CH582709A5 - 7-beta-amino-ceph-3-em 4-carboxylic acid derivs - antibiotics - Google Patents

Abstract

Title cpds. of formula (I): (where R = H or an NH2 protecting gp.; R' = H or acyl; or together R and R' form trivalent NH2 protecting gp.; and R2 = H, a salt residue, or a CO2H protecting gp.) (I) are prepd. from the corresp. 3-formyl 2-em derivs. by catalytically decarbonylating to the 2-em -4-carboxylic acid deriv., and then (a) isomerising with a weak base, or (b) oxidising to give S-oxide of (I) which is then reduced.

Description

  

  
 



   The present invention relates to a process for the preparation of 7-amino-8-oxo-5-thia-1-azabicyclo- [4.2.0] oct-en-2-carboxylic acid compounds, in particular 7ss amino-ceph-3-em - 4-carboxylic acid compounds of the formula
EMI1.1
 wherein R1 is hydrogen or an amino protecting group RIA, and Rb is hydrogen or an acyl group Ac, or RA and RX together represent a divalent amino protecting group, and R2 is hydrogen or a protected group together with the -C (= O) -O group Carboxyl group-forming organic radical R2A, or salts of such
Connections with salt-forming groups.



   An amino protective group R 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 (including formic acid), and the acyl radical of a carbonic acid half-derivative.



   A divalent amino protective group formed together by the radicals R1 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, and also the
Acyl radical of a, preferably substituted in a-position, z. B.



   α-aminoacetic acid containing an aromatic or heterocyclic radical, in which the amino group is via a, preferably substituted, e.g. two lower alkyl, like
Methylene radical containing methylene is bonded to the nitrogen atom. The radicals RA1 and Ra together can also be an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic
Ylidene radical, preferably with up to 18 carbon atoms represent.



   A protected carboxyl group of the formula -C (= O) -O-R2 is primarily an esterified carboxyl group, but can also represent a usually mixed anhydride group.



   The group R2 can represent an organic radical, preferably with 18 carbon atoms, which, together with the -C (= O) -O grouping, forms a preferably easily cleavable, esterified carboxyl group; such residues are e.g. B. aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, and heterocyclic or heterocyclic-aliphatic radicals.



   The group R2A can also represent an organic silyl radical, as well as an organometallic radical, such as a corresponding organic stannyl radical, in particular an optionally substituted by 1 to 3 hydrocarbon radicals, preferably with up to 18 carbon atoms, such as aliphatic hydrocarbon radicals, substituted silyl or stannyl radical.



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



   The general terms used in the description above and below have e.g. 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, as well as lower alkenyl or lower alkynyl, also lower alkylidene, e.g. B. can contain up to 7, preferably up to 4 carbon atoms.

  Such radicals can optionally be replaced by functional groups, e.g. by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylene dioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phenylthio or phenyl-lower alkylthio, optionally substituted lower alkoxycarbonyloxy or lower alkanitroloxy, optionally substituted by oxycarbonyloxy, or halogen Amino, e.g. B.

  Di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino or aza-loweralkylenamino, also acylamino, such as lower alkanoylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, azido, acyl, such as lower alkanoyl or benzoyl, optionally substituted carboxyl, such as lower alkanoyl, esterified carboxyl, such as salt, optionally substituted carboxyl, such as salt 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, mono-, di- or polysubstituted.



   The divalent aliphatic radical of an aliphatic carboxylic acid is z. B. lower alkylene or lower alkenylene, which optionally, z. B. as an aliphatic radical specified above, mono-, di- or polysubstituted.



   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-hydrocarbon-aliphatic radical. B.

 

  mono-, bi- or polycyclic cycloalkyl or cycloalkenyl, furthermore cycloalkylidene, or cycloalkyl- or cycloalkenyl-lower alkyl or -lower alkenyl, furthermore cycloalkyl-lower alkylidene or cycloalkenyl-lower alkylidene, in which cycloalkyl and cycloalkylidene e.g. 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. by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned optionally substituted lower alkyl groups, or then, e.g. like the abovementioned aliphatic hydrocarbon radicals, mono-, di- or polysubstituted by functional groups.



   The aromatic radical, including the aromatic radical of a corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon radical, e.g. B. a mono-, bi or polycyclic aromatic hydrocarbon radical, in particular phenyl, and biphenylyl or naphthyl, which may optionally, for. B. as the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals, mono-, di- or polysubstituted.



   The divalent aromatic radical of an aromatic carboxylic acid is primarily 1,2-arylene, especially 1,2-phenylene, which may optionally, e.g. B. as the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals, mono-, di- or polysubstituted.



   The araliphatic radical, including the araliphatic radical in a corresponding carboxylic acid, also an araliphatic ylidene radical, is e.g. 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 have the aliphatic hydrocarbon radical 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. Contain 1-3 phenyl groups and optionally, e.g. like the abovementioned aliphatic and cycloaliphatic radicals, can be mono-, di- or polysubstituted in the aromatic and / or aliphatic part.



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



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



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

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



   Lower alkyl is e.g. B. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and n-pentyl, isopentyl, n-1-hexyl, isohexyl or n-heptyl, while lower alkenyl e.g. 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. isopropylidene or isobutylidene.



   Lower alkylene is e.g. 1,2-ethylene, 1,2- or 1,3-propylene or 1,4-butylene, while lower alkenylene e.g. 1,2-Ethylene or 2-buten-1,4-ylene is.



   Cycloalkyl is e.g. B. Cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl or cycloheptyl, as well as adamantyl, cycloalkenyl z. B. cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3
Cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl, and
Cycloalkylidene e.g. B. cyclopentylidene or cyclohexylidene.



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



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



   Represents 4-biphenylyl.



   Phenyl-lower alkyl or phenyl-lower alkenyl is, for. B.



   Benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, di phenylmethyl, trityl, 1- or 2-naphthylmethyl, styryl or
Cinnamyl, phenyl lower alkylidene e.g. 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, z. 2-pyrryl or 3-pyrryl, pyridyl, e.g. 2-, 3- or 4-pyridyl, also pyridinium,
Thienyl, e.g. 2- or 3-thienyl, or furyl, e.g. 2-furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals, such as indolyl, e.g. E.g., 2- or 3-indolyl, quinolinyl, e.g. 2- or 4-quinolinyl, isoquinolinyl, e.g. 1-isoquinolinyl, benzofuranyl, e.g. B. 2- or 3-benzofuranyl, or benzothienyl, e.g. B. 2- or 3 benzothienyl, monocyclic diaza, triaza, tetraza, thiaza, thiadiaza or oxazacyclic radicals such as imidazolyl, e.g. E.g. 2 imidazolyl, pyrimidinyl, e.g. B. 2- or 4-pyrimidinyl, triazolyl, e.g. 1,2,4-triazol-3-yl, tetrazolyl, e.g.

  1- or 5-tetrazolyl, oxazolyl, e.g. 2-oxazolyl, isoxazolyl, e.g. 3-isoxazolyl, thiazolyl, e.g. 2-thiazolyl, isothiazolyl, e.g. 3-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, e.g. 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza, thiaza or oxazacyclic radicals such as benzimidazolyl, e.g. 2-benzimidazolyl, benzoxazolyl, e.g. 2-benzoxazolyl, or benzthiazolyl, e.g. B. 2-benzothiazolyl. Corresponding partially or fully saturated radicals are, for. B. tetrahydrothienyl such as 2-tetrahydrothienyl, tetrahydrofuryl such as 2-tetrahydrofuryl, or piperidyl, e.g. B. 2- or 4-piperidyl. Heterocyclic-aliphatic radicals are heterocyclic groups, especially those mentioned above, containing lower alkyl or lower alkenyl. The above-mentioned heterocyclyl radicals can, for.

  B. by optionally substituted aliphatic hydrocarbon radicals, especially lower alkyl such as methyl, or, for. B. like the aliphatic hydrocarbon radicals, be substituted by functional groups.



   Lower alkoxy is e.g. B. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, selc.-l-butyloxy, tert-butyloxy, n-pentyloxy or tert-pentyloxy. These groups can be substituted, e.g. As in halo-lower alkoxy, especially 2-halo-lower alkoxy, e.g. 2,2,2-trichloro-, 2-bromo- or 2-iodoethoxy. Lower alkenyloxy is e.g. B. vinyloxy or allyloxy, lower alkylenedioxy z. B. methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy z. B. cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy z. B.

 

     Benzyloxy or 1- or 2-phenylethoxy, or heterocydyloxy or Heterocyclniederalkoxy z. B. pyridyl lower alkoxy, such as 2
Pyridylmethoxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy.



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



   Esterified hydroxy groups are primarily halogen, e.g. B. fluorine, chlorine, bromine or iodine, and lower alkanoyloxy, z. B. acetyloxy or propionyloxy, lower alkoxycarbonyloxy, e.g. B. methoxycarbonyloxy, ethoxycarbonyloxy or tert. Butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, e.g. B. 2,2,2-Trichloräthoxycarbonyloxy, 2-Bromoäthoxycarbonyloxy or 2-Jodäthoxycarbonyloxy, 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 present in sodium or potassium salt form carboxyl or sulfo.



   Lower alkylamino or di-lower alkylamino is e.g. B. methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino z. B. pyrrolidino or piperidino, Oxaniederalkylenamino z. B. Morpholino, and Azaniederalkylenamino z. B. piperazino or 4-methylpiperazino. Acylamino particularly represents carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkanoylamino, such as acetylamino or propionylamino, also phthalimido, or optionally in salt, such as alkali metal, z. B. sodium or ammonium salt form, present sulfoamino.



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



   Lower alkenyloxycarbonyl is e.g. B. vinyloxycarbonyl, while cycloalkoxycarbonyl and phenylniederalkoxycarbonyl z. B. Adamantyloxycarbonyl, Benzyloxycarbonyl, Diphenylmethoxycarbonyl or os-4-biphenyl-ex-methyl-ethoxycarbonyl represents. Lower alkoxycarbonyl, wherein lower alkyl e.g. B. contains a monocyclic, monoaza-, monooxa- or monothiacyclic group, is z. B. furylniederalkoxycarbonyl, such as furfuryloxycarbonyl, or thienylniederalkoxycarbonyl, z. B. 2-thenyloxycarbonyl.



   An acyl group Ac stands in particular for an acyl radical of an organic carboxylic acid or a carbonic acid half derivative or an acyl radical of an organic carboxylic acid or of a carbonic acid half derivative or a preferably pharmacologically active N-acyl derivative of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid compounds which occurs naturally or which can be produced bio-, semi- or totally synthetically easily cleavable acyl radical, in particular a carbonic acid half derivative.



   An acyl radical Ac contained in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid is primarily a group of the formula
EMI3.1
 where n is 0 and R is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, preferably etherified hydroxy or mercapto or an optionally substituted amino group, or where n is 1, R1 is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has aromatic character and / or a quaternary nitrogen atom, an optionally functionally modified, preferably etherified or esterified hydroxy or mercapto group, an optionally functionally modified carboxyl group, an acyl group , represents an optionally substituted amino group or an azide group, and each of the radicals R11 and RIII is hydrogen, or in which n is 1, Rl is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has aromatic character, R "an optionally functionally modified, preferably etherified hydroxyl or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or Is sulfo group, an azido group or a halogen atom and Rlll is hydrogen, or in which n is 1, each of the radicals R 'and R11 is a functionally modified, preferably etherified or esterified hydroxy group or an optionally functionally modified carboxyl group, and Rlll is hydrogen,

   or in which n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or raliphatic hydrocarbon radical and Rl and Rlll together is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or linked by a double bond to the carbon atom represent araliphatic hydrocarbon radical, or in which n is 1, and R t is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical,

   wherein hecterocyclic radicals preferably have an aromatic character, R11 is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R 11 is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon.



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



  n for 0 and R 'for hydrogen or an optionally, preferably in the 1-position by amino or a, optionally in salt, z. B. alkali metal salt form present sulfoamino group, substituted cycloalkyl group with 5-7 ring carbon atoms, 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. 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, R 'for an optionally, preferably by analogs. such as chlorine, optionally substituted, such as hydroxy and / or halogen, e.g. Chlorine, contain des phenyloxy, amino and / or carboxy, substituted lower alkyl group, a lower alkenyl group, an optionally substituted one such as hydroxy, halogen, e.g. Chlorine, and / or optionally substituted, such as hydroxy and / or halogen, e.g. B. chlorine, containing phenyloxy, phenyl group, optionally, z.

  B. by lower alkyl, such as methyl, amino or aminomethyl, substituted pyridyl, pyridinium, thienyl, 1-imidazolyl or l-tetrazolyl, an optionally substituted lower alkoxy, e.g. 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 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 i-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 R ″ and R 111 for hydrogen, or n for 1, R 1 for an optionally, e.g. by hydroxy and / or halogen, e.g.



  Chlorine, substituted phenyl or thienyl group, also for a
1,4-cyclohexadienyl group, R1 for optionally substituted amino, such as lower alkoxycarbonylamino or 2 halo-lower alkoxycarbonylamino, e.g. tert-Butyloxycarbonylamino or 2,2,2-Trichloräthoxycarbonylamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or one, optionally in salt z. B. alkali metal salt form present sulfoamino group, an azido group, an optionally in salt, z. B. alkali metal salt form or in esterified form, e.g. B. as lower alkoxycarbonyl, e.g. B.



  Methoxycarbonyl or ethoxycarbonyl group, carboxyl group present, a cyano group, a sulfo group, optionally functionally modified hydroxy, such as lower alkoxycarbonyloxy or 2-halo-lower alkoxycarbonyloxy, e.g. B. tert-butyloxycarbonyloxy or 2,2,2-trichlorocarbonyloxy, or optionally substituted lower alkoxy or phenyloxy, or a halogen atom, e.g. B. chlorine or bromine, and R III for hydrogen, or n for 1, R 1 and R ″ each for halogen, for example bromine, or lower alkoxycarbonyl. For example methoxycarbonyl, and R'11 for hydrogen, or n for 1, and each of the groups R, R 11 and R "1 for lower alkyl, e.g. B. methyl.



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



  sulfoamino group optionally present in salt form, or one, by a, preferably slightly, e.g. when treating with an acidic agent such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, cleavable or an acyl radical that can be converted into such, preferably a suitable acyl radical of a carbonic acid half-ester, such as 2,2,2-trichloroethyloxycarbonyl , 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl, phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, as well as amino groups substituted by trityl), 2,6-dimethoxybenzoyl, tetrahydronaphthyl, 2-methoyloxy-naphthyl -Aethoxy-naphthoyl, benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 5-methyl-3-phenyl-4-isoxazolylcarbonyl,

   3- (2-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, 3 (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, hexanoyl, octanoyl, acrylyl , Crotonyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, methylthioacetyl, butylthioacetyl, allylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl or 5-amino-valino-5-caryl (optionally with As indicated, substituted amino group and / or optionally functionally modified, e.g. in salt, such as sodium salt, or in ester, such as lower alkyl, e.g.

  Methyl or ethyl ester form, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bismethoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, α-cyanopropio- nyl, phenyl, phenylacetyl, 3,3-o-phenyl, phenylacetyl, o-phenyl, phenyl acrylacetyl, phenyl acrylacetyl, methoxycarbonylacetyl -Azido-phenylacetyl, 3-chlorophenylacetyl, 4 aminomethylphenyl-acetyl, (with optionally, e.g.

   as indicated, substituted amino group), Phenacylcarbonyl, Phenyloxyacetyl, 4-trifluoromethyl-phenyloxyacetyl, benzyloxyacetyl, Phenylthioacetyl, Bromphenylthioacetyl, 2-Phenyloxypropionyl, x-Phenyloxyphenylacetyl, a-hydroxy-phenylacetyl, a-methoxy-phenylacetyl, a-ethoxy-phenylacetyl, oc - Methoxy-3,4-dichloro-phenylglycyl, z-cyano-phenylacetyl, especially phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl or 3,5-dichloro-4-hydroxyphenylglycyl (with the amino group in these radicals if necessary, e.g.



  can be substituted as indicated above), also benzylthioacetyl, benzylthiopropionyl, α-carboxyphenylacetyl (with optionally, for example, as indicated above, functionally modified carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) propionyl, 4- (3-methoxyphenyl ) -butyryl, 2-pyridylacetyl, 4-aminopyridinium acetyl (optionally with, for example, as stated above, substituted amino group), 2-thienylacetyl, 2-tetrahydrothienylacetyl, a: -Carboxy-2-thienylacetyl or a-carboxy-3 - thienylacetyl (possibly with functional, e.g.



  as stated above, modified carboxyl group), o-cyano-2-thienylacetyl, α-amino-2-thienylacetyl or α-amino-3-thienylacetyl (optionally with, for example, as stated above, substituted amino group), α-sulfo phenylacetyl (optionally with, for example, like the carboxyl group, functionally modified sulfo group), 3-thienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, 3-methyl-2-imidazolylthioacetyl, 1,2,4-triazole -3-ylthioacetyl, 1,3,4-triazol-2-ylthioacetyl, 5-methyl-1,2,4-thiadiazol-3-ylthioacetyl, 5-methyl-1,3,4-thiazol-2-ylthioacetyl or 1-methyl-5-tetrazolylthioacetyl.

 

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

  Adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, primarily a-phenyl-lower alkoxycarbonyl, in which the position is preferably polysubstituted, e.g. B. diphenylmethoxycarbonyl or ct-biphenylyl- a-methyl- äthyloxycarbonyl, or furyl-lower alkoxycarbonyl, primarily ar-furyl-lower alkoxycarbonyl, z. B. furfuryloxycarbonyl.



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



   Another bivalent radical formed by the groups Ri and Rz is z. B. a, especially in the 2-position, substituted, z. B. optionally substituted phenyl or thienyl, contained, and optionally in the 4-position by lower alkyl, such as methyl, mono- or disubstituted 1-oxo-3 aza-1,4-butylene radical, z. B. 4,4-dimethyl-2-phenyl- 1-oxa- 3-aza-
1,4-butylene. A.
An organic radical R2 which, together with the -C (= O) -O grouping, forms an esterified carboxyl group, preferably easily cleavable, is e.g. for a 2 halo-lower alkyl radical R2, in which halogen preferably has an atomic weight of more than 19.

  Such a radical, together with the -C (= O) -O grouping, forms a, upon treatment 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 one in such an easily convertible esterified carboxyl group and is z. B. 2,2,2-trichloroethyl or 2-iodine ethyl, also 2-chloroethyl or 2-bromoethyl, which can easily be converted into the latter.



   Another group R2A which, together with the -C (= O) -O grouping, also has a role in treatment with chemical reducing agents under neutral or weakly acidic conditions, e.g. when treating with zinc in the presence of aqueous acetic acid, further when treating with a suitable nucleophilic reagent, e.g. Sodium thiophenolate, easily cleavable esterified carboxyl group, is an arylcarbonylmethyl group R2, where aryl is in particular an optionally substituted phenyl group, and preferably phenacyl.



   The group RA2 can also represent the radical R2, which represents an arylmethyl group, in which aryl is in particular a monocyclic, preferably substituted aromatic hydrocarbon radical. Such a radical, together with the -C (= O) -O group, forms an esterified carboxyl group which can be easily cleaved under neutral or acidic conditions on irradiation, preferably with ultraviolet light. Such an aryl radical contains, in particular, lower alkoxy as a substituent, e.g. B. methoxy (which are primarily in the 3-, 4- and / or 5-position in the preferred phenyl radical), and / or above all nitro (in the preferred phenyl radical preferably in the 2-position). Such radicals R2 are primarily 3- or 4-methoxybenzyl, 3,5-dimethoxy-benzyl, 2-nitrobenzyl or 4,5-dimethoxy-2-nitro-benzyl.



   A group RA2 can also represent the radical R2 which, together with the (= O) -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 Rd2 is primarily a methyl group which is polysubstituted by optionally substituted hydrocarbon radicals or monosubstituted by a carbocyclic aryl group having electron-donating substituents or a heterocyclic group of aromatic character having oxygen or sulfur atoms as ring members, or then in a polycyclaliphatic hydrocarbon radical means a ring member or, in an oxa or thiacycloaliphatic radical, the ring member representing the position to the oxygen or sulfur atom.



   Preferred polysubstituted methyl groups Rd2 are z. B.



  tert-butyl, tert-pentyl, benzhydryl, 4,4'-dimethoxy-benzhy- dryl or 2- (4-biphenylyl) -2-propyl, while a methyl group Rd2 containing the above-mentioned substituted aryl group or the heterocyclic group z. B. 4-methoxy-benzyl or 3,4-dimethoxy-benzyl, or 2-furyl. A polycycloaliphatic hydrocarbon radical in which the methyl group Rd2 is a preferably three-branched ring member is, for. B. Adamantyl, such as 1-adamantyl, and an above-mentioned oxa- or thiacycloaliphatic radical R2d is 2-tetrahydrofuryl, 2-tetrahydropropyranyl or 2,3-dihydro-2pyranyl or corresponding sulfur analogs.



   The radical RA can also represent a radical R2 which, together with the -C (= O) -O grouping, is a hydrolytic, e.g. B. under weakly basic or acidic conditions, cleavable esterified carboxyl group forms. Such a radical R2 is preferably a radical which forms an activated ester with the -C (= O) -O group, such as nitrophenyl, e.g. B. 4-nitrophenyl or 2,4-dinitrophenyl, nitrophenyl lower alkyl, e.g. B. 4
Nitrobenzyl, polyhalophenyl, e.g. B. 2,4,6-trichlorophenyl or 2,3,4,5,6-pentachlorophenyl, also cyanomethyl, and acylaminomethyl, z. B. phthaliminomethyl or succinyliminomethyl.



   The group RA2 can also represent a radical R f which, together with the carboxyl group -C (= 0) -0-, forms an esterified carboxyl group which can be cleaved under hydrogenolytic conditions, and is e.g. an optionally substituted a-aryl-lower alkyl radical, such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl, benzhydryl or 4,4-dimethoxybenzhydryl.



   The group R2A can also be one, together with the
Carboxyl group -C (= 0) -0- one among physiological
Conditions forming cleavable esterified carboxyl group
Radical R8, primarily lower alkanoyloxymethyl, e.g. B. acetyl oxymethyl represent.



   A silyl or stannyl radical RA preferably contains optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, and is primarily tri-lower alkylsilyl, e.g. B. trimethylsilyl, or tri-lower alkylstannyl, e.g. B. tri-n-butylstannyl.



   A mixed anhydride group forming a, preferably hydrolytically, cleavable mixed anhydride group together with the -C (= O) -O group is z. B. the acyl radical of one of the above organic carboxylic acids or carbonic acid semi-derivatives, such as lower alkanoyl, z. B. acetyl, or lower alkoxycarbonyl, e.g. B. ethoxycarbonyl.



   Salts are especially those of compounds of the
Formula I, in which RA2 stands for hydrogen and primarily
Metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. B. sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, with primarily aliphatic, cyclo aliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for salt formation come into question, such as lower alkylamines, z. B. triethylamine, hydroxy lower alkylamines, e.g. B. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. B. 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, e.g.

  B. 1-ethyl piperidine, cycloalkylamines, z. B. bicyclohexylamine, or benzylamines, e.g. B. N, N'-dibenzyl-ethylenediamine, also bases of the pyridine type, e.g. Pyridine, collidine or quinoline. Compounds of formula I in which e.g. Ra; and R1 are hydrogen or which have a basic group in a radical Ri and R1 can also be 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 1 in which R2 is hydrogen and in which R1 b and R1 are hydrogen, or which contain a basic group in a radical R1 and R =, can also be in the form of an inner salt, i.e. H. in zwitterionic form.



   The compounds of the formula I have valuable pharmacological properties or can be used as intermediates for the preparation of such.



  Compounds of the formula 1 in which Rl is an itpharmacologically active N-acyl derivative of 6-aminopenam-3carboxylic acid or 7-amino-ceph-3-em-4-carboxylic acid compounds occurring acyl radical Ac and Rb is hydrogen, and R2 is hydrogen or means an organic residue RA which can be easily split off under physiological conditions, are against microorganisms such as gram-positive bacteria, e.g. B. Staphylococcus aureus, (e.g. in mice at doses of about 0.001 to about 0.02 g / kg p. O.) And gram-negative bacteria, e.g. B.

  Escherichia coli (e.g. in mice at doses of about 0.0001 to about 0.05 g / kg p.o.), also Klebsiella pneumoniae, proteus vulgaris or Salmonella typhosa, in particular also effective against penicillin-resistant bacteria. So they are e.g. effective against Staphylococcus aureus in dilutions up to 0.0001 v / ml. The new compounds can therefore accordingly, for.

  B. in the form of antibiotic preparations, use. a b
The compounds of the formula I in which the radicals R1 and R1 are hydrogen or Rz is an amino protective group different from the acyl radical mentioned above, and Rb is hydrogen, or Ru and R together represent a divalent amino protective group and R2 is hydrogen, or R1 and Rt1 have the meanings given above, and R2 represents an organic radical R2 which, together with the -C (= O) -O grouping, preferably forms an easily cleavable, esterified carboxyl group, are valuable intermediates which can be obtained in a simple manner, for example

   is described below, can be converted into the above-mentioned pharmacologically active compounds.



   Ceph-3-em compounds of the formula I in which X is hydrogen or a naturally occurring or bio-, semi- or totally synthetic producible, in particular pharmacologically active, such as highly active are particularly valuable
N-acyl derivative of an acyl radical containing 6-amino-penicillanic acid or 7-aminocephalosporanic acid compound or an easily cleavable acyl radical of a carbonic acid half-derivative, in particular a carbonic acid half-ester, Rl stands for hydrogen and RA2 stands for hydrogen or an organic radical Et2, which together with the -C (= Grouping a, when treating with water, with an acidic agent, with a chemical reducing agent under neutral or weakly acidic conditions, hydrolytically or hydrogenolytically,

   or then one under physiological
Conditions easily cleavable esterified carboxyl group or an esterified carboxyl group convertible into this forms, and z. B. trimethylsilyl, tert-butyl, diphenylmethyl, 2,2,2-tri chloroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, phenacyl, 4-methoxybenzyl, diphenylmethyl, 4,4'-dimethoxydiphenylmethyl, 4- Represents nitrobenzyl or acetonyl, also salts of such compounds with salt-forming groups.



   Primarily in a Ceph-3-em connection the
Formula I R, for hydrogen or pure, in fermentative (i.e.



   naturally occurring) or biosynthetically producible N acyl derivatives of 6-aminopenam-3-carboxylic acid or 7 amino-ceph-3-em-4-carboxylic acid compounds containing acyl radical, such as an optionally substituted phenylacetyl or phenyloxyacetyl radical, also an optionally substituted lower alkanoyl or lower alkenoyl radical, e.g. . B. 4 hydroxyphenylacetyl, hexanoyl, octanoyl, 3-hexenoyl, 5 amino-5-carboxy-valeryl, n-butylthioacetyl or allylthioacetyl, and especially phenylacetyl or phenyloxyacetyl, one of the highly effective N-acyl derivatives of 6-aminopenam-3-carboxylic acid - Or 7-amino-ceph-3-em-4-carboxylic acid compounds occurring acyl radical, such as formyl, 2-chloroethylcarbamoyl, cyanoacetyl or 2-thienylacetyl, especially Phenylgylcyl, wherein phenyl optionally replaced by hydroxy and / or halogen, z.

  B. chlorine, substituted phenyl, e.g. B. phenyl, or 3- or 4-hydroxy, 3-chloro-4-hydroxy or 3,5-dichloro-4-hydroxyphenyl, and wherein the amino group is optionally substituted and z. B. is an optionally present in salt form sulfoamino group or an amino group which, as substituents, a hydrolytically cleavable trityl group or an optionally substituted carbamoyl, such as an optionally substituted ureidocarbonyl group, e.g. B. ureidocarbonyl or N3-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group z. B. guanidinocarbonyl, or a, preferably light, z.

  B. when treating with an acidic agent such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, cleavable or convertible into such an acyl radical, preferably a suitable 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 with the nitrogen atom of the 7-amino group by an, optionally lower alkyl, such as two methyl, containing methyl group is connected, furthermore thienylgylcyl, such as 2-thienylgylcyl (optionally with, e.g.

  B. as indicated above, substituted amino group), or 1-amino-cyclohexylcarbonyl (optionally with, for example, as indicated above, substituted amino group), also ov-carboxy-phenylacetyl or oc-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. methyl or ethyl, or phenyl lower alkyl, e.g.



  Diphenylmethylesterform, present carboxyl group), oc-sulfo-phenylacetyl (optionally with, e.g. like the carboxyl group, functionally modified sulfo group), or or hydroxyphenylacetyl (optionally with functionally modified hydroxy group, in particular an acyloxy group, in which acyl is, preferably slightly , for example when treating with an acidic agent such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, cleavable or convertible into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as 2,2,2-trichloroethyloxycarbonyl , 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl or phenacyloxycarbonyl means), e.g.

  B. for an acyl radical of the formula IA, also for one, easily, especially under acidic conditions, e.g. When treating with trifluoroacetic acid, or reductively, e.g. with zinc in the presence of aqueous acetic acid, cleavable acyl radical of a carbonic acid half-ester, such as tert-butyloxycarbonyl, phenacylcarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or 2-bromoethoxycarbonyl which can be converted into the latter, and R, represents hydrogen, and R2 represents hydrogen or represents a radical R2A, which, together with the = = O) -O grouping, when treated with a chemical reducing agent under neutral or weakly acidic conditions, with an acidic agent, or, preferably under weakly basic conditions,

   hydrolytically, furthermore hydrogenolytically or under physiological conditions easily cleavable, esterified carboxyl group and primarily a methyl, in particular tert-butyl or diphenylmethyl, and 2,2,2-trichloroethyl, 2- Iodoethyl or 2-chloroethyl or 2-bromoethyl, or phenacyl, as well as 4-methoxybenzyl or 4-nitrobenzyl, also diphenylmethyl, 4,4'-dimethoxydiphenylmethyl, trityl or bis- (4-methoxyphenyloxy), which can easily be converted into this ) methyl, as well as acetyloxymethyl or pivaloyloxymethyl.



   The invention relates primarily to the preparation of compounds of the formula I in which Rbl is hydrogen, R is hydrogen or an acyl group of the formula
EMI7.1
 means where Ar is phenyl, 3- or 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl-, 3,5-dichloro-4-hydroxyphenyl or 2-thienyl, and where R is hydrogen or optionally protected amino, carboxy, sulfo or Hydroxy, such as acylamino, e.g. B. tert-Butyloxycarbonylamino, 2,2,2-Trichloräthoxycarbonylamino, 2-Jodäthoxycarbonylamino, 2 Bromoäthoxycarbonylamino or 3-Guanylureido, also sulfoamino or tritylamino, esterified carboxy such as diphenylmethoxycarbonyl, or acyloxy, z.

  B. tert-Butyloxycarbonyloxy, 2,2,2-Trichloräthoxycarbonyloxy, 2-Jodäthoxycarbonyloxy or Bromäthoxycarbonyloxy, or where R1 is the acyl group of the formula Ia, in which Ar has the above meaning and R is an amino group which is identified with Rb , which is methylene or isopropylidene, and R2 is hydrogen, a-polybranched lower alkyl, e.g. B. tert-butyl, 2-halo-lower alkyl, e.g. B.



  2,2,2-trichloroethyl, 2-iodoethyl or 2-bromoethyl, phenacyl, 4-nitrobenzyl or 4-methoxybenzyl, furthermore optionally substituted diphenylmethyl, e.g. Benzhydryl or 4,4'-dimethoxy-diphenylmethyl, trityl or bis- (4-methoxyphenyloxy) methyl, or salts of such compounds with salt-forming groups.



   The compounds of the formula I are obtained according to the invention if a Ceph-2-em compound of the formula
EMI7.2
 treated with a weakly basic agent and isolated the corresponding Ceph-3-em compound.



   It has surprisingly been found that, in contrast to the direct isomerization of previously known Ceph-2-em compounds which have a substituent in the 3-position, e.g. B.



  the acetyloxymethyl group, the direct isomerization of the 3-unsubstituted Ceph-2-em compounds in the presence of a weakly basic agent proceeds almost quantitatively.



   In a Ceph-2-em starting material of the formula II, the optionally protected carboxyl group in the 4-position preferably has the α-configuration.



   According to the invention, Ceph-2-em compounds of the formula I can be used in which the grouping of the formula -C (= O) -O-R2 is a free or protected, primarily esterified or a mixed anhydride group, carboxyl group, or wherein such a protected carboxyl group may be formed during the reaction.



  Preference is given to using compounds of the formula II in which R01 is different from hydrogen and represents an amino protective group, where R1 has the meaning given above.



   For example, Ceph-2-em compounds of the formula II can be isomerized by treating them with a weakly basic agent and isolating the corresponding Ceph-3-em compound. 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, as well as collidines or lutidines, also quinoline, tertiary aromatic bases, e.g. those of the aniline type such as N, N-di-lower alkyl anilines, e.g. N, N-dimethylaniline or N, N-diethylaniline, or tertiary aliphatic, azacycloaliphatic or araliphatic bases, such as N, N, N-tri-lower alkylamines, e.g. B. N, N, N-trimethylamine, N, N-dimethyl N-ethylamine, N, N, N-triethylamine or N, N, N-diisopropyl-N ethylamine, N-lower alkyl-azacycloalkanes, z. B.

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



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



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

  Nitrogen atmosphere and / or in a closed vessel.



   The thus obtainable Ceph-3-em compounds can be used in a manner known per se, e.g. B. by adsorption and / or crystallization, separate from any Ceph-3em compounds still present.



   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 Rlbzw. Rb in particular an easily cleavable acyl group, in a manner known per se, for. B. a tert-butyloxycarbonyl group by treatment with trifluoroacetic acid and a 2,2,2-trichloroethoxycarbonyl, 2-iodoethoxycarbonyl or phenacyloxycarbonyl group by treatment with a suitable metal or metal compound, e.g. B. zinc, or a chromium (II) compound such as chloride or acetate, advantageously in the presence of a hydrogen-generating, hydrogen-releasing agent, preferably of hydrous acetic acid, which nascent together with the metal or the metal compound.

  Furthermore, in a compound of formula I obtained in which a carboxyl group -C (= O) -O-R2 is preferably a z. B. by esterification, including by silylation or stannylation, e.g. B. by reacting with a suitable organic halosilicon or halogen-tin-IV compound, such as tri methylchlorosilane or tri-n-butyltin chloride, is a protected carboxyl group, a suitable acyl group Rl or Rb, in which any free functional groups present are optionally protected , by treatment with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleavage of the imino ether formed, are cleaved, a protected, e.g.

  B. a protected by an organic silyl group, carboxyl group can be released during the reaction.



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



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



   The reaction with one of the said imide halide-forming agents is preferably carried out in the presence of a suitable, in particular organic, base, primarily a tertiary amine, e.g. B. a tertiary aliphatic mono or diamine, such as a tri-lower alkyl amine, e.g. B. trimethyl, triethyl or ethyl diisopropylamine, also an N, N, N ', N' Tetraniederalkyl-lower alkylenediamine, z. B. N, N, N ', N'-tetramethyl-1,5-pentylenediamine or N, N, N', N'-tetramethyl-1,6hexyldiamine, a mono- or bicyclic mono- or diamine, such as one N-substituted, e.g. B. N-lower alkylated, alkylene, azaalkylene or oxaalkylene amine, e.g. B. N-methylpiperidine or N-methyl-morpholine, also 2,3,4,6,7,8 hexahydro-pyrrolo [1, 2-a] pyrimidine (diazabicyclonones; DBN), or a tertiary aromatic amine, such as a di-lower alkyl aniline, e.g. B.

  N, N-dimethylaniline, or primarily a tertiary heterocyclic, mono- or bicyclic base such as quinoline or isoquinoline, especially pyridine, preferably in the presence of a solvent such as an optionally halogenated, e.g. B. chlorinated, aliphatic or aromatic hydrocarbon, e.g. B. methylene chloride made. Approximately equimolar amounts of the imide halide-forming agent and the base can be used; but the latter can also be in excess or deficiency, e.g. B. in about 0.2 to about 1-fold amount or then in about to 10-fold, especially about 3 to 5-fold excess, be present.



   The reaction with the imide halide forming agent is preferably carried out with cooling, e.g. B. carried out at temperatures from about 50 C to about + 100 C, but also at higher temperatures, d. H. z. B. to about 75 "C, can work if the stability of the starting materials and products allow an elevated temperature.



   The imide halide product, which is usually processed further without isolation, is, according to the process, reacted with an alcohol, preferably in the presence of one of the abovementioned bases, to form the imino ether. Suitable alcohols are e.g. B. aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, e.g.



   chlorinated, or having additional hydroxyl groups,
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 C to about 100 C.



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



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



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



   If the intermediate imide halide product obtainable by the above process is reacted with a salt, such as an alkali metal salt of a carboxylic acid, especially a sterically hindered carboxylic acid, instead of an alcohol, a compound of the formula I is obtained in which both radicals R1 and R16 are acyl groups .



   In a compound of the formula I in which both radicals R1 and R represent acyl groups, one of these groups, preferably the less sterically hindered one, e.g. B. by hydrolysis or aminolysis, can be selectively removed. A.
In a compound of the formula I in which R1 and R1 together with the nitrogen atom represent a phthalimido group, this can e.g. by hydrazinolysis, i.e. when treating such a compound with hydrazine, are converted into the free amino group.



   Certain acyl radicals RiAeiner acylamino group in compounds obtainable according to the invention, such as. B. the 5 amino-5-carboxy-valeryl radical, in which the carboxyl and / or the amino group are optionally protected, can also be treated with a nitrosating agent, such as nitrosyl chloride, with a carbocyclic arene diazonium salt, such as benzene diazonium chloride, or with a positive Halogen donating agents 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 treating the reaction product with a hydroxyl-containing agent such as water or a lower alkanol, e.g. B. methanol, or, if the amino group is unsubstituted in the 5-amino-5-carboxy-valeryl radical R1 and the carboxy group z.

  B. is protected by esterification, and Rlb is preferably an acyl radical, but can also mean hydrogen, by standing in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, 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 Rt 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 RA1, can e.g. B.



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



   In a compound of the formula I in which Rt and Rb are hydrogen, the free amino group can by acylation methods known per se, eg. B. by treating with carboxylic acids or reactive acid derivatives thereof such as halides, e.g. Fluorides or chlorides, or anhydrides (including the internal anhydrides of carboxylic acids, i.e. ketenes, or of carbamic or thiocarbamic acids, i.e. isocyanates or isothiocyanates, or mixed anhydrides such as those which are e.g.

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



   An acyl group can also be introduced by reacting a compound of the formula I, in which Rl and Rb are hydrogen, with an aldehyde, such as an aliphatic, aromatic or araliphatic aldehyde, the Schiff base formed e.g. B. acylated by the methods given above and the acylation product, preferably in a neutral or weakly acidic medium, hydrolyzed.



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



  Bromoacetyl group, or e.g. B. by treating with a carbonic acid dihalide such as phosgene, a halocarbonyl, e.g. B. chlorocarbonyl group, and introduce a thus obtainable N (halo-lower alkanoyl) - or N- (halocarbonyl) amino compound with suitable exchange reagents, such as basic compounds, eg. B. tetrazole, thio compounds, e.g. B. 2-mercapto-1-methyl-imidazole, or metal salts, e.g. B. sodium azide, or alcohols such as lower alkanols, e.g. B. tert-butanol, implement and thus arrive at substituted N-lower alkanoyl or N-hydroxycarbonylamino compounds. Furthermore, you can z. B. a compound of formula I in which Rt is a preferably substituted glycyl group such as phenylglycyl and Rb is hydrogen, with an aldehyde, e.g. Formaldehyde, or a ketone such as lower alkanone, e.g.

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



   In both reactants, free functional groups can be temporarily protected in a manner known per se during the acylation reaction and can be released after the acylation by methods known per se. So you can preferably z. B. Amino or carboxyl groups in the acyl radical during the acylation reaction e.g. in the form of acylamino, such as 2,2,2-trichlorethoxycarbonylamino, 2 bromoethoxycarbonylamino, or tert-butyloxycarbonylamino, or in the form of esterified carboxy, such as diphenylmethoxycarbonyl, protect and subsequently, optionally after conversion of the protective group, e.g. B. a 2 Bromoäthoxycarbonyl- in a 2-Jodäthoxycarbonylgruppe, z. B.



  cleavage of such protected groups by treatment with suitable reducing agents, such as zinc in the presence of aqueous acetic acid, or with trifluoroacetic acid, or by hydrogenolysis.



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



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



   An amino group can also be protected by introducing a silyl and stannyl group. Such groups are introduced in a manner known per se, e.g. B. by treatment with a suitable silylating agent, such as a dihalodi-lower alkyl-silane or tri-lower alkyl-silyl halide, e.g. B. dichloro-dimethylsilane or trimethyl-silyl chloride, or an optionally N-mono-lower alkylated, N, N-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkyl-silyl) -amine, (see e.g. British Patent No. 1,073,530), or with a bis (tri-lower alkyl tin) oxide, e.g. Bis- (tri-n-butyl-tin) oxide, a tri-lower alkyl tin hydroxide, e.g.

  Triethyl tin hydroxide, a tri-lower alkyl-lower alkoxy tin, tetra-lower alkoxy tin or tetra-lower alkyl tin compound, and a tri-lower alkyl tin halide, e.g. B. tri-n-butyl tin chloride (see e.g. Dutch Auslegeschrift 67/17107).



   In a compound of the formula I obtainable according to the process with a group of the formula -C (= O) -O-R2, in which R2 is hydrogen, the free carboxyl group can be converted into a protected carboxyl group in a manner known per se, e.g. B.



  by treating with a diazo compound such as a diazo lower alkane, e.g. B. diazomethane or diazoethane, or a phenyldiaza-lower alkane, e.g. B. phenyldiazomethane or diphenyldiazomethane, or by reacting with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. B. dicyclohexylcarbodiimide, as well as carbonyldiimidazole, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid.

 

  Furthermore, acid halides, such as chlorides (produced e.g.



  by treatment with oxalyl chloride), activated esters (formed e.g. with N-hydroxy nitrogen compounds) or mixed anhydrides (obtained e.g. with haloformic acid lower alkyl esters, such as ethyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride) by reaction with alcohols, optionally in the presence of a base such as pyridine, converted into an esterified carboxyl group.



   Mixed anhydrides can be prepared by reacting a compound of the formula I in which R 2 is hydrogen, preferably a salt, especially an alkali metal or ammonium salt thereof, with a reactive derivative such as a halide, e.g. B. the chloride, an acid, e.g. B. a lower alkyl haloformate or a lower alkanecarboxylic acid chloride, reacted.



   In a compound obtained, a grouping of the formula -C (= O) -O-R2 can be converted into another group of this formula, e.g. B. 2-chloroethoxycarbonyl or 2-bromo ethoxycarbonyl of the formula <(= O) -ORA by treating with an iodine salt, such as sodium iodide, in the presence of a suitable solvent, such as acetone, in 2-iodoethoxycarbonyl.



   Protected by organic silyl or stannyl groups
Carboxyl groups can be formed in a manner known per se, e.g. B. by adding compounds of formula I in which R2 is hydrogen, 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 interpretation No.



   67/17107.



   In a compound of the formula I obtainable according to the invention having an esterified carboxyl group, the latter e.g. B. an easily convertible into the free carboxyl group esterified carboxyl group of the formula -C (= O) -O-RA, this can be done in a manner known per se, for. B. depending on the type of esterifying radical R2, are converted into the free carboxyl group, a grouping of the formula -C (= O) -OR2 or -C (= O) -OR, b z. 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 Grouping of the formula -C (= O) -O-Rb also by treatment with a suitable nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, a grouping of the formula -C (= O) -OR2 z. B. by irradiation, preferably with ultraviolet light, with shorter-wave ultraviolet light, e.g. B. under 290 my, if R2 z.

  B. one optionally in the 3-, 4- and / or 5-position, e.g. benzyl radical substituted by lower alkoxy and / or nitro groups, or works with longer-wave ultraviolet light, e.g. B. over 290 m, m, if R2 z. B. a benzyl radical substituted in the 2-position by a nitro group, a grouping -C (= t)) - OR2 z. B. by treating with a suitable acidic agent such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, a grouping = 0) -0R2 by hydrolysis, e.g.

  B. by treatment with an acidic or weakly basic aqueous agent such as hydrochloric acid or aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer of pH about 7 to about 9, and a grouping -C (= O) 4R2 by hydrogenolysis, e.g. B. by treating with hydrogen in the presence of a noble metal, e.g. B. Palladium catalyst.



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



   Furthermore, modified functional groups, such as acylated amino groups or esterified carboxy groups, by methods known per se, eg. B. the above-described, release or functionally modify free functional groups, such as amino or carboxy groups, by methods known per se, e.g. B. acylating or esterifying, or substituting.



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



  Furthermore, the reaction mixture of an acid addition salt of a 4-Ouaslylsemicarbazids with sodium nitrite with a compound of the formula I, wherein z. B. the amino protective group R1 represents an optionally substituted glycyl group, convert it and convert the amino group into a 3-guanylureido group.



   Salts of compounds of the formula I can be prepared in a manner known per se. Thus one can use salts of compounds of formula I in which R2 is hydrogen, e.g. by treating with metal compounds such as alkali metal salts of suitable carboxylic acid, e.g. the sodium salt of oc-ethyl-caproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formula I with basic groups are obtained in a customary manner, for. By treating with an acid or a suitable anion exchange reagent.

  Internal salts of compounds of formula I which contain a salt-forming amino group and a free carboxyl group can e.g. by neutralizing salts such as acid addition salts to the isoelectric point, e.g. with weak bases, or by treatment with liquid ion exchangers.



   Salts can be converted into the free compounds in the usual way, metal and ammonium salts e.g. 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 prepared by methods known per se, e.g. by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation processes, can be separated into the individual isomers. Racemates obtained can be used in the customary manner, if appropriate after introducing suitable salt-forming groups, e.g. by forming a mixture of diastereoisomeric salts with optically active salt-forming agents, separating the mixture into the diasteroisomeric salts and converting the separated salts into the free compounds or by fractional crystallization from optically active solvents into which antipodes are separated.



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

 

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



   The 1-oxides of the Ceph-3-em compounds of the formula 1 form another subject matter of the present invention.



   The starting materials of the formula II used according to the invention are new and are produced by a novel process.



   They are obtained by converting into compounds of the formula
EMI11.1
 the formyl group is replaced by hydrogen and, if desired, an amino protective group Rl in a compound obtained is replaced by hydrogen and, if desired, in a compound obtainable in this way protects the free amino group, and / or, if desired, a compound of the formula II obtained in another Compound of the formula II converted, and / or, if desired, a compound obtained with a salt-forming group in a salt or a salt obtained in the free compound or in another salt, and / or, if desired, a mixture of isomers obtained in the individual Separates isomers.



   In a compound of the formula III, an amino protective group R2 is in particular an acyl group Ac, in which free functional groups, e.g.



  Amino, hydroxyl or carboxyl groups, in a manner known per se, amino groups z. 15. by acylation, tritylation, silylation or stannylation, and hydroxyl or carboxy groups, e.g. B. can be protected by esterification, including silylation or stannylation, and R1 for hydrogen, while R2 primarily one, with the -C (= O) -O grouping a protected, preferably an esterified carboxyl group that can be cleaved under mild conditions represents the forming radical R2.

  Rt is preferably the organic radical of a sterically hindered alcohol, such as a methanol containing optionally substituted aliphatic or aromatic hydrocarbon radicals; this contains primarily three radicals of aliphatic character or 1 to 3, preferably 2 radicals of aromatic character as substituents. Rt primarily represents an optionally substituted, e.g. by lower alkoxy, such as methoxy, substituted diphenylmethyl radical, e.g. B. benzhydryl or 4,4'-dimethoxy-benzhydryl, but can also represent a suitably substituted benzyl radical.



  The remainder of a sterically hindered alcohol can also be that of an α-polybranched lower alkanol, e.g. B. represent a tert-butyl group, or a cycloalkanol or cycloalkenol optionally containing endo bridges; such residues are e.g. B. Adamantyl groups such as 1-adamtyl.



  Free functional groups in an amino protective group Rt and / or in an acyl radical Rl and / or in a carboxyl protective group RA are preferably protected in a manner known per se.



   The replacement of the formyl group by hydrogen in a compound of the formula III is carried out by decarbonylation. This reaction is carried out primarily by treating the latter with a carbon monoxide scavenging heavy metal complex. Such heavy metal complexes are, in particular, platinum metal complexes, a platinum metal being, apart from platinum, e.g. Understand irdium, rhodium and ruthenium, also palladium and osmium. A carbon monoxide-absorbing platinum metal complex preferably contains organic ligands, which can be connected to the platinum metal atom not only by a carbon atom but also by a heteroatom, in particular a phosphorus atom, via the minor valences (which form non-covalent bonds) of the platinum metal atom.

  In addition to these organic ligands, the complex can also contain substituents such as heteroatoms, in particular halogen, such as chlorine atoms, or carbonyl groups via the main valences (i.e. covalently bonded). Carbon monoxide-absorbing platinum metal complexes of this type are capable of carbon monoxide via main valences, i.e. in covalent bond.



   The platinum metal complexes used are e.g. Phosphine-containing platinum metal complexes, primarily phosphine-platinum metal complexes, which contain one, two or more phosphines. These phosphines preferably contain, as substituents, optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, primarily lower alkyl, e.g. n-Butyl, or in particular optionally substituted phenyl, such as phenyl, as substituents. Apart from the phosphorus-containing parts, e.g. the phosphines, the platinum metal complexes can contain further organic ligands, in particular those that can replace one, two or more phosphorus-containing ligands, such as phosphines, in an existing phosphorus-containing platinum metal complex, e.g.

  B. suitable nitriles, such as acetonitrile, in non-covalent bond with the metal atom, and / or halogen atoms, e.g. B. chlorine, or carbonyl groups in covalent bond with the metal atom.



   Preferably, bis-trisubstituted phosphine-platinum halides, bis-trisubstituted phosphine-carbonyliridium halides or tris-trisubstituted phosphine-iridium halides, primarily tris-trisubstituted phosphine-rhodium halides, in which the substituents of the phosphine are preferably lower alkyl, e.g. n-butyl, and are primarily phenyl, and the halides are primarily chlorides. Such phosphine-platinum metal complexes, which
Carbon monoxide in a covalent bond are able to include such. B.

  Bis-triphenylphosphine-platinum-II-chloride [(C6Hs) 3P] PtCl or bis-triphenylphosphine-carbonyliridium-
II-chloride [(C6Hs) 3P] 2Ir (CO) Cl, as well as tris-triphenylphosphine iridium-I-chloride [(C6Hs) 3P] 3IrCl, and primarily tris-triphenylphosphine-rhodium-I-chloride [(C6Hs) 3RhCl.



   If desired or necessary, the decarbonylation can be carried out with the above heavy metal complexes in the presence of suitable catalysts or activating agents, e.g. Lewis acid, such as boron trifluoride (which can be used e.g. together with bis-triphenylphosphine-platinum chloride), also a perchlorate, such as alkali metal perchlorate, e.g.



   Sodium perchlorate (which, for example, can be used together with bis-triphenyl phosphine carbonyl iridium chloride), be carried out.



   It is preferred to work in the presence of inert
Solvents, especially hydrocarbons, such as aliphatic or cycloaliphatic, especially aromatic hydrocarbons, z. B. benzene, toluene or xylene, halogenated hydrocarbons, such as corresponding aliphatic or aromatic chlorinated hydrocarbons, e.g.



   Methylene chloride or chlorobenzene, ethers, such as aliphatic, cycloaliphatic or aromatic, also mixed
Ethers, e.g. Di-n-butyl ether, dioxane, diphenyl ether or anisole, nitriles, such as aliphatic or aromatic nitriles, e.g. B. acetonitrile or benzonitrile, or ketones, especially aliphatic ketones, such as lower alkanones, e.g. B. acetone,
Ethyl methyl ketone or isobutyl methyl ketone, or mixtures of such solvents. Thereby the reaction is taking
Cooling, at room temperature or with warming, e.g. B. at about 10 C to about 1500 C, such as at about 40 C to about 1200 C, further if necessary, in a closed vessel and / or in an inert gas atmosphere, e.g.

  B. performed under nitrogen or argon.



   The carbon monoxide-absorbing heavy metal complexes to be used in the above reaction can be prepared in a manner known per se, e.g. by treating the corresponding heavy metal halides, such as rhodium chloride or iridium chloride, optionally in the form of hydrates, with a phosphine such as triphenylphosphine, preferably with an excess of a phosphine, in the presence of a suitable solvent such as a lower alkanol, e.g.



  Ethanol, and preferably reacted at elevated temperature; Usually the desired complex can be obtained in crystalline form.



   The intermediates of formula III can e.g. obtained by the method described in the Dutch patent application no. 6815631, by converting in a Ceph-2-em compound of the formula
EMI12.1
 the acetyloxymethyl group, e.g. B. 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 Bacterium subtilis, converted into the hydroxymethyl group, and oxidized this to a formyl group. The oxidation can e.g. B.



  by the method described in U.S. Patent No. 3,351,596, i.e. by treating with oxidizing metal compounds such as oxides, e.g. Chromium trioxide or manganese dioxide, or advantageously by treatment with aliphatic sulfoxides, such as di-lower alkyl sulfoxides, e.g. Dimethyl sulfoxide, or lower alkylene sulfoxides, e.g. B. tetramethylene sulfoxide, in the presence of aliphatic carboxylic acid anhydrides, e.g. Acetic anhydride, preferably using an excess of the sulfoxide and an equimolar amount of the anhydride compared to the sulfoxide, and at temperatures from about -50 ° C. to about + 70 ° C., if desired, in the presence of an additional inert solvent such as benzene or toluene carried out.



   The 3-formyl-ceph-2-em compounds of the formula III can also be totally synthetic, e.g. B. obtained by the method described in Austrian Patent Nos. 263,768 and 264,537.



   The invention is described in the following examples. The temperatures are given in degrees Celsius.



   example 1
A solution of 0.50 g of amorphous 7ss-phenylacetylamino ceph-2-em-4a-carboxylic acid diphenylmethyl ester in 25 ml of absolute pyridine is left to stand in the dark under nitrogen for 17 hours. The pyridine is removed under reduced pressure, the residue is treated several times with absolute toluene and again evaporated to dryness.

  The practically colorless, glass-like residue, which according to thin-layer chromatogram (silica gel; system toluene / ethyl acetate 4: 1 or toluene / acetone 9: 1) consists almost exclusively of 7ss-phenylacetylamino-ceph-3-em-4-carboxylic acid diphenylmethyl ester, Rf values 0.35 and 0.39, respectively, and contains only traces of starting material, Rf = 0.31 and 0.35, respectively, is dissolved in a little methylene chloride and treated with diethyl ether and cyclohexane while warm. The desired diphenylmethyl 7ss-phenylacetylamino-ceph-3-em-4-carboxylate crystallizes in the form of fine matted needles which melt at 162.5-164. The analysis product is crystallized again from the same solvent mixture and dried in a high vacuum at 35 for 18 hours, F.



     163.5-164.5 (uncorr.); [α] D20 = +30 # 1 (c = 0.968 in dioxane); Thin-layer chromatogram (silica gel; identification in ultraviolet light and with iodine vapor): Rf = 0.55 (system: toluene / acetone 4: 1), Rf = 0.35 (system: toluene / acetone 9: 1) and Rf = 0.40 ( System: toluene / ethyl acetate 4: 1); Ultraviolet absorption spectrum:

  A m0x = 258 m, u (# = 6100) and # min = 240 m (# = 5250) in methylene chloride) and # max = 259m (# = 6050) and # min = 239m (# = 4950) (in 95 wks aqueous ethanol); Infrared absorption spectrum: characteristic bands at 2.90, 5.57) 11.5.76, 5.91) 11, 6.09, 6.66, 7.13, 8.12, 8.63, 9.07, 10, 43 and 12.22 (in methylene chloride) and 3.01) 11, 5.60, 5.82, 6.04, 6.08 (shoulder), 6.51 and 7.13 (in mineral oil).



   The starting material can be prepared as follows: A slurry of 3.40 g of 3-acetyloxymethyl-7ssphenylacetylamino-ceph-2-em-4a: -carboxylic acid in 70 ml of distilled water is stirred with a vibromixer until the pH value is 7.3 1-n. aqueous sodium hydroxide solution added. The solution is heated to 35 in a thermostatic bath and 0.4 g of the cell lyophilisate from Bacillus substilis ATCC 6633 in 3 ml of water is added. The pH value is adjusted by adding 1-n. aqueous sodium hydroxide solution kept constant at 7.4; after about 2¸ hours, half of the theoretical sodium hydroxide consumption is reached.



  The reaction is left to complete until no more alkali is consumed and the pH of the reaction solution does not change any more even after standing for several hours at room temperature. It is covered with a layer of 300 ml of cooled ethyl acetate and acidified to pH 2.0 with 5 molar aqueous phosphoric acid while stirring well. After the layers have been separated, the aqueous phase is saturated with sodium chloride and extracted with two further portions of 250 ml each of cold ethyl acetate. The combined organic phases are washed five times with 50 ml each of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated.

  The residue consists of chromatographically uniform 3-hydroxymethyl-7ss-phenylacetylamino-ceph-2-em-4a-carboxylic acid, which, after repeated crystallization from a mixture of ethyl acetate and cyclohexane, melts in the form of white needle-shaped crystals at 156-156.5.



   A solution of 2.79 g of 3-hydroxymethyl-7ss-phenylacetylamino-ceph-2-em-4as-carboxylic acid in 85 ml of absolute dioxane is mixed with 2.29 g of 2,3-dichloro-5,6-dicyano-1,4 -benzoquinone added. The clear reaction mixture is left to stand at 45 for 20 hours and then stored at about 5 for 2 hours. The 2,3-dichloro-5,6-dicyanohydroquinone precipitated in crystalline platelets is filtered off, the filtrate is evaporated to dryness under reduced pressure, the residue is taken up in a little ethyl acetate and the solution is filtered. The ethyl acetate solution diluted to 240 ml is extracted once with 120 ml and twice with 90 ml of a 0.5 molar aqueous dipotassium hydrogen phosphate solution while cooling.

  The aqueous phases are washed with 2 portions of 150 ml of ethyl acetate, are covered with 250 ml of ice-cold ethyl acetate and the pH is adjusted to 2.1 with concentrated phosphoric acid while stirring well. The aqueous phase is separated off, saturated with sodium chloride and extracted with 150 ml and 130 ml of ethyl acetate. The organic extracts are washed four times with 70 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. An amorphous product which is almost uniform by thin layer chromatography and which is chromatographed on 180 g of silica gel is thus obtained.

  With a 4: 1 mixture of methylene chloride and ethyl acetate, the pure 3-formyl-7ss-phenylacetylamino-ceph-2-em-4a-carboxylic acid is eluted by thin layer chromatography; Thin-layer chromatogram (silica gel plates): Rf = 0.39 (system: n-butanol / acetic acid / water 75: 7.5: 21), Rf = 0.27 (system: n-butanol / ethanol / water 40:10:50) and Rf = 0.53 (system: n-butanol / acetic acid / water 40:10:40). A further amount of the pure product can be isolated from the impure fractions by repeated column chromatography.

  The substance crystallizes from a mixture of methanol and methylene chloride with inclusion of methanol, F.137.5-138.5, [α] 2D0 = + 580 # 1 (c = 1.168% in dioxane); Ultraviolet absorption spectrum (in 95% ethanol): # max = 288 m (# = 18850) and # min = 246 m (# = 2075).



   A solution of 10 g of 3-formyl-7ss-phenylacetylamino ceph-2-em-4a-carboxylic acid in 250 ml of a 4: 1 mixture of dioxane and methanol is treated with a solution of 1.5 mol equivalents of diphenyldiazomethane in cyclohexane.



  After 2 hours at room temperature, the red-violet solution is evaporated to dryness under reduced pressure.



  The residue is dissolved in hot methylene chloride; the
The solution is diluted with cyclohexane in the heat, and the 3-formyl-7ss-phenylacetylamino-ceph-2-em-4acarboxylic acid diphenylmethyl ester is obtained in practically quantitative yield in the form of fine, colorless, matted needles, F.



  175.5-176 (uncorrupted, decomposed); [α] D20 = +513 # 1 (c = 1.084 in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.35 (system: toluene / acetone 80:20) and Rf = 0.58 (system: toluene / acetone 65:35); Ultraviolet absorption spectrum (in 95% ethanol): # max = 289 m (# = 20200) and # min = 245m (# = 2100); infrared absorption spectrum: characteristic bands at 2.92, 3.53, 5.59, 5, 72, 5.91, 6.34, 6.61 and 6.67 (in methylene chloride) and at 3.00, 5.63, 5.76, 5.95 (Doopelbande), 5.99, 6.07 and 6.58 (in mineral oil).



   A solution of 1.05 g of 3-formyl-7ss-phenylacetylamino ceph-2-em-4α-carboxylic acid diphenylmethyl ester in 250 ml of absolute degassed benzene is mixed with 1.87 g of tristriphenylphosphine rhodium chloride under argon. After two hours of heating to 70 and 5¸ hours at reflux temperature, the reaction solution is left to stand for 16 hours. A fine precipitate is filtered off; the filtrate is gassed with carbon monoxide, evaporated to dryness and the residue taken up in a little methylene chloride. After standing at 4 for 20 minutes, lemon-yellow precipitate containing bis-triphenylphosphine carbonylrhodium chloride is filtered off, washed with pentane and dried. The mother liquors are evaporated to dryness under reduced pressure and chromatographed on 75 g of silica gel.

  The amorphous 7ss-phenylacetylamino-ceph-2-em-40'-carboxylic acid diphenylmethyl ester, pure according to thin layer chromatography, is eluted with a 4: 1 mixture of toluene and methylene chloride; unchanged starting material is eluted with a 3: 7 mixture of toluene and methylene chloride.



   The analytical product of the 7ss-phenylacetylamino-ceph-2 em-4α-carboxylic acid diphenylmethyl ester is purified again by chromatography on silica gel, lyophilized from dioxane and dried in a high vacuum at room temperature for 30 hours; Thin-layer chromatogram (plates; developing with iodine vapor; identification with ultraviolet light with # 254 m: Rt = 0.53 (system: toluene / acetone 4: 1), Rf = 0.75 (system: toluene / acetone 2: 1), Rf = 0 .73 (system: toluene / ethyl acetate;: 1), Rf = 0.56 (system: toluene / ethyl acetate 2: 1) and Rf = 0.36 (system:

  Toluene / ethyl acetate 4: 1); Ultraviolet absorption spectrum: # max = 248 m (# = 5200) and # min = 242 m (# = 5050) (in 95% aqueous ethanol), and # max = 247 m (# = 5300) and # min = 243 m ('= 5250) (in methylene chloride); Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.92, 5.62, 5.72, 5.93, 6.23, 6.64, 6.68, 6.88, 7.16, 7.58, 8 , 14, 8.35, 8.50, 8.65 and 10.18.



   Example 2
A solution of 0.566 g of 7ss-phenylacetylamino-ceph-3em-4-carboxylic acid diphenylmethyl ester in 2.5 ml of anisole and 10 ml of trifluoroacetic acid is left to stand for 20 minutes at room temperature and then several times with the addition of toluene until the trifluoroacetic acid is completely removed to dryness taken. The residue is taken up in ethyl acetate and 0.5 molar aqueous dipotassium hydrogen phosphate solution and the phases are separated. The aqueous solution is washed twice with ethyl acetate and the organic solution twice with 0.5 molar aqueous dipotassium hydrogen phosphate solution. The combined aqueous solutions are covered with fresh ethyl acetate and acidified with 20% aqueous phosphoric acid.

  It is extracted with ethyl acetate, the organic solution is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed on 50 times the amount of silica gel (washed with concentrated hydrochloric acid) and the 7ss-phenylacetylamino-ceph-3-em-4-carboxylic acid is eluted with methylene chloride containing 10-20% methyl acetate.

  The fractions which are uniform according to thin-layer chromatography are crystallized from a mixture of ethyl acetate and cyclohexane; the colorless crystals melt at 190-191; Thin-layer chromatogram (silica gel; development with iodine vapor or identification under ultraviolet light): Rf = 0.58 (system: n-butanol / acetic acid / water 75: 7.5: 21), Rf = 0.265 (system: n-butanol / ethanol / water 40:10:50, Rf = 0.53 (system: n-butanol / acetic acid / water 40:10:40), Rf = 0.43 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11 ) and Rf = 0.43 (system: ethyl acetate / n butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10).



   Example 3
0.720 g of trimethylchlorosilane and 0.474 g of absolute pyridine are added to a solution of 0.955 g of 7ss-phenylacetylamino-ceph-3em-4-carboxylic acid in 60 ml of absolute methylene chloride. The mixture is stirred for 60 minutes at room temperature, the mixture is cooled to below -20, and a solution of 3.20 g of absolute pyridine in 30 ml of absolute methylene chloride and 23.4 ml of an 8% solution of phosphorus pentachloride in absolute methylene chloride is then added in succession to. The mixture is stirred for 60 minutes at -10 to -12, cooled again to about -20 and then 15 ml of absolute methanol are allowed to flow in. The mixture is stirred for 25 minutes at -10, then for 35 minutes at room temperature, 15 ml of water are added, the pH of the reaction mixture is increased from 1.8 to 2.2 by the dropwise addition of triethylamine, and it is stirred for 20 minutes at room temperature.

  The pH is increased to 3.8 by adding more triethylamine, the two-phase mixture is stirred for 90 minutes while cooling in an ice bath and then filtered. The filter residue is washed with methanol, methylene chloride and diethyl ether and dried in a vacuum desiccator. The 7ss-amino-ceph-3-em-4-carboxylic acid is thus obtained in amorphous form; the product is processed further without cleaning.



   Example 4
A solution of 1.94 g of 7ss-phenylacetylamino-ceph-3-em4-carboxylic acid diphenylmethyl ester in 100 ml of absolute methylene chloride is cooled to -, then with 3.86 ml of absolute pyridine and 31.6 ml of an 8% solution of phosphorus pentachloride in methylene chloride and the reaction mixture stirred for 30 minutes at -10 and for a further 30 minutes at -5. The golden yellow solution is cooled to -20 and 26.8 ml of absolute methanol are added so quickly that the internal temperature does not rise above -10.



  The reaction mixture is stirred for one hour at -10, left to stand for a further hour at 25-30 and then 80 ml of a 0.5 molar aqueous potassium dihydrogen phosphate solution are added with vigorous stirring.



  The pH of the two-phase reaction mixture is adjusted to 2 by the dropwise addition of 20% strength phosphoric acid, the mixture is stirred for 20 minutes at room temperature and the phases are separated. The aqueous solution is washed twice with methylene chloride; the combined organic solutions are washed with two portions of 20 ml of water each and dried over anhydrous magnesium sulfate.



   The solvent is removed under reduced pressure; the oily residue is applied to a column of 110 g of silica gel (5% water content). It elutes with methylene chloride phenylacetic acid methyl ester and with methylene chloride containing 3% acetic acid methyl ester, the 7ss-amino-ceph-3em-4-carboxylic acid diphenylmethylester, which is crystallized by dissolving a small amount of methylene chloride and adding the solution in the warm with diethyl ether (needle-shaped Crystals), wash with cold diethyl ether and dry.



  F. 153-154; Thin-layer chromatogram (silica gel): Rf = 0.50 (system: toluene / acetone 4: 1), Rf = 0.65 (system: toluene / acetone 2: 1), Rf = 0.40 (system: toluene / ethyl acetate 1 : 1) and Rf = 0.33 (system: toluene / diethyl ether 1: 1); Ultraviolet absorption spectrum: # max = 257 m (e = 8150) and, in = 245 m (e = 7730) (in methylene chloride) and # max = 255m (# = 5500) and # min = 236m (e = 4650) (in 95 % Ethanol); Infrared absorption spectrum:

   characteristic bands at 2.91) 11, 2.97) 11, 5.61) 11, 5.78) 11, 6.11) 11, 7.14) 11, 8.15, 8.29, 9.14 ) 11 and 9.83 (in methylene chloride) and at 2.99, 5.65, 5.77, 6.08, 7.14, 7.74, 7.84, 8.08, 8.53, 9, 14, 9.85 and 10.35 (in mineral oil).



   Example S.
0.380 g of 7ss-amino-ceph-3-em-4-carboxylic acid diphenylmethyl ester is poured over with 2 ml of anisole and 8 ml of absolute trifluoroacetic acid, the clear solution is left to stand for 10 minutes at room temperature and then diluted with about 20 ml of absolute toluene. The mixture is evaporated under reduced pressure; the residue is taken to dryness twice more together with toluene and then suspended in 5 ml of methanol, 5 ml of diethyl ether and 0.5 ml of water.



  The pH of the suspension is adjusted to 3.5 by adding dropwise a 5% solution of triethylamine in methanol; the mixture is left to stand in an ice bath for 30 minutes and the fine precipitate is filtered using a suitable glass suction filter. The pale beige-colored filter residue is washed with a mixture of methanol and methylene chloride, then with diethyl ether and dried at 35 under reduced pressure. The 7ss-amino-ceph-3-em-4-carboxylic acid, thus available as a fine microcrystalline powder, decomposes at 215; Thin-layer chromatogram (silica gel; development with iodine):

  Rf = 0.12 (system: n-butanol / acetic acid / water 67:10:23), Rf = 0.28 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6:30) and Rf = 0.21 (system: ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10); Infrared absorption spectrum (in mineral oil): characteristic bands at 3.12) 11, 3.80, 4.12 (shoulder), 4.92, 5.54, 6.05 (shoulder), 6.19, 6.55, 7 , 05, 7.42, 8.23) 11, 8.79, 9.55, 12.08, 12.69 and 13.04) 11.



   Example 6
The 7ss-aminoceph-3-em-4-carboxylic acid described in Examples 3 and 5 can be N-acylated and converted into 7- (N-Ac-amino) -ceph-3-em4-carboxylic acids by the following general processes:
option A
0.4 mmol of an acid [AcOlKI] is dissolved in 4 ml of absolute methylene chloride with the addition of 0.056 ml (0.4 mmol) of triethylamine [stock solution: 28.0 ml (200 mmol) of triethylamine, diluted to 100 ml with methylene chloride]. 0.0452 ml (0.4 mmol) of trichloroacetic acid chloride in 0.2 ml of methylene chloride [stock solution 22.6 ml (200 mmol) of trichloroacetic acid chloride, diluted to 100 ml with methylene chloride] are added to the solution, which has been cooled to - 150 ml -15 stirred.

  The solution with the mixed anhydride [Ac-OC (= O) -CCl3j is mixed with a finely dispersed slurry, cooled to -150, of 0.040 g (0.2 mmol) of 7-amino-ceph-3-em-4-carboxylic acid and 0.056 ml (0.4 mmol) of triethylamine in 4 ml of methylene chloride are added and the mixture is vibrated for 30 minutes at -15 and then for 30 minutes at 20 in an ultrasonic bath. The usually brown reaction solution is evaporated to dryness under reduced pressure, and the residue obtained is distributed between 10 ml of a 10% strength aqueous dipotassium hydrogen phosphate solution (pH 8.9) and 5 ml of ethyl acetate. The aqueous phase is adjusted to pH 2.6 with 20% aqueous phosphoric acid and then extracted exhaustively with ethyl acetate.

  The ethyl acetate extract (30-50 ml) is washed with water and dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed preparatively on a thin-layer plate on silica gel in a suitable solvent system for 2-5 hours. After the plate has been dried at room temperature in a nitrogen atmosphere, the silica gel zone absorbing under the ultraviolet light (254 m,) is mechanically detached from the plate and three times with 10 to
30 ml of ethanol or methanol extracted. After evaporation of the extract under reduced pressure, the
7ss-Ac-amino-ceph-3-em-4-carboxylic acid as a beige or almost colorless residue.



   If the thin-layer plate has more than one zone which absorbs ultraviolet light, the individual zones are processed separately, as described above. A sample of the resulting from the different zones
Material is tested against Staphylococcus aureus in the plate diffusion test. The material from the most microbiologically active
Zone is subjected to another preparative thin-layer separation, the chromatographically uniform
Product can isolate.

 

     Variant B
0.2 mmol of the sodium salt of an acid [AcONa] in 2 ml of absolute dimethylformamide is mixed with 0.2 mmol of trichloroacetyl chloride as in variant A and with a
Solution of 0.2 mmol of 7ss-amino-ceph-3-em-4-carboxylic acid and 0.2 mmol of triethylamine in 2 ml of dimethylformamide reacted and worked up as in variant A.



  Variant C
A mixture of 0.25 mmol of an acid chloride [AcCl] in
2 ml of methylene chloride is added to a solution, cooled to -150, of 0.040 g (0.2 mmol) of 7ss-amino-ceph-3-em-4carboxylic acid and 0.070 ml (0.5 mmol) of triethylamine in 5 ml
Methylene chloride was added and reacted and worked up as in variant A.



   Example7
A slurry of 0.20 g of N- (2,2,2-trichloroethoxycarbonyl) -D-a-phenylglycine in 6 ml of a 1: 1 mixture of tetrahydrofuran and acetonitrile is mixed with 0.085 ml of triethylamine. After cooling to -100, it is added dropwise
Exclusion of moisture 0.08 ml isobutyl chloroformate and stir for 15 minutes at -100. To dissolve the mixed anhydride, a solution consisting of 0.160 g of 7ss-amino-ceph-3-em-4-carboxylic acid and 0.081 ml of triethylamine in 2 ml of a 1: 1 mixture of water and tetrahydrofuran is added dropwise so that the internal temperature does not rise above zero.

  The reaction mixture is stirred for a further 30 minutes at 0 and for 90 minutes at room temperature, then the majority of the organic solvents are evaporated under reduced pressure. The residue is diluted with 5 ml of a 0.5 molar aqueous dipotassium hydrogen phosphate solution and 5 ml of ethyl acetate.



   Undissolved material is filtered off with the aid of a glass suction filter and a diatomaceous earth preparation. The layers of the filtrate are separated; the organic phase is extracted with the dipotassium hydrogen phosphate solution and discarded. The aqueous phases are washed with ethyl acetate, covered with fresh ethyl acetate and acidified to pH 2 with concentrated phosphoric acid. The organic phase is separated off and washed several times with a saturated aqueous sodium chloride solution. The aqueous phases are extracted twice with 10 ml of ethyl acetate each time and discarded. The combined organic extracts are dried over sodium sulfate and freed from the solvent under reduced pressure. The crude product is chromatographed on 10 g of silica gel.

  Unchanged N- (2,2,2-trichloroethoxycarbonyl) -D-α-phenylglycine is eluted with a 4: 1 mixture of toluene / ethyl acetate. The 7ss- (N-2,2,2-trichloroethoxycarbonyl-D-α-glycyl) -amino-ceph-3-em-4-carboxylic acid is eluted with the toluene-ethyl acetate mixture, which is compared to the 4: 1 -Ratio of increasing proportions of ethyl acetate used, infrared absorption spectrum (in mineral oil): characteristic bands at 5.61, 5.86, 5.92 and 6.12; ultraviolet absorption spectrum (in ethanol): λ max = 252 m; Thin-layer chromatogram (silica gel; development with iodine vapor): Rf 0.8 (system: n-butanol / acetic acid / water 71.5: 7.5: 21).



   A solution of 0.120 g of 7ss- (N-2,2,2-trichloroethoxy carbonyl-D-α-phenylglycyl-amino-ceph-3-em-4-carboxylic acid in 6 ml of dimethylformamide is dissolved in 10 ml of 90% aqueous acetic acid added and then treated with 0.600 g zinc dust.



  The mixture is stirred for 1 hour at room temperature, the unreacted zinc dust is filtered off, washed with dimethylformamide and the filtrate is stirred for about 10 minutes with 25 ml of an ion exchanger (Dowex 50-16; 20-50 mesh; sulfonic acid type in the H ion form) . The exchanger is filtered off and washed with water. The filtrate is evaporated to dryness in a high vacuum at a bath temperature of less than 30 (rotary evaporator). The residue is dissolved in 5 ml of an 8: 2 mixture of methanol and water and adjusted to pH 4.3 with a 1% solution of triethylamine in methanol. The mixture is stirred for 1 hour in an ice bath, evaporated to dryness and the residue is digested with methylene chloride. It is filtered off, washed thoroughly with methylene chloride and dried in a high vacuum.

  The 7ss- (D-0'-phenylglycylamino) - ceph-3-em-4-carboxylic acid is obtained in this way in a zwitterionic form
Form, F.178-179.5 (decompose; uncorr.); [Α] D20 = + 116 # 1 (c = 0.864 in 0.1-n. Aqueous sodium hydrogen carbonate solution); Thin layer chromatogram (silica gel;
Detection with ultraviolet light, # 254 or ninhydrin):
Rf = 0.30 (system: n-butanol / acetic acid / water 67:10:23), Rf = 0.61 (system: isopropanol / formic acid / water
77: 4: 19) and Rf = 0.13 (system:

  Ethyl acetate / n
Butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10); ultra violet absorption spectrum (in water): # max = 253 with (# = 4950) and # min = 277 m (# = 4550); infrared absorption spectrum (in mineral oil): characteristic bands at 2.83,
3.10, 3.25 (shoulder), 3.78, 5.59, 5.90, 6.10 (shoulder), 6.38, 7.05, 7.35, 7.77, 7.98, 8.32 , 8.50,
8.82 8/10, 12.15, 13.20, 13.66, 13.90 and 14.33.



   Example 8
In an analogous manner, with a suitable choice of
Starting materials and optionally after additional conversions the following Ceph-3-em compounds are obtained: 7ss- (D-5-diphenylmethoxycarbonyl-5-phthalimido-n-valerylamino) - ceph-3-em-4-carboxylic acid diphenylmethyl ester, thin-layer chromatogram (Silica gel plates; detection with iodine vapor): Rf = 0.62 (system: toluene / acetone 4: 1); Rf = 0.80 (system: toluene / acetone 2: 1) and Rf = 0.79 (system: toluene /
Ethyl acetate 2: 1); 7ss- [N-tert-butyloxycarbonyl-D - (α) - phenylglycyl] -amino-ceph-3-em-4-carboxylic acid diphenylmethyl ester, F.



   126-128 (uncorr .; with a clear melt at 145) after crystallization from a mixture of methylene chloride, diethyl ether and cyclohexyn; [α] D = -40 # 1 @ (c = 1.081 in
Chloroform); Thin layer chromatogram (silica gel plates;
Identification with iodine vapor): Rf = 0.39 (system: toluene / acetone 19: 1), Rf = 0.56 (system: toluene / acetone 14: 1) and Rf = 0.61 (system:

  Toluene / ethyl acetate 2: 1); Ultra violet absorption spectrum (in 95% ethanol): # max = 255m (# = 5750) and # min = 238m (# = 4950); infrared absorption spectrum: characteristic bands at 2.89,
2.97, 5.62, 5.83, 5.89, 6.11, 6.45, 6.69,
7.30, 7.72, 8.18, 8.56, 9.52, 9.71, 10.36, 13.19,
13.71 and 14.36 (in mineral oil) and at 2.70, 2.91,
5.58, 5.78, 5.82 (shoulder), 5.88M, 6.09, 6.61 (shoulder) and 6.69; 7ss- [D] - (α) -phenylglycyl] -amino-ceph-3-em-4-carboxylic acid, pure zwitterionic form, m.p. 178-179.5 (decompose; uncorr.); [Α] D20 = +116 # 1 (C = 0.864 in 0.1-n. Aqueous
Sodium hydrogen carbonate solution); Thin-layer chromatogram (silica gel; detection with ultraviolet light, A2s4 st or
Ninhydrin):

  Rf = 0.30 (system: n-butanol / acetic acid / water
67:10:23), Rf = 0.61 (system: isopropanol / formic acid /
Water 77: 4: 19) and Rf = 0.13 (system: ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10);
Ultraviolet Absorption Spectrum (in water): # max = 253 m, lt (e = 4 950) and # min = 277 m (e = 4 550);

  Infrared absorption spectrum (in mineral oil): characteristic bands at 2.83,
3.10, 3.25 (shoulder), 3.78, 5.59, 5.90, 6.10 (shoulder), 6.38, 7.05, 7.35, 7.77, 7.98, 8.32, 8.50,
8.82, 10.08, 12.15, 13.20, 13.66, 13.90 and
14.33;
7ss-phenylacetylamino-ceph-3-em-4-carboxylic acid [di (4 methoxyphenyl) methyl] ester;
7ss-Phenylacetylamino-ceph-3-em-4-carboxylic acid benzyl ester;
7ss-Phenyloxyacetylamino-ceph-3-em-4-carboxylic acid,
Thin-layer chromatogram (silica gel): Rf = 0.4-0.5 (system: n-butanol / acetic acid / water 75: 7.5: 21);
7ss- (ss-thienylacetyl-amino) -ceph-3-em-4-carboxylic acid, thin layer chromatogram (silica gel):

  Rf = 0.5-0.6 (system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30); Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): # max at 237 m; infrared absorption spectrum (in mineral oil): characteristic band at 5.62M.



   7ss- (1-tetrazolylacetyl-amino) -ceph-3-em-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.4-0.5 (system: n-butanol / pyridine / acetic acid / water 42:24: 4:30); Ultraviolet Absorption Spectrum (in methanol): # max at255m;
7ss- (1-methyl-2-imidazolylthio-acetyl) -amino-ceph-3-em4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.3-0.4 (system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30); Ultraviolet Absorption Spectrum (in methanol): # max at 252m;
7ss- (D-α-phenyl-α-2,2,2-trichloroethoxycarbonyloxy-acetyl-amino) -ceph-3-em-4-carboxylic acid diphenylmethyl ester; 7ss- (D-α-hydroxy-α-phenyl-acetylamino) -ceph-3-em-4-carboxylic acid, m. 184-187 (decomp.); Thin layer chromatography (silica gel):

  Rf = 0.51 (system: n-butanol / acetic acid / water 75: 7.5: 21), Rf = 0.25 (system: n-butanol / ethanol / water 40: 10:50), Rf = 0, 56 (system: n-butanol / acetic acid / water 44: 12:44), Rf = 0.32 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11) and Rf = 0.51 (system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30); [α] D = +72 # 1 (c = 1.079 in dioxane);

  Ultraviolet absorption spectrum (in 95% aqueous ethanol): # max = 254 m (# = 5450) and # min = 238 m (# = 5280); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.83, 3.00, 5.67, 5.93 (shoulder), 5.96, u, 6.16, 6.75, 8.03, 8.30, 9.04, 9.25, 9.45, 12.33, 13.05, 13.3, 13.57 and 14.23;
7ss- (4-pyridylthioacetyl-amino) -ceph-3-em-4-carboxylic acid, amorphous; Thin-layer chromatogram (silica gel): Rf = 0.35-0.45 (system: n-butanol / pyridine / acetic acid / water 42: 24: 4:30), infrared absorption spectrum (in mineral oil): characteristic band at 5.62;
7ss-acetoacetyl-amino-ceph-3-em-4-carboxylic acid, thin-layer chromatogram (silica gel);

  Rf = 0.3-0.4 (system: n butanol / acetic acid / water 75: 7.5: 21); ultraviolet absorption spectrum (in 0.1 m. Aqueous sodium hydrogen carbonate solution): # max at 238 m and 265 m;
7ss-cyanoacetylamino-ceph-3-em-4-carboxylic acid, thin-layer chromatogram (silica gel); Rf = 0.45-0.55 (system: n butanol / pyridine / acetic acid / water 38: 24: 8: 30); Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): # max at 254 m; infrared absorption spectrum (in mineral oil):

   characteristic bands at 4.32 y and 5.60 y; 7ss-α-cyano-propionyl-amino-ceph-3-em-4-carboxylic acid, thin layer chromatogram (silica gel); Rf = 0.5-0.6 (system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30); Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): # max at255m; infrared absorption spectrum (in mineral oil): characteristic bands at 4.44 and 5.62; 7ss - (α-cyano-phenylacetyl) -amino-ceph-3-em-4-carboxylic acid, thin-layer chromatogram (silica gel);

  Rf = 0.3-0.4 (system: n-butanol / acetic acid / water 75: 7.5: 21); Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): # max at 260 m; infrared absorption spectrum (in mineral oil): characteristic bands at 4.42 and 5.62 y; 7ss - [α- (N-tert-butyloxycarbonyl-amino) -α-2-thienyl-acetyl] -amino] -ceph-3-em-4-carboxylic acid, thin layer chromatogram (silica gel): Rf = 0.5 -0.6 (system:

  Ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11); Decomposition point at about 155 and F.270-280; Ultraviolet absorption spectrum (in 95% aqueous ethanol): # max = 237 m (e = 5210); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.82, 3.85, 5.68, 5.95, 6.58, 7.78, 8.07, 8.62, 9.01,, 9.52, 9.76 y, 10.4, u, 11.6, 12.3, u to and 13.88 y; and
7ss - (α-amino-α-2-thienylacetyl) -amino-ceph-3-em-4-carboxylic acid as zwitterion, thin-layer chromatogram (silica gel): Rf = 0.4-0.5 (system:

  Ethyl acetate / methyl ethyl ketone / formic acid / water 50:30:10: 10).



      Example 9
In an analogous manner, the following compounds can be obtained by selecting the suitable starting materials and, if necessary, with subsequent conversion of substituents: 7ss- (D-α-tert-butyloxycarbonylamino-α-4-hydroxyphenyl-acetylamino) -ceph-3-em- 4-carboxylic acid, thin-layer chromatogram (silica gel: detection with ultraviolet light # = 254 m, ninhydrin and p, p'-bis-dimethylamino-biphenyl or iododamph):

  Rf = 0.74 (system: n-butanol / acetic acid / water 67: 10:23), Rf = 0.48 (system: n-butanol / ethanol / water 40: 10:50), Rf = 0.70 (system : Isopropanol / formic acid / water 77: 4: 19), R = 0.72 (system: n-butanol / acetic acid / water 44: 12:44) and Rf = 0.55 (system: n-butanol / pyridine / Acetic acid / water 38: 24: 8: 30);

  Ultraviolet absorption spectrum (in 95% aqueous ethanol): # max = 230 m (# = 11390), # inflexion = 262 m (# = 5070) and # min = 217 m (e = 8750); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.77, u (shoulder), 3.02, 5.64, 5.87 (shoulder), 5.92, 5.97, 6.11, 6.62 and 8 .60;
7ss- (D-a-Amino-a-4-hydroxyphenyl-acetylamino) -ceph-3-em-4-carboxylic acid in the form of the inner salt, F.220-227 (decomposition) Ultraviolet absorption spectrum (in water):

  : # Inflexion = 259 m (# = 5450), # max = 229m (# = 2250) and # min = 218 m (# = 10700); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.85 (shoulder), 3.14, 5.66, 5.94, 6.21 (shoulder), 6.27, 6.38 and 6.59, u; Thin-layer chromatogram (silica gel; detection with ultraviolet light A = 254 m, iodine vapor or ninhydrin and p, p'-bis-dimethylaminodiphenyl): Rf = 0.255 (system: n butanol / acetic acid / water 67:10:23), Rf = 0.61 (System: isopropanol / formic acid / water 77: 4: 19) and Rf = 0.12 (system:

  Ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10); Diphenylmethyl 7ss- [D-tert-butyloxycarbonylamino-α- (4-isothiazolyl) -acetylamino] -ceph-3-em-4-carboxylate, M.p. 122123; Thin-layer chromatogram (silica gel): Rf = 0.57 System:

  Toluene / acetone 2: 1) and Rf = 0.23 (system: toluene / ethyl acetate 2: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): A, njn = 250 m (e = 12050), #shoulder = 271 m (e = 4500) and amine = 235 m (e = 8200); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 3.27, 3.86, 2.91, 5.58, 5.80, 5.87, 6.11, 6.19, 7.16, 7 , 31, 8.15 and 8.64; 7ss- [D-α-amino-α- (4-isothiazolyl) -acetylamino] - ceph-3-em-4-carboxylic acid in the form of the inner salt, thin layer chromatogram (silica gel): Rf = 0.32 (system :

   n butanol / acetic acid / water 75: 7.5: 21) and Rf = 0.62 (system: isopropanol / formic acid / water 77: 4: 19); Ultraviolet absorption spectrum (in ethanol): # max = 248 m (e = 6100) and # min = 230 m (# = 4100); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.85, u, 3.10, 3.25,
5.62, 5.92, 6.10 and 8.02; and 7ss- [D-α-hydroxy-phenylacetylamino) -α-phenyl-acetylamino] - ceph-3-em-4-carboxylic acid in the form of the sodium salt, m.p. 223-225 (decomposition); [α] D20 = +45 # 1 (c = 0.978 in water); Thin layer chromatogram (in silica gel); Development with ninhydrin and iodine):

  Rf = 0.66 (system: n-butanol / acetic acid / water 67:10:23), Rf = 0.76 (system: isopropanol / formic acid / water 77: 4: 19), Rf = 0.58 (system: n-butanol / pyridine / formic acid / water 34:24: 12:30), Rf = 0.42 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11) and Rf = 0.59 (system: n-butanol / acetic acid / water 44:12:44); Ultraviolet absorption spectrum (in water): λmax = 250 m (E = 5550) and # min = 240 m (5480); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.77, 2.98, 3.03, 3.13, 5.67, 5.94, 5.99, 6.13) 11, 6.21) 11, 6 , 26) 11, 6.33) 11, 6.66) 11, 7.10) 11, 7.33) 11, 8.01) 11, 8.22) 11, 9.45) 11, 9.95 ) 11, 12.33, 13.32, 13.62 and 14.37.



   PATENT CLAIM I
1. Process for the preparation of Ceph-3-em derivatives of the formula
EMI17.1
 wherein R, a represents hydrogen or an amino protecting group R1 @, and R1b represents hydrogen or an acyl group Ac, or RA and R1b together represent a divalent amino protective group, and RA represents hydrogen or one, together with the -C (= O) -O group represents a protected carboxyl group-forming organic radical R2, or salts of such compounds with salt-forming groups, characterized in that a Ceph-2-em derivative of the formula
EMI17.2
 treated with a weakly basic agent and the corresponding Ceph-3-em derivative isolated.



   SUBCLAIMS
1. The method according to claim I, characterized in that starting materials of the formula II are used in which R1 is an acyl group and Rb1 is hydrogen, and R2A is an esterified one with the -C (= O) -O grouping which can be cleaved under mild conditions Represents carboxyl group-forming organic radical.



   2. The method according to claim I, characterized in that R2A stands for the organic radical of a sterically hindered alcohol.



   3. The method according to claim I, characterized in that R2 represents an optionally substituted diphenylmethyl or benzyl radical, e.g. B. benzhydryl or 4,4'-dimethoxybenzhydryl.



   4. The method according to claim 1, characterized in that a weak organic, nitrogen-containing base is used as the isomerizing agent.



   5. The method according to claim I, characterized in that one is a teritäre heterocyclic base aromatic
Character, a tertiary aromatic base or a tertiary aliphatic, azacycloaliphatic or araliphatic base as
Isomerizing agent used.



   6. The method according to claim I, characterized in that a base of the pyridine type, such as pyridine, is used as the Iso merisierungsmittel.



   7. The method according to claim 1, characterized in that a tri-lower alkyl amine, such as triethylamine, as
Isomerizing agent used.



   8. The method according to claim 1, characterized in that the mixture of a base of the pyridine type and one
N, N, N-tri-lower alkylamine, e.g. Pyridine and triethylamine as
Isomerizing agent used.



   9. The method according to claim I, characterized in that the isomerization is carried out in the presence of a derivative of a carboxylic acid which results in the formation of a mixed
Anhydride is suitable, as is a carboxylic acid anhydride or chloride.



   10. The method according to claim 1, characterized in that 7ss-phenylacetylamino-ceph-3-em-4-carboxylic acid diphenylmethyl ester is prepared.



      PATENT CLAIM II
Use of the compounds of formula 1 obtained according to patent claim I, in which the group -C (= O) -O-R2 means a group -C (= O) -O-R2 which can easily be converted into the free carboxyl group, characterized in that these Group -C (= O) -O-RA converted into a free carboxyl group by reduction, photolysis or solvolysis.



   SUBCLAIMS
11. Use according to claim II, characterized in that RA2 stands for a methyl group which is polysubstituted by optionally substituted hydrocarbon radicals or by a carbocyclic aryl group having an electron-donating substituent or a heterocyclic group of aromatic character having oxygen or sulfur atoms as ring members, or which is monosubstituted in a polycycloaliphatic hydrocarbon radical or a ring member in an oxa or thiacycloaliphatic radical which is in position to the ring oxygen or ring sulfur atom, and the ester group of the formula -C (= O) -O-R2 @ is cleaved by treatment with an acidic agent.

 

   12. Use according to claim II, characterized in that the 7ss-phenylacetylamino-ceph-3-em-4-carboxylic acid diphenylmethyl ester obtained according to patent claim I is converted into the 7ss-phenylacetylamino-ceph-3-em-4- by treatment with trifluoroacetic acid and anisole. carboxylic acid transferred.

** WARNING ** End of DESC field could overlap beginning of CLMS **.



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. +45 # 1 (c = 0.978 in water); Thin layer chromatogram (in silica gel); Development with ninhydrin and iodine): Rf = 0.66 (system: n-butanol / acetic acid / water 67:10:23), Rf = 0.76 (system: isopropanol / formic acid / water 77: 4: 19), Rf = 0.58 (system: n-butanol / pyridine / formic acid / water 34:24: 12:30), Rf = 0.42 (system: Ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11) and Rf = 0.59 (system: n-butanol / acetic acid / water 44:12:44); Ultraviolet absorption spectrum (in water): λmax = 250 m (E = 5550) and # min = 240 m (5480); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.77, 2.98, 3.03, 3.13, 5.67, 5.94, 5.99, 6.13) 11, 6.21) 11, 6 , 26) 11, 6.33) 11, 6.66) 11, 7.10) 11, 7.33) 11, 8.01) 11, 8.22) 11, 9.45) 11, 9.95 ) 11, 12.33, 13.32, 13.62 and 14.37. PATENT CLAIM I 1. Process for the preparation of Ceph-3-em derivatives of the formula EMI17.1 wherein R, a represents hydrogen or an amino protecting group R1 @, and R1b represents hydrogen or an acyl group Ac, or RA and R1b together represent a divalent amino protective group, and RA represents hydrogen or one, together with the -C (= O) -O group represents a protected carboxyl group-forming organic radical R2, or salts of such compounds with salt-forming groups, characterized in that a Ceph-2-em derivative of the formula EMI17.2 treated with a weakly basic agent and the corresponding Ceph-3-em derivative isolated. SUBCLAIMS 1. The method according to claim I, characterized in that starting materials of the formula II are used in which R1 is an acyl group and Rb1 is hydrogen, and R2A is an esterified one with the -C (= O) -O grouping which can be cleaved under mild conditions Represents carboxyl group-forming organic radical. 2. The method according to claim I, characterized in that R2A stands for the organic radical of a sterically hindered alcohol. 3. The method according to claim I, characterized in that R2 represents an optionally substituted diphenylmethyl or benzyl radical, e.g. B. benzhydryl or 4,4'-dimethoxybenzhydryl. 4. The method according to claim 1, characterized in that a weak organic, nitrogen-containing base is used as the isomerizing agent. 5. The method according to claim I, characterized in that one is a teritäre heterocyclic base aromatic Character, a tertiary aromatic base or a tertiary aliphatic, azacycloaliphatic or araliphatic base as Isomerizing agent used. 6. The method according to claim I, characterized in that a base of the pyridine type, such as pyridine, is used as the Iso merisierungsmittel. 7. The method according to claim 1, characterized in that a tri-lower alkyl amine, such as triethylamine, as Isomerizing agent used. 8. The method according to claim 1, characterized in that the mixture of a base of the pyridine type and one N, N, N-tri-lower alkylamine, e.g. Pyridine and triethylamine as Isomerizing agent used. 9. The method according to claim I, characterized in that the isomerization is carried out in the presence of a derivative of a carboxylic acid which results in the formation of a mixed Anhydride is suitable, as is a carboxylic acid anhydride or chloride. 10. The method according to claim 1, characterized in that 7ss-phenylacetylamino-ceph-3-em-4-carboxylic acid diphenylmethyl ester is prepared. PATENT CLAIM II Use of the compounds of formula 1 obtained according to patent claim I, in which the group -C (= O) -O-R2 means a group -C (= O) -O-R2 which can easily be converted into the free carboxyl group, characterized in that these Group -C (= O) -O-RA converted into a free carboxyl group by reduction, photolysis or solvolysis. SUBCLAIMS 11. Use according to claim II, characterized in that RA2 stands for a methyl group which is polysubstituted by optionally substituted hydrocarbon radicals or by a carbocyclic aryl group having an electron-donating substituent or a heterocyclic group of aromatic character having oxygen or sulfur atoms as ring members, or which is monosubstituted in a polycycloaliphatic hydrocarbon radical or a ring member in an oxa or thiacycloaliphatic radical which is in position to the ring oxygen or ring sulfur atom, and the ester group of the formula -C (= O) -O-R2 @ is cleaved by treatment with an acidic agent. 12. Use according to claim II, characterized in that the 7ss-phenylacetylamino-ceph-3-em-4-carboxylic acid diphenylmethyl ester obtained according to patent claim I is converted into the 7ss-phenylacetylamino-ceph-3-em-4- by treatment with trifluoroacetic acid and anisole. carboxylic acid transferred. 13. Use according to claim II, thereby characterized in that the 7ss-amino-ceph-3-em-4-carboxylic acid diphenylmethyl ester obtained according to patent claim I is converted into the 7ss-amino-ceph-3-em-4-carboxylic acid by treatment with trifluoroacetic acid and anisole.