CH594682A5 - 7-Amino-3-methylene-cephams prepn. - Google Patents

Abstract

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

Description

  

  
 



   The invention relates to a process for the preparation of 7p-amino-3-methylene-cepham-carboxylic acid compounds of the formula
EMI1.1
 where Rla represents hydrogen or an amino protective group R1A, R1b represents hydrogen or an acyl group Ac, or R1a and R1b 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, as well as l-oxides thereof, and salts of such compounds with salt-forming groups.



   The compounds of the formula I which can be prepared according to the invention, their 1-oxides or their salts can be used as intermediates for the preparation of antibiotically active cephalosporan compounds.



   In a compound of the formula I, the optionally protected carboxyl group of the formula -C (= O) -R2 preferably has the a-configuration.



   An amino protective group RIA 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 Rta and R1b 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, and also the acyl radical of a preferably substituted in a position, z. B. an aromatic or heterocyclic radical containing a-aminoacetic acid, wherein the amino group via a, preferably substituted, z. B. two lower alkyl, such as methylene 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 it can also represent a usually mixed anhydride group or an optionally substituted carbamoyl or hydrazinocarbonyl 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, and heterocyclic or heterocyclic-aliphatic radicals.



   The group R2A can also represent an organic silyloxy radical, as well as a hydroxy group etherified 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 axyloxy 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 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, in
Question come.



   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 residues can optionally pen by functional groups, eg.

  B. by free, etherified or esterified hydroxy or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyl oxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phenylthio or phenyl-lower alkylthio, optionally substituted lower alkoxycarbonyloxy or
Lower alkanoyloxy, or halogen, furthermore by oxo, nitro, optionally substituted amino, e.g. B. lower alkylamino.



  Di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino or aza-loweralkylenamino, as well as acylamino, such as lower alkanoylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, azido, acyl, such as lower alkanoyl or benzene, optionally functionally modified carboxyl, such as, if appropriate, alkoxylated carboxyl, such as substituted carboxyl, such as salted carboxyl, optionally substituted carboxyl, such as salted carboxyl, optionally substituted carboxyl, such as salt, optionally substituted carboxyl, such as optionally substituted carboxy Carbamoyl, such as N-lower alkyl- or N, N-di-lower alkylcarbamoyl, also optionally substituted ureidocarbonyl or guanidinocarbonyl, or cyano, optionally functionally modified sulfo, such as sulfamoyl or sulfo in salt form, or optionally omono- or 0,0-disubstituted phosphono, wherein substituents e.g.

  B. optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, where unsubstituted or 0-monosubstituted phosphono can also be present in salt, such as alkali metal salt form, be mono-, di- or polysubstituted.



   A divalent aliphatic radical, including the corresponding radical of a divalent aliphatic carboxylic acid, is z. B. lower alkylene or lower alkenylene, which optionally, z. B. as an aliphatic radical indicated above, mono-, di- or polysubstituted and / or interrupted by heteroatoms such as oxygen, nitrogen or sulfur.



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



  mono-, bi- or polycyclic cycloalkyl or cycloalkenyl, also cycloalkylidene, or cycloalkyl or cycloalkenyl lower alkyl or lower alkenyl, also cycloalkyl-lower alkylidene or cycloalkenyl lower alkylidene, wherein cycloalkyl and cycloalkylidene z. B. 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, e.g. 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, as well as biphenylyl or naphthyl, which may optionally, for. B. as the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals, mono-, di- or polysubstituted.



   A divalent aromatic radical, e.g. B. an aromatic carboxylic acid, is primarily 1,2-arylene, especially 1,2-phenylene, which optionally, z. B. as the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals, 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 having aliphatic hydrocarbon radicals and is primarily phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl, also phenyl-lower alkylidene, such radicals z. B. 1-3 phenyl groups and optionally, z. B. as the abovementioned aliphatic and cycloaliphatic radicals, in the aromatic and / or aliphatic part can be mono-, di- or polysubstituted.



   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, e.g. B. like the above-mentioned cycloaliphatic radicals, 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 ot- or p-position, substituted lower alkyl half esters of carbonic acid, and a lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half ester of carbonic acid which is optionally substituted in the organic radical. Acyl radicals of a carbonic acid half ester are also corresponding radicals of lower alkyl half esters of carbonic acid, in which the lower alkyl part is a heterocyclic group, e.g.

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



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



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



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

 

   An optionally substituted hydrazino group is e.g. B. hydrazino, 2-lower alkylhydrazino, 2,2-di-lower alkylhydrazino, 2-lower alkoxycarbonylhydrazino or 2-lower alkanoylhydrazino.



   Lower alkyl is e.g. B. methyl, ethyl, n-propyl, - isopropyl, n-butyl, isobutyl, sec-butyl or 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 z. B. 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-butene-t, 4-ylene. Lower alkylene interrupted by heteroatoms is e.g. B. oxane-lower alkylene, such as 3-oxa-1,5-pentylene, thian-lower alkylene, such as 3-thia-1,5-pentylene, or aza-lower alkylene, such as 3-lower alkyl Cycloalkyl is z. B. cyclopropyl, cyclubutyl, cyclopentyl, cyclohexyl or cycloheptyl, and adamantyl, cycloalkenyl z. B. cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl, and cycloalkylidene z. B. cyclopentylidene or cyclohexylidene. Cycloalkyl-lower alkyl or lower alkenyl is e.g. B.

  Cyclo propyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, vinyl or allyl, while cycloalkenyl-lower alkyl or lower alkenyl z. B. 1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl or 1-, 2- or 3-cycloheptenylmethyl, -1,1- or -1,2-ethyl, -1,1- , -1,2- or -1,3-propyl, -vinyl or -allyl. Cycloalkyl-lower alkylidene is e.g. B. cyclohexylmethylene and cycloalkenyl-lower alkylidene z. B. 3-Cyclohexenylmethylene.



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



  Represents 4-biphenylyl
Phenyl-lower alkyl or phenyl-lower alkenyl is, for. B. Ben zyl, 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 z. B. benzylidene.



   Heterocyclic radicals are primarily optionally substituted heterocyclic radicals of aromatic Charak age, eg. B. corresponding monocyclic, monoaza-, monothia- or monooxacyclic radicals, such as pyrryl, z. B. 2-pyrryl or 3-pyrryl, pyridyl, e.g. B. 2-, 3- or 4-pyridyl, also pyridinium, thienyl, z. B. 2- or 3-thienyl, or furyl, e.g. B. 2-furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals such as indolyl, e.g. E.g., 2- or 3-indolyl, quinolinyl, e.g. E.g., 2 or 4-quinolinyl, isoquinolinyl, e.g. 1-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. E.g., 2-imidazolyl, pyrimidinyl, e.g.

  B. 2- or 4-pyrimidinyf, triazolyl, e.g. 1,2,4-triazol-3-yl, tetrazolyl, e.g. E.g. 1- or 5-tetrazolyl, oxazolyl, e.g. 2-oxazolyl, isoxazolyl, e.g. B. 3- or 4lsoxazolyl, thiazolyl, z. 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-thia- diazol-3-yl or 1, 3,4-thiadiazol-2-yl, or bicyclic diaza, oxaza- or thiazacyclic radicals, such as benzimidazolyl, z. B.



  2-benzimidazolyl, benzoxazolyl, e.g. 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, especially the above-mentioned containing lower alkyl or lower alkenyl.



  The above-mentioned heterocyclyl radicals can, for. B. by optionally substituted aliphatic hydrocarbon radicals, especially 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, 2nd bromo- or 2-iodoethoxy. Lower alkenyloxy is e.g. B. vinyloxy or allyloxy, lower alkylenedioxy z. B. methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy, z. B. cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy, e.g. B. benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, or heterocyclyloxy or heterocyclyl-lower alkoxy z. B. pyridyl-lower alkoxy, such as 2-pyridylmethoxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy.



   Lower alkylthio is e.g. B. methylthio, ethylthio or n-butylthio, lower alkenylthio z. B. allylthio, and phenyl-lower alkylthio z. B. Benzylthio, while by heterocyclyl radicals or heterocyclylaliphatic radicals etherified mercapto groups, in particular pyridylthio, z. 4-pyridylthio, imidazolylthio, e.g. E.g., 2-imidazolylthio, thiazolylthio, e.g. B. 2-thiazolylthio, 1,2,4- or 1, 3,4-thiadiazolylthio, e.g. 1,2,4-thiadiazol-3ylthio 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, and lower alkanoyloxy, z. B. acetyloxy or propionyloxy, lower alkoxycarbonyloxy, e.g. B. methoxycarbonyloxy, athoxycarbonyloxy or tert-butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, e.g. B. 2,2,2-Trichloräthoxycarbonyloxy, 2-Bromoäthoxycarbonyloxy or 2-Jodäthoxycarbonyloxy, or Arylcarbonylmethoxycarbonyloxy, z. B. phenacyloxycarbonyloxy.



   Lower alkoxacarbonyl 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 present in sodium or potassium salt form carboxyl or sulfo.



   Lower alkylamino or di-lower alkylamino is e.g. B. methylamino, ethylamino, dimethylamino or diethylamino,
Lower alkylenamino e.g. B. Pyrrolidino or piperidino, Oxaniederalkylenamino z. B. morpholino, thianiederalkylen amino z. B. Thiomorpholino, and Azaniederalkylenamino z. B.



   Piperazino or 4-methylpiperazino. Acylamino is in particular special carbamoylamino, Niederalkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, Guanidi nocarbonylamino, Niederalkoxycarbonylamino, z. B. methoxy carbonylamino, ethoxycarbonylamino or tert-butyloxycar- bonylamino, 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. 0-methyl or 0-Ät hyl-phosphono, 0,0-Diiederalkyl-phosphono, z. B. 0,0-Dimet hylphosphono or 0,0-diethylphosphono, 0-Phenylniederal kyl-phosphono, z. B. 0-benzyl-phosphono, and 0-lower alkyl-0 phenyl-lower alkyl-phosphono, e.g. B. O-benzyl-methyl-phosphono.



   Lower alkenyloxycarbonyl is e.g. B. vinyloxycarbonyl, while end cycloalkoxycarbonyl and phenylniederalkoxycarbonyl, z. B. adamantyloxycarbonyl, benzyloxycarbonyl, 4-methoxy benzyloxycarbonyl, diphenylmethoxycarbonyl or a4-di phenylyl-a-methyl-ethoxycarbonyl is Niederalkoxycar bonyl, wherein lower alkyl z. B. contains a monocyclic, monoaz za-, 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-Niederalko xycarbonylhydrazino z. B. 2-methoxycarbonylhydrazino, 2-Ät hoxycarbonylhydrazino or 2-tert-butyloxycarbonylhydrazino, and lower alkanoylhydrazino z. B. 2-acetylhydrazino.



   An acyl group Ac stands in particular for a naturally occurring or bio-, semi-or totally synthetically producible, preferably pharmacologically active N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4- carboxylic acid compound containing acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, or an easily cleavable acyl radical, in particular a carbonic acid half derivative.



   An acyl radical Ac contained in a pharmacologically active N-acyl derivative of a 6-amino-penam3-carboxylic acid or 7-amino-3-cephem4-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. esterified or etherified hydroxy or mercapto or an optionally substituted amino group, or wherein n is 1, Rl 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, 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 Ril and R "'denotes hydrogen, or where n is 1, RI denotes 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 The remainder preferably has aromatic character, Ril 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 0-mono- or 0-disubstituted phosphono group, an azido group or a halogen atom, and Rlll represents hydrogen, or where n is 1, each of the radicals Rl and Rll is a functionally modified, preferably etherified or esterified hydroxy group or an optionally functionally modified carboxyl group, and Rlll is hydrogen, or where n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic , cycloaliphatic-aliphatic,

   Aromatic or araliphatic hydrocarbon radical and Rll and Grill together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical linked to the carbon atom by a double bond, or in which n is 1, and Rl is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have an aromatic character, R "an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical and 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 Rl for hydrogen or an optionally, preferably in the 1-position by optionally protected amino, such as amino, acylamino, where acyl is primarily for the acyl radical of a carbonic acid half-ester, such as a lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or Phenylniederalkoxycarbonylrest, or one, optionally in salt, z. B. alkali metal salt form present sulfoamino group, substituted cycloalkyl group with 5-7 ring carbon atoms, one optionally, preferably by hydroxy, lower alkoxy, z. B. methoxy, acyloxy, where 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, such as halogen, e.g. B. chlorine, lower alkyl containing N-substituted amino group, or n for 1, Rl for an optionally substituted, preferably by halogen, such as chlorine, by optionally substituted, such as hydroxy, acyloxy, in which acyl has the meaning given above, and / or halogen, z. B. chlorine, containing phenyloxy, or by 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. chlorine, phenyloxy containing phenyl group, an optionally protected, such as acylated amino or aminomethyl, substituted pyridyl, pyridinium, thienyl, 1-imidazolyl or 1-tetrazolyl group, an optionally substituted lower alkoxy, z. B. methoxy group, an optionally, z.

  B. by optionally acylated hydroxy and / or halogen, such as chlorine, substituted phenyloxy group, a lower alkylthio, z. B. n-butylthio, or lower alkenylthio, e.g. B. allylthio, an optionally, z. B. by lower alkyl, such as methyl, substituted phenylthio-, 2-imidazolylthio-, 1, 2,4-triazol-3-ylthio-, 1, 3,4-triazol-2-ylthio-, 1, 2,4-thiadiazole -3-ylthio-, such as 5-methyl-1,2,4-thiadiazol-3-ylthio-, 1,36-thiadiazol-2-ylthio-, such as 5-methyl-1,3,4-thiadiazol-2-ylthio -, Or 5-tetrazolylthio, such as 1-Met hyl-5-tetrazolylthio group, a halogen, especially chlorine or bromine atom, an optionally functionally modified carboxyl group, such as lower alkoxycarbonyl, z. B. Metho xycarbonyl- or ethoxycarbonyl, cyano or optionally, z.

  B. by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted Niederal kanoyl, z. B. acetyl or propionyl, or benzoyl group, or an azido group, and Rll and Rlll for hydrogen, or n for 1, Rl for an optionally, z. B. by optionally acylated hydroxy and / or halogen, z. B. chlorine, substituted phenyl, furyl, thienyl or 4-isothiazolyl group, also for a 1, 4-cyclohexadienyl group, Rll for optionally protected or substituted amino, z. B. acylated acylamino, such as lower alkoxycarbonylamino, 2-Hab- genniederalkoxycarbonylamino or phenylniederalkoxycarbonylamino, z.

  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, present carboxyl group, a cyano group, a sulfo group, an optionally functionally modified hydroxy group, especially acyloxy, such as formyloxy, and lower alkoxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy or phenylniederalkoxycarbonyloxy, z. B.



     tert-butyloxycarbonyloxy, 2,2,2-trichlorocarbonyloxy or diphenylmethoxycarbonyloxy, or optionally substituted lower alkoxy or phenyloxy, a 0-lower alkyl or 0,0-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 grill for hydrogen, or n for 1, RI and Ril each for halogen, z. B. bromine, or lower alkoxycarbonyl, e.g. B. methoxycarbonyl, and Rlll for hydrogen, or n for 1, Rl 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, Rll for optionally, for example as indicated above, protected aminomethyl, and grill for hydrogen, or n for 1 and each of the Group Rl, Rll and Rlll for lower alkyl, e.g. B. methyl.



   Such acyl radicals are, for. B. formyl, cyclopentylcarbonyl, a-aminocyclopentylcarbonyl or a-aminocyclohexylcarbonyl (with optionally substituted amino group, e.g. sulfoamino group optionally present in salt form, or one, preferably slightly, e.g. 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 acyl radical 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- Iodine ethoxycarbonyl, 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, benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 5-methyl-3-phenyl4-isoxazolylcarbonyl, 342-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, 342,6-dichlorophenylSoxazolyl4-iso, 2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, butylthioacetyl, allylthioacetyl, methyl, 3-chloroacetyl, dionoacetyl, 3-chloro-3-chloroacetyl, chloroacetyl, chloro-bromoacetyl Aminoacetyl or 5-amino-5-carboxylvaleryl (with optionally, e.g. as stated, such as by a monoacyl or diacyl radical, e.g. an optionally halogenated lower alkanoyl radical, 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, z. B. methyl or ethyl, or aryl lower alkyl, z. B. Diphenylmethylesterform, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bis-methoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, α-cyanopropionyl, 2-cyano-3,3-dimethyl-acrylacetyl, 2-cyano-3,3-dimethyl-acyl Azido-phenylacetyl, 3-chlorophenylacetyl, 4-aminomethylphenyl-acetyl (with, if necessary, e.g.



   as indicated, substituted amino group), phenacylcarbo nyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyl oxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyl oxypropionyl, a-phenyloxyphenylacetyl, a-phenyloxyphenyl acetyl, a-methoxyphenyl acetyl, a-methoxyphenyl -dichlorophenyl acetyl, a-cyano-phenylacetyl, in particular phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl, 3,5-dichloro-4-hydroxyphenylglycyl, a-aminomethyl-a-phenylacetyl or a-hydroxyphenylglycyl , wherein an amino group present in these radicals optionally, z. B. as stated above, can be substituted and / or an existing, aliphatic and / or phenolically bonded hydroxyl group, optionally analogous to the amino group, z.

  B. can be protected by a suitable acyl radical, in particular by formyl or an acyl radical of a carbonic acid half-ester), or a-0-methyl-phosphono-phenylacetyl or a-0,0-dimethylpho sphono-phenylacetyl, also benzylthioacetyl, benzylthiopropionyl , a-Carboxyphenylacetyl (with optionally, e.g. as stated above, a functionally modified carboxy group), 3-phenylpropionyl, 343-cyanophenylspropionyl, 4 (3-methoxyphenyl) -butyryl, 2-pyridylacetyl, 4-aminopyridinium acetyl ( optionally substituted with, for example, as indicated above
Amino group), 2-thienylacetyl, 3-thienylacetyl, 2-tetrahydrothienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, α-carboxy-2-thienylacetyl or α-carboxy-3-thienylacetyl (optionally with functional, e.g.

  B. as stated above, modified carboxyl group), a-cyano-2-thienylacetyl, a-amino-aX2-thienyl) -acetyl, a-amino-aX2-furyl-acetyl or a-amino-aX4-isothiazolyl-acetyl (optionally with, z. B.



  as stated above, substituted amino group), a-sulfophenylacetyl (optionally with, e.g. like the carboxyl group, functionally modified Sufo group), 3-methyl-2imidazolylthioacetyl, 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 treating 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 one, preferably on the carbon atom in a position to the oxy group multiply branched and / or aromatically substituted lower alkoxycarbonyl group or a methoxycarbonyl group substituted by aryl carbonyl, in particular benzoyl radicals, or in the 8-position by Halogen atoms substituted lower alkoxycarbonyl radical, e.g.

  B. tert-Butyl oxycarbonyl, tertPentyloxycarbony1, Phenacyloxycarbonyl, 2,2,2-Trichloräthoxycarbonyl or 2-Jodäthoxyearbonyl or a remainder convertible in the latter, such as 2-chloro- or 2-bromo ethoxycarbonyl, also, preferably polycyclic, cycloalkoxycarbonyl, z. B. adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, such as 4-methoxyphenylmethoxycarbonyl, primarily a-phenyl-lower alkoxycarbonyl, in which the a-position is preferably polysubstituted, eg. B. diphenylmethoxycarbonyl or a4-biphenylyl-amethyl-ethyloxycarbonyl, or furyl-lower alkoxycarbonyl, primarily a-furyl-lower alkoxycarbonyl, e.g. B. furfuryloxycarbonyl.

 

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



   Another divalent radical formed by the groups R, A 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 1-oxo-3-aza-1,4-butylene radical, z. 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 group forms an esterified carboxyl group, which, especially 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 (= 0) group forms a particularly easily cleavable esterified carboxyl group, is available, for. B. for 2-halo-lower alkoxy, in which halogen preferably has an atomic weight of more than 19. Such a radical, together with the -C (= O> group, forms a, when treated with chemical reducing agents under neutral or weakly acidic conditions, e.g. with zinc in the presence of aqueous
Acetic acid, easily cleavable esterified carboxyl group or one in such an easily convertible esterified carboxyl group and is z. B. 2,2,2-trichloroethoxy or 2-iodoethoxy, fer ner 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter.



   An etherified hydroxy group R2A which, together with the -C (= 0) grouping, also causes treatment with chemical reducing agents under neutral or weakly acidic conditions, e.g. B. when treating with zinc in the presence of aqueous acetic acid, also when treating with a suitable nucleophilic reagent, e.g. B. sodium thio phenolate, easily cleavable esterified carboxyl group represents, is an arylcarbonylmethoxy group, where aryl in particular special stands for 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 (= 0p 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, in particular, lower alkoxy, e.g. Methoxy (which are primarily in the 3-, 4- and / or 5-position in the case of the preferred phenyl radical), and / or above all nitro (in the case of the preferred
Phenyl radical preferably in the 2-position). Such radicals are primarily 3- or 4-methoxybenzyloxy, 3,5-dimethoxy-ben zyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitro-benzyl oxy.



   An etherified hydroxy group R2A can also be a
Represent a radical which, together with the -C (= 0) grouping, under acidic conditions, e.g. B. when treating with tri fluoroacetic acid or formic acid, easily cleavable, esterified carboxyl group forms. Such a rest is in the first place
Line a methoxy group in which methyl is substituted by optionally substituted hydrocarbon radicals, especially aliphatic or aromatic
Hydrocarbon radicals such as lower alkyl, e.g. B.

  Methyl, or
Phenyl, polysubstituted or by a,
Carbocyclic aryl group having electron-donating substituents or one, oxygen or
Sulfur as a ring member having heterocyclic group of aromatic character is monosubstituted, or then in a polycycloaliphatic hydrocarbon radical a ring member or in an oxa or thiacycloaliphatic radical which means the a-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-pentyl oxy, optionally substituted diphenylmethoxy, z. B. diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also 2- (4-biphenylyl) -2-propyloxy, while a methoxy group containing the above substituted aryl group or the heterocyclic group z. B. an α-lower alkoxyphenyl-lower alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or furfuryloxy, such as 2-furfuryloxy. A polycycloaliphatic hydrocarbon radical in which methyl of the methoxy group is a, preferably triple, branched ring member is z. B.

  Adamantyl, such as l-adamantyl, and an above-mentioned oxa- or thiacycloaliphatic radical, in which methyl of the methoxy group is the ring member representing the c: position to the oxygen or sulfur atom, means e.g. B. 2-oxa- or 2-thia-lower alkylene or lower alkenylene with 5-7 ring atoms, such as 2-tetrahydrofuryl, 2-tetrahydropropyranyl 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 (= 0) 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 (= 0) grouping, such as nitrophenyloxy, e.g. 4-nitrophenyloxy or 2,4-dinitrophenyloxy, nitrophenyl-lower alkoxy, e.g. 4-nitrobenzyloxy, polyhalophenyloxy, e.g. B. 2,4,6-trichlorophenyloxy or 2,3,4,5,6-pentachlorophenyloxy, also cyanomethoxy, and acylaminomethoxy, z. B. phthaliminomethoxy or succinyliminomethoxy.



   The group R2A can also represent an etherified hydroxyl group which, together with the carboxyl group of the formula -C (= 0) - forms an esterified carboxyl group which can be cleaved under hydrogenolytic conditions, and is e.g. B.



  optionally, e.g. B. by lower alkoxy or nitro, substituted a-phenyl-lower alkoxy, such as benzyloxy, 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 represent.



   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 (= Ot grouping, forms a, preferably hydrolytically, cleavable, mixed anhydride group contains, for example, the acyl radical of one of the above-mentioned organic carboxylic acids or carbonic acid half-derivatives, and is, for example, lower alkanoyloxy, e.g.



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



   A radical R2A which, together with a -C (= 0k grouping, forms an optionally substituted carbamoyl or hydrazinocarbonyl group is, for example, amino, lower alkylamino or di-lower alkylamino, such as methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino, e.g.



  Pyrrolidino or piperidino, oxaniederalkylenamino, e.g. B.



  Morpholino, hydroxyamino, hydrazino, 2-lower alkylhydrazino or 2,2-dimethylhydrazino.



   Salts are in particular those of compounds of the formula I having an acidic group, such as a carboxy, sulfo or phosphono group, primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. B. sodium, potassium, magnesium or calcium salts, and 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 salt formation come into question, such as lower alkylamines, for. B. triethylamine, hydroxy lower alkylamines, e.g. B. 2-hydroxyethylamine, BisX2-hydroxyät- hylpamin or tri (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, z.

  B. 4-aminobenzoic acid-2diäthylaminoäthylester, lower alkyleneamines, z. B. I-ethyl-piperidine, cycloalkylamines, z. B. bicyclohexylamine, or benzylamines, e.g. B. N, N'-dibenzyl-ethylenediamine, also bases of the pyridine type, z. B. pyridine, collidine or quinoline. Compounds of formula 1 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, form. Compounds of the formula I 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 I 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 1-oxides and 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-cephem4-carboxylic acid according to the Dutch laid-open specification No. 71116 873 with a chromium II compound or a 3-thio-substituted 7- Amino or 7-acylamino-3-thiomethyl-3-cephem4-carboxylic acid compound according to German Offenlegungsschrift No.



  2 209 020 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. In addition, as a result of longer reaction times or also through the use of elevated temperatures, 7-amino- or 7-acylamino-3-methyl-3-cephem4-carboxylic acid derivatives and in some cases also the corresponding 3-methyl-2-cephem derivatives occur as by-products 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.

  Another 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-cephem4-carboxylic acid derivatives means an additional synthesis step
The publications mentioned above show that the 7ss-amino-3-methylenceepham4-carboxylic acid compounds of the formula I themselves have little or no antibiotic properties, but that they easily become the valuable 713-amino-3-methyl.3-cephem4 .carboxylic acid compounds can be isomerized. Such 3-methyl compounds, e.g.

  B. the cephalexin (7ss- (D-a-aminophenylacetamido) -desacetoxy- cephalosporanic acid), properties and can therefore be used for the treatment of various bacterial infections in humans and animals.



   Compounds of formula 1, and their 1-oxides, 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 Rla, 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, as well as l-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 (= 0) -R2 preferably has the a-configuration.



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



   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-Aminoniedeialkyl, in which the tert-amino group is separated from the oxygen atom by at least two carbon atoms, such as 2- or 3-di-lower alkylamino-lower alkyl, e.g. B. 2-dimethylaminoethyl, 2-diethylaminoethyl or 3-dimethylaminopropyl, or etherified hydroxy-lower alkyl, wherein 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 R3 is primarily an optionally substituted phenyl-lower alkyl, in particular 1-phenyl-lower alkyl radical with 1-3 optionally substituted phenyl radicals, such as benzyl or diphenylmethyl. B. esterified or etherified hydroxy, such as halogen, e.g. B. fluorine, chlorine or bromine, or lower alkoxy, such as Met hoxy, come into question.



   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, z. 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, and their l-oxides and salts, have valuable pharmacological properties or can be used as intermediates for the preparation of such. Compounds of formula 11, wherein z. B. Ra for an acyl radical Ac and R16 occurring in pharmacologically active N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3cephem4-carboxylic acid compounds, or where Rla and R1b together are in the 2-position preferably, e.g. B. by an aromatic or heterocyclic radical, and preferably in the 4-position, for.

  B. represented by 2 lower alkyl, such as methyl, substituted l-oxo-3-aza-1,4-butylene radical, 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 Has the meaning given above, and in which the double bond is preferably in the 3,4-position of the cephem ring, or salts of such compounds with salt-forming groups, are against microorganisms such as gram-positive bacteria, e.g. B. Staphylococcus aureus, (e.g. 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 in doses of about 0.001 to about 0.05 g / kg p.o), also Klebsiella pneumoniae, Proteus vulgaris or Salmonella typhosa, especially 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 l-oxides of compounds of the formula II in which the double bond is in the 3,4-position, and in which R, a, R1b, R2 and R3 have the meanings given in connection with the formula I, or in which the double bond of the cephem ring occupies the 3,4-position, R5 has the meaning given above, the radicals R1a and R, b are hydrogen, or R1a is a different from the abovementioned acyl radical Amino protecting group and Rlb denote hydrogen, or R1a and R, b together represent a bivalent amino protecting group that is different from the abovementioned divalent radicals, and R2 is hydroxy,

   or R1a and R1b have the meanings given above, R2 represents a radical R2A which, together with the -C (= 0> grouping, forms a preferably easily cleavable, protected carboxyl group, and
R3 has the meanings given above are valuable inter mediate products that can be used in a simple manner, for. B. as will be described below, in the above-mentioned, pharmacologically active men compounds can be converted.



   Particularly valuable are the compounds of the formula I and their l-oxides, in which R1a is hydrogen or preferably one that can be produced fermentatively (ie naturally occurring) or bio-, semi- or totally synthetically, in particular pharmacologically active, such as highly active N- Acylde derivative of a 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem4-carboxylic acid compound containing acyl radical or an easily cleavable acyl radical of a carbonic acid half-derivative, in particular a carbonic acid half-ester, R, b represents hydrogen, or where R1a and Rlb together one in the 2-position preferably, for. B. by an aromatic or heterocyclic radical, and preferably in the 4-position, for.

  B. by 2 lower alkyl, such as methyl, 1-oxo-3-aza-1, 4-butylene radical substituted, and R2 for hydroxy, for optionally, z. B. by optionally substituted aryloxy, such as lower alkoxyphenyloxy, e.g. 4-methoxyphenyloxy, lower alkanoyloxy, e.g. B. acetyloxy or pivaloyloxy, or arylcarbonyl, e.g. 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. Bis4-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-bromoethoxy or 2-iodoethoxy, optionally substituted phenyl-lower alkoxy, especially 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-methoxybenzyloxy, 2-biphenylyl-2-propyloxy, 4-nitro-benzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, for acyloxy, such as lower alkoxycarbonyloxy, e.g. Methoxycarbonyloxy or athoxycarbonyloxy, or lower alkanoyloxy, e.g. B. acetyloxy or pivaloyloxy, for tri-lower alkylsilyloxy, e.g. B. trimethylsilyloxy, or for optionally, e.g. B. by lower alkyl, such as methyl, or hydroxy substituted amino or hydrazino, z. B.

  Amino, lower alkyl or di-lower alkylamino such as methylamino or dimethylamino, hydrazino, 2-lower alkyl or 2,2-di-lower alkylhydrazino, e.g. B. 2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamino, and salts of such compounds with salt-forming groups.



   In a compound of the formula 1, or an l-oxide thereof, or in a salt of such a compound with salt-forming groups, R1a is primarily hydrogen or an N-acyl derivative of 6ss- which can be fermentatively (ie naturally occurring) or biosynthetically Amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4carboxylic acid compounds containing acyl radical, such as an optionally, z. B. by hydroxy, substituted phenylacetyl or phenyloxyacetyl, 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, z.

  B. 4-hydroxyphenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl, and in particular 5-amino-5-carboxy-valeryl, wherein the amino and / or the carboxyl groups are optionally protected and z. B. present as acylamino or esterified carboxyl, phenylacetyl or phenyloxyacetyl, or an acyl radical occurring in highly effective N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem4-carboxylic acid compounds, such as formyl, Haloethylcarbamoyl, e.g. B. 2-chloroethylcarbamoyl, cyanoacetyl, phenylacetyl, thienylacetyl, e.g. B. 2-thienylacetyl, or tetrazolylacetyl, e.g. B. I-tetrazolylacetyl, especially phenylglycyl, wherein phenyl optionally, e.g. B. by optionally protected hydroxy, such as acyloxy, e.g. 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), and in which the amino group is optionally substituted and e.g. B. is an optionally present in salt form sulfoamino group or an amino group which is a hydrolytically cleavable trityl group or an optionally substituted carbamoyl, such as an optionally substituted ureidocarbonyl group, z. B. ureidocarbonyl or N'-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group z. B. guanidinocarbonyl, or a, preferably light, 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 convertible into such an acyl radical, preferably a suitable th acyl radical of a carbonic acid half ester, such as one of the above, e.g. B. optionally halogen or benzoyl-substituted Niederalkyloxycarbonylreste, z.

  B. 2,2,2-Trichloräthyloxycarbonyl, 2-Chloräthoxyearbonyl, 2-Bromoäthoxycarbonyl, 2-Jodäthoxycarbonyl, tert-Butyloxycarbonyl or Phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, also contains a-thienyl glycyl, such as a-2- or a-3-thienylglycyl, a-furylglycyl, such as a-2-furylglycyl, a-isothiazolylglycyl, such as a4-isothiazolylglycyl, 1-aminocyclohexylcarbonyl or aminopyridinium, e.g. B.



     4-aminopyridinium (optionally with, for example, as stated above, substituted amino group), furthermore a-carboxy-phenyl-acetyl or a-carboxy-2-thienylacetyl (optionally with a functionally modified one, e.g. in salt, such as Sodium salt form, or in ester form, such as lower alkyl, e.g. methyl or ethyl, or phenyl lower alkyl; e.g. diphenylmethyl ester form, carboxyl group present), α-sulfophenylacetyl (optionally with, e.g.

  B. such as the carboxyl group, functionally modified sulfo group), a-phosphono, a-0-methylphosphono or a-0,0-dimethyl-phosphono-phenylacetyl, or a-hydroxyphenylacetyl (optionally with a functionally modified hydroxy group , in particular with an acyloxy group, in which acyl has a cleavable, preferably easily, e.g., upon treatment with an acidic agent, such as trifluoroacetic acid, or with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, or can be converted into such Acyl radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as one of the above, e.g.

  B. optionally substituted by halogen or benzoyl lower alkoxycarbonyl, z. B.



     2,2,2-Trichloräthoxyearbonyl, 2-Chloräthoxycarbonyl, 2-Brom äthoxyearbonyl, 2-Jodäthoxycarbonyl, tert-Butyloxyearbo- nyl or Phenacyloxycarbonyl, also means formyl), or Pyridylthioacetyl, z. 4-pyridylthioacetyl, e.g. B. for an acyl radical of the formula A, and R1b for hydrogen, or R1a and R1b together for one, in the 2-position, preferably optionally by protected hydroxy, such as acyloxy, z. B. optionally halogen-substituted Niederalkoxyear- bonyloxy or Niederalkanoyloxy, and / or by halogen, z. 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 l-oxo-3-aza-1,4- butylene radical, which optionally contains 2 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, furthermore
Methoxy or ethoxy, 2-halo-lower alkoxy, e.g. 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, optionally through
Lower alkoxy or nitro substituted phenyl radicals, e.g. B.



     4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4-dimethoxy-diphenylmethoxy or trityloxy, lower alkoxy, 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 1, as well as l-oxides thereof, 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 by acyl radicals, such as optionally halogenated lower alkoxy carbonyl radicals, e.g. B.



     tert-butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, may be protected, as well as thienyl, e.g. B. 2- or 3-thienyl, also pyridyl, z. 4-pyridyl, aminopyridinium, e.g. 4-aminopyridinium, furyl, e.g. 2-furyl, isothiazolyl, e.g. B. 4-isothiazolyl, or tetrazolyl, e.g. B. I-tetrazolyl, X is oxygen or sulfur, n is 0 or I, and R is hydrogen or, when n is 0, optionally protected amino such as acylamino, e.g. B. a-polybranched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g.

  B. 2,2,2-Trichlorätho xyearbonylamino, 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, present sulfo, optionally protected hydroxy such as acyloxy, e.g. B. a-polybranched lower alkoxyearbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, furthermore formyloxy, or 0, 0-lower alkylphosphine -Diniederalkylpho- sphono, z.

  B. 0-methylphosphono or 0,0-dimethylphosphono, or a 5-amino-5-carboxy-valeryl radical, wherein the amino and / or carboxy groups are optionally protected and z. As acylamino, e.g. B. lower alkanoylamino, such as acetylamino, Halogenniederalkanoylamino, such as dichloroacetylamino, or phthaloylamino, or as an esterified carboxy, such as phenylniederalkoxycarbonyl, z. B.



  Diphenylmethoxycarbonyl, R2 is hydroxy, lower alkoxy, especially α-polybranched lower alkoxy, e.g. B.



     tert-butyloxy, 2-halo-lower alkoxy, e.g. B. 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally, e.g. B. by lower alkoxy, e.g. 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 or l-oxides thereof which are 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, e.g. B. a-polybranched lower alkoxycarbonylamino, such as tert. Butylocycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g. B. 2,2,2-Trichloräthoxycarbonylamino, 2-Jodäthoxycarbonylamino or 2-Bromäthoxycarbonylamino, optionally protected hydroxy, such as acyloxy, z.

  B. a-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxyearbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, or 0, lower formyloxy, or O-di-lower alkylphosphono, e.g. B. 0-methylphosphono or 0,0-dimethyl-phosphono, mean, or a 5-amino-5carboxy-valeryl radical, wherein the amino and carboxy groups are optionally protected and z. 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 in the 2-position halogen, z. B. chlorine, bromine or iodine-substituted lower alkoxy, especially a-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-7ss- (Da-tert-butyloxycarbonylamino-phenylacetylamino) -cepham4a-carboxylic acid and 3-methylene-7ss- (phenylacetylamino) -cepham-4a-carboxylic acid, as well as their salts and esters, e.g. B. the diphenyl methyl esters.



   The new process according to the invention for the preparation of 7ss-amino-3-methylenceepham-4-carboxylic acid compounds of the formula I and their salts is characterized in that a 7ss-amino-3-acyloxymethyl-3-cephem4-carboxylic acid compound of the formula
EMI10.1
 wherein R1a and Rlb are as defined above, R3o is an acyloxy group, R2o is R2 or R3 and R2o together are an epoxy group, or an l-oxide thereof, or a salt of such a compound, with the exception of a compound of Formula III, in which R3 is acetoxy,

   Rla and Rlb have the meaning given above and R2o has the meaning of R2 and salts of such a compound, which are already described in the main patent 579 090, with a metal that has a normal potential of -2.4 to -0.40 volts, or an amalgam thereof, reduced at a pH of 1 to 8, in the presence of water, and an obtained compound having a salt-forming group is isolated as a salt or as a free compound.



   Metals with a normal potential of -2.4 to -0.40 volts include, for example, 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, for. B. with 0.5 percent mercury (II> chloride solution).



   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 can be adjusted to the desired value by organic or inorganic acids and by continuously adding further amounts of acid during the
Reduction can be kept constant. Suitable organic
Acids are, in particular, acids which are water-soluble or 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, ethane 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 alkane or alkane dicarboxylic 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 chloroacetic, trifluoro acetic, p-toluenesulphonic, p-methoxyphenyl acetic, tartaric, tartaric, citric and the known amino acids, the amino groups of which may 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. fluoric 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 bind the metal cations formed in the reaction in a complex manner or to precipitate them out of the solution.



   Of the acids mentioned, for example, hydrogen fluoride with aluminum3 + cations, oxalic acid with aluminum +3, zinc +2 and chromium + cations, tartaric acid with magnesium2 + cations, citric acid with chromium3 + cations, metaphosphoric acid with magnesium2 + - and the Ethylenamine tetraacetic acid to enter into soluble complexes with aluminum + 3-, magnesium + 2-, manganese + 2-, zinc + 2-, chromium + 3-, iron + 2- and cadmium + 2-cations due to favorable complex formation constants.



   Hydrogen sulfide, for example, is able to precipitate manganese + 2-, zinc + 2-, iron + 2- and cadmium + 2-ions and phosphoric acid, magnesium + 2- and iron + 2-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. This includes in particular those reagents that 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. Preferred salts are accordingly 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, eg. 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, z. B. acetonitrile.

  When using a solvent or solvent mixture, this contains at least 10 to 20 / n 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 depend essentially on the nature of the starting material of the formula II 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 25 and 50". The reaction time varies from a few minutes to a few hours. In general, the reaction is complete after about 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 and 1-oxides thereof are known or can be prepared by known methods.



   In a starting material of the formula III or an l-oxide thereof, R3 as an acyloxy group is a lower alkyl noyloxy group having 1 to 7, preferably 1 to 4 carbon atoms, such as formyloxy, propionyloxy, butyryloxy, valeryloxy, isovaleryloxy, pivalyloxy and especially acetoxy.



   Preferably mean in a starting material
Formula II or an l-oxide thereof, the radical Rla is an amino protective group R1A, such as an acyl group Ac, in which given.



  if any free functional groups are present, e.g. B. amino, hydroxy, carboxyl or phosphono groups, in per se known ter way, amino groups z. B. by acylation, tritylation,
Silylating or stannylating, and hydroxy, carboxy or
Phosphono groups, e.g. B. by etherification or esterification, including silylation or stannylation, can be protected, Rlb
Hydrogen, R3o the acetoxy group and R2 in particular
Hydroxy, as well as one with the -C (= 0k grouping an in particular special under mild conditions, cleavable, esterified carboxylgruppe-forming, etherified hydroxy group R2A, with any functional groups present in a carboxyl protecting group R2A in a manner known per se, e.g.

  B. as indicated above, can be protected, or R3C and R2o together form an epoxy group. A group R2A is e.g. B. in particular an optionally halogen-substituted one
Lower alkoxy group such as a-polybranched lower alkoxy e.g. B. tert-butyloxy, or 2-halo-lower alkoxy, wherein Halo gene 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. Met hoxy, or nitro-containing 1-phenyl-lower alkoxy group, such as optionally, z. 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, z. B. trimethylsilyloxy.



   Preferred starting materials of the formula III are those in which Rla is an acyl group Ac which represents a 6-amino-penam3-carboxylic acid or 6-amino-penam3-carboxylic acid or in a bio-, semi- or totally synthetically producible, preferably pharmacologically active, N-acyl derivative 7-amino-3-cephem4-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, Rlb is hydrogen, R3o is the acetoxy group, and R2o is a hydroxyl group, or in which R3 and R2 together represent an epoxy group, I-oxides thereof, or the salts of such a compound.



   Preferred salts of the starting materials of the formula III, in which R2o is hydroxy, or the l-oxides thereof, 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 internal salts.



   Starting materials of the formula III, I-oxides thereof 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. by chromatography or via suitable derivatives. For example, a starting material of the formula II, in which R2 is hydroxy, or an 1-oxide thereof 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 z. B. by acylation, tritylation or silylation, free hydroxy or mercapto groups z. B. by etherification or esterification, and free carboxyl groups z. B. temporarily protected by esterification, including silylation, in a manner known per se and released in a manner known per se after each reaction has taken place, if desired.



   In a compound of formula 1 obtainable according to the invention, or an l-oxide thereof, with a protected, in particular esterified, carboxyl group of the formula -C (= 0) -R2A, this can be carried out in a manner known per se, e.g. B. depending on the type of group R2A, are converted into the free carboxyl group. An esterified, e.g. B. by a lower alkyl radical, in particular methyl or ethyl, esterified carboxyl group, can by hydrolysis in a weakly basic medium, for. 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. By treating with a chemical reducing agent such as a metal, e.g. B.



  Zinc, or a reducing metal salt, such as a chromium-III salt z. B. chromium (II) chloride, usually in the presence of a hydrogen-donating agent that 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 also 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 z. B. by irradiation, preferably with ultraviolet light, e.g. B. below 290 mull when the arylmethyl group z. B. one optionally in the 3-, 4- and / or 5-position, z. B.



  is benzyl radical substituted by lower alkoxy and / or nitro groups, or with longer-wave ultraviolet light, e.g. B. over 290 mt when the arylmethyl group z. B.



  a benzyl radical substituted in the 2-position by a nitro group, a carboxyl group esterified by a suitably substituted methyl group, such as tert-butyl or diphenylmethyl, 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 from 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. by silylation or stannylation protected carboxyl group can in a conventional manner, for. B. by treatment with water or an alcohol, are released.



   Compounds of the formula 1 obtained, or l-oxides thereof, 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 R, A or R1b, in particular an easily cleavable acyl group, in a manner known per se, for. B. an oc-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 a phenacyloxycarbonyl group by treatment with a suitable reducing metal or 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 the metal compound, preferably in the presence of hydrous acetic acid. Furthermore, in a compound of formula 1 obtained in which a carboxyl group of the formula -C (= 0) -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, represents a protected carboxyl group, an acyl group R1A or R1b, 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, a protected, e.g. B. a protected by an organic silyl group, carboxyl group 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 pyrocatacyl phosphorus trichloride, and acid halides, especially 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 one of N, N, N ', N'-Tetraniederalkyl.niederalkylenediamins, z. 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 one N-substituted, e.g. B.



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



  Methylene chloride. Approximately equimolar amounts of the imide halide-forming agent and the base can be used; but the latter can also be in excess or deficiency, e.g. B. in about 0.2 to about 1 times the amount or then in about to 10 times, in particular in about 3 to 5 times the 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. to about 75 "C, can work if the stability of the starting materials and products allow an elevated 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 give the imino ether. Suitable alcohols are e.g. B. aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, z. B. chlorinated, or having additional hydroxyl groups, lower alkanols, e.g. B. ethanol, propanol or butanol, especially methanol, also 2-halo-lower alkanols, z. 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 of about -50 "C 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, 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-toluenesulfonic acid, can set.

 

   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 imide halide intermediate product obtainable by the above process is reacted with a salt, such as an alkali metal salt of a carboxylic acid, in particular a sterically hindered carboxylic acid, instead of an alcohol, a compound of the formula 1 is obtained in which both radicals Rla and R, b Represent acyl groups.



   In a compound of formula 1 in which both radicals Rla and R, b 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 1, or an l-oxide thereof, in which R, A and R1b 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 R, A 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 alkanoyl, such as dichloroacetyl, may also be protected by treatment with a nitrosating agent such as nitrosyl chloride, with a carbocyclic arene diazonium salt such as benzene diazonium chloride, or with a positive halogen-donating agent such as an N-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 is unsubstituted in the 5-amino-5carboxy-valeryl radical R1A and the carboxy group z. B. is protected by esterification, and R1b is preferably an acyl radical, but can also mean hydrogen, by allowing to stand in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, e.g. B. methylene chloride, and, if necessary, working up the free or monoacylated amino compound by methods known per se, are split off.



   A formyl group 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. Tnsk triphenylphosphine rhodium chloride, are split off.



   A triarylmethyl, such as the trityl group R, A can, for.



  by treating with an acidic agent such as a mineral acid, e.g. B. hydrochloric acid, are split off.



   In a compound of the formula 1, or an oxide thereof, in which R1a and R, b are hydrogen, the free amino group can be removed 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 the acids corresponding cyanocarbonyl compounds, or anhydrides (including the internal anhydrides of carboxylic acids, ie ketenes, or of carbamic or thio carbamic acids, ie isocyanates or isothiocyanates, or mixed anhydrides, such as those z.

  B. with halogen ameisensätire-lower alkyl, such as chloroformic acid ethyl esters or isobutyl esters, or bil with trichloroacetic acid chloride can be understood, or activated esters, and 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, for. B. ammonium salts of compounds of formula 1, or an l-oxide thereof, in which R2 is a hydroxyl group, can start.



   An acyl group can also be introduced by adding a compound of the formula 1, in which R1a and R, b together represent a ylidene radical (which can also be added subsequently, e.g.



  by treating a compound in which Rla and R1b is hydrogen, or an 1-oxide thereof, 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 1, or l-oxide thereof, 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- (halocafbonyltamino compound with suitable exchange reagents, such as basic compounds, e.g. tetrazole, thio compounds, e.g. 2-mercapto-1-methylimidazole, or metal salts, e.g. Sodium azide or alcohols, such as lower alkanols, for example tert-butanol, are reacted and substituted N-lower alkanoyl or N-hydroxycarbonylamino compounds are obtained in this way.

  B. a compound of formula 1, or an l-oxide thereof, wherein Rla is a, preferably in a-position substituted glycyl group, such as phenylglycyl, and R, b are hydrogen, with an aldehyde, e.g. B. formaldehyde, or a ketone such as lower alkanone, e.g. B. acetone, react and thus arrive at compounds of the formula I or an l-oxide thereof, wherein R, A and R, b together with the nitrogen atom is a 5-oxo which is preferably substituted in the 4-position and optionally substituted in the 2-position Represent -1,3-diaza-cyclopentyl radical.



   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 z. B. in the form of acylamino, such as those mentioned above, e.g. B. 2,2,2-Trichloräthoxycarbonylamino-, 2-bromo äthoxycarbonylamino- or tert..Butyloxycarbonylamino- groups of acyloxy, such as those mentioned above, for. B. 2,2,2-Trichloräthoxycarbonyloxy- or 2-Bromoäthoxycarbonylgruppen, of esterified carboxy, such as those mentioned above, e.g. B. Diphenylmethoxycarbonylgruppen, or 0,0-disubstituted Phos phono-, such as the above, z.

  B. O, O-di-lower alkylphosphono-, z. B. 0, o-dimethyl-phosphono groups, protect and subsequently, if necessary after conversion of the protective group, z. B. a 2-Bromäthoxycarbonyl- in a 2-Jodäthoxycarbonylgruppe, z. B. by treating 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 method 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 formula 1, or an l-oxide thereof, in which Rla and R, b are hydrogen, the free amino group can also be removed by introducing a triarylmethyl group, e.g. B. by treatment with a reactive ester of a triarylmethanol such as trityl chloride, preferably in the presence of a basic agent such as pyridine, protected.



   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 dihalodi-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. British Patent No. 1,073,530), or with a suitable stannylating agent, such as a bis- (tri-lower alkyl tin oxide, e.g. bis (tri-n-butyl tin) oxide, a tri lower alkyl tin hydroxide, e.g.

  Triethyl tin hydroxide, a tri-lower alkyl-lower alkoxy-tin, tetra-lower alkoxy-tin or tetra-lower alkyl-tin compound, and a tri-lower alkyl tin halide, e.g. B. tri-n-butyltin chloride (see e.g. Dutch Auslegeschrift 67/11 107).



   In a compound of formula 1 obtainable according to the process, or in an 1-oxide thereof, which contains a free carboxyl group of formula -C (= 0) -R2, such a carboxyl group can be converted into a protected carboxyl group in a manner known per se. So you get z. B. by treating with a suitable diazo compound such as 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, e.g. B. boron trifluoride, or by reacting with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. B. dicyclohexylcarbodiimide, and carbonyldiimidazole, also with an N, N'-disbustituierten Obzw. 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 Nbzw. N 'substituents e.g. B. lower alkyl, especially isopropyl, cycloalkyl or phenyl, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid, an ester.



  Furthermore, acid halides, such as chlorides (produced e.g. by treatment with oxalyl chloride), activated esters (formed e.g. with N-hydroxy nitrogen compounds, such as N-hydroxy-succinimide) or mixed anhydrides (obtained e.g.



  with haloformic acid lower alkyl esters, such as ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride) by reaction with alcohols, optionally in the presence of a base such as pyridine, converted into an esterified carboxyl group.



   In a compound obtained with an esterified group of the formula -C (= 0) -R2, this can be converted into another esterified carboxy group of this formula, e.g. B. 2-Chloräthoxyearbonyl or 2-Bromäthoxycarbonyl 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 (= 0) -R2, or an l-oxide thereof, preferably a salt, in particular an alkali metal, e.g. B. sodium, or ammonium, z. B. triethylammonium salt thereof, with a reactive derivative such as a halide, e.g. B. the chloride, an acid, e.g. B. a lower alkyl haloformate or a lower alkanecarboxylic acid chloride.



   In a compound obtainable according to the process with a free carboxyl group of the formula -C (= 0) -R2, such a group can also be converted into an optionally substituted carbamoyl or hydrazinocarbonyl group, preferably reactive, functionally modified derivatives, such as the above-mentioned acid halides, generally esters, as well as the above-mentioned 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 formula 1 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 patent application No. 67/17 107.



   Furthermore, modified functional substituents in groups RlA, R, b and / or R21 + 1149fl9ab and / or R2, such as substituted amino groups, acylated hydroxyl groups, esterified carboxy groups or 0,0-disbustituted phosphono groups, according to methods known per se, e.g. B. the above-described, release, or free functional substituents in groups R, A, R1b and / or R2, such as free amino, hydroxy, carboxy or phosphono groups, by methods known per se, e.g. B. acylating or esterifying or substituting, 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 formula 1, or an l-oxide thereof, wherein z. B. the amino protecting group R, A represents an optionally substituted glycyl group, convert and so convert the amino group into a 3-guanylureido group. Furthermore, you can compounds with aliphatically bonded halogen, for. B. with an optionally substituted a-bromo-acetyl group, with esters of phosphorous acid, such as tri-lower alkyl-phosphite compounds, and thus arrive at the corresponding phosphono compounds.

 

   3-Methylenceepham compounds of the formula 1 obtained can be converted into l-oxides of the corresponding 3-methylenceepham compounds by oxidation with suitable oxidizing agents, such as those described below. Obtained l-oxides of 3-methylencepham compounds of the formula 1 can be reduced by reduction with suitable reducing agents, such as. B. that described below, to the corresponding 3-methylencepham compounds of formula I reduce. In these reactions, care must be taken to ensure that, if necessary, free functional groups are protected and, if desired, are subsequently released again.



   Suitable oxidizing agents for the 1-position oxidation of 3-methylenceepham compounds of the formula I 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, in particular organic carboxylic acids, with a dissociation constant of at least 10-5 in question. Suitable inorganic peracids are periodic and persulfuric acid. Organic peracids are corresponding percarboxylic and persulfonic acids, which can be added as such or formed in situ by using at least one equivalent of hydrogen peroxide and one carboxylic acid. It is advantageous to use a large excess of the carboxylic acid if, for. B. acetic acid is used as the solvent.

  Suitable peracids are e.g. B. 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. B.



  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. B. 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. So z. B. the oxidation with percarboxylic acids can be catalyzed by the presence of an acid with a dissociation constant of at least 10-5, the effectiveness of which depends on its strength. Acids suitable as catalysts are, for. B. 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. H. up to 10 times the amount of the oxidizing agent or more. The oxidation is carried out under mild conditions, e.g.

  B. at temperatures from about -50 "C to about +100 C, preferably from about -10" C to about +40 "C.



   The oxidation of 3-methylencepham compounds to the corresponding l-oxides can also be achieved by treatment with ozone, furthermore with organic hypohalite compounds, such as lower alkyl hypochlorites, e.g. B. tert-butyl hypochlorite, which can be obtained in the presence of inert solvents, such as optionally halogenated hydrocarbons, e.g. Methylene chloride, and used at temperatures from about -10 "C to about +30" C, with periodate compounds such as alkali metal periodates, e.g. B.

  Potassium periodate, which is preferably used in an aqueous medium at a pH of about 6 and at temperatures of about -10 "C to about +30" C, with iodobenzene dichloride, which is used in an aqueous medium, preferably in the presence of an organic base , e.g. B. pyridine, and with cooling, e.g. B. 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 l-oxides of 3-methylenceepham compounds of the formula 1 obtainable in this way, in particular in those compounds in which R, a, R, b and R2 have the preferred meanings given above, the groups R1a, R16 and / or R2 within the inserted frame into one another, split off or introduced. A mixture of isomers a- and ss-l-oxides can, for. B. chromatographically separated.



   The reduction of the l-oxides of 3-methylene-cepham compounds of the formula I can be carried out in a manner known per se by treating with a reducing agent, if necessary, in the presence of an activating agent. Possible reducing agents are: catalytically activated hydrogen, noble metal catalysts being used 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 conditions in the form of corresponding compounds or complexes of inorganic or organic nature, eg.

  B. as tin-II-chloride, -fluoride, -acetate or -formate, iron-II-chloride, -sulphate, -oxalate or -succinate, copper-1-chloride, -benzoate or -oxide, or manganese ll-chloride, sulfate, acetate or oxide, or as complexes, e.g. B. with ethylenediaminetetraacetic acid or nitrolotriacetic acid are used; reducing dithionite, iodine or iron-II-cyanide anions, which in
Form of corresponding inorganic or organic
Salts such as alkali metal, e.g. B.

  Sodium or potassium dithio nite, sodium or potassium iodide or iron-II-cyanide, or in
Form of the corresponding acids, such as hydriodic acid, can be used; reducing trivalent inorganic or organic phosphorus compounds such as phosphines, fer ner esters, amides and halides of phosphinous, phospho-nigenic or phosphorous acid, and phosphorus-sulfur compounds corresponding to these phosphorus-oxygen compounds, wherein organic radicals are primarily aliphatic, aromatic or araliphatic radicals, e.g. B. optionally substituted lower alkyl, phenyl or phenyl lower alkyl groups, such as. B.

  Triphenylphosphine, tri-n-butylphosphine, methyl diphenylphosphinate, diphenylchlorophosphine, phenyldichlorophosphine, dimethyl benzene phosphonate, methyl butanephosphonate, triphenyl phosphate, trimethyl phosphate, phosphorus trichloride, phosphorus trichloride; 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.

  B. 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 iminium salts, in particular chlorides or bromides, in which the iminium group is replaced by one divalent or two monovalent organic radicals. as substituted or unsubstituted 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 which are used together with those of the above-mentioned reducing agents which themselves do not have Lewis acid properties, i.e. H.

 

  which are primarily used together with the dithionite, iodine or iron-II-cyanide and the non-halogen-containing trivalent phosphorus reducing agents or in the catalytic reduction, are in particular organic carboxylic and sulfonic acid halides, also sulfur, phosphorus or silicon halides with the same or greater second order hydrolysis constant than benzoyl chloride, e.g. B.

  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 anhydride, furthermore suitable tricyl anhydride, furthermore suitable tricyl anhydride, such as acidic anhydride, such as acidic anhydride, such as trichloroacetic acid, furthermore, suitable tryl anhydride, such as acidic anhydride, such as acidic anhydride, 1,3 also suitable trichloroacetic acid, furthermore suitable tri-anhydride, such 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. B. lower alkanecarboxylic acids or esters thereof, such as acetic acid and ethyl acetate, in the catalytic reduction, and z. B. optionally substituted, such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. B. benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives such as lower alkanecarboxylic acid esters or nitriles, e.g. B. ethyl acetate or acetonitrile, or amides of inorganic or organic acids, e.g. B. dimethylformamide or hexamethylphosphoramide, ether, e.g. B. diethyl ether, tetrahydrofuran or dioxane, ketones, z. B.

  Acetone, or sulfones, especially aliphatic sulfones, e.g. B. dimethyl sulfone or tetramethylene sulfone, etc., together with the chemical reducing agents, these solvents preferably containing no water. Usually, temperatures of about -20 ° C. to about 100 ° C. are used, and the reaction can be carried out at lower temperatures when using very reactive activating agents.



   Salts of compounds of the formula I and their l-oxides can be prepared in a manner known per se.



  So you can salts of compounds of formula 1, or of their l-oxides, with acidic groups z. By treating with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. B. the sodium salt of a-ethylcaproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formula I or of l-oxides thereof 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 or of l-oxides thereof 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 l-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 1, their l-oxides, or their salts into other compounds of the formula 1, their l-oxides, or their salts, care must be taken that such conversions take place in a neutral or acidic environment, if possible, because under basic conditions the 3-exo-methylene group can be isomerized to a 3-methyl group with rearrangement of the double bond into the 3- and especially the 2-position of the cepham ring.



   The aforementioned valuable 3-oxocepham and 3-hydroxy and 3-substituted hydroxy-3-cephem compounds, in particular compounds of the formula II, can be prepared using the compounds of the formula 1, or their l-oxides, as follows be performed:
A compound of the formula 1 obtained according to the invention, in which R2 is a hydroxyl group, an 1-oxide or a salt thereof, is converted into a compound of the formula by one of the processes described
EMI16.1
 or an l-oxide thereof, converted and oxidatively converted into a cepham-3-one compound of the formula by the process described below
EMI16.2
 or a corresponding enol with a double bond in the 2,3- or 3,4-position, or an 1-oxide of such a compound.



   The oxidative cleavage of the methylene group in compounds of the formula la, or l-oxides thereof, with formation of an oxo group in the 3-position of the ring structure, can be carried out in various ways.



   It is preferably carried out by treating with ozone to form an ozonide intermediate compound.



  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 halo-lower alkane, such as methylene chloride or carbon tetrachloride, or a solvent mixture, including an aqueous mixture, and with cooling or gentle heating, for. B. at temperatures from about -90 "C to about +40" C.



   An ozonide formed as an intermediate is split reductively, using catalytically activated hydrogen, e.g. B. hydrogen in the presence of a heavy metal hydrogenation catalyst such as nickel, also palladium catalyst, preferably on a suitable carrier material such as calcium carbonate or coal, or chemical reducing agents such as reducing heavy metals, including heavy metal alloys or amalgams, z. B. zinc, in the presence of a hydrogen donor such as an acid, e.g. B. acetic acid, or an alcohol, e.g. B. lower alkanols, reducing inorganic salts such as alkali metal iodides, e.g. B. sodium iodide, in the presence of a hydrogen donor such as an acid, e.g. B. acetic acid, or reducing organic compounds such as formic acid, a reducing sulfide compound such as a di-lower alkyl sulfide, e.g. B.

  Dimethyl sulfide, a reducing organic phosphorus compound, such as a phosphine, which can contain optionally substituted aliphatic or aromatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphines, e.g. B. tri-n-butylphosphine, or triarylphosphines, e.g. B. triphenylphosphine, also 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 contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as hexane-lower alkyl phosphorous triamides , e.g. 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. H. in the presence of a suitable solvent or solvent mixture, and with cooling or gentle heating.



   Depending on the type of oxidation reaction, a compound of the formula IV or the corresponding l-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 l-oxide, or it can be oxidized to give uniform l-oxide of a compound of the formula IV.



   A mixture of a compound of the formula IV with the corresponding 1-0 d can be prepared in a conventional manner, for. B. by fractional crystallization or by chromatography (z. B. column chromatography, thin layer chromatography), can be separated into the individual components.



   In the conversion of the starting materials of the formula IV or their l-oxides to the enol derivatives of the formula II or the l-oxides, the starting materials of the formula IV or their l-oxides do not need to be isolated after their preparation; they can preferably be converted in the form of the crude reaction mixture after preparation from the compounds of the formula Ia or their l-oxides directly into the compounds of the formula II or their l-oxides.



   The compounds of the formula II or their l-oxides are obtained by adding 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 an l-oxide of such a compound, converted 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 or an l-oxide thereof obtained, the protected carboxyl group of the formula -C (= 0) -RA converted into the free or into another protected carboxyl group, and / or, if desired, a compound of the formula II obtained, or an l-oxide thereof, into another compound of the formula II,

   or an 1-oxide thereof, and / or, if desired, a compound obtained with a salt-forming group in a salt or a salt obtained in the free compound or in another salt, and / or, if desired, a mixture of isomers obtained separates into the individual isomers.



   Cepham-3-one starting materials of the formula IV or their 1-oxides can be present in the keto and / or in the enol form, the ring double bond in the latter being in the 2,3, but preferably in the 3,4 position . The starting materials of the formula IV are usually converted from the enol form into the enol derivatives of the formula II. Furthermore, you can z. B. also use a mixture of a compound of the formula IV and the corresponding l-oxide as 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, or of l-oxides thereof, into the enol derivatives can be carried out in a manner known per se.



   Enol ether, d. H. Compounds of the formula II, or 1-oxides thereof, in which R3 stands for an optionally substituted hydrocarbon radical, are obtained by any process suitable for etherifying enol groups, it being possible to use starting materials of the formula IV, or l-oxides thereof, in which R, a and Rlb represent hydrogen, but in which R, a preferably represents an amino protecting group R, A. The etherifying reagent used is preferably a diazo compound of the formula R3-N2 (V) corresponding to the optionally substituted hydrocarbon radical R3, or an l-oxide thereof, primarily an optionally substituted diazo lower alkane, e.g. B.

  Diazomethane, diazoethane or diazobutane, also an optionally substituted phenyldiazo lower alkane, such as a l-phenyldiazo lower alkane, e.g. B. phenyldiazomethane or diphenyldiazomethane. These reagents are used in the presence of a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon, e.g. B. methylene chloride, a lower alkanol, e.g. B. methanol, ethanol or tert-butanol, or an ether such as a di-lower alkyl ether, z. B. diethyl ether, or a cyclic ether, e.g. B.



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

 

   Enol esters, d. H. Compounds of the formula II in which R3 is an acyl group, or l-oxides thereof, are obtained by any process suitable for the esterification of enol groups, where of the groups Rla and Rlb in the starting material of the formula IV, or an l-oxide thereof, at least one is different from hydrogen if one does not want to risk simultaneous acylation of a free amino group. Carboxylic acids of the formula R3-OH (VI) corresponding to the acyl radical R3 or reactive acid derivatives thereof, such as halides, e.g. B. fluorides or chlorides, also pseudohalides, such as the cyanocarbonyl compounds corresponding to the carboxylic acids, or anhydrides (including the internal anhydrides of carboxylic acids, i.e. ketenes, or of carbamic or thiocarbamic acids, i.e.

  Isocyanates or isothiocyanates, or mixed anhydrides, such as those which z. B. with haloformic acid lower alkyl, such as chloroformic acid ethyl esters or isobutyl esters, or with trichloroacetic acid chloride are to be understood), or activated esters, such as esters with vinylogous alcohols (i.e. enols), e.g. B. esters of lower alkanecarboxylic acids with vinylogous lower alkanols, e.g. B. isopropenyl acetate, and if necessary, in the presence of suitable condensing agents, when using acids such. B. of carbodiimide compounds such as dicyclohexylcarbodiimide, or carbonyl compounds such as diimidazolylcarbonyl, when using reactive acid derivatives z. B. of basic agents such as tri-lower alkylamines, e.g. B. triethylamine, or heterocyclic bases, z. B.

  Pyridine, and when using esters with vinylogous alcohols in the presence of an acidic agent such as a mineral, e.g. B. sulfuric acid or a strong Sul fon-, z. B. p-toluenesulfonic acid works. The acylation reaction can be carried out in the absence or in the presence of a solvent or solvent mixture, with cooling, at room temperature or with heating, and, if necessary, in a closed vessel and / or in an inert gas, e.g. B. nitrogen atmosphere. Suitable solvents are e.g. B. optionally substituted, especially optionally chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as benzene or toluene, it 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 l-oxide obtainable according to the process can be separated with the aid of suitable separation methods, e.g. B. 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. can be separated. Furthermore, a mixture of a compound of the formula II and the corresponding l-oxide can either be oxidized directly to the l-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 an 1-oxide as intermediates.



   Obtained cephem compounds of the formula II in which the double bond is in 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. Obtained l-oxides of 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, such as. B. reduce the described, to the corresponding 3-cephem compounds of 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 11, 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, e.g. B. as indicated, may be temporarily protected, isomerized.



  You can z. B. use 2-cephem compounds of the formula II in which the group of the formula -C (= 0) -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. B. organic nitrogen-containing bases, especially tertiary heterocyclic bases of aromatic character, primarily bases of the pyridine type, such as pyridine itself, and collidines or lutidines, also quinoline, tertiary aromatic bases, e.g. B. those of the aniline type, such as N, N-di-lower alkyl anilines, e.g. B. N, N-dimethylaniline or N, N-diethylaniline, or tertiary aliphatic, azacycloaliphatic or araliphatic bases, such as N, N, N-tri-lower alkylamines, e.g. B. N, N, N-trimethylamine, N, N-dimethyl-N ethylamine, N, N, N-triethylamine or N, N-diisopropyl-N-ethylamine, N-lower alkyl-azacycloalkanes, z. B. N-methyl-piperidine, or N-phenyl-lower alkyl-N, N-di-lower alkyl-amines, e.g. B.



  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. B. pyridine and triethylamine. Furthermore, inorganic or organic salts of bases, in particular of medium to strong bases with weak acids, such as alkali metal or ammonium salts of lower alkanecarboxylic acids, eg. B. sodium acetate, triethylammonium acetate or N-methyl-piperidine acetate, and other analogous bases or mixtures of such basic agents can be used.



   The above isomerization with basic agents can, for. B. in the presence of a derivative of a carboxylic acid suitable for the formation of a mixed anhydride, such as a carboxylic acid anhydride or chloride, e.g. B. with pyridine in the presence of acetic anhydride.



  It is preferably carried out in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, e.g. B. chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbons or a solvent mixture, with bases used as reactants, 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. B. 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, for. B. 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 l-position, if desired, separating an available isomer mixture of the l-oxides from 3-cephem compounds of the formula II, and the l- Oxides of the corresponding 3-cephem compounds reduced.

 

   Suitable oxidizing agents for the oxidation in the l-position 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, in particular organic carboxylic acids, with a dissociation constant of at least 10-5. Suitable inorganic peracids are periodic and persulfuric acid. Organic peracids are corresponding percarboxylic and persulfonic acids, which are added as such or can be formed in situ by using at least one equivalent of hydrogen peroxide and one carboxylic acid. It is advantageous to use a large excess of the carboxylic acid if, for. B. acetic acid is used as the solvent. Suitable peracids are e.g. B.

  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-s, using low concentrations, e.g. B.



  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. B. 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. So z. B. the oxidation with percarboxylic acid can be catalyzed by the presence of an acid with a dissociation constant of at least 10-5, the effectiveness of which depends on its strength. Acids suitable as catalysts are, for. B. acetic acid, perchloric acid and trifluoroacetic acid. Usually at least equimolar amounts of the oxidizing agent are used, preferably a slight excess of about 10% to about 20/0, larger excesses also being used, i.e. H. up to 10 times the amount of the oxidizing agent or more. The oxidation is carried out under mild conditions, e.g.

  B. at temperatures from about -50 "C to about +100 C, preferably from about -10" C to about +40 "C.



   The oxidation of 2-cephem compounds to the l-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. B. tert-butyl hypochlorite, which can be obtained in the presence of inert solvents, such as optionally halogenated hydrocarbons, e.g. Methylene chloride, and used at temperatures from about -10 "C to about +30" C, with periodate compounds such as alkali metal periodates, e.g. B. potassium periodate, which is preferably used in an aqueous medium at a pH of about 6 and at temperatures of about -10 "C to about +30" C, with iodobenzene dichloride, which is in an aqueous medium, preferably in the presence of a organic base, e.g. B.

  Pyridine, and with cooling, e.g. B. at temperatures of 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 l-oxides of 3-cephem compounds of the formula II obtainable in this way, especially in those compounds in which R, a, Rlb and R2 have the preferred meanings given above, the groups R, a, Rlb and / or R2 within the inserted frame into one another, split off or introduced. A mixture of isomers a- and B-l-oxides can, for. B. chromatographically 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 in the form of corresponding compounds or complexes of inorganic or organic nature, e.g. B. as tin-II-chloride, -fluoride, -acetate or -formate, iron-II-chloride, -sulfate, -oxalate or -succinate, copper-l-chloride, -benzoate or -oxide, or manganese-II- chloride, sulfate, acetate or oxide, or as complexes, e.g.

  B. 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, z. B. 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 radicals are primarily aliphatic, aromatic or araliphatic radicals, e.g. B. optionally substituted lower alkyl, phenyl or phenyl lower alkyl groups, such as. B.

  Triphenylphosphine, tri-n-butylphosphine, methyl diphenylphosphinate, diphenylchlorophosphine, phenyldichlorophosphine, dimethyl benzene phosphonate, methyl butanephosphonate, triphenyl phosphate, triphenyl phosphate, trimethyl phosphate, trichloride, phosphorus trichloride; 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.

  B. 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 iminium salts, 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 which are used together with those of the above-mentioned reducing agents which themselves do not have Lewis acid properties, i.e. H.



  which are primarily used together with the dithionite, iodine or iron-II-cyanide and the non-halogen-containing trivalent phosphorus reducing agents or in the catalytic reduction, are in particular organic carboxylic and sulfonic acid halides, also sulfur, phosphorus or silicon halides with the same or greater second order hydrolysis constant than benzoyl chloride, e.g. B. 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 dichloride, dimethylchloride.

 

  silane or trichlorosilane, and also suitable acid anhydrides, such as trifluoroacetic anhydride, or cyclic sultones, such as ethanesultone, 1,3-propanesultone, 1,4-butanesultone or 1,3-hexanesultone.



   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. B. lower alkanecarboxylic acids or esters thereof, such as acetic acid and ethyl acetate, tion in the catalytic reduction, and z. B. optionally substituted, such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. B. benzene, Methy lenchlorid, chloroform or nitromethane, suitable Säurede derivatives, such as lower alkanecarboxylic acid esters or nitriles, z. B. It ethyl acetate or acetonitrile, or amides of inorganic or organic acids, z. B. dimethylformamide or hexamethylphosphoramide, ether, e.g. B. diethyl ether, Te trahydrofuran or dioxane, ketones, z. B.

  Acetone, or Sul fone, especially aliphatic sulfones, z. B. dimethyl sulfone or tetramethylene sulfone, etc., together with the chemical's reducing agents, these solvents preferably contain no water. Usually, temperatures of about -20 ° C. to about 100 ° C. are used, and the reaction can be carried out at lower temperatures when using very reactive activating agents.



   In the 3-cephem compounds of the formula II obtainable in this way, R, a, R1b and / or R2, as described above, can be converted into other groups R1a, R, b or R2, it being necessary to ensure that the 3-cephem compounds are opposite basic agents are much 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 or their l-oxides can, for. B. 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. So you use tablets or gelatin capsules, which the active ingredient together with diluents, eg. B. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. B. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. B.

  Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. B. 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. B. intravenously administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these e.g. B. from lyophilized preparations which contain the active ingredient alone or together with a carrier material, e.g. B. mannitol contain, can be prepared before use.

  The pharmaceutical preparations can be sterilized and / or auxiliaries, e.g. B. preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts to regulate the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are made in a manner known per se, for. B. by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain from about 0.1% to 100%, in particular from about 1% to about 50 ozone lyophilizates 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 1
A solution of 3.3 g of approx. 90 percent (5.6 mmol) 7ss- (Da-tert-butyloxycarbonylamino-a-phenylacetylamino> ce phalosporanic 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 adjusts 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 at -50 for 2 hours and the 3-methylene-7ss- (Da-tert-butyloxycarbonylamino-a-phenylacetyl-amino) -cepham4a-carboxylic acid, F. : 196-7 (corr.); [a] D20 = +350+ 10 (C = 1.0; 5-n. sodium bicarbonate).



  IR spectrum (Nujo): 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 lim. 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 100 / ethyl acetate-pyridine-glacial acetic acid-water 60: 20: 6 : 11).



   The 7ss4D-a-tert-butyloxycarbonylamino-a-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) dissolve crude 7ss4D-a-tert-butyloxycarbonylamino-a-phenyl-acetyl-aminoXcephalosporanic acid in 170 ml of dioxane with
Dilute 170 ml of ethyl acetate and slowly add 50 ml of a 50 percent solution of sodium a-ethylhexanoate in methanol while cooling. The filtered salt is washed with dioxane-ethyl acetate 2: 1 and pure ethyl acetate and digested with 1 ether, then with 200 ml of ethanol.



   The aluminum used is amalgamated as follows: 3.3 g of aluminum grit are in
100 ml of 5% sodium hydroxide solution swirled around 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 7ssAD-a-tert-butyloxycarbonylamino-phenylacetylaminoScephalosporanäure ethanolamine salt are 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-7ssAD-a-tert.-butyloxycarbonyl - aminophenylacetylaminoficepham4a-carboxylic acid.

 

   The ethanolamine salt used as starting material is obtained as follows: A solution of 30 g of 7ss- (Da-tert-butyloxycarbonylaminophenylacetylamino> 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 7I3 (D-atert-butyloxycarbonyl-aminophenylacetylamino> cephalosporanic acid, m.p.



     130-132 (corr.) Are placed in a 10 1 reaction vessel in 4.5 1 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 an ice bath and kept constant there. After 15 minutes at 46", the mixture is cooled to 29 (acetone-dry ice bath) over 10 minutes and the mixture is poured onto 3 kg of ice and 5 1 ice-cold ethyl acetate.

  It is acidified to pH 2 with concentrated phosphoric acid while stirring and saturated with common salt. After phase separation, the aqueous phase is extracted twice with 4 liters of cold ethyl acetate each time.



   The organic phases are washed Imal 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-7ssAD-a-tert-butyl-oxy carbonylamino-phenylacetylaminof4a-carboxylic acid.



   The amalgam used is prepared as follows: 200 g of aluminum grits are poured over with 2 1 percent strength aqueous sodium hydroxide solution and etched for 40 seconds while swiveling. It is decanted and washed twice with water. The residue is treated for 3 minutes while swirling with 2 1 0% aqueous mercury (II) chloride solution, decanted off and shaken again for 3 minutes with a further 2 liters of sublimate solution. After decanting and washing 3 times with water, the amalgam is used immediately as a reducing agent.



  Example 4
A solution of 19.5 7B (c-phenylacetylamino> cephalosporanic acid in 400 ml of 0.5 m. Phosphate buffer (pH 7) (without added dimethylformamide) is mixed with 20 g of aluminum amalgam for 30 minutes at 45 "and pH 5.7 stirred The ethyl acetate extract obtained at pH 2 contains 16 g of crude 3-methylene-7ss4a-phenylacetylamino> cepham4-carboxylic acid; thin-layer chromatogram: Rf (system 52): 0.56; Rf (system 100): 0.67.



   A solution of diphenyldiazomethane in acetone is added in portions to an acetone solution of the crude product over a period of 1 hour until it remains red in color.



  After adding 2 ml of glacial acetic acid and 300 ml of toluene, the mixture is evaporated and the residue is chromatographed on 800 g of silica gel (Merck). From the l-l fraction eluted with toluene / ethyl acetate 7: 3, the 3-methylene-7ss4a-phenylacetylamino-cepham4carboxylic acid benzhydryl ester of mp.



  133-6; Thin-layer chromatogram Rf (toluene-ethyl acetate 3: 1): 0.43.



  Example 5
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 dimethylformamide are mixed with the amalgam of 2.2 g aluminum grit and stirred for 30 minutes at pH 6.0 and 45 ". Example 1 Corresponding work-up and crystallization from ethyl acetate gives 3-methylene-7ss45-benzoylamino-adipolyaminof cepham4a-carboxylic acid, which is identical to the compound obtained according to Example 17 of CH patent 579 090.



   The starting material is obtained by neutralizing 15 g of N-benzoylcephalosporin C (see Example 17 of CH patent 579 090) in 75 ml of water with about 25 ml of 2N 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. The acetic acid formed as a result of deacetylation is neutralized in a pH range of 7.5-8.0 by adding 2N sodium hydroxide solution. The deacetyl compound obtained is left to stand in 150 ml of formic acid at 22 "for lk hours and converted into lactan. 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, melting point 136-138.



  Example 6
A suspension of 1.56 g of 7ssAD-a-tert-butyloxyearbonyl-amino-phenylacetylaminoScephalosporanic acid-1-oxide in 36 ml of 0.5 molar phosphate buffer (pH 7) and 4 ml of dimethylformamide is combined with the amalgam of 1.6 g of aluminum and the mixture is stirred for 30 minutes at pH 6.0 and 45 ". Work-up and crystallization from ethyl acetate carried out in accordance with Example 1 gives the 3-methylene-7ssAD-a-tert-butyloxy.carbonylamino-phenylacetylamino> cepham4a.carboxylic acid.



  re-1-oxide, melting point 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 7D-a-tert-butyloxycarbonylamino-phenylacetylamino) -cephalosporanic 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 stirred at 0 for 1 hour . The beginning crystallization is completed by adding 100 ml of ether and gives 22 g of crude product. After recrystallization from methanol / acetone, the 7ssAD-a-tert-butyloxycarbonylamino-phenylacetylamino> cephalosporanic acid-1-oxide, melting point above 300; Thin layer chromatogram Rf (system 52): 0.32; Rf (system 100): 0.27.



  Example 7
130 mg of m-chloroperbenzoic acid are added to a solution of 270 mg of 3-methylene-7ssAD-a-tert-butyloxycarbonylamino-phenylacetylamino> cepham4a-carboxylic acid in 25 ml of 95% ethanol and 5 ml of methanol and the mixture is stirred for 30 minutes. Evaporation gives a crude product which is recrystallized from methanol-acetone. The 3-methylene-7ssAD-a-tert-butyloxyearbonylaminophenylacetylamine is obtained> cepham4-carboxylic acid l-oxide, melting point 225-6 "; [a] b20 = -1070 + 10 (C = I, Dimethyl sulfoxide) The product is identical to the reduction product obtained in Example 20.

 

  Example 8
Analogously to Examples 1 to 4, starting from the 7ss-phenylacetylamino-3-propionyloxymethyl-3-cephem4carboxylic acid, the 7ss-phenylacetylamino-342,2-dimethylpropionyl-oxymethyl-3-cephem4carboxylic acid or a salt thereof, the 3-methylene-7ss- phenylacetylamino-cepham4-carboxylic acid can be obtained.



   The starting compounds can be obtained by acylation of 7ss-phenylacetylamino-3-hydroxymethyl-3-cephem4-carboxylic acid sodium salt in dimethylformamide with a mixture of propionic acid or 2,2-dimethylpropionic acid and N, N'-carbonyldiimidazole.



   The further processing of the compounds which can be prepared according to the invention is documented, for example, in CH patent 579 090.

 

Claims (1)

PATENT CLAIM Process for the preparation of 7ss-amino-3-methylene-ceppham4-carboxylic acid compounds of the formula EMI22.1 where Ría represents hydrogen or an amino protective group RIA, Ríb represents hydrogen or an acyl group Ac, or Rça and R, b together represent a divalent amino protective group, and R2 represents hydroxy or one, together with the carbonyl group - (C = 0) - a protected one Carboxyl group-forming radical R2A, or I-oxides thereof, or salts of such compounds with salt-forming groups, characterized in that that you have a 7ss-amino-3-acyloxymethyl-3-cephem4-carboxylic acid compound of the formula EMI22.2 wherein Ría and R1b have the meaning given above, R30 is an acyloxy group, R2o has the meaning of R2 or R3o and R2o together mean an epoxy group, an l-oxide thereof, or a salt of such a compound, with the exception of a compound of the formula III , wherein R3 is acetoxy and R2o has the meaning of R2, and salts of such a 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 having a salt-forming group is isolated as a salt or as a free compound. SUBCLAIMS 1. The method according to claim, characterized in that starting materials of the formula III in which R1a is an amino protective group R, A, in which any free functional groups present may be protected, bb is hydrogen, R3 is a lower alkanoyloxy group and R2o is a hydroxy group, or in which R3 and R2 together represent an epoxy group, an 1-oxide thereof 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 R1a 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, R3o is the acetoxy group and R2o is a hydroxyl group, or in which R30 and R2 together are an epoxy group, I-oxides thereof, 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 one reduces 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 one reduced 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. The method according to claim, characterized in that one reduces at temperatures between about 25-50. 14. The method according to claim or one of the dependent claims 1-13, characterized in that compounds of formula 1, and l-oxides thereof and salts of such compounds with salt-forming groups, wherein Rla is hydrogen or an acyl radical of an organic carboxylic acid with up to 18 carbon atoms or an easily cleavable acyl radical of a carbonic acid half-derivative, R, b represents hydrogen and R2 is hydroxy, optionally substituted lower alkoxy, optionally substituted phenyl-lower alkoxy, acyloxy, tri-lower alkylsilyloxy, or optionally substituted amino or hydrazino. 15. The method according to claim or one of the sub-claims 1-13, characterized in that compounds of the formula 1, I-oxides thereof, and salts of such compounds with salt-forming groups, wherein R, a, R, b and R2 have the meaning given in claim 14, or wherein R2 have the meaning given in claim 14 Has meaning, R1a and R, b together represent a l-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 sub-claims 1-13, characterized in that compounds of the formula 1, I-oxides thereof, and salts of such compounds with salt-forming groups, wherein R1a is hydrogen, an acyl radical of an organic carboxylic acid with up to to 18 carbon atoms, R, b 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 17th Process according to claim or one of the dependent claims 1-13, characterized in that compounds of the formula 1, l-oxides thereof, and salts of such compounds with salt-forming groups, in which R, a, Rlb and R2 have the meanings given in claim 16 are prepared have or where R2 has the meanings given in claim 16 and R1a and R1b together represent an 1-oxo-3-aza-1,4-butylene radical which is substituted in the 2-position by optionally substituted phenyl and optionally two in the 4-position Contains lower alkyl groups. 18. The method according to any one of claims 1-13, characterized in that compounds of the formula 1, I-oxides thereof, and salts of such compounds with salt-forming groups, in which R16 and R2 have the meanings given in claim 16, and Rla for hydrogen or a group of the formula EMI23.1 where n is 0 and Rl is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, e.g. B. esterified or etherified hydroxy 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 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 R "and R" 'denotes hydrogen, or in which n is 1, Rl denotes 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 The remainder preferably has aromatic character, Rll an optionally functionally modified, z. B. esterified or etherified hydroxy or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, an optionally Omono- or O-disubstituted phosphono group, an azido group or a halogen atom, and R is hydrogen, or where n is 1, each of the radicals Rl and Rll is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and Rlll is hydrogen, or where n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic, Cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R ″ and Riii together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical connected by a double bond to the carbon atom, or where n is 1, and Rl is an optionally substituted one 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, Rll an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and Riii denote hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. 19. The method according to claim or one of the dependent claims 1-13, characterized in that compounds of the formula 1, I-oxides thereof, and salts of such compounds with salt-forming groups, wherein Rjb and R2 in claim 16 and Rla the im Claim 18 have the meanings given, or in which R2 have the meanings given in claim 16 and R1a and R, b together represent an 1-oxo-3-aza-1,4-butylene radical which is optionally substituted in the 2-position and contains phenyl optionally contains two lower alkyl groups in the 4-position. 20. The method according to claim or one of the dependent claims 1-3, characterized in that compounds of the formula 1, l-oxides thereof, or salts of such compounds with salt-forming groups in which Rlb is hydrogen, R1a is hydrogen, an acyl group of the formula EMI23.2 wherein Ar is phenyl, hydroxyphenyl, hydroxychlorophenyl or 2-thienyl, where in such radicals hydroxy substituents can be protected by acyl radicals, X represents oxygen or sulfur, n represents 0 or 1, and R represents hydrogen or, if n represents 0, stands for optionally protected amino, carboxy, sulfo or hydroxy, or 0-lower alkylphosphono or 0,0-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 , 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 compounds of the formula 1, I-oxides thereof, and salts of such compounds with salt-forming groups are prepared, wherein Rlb and R2 have the meanings given in claim 20, and Rla is hydrogen, cyanoacetyl, an acyl group of the formula B according to claim 20, in which Ar is phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, pyridyl, aminopyridinium, furyl, isothiazolyl or tetrazolyl, and X, n and R have the meanings given in claim 20, or denote a 5-amino-5-carboxyvaleryl radical, in which the amino and carboxy groups are optionally protected. 22. The method according to claim or one of the dependent claims 1-13, characterized in that compounds of the formula 1, I-oxides thereof, and salts of those compounds with salt-forming groups in which R1a is hydrogen, the acyl radical of the formula B according to claim 20 wherein 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 0-lower alkyl- 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 R2 denotes hydroxy, optionally lower alkoxy which is halogen-substituted in the 2-position or optionally lower alkoxy-substituted diphenylmethoxy. 23. The method according to claim or one of the dependent claims 1-13, characterized in that the 3-methylene-7ssAD-a-tert.-butyloxycarbonylamino-phenylacetylami no cepham4a-carboxylic acid or salts thereof are prepared. 24. The method according to claim or one of the dependent claims 1-13, characterized in that the 3-methylene-7, BAD-a-tert.-butyloxycarbonylamino-phenylacetyl-amino> cephama-carboxylic acid diphenylmethyl ester is prepared. 25. The method according to claim or one of the dependent claims 1-13, characterized in that the 3-methyl-7ss-phenylacetyl-aminoScepham4a-carboxylic acid or salts thereof are prepared. 26. The method according to claim or one of the dependent claims 1-13, characterized in that the 3-methylene-7ss-phenylacetylaminoScepham4a-carboxylic acid diphenylmethyl ester is prepared. 27. The method according to claim or one of the dependent claims 1-13, characterized in that the 7ss-amino-3-methylene-cepham-4cl-carboxylic acid or salts thereof are prepared. 28. The method according to claim or one of the dependent claims 1-13, characterized in that the 3-methylene-7ss- (5-benzoylamino-adipoylamino) -cepham4a-carboxylic acid or salts thereof are prepared. 29. The method according to claim or one of the dependent claims 1-13, characterized in that the 3-methylene-d-a-p-methoxy-benzyloxycarbonylamino-a-phenyl-acetylamino> cephama-carboxylic acid is prepared 30. The method according to claim or one of the dependent claims 1-13, characterized in that the 3-methylene-7ss4D-a-tert.-butyloxycarbonylamino-phenylacetyl-amino> cepham4a-carboxylic acid 1-oxide is produced.