CH587268A5 - Substd carboxylic acid derivs - broad spectrum antibiotics and inters - Google Patents

Abstract

Title cpds are of formula I: where R1 = an amine protecting gp., R2 = H or acyl; or R1 + R2 tog. = a bivalent amine protecting gp.; R3 = an opt. subst. hydrocarbon residue, or acyl; and R4 = OH or a carboxyl protecting gp I are prepd. by acylating the corresp. 7 beta-amines (I, R1 = R2 = H).

Description

  

  
 



   The present invention relates to a process for the preparation of enol ethers of 7ss-amino-cephem-3-ol4-carboxylic acid derivatives of the formula
EMI1. 1
 wherein R 1 is hydrogen or an amino protecting group R, and R 1 is hydrogen or an acyl group Ac a b, or R 1 and R 1 together are a divalent amino
A represent a protective group, R 2 represents hydroxy or a radical which, together with the carbonyl group -C (= 0) - forms a protected carboxyl group, and R3 represents an optionally substituted hydrocarbon radical, and in 2,3- or 3, 4-position is a C, C double bond, and 1-oxides of compounds of the formula I in which the double bond is in the 3,4-position, or salts of such compounds with salt-forming groups, and also processes for their preparation. 



   The enol derivatives of the present invention are ethers and esters of 2-cephem-3-ol or  3-cephem-3-ol compounds. 



   In 2-cephem compounds of the formula I with a double bond in the 2,3-position, the optionally protected
O) -R A carboxyl group of the formula -C (= 2, preferably the os configuration. 



   An amino protective group R 1A is a group which can be replaced by hydrogen, primarily an acyl group Ac, furthermore a triarylmethyl group, in particular the trityl group, and an organic silyl group and an organic stannyl group.  A group Ac, which can also stand for a radical R1b, 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. 



     
One by the radicals R a and R 1 Rb
1 1 bivalent amino protecting group formed together is in particular the divalent acyl radical of an organic dicarboxylic acid, preferably with up to 18 carbon atoms, primarily the diacyl radical of an aliphatic or aromatic dicarboxylic acid, and also the acyl radical of a preferably substituted in a position, e.g.  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 containing methyl groups, methylene radical is connected to the nitrogen atom.  The radicals R1a and R1b together can also be an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably with up to 18 carbon atoms; represent. 



   A protected carboxyl group of the formula -C (= O) -R A
2 is primarily an esterified carboxyl group, but can also represent a usually mixed anhydride group or an optionally substituted carbamoyl or hydrazino carbonyl group. 



   A.
The group R2 can be a hydroxyl group etherified by an organic radical, in which the organic radical preferably contains 18 carbon atoms, which together with the -C (= O) group forms an esterified carboxyl group.  Such organic residues are e.g.  B.  aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted
Hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic-aliphatic radicals. 



     
The group R 2A can also represent an organic silyloxy
2 rest, as well as a hydroxy group etherified by an organometallic radical, like a corresponding organic
Stannyloxy group, in particular a by 1 to 3, optionally substituted hydrocarbon radicals, preferably with up to 18 carbon atoms, such as aliphatic hydrocarbon radicals, and optionally by halogen, such as chlorine, substituted silyloxy or stannyloxy group. 



   A radical R2A which forms a primarily mixed anhydride group with a -C (= O) group is in particular an acyloxy radical, in which acyl is the corresponding radical of an organic carboxylic acid, preferably with up to 18
Carbon atoms, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acid or a carbonic acid half-derivative, such as a carbonic acid half-ester. 



   One with a -C (= O) grouping is a carbamoyl
A group-forming radical R 2 is an optionally substituted amino group in which substituents are 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 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, and represent acyl radicals, preferably with up to 18 carbon atoms. 



   In a substituted hydrazinocarbonyl group of
A.
Formula -C (= O) -R 2 can be substituted for one or both nitrogen atoms, the substituents primarily being 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 acyl radicals, preferably with up to 18 carbon atoms, are possible. 



   An optionally substituted hydrocarbon radical R3 is preferably a corresponding cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, but in particular an optionally substituted aliphatic
Hydrocarbon radical, also a corresponding araliphatic hydrocarbon radical. 



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



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

  Lower alkylamino, di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino or aza-loweralkylenamino, and acylamino, such as
Lower alkanoylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, azido, acyl, such as lower alkanoyl or benzoyl, optionally functionally modified carboxyl, such as carboxyl in salt form, esterified carboxyl such as N, optionally substituted carbamoyl, such as N-lower alkyl or Di-lower alkylcarbamoyl, furthermore optionally substituted ureidocarbonyl or guanidinocarbonyl, or cyano, optionally functionally modified sulfo, such as sulfamoyl or sulfo present in salt form, or optionally O-mono- or O, O-disubstituted phosphono, where substituents are e.g. 

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



   A bivalent aliphatic residue, incl.  the corresponding residue of a divalent aliphatic carboxylic acid is z. B.  Lower alkylene or lower alkenylene, which may optionally, for.  B.  such 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-aliphatic hydrocarbon radical.  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, where 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, in particular phenyl, and biphenylyl or naphthyl, which optionally, for.  B.  like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, can be mono-, di- or polysubstituted. 



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



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



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



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



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

  B.  contains one of the above-mentioned heterocyclic groups of aromatic character, both the lower alkyl radical and the heterocyclic group may optionally be substituted.  The acyl radical of a carbonic acid semi-derivative can also be an optionally N-substituted arba- moyl group, such as an optionally halogenated N-Ni.     of the 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 e.g.  B.  Can be isopropylidene or isobutylidene. 



   Lower alkylene is e.g. B.  1,2-ethylene, 1,2- or 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, while lower alkenylene z.  B.  1, 2-ethenylene or 2-buten-1, 4-ylene is.  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 azo-lower alkylene, such as 3-lower alkyl-3-aza-1,5-pentylene, e.g. B.    3-methyl-3-aza-1,5-pentylene. 



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



  Cycloalkyl-lower alkyl or lower alkenyl is e.g.  B.  Cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, 1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, -vinyl or -allyl, while cycloalkenyl lower alkyl or lower alkenyl e.g. 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-, - Represents 1,2- or -1,3-propyl, vinyl or allyl. 



  Cycloalkyl-lower alkylidene is e.g.  B.  Cyclohexylmethylene, and cycloalkenyl-lower alkylidene z.  B.  3-cyclohexenylmethylene. 



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



  Represents 4-biphenylyl. 



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



   Heterocyclic radicals are primarily optionally substituted heterocyclic radicals of aromatic character, e.g.  B.  corresponding monocyclic, monoaza-, monothia- or monooxacyclic radicals, such as pyrryl, e.g. B.     2-pyrryl or 3-pyrryl, pyridyl, e.g.  B.  2-, 3- or 4-pyridyl, also pyridinium, thienyl, e.g.  B.  2- or 3-thienyl, or furyl, e.g.  B.  2-furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals such as indolyl, e.g.  B.     2- or 3-indolyl, quinolinyl, e.g.  B.  2- or 4-quinolinyl, isoquinolinyl, e.g.  B.  1-isoquinolinyl, benzofuranyl, e.g.  B.  2- or 3-benzofuranyl, or benzothienyl, e.g.  B.  2- or 3 benzothienyl, monocyclic diaza, triaza, tetraza, thiaza, thiadiaza or oxazacyclic radicals, such as imidazolyl, e.g.  B.  2 imidazolyl, pyrimidinyl, e.g. 

  B.  2- or 4-pyrimidinyl, triazolyl, e.g. B.  1,2,4-triazol-3-yl, tetrazolyl, e.g. B.     1- or 5-tetrazolyl, oxyzolyl, e.g.  B.  2-oxazolyl, isoxazolyl, e.g.  B.  3-isoxyzolyl, thiazolyl, e.g. B.  2-thiazolyl, isothiazolyl, e.g. B.  3-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, e.g. B.    1,2,4-thiadiazol-3-yl or 1,3,4 thiadiazol 2 yl, or bicyclic diaza, thiaza or oxazacyclic radicals, such as benzimidazolyl, e.g.  B.  Benzimidazolyl, benzoxazolyl, e.g.  B.  2-benzoxazolyl, or benzthiazolyl, e.g.  B.  2 benzthiazolyl.  Corresponding partially or fully saturated radicals are, for.  B.  Tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, or piperidyl, e.g. B.  2 or 4-piperidyl.  Heterocyclic-aliphatic radicals are heterocyclic groups, in particular those containing lower alkyl or lower alkenyl. 

  The above-mentioned heterocyclyl radicals can, for.  B.  by optionally substituted aliphatic hydrocarbon radicals, 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-bromo- or 2-iodoethoxy.  Lower alkenyloxy is e.g.  B.  Vinyloxy or allyloxy, lower alkylenedioxy e.g.  B.  Methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy z.  B.  Cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy e.g.  B.    



  Benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, or heterocyclyloxy or heterocyclic 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 e.g.  B.  Benzylthio, while mercapto groups etherified by heterocyclyl radicals or heterocyclylaliphatic radicals, in particular imidazolylthio, e.g.  B.  2-imidazolylthio, thiazolylthio, e.g.  B.  2-thiazolylthio, 1,2,4- or 1,3,4-thiadiazolylthio, e.g. B.  1,2,4-thiadiazol-3-ylthio or 1,3,4-thiadiazol2-ylthio, or tetrazolylthio, e.g.  B.  Are 1-methyl-5-tetrazolylthio. 



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



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

 

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



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



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



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



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



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



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



   O-lower alkyl phosphono is e.g.  B.  O-methyl- or 0-ethyl-phosphono, O, O-di-lower alkyl-phosphono z.  B.  0.0 dimethylphosphono or O, O-diethylphosphono, O-phenyl-lower alkyl-phosphono z.  B.  O-benzyl-phosphono, and 0 lower alkyl-O-phenyl-phosphono z.  B.  O-benzyl-O-methylphosphono. 



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



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



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



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

  B.  denotes esterified or etherified hydroxy or mercapto or an optionally substituted amino group, or in which n is 1, 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 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'11 denotes hydrogen, or in which n stands for 1, R 'denotes an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, wherein the heterocyclic radical preferably has aromatic character, R "is 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 O-mono- or 0,0 'disubstituted phosphono group, an azido group or a
Denotes halogen atom and R "'denotes hydrogen, or in which n denotes 1, each of the radicals R' and R" denotes a functionally modified, preferably etherified or esterified, hydroxy group or an optionally functionally modified carboxyl group, and R "'denotes hydrogen , or wherein n is 1, R 'is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical and R ″ and R111 together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical linked to the carbon atom by a double bond, or where n is 1, and R 'is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical in which heterocyclic preferably have aromatic character, RII an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical and R "'denotes 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 R 'for hydrogen or an optionally, preferably in the 1-position by amino or a, optionally in salt, z.  B.  Alkali metal salt form present sulfoamino group, substituted cycloalkyl group with 5-7 ring carbon atoms, an optionally, preferably by hydroxy, lower alkoxy, z.  B.  Methoxy, and / or halogen, e.g.  B. 



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

  Chlorine, phenyloxy containing, amino and / or carboxy, substituted lower alkyl group, lower alkenyl group, optionally substituted one such as hydroxy, halogen, e.g. B. 



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

  B.     by lower alkyl, such as methyl, substituted phenylthio-, 2-imidazolylthio-, 1,2,4-triazol-3-ylthio-, 1,3,4-triazole
2-ylthio-, 1,2,4-thiadiazol-3-ylthio-, such as 5-methyl-1,2,4thiadiazol-3-ylthio-, 1,3,4-thiadizol-2-ylthio-, such as 5- methyl
1,3,4-thiadiazol-2-ylthio, or 5-tetrazolylthio, such as 1 methyl-5-tetrazolylthio group, a halogen, in particular chlorine or bromine atom, an optionally functionally modified carboxy group, such as lower alkoxycarbonyl, e.g.  B.    



   Methoxycarbonyl or ethoxycarbonyl, cyano or, where appropriate, z.  B.  by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted one
Lower alkanoyl, e.g. B.  Acetyl or propionyl, or benzoyl group, or an azido group, and Rll and Rtt for hydrogen, or n for 1, Rl for an optionally, z.  B.     by Hydr oxy and / or halogen, z.  B.     Chlorine, substituted phenyl or thienyl group, also for a 1,4-cyclohexadienyl group, R for optionally substituted amino, such as lower alkoxycarbonylamino or 2-halo-lower alkoxycarbonylamino, e.g. 

  B.       tert. -Butyloxycarbonylamino or 2,2,2-Trichloräthoxycarbonylamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or one, optionally in salt z.  B.  Alkali metal salt form present sulfoamino group, an azido group, an optionally in salt, z.  B.    



     Alkalimetallsalzfonn or in esterified form, e.g.  B.     as lower alkoxycarbonyl, e.g. B.  Methoxycarbonyl or ethoxycarbonyl group, carboxyl group present, a cyano group, a sulfo group, an optionally functionally modified hydroxyl group, in particular acyloxy, such as fonmyloxy, and lower alkoxycarbonyloxy or 2-halo-lower alkoxycarbonyloxy, e.g.  B.       tert. -Butyloxycarbonyloxy or 2,2,2-trichlorocarbonyloxy, or optionally substituted lower alkoxy or phenyloxy, an O-lower alkyl or O, O-di-lower alkyl-phosphono group, e.g.  B.     O-methyl-phosphono or OsO-dimethylphosphono, or a halogen atom, e.g.  B.    



  Chlorine or bromine, and Rlll for hydrogen, or n for 1, Rl and R "each for halogen, z.    B.     Bromine, or lower alkoxycarbonyl, e.g.    B.    



  Methoxycarbonyl, and R "'for hydrogen, or n for 1, and each of the groups Rl, Rlt and Rtli for lower alkyl, e.g.  B.     Methyl stand. 



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



  optionally present in salt form sulfoamino group, or one, by a, preferably slightly, z.  B.     when treating with an acidic agent, such as trifluoroacetic acid, or with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, cleavable or convertible into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as 2,2,2-trichloroethyl oxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl, phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, and amino groups substituted by trityl), 2,6-dimethoxybenzoyl, tetrahydronaphthoyl,

   2-methoxynaphthoyl, 2-ethoxy-naphthoyl, benzyloxycarbonyl, hexa-hydrobenzyloxycarbonyl, 5-methyl-3-phenyl-4-isoxazolylcarbonyl, 3- (2-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, 3 (2,6 -Dichlorphenyl) -5- methyl-4-isoxazolylcarbonyl, 2-chloro-ethylaminocarbonyl, acetyl, propionyl, butyryl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, methylthioacetyl, butylthioacetyl, butylthioacetyl Bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl or 5-amino-5-carboxyl-valeryl (with optionally, e.g.  B.     as indicated, as indicated by a monoacyl or diacyl radical, e.g. 

  B.     an optionally halogenated lower alkanoyl radical, such as acetyl or dichloroacetyl, or phthaloyl, substituted amino group and / or optionally functionally modified, e.g.  B.     in salt, such as sodium salt, or in ester, such as lower alkyl, e.g.  B.  Methyl or ethyl, or aryl lower alkyl, z.  B. 

  Diphenylmethyl ester form, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bismethoxy carbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, cr-cyano-propionyl, 2-cyano-3,3-dimethyl-acryyl, 2-cyano-3,3-dimethyl-acryyl, 2-cyano-3,3-dimethyl-acryyl α-Azido-phenylacetyl, 3-chlorophenylacetyl, 4-aminomethylphenyl-acetyl, (with optionally, e.g. 

  B.     as indicated, substituted amino group), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, α-phenyloxypropionyl, α-phenyloxypropionyl, α-phenyloxyacetyl, α-phenyloxyphenylacetyl, α-phenyloxyphenylacetyl, α-phenyloxyphenylacetyl, α-phenyloxyphenylacetyl, α-phenyloxy-methyl acetyl, α-phenyl-acetyl-a-phenyloxyphenyl, α-phenyloxy-methyl acetyl, α-acylacetyl , α-methoxy-3,4-dichloro-phenylacetyl, a: -cyano-phenylacetyl, especially phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl or 3,5-dichloro-4-hydroxyphenylglycyl (where in these radicals the amino group optionally, z. 

  B.     as indicated above, may be substituted), or-hydroxyphenyl acetyl (where in these radicals the hydroxyl group optionally, similar 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 cg-O-methyl-phosphono-phenylacetyl or α-O, O-dimethyl-phosphono-phenylacetyl, also benzylthioacetyl, benzylthiopropionyl, α- Carboxyphenylacetyl (with optionally, e.g. 

  B.     as stated above, functionally modified carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) -propionyl, 4- (3-methoxyphenyl) -butyryl, 2-pyridylacetyl, 4-aminopyridinium acetyl (optionally with, e.g.    B.  as indicated above, substituted amino group), 2-thienylacetyl, 2-tetrahydrothienyl-acetyl, α-carboxy-2-thienylacetyl or α-carboxy-3-thienyl-acetyl (optionally with functional, e.g.  B.     as indicated above, modified carboxyl group), α-cyano-2-thieylacetyl, α-amino-2-thienylacetyl or α-amino-3-thienylacetyl (optionally with, e.g. 

  B.     as stated above, substituted amino group), a-sulfo-phenylacetyl (optionally with, z.  B. 



  such as the carboxyl group, functionally modified sulfo group), 3-thienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, 3-methyl-2-imidazolylthioacetyl, 1,2,4 triazol-3-ylthioacetyl, 1,3,4-triazole -2-ylthioacetyl, 5-methyl
1,2,4-thiadiazol-3-ylthioacetyl, 5-methyl-1,3,4-thiadiazol-2ylthioacetyl or 1-methyl-5-tetrazolylthioacetyl. 



   An easily cleavable acyl radical Ac, in particular a carbonic acid half-ester, is primarily a reduction, e.g. B.  when treated with a chemical reducing agent, or by acid treatment, e.g.  B.     with trifluoroacetic acid, cleavable acyl radical of a half ester of carbonic acid, such as a mederalkoxycarbonyl radical, preferably multiply branched in the α-position or substituted by acylcarbonyl, in particular benzoyl radicals, or in β-position by halogen atoms, e.g. 

  B.  tert. -Butyloxycarbonyl, tert. -Pentyloxycarbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a radical which can be converted into the latter, such as 2-chloro- or 2-bromoethoxycarbonyl, furthermore, preferably polycyclic, cycloalkoxycarbonyl, e.g.  B.    

 

  Adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, primarily a-phenyl-lower alkoxycarbonyl, in which the o-position is preferably polysubstituted, e.g.  B.     Diphenylmethoxycarbonyl or (x-4-biphenylyl-os-methyl-ethyloxycarbonyl, or furyl-lower alkoxycarbonyl, primarily α-furyl-lower alkoxycarbonyl, e.g.  B.     Furfuryloxy carbonyl. 



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



   A b
Another divalent radical formed by the groups R1 and R 1 is z.  B.  a, especially in the 2-position, substituted, z.  B.  optionally substituted phenyl or thienyl containing, and optionally in the 4-position by lower alkyl, such as methyl, mono- or disubstituted 1-oxo-3aza-1,4-butylene radical, e.g. B.  4,4-dimethyl-2-phenyl-1-oxo-3-aza-1,4-butylene. 



   A.
An etherified hydroxy group R 2 together with the carbonyl group forms an esterified carboxyl group, preferably easily cleavable or easily converted into another functionally modified carboxyl group, such as into a carbamoyl or hydrazinocarbonyl group.  Such a group
R A is
2 2 is e.g.  Lower alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy, which together with the carbonyl grouping 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 R A, which together with a -C (= O) group forms a particularly easily cleavable esterified carboxyl group, is available, for.  B.  for 2-halo-lower alkoxy, in which halogen preferably has an atomic weight of more than 19.  Such a radical, together with the = = O) group, forms a, when treated with chemical reducing agents under neutral or weakly acidic conditions, e.g. B.  with zinc in the presence of aqueous acetic acid, easily cleavable esterified carboxyl group or an esterified carboxyl group which can be easily converted into such and is z.  B.  2,2,2-trichloroethoxy or 2-iodoethoxy, also 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter. 



   An etherified hydroxy group R A2, which, together with the -C (= O) grouping, also has a properties when treated with chemical reducing agents under neutral or weakly acidic conditions, e.g. B.     when treating with zinc in the presence of aqueous acetic acid, further when treating with a suitable nucleophilic reagent, e.g.  B.  Sodium thiophenolate, easily cleavable esterified carboxyl group, is an arylcarbonylmethoxy group, in which aryl is in particular an optionally substituted phenyl group, and preferably phenacyloxy. 



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

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



   An etherified hydroxy group R A can also be a radical
Represent 2, which together with the -C (= O) grouping under acidic conditions, e.g. B.  when treated with trifluoroacetic acid or formic acid, easily cleavable, esterified carboxyl group forms.  Such a radical is primarily a methoxy group in which methyl is substituted by optionally substituted hydrocarbon radicals, in particular aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, e.g.  B. 



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



   Preferred polysubstituted methoxy groups of this type are e.g.  B.    tert. -Butyloxy, tert. -Pentyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or 2- (4-biphenylyl) -2propyloxy, while a methoxy group containing the above substituted aryl group or the heterocyclic group is e.g. B.  4-methoxybenzyloxy or 3,4-dimethoxy-benzyloxy, or  2-Furyloxy is.  A polycycloaliphatic hydrocarbon radical in which methyl of the methoxy group is a, preferably triple, branched ring member is, for.  B. 



  Adamantyl, such as 1-adamantyl, and an above-mentioned oxa- or thiacycloaliphatic radical, in which methyl of the methoxy group is the ring member representing the position to the oxygen or sulfur atom, means e.g.  B.  2-tetrahydrofuryl, 2-tetrahydropropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulfur analogs. 



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



     
The group R A can also be one, together with the
2
Carboxyl groups of the formula -C (= 0) represent fine, under hydrogenolytic conditions cleavable esterified Carb oxylgruppe-forming etherified hydroxyl group, and is z.  B.  optionally substituted a-phenyl-lower alkoxy, such as
Benzyloxy, 4-methoxy-benzyloxy or 4-nitrobenzyloxy. 



     
The group R A can also be one, together with the
2
Carbonyl grouping -C (= 0) - one among physiological
Conditions cleavable esterified carboxyl group-forming etherified hydroxyl group, primarily lower alkanoyloxy methoxy, e.g.  B.  Acetyloxymethyloxy or pivaloylmethoxy. 

 

     
Contains a silyloxy or stannyloxy group R A
2 preferably optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic Kohlenwas serstoffreste, such as lower alkyl, cycloalkyl, phenyl or
Phenyl-lower alkyl groups, and is primarily tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy, or tri-lower alkylstannyloxy, e.g.  B.  Tri-n-butylstannyloxy. 



   An acyloxy radical R2A, which together with a -C (= O) grouping forms a, preferably hydrolytically, cleavable mixed anhydride group contains z. B.  the acyl radical of one of the above organic carboxylic acids or carbonic acid half derivatives, and is z.  B.  Lower alkanoyloxy, e.g.  B.  Acetyloxy, or lower alkoxycarbonyloxy, e.g.  B.     Ethoxycarbonyloxy. 



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



   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 and primarily methyl, furthermore tert.  -Amino-lower alkyl, wherein the tert. -Amino group is separated from the oxygen atom by at least two carbon atoms, such as 2- or 3 di-lower alkylamino-lower alkyl, e.g.  B.  2-dimethylaminoethyl, 2-. Diethylaminoethyl or 3-dimethylaminopropyl, or etherified hydroxy-lower alkyl, in which the etherified hydroxy group, 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, where as substituents z.  B.  esterified or etherified hydroxy, such as halogen, e.g.  B.  Fluorine, chlorine or bromine, or lower alkoxy, such as methoxy, are possible. 



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



  Sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, whereby primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-.     Di- or polyamines, and heterocyclic bases for salt formation come into question, such as lower alkylamines, eg.  B.  Triethylamine, hydroxy-lower alkylamines, e.g.  B.  2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. B.  4-aminobenzoic acid-2-diethylamino ethyl ester, lower alkyleneamines, e.g.  B.  1-ethyl-piperidine, cycloalkylamines, e.g.  B.  Bicyclohexylamine, or benzylamines, e.g. B.  N, N'-dibenzyl-ethylenediamine, also bases of the pyridine type, e.g.  B.  Pyridine, collidine or quinoline. 

  Compounds of the formula I which have a basic group can also contain acid addition salts, e.g.  B.     with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g.  B.  Trifluoroacetic acid.  Compounds of the formula I with one acidic and one basic group can also be used in the form of an inner salt, i.e.  H.  in zwitterionic form.  1-Oxides of compounds of the formula I with salt-forming groups can also form salts, as described above. 



   The new compounds of the present invention have valuable pharmacological properties or can be used as intermediates for the preparation of such.  Compounds of formula I z.  B. where a R 1 is an acyl radical occurring in pharmacologically active N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds and RA b Ac and R 2 are hydrogen, R1 Hydroxy or one together with the carbonyl group one under physiological
Conditions denotes easily cleavable esterified carboxyl group-forming etherified hydroxyl group, and R3 has the meaning given above, and in which the double bond is preferably in the 3,4-position of the cephem ring, or salts of such compounds with salt-forming groups are against microorganisms,

   such as gram-positive bacteria, e.g.  B. 



  Staphylococcus aureus, (e.g.  B.  in mice at doses of about 0.001 to about 0.02 g / kg p. O. ), and gram-negative bacteria, e.g.  B.    Escherichia coli (e.g.  B.  in mice at doses of about 0.001 to about 0.05 g / kg p. O. ), also Klebsiella pneumoniae, Proteus vulgaris or Salmonella typhosa, in particular also against penicillin-resistant bacteria.  These new compounds can therefore accordingly, for.  B.  in the form of antibiotic preparations, use. 



   Compounds of the formula I in which the double bond of the cephem ring is in the 2,3-position, or 1-oxides of compounds of the formula I in which the double bond is in the 3,4 from the A position, and in which R 1, R 1, R 2 and R3 has the meanings given in connection with the formula I, or in which the double bond of the cephem ring occupies the 3,4 position, R3 has the meaning given above, the a and R ba radicals R 1 and R 1 represent hydrogen, or R 1 is an amino protective group different from the acyl residue mentioned above and R1b is hydrogen, or R1a and R1b together
A men represent a divalent amino protecting group, and R 2 a b represents hydroxy, or R 1 and R Ib represent the A given above
Have meanings, R 2 for one,

   together with the -C (= O) group a, preferably easily cleavable,
A represents a protected carboxyl group-forming radical R 2, and
R3 has the meanings given above are valuable inter mediate products that can be used in a simple manner, for.  B.  as described below, into the pharmacologically active ones mentioned above
Connections can be transferred. 



   The 3-cephem compounds of the
Formula I, wherein R is hydrogen or, preferably, in a fermentative (i.e.  H.  naturally occurring) or bio-, semi- or totally synthetically producible, in particular pharmacologically active, such as highly active N-acyl derivative one
6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem
4-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 stands for
Is hydrogen, R is hydroxy, optionally, e.g.  B. 

 

   by optionally substituted aryloxy, e.g.  B.  4-methoxy phenyloxy, lower alkanoyloxy, e.g.  B.  Acetyloxy or pivaloyl oxy, or arylcarbonyl, e.g.  B.  Benzoyl, or halogen, e.g.  B. 



   Chlorine, bromine or iodine, substituted lower alkoxy, such as lower alkoxy, e.g. B.  Methoxy, ethoxy, n-propyloxy, isopropyloxy, n
Butyloxy, tert. -Butyloxy or tert. -Pentyloxy, bis-phenyloxy-methoxy optionally substituted by lower alkoxy, e.g.  B. 



   Bis-4-methoxyphenyloxy-methoxy, phenacyloxy, lower alkanoyloxy-methoxy, e.g.  B.  Acetyloxymethyl or pivaloyloxy methoxy, or 2-halo-lower alkoxy, e.g.  B.  2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, for optionally substituted phenyl-lower alkoxy, 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-methoxy-benzyloxy, 2-biphenylyl-2propyloxy, 4-nitro-benzyloxy, diphenylmethoxy, 4,4'-dimethoxydiphenylmethoxy or trityloxy, for acyloxy, such as lower alkoxycarbonyloxy, e.g.  B.  Methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, e.g.  B.  Acetyloxy, for tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy, or optionally, e.g. 

  B.  amino or hydrazino substituted by lower alkyl such as methyl or hydroxy, e.g.  B.  Amino, lower alkyl or di-lower alkylamino such as methylamino or dimethylamino, hydrazino, 2-lower alkyl or 2,2-di-lower alkylhydrazino, e.g.  B.     2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamino, and R3 is lower alkyl, e.g.  B. 



  Methyl or ethyl, optionally substituted phenyl-lower alkyl, in particular 1-phenyl-lower alkyl with 1 or 2, optionally, e.g.  B.  by lower alkoxy, such as methoxy, substituted phenyl radicals, e.g.  B.  Benzyl or diphenylmethyl, and the 1-oxides thereof, furthermore the corresponding 2-cephem compounds, or salts of such compounds with salt-forming groups. 



   Primarily in a 3-cephem compound of the formula I, and in a corresponding 2-cephem compound, furthermore in a 1-oxide of the 3-cephem compound, or in a salt of such a compound with salt-forming groups R 1 represents hydrogen or one in fermentative (i.e.  H. 



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

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

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

  B.  when treating with an acidic agent, such as trifluoroacetic acid, or with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, an acyl radical that can be split off or converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as 2,2,2-trichloroethyloxycarbonyl, 2 -Chlor ethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl or phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, or in which the amino group with the nitrogen atom of the 7ss-amino group by one, optionally lower alkyl, such as two Methyl, containing methylene group, furthermore thienylglycyl, such as 2-thienylglycyl (optionally with, e.g. B.  as stated above, substituted amino group), or 1-amino-cyclohexylcarbonyl (optionally with, z. 

  B.  as stated above, substituted amino group), also a-carboxy-phenylacetyl or a-carboxy-2-thienylacetyl (optionally with functionally modified, e.g.  B.  in salt, such as sodium salt form, or in ester, such as lower alkyl, e.g.  B.  Methyl or ethyl, or phenyl lower alkyl, e.g. B. 



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

   when treating with an acidic agent, such as trifluoroacetic acid, or with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, an acyl radical which can be split off or which can be converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as 2,2,2-trichloroethoxycarbonyl , 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl or Phenacyloxycarbonyl, also means formyl), z.  B.  for an acyl radical of formula A, and R b for hydrogen, and R2A represents hydroxy, lower alkoxy, especially α-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, z. 

  B.  2,2,2 trichloroethoxy, 2-iodoethoxy or the easily convertible into this 2-chloroethoxy or 2-bromoethoxy, phenacyloxy, 1 phenyl-lower alkoxy with 1-3 phenyl radicals optionally substituted by lower alkoxy or nitro z.  B.  4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, lower alkanoyloxymethoxy, e.g.  B.     Acetyloxymethoxy or pivaloyloxymethoxy, lower alkoxycarbonyloxy, e.g.  B.  Ethoxycarbonyloxy, or lower alkanoyloxy, e.g.  B.  Acetyloxy, and R3 is lower alkyl, e.g.  B.  Methyl, 1-phenyl-lower alkyl, e.g.  B.  Benzyl or diphenylmethyl. 



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

 

     tert. -Butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, and represents 2-thienyl, X represents oxygen or sulfur, ¯ represents 0 or 1, and R represents hydrogen or, if a represents 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-Trichloräth- oxycarbonylamino, 2-Jodäthoxycarbonylamino or 2-Brom äthoxycarbonylamino, or 3-guanylureide, also sulfoamino or tritylamino, optionally protected carboxy, z.  B. 



  esterified carboxy such as phenyl-lower alkoxycarbonyl, e.g. B. 



  Diphenylmethoxycarbonyl, optionally protected sulfo, as in alkali metal, e.g.  B.  Sodium salt form, sulfo present, optionally protected hydroxy such as acyloxy e.g.  B.    a-poly-branched lower alkoxycarbonyloxy, such as tert. -Butyloxy carbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as
2,2,2-Trichloräthoxycarbonyloxy, 2-Jodäthoxycarbonyloxy or 2-Bromoäthoxycarbonyloxy, also formyloxy, or 0
Lower alkylphosphono or O, O-di-lower alkylphosphono, e.g.  B.  O-methylphosphono or O, O-dimethylphosphono, or a 5-amino-5-carboxy-valeryl radical, wherein the amino and / or carboxy groups are optionally protected and z.  B.  as acylamino, e.g.  B. 

  Lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, or phthaloylamino, or  as esterified
Carboxy such as phenyl-lower alkoxycarbonyl, e.g.  B.  Diphenylmeth A oxycarbonyl, R 2 represents hydroxy, lower alkoxy, especially α-polybranched lower alkoxy, e.g. B.  tert.  Butyloxy, 2-halo-lower alkoxy, e.g.  B.  2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally, e.g.  B. 



  by lower alkoxy, e.g. B.  Methoxy, substituted diphenylmethoxy, e.g.  B.  Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, and R3 is lower alkyl, z. B.  Methyl, also means the corresponding 2-cephem compounds, or salts of such compounds with salt-forming groups. 



   In 3-cephem compounds of the formula I that are to be designated as particularly valuable, and also in corresponding 2 cephem compounds, R a represents 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, 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-Trichloräthoxycarbonylamino, 2-Jodäthoxycarbonylamino, or
2-Bromoethoxycarbonylamino, optionally protected
Hydroxy, such as acyloxy, e.g. 

  B.    a-polybranched lower alkoxy carbonyloxy, such as tert. -Butyloxycarbonyloxy, or 2-halogen lower alkoxycarbonyloxy, such as 2,2,2-Trichloräthoxycarbonyl- oxy, 2-Jodäthoxycarbonyloxy or 2-Bromäthoxycarbonyloxy, also formyloxy, or O-lower alkyl or O, O-di-lower alkyl-phosphono, z. B.  O-methylphosphono or O, O-dimethyl-phosphono, mean, or for a 5-amino-5carboxy-valeryl radical, in which the amino and carboxy groups are optionally protected and z.  B.  as acylamino, e.g.  B. 



   Lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, or phthaloylamino, or  as an esterified carboxy, such as phenylniederalkoxycarbonyl, b z.  B.  Diphenylmethoxycarbonyl, R 1 represents hydrogen, RA represents hydroxy, optionally in the 2-position
2 halogen, e.g. B.  Chlorine-, bromine- or iodine-substituted lower alkoxy, especially cu-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'-dimethoxy-diphenylmethoxy, and R3 means lower alkyl, e.g.  B.  Methyl. 



   The compounds of the formula I, as well as 1-oxides thereof in which the double bond is in the 3,4-position, and their salts are obtained by reacting in a 3-cephem-3-one compound of the formula
EMI9. 1
 or in a 1-oxide thereof, the 3-hydroxy group is converted by etherification into a group of the formula -O-R3, and, if desired, a compound obtained with a salt-forming group is converted into a salt or a salt obtained is converted into the free compound.  A.
In a starting material of the formula II, R 2 preferably stands for an etherified hydroxy group R 2 which forms an esterified R A carboxyl group which can be cleaved, in particular under mild conditions, with the -C (= O) group, where functional groups which may be present are in
A is a carboxyl protecting group R 2 in a known manner, for. B.  as stated above, may be protected. 

  A group R A
2 2A is e.g.  B.  in particular an optionally halogen-substituted lower alkoxy group, such as lx-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, or 2-halo-lower alkoxy, wherein halogen z.  B.     Represents chlorine, bromine or iodine, primarily 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, or an optionally substituted one, such as lower alkoxy, e.g.  B. 



  Methoxy, or nitro-containing 1-phenyl-lower alkoxy group, such as optionally, e.g.  B.  as indicated, substituted benzyloxy or diphenylmethoxy, e.g.  B.  Benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy. 



  In a starting material of the formula a, the radical R A II, the radical R 1 is preferably an amino protective group R 1, such as an acyl group Ac, in which any free functional groups present, e.g.  B.  Amino, hydroxy, carboxyl or phosphono groups, in a manner known per se, amino groups z. B.  by acylating, tritylating, silylating or stannylating, and hydroxy, carboxy or phosphono groups, e.g.  B.  by etherification or esterification, incl.  Silylating or stannylating, may be protected, and R b is hydrogen. 

 

   Starting materials of the formula II can be in the keto and / or enol form; converted into the enol derivatives of
Formula I are the starting materials of the formula II from
Enol form. 



   The starting materials of the formula II are converted into the enol derivatives in a manner known per se. 



   Enol ethers of the formula I are obtained after any, for
Processes suitable for etherification of enol groups, it being possible to use starting materials of the formula II in which R a and R a are hydrogen, but in which preferably
1 1 b A
R 1 stands for an amino protecting group R 1.  The etherifying reagent used is preferably a diazo compound of the formula R3-N2 (III) corresponding to the optionally substituted hydrocarbon radical R3, primarily an optionally substituted diazo lower alkane, e.g.  B.     Diazomethane or diazoethane, also an optionally substituted phenyl-diazo lower alkane, such as a 1-phenyl diazo lower alkane, e.g.  B.  Phenyldiazomethane or diphenyldiazomethane. 

  These reagents are used in the presence of a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, 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 Diniederalkyläthers, 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.  Nitrogen atmosphere applied. 



   Furthermore, enol ethers of the formula I can be formed by treatment with a reactive ester of an alcohol of the formula R3-OH (IV) corresponding to the optionally substituted hydrocarbon radical R3.  Suitable esters are primarily those with strong inorganic or organic acids, such as mineral acids, e.g.  B.  Hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid, or strong organic sulfonic acids such as methanesulfonic or p-toluenesulfonic acid.  These reagents, particularly lower alkyl halides, e.g.  B.  Methyl iodide, or corresponding phenyl lower alkyl halides, are usually in the presence of a solvent such as an optionally halogenated, such as chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g.  B.    



  Methylene chloride, an ether such as dioxane or tetrahydrofuran, or a lower alkanol such as methanol, or a solvent mixture, preferably using suitable condensing agents such as a silver salt, e.g.  B.  Silver nitrate, silver perchloride or silver tetrafluoroborate, used, as well as with cooling, at room temperature or with heating, e.g. B. 



  at temperatures of about C to about 50 "C and, if necessary, in a closed vessel and / or in an inert gas, e.g.  B.  Nitrogen atmosphere applied. 



   Enol ethers can also be obtained by treatment with a compound containing two or three etherified hydroxyl groups of the formula R3-O- (V) on the same carbon atom of aliphatic character, i.  H.  with a corresponding acetal, ketal or orthoester in the presence of an acidic agent.  So you can z.  B.  gem-lower alkoxy-lower alkanes, such as 2,2-dimethoxy-propane, in the presence of a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as methanol or dimethyl sulfoxide, or tri-lower alkyl orthoformate, e.g.  B.  Triethyl orthoformate, in the presence of a strong mineral acid, e.g. B. 

  Sulfuric acid, or a strong organic sulfonic acid such as p-toluenesulfonic acid, and a suitable solvent such as ethanol or dioxane, use as an etherifying agent and obtain compounds of the formula I in which R3 is lower alkyl, e.g.  B.  Methyl, resp. 



  Ethyl stands. 



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



  by acylation, tritylation or silylation, free hydroxy or mercapto groups e.g.  B.  by etherification or esterification, and free carboxyl groups e.g.  B.  by esterification, incl. 



  Silylation, temporarily protected in a manner known per se and, if desired, released in a manner known per se in each case after the reaction has taken place. 



   In a compound of the formula I obtainable according to the invention with a protected, in particular esterified, carboxyl group of the formula -C (= O) -R A2, this can in itself
A known manner, e.g.  B.  depending on the type of group R 2, are converted into the free carboxyl group.  An esterified, e.g.  B. 



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

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

  B.  over 290 m, u when the arylmethyl group z. B.  a benzyl radical substituted in the 2-position by a nitro group, a by a suitably substituted methyl group, such as tert.  -Butyl or diphenylmethyl, esterified carboxyl group e.g.  B.  by treating with a suitable acidic agent such as formic acid or trifluoroacetic acid, 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.  protected by silylation or stannylation
Carboxyl group can in the usual way, for.  B.  can be released by treatment with water or an alcohol. 



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



   In a compound obtained, e.g.  B.  an amino protecting group R A or  R b, especially one easy
1 1 cleavable acyl group in a conventional manner, for.  B.  an α-polybranched lower alkoxycarbonyl group, such as tert.  Butyloxycarbonyl, by treating with trifluoroacetic acid and a 2-halo-lower alkoxycarbonyl group, such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treating with a suitable reducing metal or corresponding metal compound, e.g.  B. 

  Zinc, or a chromium (II) compound, such as chloride or acetate, can advantageously be split off in the presence of a hydrogen-generating agent which noses together with the metal or the metal compound, preferably in the presence of aqueous acetic acid. 



  Furthermore, in a compound of the formula I obtained in which a carboxyl group of the formula -C (= O) -R2 is preferably one, e.g.  B.     by esterification, including by silylation, e.g.  B.     by reaction with a suitable organic halosilicon or halotin IV compound, such as trimethylchlorosilane or tri-n-butyltin chloride, represents an acyl group RA or R b
1 1 'wherein any free functional groups 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, z.  B.    



  a carboxyl group protected by an organic silyl radical can be released in the course of the reaction. 



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



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



   The reaction with one of the said imide halide-forming agents is preferably carried out in the presence of a suitable, in particular organic, base, primarily a tertiary amine, e.g.  B.     a tertiary aliphatic mono or diamine, such as a tri-lower alkyl amine, e.g. B.  Trimethyl, triethyl or ethyl diisopropylamine, also an N, N, N ', N' Tetraniederalkyl- lower alkylenediamine, z.    BN, N, N ', N'-tetra-methyl-1,5-pentylenediamine or N, N, N', N'-tetramethyl-1,6-hexyldiamine, a mono- or bicyclic mono- or diamine, such as an N-substituted, e.g.  B.     N-lower alkylated, alkylene, azaalkylene or oxaalkylene amine, e.g. 

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

  Approximately equimolar amounts of the iride halide-forming agent and the base can be used; but the latter can also be in excess or deficiency, e.g.  B.     be present in about 0.2 to about 1-fold amount or then in about to 10-fold, in particular about 3 to 5-fold excess. 



   The reaction with the imide halide forming agent is preferably carried out with cooling, e.g.  B.     carried out at temperatures from about -500 ° C. to about +100 ° C., but also at higher temperatures, d. H.     z.  B.  up to about 750 C, 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 form the imino ether.  Suitable alcohols are e.g.  B.  aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, e.g.  B.    



     chlorinated, or additional hydroxyl-containing lower alkanols, e.g.  B.     Ethanol, n-propanol, isopropanol or n-butanol, in particular methanol, also 2,2,2-trichloroethanol, and optionally substituted phenyl-lower alkanols, such as benzyl alcohol.  Usually one uses, e.g.  B.     up to about 100-fold excess of the alcohol and preferably operates with cooling, e.g.  B.     at temperatures from about -50 C to about 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 by means of hydrolysis or alcoholysis.  It is preferred 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 from about 1 to about 5 which, if necessary, can be obtained by adding a basic agent such as an aqueous alkali metal hydroxide, e.g. B.  Sodium or potassium hydroxide, or an acid, e.g. 

  B.  a mineral acid, or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, trifluoroacetic acid or p-toluenesulfonic acid. 



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



   If the 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 is obtained in which both radicals R from 1 and R 1 Represent acyl groups.  a
In a compound of the formula T in which both radicals R 1 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 wherein R A and R b
1 1 represent a phthalimido group together with the nitrogen atom, this can, for.  B.  by hydrazinolysis, d. H.     at the
Treat such a compound with hydrazine, in the free
Amino group are converted. 

 

   A.
Certain acyl radicals R 1 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, especially by
Halogenniederalkanoyl, such as dichloroacetyl, optionally protected, can also be obtained by treating with a nitrosating agent such as nitrosyl chloride, with a carbocyc metallic arendiazonium salt such as benzene diazonium chloride, or with a positive halogen donating agent such as an N.
Halo-amide or -imide, e.g. B. 

  N-bromosuccinimide, vorzugswei se 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, eg. B.  Methanol, or, if the amino group in the 5-amino-carboxyvaleryl radical R1b is unsubstituted and the carboxy group z.  B.  is protected by esterification, and R is preferably an acyl radical, but can also be hydrogen, by leaving to stand in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, e.g.  B.  Methylene chloride and, if necessary, working up the free or monoacylated amino compound by methods known per se, are split off. 



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



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



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



   In a compound of the formula in which R a b and R 1 are hydrogen, the free amino group can be converted into acylation methods known per se, eg.  B. 



  by treating with carboxylic acids or reactive acid derivatives thereof such as halides, e.g.  B.  Fluorides or chlorides, also pseudohalides, such as cyanocarbonyl compounds corresponding to the acids, or anhydrides (including the internal anhydrides of carboxylic acids, i.e.  H. 



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



  Isocyanates or isothiocanates, 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, and with substituted formimino derivatives, such as substituted N, N-dimethylchloroformimino derivatives, or an N-substituted N, N -Diacylamine, such as an N, N-diacylated aniline, acylate, if necessary, in the presence of suitable condensing agents, when using acids such.  B.  of carbodiimides, such as dicyclohexylcarbodiimide, when using reactive acid derivatives, e.g.  B.  basic agents, such as triethylamine or pyridine, works, optionally also of salts such.  B.  Ammonium salts of compounds of the formula I in which R A is a hydroxyl group can start. 



   2
An acyl group can also be introduced by adding a compound of the formula I in which R1a and R1b together represent a ylidene radical (which can also be added subsequently, e.g.  B.  by treating a compound in which R 1 and R 1 is hydrogen, with an aldehyde, such as an aliphatic, aromatic or araliphatic aldehyde, can introduce) is, 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 the formulas with a free amino group a halo-lower alkanoyl, z.  B. 



   Bromoacetyl group, or e.g.  B.  by treating with one
Carbonic acid dihalide, such as phosgene, a halocarbonyl, e.g.  B.  Chlorocarbonyl group, and a so obtainable N- (halo-lower alkanoyl) or  N- (halocarbonyl) amino compound with suitable exchange reagents, such as basic compounds, e.g.  B.  Tetrazole, thio compounds, e.g. B.       2-mercapto-1-methyl-imidazole, or metal salts, e.g.  B. 



  Sodium azide or  Alcohols such as lower alkanols, e.g.  B.  tert.  Butanol, implement and so to substituted N-Niederalkanoylbzw.  N-hydroxycarbonylamino compounds arrive.  Furthermore, you can z.  B.  a compound of the formula I in which Ra1 is a glycyl group, preferably substituted in a-position, such as phenylglycyl, and R b is hydrogen, with an aldehyde, e.g. B.  Formaldehyde, or a ketone such as lower alkanone, e.g.  B.  Acetone, and thus obtain compounds of the formula I in which R1A and R1B together represent a 5-oxo-1,3-diaza-cyclopentyl radical which is preferably substituted in the 4-position and optionally substituted in the 2-position. 



   In both reactants, free functional groups can be temporarily protected in a manner known per se during the acylation reaction and can be released after the acylation by methods known per se.  So you can preferably z.  B.  Amino, hydroxy, carboxyl or phosphono groups in the acyl radical during the acylation reaction, e.g.  B.  in the form of acylamino, such as 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino or tert.  Butyloxycarbonylamino groups, from acyloxy, e.g.  B.  2,2,2-Trichloräthoxycarbonyloxy- or 2-Bromoäthoxycarbonylgruppen, of esterified carboxy, such as diphenylmethoxycarbonyl groups, or  O, O-disubstituted phosphono, such as O, O-di-lower alkylphosphono, e.g.  B.    0.0 -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 treatment with suitable reducing agents such as zinc in the presence of aqueous acetic acid, or with trifluoroacetic acid, by hydrogenolysis or by treatment with an alkali metal halide, e.g.  B.  Sodium iodide, such protected groups, optionally partially, cleave. 



   The acylation can also be carried out by replacing an existing acyl group with another, preferably sterically hindered acyl group, e.g.  B.  by the process described above, by preparing the imide halide compound, treating it with a salt of an acid and hydrolytically splitting off one of the acyl groups present in the product thus obtainable, usually the less sterically hindered acyl group.  a b
In a compound of the formula I wherein R 1 and R 1 are
Are hydrogen, the free amino group can also through
Introducing a triarylmethyl group, e.g.  B.  by treating with a reactive ester of a triarylmethanol such as trityl chloride, preferably in the presence of a basic one
By means of such as pyridine. 

 

   An amino group can also be protected by introducing a silyl and stannyl group.  Such groups are introduced in a manner known per se, e.g.  B.  by treatment with a suitable silylating agent such as a dihalo di-lower alkyl-silane or tri-lower alkyl-silyl halide, e.g.  B. 



   (See z. B.  British patent no.  1 073 530), or with a suitable
Stannylating agents such as a bis (tri-lower alkyltin) oxide, e.g.  B.  Bis (tri-n-butyl-tin) oxide, a tri-lower alkyl tin hydroxide, e.g.  B.  Triethyl tin hydroxide, a tri-lower alkyl lower alkoxy tin, tetra-lower alkoxy tin or tetra-lower alkyl tin compound, and a tri-lower alkyl tin halide, e.g.  B.  Tri-n-butyl tin chloride (see e.g.  B.  dutch
Auslegeschrift 67/17107). 



   In a compound of the
Formula I, which contains a free carboxyl group of the formula = = O) -R A, can have such a group known per se
2
Way can be converted into a protected carboxyl group. 



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



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



   In a compound obtained with an esterified grouping of the formula (= O) -R A, this can be converted into a
2 other esterified carboxy groups of this formula are converted, e.g. B.  2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable solvent, such as acetone, in 2-iodoethoxycarbonyl. 



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



   In a connection with
A of a free carboxyl group of the formula -C (= O) -R 2 can also be converted into an optionally substituted carbamoyl or hydrazinocarbonyl group, where 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 the formula I in which R2 is hydroxy, or salts such as alkali metal, e.g.  B. 



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



  67/17107. 



   Furthermore, modified functional substituents in groups R A, R bl and / or R2, such as acylated amino 1, 1 groups, acylated hydroxy groups, esterified carboxy groups or O, O-disubstituted phosphono groups, according to methods known per se, for.  B.  the above-described, release, or free functional substituents in groups R 1A, R b and / or R2, such as free amino, hydroxy, carboxy or phosphono groups, by methods known per se, for.  B.    



   Acylating or  Esterify or  Substitute, modify functionally.  So z.  B.  an amino group by treating 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 can be a
Acid addition salt of a 4-guanylsemicarbazide with Na trium nitrite with a compound of the formula I, wherein, for.  B.  the
Amino protecting group R A is an optionally substituted one
Represents a glycyl group, converting the amino group into a 3
Transfer guanylureido group. 

  Furthermore, you can connections with aliphatically bonded halogen, z. B with an optionally substituted a-bromo-acetyl group, with
Esters of phosphorous acid, such as tri-lower alkyl phosphite compounds, convert and thus arrive at corresponding phosphono compounds. 



   A mixture of a compound of the formula I and the corresponding 1-oxide obtainable according to the process can be used with
Using suitable separation methods, e.g.  B.  by chromatography (column, paper or plate chromatography) under
Use of suitable adsorbents, such as silica gel or aluminum oxide, and eluents, also through fractional crystallization, solvent distribution, etc. 



   be separated.  You can also use a mixture of a
Compound of formula I and the corresponding 1-oxide either oxidize directly to the 1-oxide or to a 3
Reduce cephem compound of formula I.  These oxidation and reduction steps are described below in connection with the isomerization of a 2-cephem to the corresponding 3
Cephem compound described using a 1-oxide as an intermediate. 



   Obtained cephem compounds of the formula I, wherein the
Double bond in 2,3- or in 3,4-position, can through
Oxidation with suitable oxidizing agents, such as those described below, can be converted into 1-oxides of the corresponding 3-Cephemver compounds.  Obtained 1-oxides of 3
Cepehm compounds of the formula I, wherein the double bond in
3,4-position can be reduced with suitable
Reducing agents, such as.  B.  those described below, reduce to the corresponding 3-cephem compounds of the formula I.  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.  So you can get 2-cephem compounds of
Formula I, in which the double bond is in the 2,3-position, into the corresponding 3-cephem compounds of the formula I in which the double bond is in the 3,4-position, by converting a 2-cephem compound of the formula I in which free functional Groups where appropriate, e.g. B.  as indicated, may be temporarily protected, isomerized.  You can z.  B.  Use 2-cephem compounds of the formula I in which the group of the formula -C (= O) -R2 represents a free or protected carboxyl group, it being possible for a protected carboxyl group to also be formed during the reaction. 



   For example, a 2-cephem compound of the formula I can be isomerized by treating it with a weakly basic one
Treated agent and the corresponding 3-cephem compound of formula I isolated. 



   Suitable isomerizing agents are e.g.  B.  organic nitrogen-containing bases, in particular tertiary heterocyclic bases of aromatic character, primarily bases of the pyridine type, such as pyridine itself, and also collidines or lutidines
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, azarcyloaliphatic or araliphatic bases, such as N, N, N-tri-lower alkylamines, e.g.  B.  N, N, N-trimethylamine, N, N-dimethyl-N-ethylamine, N, N, N-triethylamine or N, N-diisopropyl-N-ethylamine, N-lower alkyl-azacycloalkanes, e.g.  B. 



  N-methyl-piperidine, or N-phenyl-lower alkyl-N, N-di-lower alkyl-amines, e.g.  B.  N-benzyl-N, N-dimethylamine, and Gemi cal 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 triethyl amine.  Furthermore, inorganic or organic salts of bases, in particular of medium to strong bases with weak acids, such as alkali metal or ammonium salts of lower alkanecarboxylic acids, eg.  B.  Sodium acetate, triethylammonium acetate or N-methyl-piperidine acetate, and other analogous bases or mixtures of such basic agents can be used. 



   The above isomerization with basic agents can, for.  B.  in the presence of a derivative of a carboxylic acid suitable for forming a mixed anhydride such as a carboxylic acid anhydride or chloride, e.g.  B.  with pyridine in the presence of acetic anhydride.  It is preferably carried out in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, e.g.  B.  chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, whereby bases used as reactants and liquid under the reaction conditions can also serve as solvents, with cooling, at room temperature or with heating, preferably in a temperature range from about -300 ° C. to about + 1000 C, in an inert gas, e.g.  B. 

  Nitrogen atmosphere and / or in a closed vessel. 



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



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



   Suitable oxidizing agents for the 1-position oxidation of 2-cephem compounds are inorganic peracids, which have a reduction potential of at least + 1.5 volts and consist of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, especially organic carboxylic acids 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 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 a 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, e.g. H.  up to 10 times the amount of the oxidizing agent or more.  The oxidation is carried out under mild conditions, e.g. B.  carried out at temperatures from about -50 "C to about + 100" C, preferably from about -10 "C to about +40 C. 



   In the 1-oxides of 3-cephem compounds of the formula I obtainable in this way, in particular in those compounds in from us RA which R 1, R1 and R 2 have the meanings given above before ferred, the groups Rt, R b A 1 and / or R2 are converted into one another, split off or introduced within the inserted frame.  A mixture of isomers a- and ss-1-oxides can, for.  B.  chromatographically, be separated. 



   The reduction of the 1-oxides of Ceph-3-em compounds of the formula I 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 an inorganic or organic nature, e.g. 

  B.  as tin (II) chloride, fluoride, acetate or formate, iron (II) chloride, sulphate, oxalate or succinate, copper (II) chloride, benzoate or oxide, or manganese (II) chloride or sulphate , 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, esters, amides and
Halides of phosphinous, phosphonous or phosphorous acid, and phosphorus-sulfur compounds corresponding to these phosphorus-oxygen compounds, in which organic radicals are primarily aliphatic, aromatic or araliphatic radicals, e.g. B.  represent 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, etc. ; reducing halosilvanic compounds which have at least one hydrogen atom bonded to the silicon atom and which, in addition to halogen, such as chlorine, bromine or iodine, also contain organic radicals such as aliphatic or aromatic groups, e.g. 

  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, especially 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, and also sulfur, phosphorus or silicon halides equal 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, furthermore suitable tri-acid anhydride, such as aurosil anhydride, cyclorosil anhydride, or suitable trichlorosil anhydride, such as Propane sultone, 1,4-butane sultone or 1,3 hexane sultone should be mentioned. 



   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 alkanoic 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, ethers, e.g.  B.     Diethyl ether, tetrahydrofuran or dioxane, ketones, e.g.  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. 



  The process is usually carried out at temperatures of about -20 "C. to about 100" C., it being possible to carry out the reaction at lower temperatures when using very reactive activating agents. 



   In the 3-cephem compounds of the formula I obtainable in this way, R a s R b and / or R A can be used as described above,
1 1 2 into other groups R a, R b or  R A 112 whereby it must be ensured that the 3-cephem compounds are significantly more sensitive to alkaline agents than the corresponding 2-cephem compounds. 



   Furthermore, 3-cephem compounds can be isomerized in a manner known per se to 2-cephem compounds, this reaction being effected by treatment with a base, preferably an organic base, such as a heterocyclic base, e.g. B.  Pyridine, and / or a tertiary amine such as a tri-lower alkylamine, e.g.  B.  Triethylamine, and, if a free 3-cephem-4-carboxylic acid compound is used, additionally in the presence of a suitable acid derivative capable of forming a mixed anhydride group, such as a carboxylic acid anhydride such as lower alkanecarboxylic acid anhydride, e.g.  B.  Acetic anhydride, can be carried out. 



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



  by neutralizing salts such as acid addition salts to the isoelectric point, e.g. B.  with weak bases, or by treatment with liquid ion exchangers.  Salts of 1-oxides of compounds of the formula I in which the double bond is in the 3,4-position 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.   



   The starting materials of the formula II used according to the invention can, for.  B.  be prepared by in a cephem compound of the formula
EMI16. 1
   wherein R 1 preferably represents an amino protecting group R 1, and wherein R2 preferably represents hydroxy, but also represents a group R A, the acetyloxymethyl group, e.g.  B. 



   2 by hydrolysis in a weakly basic medium, such as with an aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase, such as a corresponding enzyme from Rhizobium tritolii, Rhizobium lupinii, Rhizobium japonicum or Bacillus subtilis, converted into the hydroxymethyl group, a free carboxyl group of the formula -C (= O) -R2 functionally modifies in a suitable manner, e.g.  B.    



  esterified by treatment with a diazo compound such as diphenyldiazomethane and the hydroxymethyl group, e.g.  B.  by treating with a halogenating agent such as chlorinating agents, e.g.  B.  Thionyl chloride, or iodinating agents such as N methyl-N, N'-dicyclohexyl-carbodiimidium iodide, in a halomethyl z.  B.  Chloromethyl resp.  Converts iodomethyl group.  A chloromethyl group is either directly, e.g.  B.  by treating with a suitable chromium-II compound such as an inorganic or organic salt thereof, e.g.  B.  Chromium (II) chloride or chromium (II) acetate, in a suitable solvent such as dimethyl sulfoxide or then indirectly via the iodomethyl group (which you can e.g. 

  B.  by treating the chloromethyl compound with a metal iodide such as sodium iodide in a suitable solvent such as acetone), and the iodomethyl group converted to the methylene group by treatment with a suitable reducing agent such as zinc in the presence of acetic acid.  The methylene group in a compound of the formula
EMI16. 2
 is oxidatively degraded using the process described below; in a cephem-3-one compound obtainable in this way, in which both radicals R 1 and are hydrogen, the free t and R b can replace the free amino group with an appropriate protective group, e.g.  B.  according to the procedure described above. 



   The oxidative splitting off of the methylene group in compounds of the formula VII with the formation of an oxo group in the 3-position of the ring structure is preferably carried out with the formation of an ozonide compound by treatment with ozone.  Ozone is preferably used in the presence of a solvent such as an alcohol, e.g.  B.  a lower alkanol such as methanol or ethanol, a ketone, e.g.  B.  a lower alkanone such as acetone, an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. B.  a lower halogen alkane, such as methylene chloride or carbon tetrachloride, or a solvent mixture, incl.  an aqueous mixture, as well as with cooling or gentle heating, e.g.  B.  at temperatures from about C to about + 400 C. 



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



  Hydrogen in the presence of a heavy metal hydrogenation catalyst, such as a nickel or palladium catalyst, preferably on a suitable carrier material such as calcium carbonate or carbon, or chemical reducing agents such as reducing heavy metals, incl.  Heavy metal alloys or amalgamations, e.g.  B.  Zinc, in the presence of a hydrogen donor such as an acid, e.g.  B.  Acetic acid, or an alcohol, e.g.  B. 



  Lower alkanols, reducing inorganic salts such as alkali metal iodides, e.g.  B.  Sodium iodide, in the presence of a hydrogen donor such as an acid, e.g.  B.  Acetic acid, or reducing organic compounds such as formic acid, a reducing sulfide compound such as a di-lower alkyl sulfide, e.g.  B.  Dimethyl sulfide, a reducing organic phosphorus compound, such as a phosphine, which may contain 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 phos phorigsäuretriamide, z.  B.  Hexamethylphosphorigsäuretriamid, the latter preferably in the form of a methanol adduct, or tetracyanoethylene can use.  The cleavage of the ozonide, which is usually not isolated, is normally carried out under the conditions which are used for its production, i.e.  H.  in the presence of a suitable solvent or
Solvent mixture, as well as with cooling or light
Heat. 



   Depending on the type of oxidation reaction, a compound of the formula II or the corresponding 1-oxide or a mixture of the two compounds is obtained.  Such a mixture can be converted into the compound of the formula II and the corresponding 1
Oxide can be separated, or it can be made uniform
Oxidize 1-oxide of a compound of formula I. 



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



   Furthermore, one can obtain a
A mixture of a compound of the formula II and a 1-oxide thereof can also be oxidized directly to the 1-oxide of a compound of the formula II, the oxidizing agent described above being used for the preparation of 1-oxide compounds. 



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



   The pharmacologically acceptable compounds of the present invention can e.g.  B.  be used for the production of pharmaceutical preparations which contain an effective amount of the active ingredient together or in the
Contain a mixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for enteral or, preferably, parenteral administration.  How to use tablets or
Gelatin capsules containing the active ingredient together with diluents, e.g.  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.  Preferably, the pharmacologically active compounds of the present invention are used in the form of injectable, e.g. B. 



  intravenously administrable preparations or from infusion solutions.  Such solutions are preferably isotonic aqueous solutions or suspensions, these e.g.  B.  from lyophilized preparations which contain the active ingredient alone or together with a carrier material, e.g.  B.  Mannitol, contained, can be prepared before use.  The pharmaceutical preparations can be sterilized and / or auxiliaries, e.g.  B.  Contain preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts to regulate the osmotic pressure and / or buffers. 

  The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are made in a manner known per se, for. B.  by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain from about 0.1% to 100%, in particular from about 1% to about 50X, lyophilisates up to 100% of the active ingredient. 



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



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



   example 1
A solution of 1.0 g of 3-methylene-7ss-phenylacetylamino cephem-4a-carboxylic acid diphenylmethyl ester in 250 ml of methylene chloride is treated at -70 for 8¸ minutes with an oxygen-ozone mixture (0.265 mmol ozone / minute) and that 1 ml of dimethyl sulfide are added to the reaction mixture.  The mixture is stirred for 30 minutes at -70 and for 1½ hours at room temperature and then evaporated to dryness under reduced pressure.  The residue, containing a mixture of 7ss-phenylacetylamino-cephem-3-one-4a-carboxylic acid diphenylmethyl ester and 7ss-phenylacetylamino-cepham-3-one-4kcarboxylic acid diphenylmethyl ester-1-oxide, is taken up in 50 ml of methanol and added to 0 with an excess of diazomethane (in the form of a solution in diethyl ether). 

  The mixture is stirred for 10 minutes at 0 "and then evaporated under reduced pressure.  The residue is chromatographed on 50 g of silica gel.  The 3-methoxy-7ss-phenylacetylamino-2-cephem-4a-carboxylic acid diphenylmethyl ester with Rf = 0.57 is eluted with a 4: 1 mixture of toluene and ethyl acetate (system:

  Toluene / ethyl acetate 1: 1); F.  174-177 "after crystallization from a mixture of methylene chloride and pentane; ultraviolet absorption spectrum (in 95% aqueous ethanol): # max = 258 m (# = 4000); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5 , 63, 5.74, 5.92, 6.15 and 6.66; followed by 3-methoxy-7ssphenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester with Rf -0.37 (system:

  Toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% strength aqueous ethanol): amine = 288 my (e = 6340), amine = 264 m '(8 = 6350) and shoulder = 261 m, u (± = 5600); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94tc, 3.02u, 5.621r, 5.83K, 5.93p, 6.261 (and 6.70 '; and with ethyl acetate the 3-methoxy-7ss-phenylacetylamino-3cephem-4 -carboxylic acid- diphenylmethyl ester-1-oxide with Rf = 0.31 (system:

  Ethyl acetate); F.  152-155 "after crystallization from a mixture of acetone and diethyl ether; ultraviolet absorption spectrum (in 95% aqueous ethanol) Amax = 288 m, (e = 3610) and shoulder = 247 m ,; infrared absorption spectrum (in methylene chloride); characteristic bands at 2.94, u, 5.59, u, 5.81y, 5.95, u, 6.22, and 6.61, u.    



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

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

  The precipitate is filtered off and recrystallized from a mixture of acetone and cyclohexane; the 3-hydroxymethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester thus obtained melts at 176-176.5 (uncorr. ); [α] D20 = -6 # 1 (c = 1.231% in
D chloroform); Thin-layer chromatogram (silica gel; detection with iodine vapor or ultraviolet light A 254 m, u); Rf = 0.42 (system: chloroform / acetone 4: 1), Rf = 0.43 (system: toluene / acetone 2: 1), and Rf = 0.41 (system: methylene chloride / acetone 6: 1). 

 

   1.03 g of 3-hydroxymethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester and 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimidium iodide are dissolved under a nitrogen atmosphere in 25 ml of absolute tetrahydrofuran and heated for one hour at 35 ".     Another 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimidium iodide in 15 ml of absolute tetrahydrofuran is then added and the mixture is left to stand for 17 hours at room temperature under a nitrogen atmosphere.  The reaction mixture is freed from the solvent on a rotary evaporator under reduced pressure.  The residue is taken up in methylene chloride and filtered through a column of 50 g of silica gel (addition of 10% distilled water); it is washed with 4 portions of 100 ml of methylene chloride each time. 

  The eluate is concentrated to a small volume and chromatographed on a silica gel column (90 g; deactivated by adding 10% distilled water).  With a total of 900 ml of a 3: 7 mixture of toluene and methylene chloride, non-polar impurities are eluted.  Elution with 2 portions of 200 ml of methylene chloride each yields the 3-iodomethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester; the fractions which are uniform by thin layer chromatography are lyophilized from benzene, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 5.62, 5.82, 5.95, 6.70, 7.32 and 8.16 '.    



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

  The crystal mass which spontaneously crystallizes out within a few hours is separated from the mother liquor with the aid of a glass suction filter with attached nitrogen balloon under exclusion of air, the reaction vessel is rinsed three times with 25 ml of absolute, ice-cold toluene each time and the same toluene is used to colorless the slightly yellowish crystal mass on the glass suction filter to wash.  After drying at 0.1 mm Hg for 20 hours.  and room temperature the N-methyl-N, N'-dicyclohexylcarbodiimidium iodide is obtained in the form of colorless crystals, F.  111-113 "; Infrared absorption spectrum (in chloroform): characteristic bands at 4.72 and 6.00. 



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

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



  The 3-methylene-7ss-phenylacetylamino cephem is eluted
4a-carboxylic acid diphenylmethyl ester eluted with methylene chloride and methylene chloride containing 2% methyl acetate and crystallized from a mixture of methylene chloride and hexane, F.  144-147; [α] D20 = -18 # 1 (c = 0.715 in
Chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): AmaX = 254 m, u (± = 1540) and 260 m, u (e = 1550); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.65, 5.74, 5.94, 6.26 and 6.67, and the like.    



   Example 2
A solution of 0.50 g of 3-methylene-7ss-phenylacetylamino-ephem-4a-carboxylic acid diphenylmethyl ester in 100 ml of methanol is at -70 "for 6.5 minutes with an oxygen-ozone stream containing 0.175 mmol / min.  Ozone, treated.  The reaction mixture is mixed with 0.5 ml of dimethyl sulfide and stirred for one hour at -70 ", then for 2 hours at room temperature and evaporated to dryness.  The residue in methylene chloride is chromatographed on 15 g of silica gel. 

  The amorphous 7ss-phenylacetylamino-cephem-3-one-on-one-carboxylic acid diphenylmethyl ester is eluted with methylene chloride, thin-layer chromatography (silica gel): Rf-0.47 (system: toluene / acetone / methanol / acetic acid 80: 10: 5: 5); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95, 5.61, 5.77, u, 5.85, u, 5.95, u, 6.21, u and 6.87; the compound shows a positive ferric chloride reaction. 



   Example 3
A mixture of 0.06 g of 3-methoxy-7ss-phenylacetylamino3-cephem-4-carboxylic acid diphenylmethyl ester and 0.05 ml of anisole and 1 ml of trifluoroacetic acid is left to stand for 5 minutes at room temperature and then under reduced pressure
Pressure evaporated.  The residue is taken to dryness twice together with a 1: 1 mixture of chloroform and toluene and attached to 5 g of silica gel (containing about 5%
Water) chromatographed. 

  The amorphous 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid is eluted with methylene chloride containing 30-50% acetone and lyophilized from dioxane, ultraviolet absorption spectrum (in 95% aqueous ethanol): A max = 265 m, u (e = 5800); Infrared absorption spectrum (in methylene chloride); characteristic
Bands at 3.031L, 5.60, 5.74tc, 5.92Cl, 6.241c and 6.67, and the like.    



   In an analogous manner, 3-methoxy-7ss- (D-a phenylglycyl-amino) - 3-cephem-4-carboxylic acid can be prepared by converting 3-acetyloxymethyl-7ss- (D-a-tert. -butyloxy carbonylamino-a-phenylacetyl-amino) - 3-cephem-4-carboxylic acid enzymatically cleaves the acetyloxymethyl group, the 3 -hydroxymethyl-7ss- (D -a-tert. -butyloxycarbonyl-amino-ex-phenylacetyl-amino) - 3-cephem-4-carboxylic acid with
Diphenyldiazomethane esterified and in the 3-hydroxymethyl group of 3-hydroxymethyl-7ss- (D-a-tert. -butyloxycarbonyl-amino-a-phenylacetyl-amino) -3 -cephm-4-carboxylic acid-diphenylmethyl ester by treating the hydroxy group with
N-methyl-N, N'-dicyclohexylcarbodiimidium iodide replaced by iodine;

   the 3-iodomethyl group in 3-iodomethyl-7ss- (D-a-tert. - Butyloxycarbonylamino-ex-phenylacetyl-amino) -3-cephem-4-carboxylic acid-diphenylmethyl ester is reductive, z.  B.  by
Treat with zinc in the presence of 90% aqueous
Acetic acid, converted to the methylene group, and the 3
Methylene-7ss- (D-α-tert. -butyloxycarbonylamino-α-phenyl-acetyl-amino) -cephem-4a-carboxylic acid-diphenylmethyl ester is converted into the mixture of the 7ss- (D -x-tert. by treatment with ozone, followed by dimethyl sulfide). - Butyloxycarbonylamino-aphenylacetyl-amino) -cephem-3-one-4a-carboxylic acid diphenyl methyl ester and the 1-oxide thereof converted;

   the latter is separated by chromatography of the 7ss- (D-or-tert. -Butyl oxycarbonyl-amino-os-phenylacetyl-amino) -cephem-3-on-4a-carboxylic acid diphenylmethyl ester is treated with diazomethane, and after reaction with trifluoroacetic acid in
The presence of anisole is obtained from 3-methoxy-7ss- (D n-tert. -butyloxycarbonylamino-a-phenyl-acetyl-amino) -3-cephem-4-carboxylic acid-diphenylmethyl ester the desired 3-methoxy-7ss- (D-α-phenylglycyl-amino) -3-cephem-4-carboxylic acid. 



   The 3-methoxy-7ss- (D-α-phenylglycyl-amino) -3-cephem-4-carboxylic acid can also be obtained if the
3-Methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester removed the phenylacetylamino group by treating with phosphorus pentachloride in the presence of pyridine at about -10 ", followed by methanol at about -15" and hydrolysis at a pH of about 2 splits,

   the free amino group in the 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester by treatment with the mixed anhydride from a-tert. -Butyloxycarbonylamino- a-phenylacetic acid and isobutyl chloroformate acylated and in 3-methoxy-7ss- (D -a-tert. -butyloxycarbonylamino-> a-phenyl-acetyl-amino) - 3-cephem-4-carboxylic acid diphenylmethyl ester liberates the amino and carboxy groups by treatment with trifluoroacetic acid in the presence of anisole. 



   Example 4
In a cooled solution of 5.0 g of 3-methylene7ss- (D-a-tert. -butyloxycarbonylamino-a-phenylacetylamino) cephem-4a-carboxylic acid diphenylmethyl ester in 500 ml of methylene chloride is an oxygen-ozone stream containing 0.21 mmol of ozone / min with vigorous stirring for 1 hour.  initiated.  After another 10 min.  3 ml of dimethyl sulfide are added to the reaction mixture, the mixture is stirred for one hour at -65 "and for 2 hours at room temperature and then evaporated under reduced pressure. 

  The crude product, which the 7ss- (D-a-tert. -Butyloxycarbonyl-amino-aphenylacetyl-amino) - cephem-3-one-4t-carboxylic acid contains diphenylmethyl ester, in 150 ml of methanol at 0 "with an excess amount of a solution of diazomethane in diethyl ether and stirred for 15 minutes and then evaporated.  A yellowish foam is obtained which is chromatographed on 200 g of silica gel. 



  With a 3: 1 mixture of toluene and ethyl acetate, the amorphous 3-methoxy-7ss- (D-a-tert. -butyloxy-carbonylamino-a-phenylacetyl-amino) -3-cephem4-carboxylic acid diphenylmethyl ester, thin-layer chromatogram (silica gel): Rf = 0.22 (system: toluene: ethyl acetate 3: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 ', 5.62', 5.85 ', 6.23, and 6.70'.    



   The starting material can be made as follows:
A chromatography column (diameter: 3 cm) is filled with 350 g of zinc powder, for 10 minutes with a 0.1 molar solution of mercury (II) chloride in 0.1 n.  Hydrochloric acid amalgamated and with a lot of water and finally with a small amount of 1-n.  Washed hydrochloric acid.  A solution of 55 g of green chromium III chloride hexahydrate in 55 ml of water and 11 ml of 2-n.  Sulfuric acid is poured into the reduction tube and the flow rate is regulated in such a way that a chromium (II) chloride solution of a pure blue color drips into the reaction vessel, which is kept under a nitrogen atmosphere.  The blue chromium (II) chloride solution is then mixed with a solution of 92 g of sodium acetate in 180 ml of air-free water, the solution turning red and finely crystalline chromium (II) acetate precipitating out. 



   When the precipitation is complete, the supernatant solution is removed and the chromium (II) acetate is washed twice with 250 ml of air-free water each time.  A solution of 10.0 g of 3-acetyloxymethyl-7ss- (D-atert. -butyloxycarbonyl-amino-a-phenylacetyl-amino) -3cephem-4-carboxylic acid added to 200 ml of dimethyl sulfoxide, and the reaction mixture was stirred for 15 hours under a nitrogen atmosphere at room temperature.  For working up, the reaction mixture is aerated for 30 minutes and, after the addition of 1000 g of a polystyrene sulfonic acid ion exchanger in the Na® form (Dowex 50 W) and 1000 ml of water, stirred for one hour.  After removing the ion exchanger, the pH of the solution is 6-n. 



  Hydrochloric acid adjusted to 2 and the aqueous phase extracted three times with 2000 ml of ethyl acetate each time.  The organic extracts are washed once with 1000 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. 



   The crude product obtained is in 100.     ml of methanol and stirred with a solution of 6 g of diphenyldiazomethane in 30 ml of benzene for 1 hour at room temperature.  The crude product obtained after evaporation is chromatographed on 500 g of silica gel; the 3-methylene-7ss- (D-a-tert. butyloxycarbonylamino-a-phenylacetyl-amino) -cephem-4acarboxylic acid diphenylmethyl ester is eluted with a 4: 1 mixture of petroleum ether; after crystallization from a mixture of methylene dichloride and hexane, the product melts at 156-158 "; [ajn = -50 + 10 (C = 0.713, chloroform); ultraviolet absorption spectrum in 95% aqueous ethanol): = = 258y (e = 990 );

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 ', 5.64', 5.74, ee, 5.88, u (shoulder) and 6.71 '.    



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



  The brown residue is digested several times with diethyl ether, suction filtered and dried.  The resulting, light brown, powdery trifluoroacetate of 3-methoxy-7ss- (Da phenylglycyl-amino) - 3-cephem-4-carboxylic acid is dissolved in 5 ml of methanol, 5 ml of diethyl ether and 0.5 ml of water and the pH of the Solution adjusted to about 4 by adding dropwise a 3% solution of triethylamine in diethyl ether; a fluffy, brownish precipitate separates out.  The precipitation is completed by further addition of diethyl ether, the precipitate is filtered off and reprecipitated three times from a mixture of methanol and diethyl ether. 

  The amorphous inner salt of 3-methoxy-7ss- (Da-phenylglycylamino) -3-cephem-4-carboxylic acid shows an Rf value of about 0.14 in the thin-layer chromatogram (silica gel) (system: ethyl acetate / n-butanol / pyridine / Acetic acid / water 42: 21: 21: 6: 10). 



   Example 6
A solution of 25.7 g of 3-methylene-7ss- (D-a-tert. - butyl oxycarbonylamino-a-phenyl-acetylamino) - cephem-4a-carboxylic acid diphenylmethyl ester in 2500 ml of methylene chloride is cooled to -60 "and for 110 minutes with a stream of a mixture of oxygen and ozone containing 0.45 mmol of ozone per minute , treated.  The reaction mixture is then mixed with 8 ml of dimethyl sulfide, stirred for one hour at and 2 hours at room temperature and evaporated under reduced pressure. 

  The residue is dissolved in 200 ml of methanol and the solution containing the 7ss- (D-a-tert. -Butyloxycarbonylamino-aphenyl-acetylamino) -cephem-3-one-45e-carboxylic acid-diphenylmethyl ester is mixed with a solution of diazomethane in diethyl ether until it remains yellow at 0 ".  After stirring for 15 minutes, the mixture is evaporated under reduced pressure and the residue is chromatographed on 1100 g of silica gel.  The 3-methoxy-7ss- (D-a-tert. -butyloxycarbonylamino- a-phenyl-acetylamino) - 2-cephem-4a-carboxylic acid diphenylmethyl ester is eluted with diethyl ether and crystallized from a mixture of methylene chloride and pentane, F. 

 

      166-168 "; [a] 20 = + 178" :::: 1 "(c = 0.771 in chloroform);
D Thin-layer chromatogram (silica gel; developing with iodine): Rf-0.61 (system: diethyl ether); Ultraviolet absorption spectrum (in ethanol): #max = 257 m, u (t = 3550); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2. 96, 5.63, 5.74, 5.85 (shoulder), 5.92 ', 6.16', 6.64, u (shoulder) and 6.72 '.     Further elution with diethyl ether gives the amorphous 3-methoxy-7ss- (D-a-tert. butyloxycarbonylamino-a-phenyl-acetylamino) - 3-cephem-4-carboxylic acid diphenylmethyl ester, which can be lyophilized from dioxane, thin-layer chromatogram (silica gel;

  Development with iodine): Rf¯0.33 (system: diethyl ether); [aj 2D0 1 # 1 "(c = 0.98 in chloroform); ultraviolet absorption spectrum (in ethanol) max = 264, u (# = 6300); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94u, 5.62, 5.84CL, 5.88 (shoulder), 6.25 'and 6.7t.    



   Example 7
A mixture of 8.8 g of 3-methoxy-7ss- (D-a-tert. -butyloxycarbonylamino-a-phenyl-acetylamino) - 3-cephem-4-carboxylic acid diphenylmethyl ester, 8.6 ml of anisole and 145 ml of trifluoroacetic acid is stirred for 15 minutes at 0 ", then 400 ml of pre-cooled toluene are added and the mixture is evaporated under reduced pressure .  The residue is dried under high vacuum, digested with diethyl ether and filtered off.  The trifluoroacetate of 3-methoxy-7ss- (D-a-phenyl-glycylamino) -3-cephem-4-carboxylic acid, which is dissolved in 20 ml of water, is thus obtained in powder form.  It is washed twice with 25 ml of ethyl acetate each time and the pH value is adjusted to about 5 with a 20% strength triethylamine solution in methanol, a colorless precipitate being formed. 

  The mixture is stirred for one hour in an ice bath, then 20 ml of acetone are added and the mixture is left to stand at about 4 "for 16 hours.  The colorless precipitate is filtered off, washed with acetone and diethyl ether and dried under reduced pressure.  The 3-methoxy-7ss- (D-a-phenyl-glycylamino) -3-cephem-4-carboxylic acid is thus obtained in the form of a microcrystalline powder as an inner salt, which is also present in the form of a hydrate, F.  174-176 "(with decomposition); [a] 20 = + 149" (c = 1.03 in 0.1-n.  Hydrochloric acid);
D thin-layer chromatogram (silica gel; developing with iodine): Rf¯0.36 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in 0.1-n. 



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



   Example 8
A mixture of 0.063 g of 3-methoxy-7ss- (D-a-tert. - butyl oxycarbonylamino-n-phenylacetylamino) - 2-cephem-4a-carboxylic acid diphenylmethyl ester, 0.1 ml of anisole and 1.5 ml of trifluoroacetic acid is left to stand for 15 minutes at 0 "and then evaporated under reduced pressure.  The residue is digested with diethyl ether, filtered off and dried.  The colorless and powdery trifluoroacetate of 3-methoxy-7ss- (Da-phenyl-glycylamino) - 2cephem-4a-carboxylic acid which can be obtained in this way is dissolved in 0.5 ml of water and the pH of the solution is adjusted by adding dropwise a 10% igen solution of triethylamine in methanol adjusted to about 5. 

  The mixture is stirred for one hour in an ice bath, the colorless precipitate is filtered off and dried in a high vacuum. 



   This gives the 3-methoxy-7ss- (D-a-phenyl-glycylamino)
2-cephem-4a-carboxylic acid as inner salt, thin-layer chromatogram (silica gel; developing with iodine): Rf¯0.44 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6:30); Ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution): #shoulder = 260, u.    



   A solution of 0.63 g of 3-methoxy-7ss- (D a-tert. -butyloxycarbonylamino-a-phenyl-acetylamino) - 2cephem-4a-carboxylic acid diphenylmethyl ester in 25 ml of methylene chloride is mixed with a solution of 0.20 g of 3-chloroperbenzoic acid in 5 ml of methylene chloride.  The mixture is stirred at 0 "for 30 minutes, mixed with 50 ml of methylene chloride and washed successively with 25 ml each of a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution.  The organic phase is dried over sodium sulfate and evaporated under reduced pressure. 

  The residue is crystallized from a mixture of methylene chloride and diethyl ether; the 3-methoxy-7ss- (D-α-tert. -butyloxycarbonyl- amino-a- phenyl-acetyl-amino) - 3 -cephem-4-carboxylic acid- diphenylmethyl ester- 1-oxide in the form of colorless needles, F. 



     172-175 "; thin-layer chromatogram (silica gel): Rf¯0.44 (system: ethyl acetate; development with iodine vapor); ultraviolet absorption spectrum (in ethanol): amine = 277 m, (e = 7200); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 ', 5.56', 5.71 ', 5.83, 5.90', 6.27 and 6.67. 



   A solution of 1.30 g of 3-methoxy-7ss (D-? Tert. -butyloxycarbonylamino-α-phenyl-acetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester-1-oxide in 30 ml of dimethylformamide is admixed with 2.80 g of phosphorus trichloride with exclusion of air.  After standing for 15 minutes, the reaction mixture is poured onto a mixture of ice and an aqueous dipotassium hydrogen phosphate solution; the aqueous mixture is extracted twice with 100 ml of ethyl acetate each time.  The organic extract is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. 

  The residue is chromatographed on silica gel; one elutes with diethyl ether the armophene 3-methoxy-7ss- (D-a-tert. -butyloxy carbonylamino-α-phenyl-acetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester as pure substance according to thin-layer chromatography, Rf¯0.39 (system: diethyl ether; development with iodine vapor); [α] D = 1 # to 1 "(c = 0.981 in chloroform); ultraviolet absorption spectrum (in ethanol): amine = 264 (± = 6300); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 ', 5, 62, 5.84, 5.88 ', 6.25y and 6.70'.    



   Example 9
A solution, cooled to 0 ", of 2.0 g of 7ss-phenylacetyl amino-cephem-3-one-4-carboxylic acid diphenylmethyl ester in 75 ml of methanol is treated with excess diazo-n-butane in diethyl ether.  The mixture is stirred for 15 minutes at 0 "and then evaporated under reduced pressure.  The oily residue is purified by means of preparative thin-layer chromatography (silica gel plates, 6 × 100 cm; system: toluene / ethyl acetate 3: 1).  The layer visible under ultraviolet light (A = 254 m) is removed and eluted with acetone. 



  This zone (Rf¯0.33) gives the 3-n-butyloxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, which after crystallization from a mixture of methylene chloride and diethyl ether in the form of colorless platelets at 168-170 melts, [α] D20 = +55 # 1 (c = 0.38 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #man = 264 m, u (± = 7300); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.98, 5.62, 5.81, 5.92, 6.25 and 6.62. 

 

   Example 10
A mixture of 5 g of 3-methylene-7ss- (D-a-tert. - butyloxycarbonylamino-a-phenyl-acetylamino) - cephem-4a-carboxylic acid diphenylmethyl ester and 500 ml of methylene chloride is treated at -70 "with 1.15 equivalents of ozone according to the method described in the preceding examples, then treated with 2 ml of dimethyl sulfide and during Stirred for one hour at -70 "and 2 hours at room temperature, then evaporated under reduced pressure.  The residue containing the 7ss- (D-c: -tert. -Butyloxycarbonyl- amino- a-phenyl-acetylamino) - cephem-3-one-4carboxylic acid diphenylmethyl ester, is dissolved in 150 ml of methanol and treated at 0 "with a solution of diazo-n-butane in diethyl ether until it remains yellow. 

  After 15 minutes, the solution is evaporated under reduced pressure and the residue is purified by means of preparative layer chromatography (silica gel; 1.5 mm thick; plates measuring 16 × 100 cm; system: toluene / ethyl acetate 75:25).  The zone visible under ultraviolet light with an Rf value of about 0.35 gives the 3-n-butyloxy-7ss- (Da-tert. -butyloxycarbonylaminoaphenyl-acetylamino) - 3-cephem-4-carboxylic acid diphenylmethyl ester, which is purified again by repeated chromatography on silica gel and lyophilized from dioxane, [a] D = + 11 1 "(c = 0.98 in chloroform ); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max =
264 m, se (E = 6100);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88, 5.63, 5.84 (shoulder), 5.88, 6.26y and 6.71 '.    



   Example 11
A mixture of 0.5 g of 3-n-butyloxy-7ss- (D-a-tert. - Butyl oxycarbonylamino-a-phenylacetyl-amino) -3 3-cephem-4-carboxylic acid diphenylmethyl ester, 1 ml of anisole and 15 ml of trifluoroacetic acid is left to stand for 15 minutes at 0, then diluted with 200 ml of cold toluene and evaporated under reduced pressure .  The residue is stirred with diethyl ether and the powdery, colorless residue is filtered off, washed with diethyl ether and dried under high vacuum.  This gives the trifluoroacetate salt of 3-n-butyloxy-7ss- (D-a-phenyl-glycylamino) -3-cephem-4-carboxylic acid, which is dissolved in 5 ml of water.  The solution comes up twice with each
Washed 10 ml of ethyl acetate and adjusted the pH of the aqueous phase to 5.0 by adding a solution of triethylamine in methanol. 

  The solution is then evaporated under reduced pressure; the residue is taken up in a small amount of acetone and diluted with diethyl ether until it becomes cloudy.  The 3-n-butyloxy-7ss- (D-a-phenyl-glycylamino) -3-cephem-4-carboxylic acid, which is present in the form of the inner salt, is obtained as a crystalline precipitate and filtered off, F.  141-142 "; Thin layer chromatogram (silica gel): Rf¯0.21 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11); ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution): amine = 267 m e (e = 7300). 



   Example 12
A solution of 0.2 g of 3-methoxy-7ss-phenylacetylamino
3-cephem-4-carboxylic acid in 10 ml of methanol is mixed with a solution of diazomethane in. At 0 "until it remains yellow
Diethyl ether added and then evaporated under reduced pressure.  The residue is chromatographed on silica gel. 

  The 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid methyl ester is with a 3: 1 mixture of
Toluene and ethyl acetate eluted and recrystallized from a mixture of methylene chloride and hexane, F.  171-174 "; 20 [aj D = + 102" :::: 1 (c = 0.95 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Ämax = 265 m, u (e = 6250); Infrared absorption spectrum (in
Methylene chloride): characteristic bands at 2.94y, 5.62y,
5.76, 5.93, 6.24 and 6.65. 



   Example 13
A mixture of 0.02 g of the crude 7ss- (D-a-tert. - Butyloxy carbonylamino-a-phenyl-acetylamino) -cephem-3-one-45S-carboxylic acid diphenylmethyl ester and 2 ml of acetone are mixed with 0.1 ml of dimethyl sulfate and 0.005 g of anhydrous potassium carbonate and stirred for 16 hours under a nitrogen atmosphere at room temperature.  The reaction mixture is evaporated under reduced pressure, the residue is taken up in methylene chloride, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.  The residue is purified by preparative layer chromatography (silica gel).  The two zones visible under ultraviolet light (A = 254 mAe) are isolated. 

  With Rf¯0.61 (silica gel; system: diethyl ether) the 3-methoxy-7ss- (D-a- tert. - butyloxycarbonylamino-a-phenylacetylamino) - 2cephem-4a-carboxylic acid diphenylmethyl ester, F.  166-168 "after recrystallization from a mixture of methylene chloride and pentane; and with Rf¯0.31 (silica gel; system: diethyl ether) the amorphous 3-methoxy-7ss- (D-a-tert. - butyloxycarbonylamino-a-phenylacetylamino) - 3-cephem-4-carboxylic acid diphenylmethyl ester. 



   Example 14
A solution of 8.2 g of 7ss- (D-a-tert.    Butyloxycarbonylamino-a-phenyl-acetylamino) -3-methylencephem-4a-carboxylic acid diphenylmethyl ester in 800 ml of methylene chloride is treated for 34 minutes with an oxygen / ozone stream (0.49 in moles of ozone per minute), then with 3.5 ml of dimethyl sulfide were added and the mixture was stirred at -70 "for one hour and at room temperature for 2 hours. 

  After evaporation under reduced pressure, the oily residue containing the 7ss- (D-a-tert. -Butyloxycarbonylamino-α-phenylacetylamino) - cephem-3-one-4 # - carboxylic acid diphenylmethyl ester, dissolved in 300 ml of benzene, mixed with 3.28 g of 1-ethyl-3- (4-methylphenyl) -triazene and during one Refluxed under a nitrogen atmosphere for 1 hour, then evaporated under reduced pressure. 

  The residue is chromatographed on 360 g of silica gel of the amorphous 3-ethoxy-7ss- (D-a- tert. -butyloxycarbonylamino-a-phenyl-acetylamino) - 3-cephem-4-carboxylic acid diphenylmethyl ester is eluted with a 4: 1 mixture of toluene and ethyl acetate, thin-layer chromatography (silica gel): Rf-0.28 (system: toluene / ethyl acetate 3 :1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): man = 258 m, u (± = 7000) and Ämax = 264 my (e = 6900); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 ', 5.64, 5.90, 6.28, and 6.73'.    



   Example 15
A mixture of 2.70 g of 3-ethoxy-7ss- (D-a-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) - 3-cephem-4carbonsäure- diphenylmethylester, 6.7 ml of anisole and 67 ml of formic acid is stirred for one hour at room temperature, diluted with 200 ml of toluene, then evaporated under reduced pressure and the residue under Dried under high vacuum, digested with diethyl ether and filtered off.  The formate of 3-ethoxy-7ss- (D-aphenyl-glycylamino) - 3-cephem-4-carboxylic acid obtained as a brownish powder is dissolved in 8 ml of water, the aqueous phase is mixed with 2-n.  aqueous hydrochloric acid acidified, washed with 10 ml of ethyl acetate, adjusted to a pH of about 5 with a 10% solution of triethylamine in methanol and evaporated under reduced pressure.  

  The residue is taken up in a small amount of methanol and the amorphous pale yellowish 3-ethoxy-7ss- (Da-phenyl-glycylamino) -3-cephem-4-carboxylic acid precipitated as the inner salt by adding methylene chloride and diethyl ether, thin-layer chromatogram (silica gel): Rf¯0.17 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11); Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): A = 263 my (E = 5500). 



   Example 16
A solution of 15 g of 3-methylene-7ss- (D-a-tert. - butyloxycarbonylamino-a-phenyl-acetylamino) -cephem-4a-carboxylic acid diphenylmethyl ester in 1500 ml of methylene chloride is treated at -65 "for 62 minutes with a mixture of oxygen and ozone containing 0.5 mmol of ozone per minute, and then at - 70 "with 8.7 ml of dimethyl sulfide added.  The mixture is stirred for 1 hour at -70 "and for 2 hours at room temperature and evaporated under reduced pressure.  The residue containing the crude 7ss- (D-atert. - Butyloxycarbonylamino-a-phenyl-acetylamino) - ce phem-3-one-45-carboxylic acid diphenylmethyl ester, is dissolved in 350 ml of benzene and mixed with 11 g of 1-benzyl-3- (4-methylphenyl) -triazene, then during Boiled under reflux for 4 hours. 

  After cooling, 100 ml of 2-n.  aqueous hydrochloric acid and washed with a saturated aqueous sodium chloride solution; the organic phase is dried over sodium sulfate and evaporated under reduced pressure. 



  The residue is chromatographed on 650 g of silica gel; with toluene containing 15% ethyl acetate, the amorphous 3-benzyloxy7ss- (D-a-tert.  -butyloxycarbonylamino-a- phenyl-acetylamino) - 3-cephem-4-carboxylic acid- diphenylmethyl ester eluted, thin-layer chromatogram (silica gel; development with iodine): Rf-0.34 (system:

  Toluene / ethyl acetate 3: 1); [a] D0 = +7 "1" (c = 0.97 in chloroform); Ultraviolet absorption spectrum (in 95% strength aqueous ethanol): amine = 258 m, u (e = 6800), and 264 ml (E = 6800), and shoulder = 280 my (E = 6300); Infrared absorption spectrum (in methylene chloride); characteristic bands at 2.96 ', 5.63', 5.88 ', 6.26' and 6.72 '.    



   Example 17
A mixture of 4.6 g of 3-benzyloxy-7ss- (D-a-tert. - butyloxycarbonylamino-a-phenyl-acetylamino) - 3-cephem-4carboxylic acid diphenylmethyl ester, 10 ml anisole and 100 ml trifluoroacetic acid is stirred for 15 minutes at 0 "and then diluted with 250 ml pre-cooled toluene, evaporated under reduced pressure, and the residue under high vacuum dried.  The product is stirred with diethyl ether and the powdery trifluoroacetate of 3-benzyloxy-7ss- (D-a-phenylglycylamino) -3-cephem-4-carboxylic acid is obtained, which is filtered off and dissolved in a 9: 1 mixture of water and methanol. 

  The pH is 2-n.  aqueous hydrochloric acid set to 1.7; it is washed twice with 30 ml of ethyl acetate each time (the organic washing solutions are discarded), and the pH of the aqueous phase is adjusted to 5 by adding a 10% solution of triethylamine in methanol.  It is evaporated under reduced pressure, the residue is stirred with a mixture of acetone and diethyl ether, the powdery product is filtered off and washed with acetone and with diethyl ether.  The 3-benzyloxy-7ss (Da-phenyl-glycylamino) -3-cephem-4-carboxylic acid is thus obtained in zwitterionic form, thin-layer chromatogram (silica gel): Rf = 0.17 (system: ethyl acetate pyridine / acetic acid / water 62:21 : 6:11); Ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution): man = 266 m, u (e = 6500). 



   Example 18
A solution of 1.59 g of 7ss- (5-benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methylene-cephem-4acarboxylic acid diphenylmethyl ester in 150 ml of methylene chloride is cooled to -70 "and while stirring vigorously
Treated for 12 minutes and 43 seconds with a mixture of ozone and oxygen containing 0.2 mmol of ozone per minute, then treated with 1 ml of dimethyl sulfide.  The mixture is stirred for 5 minutes at -70 "and for 30 minutes at room temperature and evaporated under reduced pressure.  The residue, containing the 7ss- (5-benzoylamino-5-diphenylmethoxycarbonylvaleryl-amino) -cephem-3-one-4 $ - carboxylic acid diphenylmethyl ester, is dissolved in 40 ml of methanol, cooled in an ice bath and mixed until it remains yellow with a solution of diazomethane in diethyl ether. 

  The reaction mixture is evaporated under reduced pressure and the residue is chromatographed on 100 g of silica gel.  The 7ss- (5-benzoylamino-5-diphenylmethoxycarbonylvaleryl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is eluted with a 1: 1 mixture of toluene and ethyl acetate and obtained as an amorphous product, thin-layer chromatogram (silica gel ): Rf = 0.45 (system: toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): shoulder = 258 m, u (e = 7450), 264 m, u (e = 7050) and 268 m, (e = 6700); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65 ', 5.78', 6.03 'and 6.64'.    



   The starting material can be made as follows:
A solution of 50 g of the sodium salt of Cephalosporin C in 1500 ml of 10% strength aqueous dipotassium hydrogen phosphate is diluted with 1200 ml of acetone and 21 g of benzoyl chloride are added at 0 ".  It is carried out at 0 "for 30 minutes and at 20" for 45 minutes, the pH being kept constant at 8.5 by adding a 50% aqueous tripotassium phosphate solution.  It is concentrated to about half its volume under reduced pressure, washed with ethyl acetate, acidified to pH 2.0 with 20% aqueous phosphoric acid and extracted with ethyl acetate. 

  The organic phase is dried and evaporated under reduced pressure; the residue, recrystallized from acetone, gives the N-benzoyl-cephalosporin C, F.  117-119 "; Thin-layer chromatogram (silica gel): Rf = 0.37 (system: n-butanol / acetic acid / water 75: 7.5: 21) and Rf: 0.08 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11).    



   A solution of 4.7 g of N-benzoyl-cephalosporin C in 85 ml of 0.5 m.  molar aqueous dipotassium hydrogen phosphate solution and 9 ml of dimethylformamide are stirred together with 4.7 g of aluminum amalgam for 45 minutes at pH 6.0 and 45 ", the pH being kept constant by adding 20% aqueous phosphoric acid.  100 ml of ice are added, a layer of cold ethyl acetate is added and the pH is adjusted to 2.0 with concentrated phosphoric acid.  The mixture is saturated with sodium chloride, the organic layer is separated off and the aqueous phase is washed twice with ethyl acetate. 

 

   The combined organic extracts, washed with saturated aqueous sodium chloride solution and dried over sodium sulphate, give a residue on evaporation under reduced pressure, which is crystallized in ethyl acetate.  It is slowly diluted with 15 ml of a 2: 3 mixture of ethyl acetate and hexane, filtered after standing at -5 "for 2 hours and, after crystallization from a 1: 4 mixture of ethyl acetate and diethyl ether, the 7ss- (5-benzoylamino -5carboxy- valerylamino) - 3-methylene-cephem-4a: - carboxylic acid, F.  82-89 "(with decomposition);

  Thin-layer chromatogram (silica gel): Rf = 0.53 (system: n-butanol / acetic acid / water 75: 7.5: 21), and Rf = 0.08 (system: ethyl acetate / pyridine / acetic acid / water 62:21 : 6: 11).   



   The aluminum amalgam used above can be prepared as follows: A mixture of 3.3 g of aluminum grit and 100 ml of 50% aqueous sodium hydroxide solution is shaken for 30 seconds and, after the supernatant liquid has been decanted off, washed three times with 300 ml of water each time.  The residue is treated with 130 ml of a 0.3% aqueous mercury (II) chloride solution for 3 minutes and washed three times with 300 ml of water each time.  The entire treatment is repeated once and the aluminum amalgam is finally washed three times with tetrahydrofuran.  About 15 ml of ethyl acetate are used to transfer the product into the reaction vessel. 



   A solution of 2.3 g of 7ss- (5-benzoylamino-5-carboxyvaleryl-amino) -3-methylene-cephem-4a-carboxylic acid in 25 ml of dioxane is added dropwise within 10 minutes with a solution of 2.5 g of diphenyldiazomethane in ml of n-pentane are added. 



  The mixture is stirred for 30 minutes at room temperature, the excess diphenyldiazomethane is decomposed by adding a few drops of acetic acid (glacial acetic acid) and the solution is evaporated under reduced pressure.  The residue is chromatographed on 80 g of silica gel, the 7ss- (5-benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methylene-cephem4a-carboxylic acid diphenylmethyl ester being eluted with a 3: 1 mixture of toluene and ethyl acetate then crystallized from a mixture of methyl acetate and cyclohexane, F.  180-181 "; thin-layer chromatogram (silica gel): Rf = 0.24 (system: toluene / ethyl acetate 2: 1) ultraviolet absorption spectrum (in 95% aqueous ethanol): no characteristic bands;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.66, 5.76, 5.95, 6.03, 6.64 and 6.70. 



   Example 19
A solution of 0.263 g of 7ss- (5-benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methoxy-3-cephem-4carboxylic acid diphenylmethyl ester in 13 ml of methylene chloride is cooled to -10 "and mixed with 0.132 ml of pyridine and 3, 52 ml of an 8% solution of phosphorus pentachloride in methylene chloride were added.  The mixture is stirred for one hour at -10 ", then cooled to -30", 2.2 ml of methanol, cooled to -30 ", is quickly added and stirring is continued for 30 minutes at -10" and at -5 ".  The reaction mixture is then mixed with 6.5 ml of a 0.5 molar aqueous solution of potassium dihydrogen phosphate, stirred for 5 minutes at room temperature and the phases are separated. 

  The aqueous phase is washed with methylene chloride; the combined methylene chloride phases are washed with concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.  The residue is dissolved in methanol and diethyl ether is added to the solution until it becomes slightly cloudy.  The 7pp amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained as an amorphous precipitate, thin-layer chromatogram (silica gel): Rf = 0.17 (system: ethyl acetate; development with iodine): ultraviolet absorption spectrum (in 95% - strength aqueous ethanol): Xmax = 258 m, u (E = 5700); Infrared absorption spectrum (in dioxane): characteristic bands at 2.87 ', 5.62', 5.85 'and 6.26'.    



   Example 20
A solution of 0.400 g 7ss- (D-> a- tert.    Butyloxycarbonylamino-a-phenyl-acetylamino) -3 - methylene cephem-4cr-carboxylic acid diphenylmethyl ester in 40 ml of methylene chloride is treated for 3.6 minutes with an ozone-oxygen mixture containing 0.21 mmol of ozone per minute, then with 0.5 ml of dimethyl sulfide are added and the mixture is then evaporated under reduced pressure.  The residue containing the 7ss- (D -x-tert. - Butyloxycarbonyl amino-a-phenylacetylamino) - cephem-3-one-4 & carboxylic acid diphenylmethyl ester, is dissolved in 10 ml of methanol and a solution of diazomethane in diethyl ether is added until it remains yellow. 

  It is evaporated under reduced pressure and the residue is subjected to preparative layer chromatography (silica gel; system: toluene / ethyl acetate 1: 1; identification with ultraviolet light $ = 254).  A mixture of the 7ss- (Da-tert. -Butyloxycarbonylamino a-phenyl-acetylamino) -3 -methylene-cephem-4a-carboxylic acid diphenylmethyl ester and the 7ss- (D-n-tert. -Butyloxycarbonyl-amino-a-phenyl-acetylamino) -3-methoxy-2-cephem-4a-carboxylic acid diphenylmethyl ester, both with an Rf value of 0.55,

   then the 7ss- (D-a-tert. - Butyloxycarbonylamino-aphenyl-acetylamino) - 3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester with an Rf value of 0.45 and finally a mixture of the 7ss- (D-a-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid-diphenylmethylester- lss-oxyds with an Rf value of 0.17 and la-oxyds with an Rf value of 0.07. 



   Instead of the 7ss- (D-a-tert. - Butyloxycarbonylamino-a-phenylacetylamino) - 3-methylen-cephem-4a-carboxylic acid-diphenylmethyl ester can be used in the above process the 7ss- (Da-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) - 3methylene-cephem-4a-carboxylic acid 4-nitro-benzyl ester or the 7ss- (D -a-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) - 3-methylene-cephem-4a-carboxylic acid 2,2,2-trichloroethyl ester, which can be obtained by treating the sodium salt of 7ss (D-a-tert. -Butyloxycarbonylamino-a-phenyl-acetylamino) - 3-methylene-cephem-4a-carboxylic acid with 4-nitro-benzyl bromide or 

   of a reactive, mixed anhydride of the 7ss- (D-a-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) - 3 -methylene-cephem-4a-carboxylic acid with 2,2,2-trichloroethanol can be used as starting materials and via the 7ss- (D-a-tert. - Butyloxycarbonylamino-a- phenylacetylamino) - cepham-3-one-45t-carboxylic acid 4-nitro-benzyl ester or  the 7ss- (D -a-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) - cepham-3-one-45-carboxylic acid- 2,2,2-trichloroethyl ester the 7ss- (D-a-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid-4nitro-benzyl ester or 

   the 7ss- (D-a-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) - 3-methoxy-3-cephem-4carboxylic acid 2,2,2-trichloroethyl ester. 



   Example 21 Crude 7ss-phenoxycetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester (Rf value: 0.13 (silica gel; toluene / ethyl acetate 3: 1; produced by ozonization of 7ss-phenoxyacetamido-3- Diphenylmethyl methylene-3-cephem-4-carboxylate analogous to Example 1) is taken up in methanol and an excess of ethereal diazomethane solution is added at 0 "C.  After a reaction time of 5 minutes, the solution is completely concentrated and the oily residue is chromatographed on silica gel thick-layer plates (toluene / ethyl acetate 3: 1).  The silica gel of the zone at Rf = 0.19 is extracted with ethyl acetate and yields 7ss-phenoxyacetamido-3methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester; Melting point 120 "C (from ether), IR spectrum (in CHCl3); 3310, 1775, 1700, 1690, 1600 cm-I.    

 

   The same compound is obtained when the etherification is carried out in chloroform. 



   A solution of 2.0 g (3.78 mmol) of 7ss-phenoxyacetamido3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride is mixed with 0.87 ml of anisole, cooled to 0 "C and after Addition of 1.2 ml of trifluoroacetic acid allowed to stand for 1 hour.  The reaction mixture is concentrated in vacuo and the residue is crystallized from acetone / ether.  The 7ss-Phenoxyacetamido-3-methoxy ceph-3-em-4-carboxylic acid with a melting point of 170 "C (dec. ).   



   Example 22
A solution of 0.50 g of the 4-methylphenylsulfonate of 7ss-amino-cepham-3-one-4-carboxylic acid diphenylmethyl ester, the majority in the enol form, i.e.  H.  as 4-methylphenylsulfonate of 7ss-amino-3-cephem-3-ol-4-carboxylic acid diphenylmethyl ester, in 25 ml of methanol a solution of diazomethane in diethyl ether is added at 0 "until it remains yellow.  The mixture is stirred for 10
Minutes in the ice bath and then evaporate.  The residue is chromatographed on silica gel. 

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



   Further elution with ethyl acetate gives the oily 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, thin-layer chromatogram (silica gel; development with iodine vapor): Rf¯0.20 (system: ethyl acetate); Ultraviolet absorption spectrum (in ethanol): #max = 265, u (e = 5900); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.98, 3.33, 5.62y, 5.81, u and 6.24 '.    



   The starting material can be made as follows:
A solution, cooled to -15 ", of 2.0 g of 3-methylene-7ssphenylacetylamino-cephem-4a-carboxylic acid diphenylmethyl ester in 80 ml of absolute methylene chloride is mixed with 3.2 ml of absolute pyridine and 32 ml of an 8% solution of phosphorus pentachloride in Methylene chloride is added and the mixture is stirred under a nitrogen atmosphere at a temperature between -10 "and for one hour.  The reaction mixture is then cooled to -25 ", mixed with 25 ml of absolute methanol and stirred for one hour at -10", then for 1.5 hours at room temperature. 

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



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

  The 4-methylphenylsulphonate of 7ss-amino-3-methylene-cepham-4acarboxylic acid diphenylmethyl ester is obtained in this way in the form of colorless needles.    153-155; [α] D = -14 1 "(c = 0.97 in methanol); ultraviolet absorption spectrum (in ethanol): amine = 257, u (e = 1500); infrared absorption spectrum (in methylene chloride): characteristic bands at 3.50, 5.60, 5.73, 8.50, 9.68 and 9.92y.    



   A stream of oxygen and ozone (containing 0.35 mmol of ozone) is passed through a solution, cooled to -60 ", of 0.553 g of the 4-methylphenylsulphonate of 7B-amino-3-methylene-cepham-4α-carboxylic acid diphenylmethyl ester in 50 ml of methanol per minute).  After a further 5 minutes, 0.3 ml of dimethyl sulfide is added to the pale blue solution.  The mixture is stirred for 15 minutes at -70 "for one hour at -12" and for one hour in an ice bath, then evaporated. 



  The residue is taken up in a small amount of methylene chloride, then diethyl ether is added until it becomes cloudy and the mixture is left to stand.  The microcrystalline, reddish colored powdery precipitate is filtered off and gives the 4-methylphenylsulfonate of 7ss-amino-cepham-3-one-4t-carboxylic acid diphenylmethyl ester, which is mainly in the enol form as 4-methylphenylsulfonate of 7ss-amino-3cephem-3 -ol-4- carboxylic acid diphenylmethyl ester is present, F = 143-145 "(with decomposition); thin-layer chromatogram (silica gel) Rf¯0.28 (system:

  Ethyl acetate / pyridine / water 85: 10: 5); Ultraviolet absorption spectrum (in ethanol): Ämax = 262 m, (e = 3050) and 282 m, u (± = 3020); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58y, 5.77, u (shoulder), 6.02 'and 6.22. 



   Example 23
A solution of 0.258 g of 3-methylene-7ss-phellylaceLyl-aminocepham-4a-carboxylic acid-diphenylmethylester-1-oxide in 50 ml of methanol is at -65 "with an oxygen / ozone mixture (20 mmol ozone per minute) up to treated to remain blue.  The reaction mixture is then treated with 0.5 ml of dimethyl sulfide, stirred for 20 minutes at -65 and 30 minutes at room temperature and evaporated under reduced pressure.  The residue, containing the 7ss-phenyl acetylamino-cephem-3-one-4 # -carboxylic acid diphenylmethyl ester-1-oxide, is taken up in 20 ml of methanol and an ethereal solution of diazomethane in diethyl ether is added at 0 "until it turns yellow .  After standing for 15 minutes, the reaction mixture is evaporated under reduced pressure. 

  The residue is purified by means of preparative layer chromatography; the zone visible under ultraviolet light (R = 254 my) with Rf¯0.20 (system: ethyl acetate; identification with iodine) is eluted with a 1: 1 mixture of acetone and methanol and the 3-methoxy7ss-phenylacetylamino- 3-cephem-4-carboxylic acid diphenylmethyl ester-1-oxide, ultraviolet absorption spectrum (in 95% aqueous ethanol): A max = 276 m, u (e = 7500); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.56, 5.81, 5.92, 6.22 and 6.67. 



   The 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid methyl ester, F. 



  171-174 "after recrystallization from methylene chloride and hexane; [α] D20 = +102 # 1 (c = 0.95 in chloroform); ultraviolet absorption spectrum (in 95% aqueous ethanol): Ämax = 265 m '(e = 6250 ); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.9Lu, 5.62, 5.76Cl, 5.93CL, 6.24 and 6.65, u.    



   The starting material used in the above example can be prepared as follows: A solution, cooled to 0 ", of 0.50 g of 3-methylene-7ss-phenylacetylamino-cepham-4a-carboxylic acid diphenylmethyl ester in 50 ml of methylene chloride is mixed with a solution of 0.19 g 3-chloroperbenzoic acid in 10 ml of methylene chloride was added and the mixture was stirred in an ice bath under a nitrogen atmosphere for 30 minutes. 



  The reaction mixture is diluted with 100 ml of methylene chloride, washed twice with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and with 50 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. 

 

  The residue is chromatographed on 50 g of silica gel.  The 3-methylene-7ss-phenylacetylaminocepham-4a-carboxylic acid diphenylmethyl ester-1-oxide is eluted with methylene chloride containing 3-5% acetone and crystallized from a mixture of acetone, diethyl ether and hexane, F = 172-175 ";
20 [α] D = -68 (c = 0.925 in chloroform): thin-layer chromatogram (silica gel; identification with iodine): Rf 0.25 (system:

  Toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): no specific absorption; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.69, 5.60, 5.74, 5.92, 6.24, 6.63 and 9.60,
Example 24
A solution of 0.100 g of 7ss- (D-a-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) - 3-methoxy-3-cephem-4carboxylic acid diphenylmethyl ester in 0.5 ml of methylene chloride is mixed with 0.09 ml of anisole and 0.100 ml of trifluoroacetic acid and stirred for 10 minutes at 0 "and then with 20 ml of a 1: 1 mixture of diethyl ether and pentane diluted.  The fine precipitate is filtered off, washed with a mixture of diethyl ether and pentane and dried under reduced pressure. 

  This gives the 7ss (D - tert. -Butyloxycarbonylamino-a-phenyl-acethylamino) - 3-methoxy-3-cephem-4-carboxylic acid in the form of a colorless powder, thin-layer chromatogram (silica gel; identification with iodine): Rf-0.64 (system: n -butanol / acetic acid / Water 67:10:23); Ultraviolet absorption spectrum (in 95% strength aqueous ethanol): #max = 264 m (# = 4100); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00 ', 5.64', 5.92 ', 6.25' and 6.72y.    



   If you treat the 7ss- (D-a-tert. - Butyloxycarbonylamino a-phenylacetylamino) - 3-methoxy-3-cephem-4-carboxylic acid 4-nitro-benzyl ester with hydrogen in the presence of a palladium-on-carbon catalyst or the 7ss- (D-a-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) - 3-methoxy3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with zinc in the presence of 90% aqueous acetic acid, the 7ss- (D-? -Tert. -Butyloxycarbonylamino-α-phenyl-acetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid, which is identical to the above product. 



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



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

  In this way, the amorphous 7ss- [D-a-tert. - Butyloxycarbonyl amino-x- (2-thienyl) -acetylamino] - 3-methoxy-3-cephem-4carboxylic acid diphenylmethyl ester, thin-layer chromatogram (silica gel: identification with ultraviolet light A = 254 m): Rf¯0.34 (system: diethyl ether) ; [α] 20 D = +26 # 1 (c = 0.86 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol); #max = 240 m (# = 12500) and 280 m (# = 6000); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.62, 5.85p, 6.26 and 6.72y.    



   Example 26
A mixture of 0.200 g of 7ss- [D-α-tert. -Butyloxycarbonyl-amino-α- (2-thienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester 0.5 ml of anisole and 10 ml of pre-cooled trifluoroacetic acid is stirred for 15 minutes at 0 ", then 50 ml of cold toluene are added and the mixture is evaporated under reduced pressure.  The residue is stirred with diethyl ether and the powdery precipitate is filtered off and dried.  The salt of 7ss- [Da-amino-a- (2-thienyl) -acetylamino] -3-methoxy-3-cephem-4carboxylic acid with trifluoroacetic acid is dissolved in about 6 ml of water, the pH of the solution is adjusted Addition of 2-n. 



  Adjusted hydrochloric acid to 1.5 and washed the aqueous solution with 20 ml of ethyl acetate and adjusted its pH to 5.0 by adding dropwise a 20% solution of triethylamine in methanol.  It is diluted with 20 ml of acetone and the mixture is left to stand at 0 "for 16 hours.  The fine, colorless and microcrystalline powder is filtered off, washed with acetone and dried, giving the 7ss- [Da-amino-a- (2-thienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid in the form of the inner salt, F.  140 "(with decomposition); thin layer chromatogram (silica gel; identification with iodine): Rf¯0.22 (system: n-butanol / acetic acid / water 67:10:23) and Rf¯0.53 (system:

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



   Example 27
A solution of 0.514 g of 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester in 30 ml
Methylene chloride is cooled to -10 "and treated with 0.8 ml of absolute pyridine and 8.0 ml of an 8% solution of phosphorus pentachloride in methylene chloride.  The reaction mixture is stirred for one hour at -10 "to -5", then cooled to -30 "and mixed with 5 ml of methanol.  The mixture is stirred for one hour at -10 to -5, one hour 0 and one hour at room temperature.  One gives 20 ml of one
0.5 molar aqueous potassium dihydrogen phosphate solution is added, the mixture is stirred at pH 2.4 for 30 minutes, diluted with methylene chloride, the aqueous phase is separated off and extracted with methylene chloride. 

  The united organic
Phases are washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.  The residue is digested with diethyl ether and left to stand for 16 hours at 0 "; the precipitate is filtered off, washed with diethyl ether and dried. 

  The 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained as a light beige powder, thin-layer chromatogram (silica gel; developed with iodine vapor): Rf-0.17 (system: ethyl acetate); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 258 m (# = 5250) and 264 m (# = 5300), and #shoulder = 290 m (# = 5200); Infrared absorption spectrum (in dioxane): characteristic bands at 2.87 (broad), 5.62, 5.85 and 6.26. 

 

   Example 28
A suspension of 0.250 g of 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 25 ml of methylene chloride is at 0 "and under a nitrogen atmosphere with
1 ml of pyridine and 0.5 ml of phenylacetic acid chloride are added and the mixture is stirred at this temperature for 30 minutes.  The reaction mixture is evaporated under reduced pressure; the residue is stirred for 10 minutes with 20 ml of a 1: 1 mixture of dioxane and water and diluted with methylene chloride.  The aqueous phase is separated off and extracted with methylene chloride.  The combined organic phases are washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. 

  The crude product is purified by means of preparative thin-layer chromatography, a 1: 1 mixture of toluene and ethyl acetate being used as the solvent.  The zone visible under ultraviolet light from A = 254 m, u (Rf¯0.35) is eluted with a 4: 1 mixture of acetone and methanol and gives the 3-methoxy-7ss-phenylacetylamino-3-cephem-4carboxylic acid diphenylmethyl ester , the one with the after
Procedure of Example 1 available product is identical. 



   Example 29
In an analogous manner, the following compounds can be obtained in an analogous manner using the suitable starting materials, optionally after additional conversions of a product obtained: 7ss- [D-α-tert. -Butyloxycarbonylamino-α- (4-hydroxy-phenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, thin-layer chromatogram (silica gel;
Identification with iodine): Rf¯0.35 (system:

  Toluene / acetic acid
20 ethyl ester 1: 1; [α] D ¯ - 1 # 1 (c = 0.566 in chloroform), ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 276 m (# = 7400); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.83, 2.96, 5.64, 5.86, 5.91 (shoulder), 6.23, 6.28, 6.65y and 6.72 '; which can be converted into 7ss- [D-a-amino-a (4-hydroxyphenyl) -acetylamino-3-methoxy-3-cephem-4carboxylic acid as follows:

  A mixture of 0.095g 7ss- [Da-tert. - Butyloxycarbonylamino-a- (4-hydroxyphenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 0.25 ml of anisole and 5 ml of precooled trifluoroacetic acid is stirred for 15 minutes at 0 ", then 50 ml of cold toluene are added and the mixture is evaporated under reduced pressure.  The residue is stirred with diethyl ether and the powdery precipitate is filtered off and dried.  The thus obtained salt of 7ss- [Da-amino-a- (4-hydroxyphenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid with trifluoroacetic acid is dissolved in about 5 ml of water, the pH value of Solution is made by adding 2-n. 

  Adjusted hydrochloric acid to 1.5, and washed the aqueous solution with 20 ml of ethyl acetate and adjusted its pH by dropwise addition of a 20% solution of triethylamine in methanol to 5.0, a colorless precipitate being formed.  It is diluted with 8 ml of acetone and the mixture is left to stand at 0 "for 16 hours.  The precipitate is filtered off, washed with acetone and diethyl ether and dried under reduced pressure. 

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

  Hydrochloric acid, and Ämax = 227 m (e = 10500) and shoulder = 262 my (± = 8000) in 0.1-n.  aqueous sodium hydrogen carbonate solution;
7ss- [D-a-tert. -Butyloxycarbonylamino-a- (4-isothiazolyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, amorphous, [α] D20 = +26 # 1 (c = 0.65 in chloroform); Thin-layer chromatogram (silica gel; identification with iodine): Rf-0.43 (system:

  Toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Ämax = 250 m, u (E = 12200) and 280 m (e = 5900); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.65, 5.71, (shoulder), 5.88, 6.28 and 6.73,
3-Methoxy-7ss-methoxycarbonylacetyl-amino-3-cephem4-carboxylic acid, thin-layer chromatogram (silica gel; system: ethyl acetate / acetic acid 9: 1):

  Rf = 0.5-0.6; Ultraviolet Absorption Spectrum (in methanol): amine at 265 my; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66 '; 7ss-Bromoacetyl-amino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 75: 7.5: 21): Rf = 0.25-0.35; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max at 264 my;
3-Methoxy-7ss- (2-thienyl) -acetylamino-3-cephem-4-carboxylic acid, melting point 164-165 C (from ethyl acetate / diethyl ether), thin-layer chromatogram (silica gel; system: butanol / pyridine / acetic acid / water 38: 24: 8: 30):

  Rf = 0.5-0.6; Ultraviolet absorption spectrum (in 95% aqueous ethanol): A max at 237 and 265 my (e 12600); IR spectrum (Nujol): bands at 3280, 1765, 1652, 1625, 1550 cm-1 [a] D = +126 :::: 1 "(c = 0.950; dioxane);
7ss- (a-Carboxy-a-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30);
7ss-Acetoacetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 75: 5: 21):

  Rf = 0.3-0.4; Ultraviolet absorption spectrum (in 95% 4 in aqueous ethanol): A max at 238 m and 265 m;
7ss-cyanoacetylamino-3-methoxy-3-cephem-4-carboxylic acid, melting point 150-155 "C (from acetone / ethyl acetate / diethyl ether), thin-layer chromatogram (silica gel; system: n butanol / pyridine / acetic acid / water 38:24: 8:30): Rf = 0.35-0.45; ultraviolet absorption spectrum (in 95% aqueous ethanol): Ämax at 265 m (e = 5500); infrared absorption spectrum (in mineral oil): characteristic bands at 3300, 2255, 1790 , 1758, 1740, 1688, 1660 cm-1; [a] D = + 180 "(c = 1.055; methanol); 7ss- (a-cyano-propionylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel;

  System: n butanol / pyridine / acetic acid / water 38: 24: 8: 30): Rf = 0.4-0.5; Ultraviolet absorption spectrum (in 95% aqueous ethanol): one at 265 my; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.44 and 5.66 '; 7ss- (a-cyano-a-phenyl-acetylamino) -3-methoxy-3-cephem-
4-carboxylic acid, thin layer chromatogram (silica gel;
System: n-butanol / acetic acid / water 75: 7.5: 21) Rf = 0.3-0.4;
Ultraviolet absorption spectrum (in 95% aqueous
Ethanol): amine at 267 m, u; Infrared absorption spectrum (in
Mineral oil):

   characteristic bands at 4.42 'and 5.65';
7ss- (2-chloroethylamino-carbonylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel); Rf = 0.3-0.4 (system: n-butanol / acetic acid / water 75: 7.5: 21); Ultraviolet absorption spectrum (in 0.1 molar hydrochloric acid): λ max at 266 my;
7ss-dichloroacetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin layer chromatogram (silica gel; system: n butanol / acetic acid / water 75: 7.5: 21):

  Rf = 0.40; Ultraviolet absorption spectrum (in 95% aqueous ethanol); Amine at 264 m infrared absorption spectrum (in mineral oil): characteristic band at 5.67; 3-Methoxy-7ss - (α-sulfo-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid in the form of the disodium salt, thin-layer chromatogram (silica gel): Rf¯0.10-0.20 (system: Butanol / acetic acid / water 67:10:23);
3-Methoxy-7ss- (a-phenylaminocarbonyl-acetylamino) -3methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 67:10:23): Rf = 0.30 ; Ultraviolet absorption spectrum (in mineral oil): characteristic band at 5.65;
3-methoxy-7ss-methoxyacetylamino-3-cephem-4-carboxylic acid, thin layer chromatogram (silica gel; system:

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

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

  Rf = 0.50; Ultraviolet absorption spectrum (in 95% strength aqueous ethanol): amine at 266 my; Infrared absorption spectrum (in mineral oil): characteristic band at 5.65 '; 7ss- (3-butenoyl-amino) -3-methoxy-4-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30): Rf = 0.65 ; 3ss-Methoxy-7ss - (α-methylthio-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30) :

  Rf = 0.60; Ultraviolet absorption spectrum (in 95% strength aqueous ethanol): amine at 266 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.7;
7ss- (bis-methoxycarbonyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 38: 24: 8: 30): Rf = 0.45 ; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): one at 268 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.64 ';
7ss-dibromoacetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n butanol / acetic acid / water 75: 7.5: 21):

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

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

  AmaX ¯ 267 my; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.66 and 5.65; 7ss-α-O, O'-dimethyl-phosphono-α-phenyl-acetylamino) -
3- methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf-0.4 (system: n-butanol / acetic acid /
Water 67:10:23); Ultraviolet absorption spectrum (in 95% ethanol): man ¯ 266 my; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66 ';
3-methoxy-7ss- (5-methyl-3-phenyl-3-isoxazolyl-carbonyl amino) - 3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel):

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

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

  Rf¯0.2-0.3 (system: n-butanol / acetic acid / water
67:10:23); Ultraviolet absorption spectrum (in 0.1-n.  Hydrochloric acid): amine = 235 nyl and 270 m ,; 7ss- [D-α-tert. -Butyloxycarbonylamino-α- (2-furyl) -acetyl-amino] -3-methoxy-3-cephem-4-carboxylic acid diphenyl methyl ester; Thin layer chromatogram (silica gel): Rf-0.35 (system:

  Diethyl ether); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Ämax ¯ 265 mAe; 7ss- [D -a-amino-n- (24uryl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf-0.25 (system: n-butanol / acetic acid / water
67:10:23); Ultraviolet absorption spectrum (in 0.1 N hydrochloric acid): # max¯265 m; 7ss- (D-α-hydroxy-α-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, melting point 157-160 "C (ethyl acetate / diethyl ether), thin-layer chromatogram (silica gel): Rf-0 .35 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30);

  Ultraviolet absorption spectrum (in 95% strength aqueous ethanol): # max¯ 265 m (e = 6300); Infrared absorption spectrum (in mineral oil): characteristic bands at
3380, 1790, 1725, 1650, 1602, 1535 cm-1 [or] D = +48 # 1 (c = 1.078; dioxane);
7ss- (1-Amino-cyclohexyl-carbonylamino) -3-methoxy-3-cephem-4-carboxylic acid, as inner salt in amorphous form, thin-layer chromatogram (silica gel):

  Rf 0.2-0.25 (system: n-butanol / acetic acid / water 67:10:23); Ultraviolet absorption spectrum (in 0.1 -n.     Hydrochloric acid): # max¯ 264 my;
Infrared absorption spectrum (in mineral oil): characteristic band at 5.56 ';
3-methoxy-7ss- (4-pyridylthio-acetylamino) -3-cephem-4carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30): Rf = 0.25- 0.30; Infrared absorption spectrum (in mineral oil): characteristic band at 5.65; 7ss - (α-4-amino-pyridinium-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, as inner salt in amorphous form, thin-layer chromatogram (silica gel):

  Rf = 0.20-0.3 (system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30); Infrared absorption spectrum (in mineral oil): characteristic band at 5.65 '; 3 -Methoxy-7ss- (1 -tetrazolyl-acetylamino) -3-cephem-4carboxylic acid, melting point 142-145 "C (from acetone / diethyl ether); thin-layer chromatogram (silica gel; system: n butanol / pyridine / acetic acid / water 42: 24: 4:30): Rf = 0.35-0.45; UV spectrum (alcohol): A ", aX = 264 m, u (e = 5800); IR spectrum (Nujol): bands at 3280, 1780, 1725, 1675, 1625, 1570, 845 cm-1; 3 -Methoxy-7ss- (1 -methyl-2-imidazolylthio-acetylamino) 3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30):

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



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



   Example 31
A suspension of 0.100 g of 7ss- (D-a-amino-n-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid in 5 ml of absolute methylene chloride is mixed with 0.0364 g of triethylamine and stirred for 10 minutes; most of the material goes into solution.  It is cooled to -5 "and a total of 0.0652 g of the triethylamine-sulfur trioxide complex (F.  89-90 ") too.  The mixture is stirred for 5 minutes at 0 "and for two hours at 20".  The solution is treated with 0.9 mmol of sodium a-ethyl hexanoate and the precipitated product is filtered off. 

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



   Example 32
To a cooled solution of 0.100 g of 4-guanylsemicarbazide dihydrochloride in 0.6 ml of water, a solution of 0.037 g of sodium nitrite in 0.4 ml of water is added with stirring, stirring is continued for 10 minutes at 0 "and then it is added dropwise at 0" with triethylamine to pH 7.5 solution of 0.186 g of 7ss- (D-a-amino-a-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid in 4 ml of water.  The mixture is stirred for one hour at 0 ", the precipitate is filtered off, washed with water and dried. 

  The crude 7ss- [D-cr- (3-guanyl-ureido) -a-phenylacetylamino] -3-methoxy-3-cephem4-carboxylic acid is obtained in this way, which in the thin-layer chromatogram (silica gel; development with iodine vapor): Rf¯0, 20-0.30 (system: n butanol / acetic acid / water 67:10:23); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Ämax = 265 m '.    



   Example 33
Dry ampoules or vials containing 0.5 g of 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid are produced as follows:
Composition (for 1 ampoule or vial) 3-methoxy-7ss-phenylacetyl-0.5 g amino-3-cephem -4-carboxylic acid mannitol 0.05 g
A sterile aqueous solution of 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid and mannitol is subjected to freeze-drying under aseptic conditions in 5 ml ampoules or 5 ml vials and the ampoules or vials 



  Vials sealed and checked. 



   Example 34
Dry ampoules or vials containing 0.5 g of the inner
Salt of 3-methoxy-7ss- (D-a-phenylglycyl-amino) -3-cephem-4-carboxylic acid are prepared as follows:
Composition (for 1 ampoule or vial)
Inner salt of 3-methoxy-7ss- 0.5 g (D -a-phenylglycyl-amino) -
3-cephem-4-carboxylic acid
Mannitol 0.05 g
A sterile aqueous solution of the inner salt of 3-Meth oxy-7ss- (D-a-phenylglycyl-amino) - 3-cephem-4-carboxylic acid and the mannitol is dissolved in 5 ml under aseptic conditions. 
Ampoules or 5 ml.  -Vials are subjected to freeze-drying and the ampoules or  Vials sealed and checked. 



   Example 35
Capsules containing 0.25 g of the inner salt of 3-methoxy-7ss- (D-a-phenyl-glycylamino) -3-cephem-4-carboxylic acid are prepared as follows:
Composition (for 4000 capsules): Inner salt of 3-methoxy-7ss- 250. 000 g (D-a-phenylglycyl-amino) 3-cephem-4-carboxylic acid corn starch 50. 000 g polyvinylpyrrolidone 15. 000 g magnesium stearate 5. 000 g of ethanol q. s. 

 

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



   Example 36
256.3 g of 3-methoxy-7ss- (D-a-tert. -butyloxy-carbonylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester with a mixture of 250 ml anisole in 1200 ml methylene chloride and treated at 0 "with
1200 ml trifluoroacetic acid pre-cooled to 0 ".  The mixture is left to stand at 0 "for 30 minutes and the reaction mixture is diluted within 15 minutes with 12000 ml of a 1: 1 mixture of diethyl ether and petroleum ether which has been cooled to 0".  The precipitated trifluoroacetic acid salt of 3-methoxy7ss- (D-a-phenylglycylamino) -3-cephem-4-carboxylic acid is filtered off, washed with diethyl ether, dried under reduced pressure and dissolved in 1900 ml of water. 

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

  Hydrochloric acid); Ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution): Ämax = 265 m (e = 6500); Infrared absorption spectrum (in mineral oil): bands at 2.72, 2.87, 3.14, 3.65, 5.68, 5.90, 6.18, 6.27, 6.37, 6.56, 6, 92, 7.16, 7.58, 7.74, 7.80, 8.12, 8.30, 8.43, 8.52, 8.65, 8.95, 9.36, 9.55, 9.70, 10.02, 10.38, 10.77, 11.70, 12.01, 12.15,
12.48, 12.60, 12.87, 13.45, and 14.30,; Microanalysis (C, 6H ,, OsN3S 2H2O; molecular weight: 399.42): calculated: C 48.11%, H 5.30%, N 10.52% and S 8.03%; found C 47.86%, H 5.27%, N 10.47% and S 8.00%.     

 

Claims (1)

PATENT CLAIMS Process for the preparation of enol ethers of 7ss-aminocephem-3-ol-4-carboxylic acid derivatives of the formula EMI29.1 where R 1 is hydrogen or an amino protecting group RA where R1 is hydrogen or an amino protecting group R1, and R1b is hydrogen or an acyl group Ac, or R1a and R1b together are a divalent amino protecting group, R2A is one, together with the carbonyl group -C (= O ) -a protected carboxyl group-forming radical, and R3 stands for an optionally substituted hydrocarbon radical, and in which there is a C, C double bond in the 2,3- or 3,4-position, and 1-oxides of compounds of the formula I in which the C, C double bond is in the 3,4-position, or salts of such compounds with salt-forming groups, characterized in that in a 3-cephem-3-ol compound of the formula EMI29.2 or in a 1-oxide thereof the 3-hydroxy group is converted into a group of the formula -O-R3 by etherification, and if desired, a compound obtained with a salt-forming group is converted into a salt or a salt obtained is converted into the free compound. SUBClaims i. Process according to patent claim, characterized in that starting materials of the formula II are used in which Rt A represents an amino protective group R 1 which represents an acyl group Ac, in which any free b functional groups present may be protected, R 1 represents hydrogen, and R2A represents an etherified hydroxyl group which forms an esterified carboxyl group with the -C (= O) group , with any existing functional Groups in an esterified carboxyl group of the formula A -C (= O) -R2 protected. 2. The method according to dependent claim 1, characterized in that R2A represents an optionally substituted 1-phenyl-lower alkoxy group such as the diphenylmethoxy group. 3. The method according to dependent claim 1, characterized in that R A is an optionally halogen-substituted 2 lower alkoxy group, such as an α-polybranched lower alkoxy radical, e.g. tert-butyloxy, or a 2-halo-lower alkoxy radical, such as 2,2,2-trichloroethoxy. 4. The method according to claim, characterized in that enol ethers are prepared by treating the starting material with a corresponding diazo compound of the formula R3-N2 (III). 5. The method according to dependent claim 4, characterized in that a diazo lower alkane, such as diazomethane, or a phenyldiazo lower alkane, such as 1-phenyldiazo lower alkane, for. B. Phenyldiazomethane or diphenyldiazomethane is used. 6. The method according to claim, characterized in that enol ethers are prepared by treating the starting material with a reactive ester of a corresponding alcohol of the formula R3-OH (EV). 7. The method according to dependent claim 6, characterized in that esters of alcohols of the formula R3-OH with strong inorganic or organic acids, such as mineral acids, eg. B. hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid, or strong organic sulfonic acids such as methanesulfonic or p-toluenesulfonic acid, optionally used in the presence of a suitable condensing agent, such as a silver salt. 8. The method according to claim, characterized in that enol ethers are prepared by treating the starting material with a compound containing two or three etherified hydroxyl groups of the formula R3-O- (V) on the same carbon atom of aliphatic character in the presence of an acidic agent. 9. The method according to dependent claim 8, characterized in that a gem-lower alkoxy-lower alkane, e.g. 2,2-Dimethoxy-propane, used in the presence of a strong organic sulfonic acid. 10. The method according to claim, characterized in that free amino groups not participating in the reaction are intermediately protected by acylation, tritylation or silylation, free hydroxyl or mercapto groups by etherification or esterification and free carboxyl groups by esterification in a starting material. 11. The method according to claim, characterized in that the protected carboxyl group -C (= O) -R A in a compound obtained by solvolysis, reduction 2 or photolysis converted into a free carboxyl group. 12. The method according to claim, characterized in that in a compound obtained in which both radicals R A and R b are acyl groups, a suitable 1 IP 1 acyl group z. B. split off by hydrolysis, aminolysis or hydrazinolysis and replaced by hydrogen. 13. The method according to claim, characterized in that a free amino group in a compound obtained is acylated by treatment with a carboxylic acid or a reactive functional derivative thereof. 14. The method according to claim, characterized in that a compound obtained with a C, C double bond in the 2,3-position is isomerized to a corresponding compound with the C, C double bond in the 3,4-position. 15. The method according to dependent claim 14, characterized in that the isomerization is carried out by treatment with a weakly basic agent. 16. The method according to dependent claim 14, characterized in that the isomerization is carried out by oxidation of the 1 position and subsequent reduction of the 1-oxide obtained of the corresponding 3-cephem compound. 17. The method according to claim or one of the dependent claims 1-16, characterized in that 3 cephem compounds of the formula I according to claim or 1-oxides thereof, furthermore the corresponding 2-cephem compounds, and salts of such compounds with salt-forming groups, wherein R a hydrogen or an acyl radical contained in a fermentatively or bio-, semi- or totally synthetically producible N-acyl derivative of a 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compound or an easily cleavable Represents acyl radical of a carbonic acid semi-derivative, R b represents hydrogen, R A2 is hydroxy, optionally substituted lower alkoxy, optionally substituted phenyl-lower alkoxy, acyloxy, tri-lower alkylsilyloxy, or optionally substituted amino or hydrazino, and R3 represents lower alkyl or optionally substituted phenyl lower alkyl. 18. The method according to claim or one of the dependent claims 1-16, characterized in that 3 cephem compounds of the formula I according to claim or 1-oxides thereof, and corresponding 2-cephem compounds, and also salts of such compounds with salt-forming groups, in which P, "hydrogen, an acyl radical contained in fermentatively or biosynthetically producible N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3cephem-4-carboxylic acid compounds, or an acyl radical contained in highly effective N-acyl derivatives of 6ss-amino penam -3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds is the acyl radical occurring, R b is hydrogen, RA is hydroxy, lower alkoxy, 2-halogen 2 lower alkoxy, phenyloxy, 1-phenyl lower alkoxy with 1-3, is phenyl radicals optionally substituted by lower alkoxy or nitro, lower alkanoyloxymethoxy, lower alkoxycarbonyloxy or lower alkanoyloxy, and R3 is lower alkyl or 1-phenyl-lower alkyl. 19. The method according to claim or one of the dependent claims 1-16, characterized in that 3 cephem compounds of the formula according to claim or 1-oxides thereof, as well as corresponding 2-cephem compounds, and also salts of such compounds with salt-forming groups, in which Ob1, RA and R3 the in 1 2 a Dependent claim 18 have given meanings, and R 1 represents hydrogen or a group of the formula EMI30.1 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, z. B. esterified or etherified hydroxy or mercapto group, or an optionally substituted amino group, or where 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 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 Rlll 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 preferably has aromatic character, R is 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 0mono- or O-disubstituted phosphono group, an azido group or a halogen atom, and 11lll is hydrogen, or where n is 1 each of the radicals Rl and R "means a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and RIII is hydrogen, or where n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic, Cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R ″ and Rlll 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, R11 an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and Rlll is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. 20. The method according to claim or one of the dependent claims 1-16, characterized in that 3 cephem compounds of the formula I according to claim or 1-oxides thereof, and corresponding 2-cephem compounds, furthermore salts of such compounds with salt R b A produces groups in which R 1, R 2 and R3 have the meanings given in a dependent claim 18, and R 1 represents hydrogen or a group of the formula EMI31.1 where n is 0 and Rl is hydrogen or an optionally, preferably in the 1-position by amino or a, optionally in salt, z. B. alkali metal salt form present sulfoamino group, substituted cycloalkyl group with 5-7 ring carbon atoms, one optionally, preferably by hydroxy, lower alkoxy, z. Methoxy, and / or halogen, e.g. B. Chlorine, substituted phenyl, naphthyl or tetrahydronaphthyl group, an optionally, e.g. B. by lower alkyl, e.g. B. methyl, and / or phenyl, which in turn have substituents such as halogen, e.g. B. chlorine, can carry substituted heterocyclic group, such as a 4-isoxazolyl group, or a preferably, z. B. by a given if substituted, such as halogen, e.g. B. chlorine, lower alkyl containing N-substituted amino group, or n for 1, for a 3-amino-3-carboxy-propyl radical with optionally protected amino and / or carboxy group, z. A silylated amino or acylamino and / or silylated or esterified carboxy group, an optionally substituted, preferably by halogen, such as chlorine, such as hydroxy and / or halogen, e.g. Chlorine, phenyloxy containing, amino and / or carboxy, substituted lower alkyl group, lower alkenyl group, optionally substituted one such as hydroxy, halogen, e.g. B. chlorine, and / or optionally substituted, such as hydroxy and / or halogen, e.g. B. chlorine, containing phenyloxy, phenyl group, optionally, z. B. by lower alkyl, such as methyl, amino or aminomethyl, substituted pyridyl, pyridinium, thienyl, 1-imidazolyl or 1-tetrazolyl, an optionally substituted lower alkoxy, e.g. Methoxy group, an optionally, e.g. by hydroxy and / or halogen, such as chlorine, substituted phenyloxy group, a lower alkylthio, e.g. B. n-butylthio, or lower alkenylthio, e.g. B. allylthio, 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, 1,3,4 thiadiazol-2-ylthio, such as 5-methyl-1,3,4-thiadiazol-2-ylthio -, or 5-tetrazolylthio, such as 1-methyl-5-tetrazolylthio group, a halogen, especially chlorine or bromine atom, an optionally functionally modified carboxy group, such as lower alkoxycarbonyl, e.g. B. methoxycarbonyl or ethoxycarbonyl, cyano or optionally, z. B. by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl, e.g. B. Acetyl or propionyl, or benzoyl group, or an azido group, and R '> and Rlll for hydrogen, or n for 1, Rl for an optionally, z. B. by hydroxy and / or halogen, e.g. B. chlorine, substituted phenyl or thienyl group, also for a 1,4 cyclohexadienyl group, R "for optionally substituted amino, such as lower alkoxycarbonylamino or 2-halo-lower alkoxycarbonylamino, e.g. tert-butyloxycarbonylamino or 2,2,2-trichloroethoxycarbonylamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or a sulfoamino group, optionally in salt, for example alkali metal salt form, an azido group, an optionally in salt, for example 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, in particular acyloxy, such as formyloxy, and lower alkoxycarbonyloxy or 2-halo-lower alkoxycarbonyloxy, z. B. tert-butyloxycarbonyloxy or 2,2,2-trichlorocarbonyloxy, or optionally substituted lower alkoxy or phenyloxy, an O-lower alkyl or O, O-di-lower alkyl-phosphono group, e.g. B. O-methyl-phosphono or 0,0-dimethylphosphono, or a halogen atom, e.g. B. chlorine or bromine, and Rlll for hydrogen, or n for 1, Rl and R "each for halogen, e.g. bromine, or lower alkoxycarbonyl, e.g. methoxycarbonyl, and R t for hydrogen, or n for 1, and each of the groups Rl, R "and Rlll for lower alkyl, e.g. B. methyl. 21. The method according to claim or one of the dependent claims 1-16, characterized in that 3 cephem or 2-cephem compounds of the formula I according to claim or salts of such compounds with salt R b prepares forming groups in which R 1 is hydrogen, a R 1 is hydrogen, an acyl group of the formula EMI31.2 wherein Ar is phenyl, hydroxyphenyl, hydroxychlorophenyl or 2-thienyl, where hydroxy substituents may be protected by acyl radicals in such radicals, X is oxygen or sulfur, n is 0 or 1, and R is hydrogen or, if n is 0 , for optionally protected amino, carboxy, sulfo or hydroxy, or O-lower alkylphosphono or O, O-di-lower alkyl-phosphono, or is a 5-amino-5-carboxy-valeryl radical, wherein the amino and carboxy groups are optionally protected, RA hydroxy, lower alkoxy, 2-halo-lower alkoxy or 2 is optionally substituted diphenylmethoxy and R3 is lower alkyl. 22. The method according to claim or one of the dependent claims 1-16, characterized in that 3 cephem or 2-cephem compounds of the formula I according to claim or salts of such compounds with salt-forming groups in which R 1 is hydrogen, the acyl radical of the formula B according to dependent claim 21, in which Ar is phenyl, X is oxygen, n is 0 or 1, and R is hydrogen, or, if n is 0, optionally protected amino or hydroxy, or O -Lower-alkyl- or O, O-di-lower alkylphosphono, or a 5-amino-5-carboxy-valeryl radical, in which the amino and carboxy groups are optionally protected, R2A is hydroxy, optionally lower alkoxy which is halogen-substituted in the 2-position or optionally lower alkoxy-substituted diphenylmethoxy , and R3 represents lower alkyl. 23. Method according to claim or one of the Dependent claims 1-16, characterized in that the 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester. 24. The method according to claim or one of the dependent claims 1-16, characterized in that the 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid or salts thereof are prepared. 25. The method according to claim or one of the dependent claims 1-16, characterized in that the 3-methoxy-7ss- (Da-tert-butyloxycarbonylamino-a-phenyl-acetylamino) - 3-cephem-4-carboxylic acid diphenylmethyl ester is prepared . 26. The method according to claim or one of the dependent claims 1-16, characterized in that the 3-methoxy-7ss- (D -a-phenylglycylamino) -3-cephem-4carboxylic acid or salts thereof are prepared. 27. The method according to claim or one of the dependent claims 1-16, characterized in that the 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is prepared.