in the enol form, i. as 4-methylphenylsulfonate of 7ss-amino-3-cephem-3-ol-4-carboxylic acid diphenylmethyl ester, in 25 ml of methanol a solution of diazomethane in diethyl ether is added at 0 to a permanent yellow color. The mixture is stirred in an ice bath for 10 minutes and then evaporated. The residue is chromatographed on silica gel.

  The oily 7ss-amino--3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is eluted with a 2: 1 mixture of toluene and ethyl acetate. Thin-layer chromatogram (silica gel; development with iodine vapor): Rf ¯ 0.39 (system: ethyl acetate) ; Ultraviolet Absorption Spectrum (in ethanol): Amax = 265 (= 6100); Infrared absorption spectrum (in methylene chloride): characteristic bands of 3.33, 5.63, 5.81 and 6.23.



   Further elution with ethyl acetate gives the oily 7ss-dimethylamino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, thin chromatogram (silica ball; development with iodine vapor): Rf ¯ 0.20 (system: ethyl acetate); Ultraviolet Absorption Spectrum (in ethanol): #max = 2.65 (± = 5900); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.98 x, 3.33, 5.62, 5.81 and 6.24.



   The starting material can be made as follows:
A solution, cooled to -150, of 2.0 g of 3-methylene-7- phenylacetylamino-cepham-4x-carboxylic acid diphenylmethyl ester in 80 ml of absolute methylene chloride is mixed with 3.2 ml of absolute pyridine and 32 ml of an 8% solution added phosphorus pentachloride in methylene chloride and stirred for one hour under a nitrogen atmosphere at a temperature between 100 and -5. The reaction mixture is then cooled to 250 ml, 25 ml of absolute methanol are added and the mixture is kept at -10 for one hour. then stirred for 1.5 hours at room temperature.

  80 ml of a 0.5 molar aqueous solution of potassium dihydrogen phosphate are then added, the pH is adjusted to 2 with 20% aqueous phosphoric acid and the mixture is stirred at room temperature for 30 minutes.



   The; organic; Phase is separated; the aqueous phase is extracted twice with 150 ml of methylene chloride each time and the organic solutions are combined, dried over sodium sulfate and evaporated. The oily residue is taken up in 25 ml of ethyl acetate and, at 0, a solution of 1.14 g of 4-methylphenylsulfonic acid monohydrate in 25 ml of methylene chloride is added. A voluminous precipitate separates out, which is filtered off, washed with cold ethyl acetate and diethyl ether, dried and recrystallized from a mixture of methylene chloride and diethyl ether. The 4-methylphenylsulfonate of 7'p-amino.3-methylene is thus obtained in the form of colorless needles.



     -cepham-4α-carboxylic acid diphenylmethyl ester F. 153-155; [α] = -14 # 1 (c = 0.97 in methanol); Ultraviolet absorption spectrum (in ethanol); #max = 257 (# = 1500); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.5 Sa, 5.60 a, 5.73 8.50., 9.68 @ and 9.92.



   Through a solution, cooled to 600, of 0.553 g of the 4-methylphenylsulfonate of 7p-amino-3-methylene-cepham- -4a-carboxylic acid diphenylmethyl ester in 50 ml of methanol, a stream of oxygen and ozone (containing 0.35 mmol of ozone per Minute). After a further 5 minutes, 0.3 ml of dimethyl sulfide is added to the pale blue solution. The mixture is stirred for 15 minutes at 700, for one hour at 120 and for one hour in an ice bath, then evaporated. The residue is taken up in a small amount of methylene chloride, then diethyl ether is added until it becomes cloudy and the mixture is left to stand.

  The microcrystalline, reddish colored powdery precipitate is filtered off and gives the 4-methylphenylsulphonate of 7p-amino-cepham- -3-one-4α-carboxylic acid dipheylmethyl ester, which is mainly in the enol form as 4-methylphenylsulphonate of 7f3-amino- 3-cephem-3-ol-4-carboxylic acid diphenylmethyl ester is present, F. 143-145 (with decomposition); Thin layer chromatogram (silica gel) Rf ¯ 0.28 (system:

  Ethyl acetate / pyridine / water 85: 10: 5); Ultraviolet absorption spectrum (in ethanol): #max = 262 ma (± = 3050) and 282 ma (s = 3020); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58, 5.57 (shoulder) 6.02 and 6.22.



   Example 16
A suspension of 0.250 g of 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 25 ml of methyl chloride is mixed with 1 ml of pyridine and 0.5 ml of phenylacetic acid chloride at 0 and under a nitrogen atmosphere and for 30 minutes stirred at this temperature. The reaction mixture is evaporated under reduced pressure; the residue is stirred for 10 minutes with 20 ml of a 1: 1 mixture of dioxane and water and diluted with methylene chloride. The aqueous phase is separated off and extracted with methylene chloride. The combined organic phases are washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.

  The crude product is purified by means of preparative thin-layer chromatography, the 1: 1 mixture of toluene and ethyl acetate being used as the solvent. The zone visible under ultraviolet light from # = 254 m (Rf ¯ 0.35) is eluted with a 4: 1 mixture of acetone and methanol to give the 3-methoxy-7ss - (α-phenylacetylamino) - 3-cephem- Diphenylmethyl 4-carboxylate, which is identical to the product obtainable by the process of Example 9.



   Example 17
A solution of 4.7 g of N-benzoyl-cephalosporin C in 85 ml of 0.5-m. Phosphate buffer (pH 7) and 9 ml of dimethylformamide are stirred together with 4.7 g of aluminum amalgam for 45 minutes at pH 6.0 and 45 ". Example 1 corresponding work-up and crystallization from ethyl acetate-ether 1: 4 gives 3-methylene-7 , 3- (5-benzoylamino-adipoylamino) -cepham- -4a-carboxylic acid, m.p. 82-89 dec. Thin-layer chromatogram on silica gel: Rf (system 52 / n-butanol-glacial acetic acid-water 75: 7.5: 21): 0.53, Rf (system 100 / ethyl acetate-pyridine-glacial acetic acid-water 60: 20: 6: 1): 0.08.



   To prepare the starting material, 50 g of cephalosporin G sodium salt are dissolved in 1.5 liters of 10 percent dipotassium hydrogen phosphate solution, 1.2 liters of acetone are added and 21 g of benzoyl chloride are added at 0. The mixture is stirred for 30 minutes at 0 and 45 minutes at 20, the pH being kept constant at 8.5 by adding 50 percent tripotassium phosphate solution. It is concentrated to about half the volume, washed with ethyl acetate, acidified to pH 2.0 and extracted with ethyl acetate. The evaporation residue crystallizes from acetone and N-benzoyl-cephalosporin C, F. 117 is obtained
119. Thin layer chromatogram: Rf (system 52): 0.37; (System 100): 0.08.



   Example 18
A solution of 2.24 g of N-benzoyl-deacetyl-cephalosporin-C-lactone in 55 ml of 0.5 m. Potassium phosphate buffer pH 7 and 5 ml of dimethylformamide is mixed with the amalgam of 2.2 g of aluminum powder and takes 30 minutes at pH 6.0 and 45 ". Example 1 corresponding work-up and crystallization from ethyl acetate gives 3-methylene-7ss- (5-benzoylamino-adipoylamino) -cepham-4α-carboxylic acid, which is identical to the compound obtained according to Example 17 is.



   The starting material is obtained by neutralizing 15 g of N-benzoylcephalosporin C (see Example 17) in 75 ml of water with about 25 ml of 2 normal sodium hydroxide solution to pH 7.5, with 0.5 g of enriched enzyme from Bacillus subtilis A7 CC 6633 (cf. English Patent 1 080 904) are added and the mixture is stirred at 20 for 6 hours. By adding 2 normal sodium hydroxide solution, the es acetic acid formed as a result of deacetylation is neutralized in the pH range 7.5-8.0. The deacetyl compound obtained is left to stand in 150 ml of formic acid at 22 for 11 hours and is converted into the lactone in the process. It is evaporated, the residue is dissolved in 1 molar dipotassium hydrogen phosphate solution and washed with ethyl acetate.



  Acidification of the aqueous phase to pH 2.0, extraction with ethyl acetate and crystallization from ethyl acetate-ether gives the N-benzoyl-deacetyl-cephalosporin-C-lactone, F. 136-138.



   Example 19
3.3 g of 7ss- (D-α-p-methoxybenzyloxycarbonylamino-α-phenylacetamido) -cephalosporanic acid are mixed according to Example 1 in 170 ml of buffer dimethylformamide 9: 1 with 3.3 g of aluminum amalgam for 1 hour at 45 ° "and pH 6 stirred.



  It is washed with ethyl acetate-ether 1: 3 and finally extracted at pH 2.0 with ethyl acetate. The crude 3-methylene-7p- (D-0c-p-methoxybenzyloxycarbonylamino-a-phenyl-acetylamino) -cepham-4a-carboxylic acid is obtained in this way. Thin layer chromatogram on silica gel: Rf (system 52): 0.57, Rf (system 100): 0.36.



   The starting material is obtained as follows: 63 gp of methoxybenzyloxycarbonyl-D-phenylglycine (from chloroformic acid p-methoxybenzyl ester and D-phenylglycine) are dissolved in 700 ml of tetrahydrofuran and 27.4 ml of triethylamine and, after addition of 26 ml of isobutyl chloroformate, for 15 minutes -100 stirred. A cold solution of 52 g of 7SS-aminocephalosporanic acid in 600 ml of tetrahydrofuran-water 1: 1 and 26 ml of diethylamine are added. The mixture is stirred for 1 hour at 0 and 1 hour at 20. The concentrated mixture is extracted with ethyl acetate at pH 2.0 and crystallized.

  The 7ss- (D-p-methoxybenzyloxycarbonyl-amino-la-phenylacetylamino) -cephalosporanic acid is obtained; F. 154-155 thin layer chromatogram: Rf (system 100): 0.42.



   Example 20
A suspension of 1.56 g of 7P- (Da-tert-butyloxycarbonylamino-phenylacetylamino) -cephalosporanic acid-1-oxide in 36 ml of 0.5-molar phosphate buffer (pH 7) and 4 ml of dimethylformamide is mixed with the amalgam of 1 , 6 g of aluminum are added and the mixture is stirred for 30 minutes at pH 6.0 and 45 ". According to Example 1, by working up and crystallizing from ethyl acetate, there is 3-methylene-7p- (Da-tert-butyloxycarbonylamino-phenylacetylamino) -cepham. 4-carboxylic acid 1-oxide, m.p. 222-5; thin-layer chromatogram Rf (system 52): 0.33; Rf (system 100): 0.21.



   The raw material is produced as follows:
A solution of 16 g of 7p- (Da-tert-butyloxycarbonyl-aminophenylacetylamino) .cepbalosporanic acid in 160 ml of 95 percent alcohol is mixed at 0 with a solution of 7.05 g of m-chloroperbenzoic acid in 25 ml of alcohol and 1 hour stirred at 0. The beginning crystallization is completed by adding 100 ml of ether and gives 22 g of crude product. After recrystallization from methanol / acetone, the 7ss- (D-α-tert-butyloxycarbonylamino-phenyl-acetylamino) -cephalosporanic acid-1-oxide, m.p. over 3000; Thin layer chromatogram Rf (system 52): 0.32; Rf (system 100): 0.27.



   Example 21
A solution of 270 mg of 3-methylene-7ss- (Da-tert-butyloxycarbonylamino-phenylacetylamino) -cepham-4a-carboxylic acid in 25 ml of 95 percent ethanol and 5 ml of methanol is treated with 130 mg of m-chloroperbenzoic acid and stirred at 22 for 30 minutes. Evaporation gives a crude product which is recrystallized from methanol-acetone. The 3-methylene-7p- (D-, a-tert-butyloxycarbonylamino-phenyl-acetylamino) -cepham-4-carboxylic acid-1-oxide, mp 225-6; lb20 = - 1070 + 10 (C = 1, dimethyl sulfoxide). The product is identical to the reduction product obtained in Example 20.



   Example 22
100 g (0.177 mol) of 7ss- (D-α-tert-butyloxycarbonylamino-phenylacetylamino) -cephalosporanic acid-ethanolamine salt are dissolved in a mixture of 2.2 1 double-distilled water, 0.3 1 1-m. Dissolved potassium phosphate buffer (pH 6.0), 0.41 methanol and 0.3 l ethyl acetate. Amalgam prepared from 50 g of aluminum grit is added and the mixture is adjusted to pH 6.7 by adding concentrated phosphoric acid.

 

  This value is kept constant throughout the reduction by adding more acid. The mixture is stirred vigorously for 1 hour at 35 ". To prevent excessive foaming, about 70 ml of ethyl acetate are gradually added.



   For working up, the mixture is poured onto 1.5 kg of ice and 11% of ethyl acetate and adjusted to pH 2.1 with about 220 ml of concentrated phosphoric acid. The excess amalgam is sieved through a steel wire mesh and washed ge with 1.5 l of ethyl acetate. The phases of the filtrate combined with the washing liquid are separated and the organic phase is washed twice with 1.5 l of ice water each time containing 4 ml of phosphoric acid. The aqueous phases are extracted twice with 21 ethyl acetate each time. The combined ethyl acetate extract is dried over sodium sulfate, filtered off and concentrated to about 300 g in vacuo. The beginning crystallization is completed by cooling and slowly adding 460 ml of ethyl acetate, hexane 2: 3.

  The crystalline 3-methylene-7p - (D-x-t-butyloxycarbonylamino-phenylacetylamino) -cepham--4x-carboxylic acid is filtered off and washed with cold ethyl acetate, hexane 7: 3. The compound is identical to the compounds obtained according to Examples 1-3.



   By evaporating the filtrate and the washing liquid and crystallizing the residue as before, further amounts of the desired acid can be obtained.



   Example 23
4.67 g of 7j3-phenoxyacetylamino-cephalosporanic acid-ethanolamine salt are added to a mixture of 104 ml of water (double-distilled), 14 ml of l-m. Dissolved potassium phosphate buffer (pH 6.5), 17 ml of acetonitrile and 17 ml of methanol and stirred in the presence of amalgam prepared from 2.64 g of aluminum grit for 1 hour at 35 and pH 6.7. The pH is kept constant by adding concentrated phosphoric acid.

  The reaction, work-up and crystallization carried out according to Example 22 gives the crystalline 3-methylene-7p-phenoxyacetylamino-cepham-4a-carboxylic acid, mp 185-1880
To prepare the starting material, a solution of 15.6 g of 7p-phenoxyacetylamino-cephalosporanic acid in 50 ml of methanol and 25 ml of ether is added at -10 "with a solution of 2.5 ml of ethanolamine in 12.5 ml of methanol and the crystal slurry after a short time The crystalline 7ss-phenoxyacetylamino-cephalosporanic acid-ethanolamine salt, F 1640, is obtained.



   Example 24
A mixture of 45 mg of 3-methylene-7- (D- -tert.-butyloxycarbonylamino-phenylacetylamino) -cepham-4-carboxylic acid in 1 ml of pyridine is mixed with 0.05 ml of trimethylchlorosilane and the clear solution for 17 hours left standing at 22. The solution is added to an ice-cold mixture of ethyl acetate-5 percent aqueous phosphoric acid, the phases are separated and the ethyl acetate extract is evaporated after drying over sodium sulfate. The uniform 3-methyl-7ss - (D-α-tert-butyloxycarbonylamino-phenylacetylamino) -ceph--3-em-4-carboxylic acid is obtained; Thin layer chromatogram Rf (system 52): 0.67; Rf (system 100): 0.60.



   Example 25
Dry ampoules or vials containing 0.5 g of 3-methoxy-7p - (, x-phenylacetylamino) -3-cephem-4-carboxylic acid are prepared as follows: Composition (for 1 ampoule or vial) 3-methoxy-7p- (x-phenylacetylamino) -3- -cephem-4-carboxylic acid 0.5 g mannitol 0.05 g
A sterile aqueous solution of 3-methoxy-7ss- (a-phenyl-acetylamino) -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 sealed and checked.

 

   Example 26
Dry powder or vials containing 0.5 g of the inner salt of 3-methoxy-7- (D-phenylglycyl-amino) -3-cephem- -4-carboxylic acid are prepared as follows: Composition (for 1 ampoule or vial) Inner salt of 3-methoxy-7,3- (Da-phenyl-glycyl-amino) -3 -cephem-4-carboxylic acid 0.5 g mannitol 0.05 g
A sterile aqueous solution of the inner salt of 3-methoxy-7f3- (Da-phenylglyycyl-amino) .3 -cephem-4-carboxylic acid and mannitol is freeze-drying under aseptic conditions in 5 ml ampoules or 5 ml vials subjected and the ampoules or vials sealed and checked.

 

Claims (1)

PATENT CLAIM Process for the preparation of 7p-asnino-3-methylene-cepham-4-carboxylic acid compounds of the formula EMI23.1 where R1a represents hydrogen or an amino protective group R1A, R, b represents hydrogen or an acyl group Ac, or Rla and Rtb together represent a divalent amino protective group, and RT represents hydroxy or a protected one together with the carbonyl group -C (= O) - Carboxyl group-forming radical R2A, and salts of such compounds with salt-forming groups, characterized in that a 70-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid compound of the formula EMI23.2 or a salt of this compound, with a metal, which has a normal potential of -2.4 to -0.40 volts, or an amalgam thereof, at a pH of 1 to 8, reduced in the presence of water, and a compound 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 III, wherein Rla is an amino protective group R1A, in which any free functional groups present may be protected, Rlb is hydrogen and R2 is a hydroxyl group, or a salt of such a compound is used. 2. The method according to claim, characterized in that starting materials of the formula III, wherein Rla is an acyl group Ac, which represents an acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, or an easily cleavable acyl radical, in particular a carbonic acid half derivative, Rlb is hydrogen and R2 is a hydroxyl group or a salt of such a compound, in particular an alkali, such as sodium salt, is used. 3. The method according to claim, characterized in that magnesium, manganese, zinc, iron, chromium, cadmium, aluminum or an amalgam of these metals is used. 4. The method according to claim, characterized in that amalgamated aluminum is used. 5. The method according to claim, characterized in that aluminum grit amalgamated with mercury (II) chloride solution is used. 6. The method according to claim, characterized in that the pH is adjusted to 2-7, in particular to 5 to 6, by adding a water-soluble organic or inorganic acid. 7. The method according to claim, characterized in that one reduces in the presence of reagents which increase the reducing power of the metals used. 8. The method according to claim, characterized in that reducing in the presence of such acids or salts, the anions of which bind the cations formed in the reaction complex or precipitate. 9. The method according to claim, characterized in that one reduces in the presence of anions of hydrofluoric, oxalic, tartaric, citric, metaphosphoric, ethyleneamine tetraacetic, hydrogen sulfic or phosphoric acid. 10. The method according to claim, characterized in that one or more organic solvents are reduced in the presence of at least 10 to 20% water. 11. The method according to claim, characterized in that in the presence of an amide disubstituted with lower alkyl, such as diethylformamide or dimethylformamide: 12. The method according to claim, characterized in that one reduces at temperatures between about 0-100. 13. Process according to claim, characterized in that one reduces at temperatures between about 25-50 ". 14. The method according to claim or dependent claims 1-13, characterized in that compounds of the formula I, and salts of those compounds with salt-forming groups, in which Rla is hydrogen or an acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms or a light one represents cleavable acyl radical of a carbonic acid half derivative, Rib represents hydrogen and R2 is hydroxy, optionally substituted lower alkoxy, optionally substituted phenyl-lower alkoxy, acyloxy, -tri-lower alkylsilyloxy, or optionally substituted-mino- or hydrazino. 15. The method according to claim or one of the subclaims 1-13, characterized in that compounds of the formula I, and salts of those compounds with salt-forming groups, in which Rla, Rlb and R2 have the meanings given in dependent claim 14, or in which R2 and R3 have the meanings given in dependent claim 14 and Rla and Rlb together represent a 1-oxo-3-aza-1,4-butylene radical which is preferably substituted in the 2-position and optionally substituted in the 4-position. 16. The method according to claim or one of the dependent claims 1-13, characterized in that compounds of the formula I, as well as salts of those compounds with salt-forming groups in which Rla is hydrogen, an acyl radical of an organic carboxylic acid with up to 18 carbon atoms, Rlb is hydrogen, and 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. 17. The method according to claim or dependent claims 1-13, characterized in that compounds of the formula I, and salts of those compounds with salt-forming groups, in which Rla, Rlb and R, have the meanings given in dependent claim 16 or in which R2 is the im Dependent claim 16 have given meanings and Rla and Rlb together stand for an 1-oxo-3-aza-1,4-butylene radical which is substituted in the 2-position by optionally substituted phenyl and optionally contains two lower alkyl groups in the 4-position. 18. The method according to claim or one of the dependent claims 1-13, characterized in that compounds of the formula I, and salts of those compounds with salt-forming groups, in which Rlb and R2 have the meanings given in dependent claim 16, and Rla for hydrogen or a group of the formula EMI24.1 where n is 0 and RI is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, e.g. esterified or etherified hydroxyl or mercapto group, or an optionally substituted amino group, or in which n is 1, R1 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 an 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 RII and RIII is hydrogen, or in which n is 1, RI 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 has aromatic character, RII an optionally functionally modified, e.g. an esterified or etherified hydroxy or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, an optionally O-mono- or O-disubstituted phosphono group, an azido group or a halogen atom, and RIII stands for hydrogen, or where n is 1, each of the radicals R1 and RII is a functionally modified, preferably etherified or esterified hydroxy group or an optionally functionally modified carboxyl group, and RIII is hydrogen, or where n is 1, RI is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, denotes aromatic or araliphatic hydrocarbon radical and RII and RIII together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical connected to the carbon atom by a double bond, or in which n stands for 1, and R1 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, RIt is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and RIII is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. 19. The method according to claim or one of the subclaims 1-13, characterized in that compounds of the formula I, and salts of compounds with salt-forming groups, in which Rlb and R2 have the meanings given in dependent claim 16 and Rla have the meanings given in dependent claim 18 , or where R2 have the meanings given in dependent claim 16 and R? and R, b together represent a 1-oxo-3-aza-1,4-butylene radical containing phenyl which is optionally substituted in the 2-position and which optionally contains two lower alkyl groups in the 4-position. 20. The method according to claim or dependent claims 1-13, characterized in that compounds of the formula I or salts of those compounds with salt-forming groups in which Rlb is hydrogen, R1a is hydrogen, an acyl group of the formula EMI25.1 in which Ar is phenyl, hydroxyphenyl, hydroxylchlorophyl or 2-thienyl, hydroxy substituents in such radicals being protected by acyl radicals, .X is oxygen or sulfur, n is 0 or 1, and R is hydrogen or, if n means 0, for optionally protected amino, carboxy, sulfo or hydroxy, or O-lower alkylphosphono or O, O-di-lower alkylphosphono, or a 5-amino-5-carboxy-valeryl radical, in which the amino and carboxy groups are optionally protected and R 2 is hydroxy, lower alkoxy, 2-halo-lower alkoxy, or optionally substituted diphenylmethoxy. 21. The method according to claim or one of the dependent claims 1-13, characterized in that one connec-. Preparations of formula I or salts of such.Verbindungen- with salt-forming groups, wherein R1b and R2 have the meanings given in dependent claim 20, and Ria is hydrogen, cyanoacetyl, an acyl group of the formula B according to dependent claim 20, wherein Ar is phenyl, hydroxyphenyl, hydroxy -chlorophenyl, thienyl, pyridyl, aminopyridinium, furyl, isothiazolyl or tetrazolyl, and X, n and R have the meanings given in dependent claim 20, or a 5-amino-5-carboxyvaleryl radical, in which the amino and carboxy groups are optionally. are protected .. 22. Method according to claim or. one of the dependent claims 1-13, characterized in that compounds of the formula I or salts of such compounds with salt-forming groups are prepared, in which R1a is hydrogen, the acyl radical of the formula B according to dependent claim 20, in which Ar is phenyl, X is oxygen, n is 0 or 1, and R. is hydrogen, or if n is 0, optionally protected amino or hydroxy, or O-lower alkyl or O, O-di-lower alkyl phosphono, or a 5-amino-5-carboxy-valeryl radical in which the Amino and carboxy groups are optionally protected, and R2 is hydroxy, optionally lower alkoxy which is halogen-substituted in the 2-position or optionally. Low. - denotes alkoxy-substituted diphenylmethoxy. 23. The method according to patent claim or one of the dependent claims 1-13, characterized in that the 3-methylene-7p- (D-cc-tert-butyloxycarbonylamino-phenylamino) -cepham-4α-carboxylic acid or Manufactures salts thereof. 24. The method according to claim or one of the dependent claims 1-13, characterized in that the - 3-methylene-7ss- (D-α-tert-butyloxycarbonylamino-phenylacetylamino) -cepham-4-carboxylic acid diphenylmethyl ester. her-; represents. - - 25..Process according to claim or one of the sub-claims 1-13, characterized in that the 3-methylene-7D, - (phenylacetylamino) -cepham-4xc.carbotic acid or salts thereof are produced. 26. The method according to claim or subclaims. 1-13, characterized in that the 3-methylene-7ss- (phenylacetylamino) -cepham-4a-carbopsäu thylester is produced.