CH591501A5 - 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 O-acylated 7t3-amino-cephem-3-014-carboxylic acid derivatives of the formula
EMI1. 1
 wherein R1a is hydrogen or an amino protecting group R1A, and Rlb is hydrogen or an acyl group Ac.  or Rla and Rlb together represent a divalent amino protective group, R2A stands for hydroxy or a radical which together with the carbonyl group -C (= O) - forms a protected carboxyl group, and R3 stands for an acyl group, and which has a C, C- Contain double bond in 2,3- or in 3,4-position, as well as of 1-oxides of compounds of the formula I, wherein the C. C double bond is in the 3,4-position, or salt of such compounds with salt-forming groups. 



   The enol derivatives of the present invention are enol esters of 2-cephem-3-ol and 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 carboxyl group of the formula -C (= O) -R2A preferably has the o-configuration. 



   An amino protective group R1A is a group which can be replaced by hydrogen, primarily an acyl group Ac, furthermore a triarylmethyl, in particular the trityl group, and an organic silyl and an organic stannyl group. 



  A group Ac primarily represents the acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid (incl. 



  Formic acid), as well as the acyl radical of a carbonic acid half derivative. 



   A divalent amino protective group formed together by the radicals Rla and Rlb is in particular the divalent acyl radical of an organic dicarboxylic acid, preferably with up to 18 carbon atoms, primarily the diacyl radical of an aliphatic or aromatic dicarboxylic acid, furthermore the acyl radical of a, preferably substituted in a position, z.  B.  an aromatic or heterocyclic radical containing 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 Rla and Rlb together can also represent an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably with up to 18 carbon atoms. 



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



   The group R2A 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> grouping forms an esterified carboxyl group.  Such organic residues are e.g.  B.  aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic-aliphatic radicals. 



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



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



   A radical R2A which forms a carbamoyl group with a -C (= O> grouping is an optionally substituted amino group in which substituents are optionally substituted monovalent or divalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic , aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms and / or functional groups.  such as optionally functionally modified, in particular free hydroxy, also etherified or esterified hydroxy, in which the etherifying or 

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



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

 

   An acyl group R3 is primarily the acyl radical of an organic carboxylic acid, incl.  Formic acid, such as a cycloaliphatic, cycloaliphatic-aliphatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid, in particular the acyl radical of an aliphatic carboxylic acid, furthermore an aromatic carboxylic acid, and a carbonic acid half derivative. 



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

  B.  by free, etherified or esterified hydroxy or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phenylthio or phenyl-lower alkylthio, optionally substituted lower alkoxycarbonyloxy, optionally substituted lower alkoxycarbonyloxy, or lower alkanitroloxy, amino, optionally substituted by z .  B. 

  Lower alkylamino, di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino or aza-loweralkylenamino, as well as acylamino, such as lower alkanoylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, azido, acyl, such as lower alkanoyl or benzoyl, such as lower alkanoyl or benzoyl, such as lower alkanoyl or benzoyl, such as carboxyl modified, carboxyl in the form of a carboxyl, such as carboxyl, modified in salt form, carboxyl, such as alkanoyl carboxyl, such as carboxyl, such as salt alkanoyl, such as carboxyl, such as carboxyl modified optionally substituted carbamoyl, such as N-lower alkyl- or N, N-di-lower alkylcarbamoyl, also optionally substituted ureidocarbonyl or guanidinocarbonyl, or cyano, optionally functionally modified sulfo, such as sulfamoyl or sulfo present in salt form, or optionally 0-mono- or 0.0 -disubstituted phosphono, wherein substituents z. 

  B.  optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, where unsubstituted or omono-substituted 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 optionally, e.g.  B.  such as an aliphatic radical indicated above, mono-, di- or poly-substituted 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 hydrochloride.  B. 



  mono-, bi- or polycyclic cycloalkyl or cycloalkenyl, also cycloalkylidene, or  Cycloalkyl or cycloalkenyl lower alkyl or lower alkenyl, also cycloalkyl lower alkylidene or cycloalkenyl lower alkylidene, wherein cycloalkyl and cycloalkylidene z.  B.  contains up to 12, such as 3-8, preferably 3-6 ring carbon atoms, while cycloalkenyl z.  B. 



  up to 12, such as 3-8, e.g.  B.  5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic radical z.  B.  can contain up to 7, preferably up to 4 carbon atoms.  The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, e.g.  B.  by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned, optionally substituted lower alkyl groups, or then, e.g.  B.  like the abovementioned aliphatic hydrocarbon radicals, mono-, di- or polysubstituted by functional groups. 



   An aromatic radical, including the aromatic radical of a corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon radical, e.g.  B.  a mono-, bi- or polycyclic aromatic hydrocarbon radical, in particular phenyl, and also biphenylyl or naphthyl, which optionally, for.  B.  such as the above-mentioned aliphatic and dycloaliphatic 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, also phenyl-lower alkylidene, such radicals being e.g.  B.  1-3 phenyl groups and optionally, z.  B.  how the abovementioned aliphatic and cycloaliphatic radicals can be mono-, di- or polysubstituted in the aromatic and / or aliphatic part. 



   Heterocyclic groups, including those in erocyclic-aliphatic radicals, including heterocyclic or heterocyclic-aliphatic groups in corresponding carboxylic acids, are in particular monocyclic, as well as bi-l or polycyclic, aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza -, diaza, triaza or tetrazacyclic radicals of aromatic character, and also corresponding partially or fully saturated radicals, these heterocyclic radicals optionally, z.  B.  like the above-mentioned cycloaliphatic radicals, can be mono-, di- or polysubstituted.  The aliphatic part in heterocyclic-aliphatic radicals has z.  B.  the meaning given for the corresponding cycloaliphatic-aliphatic or araliphatic radicals. 



   The acyl radical of a carbonic acid half derivative is preferably the acyl radical of a corresponding half ester, in which the organic radical of the ester group is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or a heterocyclic-aliphatic radical, primarily the acyl radical of an optionally, z.  B.  in 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.  one of the above-mentioned heterocyclic groups of aromatic character, both the lower alkyl radical and the heterocyclic group may optionally be substituted.  The acyl radical of a carbonic acid half derivative can also be an optionally N-substituted carbamoyl group, such as an optionally halogenated N-lower alkylcarbamoyl group. 



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

 

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



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



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



   Lower alkyl is e.g.  B.  Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, seL-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-E3; utylene, 1,5-pentylene or 1,6-hexylene, while lower alkenylene e.g.  B.  Is 1,2-athenylene or 2-buten-1,4-ylene.  Lower alkylene interrupted by heteroatoms is e.g.  B.  Oxane-lower alkylene, such as 3-oxa-1,5-pentylene, thiane-lower alkylene, such as 3-TI1ia-1,5-pentylene, or aza-lower alkylene, such as 3-lower alkyl 3-a: a-15-pentylene.     z.  B.    3-methyl-3-aza-1,5-pentylene.    



   Cycloalkyl is e.g.  B.  Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl, cycloalke nyl l z.     B.  Cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2 or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl, and cycloalkylidene z.  B.  Cyclopentylidene or cyclohexylidene.  Cycloalkyl-lower alkyl or lower alkenyl is e.g.    B.  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 z.  B.  1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl or 1-, 2- or 3-cycloheptenyl-methyl, -1,1- or -1,2-ethyl, -1,1- , -1,2- or -1,3-propyl, -vinyl or -allyl. 

  Cycloalkyl-ni ederalkyliden is z.  B.  Cyclohexylmethylene, and Cycloal kenylrniederalkyliden z.  B.  3-cyclohexenylmethylene. 



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



     4-Biplienylyl represents Ptlenyl-lower alkyl or phenyl-lower alkenyl is z.  B.  Benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, Diphe nylmethyl, 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, irhienyl, z.  B.  2- or 3-thienyl, or furyl, e.g.  B.  2-furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals, such as indolyl, e.g.  2- or 3-indolyl, quinolinyl, e.g.  B.  2 or 4-IChinolinyl, isoquinolinyl, e.g.  B.    1-isoquinolinyl, benzofuranyl, e.g. .  B.  2- or 3-benzofuranyl, or benzothienyl, e.g.  B.  2 or 3-l3enzothienyl, monocyclic diaza, triaza, tetraza, thiaza, thiadiaza or oxazacyclic radicals, such as imidazolyl, e.g. 

  B.    2-irhidazolyl, 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, oxate: olyl, e.g.  B.  2-oxazolyl, isoxazolyl, e.g.  B.  3-isoxazolyl, thiazolyl, e.g.  B.  2-thiazolyl, isothiazolyl, e.g.  B.  3isothiazolyl 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 oxalzacyclic radicals, such as benzimidazolyl, e.g.  B.  2-benzimidazoll, benzoxazolyl, e.g.  B.  2-benzoxazolyl, or benzthiazolyl, e.g.  B.  2-benzothiazolyl.  Corresponding partially or completely saturated residues are, for.  B. 

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



   Lower alkoxy is e.g.  B.  Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec. -Butyloxy, tert. -Butyloxy, n-pentyloxy or tert. -Pentyloxy.  These groups can be substituted, e.g.  B.  as in halo-lower alkoxy, especially 2-halo-lower alkoxy, e.g.  B.  2,2,2-trichloro-, 2-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, like furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy. 



   Lower alkylthio is e.g.  B.  Methylthio, ethylthio or n-butylthio, lower alkenylthio e.g.  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 t, 3,4-thiadiazoylthio, e.g.  B.    1, 2,4-thiadiazol-3-ylthio or 1,3,4-thiadiazol-2-yl-thio, or tetrazolylthio, e.g.  B.    Are I-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-Trichloräthoxycarbonyloxy, 2-Bromäthoxycar- bonyloxy or 2-) odäthoxyearbonyloxy, or Phenylcarbonylmethoxycarbonyloxy, z.  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. 



     Qiederalkylamino- 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 O-ethylphosphones, O, O-di-lower alkyl-phosphono z.  B.  O, O-dimethylphosphono or O, O-diethylphosphono, O-phenyl-lower alkylphosphono e.g.  B.  O-benzyl-phosphono, and O-lower alkyl-O-phenyl-phosphono, e.g.  B.  O-benzyl-O-methyl-phosphono. 



   Lower alkenyloxycarbonyl is e.g.  B.  Vinyloxycarbonyl, while cycloalkoxycarbonyl and phenylniederalkoxycarbonyl z.  B.  Adamantyloxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl or α4-biphenylyl-α-methyl-ethoxy-carbonyl represents.  Lower alkoxycarbonyl, wherein lower alkyl e.g.  B. 



  contains a monocyclic, monoaza-, monooxa- or monothiacyclic group is, for example     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,% 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-carboxylic acid compound which is naturally occurring or which can be bio-, semi-synthetically or totally synthetically produced, preferably pharmacologically active contained acyl radical of an organic carboxylic acid or an easily cleavable acyl radical, in particular a carbonic acid semi-derivative. 



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

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

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

  B.  esterified or etherified hydroxyl or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, an optionally O-mono- or O, O'-disubstituted phosphono group, an azdio group or a halogen atom, and Grill represents hydrogen, or where n is 1, each of the radicals RI and Ril is a functionally modified, preferably etherified or esterified hydroxy group or an optionally functionally modified carboxyl group, and Rill is hydrogen, or where n is 1, R1 is hydrogen or an optionally substituted aliphatic, cycloaliphatic , cycloaliphatic-aliphatic,

   denotes aromatic or araliphatic hydrocarbon radical and Rll and Rlll together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical connected to the carbon atom by a double bond, or in which n stands for 1, and Rl an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic -aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have an aromatic character, Ril an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical and grill is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. 



   In the above acyl groups of the formula A, for.  B.  n for 0 and Rl for hydrogen or an optionally, preferably in the 1-position by 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, such as halogen, e.g.  Chlorine, lower alkyl containing N-substituted amino group, or n for 1, Rl for a 3-amino-3-carboxy-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, I-imidazolyl or 1-tetrazolyl, an optionally substituted lower alkoxy, e.g.  B.  Methoxy group, an optionally, e.g.  B.  by hydroxy and / or halogen, such as chlorine, substituted phenyloxy group, a lower alkylthio, e.g.  B.  n-butylthio, or lower alkenylthio, e.g.  B.  Allylthio group, an optionally, e.g. 

  B.  by lower alkyl, such as methyl, substituted phenylthio-, 2-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, e.g.  B. 

 

  by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl, e.g.  B.  Acetyl or propionyl, or benzoyl group, or an azido group, and Rll and Grill 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.  B.  tert.  Butyloxycarbonylamino or 2,2,2-Trichloräthoxycarbonyl- amino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or one, optionally in salt z.  B. 

  Alkali metal salt form present sulfoamino group, an azido group, an optionally in salt, z.  B. 



  Alkali metal salt form or in esterified form, e.g.  B.  as lower alkoxycarbonyl, e.g.  B.  Methoxycarbonyl or ethoxycarbonyl group, carboxyl group present, a cyano group, a sulfo group, an optionally functionally modified hydroxyl group, in particular acyloxy, such as formyloxy, and 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 O, O-dimethylphosphono, or a halogen atom e.g.  B.  Chlorine or bromine, and Rlll for hydrogen, or n for 1, Rl and Rll each for halogen, z.  B.  Bromine, or lower alkoxycarbonyl, e.g.  B. 

  Methoxycarbonyl, and grill for hydrogen, or n for 1, and each of the groups Rl, Rll and grill for lower alkyl, z.  B.  Methyl stand. 



   Such acyl radicals Ac are z.  B.  Formyl, cyclopentylcarbonyl, a-aminocyclopentylcarbonyl or a-amino-cyclohexylcarbonyl (with optionally substituted amino group, e.g.  B.  optionally present in salt form sulfoamino group, or one, by a, preferably slightly, z.  B. 



  when treating with an acidic agent, such as trifluoroacetic acid, or with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, an acyl radical which can be split off or which can be converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester such as 2,2,2-trichloroethyloxyearbonyl 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl, phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, as well as amino groups substituted by trityl), 2,6-dimethoxybenzoyl, tetrahydronaphthoyl, 2-methoxy-naphthoyl, 2-ethoxy-naphthoyl, hexoxahydrobenzoyl, hexoxy-carbonyl, methylbenzyl, 3-phenyl4-isoxazolylcarbonyl,

   3- (2-chlorophenyl) -5-methyl4-isoxazolylcarbonyl-, 3 (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, methylthioacetyl, 13ut-lthioacetyl, allylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl or 5-amino-5-carboxylvaleryl (optionally with  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, e.g.  B. 

  Diphenylmethyl ester form, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bismethoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, a-cyanopropionyl, a-cyano-propionyl, a-cyano-3,3-aryl-phenyl-acetyl, 2-cyano-3,3-dimethyl-acetyl, 2-cyano-3,3-dimethyl-acetyl, phenyl, phenyl-phenyl-phenyl, a-phenyl-a-phenyl-phenyl-acetyl, a-phenyl-3,3-arylacetyl, methoxycarbonylacetyl, methoxycarbonylacetyl, 3-chlorophenylacetyl, 4-aminomethylphenyl-acetyl, (with optionally, e.g.  B. 



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

  B.  can be protected by a suitable acyl radical, in particular by formyl or an acyl radical of a carbonic acid half ester) or a. 0. Methyl-phosphono-phenylacetyl or α-0,0-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 you can read above.  substituted amino group), 2-thienylacetyl, 2-tetrahydrothienylacetyl, α-carboxy-2-thienylacetyl or a. Carboxy-3-thienylacetyl (optionally with functional, e.g. 

  B.  as stated above, modified carboxyl group), a-cyano. 2-thienylacetyl, a-amino2-thienylacetyl or a-amino-3-thienylacetyl (optionally with, e.g.  B.  as stated above, substituted amino group), a-sulfo-phenylacetyl (optionally with, z.  B.  such as the carboxyl group, functionally modified sulfo group), 3-thienyl acetyl, 2-furylacetyl, I-imidazolylacetyl, 1-tetrazolylacetyl, 3-methyl. 2-imidazolyl-thioacetyl, 1,2,4-triazol-3-ylthioacetyl,
1,3,4-Triazol-2-ylthioacetyl, 5-methyl-1,2,4-thiadiarol-3-ylthioa- - cetyl, 5-methyl-1,3,4-thiadiazol-2-ylthioacetyl or 1-methyl -5-tetrazolylthioacetyl.    



   An easily cleavable acyl radical Ac, in particular a carbonic acid half-ester, is primarily a reduction, e.g.  B.  when treated with a chemical reducing agent, or by acid treatment, e.g.  B.  with trifluoroacetic acid, cleavable acyl radical of a half ester of carbonic acid, such as a lower alkoxycarbonyl radical, preferably multiply branched in the a-position or substituted by acylcarbonyl, especially benzoyl radicals, or in the p-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 α-phenyl-lower alkoxycarbonyl, in which the α-position is preferably polysubstituted, e.g.  B.  Diphenylmethoxycarbonyl or a4-biphenylyl-a-methyl-ethyloxyearbonyl, or furyl-lower alkoxycarbonyl, primarily a-furyl-lower alkoxycarbonyl, e.g.  B.  Furfuryloxycarbonyl. 



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



   Another divalent radical formed by the groups R1A and Rlb is z.  B.  a, especially in the 2-position, substituted, z.  B.  optionally substituted phenyl or thienyl containing, and optionally in the 4-position by lower alkyl, such as methyl, mono- or disubstituted 1-oxo-3-aza-1,4-butylene radical, e.g.  B.    4,4-dimethyl-2-phenyl-1-oxo-3-aza-1,4-butylene. 

 

   An etherified hydroxy group R2A together with the carbonyl group forms an esterified carboxyl group, preferably easily cleavable or easily converted into another functionally modified carboxyl group, such as a carbamoyl or hydrazinocarbonyl group.  Such a group R2A is e.g.  B.  Lower alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy, which together with the carbonyl grouping forms an esterified carboxyl group which, particularly in 2-cephem compounds, can easily be converted into a free carboxyl group or into another functionally modified carboxyl group. 



   An etherified hydroxy group R2A, which together with a -C (= O) group forms a particularly easily cleavable esterified carboxyl group, is available, for.  B.  for 2-halogen-lower alkoxy, in which halogen preferably has an atomic weight of more than 19.  Such a radical, together with the -C (= O) group, forms a, when treated with chemical reducing agents under neutral or weakly acidic conditions, e.g.  B.  with zinc in the presence of aqueous acetic acid, easily cleavable esterified carboxyl group or an esterified carboxyl group which can be easily converted into such and is z.  B.  2,2,2-trichloroethoxy or 2-iodoethoxy, also 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter. 



   An etherified hydroxy group R2A, which together with the -C (= O) group, also when treated with chemical reducing agents under neutral or weakly acidic conditions, e.g.  B.  when treating with zinc in the presence of aqueous acetic acid, further when treating with a suitable nucleophilic reagent, e.g.  B.  Sodium thiophenolate, easily cleavable esterified carboxyl group, is an arylcarbonylmethoxy group, in which aryl is in particular an optionally substituted phenyl group and preferably phenacyloxy. 



   The group R2A can also stand for an arylmethoxy group, in which aryl is in particular a monocyclic, preferably substituted aromatic hydrocarbon radical.  Such a radical, together with the -C (= O) group, forms an esterified carboxyl group which can be easily cleaved under neutral or acidic conditions on irradiation, preferably with ultraviolet light.  An aryl radical in such an arylmethoxy group contains, as substituents, in particular lower alkoxy, e.g.  B.  Methoxy (which are primarily in the 3-, 4- and / or 5-position in the preferred phenyl radical) and / or especially nitro (in the preferred phenyl radical preferably in the 2-position).  Such radicals are primarily 3- or 4-methoxybenzyloxy, 3,5-dimethoxy-benzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy. 



   An etherified hydroxy group R2A can also represent a radical which, together with the -C (= O) grouping, is an acidic group, e.g.  B.  when treated with trifluoroacetic acid or formic acid, easily cleavable, esterified carboxyl group forms.  Such a radical is primarily a methoxy group in which methyl is substituted by optionally substituted hydrocarbon radicals, in particular aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, e.g.  B. 

  Methyl, or phenyl, polysubstituted or monosubstituted by a carbocyclic aryl group containing electron-donating substituents or a heterocyclic group of aromatic character containing oxygen or sulfur as a ring member, or is then a ring member in a polycycloaliphatic hydrocarbon radical or in an oxa or thiacycloaliphatic radical which denotes the a-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) -2-propyloxy, 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 l-adamantyl, and an above-mentioned oxaoder thiacycloaliphatic radical, in which methyl of the methoxy group is the ring member representing the a-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 radical R2A can also represent an etherified hydroxyl group which, together with the -C (= O) grouping, is a hydrolytic, e.g.  B.  under weakly basic or acidic conditions, cleavable esterified carboxyl group forms.  Such a residue is preferably one with the. C (= O) grouping an activated ester group-forming etherified hydroxy group, such as nitrophenyloxy, z.  B.  4-nitrophenyloxy or
2,4-dinitrophenyloxy, nitrophenyl lower alkoxy, e.g.  B.  4-nitro benzyloxy, polyhalophenyloxy, e.g.  B.  2,4,6-Trichlorpheny loxy or 2,3,4,5,6-pentachlorophenyloxy, also Cyanrnet hoxy, and acylaminomethoxy, z.  B.  Phthaliminomethoxy or succinyliminomethoxy. 



   The group R2A can also be one, together with the carboxyl grouping of the formula -C (= O) - an esterified carboxyl group cleavable under hydrogenolytic conditions, forming an etherified hydroxy group, and is, for.  B. 



   optionally substituted a-phenyl-lower alkoxy, such as benzyloxy, 4-methoxy-benzyloxy or 4-nitrobenzyloxy. 



   The group R2A can also be one, together with the carbonyl group -C (= O) - an esterified carboxyl group cleavable under physiological conditions forming etherified hydroxyl group, primarily Niedeialkanoyloxymethoxy, z.  B.  Acetyloxymethyloxy or pivaloylmethoxy. 



   A silyloxy or stannyloxy group R2A preferably contains optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, cacloalkyl, phenyl or phenyl-lower alkyl groups, and is primarily tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy, or tri-lower alkylstannyloxy, e.g.  B. 



  Tri-n-butylstannyloxy. 



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



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



   A radical R2A which, together with a -C (= O) grouping, forms an optionally substituted carbamoyl or hydrazinocarbonyl group is z.  B.  Amino, lower alkylamino or di-lower alkylamino, such as methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino, e.g.  B. 



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



  Morpholino, hydroxyamino, hydrazino, 2-lower alkylhydrazino or 2,2-di-lower alkylhydrazino, e.g.  B.  2-methylhydrazino or 2,2-dimethylhydrazino. 



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



  Acetyl, propionyl or pivaloyl, such radicals such.  B. 



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

 

   Salts are in particular those of compounds of the formula I having an acidic group, such as a carboxy, sulfo or phosphono group, primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g.  B.  Sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, with primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for the salt formation come into question, such as lower alkylamines, e.g.  B.  Triethylamine, hydroxy lower alkylamines, e.g.  B.  2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g.  B.  4-aminobenzoic acid-2diäthylaminoäthylester, lower alkyleneamines, z.  B.  I-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 Formula 1.  which have a basic group can also 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 second-terionic 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 Rla is an acyl radical Ac occurring in pharmacologically active N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem4-carboxylic acid compounds and Rlb is hydrogen, R2 is hydroxy or one together with the Carbonyl group is an esterified carboxyl group-forming etherified hydroxyl group R2A which is easily cleavable under physiological conditions, 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 1 in which the C, C double bond of the cephem ring is in the 2,3-position, or 1-oxides of compounds of the formula 1 in which the C, C double bond is in the 3,4-position, and in which R > a, R1b, R2A 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 radicals Rla and Rlb represent hydrogen, or Rla is an amino protective group different from the above acyl radical and Rlb is hydrogen, or Rla and Rlb together represent a divalent amino protective group and R2 is hydroxy, or RIQ and Rtb have the meanings given above, R2A is a,

   together with the -C (= 0) grouping represents a preferably easily cleavable, protected carboxyl group-forming radical R2A, and R3 has the meanings given above, are valuable intermediates which can be obtained in a simple manner, e.g.  B.  as described below, can be converted into the above-mentioned pharmacologically active compounds. 



   The 3-cephem compounds of the formula 1, in which Rla 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 of a 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem4-carboxylic acid compound or an easily cleavable acyl radical of an acyl radical Carbonic acid half-derivative, in particular a carbonic acid half-ester, Rlb represents ii hydrogen, R2A represents hydroxy, for optionally, e.g.  B.     - By optionally substituted aryloxy, e.g.  B.    4-methoxy-f phenyloxy, lower alkanoyloxy, e.g.  B.  Acetyloxy or pivaloy- s loxy, 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, optionally substituted by lower alkoxy bis-phenyloxy-met- - - hoxy, z.  B.  Bis4-methoxyphenyloxy-methoxy, phenacyloxy, lower alkanoyloxy-methoxy e.g.  B.  Acetyloxymethoxy or pivaloyloxymethoxy, or 2-halo-lower alkoxy.  z.    B.    



  2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-yo - däthoxy, for optionally substituted phenyl-lower alkoxy, especially 1-phenyl-lower alkoxy, such as phenylmethoxy, such radicals 1-3 optionally, e.g.  B.  substituted by lower alkoxy such as methoxy, nitro or phenyl
May contain phenyl radicals, e.g.  B.  Benzyloxy, 4-methoxybenzyloxy, 2-biphenylyl-2-pyropyloxy, 4-nitro-benzyloxy, diphenylmethoxy, 4,4-dimethoxydiphenylmethoxy or trityloxy, for acyloxy, such as lower alkoxycarbonyloxy, e.g.  B.  Methoxycarbonyloxy or Äthoxycarbonyloxy, or Niederalkanoy- loxy, z.  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 alkanoyl, e.g.  B.  Acetyl or propionyl, and optionally, z.  B.  by lower alkyl such as methyl, lower alkoxy, e.g.  B.  Methoxy, or halogen, e.g.  B.  Represents fluorine or chlorine, substituted benzoyl, and the l-oxides thereof, furthermore the corresponding 2-cephem compounds, or salts of such compounds with salt-forming groups. 



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



  naturally occurring) or biosynthetically producible N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds, such as an optionally substituted phenylacetyl or phenyloxyacetyl radical, and an optionally substituted lower alkanoyl - or lower alkenoyl radical, e.g.  B. 



  4-hydroxyphenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl, and in particular 5-amino-5-carboxy-valeryl, in which the amino and / or the carboxyl group are optionally protected and e.g.  B.  as acylamino or  esterified carboxyl are present, phenylacetyl or phenyloxyacetyl, or an acyl radical occurring in highly effective N-acyl derivatives of 6ss-amino-pennam-3-carboxylic acid or 7ss-amino-3-cephem4-carboxylic acid compounds, such as formyl, 2-chloroethylcarbamoyl , Cyanoacetyl, 2-thienylacetyl or l-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 wherein the amino group is optionally substituted and z.  B.  represents an optionally present in salt form sulfoamino group or an amino group which, as substituents, is a hydrolytically cleavable trityl group or an optionally substituted carbamoyl, such as an optionally substituted ureidocarbonyl group, e.g.  B.  Ur eidocarbonyl or N'-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group z.  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 which 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-chloroethoxycarbonyl.  2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl or phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, or in which the amino group is connected to the nitrogen atom of the 7ss-amino group by a methylene group, optionally lower alkyl, such as two methyls, and also thienylglycyl, such as 2-thienylglycyl (optionally with, e.g. 

  B.  as stated above, substituted amino group), or l-amino-cyclohexylcarbonyl (optionally with, z.  B. 



  as stated above, substituted amino group), also α-carboxy-phenylacetyl or α-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), a-sulfo-phenylacetyl (optionally with, z.  B.  such as the carboxyl group, functionally modified sulfo group), a-phosphono, a-0-methylphosphono or a-0,0-dimethyl-phosphono-phenylacetyl, or a-hydroxyphenylacetyl (optionally with a functionally modified hydroxy group, in particular with an acyloxy group wherein acyl is one, preferably slightly, e.g. 

  B.  when treating with an acidic agent such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, an acyl radical that can be split off or converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as 2,2,2-trichloroethoxycarbonyl, 2 -Chloräthoxycarbonyl, 2-bromoethoxycarbonyl, 2-Jodäthoxycarbonyl, tert. -Butyloxycarbonyl or Phenacyloxycarbonyl, also means formyl), z.  B. 



  for an acyl radical of the formula A, and R> b for hydrogen, and R2A represents hydroxy, lower alkoxy, in particular α-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, z.  B.  2,2,2-trichloroethoxy, 2-iodoethoxy or the easily convertible into this 2-chloroethoxy or 2-bromoethoxy, phenacyloxy, I-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 alkanoyl, e.g.  B.  Acetyl or propionyl, or benzoyl. 



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



  tert. -Butyloxycarbonyl or 2,2,2-Trichloräthoxycarbonyl, can be protected, and 2-thienyl is, X is oxygen or sulfur, n is 0 or 1, and R is hydrogen or, if n is 0, optionally protected amino, such as acylamino, e.g.  B.  a-polybranched lower alkoxycarbonylamino, such as tert. -Butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g.  B.  2,2,2-Trichloräthoxycarbonylamino, 2-Jodäthoxycarbonylamino or 2-Bromäthoxycarbonylamino, or 3-Guanylureido, also sulfoamino or tritylamino, optionally protected carboxy, z.  B. 



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



  Diphenylmethoxycarbonyl, optionally protected sulfo, as in alkali metal, e.g.  B.  Sodium salt form, sulfo present, optionally protected hydroxy such as acyloxy e.g.  B.  a-polybranched lower alkoxycarbonyloxy, such as tert. - Butyloxycarbonyloxy, or 2-Halogenniederalkoxycarbonyloxy, such as 2,2,2-Trichloräthoxycarbonyloxy, 2-Jodäthoxycarbonyloxy or 2-Bromäthoxycarbonyloxy, also formyloxy, or 0-Niederalkylphosphono or 0,0-Diiederalkylphosphono, z.  B.  0-methylphosphono or 0,0-dimethylphosphono, or a 5-amino-5-carboxy-valeryl radical, wherein the amino and / or carboxy group are optionally protected and z.  B.  as acylamino, e.g.  B.  Lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, or phthaloylamino, or  as an esterified carboxy, such as phenyl-lower alkoxycarbonyl, e.g.  B. 



  Diphenylmethoxycarbonyl, R2A is hydroxy, lower alkoxy, especially α-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, 2-halo-lower alkoxy, e.g.  B.  2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally, e.g.  B.  by lower alkoxy, e.g.  B.  Methoxy, substituted diphenylmethoxy, e.g.  B.  Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, and R3 is lower alkanoyl, e.g.  B.  Acetyl or propionyl, also denotes the corresponding 2-cephem compounds, or salts of such compounds with salt-forming groups. 



   In 3-cephem compounds of the formula 1, which are to be designated as particularly valuable, and also in corresponding 2-cephem compounds, Rla stands for hydrogen, for the acyl radical of the formula B, where Ar is phenyl, X is oxygen, n is 0 or 1, and R is hydrogen or when n 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-Trichloräthoxycarbonylamino, 2-Jodäthoxycarbonylamino, or 2-Bromäthoxycarbonylamino, optionally protected hydroxy, such as acyloxy, z.  B.  a-polybranched lower alkoxycarbonyloxy, such as tert; Bu tyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, furthermore formyloxy-or 0-di-lower alkyl or 0-di-lower alkyl z.  B.  0-methylphosphono or 0,0-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 phenyl-lower alkoxycarbonyl, e.g.  B.  Diphenylmethoxycarbonyl, R> b represents hydrogen, R2A denotes hydroxy, optionally halogen in the 2-position, e.g.  B.  Chlorine-, bromine- or iodine-substituted lower alkoxy, in particular α-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, or 2-halo-lower alkoxy, e.g.  B. 



  2,2,2-trichloroethoxy, 2-iodoethoxy or Z-bromoethoxy, or optionally lower alkoxy, such as methoxy-substituted diphenylmethyloxy, e.g.  B.  Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, and R3 means lower alkanoyl, e.g.  B.  Acetyl. 



   The compounds of the formula 1, as well as 1-oxides thereof in which the C, C double bond is in the 3,4-position, and salts thereof are obtained by reacting in a 3-cephem-3-ol compound of the formula
EMI9. 1
 or in a 1-oxide thereof, the 3-hydroxy group is converted by acylation into a group of the formula -O-R3, and a compound obtained is isolated as a salt or in free form. 



   In a starting material of the formula II, R2A is preferably a, with the -C (= O) grouping an, in particular under mild conditions, cleavable, esterified carboxylgruppe-forming, etherified hydroxy group R2A, with any functional groups present in a carboxyl protecting group R2A in a manner known per se, e.g.  B.  as stated above, may be protected.  A
Group R2A is e.g.  B.  in particular an optionally halogen-substituted lower alkoxy group, such as a-polybranched
Lower alkoxy, e.g.  B.    tert; butyloxy, or 2-halo-lower alkoxy, wherein halogen z.  B.  Represents chlorine, bromine or iodine, primarily 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, or an optionally substituted one, such as Niederal koxy, z.  B.  Methoxy, or nitro-containing 1-Phenylniederal koxygruppe, such as optionally, z. 

  B.  as indicated, substituted benzyloxy or diphenylmethoxy, e.g.  B.  Benzyl, 4-Met hoxybenzyl, 4-Nitrobenzyl, Diphenylmethoxy or 4,4-Dimethoxy-diphenylmethoxy, also an organic silyloxy or
Stannyloxy group such as tri-lower alkylsilyloxy, e.g.  B.  Trimethyl silyloxy.  In a starting material of the formula II, the radical Rla preferably denotes an amino protective group R1A, such as an acyl group Ac, in which any free functional groups present, e.g.  B.  Amino, hydroxycarboxyl or phosphono groups, in a manner known per se, amino groups e.g.  B.  by acylating, tritylating, silylating or stannylating, and hydroxy, carboxy or phosphono groups, e.g.  B.  by etherification or esterification, incl.  Silylating or stannylating, and R1b hydrogen. 



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



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



   Enol esters of the formula 1, in which R3 stands for an acyl group, are obtained by any process suitable for esterifying enol groups, at least Rla in the starting material of the formula II being different from hydrogen, if one does not want to risk simultaneous acylation of a free amino group.  Carboxylic acids of the formula R3-OH (V) corresponding to the acyl radical R3 or reactive acid derivatives thereof, such as halides, e.g.  B.  Fluorides or chlorides, also pseudohalides, such as cyanocarbonyl compounds corresponding to the carboxylic acids, or anhydrides (including the internal anhydrides of carboxylic acids, i.e.  H.  Ketenes, or from carbamic or thiocarbamic acids, d.  H.  Isocyanates or isothiocyanates, or mixed anhydrides, such as those which z.  B.  with haloformic acid lower alkyl, such as chlorine. 



  formic acid ethyl esters or isobutyl esters, or can be formed with trichloroacetic acid chloride, are to be understood), or activated esters, such as esters with vinylogous alcohols (d.  H.  Enols), e.g.  B.  Esters of lower alkanecarboxylic acids with vinylogous lower alkanols (enol form of lower alkanols or lower alkanols), e.g.  B.  with isopropenyl acetate, if necessary, in the presence of suitable condensing agents, when using acids z.  B.  of carbodiimide compounds such as dicyclohexylcarbodiimide, or carbonyl compounds such as diimidazolylcarbonyl, when using reactive acid derivatives z.  B.  of basic agents such as tri-lower alkylamines, e.g.  B.  Triethylamine, or heterocyclic bases, e.g.  B.  Pyridine, and when using esters with vinylogous alcohols in the presence of an acidic agent such as a mineral, e.g.  B. 

  Sulfuric acid or a strong sulphonic, e.g.  B.  p-toluenesulfonic acid, works. 



   The acylation reaction can be carried out in the absence or in the presence of a solvent or solvent mixture, with cooling, at room temperature or with heating, and, if necessary, in a closed vessel and / or in an inert gas, e.g.  B.  Nitrogen atmosphere.  Suitable solvents are e.g.  B.  optionally substituted, in particular optionally chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as benzene or toluene, it also being possible to use suitable esterification reagents, such as acetic anhydride, as diluents. 



   In the process according to the invention and in any additional measures to be carried out, if necessary, free functional groups not participating in the reaction can be present in the starting materials or in the compounds obtainable according to the process, e.g.  B.  free amino groups e.g.  B.  by acylation, tritylation or silylation, free hydroxyl or mercapto groups e.g.  B.  by etherification or esterification, and free carboxyl groups e.g.  B.  through esterification, incl.  Silylation, temporarily protected in a manner known per se and each time after the reaction has taken place, if desired, are released in a manner known per se. 



   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) -R2A, this can be carried out in a manner known per se, e.g.  B.  depending on the type of group R2A, can be converted into the free carboxyl group.  An esterified, 2. B.     carboxyl group esterified by a lower alkyl radical, in particular methyl or ethyl, in particular in a 2-cephem compound of the formula 1, 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 mu 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 mull if 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 treatment 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 a conventional manner, for.  B.  can be released by treatment with water or an alcohol. 



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



   In a compound obtained, e.g.  B.  an amino protective group RIA or  Rlb, in particular an easily cleavable acyl group, in a manner known per se, for.  B.  an α-polybranched lower alkoxycarbonyl group, such as tert. -Butyloxycarbonyl, by treatment with trifluoroacetic acid and a 2-halo-lower alkoxycarbonyl group, such as 2,2,2-trichloro ethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treatment with a suitable reducing metal or corresponding metal compound, e.g.  B.  Zinc, or a chromium (II) compound, such as chloride or acetate, can advantageously be split off in the presence of a hydrogen-generating agent nascent together with the metal or the metal compound, preferably in the presence of hydrous acetic acid. 

  Furthermore, in a compound of formula 1 obtained in which a carboxyl group of the formula -C (= 0) -R2A is preferably one, e.g.  B.  by esterification, including by silylation, e.g.  B.  by reacting with a suitable organic halosilicon or halotin IV compound, such as trimethylchlorosilane or tri-n-butyltin chloride, is a protected carboxyl group, an acyl group RIA or Grab, in which any free functional groups that may be present are optionally protected, by treatment with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleavage of the imino ether formed, with a protected, e.g.  B.  a carboxyl group protected by an organic silyl radical can be released during the reaction. 



   Imide halide-forming agents in which halogen is bonded to an electrophilic central atom are primarily acid halides, such as acid bromides and especially acid chlorides.  These are primarily acid halides of inorganic acids, especially phosphorus-containing acids, such as phosphorus oxy-, phosphorus tri- and especially phosphorus petahalides, e.g.  B.  Phosphorus oxychloride, phosphorus trichloride, and primarily phosphorus pentachloride, also pyrocatechyl phosphorus trichloride, and acid halides, in particular chlorides, of sulfuric acids or of carboxylic acids such as thionyl chloride, phosgene or oxalyl chloride. 



   The reaction with one of the mentioned 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.  Tri methyl, triethyl or ethyldiisopropylamine, also an N, N, N ', N'-tetraniederalkyl-lower alkylenediamine, e.g.  B. 



     N, N, N ', N'. Tetramethyl-1,5-pentylenediamine or N, N, N ', N'-Te tramethyl-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-methyl-piperidine or N-methyl-morpholine, also 2,3,4,6,7,8-hexahydro-pyrrolo [1, 2-a] pyrimidine (diazabicyclonones; DBN), or a tertiary aromatic amine, such as one Di-lower alkyl aniline, e.g.  B.  N, N-dimethylaniline, or primarily a tertiary heterocyclic, mono- or bicyclic base such as quinoline or isoquinoline, especially pyridine, preferably in the presence of a solvent such as an optionally halogenated, e.g.  B.  chlorinated, aliphatic or aromatic hydrocarbon, e.g.  B. 



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



   The reaction with the imide halide forming agent is preferably carried out with cooling, e.g.  B.  carried out at temperatures of about -50 "C to about +10" C, but also at higher temperatures, d.  H.  z.  B.  up to about 75 C, if the stability of the starting materials and products allow an elevated temperature. 



   The imide halide product, which is usually processed further without isolation, is, according to the process, reacted with an alcohol, preferably in the presence of one of the abovementioned bases, to give the imino ether.  Suitable alcohols are e.g.  B.  aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, 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 iminoether 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.  It is preferable to use water or an aqueous mixture of an organic solvent such as an alcohol, especially a lower alkanol, e.g.  B.  Methanol.  One usually works in an acidic medium, e.g.  B.  at a pH of about 1 to about 5 which, if necessary, can be obtained by adding a basic agent such as an aqueous alkali metal hydroxide, e.g.  B.  Sodium or potassium hydroxide, or an acid, e.g.  B.  a mineral acid, or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, trifluoroacetic acid or p-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 formula 1 is obtained in which both radicals Rla and Rlb are acyl groups . 



   In a compound of formula 1 in which both radicals Rla and R> b represent acyl groups, one of these groups, preferably the less sterically hindered one, e.g.  B.  by hydrolysis or aminolysis, can be selectively removed. 



   In a compound of formula 1 in which R> A and Rlb together with the nitrogen atom represent a phthalimido group, this can, for.  B.  by hydrazinolysis, d.  H.  when treating such a compound with hydrazine, are converted into the free amino group. 



   Certain acyl radicals R1A of an acylamino group in compounds obtainable according to the invention, such as.  B.  the 5-amino-5-carboxy-valeryl radical in which carboxyl, e.g.  B.  by esterification, especially by diphenylmethyl, and / or the amino group, e.g.  B.  by acylation, especially by halo-lower alkanoyl, such as dichloroacetyl, can also be protected by treatment with a nitrosating agent such as nitrosyl chloride, with a carbocyclic arene diazonium salt such as benzene diazonium chloride, or with a positive halogen-releasing agent such as an N-halo-amide or imide, e.g.    B N-bromosuccinimide, preferably in a suitable solvent or solvent mixture,

   such as formic acid together with a nitro or cyano-lower alkane and treatment of the reaction product with a hydroxyl-containing agent such as water or a lower alkanol, e.g.  B.  Methanol, or, if the amino group is unsubstituted in the 5-amino-5carboxy-valeryl radical RIA and the carboxy group z.  B.  is protected by esterification, and R1b is preferably an acyl radical, but can also mean 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 RIA 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 acid, e.g.  B.  Hydrochloric acid. 



   In a compound of formula 1 obtained in which R1a and R1b are hydrogen, the free amino group can be obtained by acylation methods known per se, eg.  B. 



  by treating with carboxylic acids or reactive acid derivatives thereof such as halides, e.g.  B.  Fluorides or chlorides, also pseudohalides, such as cyanocarbonyl compounds corresponding to the acids, or anhydrides (including the internal anhydrides of carboxylic acids, i.e.  H.  Ketenes, or from carbamic or thiocarbamic acids, d.  H.  Isocyanates or isothiocyanates, or mixed anhydrides, such as those which z.  B.  with haloformic acid lower alkyl esters, such as ethyl chloroformate 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-dia. 



  cylamine, 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 1 in which R2 is a hydroxyl group can start. 



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



  by treating a compound in which R> a- and Rlb are hydrogen with an aldehyde such as an aliphatic, aromatic or araliphatic aldehyde) stands, e.g.  B.  acylated by the methods given above, and the acylation product, preferably in a neutral or weakly acidic medium, hydrolyzed. 



   An acyl group can also be introduced in stages.  So you can z.  B.  in a compound of formula I with a free amino group a halo-lower alkanoyl, z.  B.  Bromoacetyl group, or e.g.  B.  by treating with a carbonic acid dihalide such as phosgene, a halocarbonyl; z.  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.  13.  2-mercapto-1-methyl-imidazole, or metal salts, e.g.  B.  Sodium azide or  Alcohols such as lower alkanols, e.g.  B.  tert. -Butanol, convert and so to substituted N-lower alkanoyl or  N-hydroxycarbonylamino compounds arrive.  Furthermore, you can z. 

  B.  a compound of formula 1, wherein Rla is a glycyl group, preferably substituted in the α-position, such as phenylglycyl, and Rlb 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 RXA and Rlb together represent a 5-oxo-1,3diaza-cyclopentyl radical which is preferably substituted in the 4-position and optionally substituted in the 2-position. 



   In both reactants, free functional groups can be temporarily protected in a manner known per se during the acylation reaction and can be released after the acylation by methods known per se.  So you can preferably z.  B.  Amino, hydroxy, carboxyl or phosphono groups in the acyl radical during the acylation reaction, for.  B.  in the form of acylamino, such as 2,2,2-trichloroethoxycarbonylamino- 2-bromoethoxycarbonylamino or tert-butyloxycarbonylamino groups, from acylo xy, z.  B.    2,2,2-Trichloräthoxycarbonyloxy- or 2-Bromoäthoxycarbonylgruppen, of esterified carboxy, such as diphenylmethoxycarbonyl groups, or  0,0-disubstituted phosphono; such as 0,0-di-lower alkylphosphono-, e.g.  

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



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



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



   An amino group can also be protected by introducing a silyl and stannyl group.  Such groups are introduced in a manner known per se, e.g.  B.  by treatment with a suitable silylating agent such as a dihalodin lower alkyl silane or tri lower alkyl silyl halide, e.g.  B.  Dichloro-dimethylsilane or trimethyl-silyl chloride, or an optionally N-mono-lower alkylated, N, N-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated, N- (tri-lower alkyl-silyl) amine, (see e.g. .  B.  British patent no.  1,073,530), or with a suitable stannylating agent such as a bis (tri-lower 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 publication 67/17107). 



   In a compound of formula 1 obtainable according to the process which contains a free carboxyl group of formula -C (= 0) -RA, such a carboxyl group can be converted into a protected carboxyl group in a manner known per se.  So you get z.  B.  by treating with a suitable diazo compound, such as e.g.  B.  Diazomethane, if necessary, in the presence of a Lewis acid, such as.  B.  Boron trifluoride or by reaction with an alcohol suitable for esterification in the presence of an esterification agent such as a carbodiimide, e.g.  B.  Dicyclohexylcarbodiimide and carbonyldiimidazole, furthermore with an N, N'-disubstituted O- or 



  S-substituted isourea or isothiourea, in which a 0- and S-substituent e.g.  B.  Lower alkyl, especially tert. -Butyl, phenyl-lower alkyl or cycloalkyl, and N- or  N 'substituents e.g.  B.  Lower alkyl, especially isopropyl, cycloalkyl or phenyl, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, and a strong organic sulfonic acid, an ester.  Furthermore can
Acid halides, such as chlorides (manufactured e.g.  B.  by treating with oxalyl chloride), activated esters (formed e.g.  B.  With
N-hydroxy nitrogen compounds, such as N-hydroxy-succinic mid) or mixed anhydrides (obtained e.g. 

  B.  with halogenated lower alkyl esters, such as ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride) by reacting with alcohols, optionally in the presence of a
Base, such as pyridine, can be converted into an esterified carboxyl group. 



   In a compound obtained with an esterified group of the formula -C (= 0) -RA, this can be converted into another esterified carboxy group of this formula, e.g.  B.    2-Chloräthoxyearbonyl or 2-Bromäthoxycarbonyl by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable solvent, such as acetone, in 2-Jodäthoxycarbonyl. 



   Mixed anhydrides can be made.    



  a compound of the formula I with a free t group of the formula -C (= 0) -R2, preferably a salt, in particular an alkali metal, z.  B.  Sodium, or ammonium.    



  z.  B.  Triethylammonium salt thereof with a reactive derivative such as a halide, e.g.  B.  the chloride, an acid, e.g.  B.  e i 13.  H a lower alkyl haloformate or a lower alkanecarboxylic acid chloride. 



   In a compound obtainable according to the process with a free carboxyl group of the formula -C (= 0) -R2A, such a group can also be converted into an optionally substituted carbamoyl or hydrazinocarbonyl group, preferably reactive, functionally modified derivatives, such as the above-mentioned acid halides, generally esters, as well as the above-mentioned activated esters or mixed anhydrides of the corresponding acid with ammonia or amines, including hydroxylamine, or hydrazines. 



   A carboxyl group protected by an organic silyl or stannyl group can be formed in a manner known per se, e.g.  B.  by using compounds of formula 1 in which R2 is hydroxy, or salts such as alkali metal, e.g.  B.  Sodium salts thereof treated with a suitable silylating or stannylating agent such as one of the aforementioned silylating or stannylating agents; see e.g.  B.  British patent no.  1 073 530 or  Dutch publication Nn 67/17107. 



   Furthermore, modified functional substituents in groups R1A, R1b and / or R2A, such as acylated amino groups, acylated hydroxy groups, esterified carboxy groups or 0,0-disubstituted phosphono groups, according to methods known per se, eg.  B.  the above-described, release, or free functional substituents in groups RIA, Rlb and / or R2A, such as free amino, hydroxy, carboxy or phosphono groups, according to methods known per se, e.g.  B. 



  Acylating or  Esterify or  Substitute, modify functionally.  So z.  B.  an amino group by treatment with sulfur trioxide, preferably in the form of a
Complex with an organic base such as a tri-lower alkylamine, e.g.  B.  Triethylamine, convert into a sulfoamino group.  Furthermore, the reaction mixture of an acid addition salt of 4-guanylsemicarbazide with sodium nitrite with a compound of formula 1, wherein z.  B.  the amino protective group R> A represents an optionally substituted glycyl group, convert and thus convert the amino group into a 3-guanylureido group.  Furthermore, you can compounds with aliphatically bonded halogen, for. 

  B.  with an optionally substituted a-bromo-acetyl grouping, with esters of phosphorous acid, such as tri-lower alkyl phosphite compounds, and thus arrive at corresponding phosphono compounds. 



   A mixture of a compound of the formula I and the corresponding l-oxide obtainable according to the process can be separated with the aid of suitable separation methods, e.g.  B.  by chromatography (column, paper or plate chromatography) using suitable adsorbents, such as silica gel or aluminum oxide, and eluents, further by fractional crystallization, solvent distribution, etc.  be separated.  Furthermore, a mixture of a compound of the formula I and the corresponding l-oxide can either be oxidized directly to either the l-oxide or reduced to a 3-cephem compound of the 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 using an 1-oxide as an intermediate. 



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



   Obtained cephem compounds can be isomerized.  Thus obtained 2-cephem compounds of the formula 1, in which the double bond is in the 2,3-position, can be converted into the corresponding 3-cephem compounds of the formula 1, in which the C, C-double bond is in the 3,4-position, by a 2-cephem compound of formula 1, wherein free functional groups optionally, z.  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 (= 0) -RA 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 agent and isolating the corresponding 3-cephem compound of the formula I. 



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



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



   The above isomerization with basic agents can, for.  B.  in the presence of a derivative of a carboxylic acid suitable for 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 -30 "C to about +100 "C, in an inert gas, e.g.  B.  Nitrogen atmosphere and / or in a closed vessel. 



   The 3-cephem compounds of the formula 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 available isomer mixture of the 1-oxides from 3-cephem compounds of the formula I, and the l- Oxides of the corresponding 3-cephem compounds reduced. 



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



  with a dissociation constant of at least 10-5.  Suitable inorganic peracids are periodic and persulfuric acid.  Organic peracids are corresponding 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 / 0 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 10/0 to about 20%, larger excesses also being used, ie.  H.  up to 10 times the amount of the oxidizing agent or more.  The oxidation is carried out under mild conditions, e.g. 

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



   In the l-oxides of 3-cephem compounds of the formula 1 obtainable in this way, especially in those compounds in which Rla, R> b and R2 have the preferred meanings given above, the groups R> a, Rlb and / or R2A be guided, split off or introduced into one another within the inserted frame.  A mixture of isomers a- and -I-oxides can, for.  B.  chromatographically, be separated. 



   The reduction of the l-oxides of Ceph-3-em compounds of the formula I can be carried out in a manner known per se by treating with a reducing agent, if necessary, in the presence of an activating agent. 

 

   Possible reducing agents are: catalytically activated hydrogen, noble metal catalysts being used which contain palladium, platinum or rhodium and which are optionally used together with a suitable carrier material such as carbon or barium sulphate; reducing tin, iron, copper or Mangankatio NEN, which in the form of appropriate compounds or complexes of inorganic or organic nature, z.  B. 



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

  Sodium or potassium dithionite, sodium or potassium iodide or iron-II-cyanide, or in the form of the corresponding acids, such as hydriodic acid, can be used; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, also esters, amides and halides of phosphinous, phosphonous or phosphorous acid, as well as phosphorus-sulfur compounds corresponding to these phosphorus-oxygen compounds, in which organic radicals are primarily aliphatic, aromatic or araliphatic radicals, e.g.  B.  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, in particular chlorides or bromides, in which the iminium group is substituted by one divalent or two monovalent organic radicals, such as optionally substituted lower alkylene or lower alkyl groups, such as N-chloromethylene-N, N-diethyliminium chloride or N-chloromethylene pyrrolidinium chloride; and complex metal hydrides such as sodium borohydride in the presence of suitable activating agents such as cobalt II chloride. 



   Activating agents which are used together with those of the above-mentioned reducing agents which themselves do not have Lewis acid properties, d.  H.  Which are primarily used together with the dithionite, iodine or iron-II cyanide and the non-halogen-containing trivalent phosphorus reducing agents or in the catalytic reduction, are in particular organic carboxylic and sulfonic acid halides, also sulfur, phosphorus or Silicon halides with the same or greater second order hydrolysis constant than benzoyl chloride, e.g.  B. 

  Phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride; Pivalic acid chloride, 4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride, p-toluenesulphonic acid chloride, methanesulphonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenephosphonous acid dichloride, furthermore suitable sylorosil anhydride, cycloric acid dichloride,, furthermore, sylorosil anhydride, dimethylchlorosil anhydride,, furthermore, trichluorosil anhydride,, furthermore, sylorosil anhydride,, furthermore, trichluorosil anhydride,, furthermore, sylorosil anhydride,, like Propane sultone, 1,4-butane sultone or 1,3-hexane sultone. 



   The reduction is preferably carried out in the presence of solvents or mixtures thereof, the selection of which is primarily determined by the solubility of the starting materials and the choice of reducing agent, e.g.  B.  Lower 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.  Usually, temperatures of about -20 ° C. to about 100 ° C. are used, and the reaction can be carried out at lower temperatures when using very reactive activating agents. 



   In the 3-cephem compounds of the formula I obtainable in this way, Rla, Rlb and / or R2A can, as described above, be converted into other groups Rla, R> a, R1b or  R2A must be transferred, whereby it must be ensured that the 3-cephem compounds are significantly more sensitive to alkaline agents than the corresponding 2-cephem compounds. 



   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 acids, e.g.  B.  form 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 the usual way, e.g.  B.  by treatment with an acid or a suitable anion exchange reagent.  Internal salts of compounds of formula 1 which contain a salt-forming amino group and a free carboxyl group can, for. 

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



   Salts can be converted into the free compounds in the usual way, metal and ammonium salts z.  B. 



  by treatment with suitable acids, and acid addition salts e.g.  B.  by treating with a suitable basic agent. 



   Mixtures of isomers obtained can be separated into the individual isomers by methods known per se, mixtures of diastereomeric isomers, for.  B.  by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation processes.  Racemates obtained can be used in a customary manner, if appropriate 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 method also includes those embodiments according to which compounds obtained as intermediate products are used as starting materials and the remaining method steps are carried out with these, or the method 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
EMI15. 1
 where R> a preferably stands for an amino protective group RIA, and where R2A preferably stands for hydroxy, but also stands for another group R2A, the acetyloxymethyl group, e.g.  B.  converted into the hydroxymethyl group by hydrolysis in a weakly basic medium, such as with an aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase, such as a corresponding enzyme from Rhizobium tritolii, Rhizobium lupinii, Rhizobium japonicum or Bacillus subtilis functionally modifies free carboxyl group of the formula -C (= 0) -R2A 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 iodizing agents such as N-methyl-N, N'-dicyclohexyl-carbodiimidium iodide, in a halomethyl z.  B.  Chloromethyl or  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 can be used e.g. 

  B.  by treating the chloromethyl compound with a metal iodide such as sodium iodide in a suitable solvent such as acetone), and the iodomethyl group converted to the methylene group by treatment with a suitable reducing agent such as zinc in the presence of acetic acid.  The methylene group in a compound of the formula
EMI15. 2
 is oxidatively degraded using the process described below; in such a obtainable Cepham-3-one compound.  in which both radicals Rla and R> b are hydrogen. 



  the free amino group can be replaced by an appropriate protecting 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 -90 "C to about +40 C.    



   An ozonide formed as an intermediate is split reductively, using catalytically activated hydrogen, e.g.  B.  Hydrogen in the presence of a heavy metal hydrogenation catalyst, such as a nickel catalyst, and also a palladium catalyst. 



  preferably on a suitable carrier material such as calcium carbonate or carbon, or chemical reducing agents. 



  like reducing heavy metals, incl.  Heavy metal alloys or amalgams, e.g.  B.  Zinc, in the presence of a hydrogen donor such as an acid, e.g.  B.  Acetic acid, or an alcohol, e.g.  B.  Lower alkanol.  reducing inorganic salts such as alkali metal iodides, e.g.  B.  Sodium iodide, in the presence of a hydrogen donor such as an acid, e.g.  B.  Acetic acid, or reducing organic compounds such as formic acid, a reducing sulfide compound such as a di-lower alkyl sulfide, e.g.  B.  Dimethyl sulfide, a reducing organic phosphorus compound, such as a phosphine, which can contain optionally substituted aliphatic or aromatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphines, e.g.  B.  Tri-n-butylphosphine, or triarylphosphines, e.g.  B. 

  Triphenylphosphine, also phosphites which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphites, usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphorous acid triamides, which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as hexane-lower alkyl phosphorous acid triamides .  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, normally takes place under the conditions that are used for its production, i.e.  H.  in the presence of a suitable solvent or solvent mixture, and with cooling or gentle heating. 



   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 separated into the compound of the formula II and the corresponding l-oxide, or it can be oxidized to the uniform l-oxide of a compound of the formula I. 



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



   Furthermore, a mixture of a compound of the formula II and an l-oxide thereof obtainable according to the process can also be oxidized directly to the l-oxide of a compound of the formula II, the oxidizing agents described above being used to prepare l-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 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.  can be used for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for enteral or, preferably, parenteral administration.  So you use tablets or gelatin capsules, which the active ingredient together with diluents, eg.  B.  Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g.  B. 



  Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g.    B. Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g.  B.  Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, colorants, flavorings and sweeteners.  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, sugar-coating, dissolving or lyophilizing processes and containing from about 0.1 0/0 to 100/0, in particular from about 1 0/0 to about 50/0, lyophilisates up to 100/0 0 of the active ingredient. 



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



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



  example 1
A solution of 0.50 g of 3-methylene-7ss-phenylacetylamino-cepham-4a-carboxylic acid diphenylmethyl ester in 50 ml of methanol is treated at -70 "with an oxygen-ozone mixture until it begins to turn blue.  The excess ozone is driven off with nitrogen and the reaction mixture, containing a mixture of the 7ss-phenylacetylamino-cepham-3-one-4a-carboxylic acid diphenylmethyl ester and the 7 8 phenyl acetylamino-cepham-3-one-4 a - carboxylic acid diphenylmethyl ester I-oxyds, 0.5 ml of dimethyl sulfide is added and the mixture is stirred at room temperature for 1 k hours. 

  It is then evaporated to dryness under reduced pressure, the residue is taken up in 10 ml of pyridine, 5 ml of acetic anhydride are added and the mixture is left to stand at 0 for 16 hours. 



  It is evaporated to dryness under high vacuum; the residue is taken up in ethyl acetate and the organic solution is 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 residue is chromatographed on 30 g of silica gel, the 3-acetyloxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester being eluted with a 4: 1 mixture of toluene and ethyl acetate.  The product is crystallized from a mixture of acetone and diethyl ether, F. 



     158-160; Ultraviolet absorption spectrum (in 950/0 aqueous ethanol): λ max = 258 mu (± = 6580) and 264 mu (e = 6550); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95 u 5.59 pL, 5.69 u (shoulder), 5.78 u 5.91 I1, 6.06 u (shoulder) and 6.67 u.    



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

  The solution is mixed with excess diphenyldiazomethane, left to stand for 3 hours at room temperature and then the granular crystalline precipitate is filtered off. 



   The filtrate is concentrated to about 200 ml, cyclohexane is added while warm and, after cooling to room temperature, left to stand at about 4 "for some time.  The precipitate is filtered off and recrystallized from a mixture of acetone and cyclohexane; the 3-hydroxymethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester thus obtained melts at 176-176.50 (uncorr. ); [a] D20 = -6 "* 10 (c = 1.231 0/0 in chloroform); thin-layer chromatogram (silica gel; detection with iodine vapor or ultraviolet light B254m, 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). 



   Dissolve 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 under a nitrogen atmosphere in 25 ml of absolute tetrahydrofuran and heated for a 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 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 according to     5.62 lt.     5. 82 lt, 5.95 lt.     6.70 lt.    



     7th 32 lt and 8.16 lt-
The iodination reagent used above can be prepared as follows:
In a 250 ml round bottom flask with magnetic stirrer, reflux condenser and attached nitrogen balloon, 42 g of freshly distilled N, N'-dicyclohexylcarbodiimide are dissolved in 90 ml of methyl iodide under a nitrogen atmosphere at room temperature and the colorless reaction mixture is stirred for 72 hours at a bath temperature of 70 ".  After the reaction time has elapsed, 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 for 20 hours at 0.1 mm Hg and room temperature, the N-methyl-N, N'-dicyclohexylcarbodiimidium iodide is obtained in the form of colorless crystals, F. 



     111-113; Infrared absorption spectrum (in chloroform): characteristic bands at 4.72 lt and 6.00 u. 



   A solution of 0.400 g of 3-iodomethyl-7 ß-phenylacetylamino-3-cephem4-carboxylic acid diphenylmethyl ester in 15 ml of 90% aqueous acetic acid is cooled to 0 in an ice bath and 2.0 g of zinc dust are added in portions while stirring well.  After a reaction time of 30 minutes at 0, the unreacted zinc dust is filtered off using a suction filter with a diatomaceous earth pad; 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 taken up with stirring in 50 ml of methylene chloride and 30 ml of a 0.5 molar aqueous dipotassium hydrogen phosphate solution; 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 chromatographed on a column of 22 g of silica gel (addition of 10% water). 

  The 3-methylene-7s-phenylacetylamino-cepham4 ot-carboxylic acid diphenylmethyl ester is eluted with methylene chloride and methylene chloride.     containing 2 0/0 methyl acetate and crystallized from a mixture of methylene chloride and hexane.  F. 

 

     144-147 "; [a] D20 = -18 + 10 (c = 0.715 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): man = 254 m, u (± = 1540) and 260 m, u (± = 1550); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 lt.     5.65 lt.     5.74 lt.     5.94 lt.     6.26 lt and 6.67 u.     

 

Claims (1)

PATENT CLAIM Process for the preparation of 0-acylated 7ss-amino-cephem-3-01-4-carboxylic acid derivatives of the formula EMI17.1 where R, a represents hydrogen or an amino protective group R> A, and Rlb represents hydrogen or an acyl group Ac, or R> a and R> 6 together represent a divalent amino protective group, R2A represents one, together with the carbonyl group -C (= 0 ) - represents a protected carboxyl group-forming radical, and R3 represents an acyl group, and which contain a C, C double bond in the 2,3- or 3,4-position. as well as l-oxides of compounds of the formula 1 in which the C, C double bond is in the 3,4-position, or salts of such compounds with salt-forming groups, characterized. that in a 3-cephem-3-ol compound of the formula EMI17.2 or in an 1-oxide thereof, the 3-hydroxy group is converted into a group of the FORMULA -O-R3 by acylation, and a compound obtained is isolated as a salt or in free form. SUBClaims E. 1. The method according to claim, characterized in that starting materials of the formula II are used in which Ria is an amino protective group R> A, which stands for an acyl group Ac, in which any free functional groups present may be protected, R> h is hydrogen, and R2A represents an etherified hydroxyl group which forms an esterified carboxyl group with the -C (= 0) group, it being possible for functional groups which may be present in an esterified carboxyl group of the formula -C (= 0) -R2A to be protected. 2. The method according to dependent claim 1, characterized in that R2A represents an optionally substituted l-phenyl-lower alkoxy group, such as the diphenylmethoxy group. 3. The method according to dependent claim 1, characterized in that R2A is an optionally halogen-substituted lower alkoxy group, such as an α-polybranched lower alkoxy radical, e.g. B. tert-butyloxy, or a 2-halo-lower alkoxy radical, such as 2,2,2-trichloroethoxy. 4. Method according to claim. characterized in that enol esters are prepared by treating the starting material with a carboxylic acid of the formula R3-OH (V) corresponding to the acyl radical R3 or with a reactive acid derivative thereof. 5. The method according to dependent claim 4, characterized. that as reactive acid derivatives of the formula R3-OH (V), corresponding acid halides, e.g. B. fluorides or chlorides, pseudohalides, acid anhydrides or activated esters, if necessary, in the presence of suitable condensing agents used. 6. 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. 7. The method according to claim, characterized in that the protected carboxyl group -C (= 0) -R2A in a compound obtained is converted into a free carboxyl group by solvolysis, reduction or photolysis. 8. The method according to claim, characterized in that in a compound obtained in which both radicals R1A and R1b are acyl groups, a suitable acyl group z. B. split off by hydrolysis, aminolysis or hydrazinolysis and replaced by hydrogen. 9. The method according to claim, characterized in that in a compound obtained in which RIA or R> b is an acyl group, a suitable acyl group by treatment with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleaving the imino ether formed split off and replaced by hydrogen. 10. 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. 11. 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. 12. The method according to dependent claim 11, characterized in that the isomerization is carried out by treatment with a weakly basic agent. 13. The method according to dependent claim 11, characterized in that the isomerization by oxidation of the 1-position and subsequent reduction of the resulting l-oxide of the corresponding 3-cephem compound is carried out. 14. The method according to claim or one of the dependent claims 1-13, characterized in that 3-cephem compounds of the formula I according to claim or l-oxides thereof, furthermore the corresponding 2-cephem compounds, and salts of such compounds with salt-forming groups are prepared in which Rla is hydrogen or an acyl radical contained in an N-acyl derivative of a 65-amino-penam-3-carboxylic acid or 75-amino-3-cephem-4-carboxylic acid compound, which can be prepared by fermentation or bio-, semi- or totally synthetically, or a slightly represents cleavable acyl radical of a carbonic acid half-derivative, R> b represents hydrogen, R2A is hydroxy, optionally substituted lower alkoxy, optionally substituted phenyl-lower alkoxy, acyloxy, tri-lower alkylsilyloxy, or optionally substituted amino or hydrazino, and R3 is lower alkanoyl or benzoyl. 15. The method according to claim or one of the dependent claims 1-13, characterized in that 3-cephem compounds of the formula I according to claim or l-oxides thereof, and corresponding 2-cephem compounds, and also salts of such compounds with salt-forming groups, wherein Ria is hydrogen, a fermentatively or biosynthetically producible N-acyl derivative of 6ss-aminopenam-3-carboxylic acid or 7p-amino-3-cephem-4-carboxylic acid compounds, or an acyl radical contained in highly effective N-acyl derivatives of 6ss-amino-penam- 3-carboxylic acid or 7p.amino-3-cephem-4-carboxylic acid compounds occurring acyl radical, Rlb is hydrogen, R2A is hydroxy, lower alkoxy, 2-halo-lower alkoxy, Phenyloxy, I-phenyl-lower alkoxy with 1-3 phenyl radicals optionally substituted by lower alkoxy or nitro, lower alkanoyloxymethoxy, lower alkoxycarbonyl oxy or lower alkanoyloxy, and R3 is lower alkanoyl or benzoyl. 16. The method according to claim or one of the dependent claims 1-12, characterized in that 3-cephem compounds of the formula I according to claim or l-oxides thereof, as well as corresponding 2-cephem compounds, and also salts of such compounds with salt-forming groups, in which R > b, R2 and R3 have the meanings given in dependent claim 15, and Rla is hydrogen or a group of the formula EMI18.1 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 Rll and Grill is hydrogen, or where n is 1, Rl is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical is preferably has aromatic character, Rll an optionally functionally modified, z. B. esterified or etherified hydroxy or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, an optionally 0-mono or 0-disubstituted phosphono group, an azido group or a halogen atom, and Rlll is hydrogen, or where n is 1 each of the radicals Rl and Rll is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and Grill is hydrogen, or where n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic aliphatic, means aromatic or araliphatic hydrocarbon radical and Rll 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 in which n is 1, and Rl is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or an aromatic or araliphatic hydrocarbon optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have aromatic character, Rll an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and grill is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. 17. The method according to claim or one of the dependent claims 1-13, characterized in that 3-cephem compounds of the formula I according to claim or l-oxides thereof, and corresponding 2-cephemy compounds, and also salts of such compounds with salt-forming groups, in which R > b, R2 and R3 have the meanings given in dependent claim 15, and Rla is hydrogen or a group of the formula EMI19.1 where n is 0 and Rl is hydrogen or an optionally, preferably in; -position by amino or an, 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 an optionally substituted, such as halogen, e.g. B. chlorine, lower alkyl containing N-substituted amino group, or n for 1, Rl for a 3-amino-3-carboxy-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, preferably by halogen, such as chlorine, optionally substituted, such as hydroxy and / or halogen, z. B. Chlorine, phenyl containing oxy, amino and / or carboxy, substituted lower alkyl group, a lower alkenyl group, an 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, e.g. B. by lower alkyl, such as methyl, amino or aminomethyl, substituted pyridyl, pyridinium, thienyl; I-imidazolyl or 1-tetrazolyl group, an optionally substituted lower alkoxy; z. B. methoxy group, an optionally, z. B. by hydroxy and / or halogen, such as chlorine, substituted phenyloxy group, a lower alkylthio; z. B. n-butylthio, or lower alkenylthio, e.g. B. allylthio, an optionally, z. B. by lower alkyl, such as methyl, substituted phenylthio, 2lmidazolylthio. 1.2.4-Triazol-3-ylthio-, 1.3,4-triazol-2-ylthio-, 1,2,4-thiadiazol-3-ylthio-, such as 5-methyl-1,2,4-thiadiazol-3- ylthio-. 1,3,4-thiadiazol-2-ylthio-, such as 5-methyl-1, 3,4-thiadiazol-2-ylthio-, or 5-tetrazolylthio-. such as l-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 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 Ril and Rill 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-cyclohexandienyl group, Rll for optionally substituted amino, such as lower alkoxycarbonylamino or 2-halo-lower alkoxycarbonylamino, e.g. B. tert-Butyloxycarbonylamino or 2,2,2-Trichloräthoxyearbonylamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or one, optionally in salt z. B. alkali metal salt form present sulfoamino group, an azido group, an optionally in salt, z. B. alkali metal salt form or in esterified form, e.g. B. as Niederalkoxycarbonyl- z. B. Methoxycarbonyl or ethoxycarbonyl group, carboxyl group present, a cyano group, a sulfo group, an optionally functionally modified hydroxyl group, especially acyloxy, such as formyloxy, and lower alkoxycarbonyloxy or 2-halo-lower alkoxycarbonyloxy, e.g. B. tert-butyloxycarbonyloxy or 2,2,2-trichlorocarbonyloxy, or optionally substituted lower alkoxy or phenyloxy, a 0-lower alkyl or 0,0-di-lower alkyl-phosphono group, e.g. B. 0-methyl-phosphono or 0,0-dimethylphosphono, or a halogen atom, e.g. B. chlorine or bromine, and Rill for hydrogen, or n for 1, Rl and Riss 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, R and Rlil for lower alkyl, e.g. B. methyl. 18. The method according to claim or one of the dependent claims 1-13, characterized in that 3-cephem or 2-cephem compounds of the formula I according to claim or salts of compounds with salt-forming groups in which R1b is hydrogen and Rra is hydrogen , an acyl group of the formula EMI19.2 wherein Ar is phenyl, hydroxyphenyl, hydroxychlorophenyl or 2-thienyl, where in such radicals hydroxy substituents can be protected by acyl radicals, X represents oxygen or sulfur, n represents 0 or 1, and R represents hydrogen or, if n represents 0, represents optionally protected amino, carboxy, sulfo or hydroxy, or 0-lower alkylphosphono or 0,0.Diniederalkyl-phosphono, or represents a 5-amino-5-carboxy-valeryl radical, wherein the amino and carboxy groups are optionally protected, R2A is hydroxy, lower alkoxy, 2-halo-lower alkoxy or optionally substituted diphenylmethoxy and R3 is lower alkanoyl. 19. The method according to claim or one of the dependent claims 1-13, characterized in that 3-cephem or 2-cephem compounds of the formula 1 according to Pa Tent claim or prepares salts of compounds with salt-forming groups in which Rla is hydrogen, the acyl radical of the formula B according to dependent claim 18, 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 0-lower alkyl or 0,0-di-lower alkylphosphono, or a 5-amino-5-carboxyvaleryl 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 Rl represents lower alkanoyl. 20. The method according to claim or one of the dependent claims 1-13, characterized in that the 3-acetyloxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester is prepared. 21. The method according to claim or one of the dependent claims 1-13, characterized in that the 3-acetyloxy-7P-phenylacetylamino-3-cephem-4-carboxylic acid or salts thereof are prepared.