CH556875A - 7-amino 2, 2-dimethylceph 3-em 4-carboxylic acid derivs - antibiotic intermediates - Google Patents

Abstract

Cephem derivs of formula (I) and their salts, where R2 is H or a carboxyl-protecting gp. such as an ester anhydride, organosilyl or organostannyl residue, are of use as antibiotic intermediates. I are prepd. from the corresp. N-acyl derivs. by a) conversion to the imidohalide with PX5, POX3 etc. and a base, (b) reacting the imidohalide with an alcohol, to the corresp. imidoether. (c) Hydrolysing the ether with H2O at pH 1-5.

Description

  

  
 



   The present invention relates to a process for the preparation of 7-amino-2,2-dimethyl-ceph (3) em-4-carboxylic acids and their esters of the formula I
EMI1.1
 where R2 is hydrogen, or a radical R A which forms an esterified carboxyl group together with the -C (= O) group, and salts of such compounds.



      A.
A radical R 2 is e.g. il. an organic radical which, together with the carboxyl group, forms an esterified carboxyl group, preferably easily cleavable; such radicals can be aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, and also heterocyclic or heterocyclic-aliphatic radicals.



   The RA radical can also be an organic silyl, germanyl or stannyl radical which forms an easily cleavable esterified carboxyl group with the -C (= O) -O grouping, in particular a trisubstituted silyl radical, such as the above-mentioned trisubstituted silyl radical Represent stannyl group.



   An aliphatic radical is an optionally substituted aliphatic hydrocarbon radical, such as an alkyl, alkenyl or alkynyl, in particular a lower alkyl or lower alkenyl, and also a lower alkynyl radical, the z. B. can contain up to 7, preferably up to 4 carbon atoms. Such radicals can optionally be replaced by functional groups, e.g.

  B. by free, etherified or esterified hydroxy or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkyl mercapto or optionally substituted phenyl mercapto or phenyl-lower alkyl mercapto, lower alkoxycarbonyloxy or lower alkanoyl groups, furthermore by Oxo groups, nitro groups, optionally substituted amino groups, azido groups, acyl, such as lower alkanoyl or benzoyl groups, optionally functionally modified carboxy groups, such as carboxyl groups in salt form or lower alkoxycarboyl, optionally N-substituted carbamyl or cyano groups, or optionally functionally modified sulfo groups, such as Sulfamoyl groups or sulfo groups present in salt form, mono-, di- or polysubstituted.



   A cycloaliphatic or cycloaliphatic-aliphatic radical is an optionally substituted cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, e.g. B. a mono-, di- or polycyclic cycloalkyl or cycloalkenyl group, or cycloalkyl or cycloalkenyl-lower alkyl or lower alkenyl group, wherein a cycloalkyl radical z. B. contains up to 12, such as 3-8, preferably 3-6 ring carbon atoms, while a cycloalkenyl radical z. B.



  up to 12, such as 3-8, e.g. B. 5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic radical z. B. can contain up to 7, preferably up to 4 carbon atoms. The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, e.g. B.



  by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned, optionally substituted lower alkyl groups, or then, e.g. B. like the abovementioned aliphatic hydrocarbon radicals, mono-, di- or polysubstituted by functional groups.



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



   The araliphatic residue 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 containing aliphatic hydrocarbon radicals and is primarily a phenyl-lower alkyl or phenyl-lower alkenyl, and phenyl-lower alkynyl radical, such radicals being e.g. B. 1-3 phenyl groups and optionally, z. E. As the above-mentioned aliphatic and cycloaliphatic radicals, in the aromatic and / or aliphatic part can be mono-, di- or polysubstituted.



   Heterocyclic groups, including those in heterocyclic-aliphatic radicals, are, in particular, monocyclic, as well as bi- or polycyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triaza- or tetrazacyclic radicals of aromatic character, which optionally, z . B. like the above-mentioned cycloaliphatic radicals, mono-, di- or polysubstituted. The aliphatic part in heterocyclic aliphatic radicals has e.g. B. the meaning given for the corresponding cycloaliphatic-aliphatic or araliphatic radicals.



   A lower alkyl radical is e.g. B. a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, as well as n-pentyl, isopentyl, n-hexyl, Isohexyl or n heptyl group, while a lower alkenyl group, for example a vinyl, allyl, isopropenyl, 2- or 3-methalallyl or 3-butenyl group, and a lower alkynyl radical e.g. B. may be a propargyl or 2-butynyl group.



   A cycloalkyl group is e.g. B. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and adamantyl group, and a cycloalkenyl, z. B. a 2-cyclopentyl, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl or 3-cycloheptenyl group. A cycloalkyl-lower alkyl or -niederalkenylrest is z. B. a cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, 1,1 or -1,2-ethyl-, -1,1-, -1,2-, or -1,3-propyl, -vinyl- or allyl group, while a cycloalkenyl lower alkyl or lower alkenyl group, e.g. B. a 1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl- or 1-, 2- or 3-cycloheptenylmethyl-, -1,1- or -1,2-ethyl, Represents -1,1-, -1,2- or -1,3-propyl, -vinyl or -allyl group.

 

   A naphthyl radical is a 1- or 2-naphthyl radical, while a biphenylyl group z. B. represents a 4-biphenylyl radical.



   A phenyl-lower alkyl or phenyl-lower alkenyl radical is, for. B. a benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl, trityl, 1- or 2-naphthylmethyl, styryl or cinnamyl radical.



   Heterocyclic radicals are e.g. B. monocyclic, monoaza-, monothia- or monooxacyclic radicals of aromatic character, such as pyridyl, z. B. 2-pyridyl, 3-pyridyl or 4-pyridyl, also pyridinium radicals, thienyl, z. B. 2-thienyl radicals, or Fujyl, z. B. 2-furyl radicals, or bicyclic monoazacyclic radicals of aromatic character, such as quinolinyl, z. B. 2-quinolinyl or 4-quinolinyl, or isoquinolinyl, e.g. B. 1-Isoquinolinyl radicals, or monocyclic diaza, triaza, tetraza, thiaza or oxazacyclo radicals of aromatic character, such as pyrimidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl radicals.



  Heterocyclic-aliphatic radicals are heterocyclic groups, in particular the lower alkyl or lower alkenyl radicals containing the above.



   Etherified hydroxyl groups are primarily lower alkoxy, e.g. B. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert. Butyloxy, n-pentyloxy or tert-pentyloxy groups, and substituted lower alkoxy, such as halo-lower alkoxy, especially 2-halo-lower alkoxy, e.g. B. 2,2,2-trichloro, 2 bromine or 2-iodoethoxy groups, also lower alkenyloxy, z. B. vinyloxy or allyloxy groups, lower alkylenedioxy, z. B. methylene, ethylene or isopropylidenedioxy groups, cycloalkoxy, z. B. cyclopentyloxy, cyclohexyloxy or adamantyloxy groups, phenyloxy groups, phenyl-lower alkoxy, z. B. benzyloxy or 1- or 2-phenylethoxy groups, or by monocyclic, monoaza-, monooxa- or monothiacyclic groups of aromatic character substituted lower alkoxy, such as pyridyl-lower alkoxy, z.

  B. 2 pyridylmethoxy, furyl-lower alkoxy, e.g. B. furfuryloxy, or thienyl-lower alkoxy, z. B. 2-thenyloxy groups to understand.



   As etherified mercapto groups, lower alkyl mercapto, z. B. methyl mercapto, sithyl mercapto or n-butyl mercapto groups, lower alkenyl mercapto, z. B. Allylmer captogrupp s, phenyl mercapto groups or phenyl-lower alkyl mercapto, z. B. benzyl mercapto groups to mention
Esterified hydroxy groups are primarily halogen, e.g. B. fluorine, chlorine, bromine or iodine atoms, and lower alkanoyloxy, z. B. acetyloxy or propionyloxy groups.



   Substituted amino groups are mono- or disubstituted amino groups in which the substituents are primarily optionally substituted monovalent or divalent aliphatic, cycloaliphatic hydrocarbon radicals and acyl groups. Such amino groups are in particular lower alkylamino or di-lower alkyl-amino, e.g. B. methylamino, ethylamino, dimethylamino or diethylamino groups, or optionally by heteroatoms such as oxygen, sulfur or optionally, z. B.



  lower alkyleneamino groups interrupted by lower alkyl groups, substituted nitrogen atoms, such as pyrrolidino, piperidino, morpholino, thiomorpholino or 4-methylpiperazino groups. Substituted amino groups are also acylamino, especially lower alkanoylamino, such as acetylamino or propionylamino groups, or optionally in salt, such as alkali metal, z. B. sodium, or ammonium salt form, present sulfoamino groups.



   A lower alkanoyl radical is e.g. B. an acetyl or propionyl group.



   A carboxyl group present in salt form is e.g. B.



  a carboxyl group present in alkali metal or ammonium salt form.



   A lower alkoxycarbonyl radical is e.g. B. a methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl or tert-pentyloxycarbonyl group.



   Optionally N-substituted carbamoyl groups are e.g. B. N-lower alkyl or N, N-di-lower alkyl-carbamoyl, such as N-methyl, N-ethyl, N, N-dimethyl or N, N-diethylcarbamoyl, and N-halo-lower alkyl-carbamoyl, z . B. N-2 chloroethylcarbamoyl groups.



   A sulfamoyl group may optionally be substituted and e.g. B. represent an N-lower alkyl-sulfamoyl, such as N-methyl or N, N-dimethylsulfamoyl group. Sulfo groups present in salt form are e.g. B. in alkali metal, e.g. B.



  Sulfo groups present in the sodium salt form.



   A radical R A, together with the -C (= O) -O group, preferably forms a, under neutral or acidic aqueous weakly basic conditions when treating with a reducing metal, with a reducing metal alloy, e.g. B. with a reducing metal amalgam, or a metal salt, when irradiated, preferably with ultraviolet light, or when treated with an acidic and weakly basic agent, or under neutral conditions hydrolytically or alcoholytically easily cleavable esterified carboxyl group.



      A.
An organic radical R 2 is z. 3. the group R a which means a 2-halo-lower alkyl radical, in which halogen preferably has an atomic weight of more than 19; such a radical forms, together with the -C (= O) -O grouping, a reducing metal alloy when treated with a reducing metal, e.g. B. a reducing Me tall am algam or a metal salt under neutral or weakly acidic, aqueous 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. The radical R a can be one, two or more halogen, e.g. B.

  Chlorine, bromine or iodine atoms, contain, in particular 2-chlorine, but also 2-bromo-lower alkyl radicals several, preferably three, chlorine or. Contain bromine atoms, while a 2-iodine-lower alkyl radical has primarily only one iodine atom. The R0a radical represents in particular a 2-polychloro-lower alkyl, such as 2-polychloroethyl radical, primarily the 2,2,2-trichloroethyl radical, and the 2,2,2-trichloro-1-methyl-ethyl radical, can but also z. B. a 2-bromo-lower alkyl, such as 2-polybromo-lower alkyl, e.g. B. the 2,2,2-tribromoethyl, also the 2-bromoethyl radical, or a 2-iodine-lower alkyl, especially the 2-iodoethyl radical.



   Another group RA which, together with the -C (= O) O grouping, produces a upon treatment with one of the above-mentioned metallic reducing agents under neutral or weakly acidic conditions, e.g. B. when treating with zinc in the presence of aqueous acetic acid, represents easily cleavable esterified carboxyl group, is an arylcarbonylmethyl group R b. In this the aryl radical stands for a bi- or
0 polycyclic, but especially a monocyclic, optionally substituted aromatic hydrocarbon radical, e.g. B. an optionally substituted phenyl group.



  Substituents of such groups are e.g. B. optionally substituted hydrocarbon radicals such as lower alkyl, e.g. B.



  Methyl, ethyl or isopropyl, also trifluoromethyl, Phe nyl, or phenyl-lower alkyl, z. B. benzyl or phenyl ethyl radicals, or functional groups such as free or functionally modified carboxyl groups, eg. B. carboxy, lower alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, also carbamoyl or cyano groups, optionally functionally modified, such as esterified hydroxyl or mercapto groups, eg. B. halogen atoms, or etherified hydroxy or mercapto groups, such as lower alkoxy, e.g. B. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or tert. Butyloxy groups, and / or optionally substituted amino, such as di-lower alkyl, z. B. dimethylamino or diethylamino, or lower alkanoyl amino, z. B. acetylamino groups.

 

   The methyl part of an Arylcarbonylmethylrestes R0b is preferably unsubstituted, but can also be an organic radical, for. B. an optionally substituted aliphati rule hydrocarbon radical, such as a lower alkyl, z. B.



  Methyl, ethyl, n-propyl, isopropyl, n-butyl or tert. - Butyl group, or a cycloaliphatic, aromatic or araliphatic radical, such as an aryl, z. B. optionally substituted phenyl group, and an optionally substituted cycloalkyl, z. B. cyclohexyl, or an optionally substituted phenyl-lower alkyl, z. B. benzyl group as a substituent.



   An Arylcarbonylmethylrest R are preferably the unsubstituted Phenacylrest, but can also be substituted in the aromatic part, such as by lower alkyl, z. B. methyl groups, lower alkoxy, e.g. B. methoxy groups, or halogen, e.g. B. fluorine, chlorine or bromine atoms, substituted phenacyl.



     
The group R A can also represent the group R c,
2 which stands for an arylmethyl group, in which aryl is a bicyclic or polycyclic, but 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. An aryl radical is primarily an optionally substituted phenyl group, but can also be a naphthyl, such as 1- or 2-naphthyl group. Substituents of such groups are e.g.

  B. optionally substituted hydrocarbon radicals, such as lower alkyl, phenyl or phenyl-lower alkyl radicals, which may optionally contain functional groups, such as those below, as substituents, or primarily functional groups, such as free or functionally modified carboxyl groups, e.g. B. carboxy, lower alkoxycarbonyl, such as methoxycarbonyl or ethylcarbonyl, carbamoyl or cyano groups, optionally substituted amino, such as di-lower alkylamino groups, or acyl, such as lower alkanoyl, e.g. B. acetyl groups, especially esterified hydroxy or mercapto groups, such as acyloxy, z. B. lower alkanoyloxy, such as acetyloxy groups, or halogen, e.g. B.

  Fluorine, chlorine or bromine atoms, primarily etherified hydroxyl or mercapto groups, such as lower alkoxy, e.g. 3. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or tert. Butyloxy, also lower alkyl mercapto, z. B. methyl mercapto or ethyl mercapto groups (which are primarily in the 3-, 4- and / or 5-position in the preferred phenyl radical) and / or especially nitro groups (in the preferred phenyl radical preferably in the 2-position).



   The methyl part of an arylmethyl radical R0c can optionally, e.g. like the methyl part in an arylcarbonyl methyl radical R b, preferably an optionally substituted
0 tuierten hydrocarbon radical, have as substituents.



      c
A radical R c, preferably an optionally substituted α-phenyl-lower alkyl or benzhydryl radical, such as an optionally substituted by lower alkoxy, such as methoxy groups, preferably in the 3-, 4- and / or 5-position, and / or by nitro groups, preferably in 2-position, substituted 1 phenylethyl or benzhydryl, primarily benzyl, especially the 3- or 4-methoxybenzyl, 3,5-dimethoxybenzyl, 2-nitrobenzyl or 4,5-dimethoxy-2-nitrobenzyl radical .



   A group R A can also represent the radical R d which, together with the -C (= O) -O grouping, is a under acidic conditions, e.g. B. when treated with trifluoroacetic acid or formic acid, easily cleavable, esterified carboxyl group forms. Such a radical R d 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 polycycloaliphatic hydrocarbon radical a ring member or in an oxa or thiacycloaliphatic radical the ring member representing the a-position to the oxygen or sulfur atom.



   Substituents of polysubstituted, e.g. B. di- or trisubstituted methyl groups R d are primarily optionally substituted aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, z. B. methyl or ethyl groups, as well as phenyl or biphenylyl, z. B. 4-biphenylyl groups. Polysubstituted methyl groups R d are, for. B. tert-butyl or tert-pentyl, and benzhydryl or 2- (4-biphenylyl) -2-propyl radicals.



   A carbocyclic aryl group containing electron-donating substituents in the aryl radical is a bi- or polycyclic, in particular monocyclic, aryl, e.g. B. naphthyl and primarily phenyl. Electron-donating substituents, which are preferably in the p- and / or o-position of the aryl radical, are, for. B. free or preferably functionally modified, such as esterified and primarily etherified hydroxy groups, such as lower alkoxy, z. B.



  Methoxy, also ethoxy or isopropyloxy groups, as well as corresponding free or functionally modified mercapto groups, also aliphatic, cycloaliphatic, aromatic or araliphatic, optionally suitably substituted hydrocarbon radicals, especially lower alkyl, e.g. B. methyl or tert-butyl groups, or aryl, e.g. B. phenyl groups.



   A heterocyclic group of aromatic character containing oxygen or sulfur atoms as ring members can be bi- or polycyclic, but is primarily monocyclic and is primarily a furyl, e.g. B. 2-furyl, or a thienyl, z. B. 2-thienyl radical.



   Polycycloaliphatic hydrocarbon radicals in which the methyl group R d is a preferably three-branched ring member are, for. B. Adamantyl, such as 1-adamantyl radicals.



   An oxa- and thiacyclo-aliphatic radical linked in a-position is primarily a 2-oxa- or 2-thlacycla alkyl, as well as 2-oxa or 2-thiacycloalkenyl group, in which the methyl group R d represents the ring oxygen or
0 ring sulfur atom is adjacent, with the oxygen atom of the group of the formula -O-R d linked ring member, and which preferably contains 4 = 6 ring carbon atoms. B. 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl radicals or corresponding sulfur analogs.

 

   Preferred radicals R d are tert-butyl, tert-pentyl, 4 methoxybenzyl and 3,4-dimethoxybenzyl radicals, and 1 adamantyl, 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2- pyranyl groups.



   The radical R A can also represent the group R e which
2 together with the -C (= O) -O grouping under weakly basic conditions, e.g. B. at pH 7-9, cleavable esterified carboxyl group forms. Such a radical R e is preferably a radical which forms an activated ester with the -C (= O) -O grouping, in particular a hydrocarbon, in particular aliphatic or aromatic hydrocarbon radical substituted by electron-attracting groups. Electron-attracting groups are primarily nitro groups or, advantageously, functionally modified carboxyl or sulfo groups, such as cyano or sulfamoyl groups, and also halogen, e.g. B. chlorine atoms; these preferably substituted the ol position of the hydrocarbon radical or are in conjugation with this via, preferably aromatic, double bonds.

  Preferred radicals R e are
0 nitrophenyl, e.g. B. 4-nitrophenyl or 2,4-dinitrophenyl, polyhalophenyl, e.g. B. 2,4,6-trichlorophenyl or 2,3,4,5,6 pentachlorophenyl, or cyanomethyl radicals.



   The group RA can also represent a radical which, together with the carboxyl group -C (= O) -O-, forms an esterified carboxyl group which can be cleaved under physiological conditions, primarily a methyl radical substituted by an acyloxy group, in which the acyl radical is the acyl radical of an organic carboxylic acid, such as an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid, in which the organic radicals have the above meaning, in particular a lower alkanoyl, e.g. B. acetyl radical, as well as the acyl radical of a carbonic acid half derivative means.



   A silyl or stannyl group R2A is e.g. for an optionally substituted aliphatic, aromatic or araliphatic hydrocarbon radicals, in particular lower alkyl, e.g. B. methyl, ethyl or n-butyl, phenyl or phenyl lower alkyl, z. B. benzyl groups, trisubstituted silyl such as trimethylbutyl, and stannyl, such as tri-n-butyl-stannyl group.



   Salts of compounds obtainable according to the process are in particular those of compounds of the formula I in which R2 stands for hydrogen; these are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. B. sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, with primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and aliphatic primary, secondary or tertiary mono-, di- or polyamines for the salt formation come into question, such as lower alkylamines, e.g. B. triethylamine, hydroxy lower alkylamines, e.g. B. 2-hydroxy-ethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. B. 4-aminobenzoic acid-2-diethyl ester, alkylene amines, z. B. 1-ethyl-piperidine, cycloalkylamines, e.g. B.



  Bicyclohexylamine, or benzylamines, e.g. B. N, N'-dibenzyl ethylenediamine. The compounds of the formula I can also contain acid addition salts, e.g. B. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid or with suitable organic carboxylic or sulfonic acid. Furthermore, compounds in which R2 is hydrogen can be used in the form of internal salts, i.e. H. are in the zwitterionic form.



   The compounds obtainable according to the invention, in particular the 7-amino-ceph (3) em-4-carboxylic acid, are valuable intermediates which are particularly useful for the preparation of pharmacologically usable, e.g. B. against microorganisms such as gram-positive and gram-negative bacteria.



   The compounds of the formula I are obtained according to the invention if Ceph (3) em compounds of the formula II
EMI4.1
 wherein Ac represents the acyl radical of a carboxylic acid, or a salt of such a compound with a salt-forming group is treated with an imide halide-forming agent, the imide halide formed is converted into the corresponding imino ether by treatment with an alcohol and cleaved by treatment with an aqueous agent. If desired, a compound obtained can be converted into another compound of the formula I and / or, if desired, a mixture of isomers obtained can be separated into the individual isomers.



   In the starting material there is an acyl group Ac z. B. for the acyl radical of an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acid or a heterocyclic or heterocyclic aliphatic carboxylic acid, such as. B. one of the above residues.

  The acyl radical Ac stands primarily for an acyl radical of an organic carboxylic acid contained in pharmacologically active N-acyl derivatives of 6-aminopenicillanic or 7-amino-cephalosporanic acid and in particular for an N-acyl derivative of 6-amino-penicillan which occurs naturally or is biosynthetically available - Or 7-amino-cephalosporanic acid occurring acyl radical, such as an optionally substituted phenylacetyl or phenyloxyacetyl radical, also an optionally substituted lower alkanoyl or lower alkenoyl radical, e.g. B. the 4-hydroxyphenylacetyl, hexanoyl, octanoyl, 3-hexenoyl, 5-amino5-carboxyvaleryl, n-butylmercaptoacetyl or allylmercaptoacetyl, and especially the phenylacetyl or phenyloxyacetyl radical.



     
In the starting material of formula II, R B comes first
2 line for the radical R A2 X in particular a radical which, together with the -C (= O) -O grouping, forms an easily cleavable esterified carboxyl group, e.g. B. one of the leftovers
R0a, R0b, R0c, R0d, R0e.



     
R @ B can also represent an organic silyl or stannyl
2 rest, e.g. B. the trimethylsilyl or tri-n-butylstannyl radical.



      3
In the starting material of the formula II, R 2 can also represent the amine of a metal or an ammonium ion which is optionally substituted by organic radicals. An acid addition salt of a compound of the formula II in which the acyl radical contains a basic group can also be used as starting material.

 

   According to the method, imide halide-forming agents in which halogen is bonded to an electrophilic central atom are above all acid halides, such as acid bromides and in particular 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 of the starting material of the formula II 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 ethyldiisopropylamine, also an N, N, N ', N'-Tetraniederalkylniederalkylenediamines, z. B. N, N, N ', N'-tetramethyl-1,5-pentylenediamine or N, N, N', N'-tetramethyl-1,6-hexylenediamine, a mono- or bicyclic mono- or diamine, such as one N-substituted, e.g. B. N-lower alkylated, alkylene, azaalkylene or oxaalkenamine, e.g. B. N-methyl-piperidine or N-methyl-morpholine, also 2,3,4,6,7,8-hexahydro-pyrro 10 [1,2-] 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, 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 up to 10-fold, especially about 3-5-fold excess.



   The reaction of the starting material with the imide halide forming agent is preferably carried out with cooling, e.g. B.



     carried out at temperatures from about + 100 ° C. to about -500 ° C., but also at higher temperatures, d. H. z. B. to about 750 C, can work if the stability of the starting materials and products allow an elevated temperature.



   The icidhalide product, which is usually processed further without isolation, is reacted according to the process with alcohols, preferably in the presence of the abovementioned bases, to give the imino ether. Alcohols are e.g. B. aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, z. B. chlorinated, or having additional hydroxyl groups, lower alkanols, e.g. B. ethanol, 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 of about 100 C to about-SO0 C.



   The imimo ether product can advantageously be subjected to cleavage without isolation. The cleavage of the imino ether to give the corresponding amine compound of the formula I can be achieved by treatment with an aqueous agent. It is preferable to use water or an aqueous mixture of an organic solvent such as an alcohol, especially a lower alkanol, e.g. B.



  Methanol. One usually works in an acidic medium, e.g. B. at a pH of 1 to 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 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, undi or in an inert gas atmosphere such as a nitrogen atmosphere.



   In a starting material used according to the method and having a carboxyl group protected by a silyl or stannyl group, the latter is also released in the course of the cleavage of the acylamino group, in particular in the presence of water or an alcohol.



   Connections obtained can be converted into one another within the defined framework. So z. B. in a compound of the formula A 1 obtainable according to the process, in which R2 represents a group R 2, an esterified carboxyl group of the formula -C (= O) -O-R A can be converted into a free carboxyl group. 2
So you can e.g. a carboxyl group esterified by a radical R0a or R0 @ by treatment with one of the metallic reducing agents mentioned in the presence of at least an equimolar amount, usually in the presence of an excess of water. You work under mild conditions, usually at room temperature or even with cooling.



   Reducing metals, as well as reducing metal alloys or amalgams, and also strongly reducing metal salts are z. B. zinc, zinc alloys, e.g. B. zinc copper, or zinc amalgam, also magnesium, which are preferably used in the presence of hydrogen-releasing agents that are able to generate nascent hydrogen together with the metals, metal alloys and amalgams, zinc, z. B. advantageously in the presence of acids such as organic carbon, e.g. B. lower alkanecarboxylic acids, primarily acetic acid, or acidic agents such as ammonium chloride or pyridine hydrochloride, preferably with the addition of water, and in the presence of alcohols, especially aqueous alcohols such as lower alkanols, e.g. B.

  Methanol, ethanol or isopropanol, which can optionally be used together with an organic carboxylic acid, and alkali metal amalgams, such as sodium or potassium amalgam, or aluminum amalgam in the presence of moist solvents such as ethers or lower alkanols.



   Strongly reducing metal salts are primarily chromium II salts, e.g. B. chromium (II) chloride or chromium (II) acetate, which is preferably in the presence of aqueous media containing water-miscible organic solvents such as lower alkanols, carboxylic acids such as lower alkanecarboxylic acid, or derivatives, such as optionally substituted, e.g. B. lower alkylated, amides thereof, or ethers, e.g. B. methanol, ethanol, acetic acid, dimethylformamide, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether can be used.



   In a compound of the formula I obtainable according to the process in which R2 represents a group R c, the esterified carboxyl group of the formula -C (= O) -O-R c can be cleaved by irradiating with light, preferably with ultraviolet light. Depending on the nature of the substituent R c, longer or shorter wavelength light is used. So z. B. groups of the formula -C (= O) -O-R c0, wherein R c is a
0 substituted by a nitro group in the 2-position of the aryl radical, optionally other substituents such as lower alkoxy, z. B. methoxy groups, having arylmethyl, especially benzyl radical, z. B. the 4,5-dimethoxy-2-nitrobenzyl radical, represents, by irradiation with ultraviolet light with a wavelength range of over 290 m, a, those in which R c z.

  B. one optionally in 3, 4 and / or
0 5 position, e.g. B. by lower alkoxy and / or nitro groups, substituted arylmethyl, z. B. Benzyl radical, is split by irradiation with ultraviolet light with a wavelength range of less than 290 m, sb. In the first case, a high-pressure mercury vapor lamp is used, preferably using Pyrex glass as the filter, e.g. B. at a main wavelength range of about 315 m, u, in the latter case with a low pressure mercury vapor lamp, z. B. at a main wavelength range of about 254 m, u.



   The irradiation reaction is carried out in the presence of a suitable polar or non-polar organic solvent or a mixture; Solvents are e.g. B. optionally halogenated hydrocarbons, such as optionally chlorinated lower alkanes, e.g. B. methylene chloride, or optionally chlorinated benzenes, e.g. B. benzene, also alcohols such as lower alkanols, z. B. methanol, or ketones, such as lower alkanones, e.g. B. acetone. The reaction is preferably carried out at room temperature or, if desired, with cooling, usually in an inert gas, e.g. B. nitrogen atmosphere. It is preferably carried out in the presence of water; but you can also treat the irradiation product subsequently with water, for. B. by carrying out the work-up of the product obtained in the presence of water.



   In a compound of the formula I obtainable according to the invention, in which R2 represents a group R d, the grouping of the formula -C (= O) -OR d can be removed by treatment with an acidic agent, in particular with an acid such as a strong organic carboxylic acid, e.g. . B. an optionally substituted, preferably containing halogen atoms, lower alkanecarboxylic acid, such as acetic acid or trifluoroacetic acid, also with formic acid or a strong organic sulfonic acid, e.g. B. p-toluenesulfonic acid are cleaved. Usually, an excess of an acidic reagent which is liquid under the reaction conditions is used as the diluent and the reaction is carried out in the presence of at least an equivalent amount of water, and at room temperature or with cooling, e.g.

  B. to about - 200 C to about + 100 C.



   An esterified carboxyl group of the formula -C (= O) - O-R e in a compound obtainable according to the process
0 can be used under weakly basic conditions, e.g. B. at a pH of about 7 to about 9 by treatment with a weakly basic agent such as an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, or a suitable buffer solution such as a dipotassium hydrogen phosphate buffer, in the presence of water and preferably an organic solvent such as methanol or Acetone are cleaved.



     
One through an organic silyl or stannyl radical R A
2 esterified carboxyl group in a compound of the formula I obtainable according to the invention can be obtained by mild hydrolysis, e.g. B. when treating with water or an alcohol such as a lower alkanol, e.g. B. Ethanol can be converted into the free carboxyl group. Usually such a group R A is already in the course of the inventive Ver
2 driving, e.g. B. when cleaving the imino ether intermediate with water, cleaved to form the free carboxyl group.



   Before an esterified carboxyl group of the formula -C (= O) -O-R2 is cleaved, it can be converted into another esterified carboxyl group in a starting material obtained in a manner known per se. So you can e.g. in a radical R0a representing the group R2A an aliphatically bonded chlorine or bromine atom, as in a 2-bromoethyloxy radical R a z. By treating with an iodized salt such as an alkali metal, e.g. B. potassium iodide, in a suitable solvent such as acetone, replace this with an iodine atom.



   In a compound with a group of the formula -C (= O) O-R2, in which R2 is hydrogen, the free carboxyl group can be used 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 phenyl-diazo 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), or activated esters, e.g. B.



  those with N-hydroxy nitrogen compounds, or z. B.



  mixed anhydrides formed with haloformic acid lower alkyl esters, such as ethyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride, are converted into esters by reaction with alcohols, optionally in the presence of a base such as pyridine.



   Salts of compounds of the formula I can be prepared in a manner known per se. So you can salts of compounds of formula I, wherein R2 is hydrogen, z. B. by treatment with metal compounds such as alkali metal salts of suitable carboxylic acid, e.g. B. the sodium salt of a-sithyl-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 are usually obtained, for. B. by treatment with an acid or a suitable ion exchange reagent.



  Salts can be converted into the free compounds in the usual way, metal and ammonium salts z. B. by treatment with suitable acids, and acid addition salts z. B. by treating with a suitable basic agent.



   Mixtures of isomers obtained can be prepared by methods known per se, e.g. B. 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 in the usual way, optionally after the temporary introduction of salt-forming groups, eg. B. by forming a mixture of diastereoisomeric salts with optically active salt-forming agents, separating the mixture into the diastereoisomeric salts and converting the separated salts into the free compounds or by fractional crystallization from optically active solvents into which antipodes are separated.

 

   The process also includes those embodiments according to which starting materials are used in the form of a crude reaction mixture formed under the reaction conditions.



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



   The starting materials of the formula II used according to the process can, for. B. be prepared by adding a penam-3-carboxylic acid compound IIIa having the formula
EMI7.1
 wherein free functional groups such as hydroxyl, mercapto and especially amino and carboxyl groups, optionally in the acyl radical Ac, z.

  B. are protected by acyl groups or in the form of ester groups, and Ro is a carboxyl group -C (= O) -OH (compound IIIa), or a salt thereof in the corresponding acid azide compound with the formula III wherein Ro is the azidocarbonyl radical -C (= O) -N3 represents (compound IIIb), converted, this with elimination of nitrogen to the corresponding isocyanate compound with the formula III, wherein Ro is the isocyanato group -N = C = O (compound IIIc), and simultaneously or subsequently with a Treated compound of formula H-Xo (IV).

  In the compound of the formula IV, XO denotes an etherified hydroxyl or mercapto group of the formula -OR a -OR b or -OR c in which, together with a carbonyl group, forms an esterified carboxyl or thiocarboxyl group which is easily cleavable under mild, in particular neutral to weakly acidic conditions Ra Rb and o '0 0' 0 '0 R c have the meanings given above and in particular for the 2,2,2-trichloroethyl or 2-iodoethyl, as well as the 2-bromoethyl radical which can be converted into these, also-the phenacyl or 4 , 5-dimethoxy-2-nitrobenzyl radical.



   A penam compound of the formula is obtained in this way
EMI7.2
 in which, if desired, an acyl radical Ac, z. B.



  by the method described above, replace with hydrogen and the free amino group, e.g. B. can re-acylate according to acylation methods known per se, and the cleavage of the esterified carboxyl group of the formula -C (= O) -XO in the presence of water into a penam compound of the formula
EMI7.3
 is transferred. If a compound of the formula VI is treated with a hydride reducing agent which is inert towards amide groups, a compound of the formula is obtained
EMI7.4
 in which, optionally after converting the acylamino group of the formula Ac-HN- into a free amino group and reacylation of the free amino group, the primary hydroxyl group is converted into a hydroxyl group esterified by the acyl radical of the formula -C (= O) -X.

  A 4ss- (2-0- esterified hydroxymethyl-2-propylmercapto) -3ss-N-Ac-amino-azetidin-2-one of the formula which can be obtained in this way
EMI7.5
 is made with a compound of the formula
EMI7.6
 wherein R2B is one of the above-mentioned organic radicals R A, in particular a group of the formula R a, R b, R c or R O, which form an easily cleavable esterified carboxyl group with the carboxyl group, or a reactive
0 0 0 0 gene derivative thereof reacted, and in the compound of the formula thus prepared
EMI7.7
 the secondary hydroxy group is converted into a reactive esterified hydroxy group.



   A compound of the formula
EMI7.8
 in which in an acyl radical Ac any free reactive functional groups present may be protected, and in which Z is a reactive esterified hydroxyl group, primarily a halogen, in particular chlorine or bromine atom, and an organic sulfonyloxy, z. B. 4-methylphenylsulfonyloxy or methylsulfonyloxy group, is with a phosphine compound of the formula
EMI7.9
   wherein each of the radicals Ra, Rb and RG represents an optionally substituted hydrocarbon radical, reacted and in the resulting phosphoranylidene compound of the formula
EMI8.1
 optionally after cleavage of the elements of an acid H-Z from a phosphonium salt compound of the formula available as an intermediate
EMI8.2
 the esterified carboxyl group of the formula -C (= O) -X cleaved.

  A phosphorarylidene compound of the formula is thus obtained
EMI8.3
 in which the carbinol group of the formula -CH2-OH is oxidized to the formyl group of the formula -CHO, with simultaneous ring closure with the formation of a Ceph (3) em compound of the formula
EMI8.4
 takes place. In this connection, an organic radical R B2 which can easily be replaced by hydrogen can be replaced by hydrogen in a manner known per se, and, if desired,
2 A of this can be exchanged for a radical R 2.



   The conversion of an acid compound IIIa or a suitable salt, in particular an ammonium salt, into the corresponding acid azide IIIb can, for. B. by converting it into a mixed anhydride (e.g. by treating with a lower alkyl haloformate, such as ethyl chloroformate, or with trichloroacetic acid chloride in the presence of a basic agent such as triethylamine or pyridine) and treating such an anhydride with an alkali metal azide, such as sodium azide, or an ammonium azide, e.g. B. benzyltrimethylammonium azide. The so obtainable acid azide compound IIIb can in the presence or absence of a compound of formula IV under the reaction conditions, for.

  B. on heating, converted into the desired isocyanate compound III, which usually does not need to be isolated and can be converted directly into the desired compound of formula V in the presence of a compound of formula IV.



   The reaction with a compound of the formula IV, in particular with an alcohol of the formula R 0a -OH, R 0b -OH or R 0c -OH, such as with a 2-haloethanol R 0a -OH, e.g. B. with 2,2,2-trichloro- or 2-bromoethanol, an arylcarbonylmethanol R b0 .OH, z. 3. phenacyl alcohol, or an aryl methanol R c -OH, e.g. B. 4,5-dimethoxy-2-nitrobenzyl alcohol, is optionally in an inert solvent, e.g. B. in a halogenated hydrocarbon such as carbon tetrachloride, chloroform or methylene chloride, or in an aromatic solvent such as benzene, To luene or chlorobenzyl, preferably carried out with heating.



   The cleavage of an esterified carboxyl group of the formula -C (= O) -Xo in a compound of the formula V is carried out as described above for the cleavage of an esterified carboxyl group -C (= O) -O-R2. If Xo represents the group -O-R a or -O-R b, the cleavage is carried out by treatment with one of the abovementioned metallic reducing agents, e.g. B. zinc or chromium (II) salt, e.g. B. chromium (II) chloride, usually in the presence of a hydrogen-donating agent that is able to generate nascent hydrogen together with the metal, such as an acid, primarily acetic acid, or an alcohol, preferably adding water, and if X0 is a group of the formula -OR 0c, by irradiation, preferably with ultraviolet light, with shorter-wave ultraviolet light, e.g. B. under 290 m, lb works when R c z. B.



   0 an optionally in the 3-, 4- and / or 5-position, e.g. B. is substituted by lower alkoxy and / or nitro groups arylmethyl radical, or with longer-wave ultraviolet light, z. B. over 290 m, m, if R e z. B. means an arylmethyl radical substituted in the 2-position by a nitro group, made.

 

   An amide group non-reducing hydride reducing agents Re are primarily boron-containing hydrides such. B. diborane and especially alkali metal or alkaline earth metal borohydrides, especially sodium borohydride. Complex organic aluminum hydrides, such as alkali metal tri-lower alkoxy-aluminum hydrides, e.g. B. lithium tri-tert-butyloxy-aluminum hydride can also be used.



   These reducing agents are preferably used in the presence of suitable solvents or mixtures thereof, alkali metal borohydrides z. B. in the presence of
Hydroxy or ether groups-containing solvents, such as lower alkanols, z. B. methanol or ethanol, and isopropanol, also tetrahydrofuran or diethylene glycol dimethyl ether, if necessary, with cooling or
Heat.



   In the compound of formula VII obtained, the primary hydroxyl group is acylated in a manner known per se, the usual acylating agents being used in the acylation reaction, in particular suitable reactive derivatives of acids which, if necessary, in the presence of a, preferably basic agent, such as a organic tertiary base, e.g. B. triethylamine or pyridine can be used. Reactive derivatives of acids are e.g. B. anhydrides, including. Internal anhydrides, such as ketenes, or isocyanates, or mixed, especially with haloformic acid esters, z. B. ethyl chloroformate, or haloacetic acid halides, z. B.

  Trichloroacetic acid chloride, anhydrides that can be prepared, also halides, primarily chlorides, or reactive esters, such as esters of acids with alcohols or phenols containing electron-attracting groups, and with N-hydroxy compounds, e.g. B. cyanmethanol, p-nitrophenol or N-hydroxysuccinimide. The acylation reaction can be carried out in the presence or absence of solvents or solvent mixtures, if necessary, with cooling or heating, in a closed vessel under pressure and / or in an inert gas, e.g. B. nitrogen atmosphere, optionally be carried out in stages.



   The addition of the glyoxylic acid compound to the nitrogen atom of the lactam ring of a compound of the formula VIII takes place preferably at elevated temperature, primarily at about 50 ° C. to about 150 ° C., in the absence of a condensing agent and / or without the formation of a salt. In this case, instead of the free glyoxylic acid compound, a reactive oxo derivative thereof, primarily a hydrate, can be used, with water formed when using the hydrate, if necessary, by distillation, e.g. B. azeotropic, can remove.



   Preferably one works in the presence of a suitable solvent, such as. B. dioxane or toluene, or solvent mixture, if desired or necessary, in a closed vessel under pressure and / or in the atmosphere of an inert gas such as nitrogen.



   In a compound of the formula X, the secondary hydroxyl group can be converted in a manner known per se into a reactive hydroxyl group esterified by a strong acid, in particular into a halogen atom or into an organic sulfonyloxy group. This esterification can, for. By treating the hydroxy compound with a suitable halogenating agent such as a thionyl halide, e.g. B. chloride, a phosphorus oxyhalide, especially chloride, or a halophosphonium halide, such as triphenylphosphonium dibromide or -diiodide, and by treating with a suitable organic sulfonic acid halide, such as chloride, preferably in the presence of a basic, primarily an organic basic agent such as such as an aliphatic tertiary amine, e.g. B.

  Triethylamine or diisopropylethylamine, or a heterocyclic base of the pyridine type, e.g. B. pyridine or collidine can be carried out. It is preferred to work in the presence of a suitable solvent, e.g. B. dioxane or tetrahydrofuran, or a solvent mixture, if necessary, with cooling and / or in the atmosphere of an inert gas such as nitrogen.



   In a compound obtained with a reactive esterified hydroxyl group, this can be converted into another reactive esterified hydroxyl group in a manner known per se. So you can z. B. replace a chlorine atom by treating the corresponding chlorine compound with a suitable bromine or iodine reagent, especially with an inorganic bromide or iodide salt such as lithium bromide, preferably in the presence of a suitable solvent such as ether, by a bromine or iodine atom.



   In the phosphine compound of the formula XI, each of the groups RaX Rb and Re denotes an optionally, e.g. B. by etherified or esterified hydroxyl groups, such as lower alkoxy groups or halogen atoms, substituted lower alkyl or an optionally, e.g. B. by aliphatic hydrocarbon radicals, such as lower alkyl groups, or etherified or esterified hydroxy groups, such as lower alkoxy groups or halogen atoms, or nitro groups, substituted phenyl radical.

  The reaction of a compound of formula Ia with the phosphine compound in which each of the groups R ,,
Rb and Re primarily represent phenyl and a lower alkyl, in particular the n-butyl radical, is preferably used in the presence of a suitable inert solvent, such as an aliphatic, cycloaliphatic or aromatic
Hydrocarbon, e.g. B. hexane, cyclohexane, benzene or toluene, or an ether, e.g. B. dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, or a solvent mixture. If necessary, one works with cooling or at elevated temperature and / or in the atmosphere of an inert gas such as nitrogen.



   A phosphonium salt compound of the formula XIIa formed as an intermediate usually spontaneously loses the elements of the acid H-Z; if necessary, the phosphonium salt compound can be prepared by treating with a weak base such as an organic base, e.g. B. diisopropylethylamine or pyridine, decomposed and converted into the phosphoranylidene compound of the formula XII.



   The cleavage of the esterified carboxyl group of the formula -C (= O) -X in a compound of the formula XII can, for. B.



  be carried out in the manner described above and adapted to the type of group X; d. H. a group of the formula -C (= O) -O-R or -C (= O) -O-R b can be replaced by Be
0 act with one of the above metallic reducing agents, a group of the formula -C (= O) -O-R c by irradiating, and a group of the formula -C (= O) -O-R d or



     0 -C (= O) -O-R e by treating with an acidic resp.



   0 weakly basic agents are split. In a compound of the formula XII, the esterified carboxyl groups of the formulas -C (= O) -X and -C (= O) -O-RB preferably differ from one another in such a way that under the conditions of cleavage of the esterified carboxyl group of the formula = = O) -X the esterified carboxyl group of the formula -C (= O) OR B remains intact.



   The oxidation of the primary carbinol group in a compound of the formula XIII, which takes place with simultaneous ring closure to a compound of the formula Ia, can surprisingly be carried out by treatment with an oxidizing sulfoxide compound, such as a di-lower alkyl sulfoxide, in particular dimethyl sulfoxide, in the presence of a dehydrating or dehydrating agent, such as an acid anhydride, especially acetic anhydride, a carbodiimide or ketene imine or sulfur trioxide. It is preferable to use an excess of the oxidizing agent which, if liquid under the reaction conditions, can also be used as a diluent.

  The reaction is preferably carried out in an approximately 1: 1 mixture of dimethyl sulfoxide and acetic anhydride, working with cooling if desired, but mostly at room temperature or at a slightly elevated temperature.



   In a compound of the formula Ia obtained, the esterified carboxyl group of the formula -C (= O) -O-O-R 32 can be used in the usual manner. z. B. as described above, converted into the free car boxyl group, z. B. by treating with a chemical reducing agent, such as zinc, in the presence of aqueous acetic acid, a compound of the formula Ia with an esterified carboxyl group of the above formula, wherein R B represents a radical, together with the carboxyl group, forming a reductively removable esterified carboxyl group, e.g. B. the phenacyl, 2,2,2-trichloroethyl or 2-iodoethyl radical (the latter before the cleavage of the esterified carboxyl group, e.g. from the corresponding 2-bromo ethyl radical, z.

  B. by treating with an alkali metal iodide such as sodium iodide, in the presence of a suitable solvent such as acetone, can be formed), or by treating with an acidic agent such as trifluoroacetic acid, a compound of formula X having an esterified carboxyl group of the above formula, wherein RB for one, too
2 together with the carboxyl group forming an esterified carboxyl group cleavable in the presence of a suitable acidic agent, e.g. 3. the tert-butyloxy group is.



   In a starting material of the formula II obtained, a free carboxyl group -C (= O) -O-R2 can be used in a manner known per se, e.g. B. as stated above, can be converted into an esterified carboxyl group and the latter into another carboxyl group. Silyl and stannyl groups R 2 can also be introduced in a manner known per se, e.g. B.



  by treating compounds of formula II in which R B is hydrogen, as well as salts such as alkali metal, e.g. Sodium salt thereof, with a suitable silylating agent such as a tri-lower alkylsilyl halide, e.g. B. trimethylsilyl chloride, or an N- (tri-lower alkyl-silyl) -N-Rd-N-Re-amine, where Rd is a hydrogen atom or a lower alkyl group and Re is a hydrogen atom, a lower alkyl group or a tri-lower alkyl-silyl group (see e.g. British Patent No. 1,073,530), or with a suitable stannylating agent such as a bis (tri-lower alkyl-tin) oxide, e.g. B. bis (tri-n-butyl-tin) oxide, a tri-lower alkyltin hydroxide, e.g. B.

  Tri-ethyl-tin hydroxide, a tri-lower alkyl-lower alkoxy-tin, tetra-lower alkoxy-tin or tetra-lower alkyl-tin compound, and a tri-lower alkyl tin halide, e.g. B. tri-n-butyltin chloride (see e.g. Hol- Händische Auslegeschrift 67/17107).



   In the preparation of the starting material, if necessary, free functional groups not participating in the reaction in the reactants, e.g. B. free hydroxy, mercapto or amino groups, e.g. By acylation, and free carboxy groups, e.g. B. by esterification, including silylation, protected in a manner known per se from transient, and each time after the reaction, if desired, are released in a manner known per se.



   As mentioned, the compounds of the formula I are valuable intermediates which are particularly useful in the preparation of pharmacologically valuable 7- (N-acyl-amino) ceph (3) -em-4-carboxylic acid compounds with effects against microorganisms such as gram-positive bacteria , e.g. B. Staphylococcus aureus, and gram negative bacteria, e.g. B. Escherichia coli, including penicillin-resistant bacteria, can be carried over.



   In a 7- (N-acyl-amino) -2,2-dimethyl-ceph (3) em-4-carboxylic acid compound with pharmacological properties, there is an acyl group, in particular a pharmacologically active N-acyl derivative of 6-amino-penicillic acid - and 7 amino-cephalosporanic acid compounds containing acyl radical of an organic carboxylic acid.

  Such an acyl radical is primarily a group of the formula
EMI10.1
 where n is 0 and RI is an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, preferably etherified hydroxyl or mercapto group or an optionally substituted amino group, or where n is 1, RI is hydrogen or an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical, preferably aromatic in character, an optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto group, an optionally functionally modified carboxyl group, an acyl group,

   represents an optionally substituted amino group or an azido group, and each of the radicals RII and RIII represents hydrogen, or in which n represents 1, RI represents an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical, preferably of aromatic character, RII denotes an optionally functionally modified, preferably etherified, hydroxy or mercapto group, an optionally substituted amino group or an optionally functionally modified carboxyl group, and RIII stands for hydrogen, or in which n stands for 1, each of the radicals RI and RII is a functionally modified,

   preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and RIII is hydrogen, or in which n is 1, RI is hydrogen or an optionally substituted aliphatic hydrocarbon radical, and RII and RIII together is an optionally substituted, by a double bond with the carbon atom represent linked aliphatic hydrocarbon radical, or in which n is 1, and RI is an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical,

   preferably of aromatic character, RII is an optionally substituted aliphatic or aromatic hydrocarbon radical and RIII is hydrogen or an optionally substituted aliphatic or aromatic hydrocarbon radical.



   In the above definitions, an aliphatic hydrocarbon radical means e.g. B. a straight-chain or branched lower alkyl, and lower alkenyl or lower alkynyl group.



  Such a radical, in particular a lower alkyl radical, can be used as substituents, for. B. optionally substituted cycloaliphatic or aromatic hydrocarbon radicals, e.g. B. phenyl radicals, or optionally substituted heterocyclic radicals, preferably of aromatic character, also optionally functionally modified, preferably etherified or esterified hydroxy or mercapto, z. B. by optionally substituted aliphatic, aromatic or araliphatic hydrocarbon radicals, as well as heterocyclic or heterocyclic-aliphatic groups etherified hydroxy or mercapto groups, such as optionally substituted lower alkoxy, phenyloxy, phenyl-lower alkoxy or lower alkyl mercapto groups, or halogen atoms, nitro groups, such as substituted amino groups Di-lower alkyl-amino, alkylenamino, lower alkanoyl-amino or sulfoamino groups, acyl, e.g.

  B. optionally substituted lower alkanoyl or benzoyl radicals, or optionally functionally modified carboxyl, z. B. lower alkoxycarbonyl, car bamoyl or cyano groups, azido groups or optionally functionally modified sulfo, z. B. sulfamoyl groups contain.



   A cycloaliphatic hydrocarbon radical preferably contains 3-7 ring carbon atoms and is an optionally, z. B. by aliphatic radicals or then like the above aliphatic radical, substituted cycloalkyl and cycloalkenyl groups, primarily with 5 or 6 ring carbon atoms. Such a cycloaliphatic radical, primarily a cycloalkyl radical, preferably contains an amino group in the 1-position as a substituent.



   The abovementioned aromatic hydrocarbon radicals are, in particular, optionally substituted, bicyclic, but primarily monocyclic aromatic hydrocarbon radicals which can be partially saturated, such as naphthyl or tetrahydronaphthyl, primarily phenyl radicals. These residues can e.g. B. by optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon, z. B. lower alkyl, trifluoromethyl or optionally substituted cycloalkyl or phenyl radicals, or by functional groups, such as optionally functionally modified, z. B. etherified or esterified, hydroxy or mercapto, z. B. the above, optionally functionally modified, such as etherified or esterified, hydroxyl or mercapto groups, nitro groups, optionally substituted amino groups, e.g.

  B. the above amino groups, acyl groups, e.g. B. the above acyl radicals, optionally functionally modified carboxyl, z. B. the above groups of this type, or optionally functionally modified sulfo groups, eg. B. the above Sulforeste be substituted.



   An optionally substituted heterocyclic radical, preferably of aromatic character, is primarily a monocyclic monoaza-, monothia-, monooxa-, diaza, oxaza-, thiaza, triaza or tetrazacyclic radical, preferably of aromatic character, e.g. B. a pyridyl, pyridinium, thienyl, furyl, imidazolyl, isozolyl, thiazolyl, triazolyl, tetrazolyl or isoxazolyl radical, the z. B. how one of the above aromatic radicals can be substituted.



   An etherified hydroxy or mercapto group contains as an etherifying radical z. B. an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical, and means z. B. an optionally substituted lower alkoxy, lower alkenyloxy, phenyloxy, phenyl-lower alkoxy, lower alkyl mercapto, lower alkenyl mercapto, phenyl mercapto or phenyl lower alkyl mercapto group. Further radicals occurring in etherified hydroxyl and especially mercapto groups are optionally substituted heterocyclic groups, preferably of aromatic character, such as, for. B. the above-mentioned heterocyclic radicals.



   Esterified hydroxyl groups are e.g. B. hydroxy groups esterified by inorganic or organic acids, in particular halogen atoms, and also optionally substituted lower alkanoyloxy or benzoyloxy groups.



   Substituted amino groups contain as substituents one or two optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, wherein such radicals, in particular aliphatic radicals, can also be bivalent, and are, for. B. optionally, such as by halogen atoms, substituted lower alkyl or di-lower alkylamino groups or optionally substituted lower alkylene amino groups with 5-7 ring members, in which the carbon atoms of the lower alkylene radical by an oxygen or sulfur atom or, optionally a substituent, z. B. a lower alkyl group, containing nitrogen atom may be interrupted.



   Optionally functionally modified carboxyl groups are z. B. esterified or amidated carboxyl groups, such as lower alkoxycarbonyl or optionally N-substituted ones, such as N-lower alkyl or N, N-di-lower alkylcarbamoyl groups, and also cyano groups.



   An acyl group is e.g. B. an optionally substituted lower alkanoyl, lower alkenoyl or benzoyl group.



   In the above-mentioned functional groups substituted by organic radicals, such as etherified hydroxyl or mercapto groups or substituted amino groups, the organic radicals, e.g. B. aliphatic, cycloaliphatic or aromatic groups, and optionally heterocyclic radicals, for. B. like the above radicals of this type, be substituted.



   In the above acyl groups of the formula A, for. B. n for 0 and RI for one optionally, preferably in the 1-position by amino or one, optionally in salt, z. B. alkali metal salt form present sulfoamino group, substituted cycloalkyl group with 5-7 ring carbon atoms, an optionally, preferably by lower alkoxy, substituted phenyl, naphthyl or tetrahydronaphthyl group, an optionally, z. B. by lower alkyl and / or phenyl groups which in turn have substituents such as halogen, e.g. B. chlorine, can carry substituted heterocyclic group, such as a 4-isoxazolyl, or preferably, z. B.



  by an optionally substituted one such as halogen, e.g. B.



  Chlorine-containing lower alkyl radical N-substituted amino group, or n for 1, RI for an optionally substituted lower alkyl group, preferably by halogen, such as chlorine, optionally substituted phenyloxy, amino and / or carboxy, a lower alkenyl group, an optionally substituted one, such as hydroxy. Halogen, e.g. B. chlorine, or optionally substituted phenyloxy-containing phenyl group, an optionally, z. B. by amino, substituted pyridyl, pyridinium, thienyl 1-imidazolyl or 1-tetrazolyl group, an optionally substituted lower alkoxy or phenyl oxo group, a lower alkyl mercapto or lower alkenyl mercapto group, an optionally, z.

  B. by lower alkyl, substituted phenylmercapto, 2-imidazolylmercapto or 1,24-triazol-3-ylmercapto group, a halogen, in particular chlorine or bromine atom, a carboxy, lower alkoxycarbonyl, cyano or optionally, z. B. by phenyl, N-substituted carbamoyl group, an optionally substituted lower alkanoyl or benzoyl group, or an azido group, and RIT and RIII for hydrogen, or n for 1, RI for an optionally substituted phenyl or thienyl group, RII for an amino or cyano group, an optionally in salt, z.

  B. alkali metal salt form present carboxyl or sulfoamino group, or an optionally substituted NiederalLoxy- or phenyloxy group, and RJII for 1, RT and RII each for a halogen, z. B. bromine atom, or a lower alkoxycarbonyl, e.g. B. methoxycarbonyl group, and RIII for hydrogen, or n for 1, and each of the groups RI, RI1: and RIII for a lower alkyl group.



   The above acyl groups can e.g. B. by the radical of the formula Y- (C, H ,,) - C (= O) -, in which m is 0, 1 or 2, preferably 1, and a carbon atom of a, preferably unbranched, alkylene radical of the formula - (C, nHeni) - e.g. B. by an optionally substituted amino group, a free, etherified or esterified hydroxy or mercapto group, a free or functionally modified carboxyl group or an oxo group, e.g. B. can be substituted by one of the above groups of this type, and wherein Y is a, optionally in the nucleus, z. B. as the above alkylene radical, as well as aromatic or cycloaliphatic hydrocarbon radicals substituted by nitro or optionally functionally modified sulfo groups, such as phenyl or cycloalkyl radical, or, if appropriate, e.g.

  B. as the above aromatic or cycloaliphatic radical, substituted he terocyclic group, preferably aromatic character, such as an optionally substituted pyridyl, pyridinium, thienyl, furyl, imidazolyl, tetrazolyl or isoxazolyl group, also one, by one, optionally as indicated substituted, aromatic or cycloaliphatic hydrocarbon radical or heterocyclic radical, z. 3. of aromatic character, etherified hydroxyl or mercapto group means.

  Such acyl radicals are, for. 3. 2,6-dimethoxybenzoyl-, tetrahydronaphthoyl-, 2-methoxy-naphthoyl-, 2-ethoxy-naphthoyl-, cyclopentylcarbonyl-, a-amino-cyclopentylcarbonyl- or a-amino-cyclohexylcarbonyl- (optionally with substituted amino, z 3. a sulfoamino group, optionally present in salt form), benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 2-phenyl-5-methyl-4-isoxazolyl carbonyl, 2- (2-chlorophenyl) -4-methyl-4-isoxazolylc 2- (2,6-dichlorophenyl) -5-methyl-4-isox.o phenyl acetyl, phenacylcarbonyl, phenyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, a phenyloxy-phenylacetyl,

   α-methoxy-phenylacetyl-, z-ethoxy-phenylacetyl-, α-methoxy-3,4-dichloro-phenylacetyl-, α-cyanophenylacetyl-, phenylglycyl- (optionally with substituted amino, such as one, optionally in Salt form present, sulfoamino group), benzylthioacetyl, benzylthiopropionyl, α-carboxyphenylacetyl (optionally with functionally modified, e.g. 3. present in salt form, carboxyl group), 2-pyridylacetyl, 4-amino-pyn.diniumacetyl, 2-thienyl acetyl-, o-carboxy-2-thienylacetyl- or a-carboxy-3 4hienylacetyl- (optionally with functionally modified, e.g. 3.



  carboxyl group present in salt form), a-cyano-2-thienylacetyl-, a-amino-2-thienylacetyl- or a-amino-3-thienyl-acetyl- (optionally with substituted amino-, e.g. 3. optionally in salt form , Sulfoamino group), 3-thienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-methyl-5-tetrazolylacetyl, 3-methyl-2-imidazolylthioacetyl or 1,2,4-triazol-3-yl-thioacetyl group.

  An acyl radical is e.g. 3. also a group of the formula CnH2n + 1-C (= O) - or CnH2h-1-C (= 0) -, where n is an integer up to 7 and the chain is straight or branched and optionally from an oxygen or sulfur atom interrupted and / or z. 3. may be substituted by halogen atoms, free or functionally modified carboxyl, such as lower alkoxycarbonyl or cyano groups, free or substituted amino groups, or oxo, azido or nitro groups, e.g. 3. a propionyl, butyryl, hexanoyl, octanoyl, acrclyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, methylthloacetyl, butylthioacetyl, allylthioacetyl, chloroacetyl,

   Bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl, 5-aminocarboxyvaleryl (optionally with substituted amino and / or optionally functionally modified carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl -, Äthoxycarbonylacetyl-, bismethoxycarbonylacetyl-, N-phenylcarbamoylacetyl-, cyanoacetyl, a cyanopropionyl or 2-cyano-3-dimethylacrylyl group, also a radical of the formula Z-NH-CO-, where Z is an optionally substituted aromatic or aliphatic in particular a lower alkyl radical, optionally substituted by lower alkoxy groups and / or halogen atoms,

   z. 3. means the N-2-chloroethylcarbamoyl radical.



   Acyl groups in pharmacologically active 7- (N-acyl-amino) -2,2-dimethyl-ceph (3) em-4-carboxylic acid compounds are primarily those found in highly active N-acyl derivatives of 6-amino-penam-3-carboxylic acid or 7-Anfino-ceph (3) em-4-carboxylic acid compounds occurring acyl radicals, such as 2-chloroethylcarbomoyl, cyanoacetyl, phenylglycyl (optionally with substituted amino group), 2-thlenylacetyl, α-amino-2-thienylacetyl (optionally with substituted amino group), 1-amino-cyclohexylcarbonyl- (optionally with substituted amino group) or the a-carboxy-phenylacetyl- or <RTI

    ID = 12.57> z-carboxy-2-thlenylacetyl radical (optionally with substituted carboxy group).



   To prepare such compounds, the unsubstituted amino group is acylation methods known per se, e.g. 3. by treating with carboxylic acids or acid derivatives thereof such as halides, e.g. 3. Chlorides, or anhydrides (including the internal anhydrides of carboxylic acids, i.e. ketenes, or of carbamic or thio-carbamic acids, i.e.

  Isocyanates or isothiocyanates are to be understood) or activated esters acylated, using, if necessary, suitable condensing agents such as carbodiimides, eg. 3. Dicyclohexylcarbodiimide, or basic agents such as triethylamine or pyridine, are used. An acyl group can also be introduced in stages;

   z. 3. you can in a free amino group a halo-lower alkanoyl, z. 3. Bromoacetyl group, and a thus obtainable N halo-lower alkanoylamino compound with suitable exchange reagents, such as basic compounds, e.g. 3. Tetrazole, thlo compounds, e.g. 3. 2-mercapto-1-methyl-imidazole, or metal salts, e.g. 3. Sodium azide, react and thus arrive at substituted N-lower alkanoylamino compounds.

  In both reaction participants, free functional groups can be temporarily protected during the acylation reaction in a manner known per se and released after the acylation in a manner known per se.



   The 7- (N-acyl-amino) -2,2-dimethyl-ceph (3) em-4-carboxylic acid compounds obtainable in this way, in particular those with free or under pharmacological conditions cleavable esterified carboxyl group with pharmacological effects can, for. 3. be used in the form of pharmaceutical preparations which contain them in admixture with a solid or liquid pharmaceutical carrier material and which are suitable for enteral, parenteral or topical administration.

  Suitable carriers which are inert towards the active substances are, for. 3. Water, gelatin, saccharides such as actose, glucose or sucrose, starches such as corn, wheat or arrowroot starch, stearic acid or salts thereof such as magnesium or calcium stearate, talc, vegetable fats and oils, alginic acid, benzyl alcohols, glycols or other known carriers. The preparations can be in solid form, e.g. 3. as tablets, dragees, capsules or suppositories, or in liquid form, e.g. 3. as solutions, suspensions or emulsions.



  They can be sterilized and / or contain auxiliaries such as preservatives, stabilizers, wetting or emulsifying agents, solubilizers, salts to regulate the osmotic pressure and / or buffers. They can also contain other pharmacologically usable substances. The pharmaceutical preparations which are also encompassed by the present invention can be produced in a manner known per se.

 

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



   example 1
A solution of 0.347 g of 2,2-dimethyl-7 (N-phenylacetylamino) -ceph (3) em-4-carboxylic acid (lyophilized from dioxane and dried under high vacuum at 300) in 20 ml of absolute methylene chloride is mixed with 0.239 g of trimethylchlorosilane and 0.158 g of absolute pyridine were added and the mixture was stirred at room temperature for 60 minutes. The almost colorless solution is cooled to below 200, whereupon a solution of 1.07 g of absolute pyridine in 9.9 ml of absolute methylene chloride and 7.8 ml of an 8% solution of phosphorus pentachloride in absolute methylene chloride is added one after the other.



  The mixture is stirred for 60 minutes at -10 to 120, the solution turning a pale yellow. After cooling again to about ¯ 200, 5 ml of absolute methanol are allowed to flow in and the mixture is stirred for 25 minutes at -100, then for 35 minutes at room temperature. 5 ml of water are added, the pH of the reaction mixture is increased from 1.8 to 2.2 by the dropwise addition of diethylamine, and it is stirred for 20 minutes at room temperature. The pH value is increased to 3.4 by adding more triethylamine, the cloudy, 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 7-amino-2,2-dimethylceph (3) em-4-carboxylic acid of the formula is obtained in this way
EMI13.1
 Ultraviolet absorption spectrum (in 0.1 N aqueous sodium hydrogen carbonate solution): λ max = 254 mlt (e = 6350) and imin = 234 m (# = 4250); Infrared absorption spectrum: characteristic bands at 3.10, 3.75, 5.51, 6.17, 6.52, 7.03 lt, 7.30 lt and 7.40 (in mineral oil) and at 2.88, u , 3.10, 3.82, 5.52, 6.17, 6.50, 6.82, 7.04, 7.40, 8.13, 9.57, 12.10 and 12.67 (in Potassium bromide); Paper chromatogram (running distance 24 cm, system n-propanol / water 7: 3; detection with ninhydrin / collidine reagent):

  Rf = 0.44, thin-layer chromatogram (cellulose; distance 15.5 cm; system n-butanol / water / ethanol; detection with Reindel-Hoppe reagent); Rf = 0.37.



   The starting material can be made as follows:
15 ml of a sulfonic acid type ion exchanger (H + form) are introduced into the triethylammonium salt form by treatment with a solution of 5 ml of triethylamine in 100 ml of water, the column is washed neutral with 300 ml of water and treated with a solution of 2 g of the Sodium salt of penicillin-G in 10 ml of water and then eluted with water. A volume of 45 ml is withdrawn and lyophilized at a pressure of 0.01 mm Hg. The crude triethylammonium salt of penicillin-G thus obtained is dissolved in methylene chloride, and the solution is dried over sodium sulfate, filtered and evaporated.



   A solution of the penicillin-G-triethylammonium salt thus obtainable in a mixture of 40 ml of methylene chloride and 40 ml of tetrahydrofuran is cooled to -100 and 2.9 ml of a 10 ml solution of 2 ml of ethyl chloroformate in tetrahydrofuran are slowly added with stirring.



     The mixture is stirred for 90 minutes at ¯ 50 to 0, then mixed with a solution of 0.395 g of sodium azide in 4 ml of water and the mixture is stirred for 30 minutes at -50 to 00. It is diluted with 100 ml of ice water and extracted three times with 75 ml each time Methylene chloride; the organic extracts are washed with water, dried and evaporated at room temperature under reduced pressure.



  The amorphous penicillin G-azide is obtained in this way, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 4.71, 5.62, 5.80, 5.94, 6.69 and 8.50 liters
A solution of 1.72 g of penicillin G azide in 30 ml of benzene is mixed with 1.5 ml of 2,2,2-trichloroethanol and stirred at 700 for 25 hours. A regular evolution of nitrogen is observed during the first 15 minutes and after a few hours the product separates out of the solution. The mixture is diluted with 60 ml of hexane while stirring, cooled and filtered after 15 minutes. The filter residue is washed with a 2: 1 mixture of benzene and hexane and with cold ether.

  The pure 2,2-dimethyl-6- (N-phenylacetyl-amino) -3- (N-2,2,2-tri chloroethoxycarbonylamino) -penam is obtained, which melts at 223-223.5; [a D0 = + 1720 (c = 1.018 in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 5.61, 5.77, 6.97, 6.70, 8.30, 9.17, 9.62 and 11.85.



   The product can also be obtained by heating 0.03 g of penicillin-G azide in 2 ml of benzene to 700 for 20 minutes, and by evaporating the reaction mixture under reduced pressure to obtain 3-isocyanato-2,2-dimethyl-6 ( N-phenylacetyl-amino) -penam; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.06, 4.48, 5.62, 5.96 and 6.70; obtained and this method shown in Example 4 by reacting with 2,2,2 trichloroethanol in the desired 2,2-dimethyl-6- (N-phenyl acetylamino) -3- (N-2,2,2-trichloroethoxycarbonyl-amino ) -pen- am transferred.



   A solution of 2.49 g of 2,2-dimethyl-6- (N-phenylacetylamino) -3- (N-2,2,2-trichloroethoxycarbonyl-amino) -penam in 50 ml of dimethylformamide, 25 ml of acetic acid and 5 ml of water is prepared at room temperature, then cooled to 0 and a total of 25 g of zinc dust is added in portions within 10 minutes while stirring. It is stirred for 20 minutes at 0, then the mixture is filtered into a template of 500 ml of a saturated aqueous sodium chloride solution and the filter residue is washed out with 25 ml of acetic acid. The filtrate is extracted three times with 300 ml of benzene each time; the organic extracts are washed with water, dilute aqueous sodium hydrogen carbonate solution and water, combined, dried and evaporated under reduced pressure.

  The residue is chromatographed on 45 g of acid-washed silica gel. Fractions of 100 ml each are taken, with 300 ml of benzene, 300 ml of a 9: 1, 500 ml of a 4: 1, 600 ml of a 2: 1 and 200 ml of a 1: 1 mixture of benzene and Wash out ethyl acetate and 100 ml ethyl acetate. Fractions 8 and 9 contain crystalline starting material, while the 3-hydroxy-2,2-dimethyl-6- (N-phenylacetylamino) penam is obtained from fractions 11-15 as a colorless oil; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90, 3.05, 5.64, 5.99, 6.70 and 9.28.



   A solution of 0.3 g of 3-hydroxy-2,2-dimethyl-6- (N-phenylacetyl-amino) -penam in 8 ml of tetrahydrofuran is at 0 with 0.5 ml of a solution of 0.38 g of sodium borohydride in 5 ml of water treated. The reaction mixture is stirred for 20 minutes at 0, then acidified with 20 drops of acetic acid and diluted with 50 ml of methylene chloride. The organic solution is washed with a saturated aqueous sodium chloride solution, dried and evaporated.

 

  After crystallization from benzene, the residue gives 4ss (2-hydroxymethyl-2-propyl-mercapto) -3ss- (N-phenylacetylamino) -azetidin-2-one, which melts at 129-129.5; [α] 20 D = 10 1 10 (c = 0.984 in chloroform); Ultraviolet absorption spectrum (in ethanol): #max = 252 mlt (8 = 170), 258 rult (E = 200) and 265 mlt (e = 150); Infrared absorption spectrum: characteristic bands in methylene chloride at 2.75, 2.92, 5.61, 5.97, 6.23, 6.62, 6.68 (shoulder) and 9.48, and in mineral oil at 3.12, 3.18 (shoulder), 3.23, 5.62, 5.75, 6.08, 6.23, 6.42, 8.02 and 9.45; Thin-layer chromatogram (silica gel):

  Rf = 0.10 (chloroform / acetone 4: 1), Rf = 0.33 (chloroform / methanol 19: 1) and Rf = 0.63 (chloroform / methanol 9: 1).



   A solution of 1.55 g of 4ss- (2-hydroxymethyl-2-propyl-mercapto) -3ss- (N-phenylacetylamino) -azetidin-2-one and 1.42 g of 2,2,2-trichloroethyl chloroformate in 20 ml of absolute tetrahydrofuran is cooled to 0 and, while stirring, a solution of 0.81 ml of absolute pyridine (0.79 g) in 10 ml of absolute tetrahydrofuran is added over the course of 3 minutes. After the addition has ended, the temperature is allowed to rise to about 200 and stirring is continued for 2 hours. The reaction mixture is diluted with 150 ml of methylene chloride and 40 ml of water, shaken and the phases are separated. The aqueous phase is washed twice with 50 ml of methylene chloride each time and the combined organic phases are washed twice with 30 ml of water each time, dried over magnesium sulfate and freed from the solvent under reduced pressure.

  The residue is chromatographed on a column of 165 g of silica gel. Bis (2,2,2-trichloroethyl) carbonate and a little 2,2,2-trichloroethanol are washed out with a 19: 1 mixture of methylene chloride and methyl acetate; the 3ss- (N-phenylacetylamino) -4ss- [2- (2,2,2- trichlorethoxyloxy-carbonyloxymethyl) -2-propylmercapto] - azetidin-2-one- is an amorphous and thin-layer chromatographically pure product with a 9: 1- Eluted mixture of methylene chloride and methyl acetate and lyophilized from benzene.

  The lyophilizate is dried in a high vacuum for 20 hours at room temperature; [α] 20 D = -3 # 1 (c = 1.097 in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.24 (toluene / ethyl acetate 1: 1) and Rf = 0.78 (chloroform / acetone 2: 1);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.91 k, 5.61 k, 5.64 lt (shoulder), 5.93 to 6.62, 7.22, 8.08 to 10.00 lt and 12, 25 lt
A solution of 3.2 g of glyoxylic acid tert-butyl ester hydrate in 80 ml of toluene is concentrated to half the volume to remove water and, after cooling, with 0.880 g of 3ss- (N-phenylacetylamino) -4ss- (2- [2,2,2-trichloroethoxy-carbonyloxymethyl) -2-propylmercapto] -azetidin-2-one added. The mixture is then heated at 900 for 41/2 hours and, after cooling, the reaction mixture is drawn onto a column of 120 g of silica gel.

  The α-hydroxy α - {2-oxo-3ss- (N-phenylacetylamino) -4ss- [2- (2,2,2-trichloroethoxy-carbonyloxymethyl) is eluted with a 3: 1 mixture of toluene and ethyl acetate -2-propylmercapto] - 1-azetidinyl} - a-hydroxy-acetic acid tert-butyl ester which in the thin layer chromatogram (silica gel) has an Rf value of 0.36 (system: benzene / ethyl acetate 1: 1) and shows a uniform Represents a product that is processed without further purification.



   A solution, cooled to ¯ 100, of 0.932 g of a-hydroxy a- {2-oXo-3ss- (N-phenylacetylamino) -4ss- [2- (2,2,2-trichloroethoxycarbonyloxymethyl) -2-propylmercapto] -1 -azetidinyl} acetic acid tert-butyl ester in 18 ml of a 1: 1 mixture of dioxane and tetrahydrofuran is mixed with 0.366 ml of pyridine and then with a solution of 0.328 ml of thionyl chloride in 10 ml of a 1: 1 mixture of dioxane and tetrahydrofuran . The reaction mixture is stirred for one hour at 0 and for a further hour at room temperature; the resulting precipitate is filtered off and the filtrate is evaporated in a rotary evaporator.

  The oily residue containing the α-chloro-α - {2-oxo-3ss- (N-phenylacetyl-amino) -4ss- [2- (2,2,2-trichloroethoxycarbonyloxymethyl) -2-pro pylmercapto] - Contains 1-azetidinyl} -acetic acid tert-butyl ester, is evaporated to dryness twice with 50 ml of benzene each time, then taken up in 20 ml of dioxane and heated to 550 with 0.769 g of triphenylphosphine and 0.122 ml of pyridine for 17 hours. After cooling, the reaction mixture is filtered through a diatomaceous earth preparation and the filtrate is evaporated to dryness. A dark brown oily residue is obtained, which is chromatographed on 25 times the amount of silica gel.

  The a- {-oxo-3ss- (N-phenylacetylamino) -4ss- [2- (2,2,2-trichloroethoxy-carbonyloxymethyl) -L-propylmercapto] -l -azetinyl) is eluted with ethyl acetate. - at} iphenylphosphoranyliden-acetic acid tert-butyl ester thin-layer chromatogram (silica gel): Rf = 0.16 (benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, u, 3.45, u, 5.68, 5.96, 6.14 and 6.63; Ultraviolet absorption spectrum (in ethanol: final absorption at 220 m.



   A solution, cooled to about 150, of 0.614 g of CL- {2-oxo-3ss- (N-phenylacetylamino) -4ss- [2- (2,2,2-trichloroethoxycarbonyloxymethyl) -2-propyimercapto] -1-azetidinyl } - a-triphenylphosphoranylidene-acetic acid tert-butyl ester in 30 ml of glacial acetic acid is mixed with 6.0 g of zinc dust and 3.0 ml of water and stirred at about 150 for 30 minutes. The zinc dust is filtered off and the filtrate is evaporated in a rotary evaporator. The residue is taken up in 250 ml of benzene and washed with 75 ml of distilled water, 75 ml of a saturated aqueous sodium hydrogen carbonate solution and 75 ml of distilled water. The aqueous phases are re-extracted with 100 ml of benzene and the combined organic extracts are dried over magnesium sulfate and evaporated.

  The residue obtained is a [4ss- (2-hydroxymethyl-2-propylmercapto) -2-oxo-3ss- (N-phenylacetylamino) -l -azetidinyl] - (r-triphenylphosphoranylidene-esetic acid tert-butyl ester Thin-layer chromatogram: Rf = 0.145 (ethyl acetate); infrared absorption spectrum (methylene chloride): characteristic bands at 3.00, 3.47, 5.68, 6.00, 6.10 and 6.61; which is further processed without purification.



   A solution of 0.5205 g of a- [4ss- (2-hydroxymethyl-2 propylmercapto) -2-oxo-3ss- (N-phenylacetylamino) -1-azetidinyl] -a-triphenylphosphoranylidene-acetic acid tert-butyl ester in 10 ml of absolute dimethyl sulfoxide is mixed with 10 ml of acetic anhydride and left to stand for 16 hours under a nitrogen atmosphere at room temperature, then heated for 2 hours at 500 and evaporated to dryness. The residue is purified by means of preparative thin layer chromatography (silica gel; plates 100 cm × 10 cm × 1.5 mm).

  It is developed with a 2: 1 mixture of toluene and ethyl acetate and the desired 2,2-dimethyl-7- (N-phenylacetyl-amino) -ceph (3) em-4-carboxylic acid tert-butyl ester Rf N 0 is obtained , 55-0.58, which is formed by ring closure from the intermediately obtained and non-isolated α- [4ss- (2-formyl-2-propylmercapto) -2-oxo-3ss- (N-phenylacetylamino) -1- azetidinyl] -? -triphenylphosphoranylidene-esetic acid tert-butyl ester is formed and crystallizes on spraying with ethanol.

  The colorless crystals melt at 86900, solidify again and finally melt at 1591620; [α] 20 D = + 950 + 100 (c = 0.1 in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.38 (system: hexane / ethyl acetate 3: 2); Ultraviolet absorption spectrum (in ethanol): imax 258 m, (e = 7100); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.44, a, 5.62, u, 5.82, u, 5.92 lt '6.11, 6.67 lt' 7.18, 7 , 34, 7.75 and 8.66.

 

   A solution of 0.58 g of 2,2-dimethyl-7- (N-phenylacetylamino) -ceph (3) em-4-carboxylic acid tert-butyl ester in 10 ml of absolute trifluoroacetic acid is left to stand for one hour at room temperature. The pale yellow solution is evaporated under reduced pressure and the residue is taken to dryness twice with a small amount of absolute toluene. The residue is chromatographed on 30 g of silica gel (5% water; column). Impurities are washed out with methylene chloride containing 2-4% acetone; with 19: 1 and 9: 1 mixtures of methylene chloride and acetone, the chromatographically pure 2,2 dimethyl-7- (N-phenylacetyl-amino) -ceph (3) em-4-carboxylic acid and with 4: 1 - and 1: 1 mixtures of the same solvent mixture, slightly contaminated product eluted.

  The pure acid is obtained as a colorless, vitreous material; Ultraviolet absorption spectrum (in ethanol): Man = 257 m (# = 6450) and amine = 232 mu (e = 4400); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90, 5.57, 5.72, 5.83, 5.90, 6.11, 6.64, 7.08.



     7.31 liters, 8.20 liters and 9.08; Thin-layer chromatogram (silica gel): Rf = 0.41 (system n-butanol / ethanol / water 40:10:50), Rf = 0.68 (system n-butanol / acetic acid / water 44:12:44), Rf = 0 , 53 (system ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11), Rf = 0.62 (system n-butanol / pyridine / acetic acid / water 38: 24: 8: 30 and Rf = 0.61 ( System n-butanol / acetic acid / water 75: 7.5: 21).



   If the 2,2-dimethyl-7- (N-phenylacetylamino) ceph (3) em-4-carboxylic acid is mixed with a slight excess of a 3 molar solution of the sodium salt of α-ethyl caproic acid in methanol, the result is on dilution with acetone, the sodium salt of 2,2-dimethyl-7- (N-phenylacetyl-amino) ceph (3) em-4-carboxylic acid, which decomposes at 2180 (uncorrupted); Ultraviolet absorption spectrum (in water: Ämax 252 mlt (# = 7300) and #min = 232 mlu (E = 5500); infrared absorption spectrum (in mineral oil): characteristic bands at 2.99, 5.65, 5.98, 6.22, 6.50, 6.67, 7.05, 7.29, 8.64, 9.03 and 9.48.



   In an analogous manner, the 2,2-dimethyl-7- (N-phenyloxyacetyl-amino) -ceph (3) -em-4-carboxylic acid can be used to prepare the 7-amino-2,2-dimethyl-ceph (3) em Use -4-carboxylic acid.



   The above starting material can be made as follows:
A solution of 2.625 g of penicillin-V in 30 ml of tetrahydrofuran is mixed with 5.31 ml of a 10 ml solution of 2 ml of triethylamine in tetrahydrofuran while stirring and cooling to ¯ 100. Then 3.6 ml of a 10 ml solution of 2 ml of ethyl chloroformate in tetrahydrofuran are slowly added at ¯ 100 and, after the addition is complete, stirred for 90 minutes at ¯ 100 to -5.



   The reaction mixture is treated with a solution of 0.51 g of sodium azide in 5.1 ml of water, stirred for 30 minutes at 0 to ¯ 5a and diluted with 150 ml of ice water. It is extracted three times with methylene chloride; the organic extracts are washed with water, dried and evaporated at 250 ° and under reduced pressure. The amorphous penicillin V-azide is thus obtained as a slightly yellowish oil; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 4.70 lt '5.61, 5.82 (shoulder), 5.93, 6.26, 6.71, 8.50 and 9.40, a .



   A solution of 2.468 g of penicillin V azide in 30 ml of benzene is heated to 700 for 30 minutes. The pure 3-isocyanato-2,2-dimethyl-6- (N-phenyloxyacetylamino) -penam can be obtained by evaporating the solution under reduced pressure; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 4.46, 5.59, 5.93, 6.26, 6.62, 6.70, 7.53, 8.28, 8.53, 9 , 24 and 9.40.



   The above solution of 3-isocyanato-2,2-dimethyl-6- (N-phenyloxyacetyl-amino) -penam is mixed with 3.4 ml of a 10 ml solution of 2 ml of 2,2,2-trichloroethanol in benzene and that Reaction mixture held at 700 for 95 minutes. The solvent is removed under reduced pressure and the residue is purified on 40 ml of acid-washed silica gel (column). It is washed with 300 ml of benzene and 300 ml of a 19: 1 mixture of benzene and ethyl acetate by-products and the pure 2,2-dimethyl-6- (N-phenyloxyacetylamino) -3- (N-2,2,2- trichlorethoxycarbonyl-amino) -penam with 960 ml of a 9: 1 mixture of benzene and ethyl acetate.

  The product melts at 169-171 (decompose); [a] D0 = + 830 (c = 1.015 in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.5 in a 1: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.62, 5.77, 5.93, 6.27, 6.62, 6.70, 8.30, 9.23 and 9.50.



   A solution of 3 g of crystalline 2,2-dimethyl-6- (N-phenyloxyacetyl-amino) -3- (N-2,2,2-trichlorethoxycarbonylamino) -penam in 65 ml of 90% aqueous acetic acid and 30 ml of dimethylformamide is 32.6 g of zinc dust were added within 20 minutes while cooling in ice and the mixture was stirred for 20 minutes. The excess zinc is filtered off and the filter residue is washed with benzene; the filtrate is diluted with 450 ml of benzene, washed with a saturated aqueous sodium chloride solution and water, dried and evaporated under reduced pressure. The residue is purified on a column of 45 g of acid-washed silica gel. Elution is carried out with 100 ml of benzene and 400 ml of a 9: 1 mixture of benzene and ethyl acetate, and apolar products are obtained.

  Starting material is washed out with 100 ml of a 4: 1 mixture of benzene and ethyl acetate and with another 500 ml of the 4: 1 mixture of benzene and ethyl acetate, and with 200 ml of a 2: 1 mixture of benzene and ethyl acetate, the 3- Hydroxy-2,2-dimethyl-6- (N-phenyloxyacetyl-amino) - penam, which spontaneously crystallizes as a hydrate and, after trituration with water-saturated ether, melts indistinctly in the range of 62-85.



   If chromatographed but non-crystalline 2,2-dimethyl-6- (N-phenyloxyacetyl-amino) -3- (N-2,2,2-trichloroethoxycarbonyl-amino) -penam is used and reduced in dilute acetic acid without adding dimethylformamide the pure product is obtained, melting at 62-70; Thin-layer chromatogram (silica gel): Rf = 0.35 in a 1: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.93, 3.09, 5.65, 5.96, 6.29, 6.65, 6.75, 8.57, 9.27, 10.00 and 11 , 95.



   A solution of 0.18 g of 3-hydroxy-2,2-dimethyl-6- (Nphenyloxyacetyl-amino) -penam hydrate in 5 ml of tetrahydrofuran is treated at 0 with 0.3 ml of a solution of sodium borohydride in 5 ml of water. The mixture is stirred at 0 for 20 minutes, then adjusted to pH ¯ 4 by adding 12 drops of acetic acid and diluted with 50 ml of methylene chloride. The organic solution is washed twice with saturated aqueous sodium chloride solution, the aqueous washing liquids are backwashed with methylene chloride and the combined organic solutions are dried and evaporated under reduced pressure.

  The crystalline residue is recrystallized from a mixture of methylene chloride and ether, the 4ss- (2-hydroxymethyl-2-propyl-mercapto) -3ss- (N-phenyloxyacetyl-amino) -azetidin-2-one being obtained after repeated recrystallization obtained in needles, F. 156-1570; [CL] 20 D = + 1300 + 10 (c = 0.708 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 4.46, 5.59, 5.93, 6.26, 6.62, 6.70, 7.53, 8.28, 8.53, 9 , 24 and 9.40.



   A solution of 0.4 g of 4ss- (2-hydroxymethyl-2-propylmercapto) -3ss- (N-phenyloxyacetyl-amino) -azetidin-2-one and 0.52 g of 2,2,2-trichloroethoxycarbonyl chloride in 6 ml of dry tetrahydrofuran is slowly added with stirring and at 0 with a solution of 0.6 ml of pyridine in 4 ml of dry tetrahydrofuran. After the addition has ended, the mixture is stirred for 3 hours, then diluted with 100 ml of methylene chloride; the organic solution is washed with water, dried and evaporated. The residue is chromatographed on 40 g of acid-washed silica gel. By-products, mainly bis2,2,2-trichloroethyl carbonate, are washed out with benzene and 9: 1 and 4: 1 mixtures of benzene and ethyl acetate.

  The 3ss- (N-Phe nyloxyacetyl-amino) -4ss- [2- (2,2,2-trichlorethoxy-carbonyloxymethyl) -2-propylmercapto] -azetidin-2-one is with a 1: 1 mixture of benzene and ethyl acetate eluted and recrystallized from a mixture of ether and pentane, F.



  93-95; [α] 20 D = -6 # 1 (c = 1.17 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 5.63, 5.68, 5.92, 6.26, 6.69, 6.70, 7.25 and 8.08.



   A solution of 0.4 g of tert-butyl glyoxylate hydrate in 5 ml of toluene is azeotropically dried by distilling off 2 ml of toluene under normal pressure. It is cooled to 900 and 0.121 g of 3ss- (N-phenyloxyacetyl-amino) -4ss [2- (2,2,2-trichloroethoxy-carbonyloxymethyl) -2-propylmercapto] -azetidin-2-one in 2 ml of anhydrous toluene is added . The mixture is heated at 900 for 90 minutes; the volatile constituents are distilled off under a pressure of 0.01 mm Hg. The oily residue is taken up in a mixture of benzene and pentane and washed with water. The organic phase is dried and the solvent is distilled off under reduced pressure.

  The residue is chromatographed on 3.5 g of acid-washed silica gel, and the amorphous mixture of the isomers of α-hydroxy-α - {2-oxo-3ss- (N-phenyloxyacetyl-amino) -4ss- [2- ( 2,2,2-trichlorethoxy-carbonyloxymethyl) -2-propylmercapto] -1-azetidinyl} -acetic acid tert-butyl ester by eluting with a 4: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.64, 5.80, 5.94, 6.27, 7.32, 8.17 and 8.69.



   A solution of 0.254 g of a-hydroxy-a- {2-oxo-3ss- (N-phenyloxyacetyl-amino) -4ss- [2- (2,2,2-trichloroethoxy-carbonyl-oxymethyl) -2-propylmercapto-1 -azetidinyl} -acetic acid tert-butyl ester in 5 ml of dioxane (dried by filtering through aluminum oxide, activity I) is cooled to 0 and treated with 0.320 g of polymeric Hünig base (diisopropylaminomethylene polystyrene; prepared by heating a mixture of 100 g of chloromethyl polystyrene [J. Am Chem.

  Soc. 85, 2149 (1963)], 500 ml of benzene, 200 ml of methanol and 100 ml of diisopropylamine to 1500 with shaking, filtering, washing with 1000 ml of methanol, 1000 ml of a 3: 1 mixture of dioxane and triethylamine, 1000 ml of methanol, 1000 ml of methanol and drying for 16 hours at 1000/10 mm Hg; the product neutralizes 1.55 milliequivalents of hydrochloric acid per gram in a 2: 1 mixture of dioxane and water) and 0.6 ml of a solution of thionyl chloride in dry dioxane (1 ml of thionyl chloride per 10 ml of solution) is added. After 2 hours the mixture is filtered, the filter residue is washed with dry dioxane and the filtrate is evaporated to dryness under high vacuum.

  The residue containing the α-chloro-α - {2-oxo-3ss- (N-phenyloxyacetyl-amino) -4ss- [2- (2,2,2-trichloroethoxy-carbonyloxymethyl) -2-propylmercapto] - tert-butyl l-azetidinyl} acetic acid is dissolved in 5 ml of dioxane, 0.2 g of triphenylphosphine and 0.2 g of the polymeric Hünig base are added and the mixture is stirred at 55 for 16 hours. It is filtered, the filter residue is washed with benzene and the filtrate is evaporated under reduced pressure. The residue is chromatographed on 15 g of acid-washed silica gel.

  The fractions washed out with a 4: 1 mixture and the first with a 2: 1 mixture of benzene and ethyl acetate contain unreacted starting material, while the other fractions with the 2: 1 mixture of benzene and ethyl acetate and those with a 1: 1-mixture of the same solvent eluted fractions the amorphous a- (2-oxo-3ss- (Nphenyloxyacetyl-amino) -41e- [2- (2,2,2-trichlorethoxycarbonyl-oxy-methyl) -2-propylmercapto] -1-azetidinyl} α-triphenylphosphoranylidene-acetic acid-tert-butyl ester, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 5.69, 5.94, 6.2 and 8.9, contain and the other fractions have some triphenylphosphine oxide.



   A solution of 0.127 g of a- {2-Oxo-3ss- (N-phenyloxy acetyl-amino) -4ss- [2- (2,2,2-trichloroethoxycarbonyloxymethyl) -2-propylmercapto] -1-azetidinyl} -? -triphenylphosphoranyldene-acetic acid-tert-butyl ester in 10 ml of 90% aqueous acetic acid is mixed with 1.0 g of zinc dust and stirred at 0 for 30 minutes. The mixture is filtered, the filtrate is diluted with 100 ml of benzene, washed with water, a dilute aqueous sodium hydrogen carbonate solution and water and the aqueous solutions are re-extracted with benzene.

  The combined organic solutions are evaporated under reduced pressure to give the amorphous α- [4ss- (2-hydroxymethyl-2-propylmercapto) -2-oxo-3ss- (N-phenyloxyacetylamino) -1-azetidinyl] -α-triphenylphosphorus - anylideneacetic acid tert-butyl ester as a colorless, gummy substance; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5.69, 5.97, 6.12, 6.55, 6.69, 7.33, 7.50, 8.55, 9.03, 9 , 23 and 9.40.



   A solution of 0.0530 g of a- [4ss- (2-hydroxymethyl-2 propylmercapto) -2-oxo-3ss- (N-phenyloxyacetylamino) -1-azetidinyl] -a-triphenylphosphoranylidene-acetic acid tert-but ester in 1 ml of absolute dimethyl sulfoxide and 1 ml of acetic anhydride are left to stand for 16 hours at room temperature, then heated for 90 minutes at 500 and evaporated under high vacuum. The residue is purified by means of preparative thin-layer chromatography (silica gel plates 20 cm × 20 cm × 1.5 mm; toluene / ethyl acetate system 9: 1).

  Elution of the strip which is active under ultraviolet light with methanol gives the pure 2,2-dimethyl-7- (N-phenyloxy acetyl-amino) -ceph (3) by thin-layer chromatography (Rf = 0.44; silica gel; system hexane / ethyl acetate 3: 2) em-4-carboxylic acid tert-butyl ester Ultraviolet absorption spectrum (in ethanol): jma. = 263 mlt; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 5.61, 5.83, 5.91, 6.11 and 6.26; of the a- [4ss- (2-formyl-2-propylmercapto) - 2-oxo-3ss (N-phenyloxyacetylamino) 1-azetidinyl] -a-tripheny, lphosphoranylidene obtained by ring closure from the intermediately obtained and not isolated acetic acid tert-butyl ester is formed.

 

   A solution of 0.0146 g of 2,2-dimethyl-7- (N-phenyloxy acetyl-amino) -ceph (3) em-4-carboxylic acid tert-butyl ester in 1 ml of trifluoroacetic acid is left to stand for one hour at 230, then evaporated under reduced pressure. The oily residue is taken to dryness twice with a mixture of toluene and chloroform and dried under reduced pressure. The 2,2-dimethyl-7 (N-phenyloxyacetyl-amino) -ceph (3) em-4-carboxylic acid is thus obtained, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.34, 3.49, 5.62, 5.64, 5.92, 6.12, 6.27, 6.61 and 6.72.



   The compounds obtainable according to the invention can, for. B. can be used as starting materials as follows:
Example 2
A suspension of 0.080 g of 7-amino-2,2-dimethylceph (3) -em-4-carboxylic acid in 2 ml of absolute methylene chloride is mixed with 0.0354 g of triethylamine in 0.36 ml of methylene chloride. The suspension is diluted with 5 ml of absolute tetrahydrofuran and stirred for 30 minutes, sometimes in an ultrasonic bath.



   0.113 g of tert-butyloxycarbonyl-D-a-phenylglycine is dissolved in 5 ml of absolute methylene chloride, mixed with 0.0455 g of 4-methylmorpholine, diluted with 10 ml of acetonitrile and cooled to ¯ 200. 0.0605 g of isobutyl chloroformate is added with stirring, whereupon the mixture is allowed to react at −150 for 30 minutes. After cooling again to below ¯ 200, the milky suspension of the triethylammonium salt of 7-amino-2,2-dimethyl-ceph (3) em-4-carboxylic acid is added and the reaction mixture is stirred for 30 minutes at-150, for a further 30 minutes at 0 and finally for 2 hours at room temperature. Unreacted starting material is filtered off, washed with acetonitrile, methylene chloride and diethyl ether and dried.

  The filtrate is evaporated to dryness and the residue is taken up in ethyl acetate and water. With thorough stirring and cooling with ice, the mixture is acidified to pH 2 by adding 5 molar aqueous phosphoric acid. The organic phase is separated off and washed four times with a small amount of a saturated aqueous sodium chloride solution. The aqueous extracts are re-extracted with 2 portions of ethyl acetate and the combined organic extracts are dried over anhydrous magnesium sulfate and freed from the solvent under reduced pressure.



   The yellowish foam obtained as residue is chromatographed on 10 g of silica gel (column; addition of 5% water). With nine 40 ml portions of methylene chloride containing 1-4% acetone, a material consisting mainly of unreacted tert-butyloxycarbonyl-da-phenylglycine is eluted, with three 40 ml portions of methylene chloride containing 5 / o acetone, a Mixture of the tert-butyloxycarbonyl-Da-phenylglycine and the 2,2-dimethyl-7- [N- (N-tert-butyloxycarbonyl-D-α-phenylglycyl) -amino] -ceph (3) -em-4 carboxylic acid of the formula
EMI17.1
 receive.



   The pure product is obtained with methylene chloride containing 7-50% acetone, infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, u, 3.32, 5.60, 5.86, 5.92, 6 , 12, 6.62 (shoulder), 6.69, 7.18, 7.31, 7.80, 8.12, 8.60, 9.10 and 9.52; Thin-layer chromatogram (silica gel with calcium sulfate addition; detection with iodine vapor or by spraying with trifluoroacetic acid, followed by ninhydrin / collidine reagent):

  Rf = 0.67 (system n-butanol / acetic acid / water 75: 7.5: 21), Rf = 0.71 (system n-butanol / acetic acid / water 44:12:44), Rf = 0.58 ( System ethyl acetate / pyridine / acetic acid / water 61: 21: 6: 11) and Rf = 0.68 (system ethyl acetate / n butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10); Ultraviolet absorption spectrum (in ethanol): imax 256 mlt (e = 5700).



   Example 3
A solution of 0.0237 g of 2,2-dimethyl-7- [N- (N4ert-butyloxycarbonyl-Da-phenylglycyl) -aminoj-ceph (3) -em-4-carboxylic acid (uniformly by thin layer chromatography and lyophilized from benzene) in 5 ml of pure formic acid is left to stand at room temperature for 2 hours.

  The clear, colorless solution is freeze-dried in a high vacuum and the lyophilizate is dried for 16 hours at 0.001 mm Hg and at 350 to completely remove the formic acid. The 2,2-dimethyl-7- [N- (D-α-phenylglycyl) - amino] - ceph (3) em-4-carboxylic acid in the zwitterionic form of the formula
EMI17.2
 is obtained in the form of a fine white powder; Thin-layer chromatography (silica gel with calcium sulfate addition; detection using ultraviolet light or ninhydrin / collidine reagent):

  Rf = 0.29 (system n-butanol / acetic acid / water 67: 10:23), Rf = 0.34 (system n-butanol / pyridine / acetic acid / water 42: 24: 4:30), and Rf = 0 , 16 (system ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10); Infrared absorption spectrum (in ralium bromide): characteristic bands at 2.90, 3.09, u, 3.22 lt '5.61 lt' 5.89, u, 6.12, 6.52, 6.85, 7.10 , 7.32, 7.79, 8.15, 8.50, 9.05, 9.54, 9.80, 13.64 and 14.37.



   Example 4
The 7-amino-2,2-dimethylceph (3) em-4-carboxylic acid described in Example 1 can be N-acylated and converted into 7- (N-acyl-amino) -2,2-dimethyl-ceph (3) em-4-carboxylic acids of the formula
EMI17.3
 be transferred:
Option A:
0.4 mmol of an acid [AcOH] is dissolved in 0.2 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 containing 22.6 ml (200 mmol) of trichloroacetic acid chloride with, diluted to 100 ml with methylene chloride] is added to the solution, which has cooled to -150 mm stirred at ¯ 150.

  The solution with the mixed anhydride [Ac-OC (= O) -CCl3j is mixed with a finely dispersed slurry of 0.046 g (0.2 mmol) 7-amino-2,2-dimethyl-ceph (3) em, cooled to ¯ 150 -4-carboxylic acid and 0.056 ml (0.4 mmol) of triethylamine in 0.4 ml of methylene chloride are added and the mixture is vibrated in an ultrasonic bath for 30 minutes at 150 and then for 30 minutes at 200. The usually brown reaction solution is evaporated to dryness under reduced pressure, and the residue obtained is partitioned between 2 ml of a 100% aqueous dipotassium hydrogen phosphate solution (pH 8.9) and 1 ml of ethyl acetate. The aqueous phase is adjusted to pH 2.6 with 200% aqueous phosphoric acid and then extracted exhaustively with ethyl acetate.

  The ethyl acetate extract (6-10 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 drying the plate at room temperature in a nitrogen atmosphere, the silica gel zone absorbing under the ultraviolet light (254 m, ez) is mechanically detached from the plate and extracted three times with 10 to 30 ml of ethanol or methanol. After evaporating the extract under reduced pressure, 7- (N-acylamino) 2,2-dimethyl-ceph (3) em-4-carboxylic acid is obtained 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 material resulting from the different zones is tested against Staphylococcus aureus in the plate diffusion test. The material from the microbiologically most active zone is subjected to another preparative thin-layer separation, whereby the chromatographically uniform product can be isolated.



   Variation B:
0.2 mmol of the sodium salt of an acid [AcONa] in 0.2 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 7-amino-2,2-dimethyl- ceph (3) -em-4-carboxylic acid and 0.2 mmol of triethylamine in 0.2 ml of dimethylformamide reacted as in variant A and worked up.



   Variant C:
A mixture of 0.25 mmol of an acid chloride [AcCl] in 0.2 ml of methylene chloride is added to a solution, cooled to - 150, of 0.046 mg (0.2 mmol) of 7-amino-2,2-dimethylceph (3) -em- 4-carboxylic acid and 0.070 ml (0.5 mmol) of triethylamine in 0.5 ml of methylene chloride were added and reacted and worked up as in variant A.



   PATENT CLAIM 1
Process for the preparation of 7-amino-2,2-dimethylceph (3) em-4-carboxylic acids and their esters of the formula I.
EMI18.1
 where R2 is hydrogen or an organic radical R A which forms an esterified carboxyl group together with the -C (= O) -O grouping, or salts of such
2 compounds, characterized in that a Ceph (3) em compound of the formula II
EMI18.2
 wherein Ac represents the acyl radical of a carboxylic acid, or a salt of such a compound with a set-forming group, treated with an imide halide-forming agent, the imide halide formed is converted into the corresponding imino ether by treatment with an alcohol and cleaved by treatment with an aqueous agent.



   SUBCLAIMS
1. The method according to claim I, characterized in that starting materials of the formula II according to claim I are used in which Ac is the acyl radical of an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid
2. The method according to claim I, characterized in that starting materials of the formula II according to claim I are used, wherein Ac is an acyl radical occurring in naturally occurring or biosynthetically available N-acyl derivatives of 6-amino-penicillanic or 7-amino-cephalosporanic acid .



   3. The method according to claim I, characterized in that starting materials of the formula II according to claim I are used, wherein Ac is an optionally substituted phenylacetyl, phenyloxyacetyl, lower alkanoyl or lower alkanoyl radical.



   4. The method according to claim I, characterized in that R2 in the starting material of the formula II ge according to claim I for the group R A2 is due
2 together with the -C (= O) -O group preferably one, when treating under neutral or acidic aqueous conditions with a reducing metal, a reducing metal alloy, e.g. B. a reducing metal amalgam, or a metal salt, upon irradiation, upon treatment with an acidic or weakly basic agent, or under neutral conditions hydrolytically or alcoholytically easily cleavable esterified carboxyl group.



   5. The method according to claim I, characterized in that R A2 in the starting material of the formula II according to claim I is an organic silyl or stannyl radical.

 

   6. The method according to claim I, characterized in that R A2 in the starting material of the formula II according to claim I represents the trimethylsilyl or tri-n-butylstannyl radical.



   7. The method according to claim I, characterized in that the imide halide-forming agent used is acid chlorides or bromides of phosphorus-containing or sulfur-containing acids or of carboxylic acids.



   8. The method according to claim I, characterized in that phosphorus pentachloride is used as an imide halide-forming agent.



   9. The method according to claim I, characterized in that the reaction with the imide halide-forming agent is carried out in the presence of a base.

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



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. vibrates. The usually brown reaction solution is evaporated to dryness under reduced pressure, and the residue obtained is partitioned between 2 ml of a 100% aqueous dipotassium hydrogen phosphate solution (pH 8.9) and 1 ml of ethyl acetate. The aqueous phase is adjusted to pH 2.6 with 200% aqueous phosphoric acid and then extracted exhaustively with ethyl acetate. The ethyl acetate extract (6-10 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 drying the plate at room temperature in a nitrogen atmosphere, the silica gel zone absorbing under the ultraviolet light (254 m, ez) is mechanically detached from the plate and extracted three times with 10 to 30 ml of ethanol or methanol. After evaporating the extract under reduced pressure, 7- (N-acylamino) 2,2-dimethyl-ceph (3) em-4-carboxylic acid is obtained 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 material resulting from the different zones is tested against Staphylococcus aureus in the plate diffusion test. The material from the microbiologically most active zone is subjected to another preparative thin-layer separation, whereby the chromatographically uniform product can be isolated. Variation B: 0.2 mmol of the sodium salt of an acid [AcONa] in 0.2 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 7-amino-2,2-dimethyl- ceph (3) -em-4-carboxylic acid and 0.2 mmol of triethylamine in 0.2 ml of dimethylformamide reacted as in variant A and worked up. Variant C: A mixture of 0.25 mmol of an acid chloride [AcCl] in 0.2 ml of methylene chloride is added to a solution, cooled to - 150, of 0.046 mg (0.2 mmol) of 7-amino-2,2-dimethylceph (3) -em- 4-carboxylic acid and 0.070 ml (0.5 mmol) of triethylamine in 0.5 ml of methylene chloride were added and reacted and worked up as in variant A. PATENT CLAIM 1 Process for the preparation of 7-amino-2,2-dimethylceph (3) em-4-carboxylic acids and their esters of the formula I. EMI18.1 where R2 is hydrogen or an organic radical R A which forms an esterified carboxyl group together with the -C (= O) -O grouping, or salts of such 2 compounds, characterized in that a Ceph (3) em compound of the formula II EMI18.2 wherein Ac represents the acyl radical of a carboxylic acid, or a salt of such a compound with a set-forming group, treated with an imide halide-forming agent, the imide halide formed is converted into the corresponding imino ether by treatment with an alcohol and cleaved by treatment with an aqueous agent. SUBCLAIMS 1. The method according to claim I, characterized in that starting materials of the formula II according to claim I are used in which Ac is the acyl radical of an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid 2. The method according to claim I, characterized in that starting materials of the formula II according to claim I are used, wherein Ac is an acyl radical occurring in naturally occurring or biosynthetically available N-acyl derivatives of 6-amino-penicillanic or 7-amino-cephalosporanic acid . 3. The method according to claim I, characterized in that starting materials of the formula II according to claim I are used, wherein Ac is an optionally substituted phenylacetyl, phenyloxyacetyl, lower alkanoyl or lower alkanoyl radical. 4. The method according to claim I, characterized in that R2 in the starting material of the formula II ge according to claim I for the group R A2 is due 2 together with the -C (= O) -O group preferably one, when treating under neutral or acidic aqueous conditions with a reducing metal, a reducing metal alloy, e.g. B. a reducing metal amalgam, or a metal salt, upon irradiation, upon treatment with an acidic or weakly basic agent, or under neutral conditions hydrolytically or alcoholytically easily cleavable esterified carboxyl group. 5. The method according to claim I, characterized in that R A2 in the starting material of the formula II according to claim I is an organic silyl or stannyl radical. 6. The method according to claim I, characterized in that R A2 in the starting material of the formula II according to claim I represents the trimethylsilyl or tri-n-butylstannyl radical. 7. The method according to claim I, characterized in that the imide halide-forming agent used is acid chlorides or bromides of phosphorus-containing or sulfur-containing acids or of carboxylic acids. 8. The method according to claim I, characterized in that phosphorus pentachloride is used as an imide halide-forming agent. 9. The method according to claim I, characterized in that the reaction with the imide halide-forming agent is carried out in the presence of a base. 10. The method according to claim I, characterized draws that the reaction with the imide halide-forming agent is carried out in the presence of pyridine. 11. The method according to claim I, characterized in that the alcohol used is methanol. 12. The method according to claim I, characterized in that it is treated with the alcohol while cooling. 13. The method according to claim I, characterized in that the imino ether is cleaved by treatment with water or an aqueous mixture of an organic solvent. 14. The method according to claim I, characterized in that the imino ether is cleaved in an acidic medium at a pH of 1 to 5. 15. The method according to claim I or one of the dependent claims 1-14, characterized in that the 7-amino-2,2-dimethyl-ceph (3) em.4-carboxylic acid is produced. PATENT CLAIM II Use of the compounds of the formula I obtained by the process of claim I, in which R2 is an organic radical RA which, together with the -C (= O) -O grouping, forms an esterified carboxyl group for the preparation of compounds of the formula I in which R2 is hydrogen, characterized in that the esterified carboxyl group of the formula -C (= O) -OR A 2 converted into a free carboxyl group by treatment with an ester-cleaving agent.