CH537415A - Thiazabicyclic compns - Google Patents

Abstract

Compds of formula (I) (where R1 = H or ester residue; R2 is H or acyl and R is methylene mono- or di-substd. aromatic-heterocyclic a heterocyclic-aliphatic residues opt. substd. by hydrocarbon residues themselves opt. substd) are prepd. by ring closure of an appropriately substd. 2, 6-diazo-bicyclo 3.2.0 heptane to form the "cephem" ring system. Medicaments are in forms suitable for enteral or parenteral administration.

Description

  

  
 



   The present invention relates to the preparation of 7-amino-8-oxo-5-thia-1-azabicyclo [4,2, Oloct-2-en-2-carboxylic acid compounds of the formula
EMI1.1
 wherein R1 represents a hydrogen atom or the organic radical of an alcohol and R represents a methylene radical substituted by one or two optionally substituted hydrocarbon radicals or optionally substituted heterocyclic radicals, as well as salts of such compounds with salt-forming groups.



   The compounds of the formula I have the configuration of 7-aminocephalosporanic acid.



   The group R1 can mean the organic radical of any alcohol, but in particular an optionally substituted aliphatic or araliphatic hydrocarbon radical.



   A hydrocarbon radical substituting the methylene group R is primarily an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical, such a hydrocarbon radical also being of a divalent nature and e.g. B. may represent a divalent aliphatic hydrocarbon radical.



   An aliphatic hydrocarbon radical is 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 etherified or esterified hydroxy or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylmercapto or optionally substituted phenylmercapto or phenyl-lower alkylmercapto, lower alkoxycarbonyloxy or lower alkanoyloxy groups, and also by Nitro groups, optionally substituted amino groups or optionally functionally modified carboxy groups, such as carbo-lower alkoxy, optionally N-substituted carbamyl, or cyano groups, can be mono-, di- or polysubstituted.



   Cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radicals are, for. B. mono-, bi- or polycyclic cycloalkyl or cycloalkenyl groups, or cycloalkyl or cycloalkenyl lower alkyl or lower alkenyl groups, wherein cycloalkyl radicals z. B. contain up to 12, such as 3-8, preferably 3-6 ring carbon atoms, while cycloalkenyl radical z. B. have up to 12, such as 5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of cycloaliphatic-aliphatic radicals 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.

  B. the above-mentioned, optionally substituted lower alkyl groups, or then, like the above-mentioned aliphatic hydrocarbon radicals, be mono-, di- or polysubstituted by functional groups.



   An aromatic hydrocarbon radical is e.g. B. a mono- or bicyclic aromatic hydrocarbon radical, especially 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.



   An araliphatic hydrocarbon radical is an optionally substituted, e.g. B. to three, optionally substituted, mono- or bicyclic, 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 containing 1-3 phenyl groups and optionally , e.g. B. as the above-mentioned aliphatic and cycloaliphatic radicals, in the aromatic and / or aliphatic part can be mono-, di- or polysubstituted.



   A divalent aliphatic hydrocarbon radical is primarily a lower alkylene and a lower alkenylene radical, the z. B. contains up to 8, preferably 4 to 5 carbon atoms, and, if desired, e.g. B. as the above-mentioned cycloaliphatic radicals, may be substituted.



   An aliphatic hydrocarbon radical can also be substituted by one or more heterocyclic groups of aromatic character.



   The heterocyclic part of a heterocyclic or heterocyclic-aliphatic radical is in particular a monocyclic, as well as bicyclic or polycyclic aza-, thia-, oxa-, thiaza-, oxaza- or diazacyclic radical of aromatic character, which is optionally z. B. how the aforementioned cycloaliphatic radicals can be mono-, di- or polysubstituted. The aliphatic part in heterocyclic-aliphatic radicals has z. B. the meaning given for the corresponding cycloaliphatic or araliphatic radicals.



   A hydroxyl group etherified by an optionally substituted aliphatic hydrocarbon radical is z. B. an alkoxy, as well as alkenyloxy or alkynyloxy, especially a lower alkoxy, and also lower alkenyloxy or lower alkynyloxy, the alkyl, alkenyl or alkynyl, especially lower alkyl, lower alkenyl or lower alkynyl radicals of these groups such as the aliphatic groups given above Hydrocarbon radicals can be mono-, di- or polysubstituted by functional groups such as etherified or esterified hydroxyl or mercapto groups, nitro groups, substituted amino groups or functionally modified carboxy groups.



   Etherified hydroxyl groups are further optionally substituted phenyloxy, phenyl-lower alkoxy or phenyl-lower alkenyloxy groups, it being possible for the hydrocarbon radicals of hydroxyl groups etherified in this way to be mono-, di- or poly-substituted as indicated above by hydrocarbon or functional groups.



   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 radical z. B. a vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl group, and a lower alkynyl radical z. B. may be a propargyl or 2-butynyl group.

 

   Optionally substituted aliphatic hydrocarbon radicals, in particular lower alkyl groups, which u. a.



  can also substitute cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radicals, contain z. B. the above substituents and are, for. B. halo-lower alkyl groups, such as mono-, di- or polyhalogenated lower alkyl, e.g. B. methyl, ethyl or 1- or 2-propyl groups; Residues of this type, in particular 2-halo-lower alkyl radicals such as 2,2,2-trichloroethyl or 2-iodoethyl groups, primarily represent halogenated lower alkyl radicals R1, or form the organic part of corresponding 2-halo-lower alkoxy groups R.



   A cycloalkyl group is e.g. B. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and adamantyl group and a cycloalkenyl z. B. a 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 cycloheptyl-methyl, -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 z. B.



  a 1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl or 1-, 2- or 3-cycloheptenyl-methyl-, -1,1- or -1,2 ethyl-, -1, Represents 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 is primarily a 4-biphenylyl group.



  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.



   A lower alkylene or lower alkenylene radical is z. B.



  by a 1,2-ethylene, 1,3-propylene, 2,2-dimethyl-1,3propylene, 1,4-butylene, 1- or 2-methyl-1,4-butylene, 1, 4 Dimethyl-1,4-butylene, 1,5-pentylene, 1-, 2- or 3-methyl
1,5-pentylene, 1,6-hexylene, 2-buten-1,4-ylene or 2- or 3-penten-1,5-ylene group.



   Heterocyclic radicals of aromatic character are z. B.



  monocyclic monoaza-, monothia- or monooxacyclic
Residues of aromatic character, such as pyridyl, e.g. B. 2-, 3 or 4-pyridyl radicals, thienyl, e.g. B. 2-thienyl, or furyl, z. B. 2-furyl radicals, or bicyclic, monoazacyclic radicals of aromatic character, such as quinolinyl, z. B.



  2-quinolinyl or 4-quinolinyl radicals, or isoquinolinyl, e.g. B. l-Isoquinolinyl radicals, or monocyclic thiaza or oxazacyclic radicals of aromatic character, such as oxazolyl, isoxazolyl, thiazolyl or isothiazolyl radicals. Heterocyclic-aliphatic radicals are heterocyclic radicals, such as the above-mentioned lower alkyl or lower alkenyl radicals containing.



   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-Trichloräthoxy- or 2-Jodäthoxygruppen, also lower alkenyloxy, z. B.



  Vinyloxy or allyloxy groups, lower alkylenedioxy, e.g. B.



  Methylene or ethylenedioxy groups, phenyloxy groups, or phenyl-lower alkoxy, e.g. 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 mederalkoxy, e.g. B. 2-thenyloxy groups.



   Among the etherified mercapto groups are lower alkyl mercapto, z. B. methyl mercapto or ethyl mercapto groups, phenyl mercapto groups or phenyl-lower alkyl mercapto, z. B. benzyl mercapto groups to understand.



   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 aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals. Such amino groups are in particular lower alkylamino or di-lower alkylamino, e.g. B. methylamino, sithylamino, 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, thiamorpholino or 4-methylpiperazino groups.



   A carbo-lower alkoxy radical is z. B. a carbomethoxy, carbethoxy, carbo-n-propyloxy, carbo-isopropyloxy, carbo-tert-butyloxy or carbo-tert-pentyloxy group.



   Optionally N-substituted carbamyl groups are e.g. B. N-lower alkyl or N, N-di-lower alkyl-carbamyl, such as N-methyl, N-ethyl, N, N-dimethyl or N, N-diethylcarbamyl groups.



   The compounds of the present invention can exist in the form of mixtures of isomers or as pure isomers.



   The compounds according to the invention can be used as starting materials for the preparation of compounds with valuable pharmacological properties. Thus, by acylation, they can be converted into compounds of the formula I, in which R1 preferably stands for a hydrogen atom, and in which the amino group is replaced by an acyl, in particular one of the pharmacologically active N-acyl derivatives of 6-amino-penicillanic acids or 7- Acyl radical occurring in amino-cephalosporanic acids is acylated, effective against microorganisms, in particular against gram-positive bacteria such as Staphylococcus aureus and Proteus vulgaris. In vitro tests with these compounds show, for. B. Growth inhibiting effects on the above-mentioned organisms in dilutions up to 0.0001! O.



   In contrast to the known 7-amino-cephalosporanic acid compounds, which also have the 7-amino-8-oxo-5-thia-1 azabicyclo [4.2.0] oct-2-en-2-carboxylic acid basic structure, in the present compounds are not isomerized to the corresponding t3X4 compounds; It is known that this isomerization, which leads to the structurally more stable t3s4 isomers in the 7-amino-cephalosporanic acid series, is associated with a complete loss of pharmacological activity.

 

   The invention relates primarily to compounds of the formula
EMI2.1
 with the configuration of 7-amino-cephalosporanic acid or salts of such compounds with salt-forming groups, where R1 'represents a hydrogen atom, a lower alkyl, such as methyl or ethyl, especially tert-butyl, and tert. Pentyl, a halo-lower alkyl, primarily a 2-halo-lower alkyl, such as 2,2,2-trichloroethyl, a cycloalkyl, z. B. adamantyl radical, or a phenyl-lower alkyl, especially diphenylmethyl radical, in particular an easily cleavable radical of the above type, and R 'is a by lower alkyl, especially methyl, or by, optionally substituents, eg. B. the above, such as aliphatic hydrocarbon radicals, e.g. B. lower alkyl groups, or etherified or esterified hydroxy groups, e.g. B.

  Never represents a methylene group substituted by alkoxy groups or halogen atoms, or phenyl radicals containing nitro groups, it being possible for this group to contain only one (e.g. a phenyl group) or up to two (e.g. lower alkyl groups) or the above-mentioned substituents.



   7-Amino-8-oxo-4-methylene-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acids or lower alkyl esters thereof are particularly valuable as pharmacologically active substances and as intermediates , as well as salts of those compounds in which the methylene group in the 4-position is substituted by one or two lower alkyl, especially methyl radicals, or by a phenyl radical optionally containing lower alkyl, lower alkoxy, or nitro groups or halogen atoms, and the lower alkyl radical of the ester grouping optionally , preferably in the 2-position, can have one or more halogen atoms, and primarily represents the tert-butyl and 2,2,2-trichloroethyl radicals.



   The compounds of the present invention can be obtained by using a compound of the formula
EMI3.1
 in which R1 has the meaning given above and R2 is hydrogen or an acyl radical Ac which can be split off under the acidic conditions of the reaction, and in which R3 is an organic radical and R4 is a hydrogen atom when R2 is an acyl group Ac, or in which Rs and R4 together A disubstituted carbon atom, when R2 represents a hydrogen atom or an acyl group Ac, and Ro stands for one, containing at least one hydrogen atom, by one or two optionally substituted hydrocarbon radicals, optionally substituted heterocyclic radicals or optionally substituted heterocyclic-aliphatic radicals, in which a heterocyclic group is aromatic in character Has,

   substituted methyl radical, ring closes under acidic conditions.



   If desired, a suitable esterified carboxyl group -COOR1 can be liberated in a compound obtained or a free carboxyl group -COOR1 can be esterified and / or, if desired, a salt-forming compound can be converted into a salt or a salt obtained can be converted into the free compound or into another salt converted, and / or, if desired, a mixture of isomers obtained are separated into the individual isomers.



   In the starting material of the formula II, R1 is primarily a hydrogen atom or an easily split off organic residue of an alcohol, e.g. B. a reductively cleavable organic residue of an alcohol, for. B. a 2-halogen lower allyl, such as the 2,2,2-trichloroethyl radical, or then an organic radical of an alcohol which can be split off under acidic conditions, such as a methyl radical polysubstituted by aliphatic or aromatic, optionally substituted hydrocarbon radicals, e.g. B. the benzhydryl, trityl, tert-butyl, tert-pentyl or adamantyl radical.



   A light, e.g. B. under acidic conditions, cleavable acyl radical Ac is in particular z. B. the carbo-tert-butyloxy, as well as carbo-tert-pentyloxy, carbo-vinyloxy, carbo-adamantyloxy or carbo-furfuryloxy radical.



   In the starting material of the formula II, an optionally substituted hydrocarbon radical R3 primarily represents a cleavable, preferably unsaturated aliphatic hydrocarbon radical, such as lower alkenyl, in particular 2-propenyl radical, or a hetero radical, e.g. B. by an etherified or esterified hydroxy group, e.g. B. a lower alkoxy or lower alkanoyloxy group or a halogen atom substituted aliphatic hydrocarbon radical, such as lower alkyl, e.g. B. methyl, ethyl, n-propyl or isopropyl radical, and a corresponding, preferably unsaturated in the linkage position or substituted by a hetero radical, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical.



   Substituents of a disubstituted carbon atom, which is represented by the two radicals Rs and R4 together, are optionally substituted hydrocarbon radicals, such as optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals. The two substituents of the disubstituted carbon atom can also be taken together and z. B. represent an optionally substituted and / or interrupted by heteroatoms, divalent, aliphatic hydrocarbon radical. The two radicals Rs and R4 together represent a carbon atom which is preferably disubstituted by lower alkyl, in particular methyl groups.



   The above ring closure is achieved by treatment with a strong, preferably oxygen-containing, inorganic or organic acid, e.g. B. organic carboxylic or sulfonic acid, in particular with a strong, optionally substituted by hetero radicals, preferably halogen-substituted lower alkanecarboxylic acid, such as an α-haloacetic acid or o-halopropionic acid, in which halogen is preferably fluorine and chlorine, primarily Trifluoroacetic acid carried out, being carried out in the absence or in the presence of an inert solvent, for. B. dioxane, or a mixture of diluents, preferably with cooling, e.g.

  B. at temperatures from about -300 ° C. to about + 100 ° C., preferably from about -250 ° C. to about 0 ° C., if necessary can work in an inert gas atmosphere.



   In a compound obtainable according to the process, a suitably esterified carboxyl group can be released in a manner known per se. So a z. B. a polysubstituted methyl group, such as the benzhydryl, tert-butyl, tert-pentyl or adamantyl group-containing, esterified carboxyl group can be released by treatment with an acid such as trifluoroacetic acid. This reaction can be carried out simultaneously with the inventive, i. H. ring closure carried out under acidic conditions, especially in the presence of trifluoroacetic acid. Furthermore, z. B. by a 2-halo-lower alkyl group, such as the 2,2,2-trichloroethyl group, esterified carboxyl group, reductively, z. B. by treating with nascent hydrogen obtained e.g.

  B. by the action of metals, metal alloys or amalgams on hydrogen-releasing agents such as zinc, zinc alloys, e.g. B. zinc copper, or zinc amalgam in the presence of acids such as organic carboxylic acids, especially lower alkanecarboxylic acids, e.g. B.



  Acetic acid, such as aqueous acetic acid, or alcohols such as lower alkanols, optionally in the presence of acids, or alkali metal, e.g. B. sodium or potassium amalgam or aluminum amalgam, in the presence of moist ether or lower alkanols, furthermore with reducing metal salts, such as chromium-II compounds, e.g. B. chromium II chloride or chromium II acetate, preferably in the presence of aqueous media containing water-miscible organic solvents such as lower alkanols, lower alkanecarboxylic acid or ethers, e.g. B. methanol, ethanol, acetic acid, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether are released.



   Compounds with a free carboxyl group can in a conventional manner, for. B. in their salts, such as. B. sodium or potassium, alkali or alkaline earth metal, e.g. Calcium or magnesium or ammonium salts are converted, e.g. B. be released with ammonia or amines or from these.



   Free carboxy groups can be prepared by methods known per se, e.g. B. by treating with a diazo compound such as a diazo-lower alkane, e.g. B. diazomethane or diazo ethane, or a phenyl-diazo-lower alkane, z. B. phenyldiazomethane or diphenyldiazomethane, or by reaction with a hydroxy compound suitable for esterification, such as. An alcohol, 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 or the acid with a reactive ester of the hydroxy compound, especially an alcohol, and a strong organic acid or a strong organic sulfonic acid. Furthermore, acid halides, in particular chlorides, and activated esters, such as. B.

  Esters with N-hydroxy nitrogen compounds, or mixed anhydrides formed with haloformic acid esters, can be converted into esters by reaction with hydroxy compounds such as alcohols, if appropriate in the presence of a base such as pyridine.



   Mixtures of isomers obtained can be prepared by methods known per se, e.g. B. be separated into the individual isomers by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other processes. Racemates obtained can in the usual way, for. 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 in the antipodes, preferably the more active Antipode isolated.



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



   The starting materials used according to the process are obtained by using a compound of the formula
EMI4.1
 with a glycoxylic acid ester of the formula O = CH-COOR10 (IIIb), in which R1ss is the organic radical of an alcohol, in particular one of the above easily cleavable radicals, or a derivative, e.g. B. a hydrate thereof, at elevated temperature, primarily at about 500 ° C. to about 1500 ° C., in the absence of a condensing agent and / or without the formation of a salt, with water formed when the hydrate is used, if necessary, by Distillation, e.g. B. azeotropic, can remove.



   In such a obtainable compound of the formula
EMI4.2
 the hydroxy group can be obtained by treatment with a suitable esterifying agent, e.g. B. a halogenating agent such as a thionyl halide, e.g. B. chloride, a phosphorus oxyhalide, especially chloride, or a halophosphonium halide such as triphenylphosphine dibromide or iodide, or a suitable organic sulfonic acid halide such as chloride, preferably in the presence of a basic, primarily an organic basic agent such as an aliphatic tertiary Amines, e.g. B. triethylamine or diisopropylethylamine, or a heterocyclic base of the pyridine type, e.g. B. pyridine or collidine, can be converted into a reactive esterified hydroxyl group, primarily into a halogen atom, or into an organic sulfonyloxy group.



   By reacting a compound of the formula thus obtainable
EMI4.3
 wherein X is the reactive esterified hydroxyl group, primarily a halogen, especially a chlorine or bromine, and an iodine atom, but also an organic, primarily an aliphatic or aromatic sulfonyloxy, z. B. an optionally substituted lower alkylsulfonyloxy, such as methylsulfonyloxy, ethylsulfonyloxy or 2 hydroxy-ethylsulfonyloxy, or an optionally substituted phenylsulfonyloxy, z. B. 4-methylphenylsulfonyloxy, 4-bromo-phenylsulfonyloxy or 3-nitro-phenylsulfonyloxy group, with a phosphine compound of the formula
EMI4.4
 wherein each of the groups Raf Rb and Re represents an optionally substituted hydrocarbon radical, primarily an optionally substituted lower alkyl or phenyl, e.g.

  B. n-butyl or phenyl radical, preferably in the presence of an inert solvent, is obtained, if necessary, after splitting off the elements of the acid of the formula H-X, which z. B. by treating with a weak Chen, especially an organic base, e.g. B. Diisopyläthylamin or pyridine can happen from a phosphonium salt compound available as an intermediate egg ne phosphoranylidene compound of the formula
EMI5.1
 When treating with a compound of the formula
EMI5.2
 or a reactive derivative, especially a hydrate thereof, preferably at elevated temperature, e.g. B.



  at about 500 ° C. to about 1500 ° C., the desired starting material of the 'is obtained from compounds of the formula IVa
Formula II, wherein easily split off radicals R Ol and / or R 2 in a conventional manner, for. B. as stated above, can be split off.



   The intermediates of the formula (IIIa) used in the preparation of the starting materials, in which R3 and R4 together represent a disubstituted carbon atom, are known. Others, in which R3 is a removable organic radical and R4 is a hydrogen atom, can, for. B. be obtained if the carboxyl group in a 6-N acylamino-ss-penicillanic acid compound is converted into an isocyanato group in a manner known per se, the compound thus obtained with a 2-halo-lower alkanol, e.g.

  B. 2,2,2-trichloroethanol or 2-iodoethanol, treated, and in the 6-acylamino-2- (N-carbo-2-halo-lower alkoxy-amino) -3,3-dimethyl 4-thial-1-azabicyclo [3.2.0] heptan-7-one compound removes the substituent in the 2-position by treatment with a chemical reducing agent, e.g. B. zinc in the presence of 900 / above acetic acid, splits. This gives the corresponding 6-acylamino-2-hydroxy-3,3-dimethyl-4-thia-1-azabi cyclo [3.2.0] heptan-7-one compound, which on treatment with a heavy metal acylate Oxidizing agents, especially a lead IV carboxylate, such as lower alkanoate, e.g. B.

  Lead tetraacetate, usually with illumination, preferably with ultraviolet light, can be converted into a 3-acylamino-2- (2-acyloxy-2-propylmercapto) -1-formyl-azetidin-4-one compound. By heating, the acyloxy group can, if desired, be split off together with hydrogen and with formation of the 2-propenyl mercapto group in the form of the corresponding acid. The formyl group attached to the ring nitrogen atom can be removed by treatment with a suitable decarbonylating agent such as a tris (tri-organically substituted phosphine) rhodium halide, e.g. B. tris (triphenyl-phosphine) rhodium chloride, in a suitable solvent, e.g. B. benzene, or with conversion into the carbinol group z. B. by treatment with catalytically activated hydrogen in the presence of a palladium catalyst and glacial acetic acid or hydrochloric acid tetrahydrofuran removed.

  If desired, in a compound obtainable by the above process, the 2 acyloxy-2-propyl radical by treating with a weakly basic agent such as an alkali metal hydrogen carbonate or pyridine, in the presence of a reactive ester of an alcohol such as a suitable halide, by another organic Rest to be replaced.



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



   example 1
A solution of 0.1211 g of isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3.2.0 ] heptyl) a (phenylacetylmethylene) acetic acid tert-butyl ester in 1.2 ml of precooled trifluoroacetic acid is left to stand for 21 hours at -200, then diluted with 9 ml of dioxane. The mixture containing the 7-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) a solution of 0.129 g of phenyloxyacetyl chloride in 1 ml of dioxane is added. After standing at room temperature for 2112 hours, the reaction mixture is treated with 1 ml of water and left to stand for a further hour.

  The volatile components are removed by lyophilization under high vacuum and the residue is chromatographed on 9 g of acid-washed silica gel. With a 100: 5 mixture of benzene and acetone, phenyloxyacetic acid and a small amount of a neutral material, and with a 2: 1 mixture of benzene and acetone, the 4-benzylidene-7-N-phenyloxyacetylamino-8-oxo-5-thia-1- azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI5.3
 eluted after recrystallization from a mixture of
Acetone and benzene melt in the form of yellowish crystals in 191-1930 (decomposition); Thin layer chromatogram:

  Rf 0.36 (silica gel; in the system toluene / acetic acid / water 5: 4: 1); Ultraviolet absorption spectrum: in ethanol,? .Ax 349 m, and 250-265 m (shoulder); in potassium hydroxide / ethanol, one 345 mp and 250-265 m (shoulder); and in hydrogen chloride / ethanol, sIIlaY 357 m, u and 250 to 265 m1I '(shoulder);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90! (Shoulder), 3.20-4.15, 5.62, 5.70 (shoulder), 5.82-5.95, 6.00 (shoulder), 6.10-6.15 Xt and 6.23-6.33 M (inflection).



   Example 2
A solution of 0.5625 g of the isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bi cyclo [3, 2.0] heptyl) -α- (phenylacetylmethylene) -acetic acid tert-butyl ester in 4 ml of trifluoroacetic acid precooled to -200 is left to stand for 20 hours at -20 and for one hour at room temperature. It is diluted with 30 ml of dry dioxane and the mixture, containing the 7-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid ( Configuration of the 7 amino-cephalosporanic acid), with a solution of 0.5 g of freshly distilled phenylacetic acid chloride in 5 ml of dioxane.



  The reaction mixture is left to stand for 3 hours at room temperature, then 2 ml of water are added; it is allowed to stand for one hour at room temperature, then cooled to -100 and the volatile components evaporated by lyophilization under high vacuum. The residue is taken up in 4 ml of benzene, whereupon crystallization begins.

  The crystalline material is filtered off after 24 hours and washed with benzene; the 4 benzylidene-7-N-phenylacetyl-amino-8-oxo-5-tlda-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (configuration of 7-aminocephalosporanic acid) is obtained ) of the formula
EMI6.1
 which, after recrystallization from 90% strength aqueous ethanol, melts to 224-226; Thin layer chromatogram;

  Rf 0.30 (silica gel; in the system toluene / acetic acid / water 5: 4: 1); Ultraviolet absorption spectrum: in ethanol, A max 353 mjt and 250-265 m, u, (shoulder); in potassium hydroxide / ethanol, #max 347 m 250-265 m and 240 m (shoulder); and in hydrogen chloride / ethanol, #max 358 m and 250-265 m; Infrared absorption spectrum (in potassium bromide): characteristic bands at 3.00 (shoulder), 3.10-4.10, 5.65, 5.75 (shoulder), 5.80 (shoulder), 5.90-5.95, 6.00 (shoulder), 6.15, 6.24 (shoulder, 6.28 (shoulder), 6.55, 6.65 and 6.73 (shoulder).



   The mother liquor is chromatographed on 10 g of acid-washed silica gel; with a 100: 5 mixture of benzene and acetone is phenylacetic acid together with a yellow neutral material and then with a 2: 1 mixture of benzene and acetone another amount of the 4-benzylidene-7-N-phenylacetyl-amino-8- oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid eluted, which crystallized after adding a little acetone, m.p. 223-2250.



   Example 3
A solution of 0.0917 g of the isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza 6-bicyclo [3.2.0 ] Heptyl) -α-phenylacetylmethylene) -acetic acid tert-butyl ester in 1 ml of precooled trifluoroacetic acid is left to stand for 21 hours at -20, then diluted with 7 ml of dioxane. The resulting mixture, containing the 7-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) is treated with 10 drops of acetic acid chloride. The reaction mixture is left to stand for 3 hours at room temperature, the excess acetic acid chloride is removed under reduced pressure (oil pump), and 0.8 ml of water is added.

  After a further hour at room temperature, the volatile components are evaporated off under reduced pressure (oil pump) and the residue is dissolved in 0.7 ml of benzene. The 7-N-acetyl-amino-4-benzylidene-8-oxo-5 thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI6.2
 crystallizes from, m.p. 160-1640; Thin-layer chromatogram: Rf 0.16 (silica gel; in the system toluene / acetic acid / water 5: 4: 1); Ultraviolet absorption spectrum: in ethanol, #max 354 m and 250-265 m, (shoulder); in ethanol / potassium hydroxide, #max 346 m, 250-265 m and 240 m (shoulder), and in ethanol / hydrogen chloride, #max 357 m and 250-265 m (shoulder);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90 (shoulder), 3.15-4.20 m, 5.63-5.71 (shoulder), 5.80-5.94 (infection), 6.00 (Shoulder), 6.04-6.13 and 6.40-6.70 (infection),
The mother liquor is chromatographed on 5 g of acid-washed silica gel; a further amount of the desired 7 N-acetylamino-4-benzylidene-8-oxo-5-tial-1-azabicyclo [4.2.0] oct-2-ene is eluted with a 4: 1 mixture of benzene and acetone -2-carboxylic acid together with a neutral product that is enriched in the first fractions.



   Example 4
A suspension, cooled in ice water, of 0.0198 g of 4-benzylidene-7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid in 1 , 5 ml of methanol is treated in portions with an excess of a 2% solution of diazomethane in ether; the development of nitrogen begins immediately and the solid material dissolves. The addition of diazomethane is stopped as soon as the yellow discoloration persists for 2-3 minutes. The volatile components are removed in a rotary evaporator and the residue is crystallized by adding a few drops of methanol.

  The 4-benzylidene-7-N-phenylacetylamino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid methyl ester (configuration of the 7-amino-cephalosporanic acid) obtained in this way formula
EMI7.1
 melts at 193-195.5; [α] 20 D = -325 # 1 (c = 1 in chloroform); Thin layer chromatogram:

  Rf 0.22 (silica gel; in the system hexane / ethyl acetate 2: 1); Ultraviolet absorption spectrum; in ethanol, #max 360 m (± = 24800) and 262 m, u (# = 8100; shoulder); in potassium hydroxide / ethanol, one 3.62 ml and 250 m (shoulder); and in hydrogen chloride / ethanol, # max 362 m and 250-265 m (shoulder); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.06, 5.62, 5.82, 5.95, 6.00 (shoulder), 6.24, 6.30 Ec (shoulder), 6.62 lt (shoulder ) and 6.65-6.73 t.



   Example 5
A mixture of 0.1158 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl ) -α- (isobutyrylmethylene) -acetic acid tert-butyl ester (isomer A) in 1 ml of pre-cooled trifluoroacetic acid is left to stand at -200 for 22 hours. 5 ml of dry dioxane are added and the mixture containing the 7-amino-4isopropylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (configuration of 7-Amino-cephalosporanic acid), with 0.123 g of phenylacetyl chloride. After standing for 3 hours at room temperature, 10 drops of water are added and, after a further hour, the volatile components are distilled off under high vacuum. The oily residue is chromatographed on 10 g of acid-washed silica gel.



  With a 100: 5 mixture of benzene and acetone, phenylacetic acid and a small amount of a neutral product are eluted. The 4-isopropylidene-7-N-phenylacetyl-amino-8oxo-5-thia-1-azabicyclo- [4.2.0] oct-2-ene-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI7.2
 is washed out with a 2: 1 mixture of benzene and acetone.

  Upon crystallization from benzene containing a small amount of acetone, it melts at 216-219; Infrared absorption spectrum: in ethanol, #max 326 ml; in potassium hydroxide / ethanol, ilSmaX 317 m and in hydrogen chloride / ethanol, #max 332 mu; Infrared absorption spectrum (in potassium bromide): characteristic bands at 3.00 lt (shoulder), 3.15-4.35, 5.60 lt, 5.65 (shoulder), 5.90 lt, 6.04 lt, 6.25 lt 6.30 (shoulder) and 6.45-6.55.



   Example 6
A mixture of 0.128 g of isomer A of a- (2-Carbotert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl ) -? - [(4-nitro-phenylacetyl) -methylene] -acetic acid tert-butyl ester in 1 ml of trifluoroacetic acid is left to stand at -200 for 44 hours. The orange-colored reaction mixture containing the 7-amino-4- (4-nitrobenzylidene) 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino -cephalosporanic acid), is then diluted with 5 ml of dry dioxane and mixed with a solution of 0.155 g of phenylacetyl chloride in 2 ml of dioxane.

 

  After standing for three hours at room temperature, 9.5 ml of water are added and, after a further 60 minutes at room temperature, the volatile components are removed under an oil pump vacuum. A few drops of methylene chloride and benzene are added to the residue; an orange-yellow precipitate forms, which is filtered off and washed on the filter with a few drops of methylene chloride.



  The 4- (4-nitro-benzylidene) -7-N-phenylacetyl am.no-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid is obtained in this way (Configuration of 7-amino-cephalosporanic acid) of the formula
EMI8.1
 which, after recrystallization from a mixture of acetone and benzene, melts at 202-204; Ultraviolet absorption spectrum in ethanol; one 390 m and 273 mlt (weak), in potassium hydroxide / ethanol; A max 398 m and 275 mlt (weak), and in hydrochloric acid / ethanol: one 392 m and about 275 mlt (weak);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.9-4.2 lt (broad), 5.60-5.65, 5.80-6.0, 6.05, 6.25, 6.60 and 7 , 45
Example 7
A solution of 0.023 g of crude 4- (4-nitro-benzylidene) -7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct- obtained from crystallization mother liquor 2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) in 1 ml of methanol is treated with an excess of diazomethane in ether and left to stand for a few minutes at room temperature, then evaporated in a rotary evaporator.



   The residue is purified by thin layer chromatography (silica gel plate; 20 × 10 × 0.15 cm), developing with a 2: 1 mixture of hexane and ethyl acetate and with ethyl acetate alone. The orange band is extracted with ethyl acetate and the 4- (4-nitro-benzylidene) -7-N-phenylacetylamino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- en-2-carboxylic acid methyl ester (configuration of 7-amino-cephalosporanic acid) of the formula
EMI8.2
 which crystallizes after standing for a long time, F. 185-187 (with decomposition);

  Ultraviolet absorption spectrum in ethanol: #max 382 mlt and 278 mlt (shoulder), in potassium hydroxide / ethanol: #max 380 mlu and 278 m, ez (shoulder), and in hydrochloric acid / ethanol; One 378 mlt and 278 mlt (shoulder); Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 3.03, 5.60, 5.81, 5.95, 6.24 to 6.30, 6.60-6.65, 6.70 (shoulder) and 7.46
Example 8
A solution of 0.12 g of the isomer A of a- (2-carbo tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo- [3, 2 , 0] heptyl) -a- [(4-methoxyphenylacetyl) -methylene] -acetic acid tert-butyl ester in 1 ml of precooled trifluoroacetic acid is left to stand at -200 for 2 hours. The reaction mixture containing the 7-amino-4 (4-methoxybenzylidene) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino cephalosporanic acid), 5 ml of dioxane are added and the mixture is treated with a solution of 0.154 g of phenylacetyl chloride in 2 ml of dry dioxane.



  After 3 hours at room temperature, 10 drops of water are added and the solution is left to stand for a further hour. The volatile components are then evaporated off under high vacuum and the oily residue is chromatographed on 10 g of acid-washed silica gel (column). The excess phenylacetic acid is washed out with benzene containing 5% acetone together with a yellow colored product.

  The 4- (4-methoxybenzylidene) -7 N-phenylacetylamino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (configuration of the 7-amino-cephalophosphoric acid) of Formula is eluted with a 2: 1 mixture of benzene and acetone and, after crystallization from a mixture of acetone and benzene, melts as a yellow product at 201-203; Ultraviolet absorption spectrum in ethanol: #max 366 and 275 m (shoulder), in potassium hydroxide / ethanol: #max 356 m and 272 m, st (shoulder), and in hydrochloric acid / ethanol: #max 372 m and 277 m (shoulder);

  Infrared absorption spectrum (in potassium bromide); characteristic bands at 2.95 (shoulder), 30.1-4.40, 5.64-5.70, (inflection), 6.04-6.10 lt, 6.28 lt and 6.61 lt
Example 9
A mixture of 0.0052 g of 4- (4-methoxybenzylidene) -7-N phenylacetyl-amino-8-oxo-5-thia-I-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid ( Configuration of 7-amino-cephalosporanic acid) in 2 ml of methanol is mixed with 2 ml of a 2% ethereal diazomethane solution. The mixture is left to stand for 3 minutes at room temperature, the volatile components are then evaporated and the residue is crystallized from a mixture of methanol and ether.

  The 4- (4 methoxybenzylidene) -7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid methyl ester (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI9.1
 melts at 210-211; Ultraviolet absorption spectrum in ethanol: one 378 mlt and 278 mlt (shoulder), in potassium hydroxide / ethanol: one 376 mlt and 278 mlt (shoulder), and in hydrochloric acid / ethanol: #max 374 mlt; Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 30.2, 5.60 Xt, 5.80 lt, 5.91, 6.26 / t, 6.60-6.65 lt and 7.12 lt.



   Example 10
A solution of 0.232 g of the isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza 6-bicyclo [3.2, 0] heptyl) -? - [(4-chlorophenylacetyl) -methylene) -acetic acid tert-butyl ester in 2 ml of trifluoroacetic acid at -200 for 21 hours. After a further 20 minutes at room temperature, 15 ml of dry dioxane are added and 0.25 g of freshly distilled phenylacetyl chloride is added to the mixture containing the 7-amino-4- (4-chlorobenzylidene) -8-oxo5-thia-1-azabicyclo [4,2,0] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-amino-2- (4 chlorobenzylidene) - # -cephem-4-carboxylic acid.

  The reaction solution is kept at room temperature for 3 hours, then 0.3 ml of water is added and the mixture is left to stand at room temperature for one hour. The volatile constituents are removed under reduced pressure (oil pump, room temperature) and the residue is chromatographed on 10 g of acid-washed silica gel. With 250 ml of a 100: 5 mixture of benzene and acetone, phenylacetic acid and a small amount of a neutral by-product are washed out.

  With a 2: 1 mixture of benzene and acetone, the 4- (4-chlorobenzylidene) -7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2 -en-2carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2- (4-chlorobenzylidene) -7-N-phenylacetylamino- # -ce- phem-4-carboxylic acid of the formula which elutes on addition
EMI9.2


 <tb> <SEP> cloolf
 <tb> <SEP> o = iX <SEP> \ <SEP> tI
 <tb> <SEP> II <SEP> 1
 <tb> <SEP> C <SEP> rf <SEP> c-Gtri
 <tb> <SEP>. & <SEP> \ /
 <tb> <SEP> CII,
 <tb> " <SEP> II
 <tb> <SEP> II
 <tb> e <SEP> from <SEP> something <SEP> benzene <SEP> and <SEP> ethyl acetate <SEP> example <SEP> 11
 <tb> ester crystallized in the form of yellowish crystals, F. 226 to 2270; Ultraviolet absorption spectrum:

  : AmaX 359 m, u (in ethanol); AmaX 351 mlt (in potassium hydroxide / ethanol) and #max 362 mlt (in hydrogen chloride / ethanol); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.85-4.30 (broad), 3.02, 5.62, 5.88, 6.15, 6.26, 6.55 and 6.70.



   A solution of 0.3285 g of the isomer A (trans) of a (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) -α- (cyclohexylacetyl-methylene) -acetic acid tert-butyl ester in 2.3 ml of precooled trifluoroacetic acid is left to stand at -20 for 16 to 12 hours. The reaction mixture containing the 7-amino-4-cyclohexylme thylen-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) or 7-amino-2-cyclohexylmethylene-t8-cephem-4-carboxylic acid, 0.13 g of phenylacetyl chloride in 14 ml of dioxane is added and the mixture is kept at room temperature for 3 hours.



  After a further hour, 0.3 ml of water is added, the volatile components are removed under reduced pressure (oil pump; room temperature) and the residue is chromatographed on 10 g of acid-washed silica gel.



  Phenylacetic acid and a small amount of neutrals are removed with a 100: 5 mixture of benzene and acetone, and the 4-cyclohexylmethylene-7-N-phenylacetylamino-8-oxo is eluted with a 2: 1 mixture of benzene and acetone -5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2-cyclohexylmethylene-7-N-phenylacetylamino-t3-cephem-4 -carboxylic acid of the formula
EMI10.1
 which, after crystallization from benzene, melts at 120121; Ultraviolet absorption spectrum: A max 317 mlt (in ethanol), A max 309 m (in potassium hydroxide / ethanol) and AmaX 323 m (in hydrogen chloride / ethanol);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 lt '3.45 lt' 3.53 lt '2.85-4.3 (broad), 5.61 lt' 5.70-5.85 lt (broad ), 5.94 lt '6.05 lt (shoulder), 6.24 and 6.60-6.70 lt
Example 12
A mixture of 0.4 g of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2a6-diaza-6-bicyclo [3v20] heptyl) -a - (Phenylacetylmetyhlen) -acetic acid tert-butyl ester in 4 ml trifluoroacetic acid is left to stand at 200 for 20 hours;

   the trifluoroacetic acid is removed under reduced pressure (oil pump) and the orange residue containing the 7-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acid (configuration of 7-aminocephalosporanic acid) or 7-amino-2-benzylidene- # -cephem- 4-carboxylic acid, mixed with 4 ml of a solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride, cooled to 150. (The mixed anhydride can be obtained as follows: 1.1 ml of triethylamine are added to a mixture of 1.45 g of cyanoacetic acid in 3 ml of methylene chloride and the resulting solution, cooled to -5, to a solution of - 150, while stirring 1.45 g of trichloroacetyl chloride are added to 3 ml of methylene chloride.

  The result is a suspension which is brought to a volume of 14 ml with methylene chloride at -150 and is used in this form. 2 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride are added to the reaction mixture , stirred for 2 hours at room temperature and then diluted with 30 ml of ethyl acetate. It is washed with a concentrated sodium chloride solution containing hydrochloric acid in water (15 ml of the sodium chloride solution contains 1.5 ml of 1N hydrochloric acid) and with concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. About 1 ml of ethyl acetate is added to the residue and the mixture is carefully diluted with ether and then left to stand.

  The crystalline 4-benzylidene-7-N-cyanoacetylamino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) is obtained in this way ) or 2-benzylidene-7-N-cyanoacetyl amino- # -cephem-4-carboxylic acid of the formula
EMI10.2
   P. 215-216 (with decomposition).



   The residue from the mother liquor is chromatographed on 20 g of acid-washed silica gel, using a 100: 5 mixture of benzene and acetone, neutral components, cyanoacetic acid and trichloroacetic acid and a 2: 1 mixture of benzene and acetone, a further amount of the desired product eluted, which after crystallization from ethyl acetate and ether melts at 225227 (decomposition), ultraviolet absorption spectrum:

  : Ämax 353 mlt and 240-265 m (broad shoulder) (in ethanol), Ämax 346 m and 248 m, (shoulder) (in potassium hydroxide / ethanol) and Ämax 356 m, and 247 mlt (shoulder) (in hydrogen chloride / etha nol);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90-4.20 st, 4.42 st, 5.60, 5.85 to 5.90 st, 5.98, 6.22 and 6.45,
Example 13
A solution of 0.023 g of 4-benzylidene-7-N-cyanoacetylamino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid ) in about 2 ml of methanol is treated with a large excess of a 20% solution of diazomethane in ether.

  After standing for two minutes at room temperature, the excess of the diazomethane and the solvents are evaporated and the crystalline residue is purified by preparative thin layer chromatography on a silica gel plate using a 95: 5 mixture of chloroform and methanol.

  The 4-benzylidene-7-N-cyano-acetylamino-8-oxo5-thia-1-azabicyclo [4,2.0] oct-2-en-2-carboxylic acid methyl ester (configuration of the 7-amino-cephalosporanic acid) or 2 Benzylidene-7-N-cyanoacetylamino-2t3-cephem-4-carboxylic acid methyl ester of the formula
EMI11.1
 is obtained in crystalline form, m.p. 232-234; Ultraviolet absorption spectrum: #max 356 m and 247-265 in (broad shoulder) (in ethanol), #max # 364 mlt and 253 m (in potassium hydroxide / ethanol) and, tm3x 364 m, u and 254 mlt (with acidification the alkaline sample with hydrogen chloride / ethanol); Infrared absorption spectrum (in mineral oil): characteristic bands at 3.1, 5.60-5.64, 5.80, 5.98, 6.20, 6.45 and 6.50 (shoulder).



   Example 14
A mixture of 0.328 g of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - α- (4-nitrophenylacetyl-methylene) -acetic acid tert-butyl ester and 3 ml of trifluoroacetic acid are left to stand at -20 for 22 hours.

  The trifluoroacetic acid is removed under reduced pressure (oil pump) and the residue, containing the 7-amino-4- (4-nitrobenzylidene) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- en-2-carboxylic acid (configuration of 7-aminocephalo-sporanic acid) or 7-amino-2- (4-nitro-benzylidene) # ê-cephem-4-carboxylic acid, with 3 ml of a solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in Methylene chloride (for preparation see Example 12), followed by 1.5 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride.

  The reaction mixture is kept at room temperature for 2 hours, then diluted with 15 ml of ethyl acetate and washed with concentrated aqueous sodium chloride solution containing hydrochloric acid (10 ml of sodium chloride solution contain 1 ml of 1 ml of N-hydrochloric acid) and with concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on 10 g of acid-washed silica gel.

  With a 100: 5 mixture of benzene and acetone the excess of cyanoacetic acid and trichloroacetic acid and an orange neutral component and with a 2: 1 mixture of benzene and acetone the amorphous yellow-orange 7-N-cyanoacetyl amino-4- (4-nitro -benzylidene) -8-oxo-5-thia-1-azabicyclo [4,2.0] - oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-N-cyanoacetyl-amino 2- (4-nitro-benzylidene) -t3-cephem-4-carboxylic acid of the formula
EMI11.2
 eluted;

  Ultraviolet absorption spectrum: #max 388 mlt and 275 mlt (in ethanol), #max 453 with and 263 m, u (in potassium hydroxide / ethanol) and #max 420 m, cl and 263 rult (after acidification of the alkaline sample with hydrogen chloride / ethanol) ; Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.8-4.2, 5.60-5.65, 5.80-6.07, 6.25, 6.60 and 7.45.



   Example 15
A solution of 0.058 g of the isomer A of α- [2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2, 0] heptyl] -α- (phenylcetylmethlen) -acetic acid tert-butyl ester in 1.5 ml acetic acid, which contains 0.015 g p-toluenesulfonic acid, is left to stand for 18 hours at room temperature, then diluted with 12 ml dioxane . The solution obtained is treated with 0.08 g of phenylacetyl chloride and after 3 hours with 0.5 ml of water. The reaction mixture is left to stand at room temperature for one hour, the volatile components are then evaporated off under high vacuum and at room temperature and the residue is chromatographed on 10 g of acid-washed silica gel.

  The excess phenylacetic acid and a neutral fraction containing a small amount of 4-benzylidene-7-N-phenylacetyl) -amino-8-oxo-5-thia-1-azabicyclo are washed out with a 100: 5 mixture of benzene and acetone [4,2,0] oct-2-ene-2-carboxylic acid tert-butyl ester (configuration of 7-aminocephalosporanic acid) or 2-benzylidene-7-N-phenylacetyl-amino- # -cephem-4-carboxylic acid tert .-butyl ester of the formula
EMI12.1
 contains; Ultraviolet absorption spectrum: Ämax 356 mlt (in ethanol, potassium hydroxide / ethanol or hydrogen chloride / ethanol). The 4-benzylidene-7-N-phenylacetyl-amino-8-oxo5-thia-1-aza-bicyclo [4.2.0] oct-2-ene is eluted with a 2: 1 mixture of benzene and acetone 2-carboxylic acid, which is identical to the product of the process described in Example 2.



   Example 16
A mixture of 0.35 g of isomer A of a- (2-Carbotert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0 ] heptyl) -α- (isobutylmethylene) -acetic acid tert-butyl ester in 2.8 ml of trifluoroacetic acid is left to stand for 24 hours at -20 and then the trifluoroacetic acid is distilled off in a high vacuum at room temperature.

  The residue containing the 7-amino-4-isopropylidene-8-oxo-5 thia-1-azabicyclo [4.2.0] oct-2-ene-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) or 7-amino -2-isopropylidene-ta-cephem-4-carboxylic acid is mixed with 4 ml of a pre-cooled solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride (preparation: see Example 12), then with 2 ml of a solution of 0.3 ml Acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride. The resulting solution is left to stand for 2 hours at room temperature. It is diluted with 40 ml of ethyl acetate and the organic solution is washed with 15 ml of water, 2 ml of 2-n. Hydrochloric acid and twice with a saturated aqueous sodium chloride solution.

  The aqueous phases are extracted with a small amount of ethyl acetate and the combined organic solutions are dried over sodium sulphate and then evaporated. The residue is treated with a mixture of benzene and acetone; 7-N-cyanoacetyl-amino-4-isopropylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is obtained as a solid product (configuration of 7-Amino-cephalosporanic acid) or 7-N-cyanoacetyl-amino-2 isopropylidene- # 9-cephem-4-carboxylic acid of the formula
EMI12.2
 F. over 2750; Ultraviolet absorption spectrum:

   in ethanol Ämax 327 mlt; in ethanol / potassium hydroxide Am3X 320 rnlt; and in ethanol / hydrogen chloride 333 mlt; Infrared absorption spectrum (potassium bromide): characteristic bands at 2.90 to 4.20, 5.64, 5.75 (shoulder), 5.98, 6.22-6.40 and 6.45.



   The mother liquor is purified on 10 g of acid-washed silica gel; with a 100: 5 mixture of benzene and acetone is prewashed and with a 2: 1 mixture of benzene and acetone, after treating with a few drops of benzene and acetone, a further amount of the 7-N cyanoacetyl-amino-4- isopropylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid.



   Example 17
A mixture of 0.42 g of the isomer A of a (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-b-bicyclo [3, 2.0] heptyl) -α- [(4-chlorophenylacetyl) -methylene] -acetic acid tert-butyl ester in 3.1 ml trifluoroacetic acid for 23 hours at -20 and then the trifuloroacetic acid is distilled under high vacuum at room temperature from.

  The residue containing the 7-amino-4- (4-chlorobenzyli den) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7- Amino-cephalosporanic acid) or 7-amino-2- (4-chlorobenzylidene) -t3-cephem-4-carboxylic acid, 4 ml of a pre-cooled solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride (preparation: see Example 12) are added , then treated with 2 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride. The solution is left to stand for 2 hours at room temperature, then diluted with 40 ml of ethyl acetate and shaken with 15 ml of water, with 2 ml of a 2-n. Hydrochloric acid and twice with a concentrated aqueous sodium chloride solution; the aqueous solutions are each extracted with a small amount of ethyl acetate.

  The combined organic solutions are dried over sodium sulfate and evaporated; the residue is treated with 3 ml of ethyl acetate and 4 ml of ether and the 4- (4-chlorobenzylidene) -7-Ncyanacetyl-amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0 ] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2- (4-chlorobenzylidene) -7-N-cyanoacetylamino- / X3-cephalosporanic acid of the formula
EMI13.1
 M.p. 252-2530; Ultraviolet protection spectrum:

   in ethanol? .max 358 mlt; in ethanol / potassium hydroxide Ämax 365 mlt, and after acidification of the ethanol / potassium hydroxide sample with hydrogen chloride Ämax 369 mlt; Infrared absorption spectrum (potassium bromide): characteristic bands at 2,874.30, a, 5.60, 5.65 (shoulder), 5.85 lt (shoulder), 6.00, u, 6.39 to 6.42, 6.47 (Shoulder) and 6.57 - 6.62 (shoulder).



   The residue from the mother liquor is chromatographed on 10 g of acid-washed silica gel. It is pre-washed with a 95: 5 mixture of benzene and ethyl acetate and a further amount of 4- (4-chlorobenzylidene) - 7-N-cyanoacetyl-amino-8-oxo is eluted with a 2: 1 mixture of benzene and ethyl acetate -5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid, which is purified by crystallization from a mixture of ethyl acetate and ether.



   Example 18
A mixture of 0.367 g of the isomer A of a- (2-Carbotert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -? - [(3-phenyloropropionyl) -methylene] -acetic acid tert-butyl ester in 3 ml of trifluoroacetic acid is left to stand for 22 hours at -200 and then the trifluoroacetic acid is distilled off under high vacuum at room temperature.



  The residue containing the 7-amino-8-oxo-4- (2-phenyl 1,1-ethylidene) -5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid re (configuration of 7-amino-cephalosporanic acid) or 7-amino-2- (2-phenyl-1,1-ethylidene) - # -cephem-4-carboxylic acid, is mixed with 4 ml of a pre-cooled solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride (preparation: see Example 12), then treated with 2 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride. After standing for 2 hours at room temperature, it is diluted with 40 ml of ethyl acetate and the mixture with 15 ml of water, with 2 ml of 2-n. Hydrochloric acid and washed twice with a saturated aqueous sodium chloride solution; the aqueous solutions are each extracted with ethyl acetate.

  The combined organic solutions are dried over sodium sulfate and evaporated. The 7-N-cyanoacetyl amino-442-phenyl-1,1-ethylidene) -8-oxo-5-thia-1-azabicyclo- [4.2.0] oct-2-en-2-carboxylic acid is obtained ( Configuration of 7-aminocephalosporanic acid) or 7-N-cyanoacetyl-amino-2- (2-phenyl-1,1-ethylidene) - # -cephem-4-carboxylic acid of the formula
EMI13.2
 by triturating the residue with benzene, m.p. 217-2180 (with decomposition);

  Ultraviolet absorption spectrum: in ethanol and ethanol / hydrogen chloride λ max 323 ml and in ethanol / potassium hydroxide one 315 m, u; Infrared absorption spectrum (potassium bromide): characteristic bands at 2.85-4.2ss, 5.58 ju, 5.62 (shoulder), 5.81 (shoulder), 5.97, u, 6.05 lt (shoulder), 6 , 25 lt and 6.40 lt
The residue of the mother liquor is chromatographed on 10 g of acid-washed silica gel.

  Cyanoacetic acid and trichloroacetic acid are washed out with a 2: 1 mixture of benzene and acetone, and a further amount of the 7-N-cyanoacetylamino-4- (2-phenyl-1) is eluted with a 2: 1 mixture of benzene and acetone , 1-ethylidene) -8-oxo-5thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid, which is purified by trituration with benzene.



   Example 19
A mixture of 0.2 g of the isomer A (trans) of a- (2 carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bi cyclo [ 3, 2.0] heptyl) -a- (phenylacetyl-methylene) -acetic acid-tert-butyl ester in 1.5 ml of trifluoroacetic acid is left to stand at -200 for 19 hours. The trifluoroacetic acid is evaporated at room temperature, finally under high vacuum. The residue which is 7-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7 amino-2-benzylidene- # -cephem-4-carboxylic acid is dissolved in 2 ml of methylene chloride which contains 0.11 ml of triethylamine.



   A solution of 0.052 ml of isobutyl chloroformate in 0.5 ml of tetrahydrofuran is added at - 100 with 0.101 g of D-N-carbo-tert-butyloxyphenylglycine and 0.055 ml of triethylamine in 2 ml of tetrahydrofuran; after 10 minutes, the above-mentioned solution of the cyclization product is added. The mixture obtained is left to stand at 100 for one hour and at room temperature for a further hour. The volatile components are distilled off under reduced pressure, the residue is dissolved in 25 ml of ethyl acetate and extracted 3 times with water. The combined aqueous extracts are with 2-n. Hydrochloric acid acidified to pH 3 and extracted with ethyl acetate. The organic solution is dried over sodium sulfate and evaporated under reduced pressure.



  The residue is chromatographed on 3 g of acid-washed silica gel, a mixture of benzene and ethyl acetate with a proportion of ethyl acetate increasing from 2-50% being used as the mobile phase. So first D-phenylglycine and then the non-crystalline 4-benzylidene-7-N- (N-carbo-tert-butyloxy-3-phenyl-glycyl) -amino-8-oxo-5-thia-1-azabicyclo [ 4,2,0] oct-2-en-2carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2-benzylidene-7-N- (N-carbo-tert-butyloxy-D-phenyl-glycyl) - n3-cephem-4-carboxylic acid, ultraviolet absorption spectrum:

   in ethanol max 352 ml, in ethanol / potassium hydroxide 347 ml, and in ethanol / hydrogen chloride max 359 ml; Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 2.95, 2.80-4.40, 5.60, 5.80 (shoulder), 5.85-5.95 to 6.05 lt (shoulder), 6.20-6.30 lt and 6.65-6.75
A further amount of this product can be isolated from the residue of the first ethyl acetate solution; it contains a small amount of 4-benzylidene-7-N- (N-carbotert. -butyloxy-D-phenyl-glycyl) -amino-8-oxo-5-thia-1-azabicylo [4,2.0] oct -2-en-2-carboxylic acid tert-butyl ester (configuration of 7-amino-cephalosporanic acid) or 2-benzylidene 7-Nt (N-carbo-tert-butyloxy-D-phenyl-glycyl) -amino-A3- cephem-4-carboxylic acid tert-butyl ester.



   A mixture of 0.0304 g of 4-benzylidene-7-N- (N-carbo tert-butyloxy-D-phenyl-glycyl) -amino-8-oxo-5-thia-1-azabicyclo [4.2 , 0] oct-2-en-2-carboxylic acid and 0.4 ml of formic acid (99 0 / o) is left to stand for 21/2 hours at room temperature. The formic acid is then removed under reduced pressure (water bath) and the residue is dried at 500 ° under high vacuum (diffusion pump).

  The non-crystalline 4-benzylidene-7-N- (D-phenylglycyl) -amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2-benzylidene-7-N- (D-phenyl-glycyl) -amino-A3-cephem-4-carboxylic acid of the formula
EMI14.1
 which can be obtained in the form of a salt including an inner salt; Ultraviolet absorption spectrum: in ethanol AwmaX 347 mlt, in ethanol / potassium hydroxide one 346 mlt, and in ethanol / hydrogen chloride Ämax 357 mlt; Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.95-4.30, 5.60-5.72, 5.90-6.00, 6.25-6.65 and 6.70 (shoulder).



   Example 20
A solution of 0.255 g of the isomer A (trans) of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) -α- [(4-chlorobutyryl) -methylene] -acetic acid tert-butyl ester in 5 ml of precooled trifluoroacetic acid is left to stand at -200 for 20 hours. 4 ml of trifluoroacetic acid are evaporated off and the solution which contains the 7-amino-4- (3-chloro-1,1-propylidene) -8-oxo-5-thla-1-azabicyclo [4.2.0] oct -2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) or 7-amino-2- (3-chloro-1,1-propylidene) -t3-cephem-4-carboxylic acid is mixed with 15 ml of dioxane and 0.25 g of phenylacetic acid chloride.

  The reaction mixture is left to stand at room temperature for 3 hours, then treated with 0.1 ml of water and, after a further hour, evaporated under reduced pressure. The residue is chromatographed on 10 g of acid-washed silica gel; With a 19: 1 mixture of benzene and acetone, phenylacetic acid and neutral components are washed out and with a 2: 1 mixture of benzene and acetone the 4- (3-chloro-1,1-propylidene) -7-N-phenylacetyl- amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2- (3-chloro-1,1-propylidene) -7-N-phenylacetyl-amino-, 3-cephem-4-carboxylic acid of the formula
EMI15.1
 eluted, which crystallized in platelets on standing.

  F. 84 to 870; Thin-layer chromatogram (silica gel; system toluene / acetic acid / water 5: 5: 1): Rf = 0.34; Ultraviolet absorption spectrum: in ethanol #max 314 mp, and in ethanol / potassium hydroxide #max 306 ml; Infrared absorption spectrum (potassium bromide): characteristic bands at 2.80-4.10 5.55-5.70, 6.05, 6.24 and 6.50-6.60.



   A solution of 0.03 g of 4- (3-chloro-1,1-propylidene) -7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en2 -carboxylic acid in 2 ml of tetrahydrofuran is treated with a solution of 0.05 g of diazomethane in 2.5 ml of ether.



  After standing for 5 minutes at room temperature, the solvents are evaporated off under reduced pressure. The residue crystallizes on standing and, after recrystallization from a mixture of methylene chloride and hexane, gives 4- (3-chloro-1,1-propylidene) -7-N-phenylacetyl-amino-8-oxo-5-thia-1- azabicyclo [4.2.0] oct-2-en-2-carboxylic acid methyl ester of the formula
EMI15.2
 in yellow needles, F. 174-176; [al Du = + 580 1 20 (c
D 0.59 in chloroform); Thin-layer chromatogram (system: benzene / ethyl acetate 1: 1): Rf = 0.43; Ultraviolet absorption spectrum: RIliax 321 m, u (in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97, 3.30-3.50, 5.61, 5.81, 5.94, 6.23 and 6.74.



   The starting materials used in the preceding examples can, for. B. be manufactured as follows:
Example 21
A mixture of 5 g of 2-carbo-tert-butyloxy-3,3-dimethyl-4-thia-2,6-diaza-bicyclo [3.2.0] heptane-7-yne and 5.5 g of glyoxylic acid tert-butyl ester hydrate in 40 ml of dioxane is stirred in a closed vessel for 13 1/2 hours at 950 and then evaporated. The residue is dissolved in 1000 ml of pentane, washed three times with 500 ml of water and once with 200 ml of a saturated aqueous sodium chloride solution, dried over dry sodium sulfate and evaporated.

  An approximately 50:50 mixture of the two isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4 thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) -rt-hydroxy-acetic acid tert-butyl ester of the formula
EMI15.3
 0.9 g of the mixture obtained is crystallized from pentane and recrystallized from a mixture of ether and pentane, an isomer of the above compound, F.



  134-137, obtained; [a] D = -3650 + 1C (c = 1.102 in chloroform); Thin-layer chromatogram: Rf = 0.49 in a 1: 1 mixture of benzene and ethyl acetate; Infrared spectrum (in methylene chloride), bands at 2.94, 5.62, 5.77 and 5.85.



   Example 22
A mixture of 6 g of a 1: 1 mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-di aza-6-bicyclo [3.2.0] heptyl) -a-hydroxy-acetic acid tert-butyl ester and 10.5 g of the so-called polystyrene: Hünig base (produced 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 dioxane and 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) in a 1: 1- Mixture of dioxane and tetrahydrofuran is stirred for 20 minutes.

  After cooling, it is treated dropwise over 20 minutes with a solution of 6 g of thionyl chloride in 50 ml of dioxane and the mixture is stirred at 200 for 140 minutes, then filtered. The filtrate is evaporated, the residue is taken up in 200 ml of pentane and the solution is treated with 1 g of an activated charcoal preparation, then filtered. This gives an approximately 1: 1 mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [ 3,2,0] - heptyl) -a-chloro-acetic acid tert-butyl ester.



   Example 23
A solution of 11.3 g of a crude mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) -a-chloroacetic acid tert-butyl ester in 150 ml of absolute dioxane is mixed with 11.4 g of triphenylphosphine and 10.8 g of polystyrene Hünig base or diisopropylaminomethyl polystyrene (prepared by heating a mixture of 100 g chloromethyl polystyrene [J.



  At the. 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 dioxane and 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), stirred for 17 hours under a nitrogen atmosphere at 550, then cooled and filtered through a glass filter. It is washed with 100 ml of benzene; the filtrate is evaporated under a water jet vacuum; the residue is dried under high vacuum, dissolved in 100 ml of a 9: 1 mixture of hexane and ethyl acetate and chromatographed on a column (height 48 cm; diameter 6 cm) with acid-washed silica gel.

  With 2000 ml of a 3: 1 mixture of hexane and ethyl acetate, triphenylphosphine and a little triphenylphosphine sulfide are added, with a further 4000 ml of the 3: 1 mixture of hexane and ethyl acetate of a (2-carbo-tert-butyloxy-3,3 -dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) -a- (triphenylphosphoranylidene) -acetic acid tert-butyl ester of the formula
EMI16.1
 eluted; a further amount of the impure product can be obtained with 1500 ml of the same solvent mixture.

  The product has an Rf value of 0.5 in the thin layer chromatogram (silica gel; system: 1: 1 mixture of benzene and ethyl acetate) and crystallizes from a mixture of ether and pentane, mp 121-1220; [a] n = - 219 "+1" (c = 1.145 in chloroform); Ultraviolet absorption spectrum (in ethanol): λ max = 225 m, (e = 30,000) and 260 mlt (e = 5400); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.761u, 5.801u (shoulder), 5.97 lt '6.05, lot (shoulder) and 6.17, u. A further amount of the product can be isolated from the mother liquor by crystallization in an ether-pentane mixture.



   Example 24
A solution of 2 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) -a- (triphenylphosphoranylidene) -acetic acid tert-butyl ester and 0.7 g of benzylglyoxal in 30 ml of dry toluene is heated under a nitrogen atmosphere for 23 hours at 800 (bath temperature), then with a further amount of 0.2 g Benzylglyoxal is added and the mixture is heated at 800 for 22 hours. The solvent is removed under reduced pressure and the viscous residue is chromatographed on a column containing 60 g of acid-washed silica gel.

  With 450 ml of benzene, the excess benzylglyoxal becomes, with 250 ml (10 fractions) of a 95: 5 mixture of benzene and ethyl acetate, a mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo) -4-thia-2,6-diaza-6-bicyclo- [3.2.0] heptyl) -a- (phenylacetylmethylene) -acetic acid tert-butyl ester of the formula
EMI16.2
  and washing out a polar material with another amount of the same solvent mixture.



   The above mixture of isomers is chromatographed again on 60 g of acid-washed silica gel, washing out with a 99: 1 mixture of benzene and ethyl acetate. A product consisting mainly of benzylglyoxal is obtained in the forerun, then with 125 ml a fraction I consisting mainly of isomer A, with 250 ml a fraction II consisting of a mixture of the two isomers and with 300 ml a fraction consisting mainly of isomer B III.

  The above three fractions are recrystallized from hexane, from fraction I the isomer A; F. 108-1100; Thin-layer chromatogram: Rf 0.49 (silica gel; in the system hexane: diethyl acetate 2: 1); Ultraviolet absorption spectrum #max 299 mlt (in ethanol), 337 mlt (in potassium hydroxide / ethanol) and 337 mlt (when acidifying a basic solution in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63, u, 5.83 (shoulder), 5.85 to 5.95 lt and 6.29 lt; and from fractions II and III the isomer B; F. 156157; Thin-layer chromatogram: Rf 0.42 (silica gel; in the hexane system:

  Ethyl acetate 2: 1); Ultraviolet absorption spectrum: imax 294 m, u (in ethanol), 335 nilt (potassium hydroxide / ethanol) and 335 m, u (when acidifying a basic solution in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63, 5.80 (shoulder), 5.85-5.96 and 6.34; is obtained. Further amounts of the two isomers can be isolated from the mother liquors in the same way.



   Example 25
A solution of 0.0162 g of the isomer B of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicy clo [3, 2.0] heptyl) - α- (phenylacetylmethylene) -acetic acid tert-butyl ester in 10.6 ml of benzene is irradiated with ultraviolet light in a vessel made of Pyrex glass under a nitrogen atmosphere at room temperature. After 90 minutes the solvent is distilled off; According to the nuclear magnetic resonance spectrum, the non-crystalline residue consists of an approximately 42:58 mixture of isomer A and isomer B of a- (2-carbo tert-butyloxy-3,3-dimethyl-7-oxo-4-thia- 2,6-diaza-6-bicyclo- [3.2.0] heptyl) -α- (phenylacetylmethylene) -acetic acid tert-butyl ester.



   Crystalline isomer B and fractions consisting mainly of isomer B of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7 oxo-4-thia-2,6-diaza-6-bicyclo [3.2 , 0] heptyl) -α- (phenylacetylethylene) -acetic acid tert-butyl ester can be converted in the same way to isomer mixtures containing isomer A and isomer B of a- (2-carbo-tert-butyloxy -3,3-dimethyl 7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (phenylacetyl methylene) -acetic acid tert-butyl ester can be isomerized.



   Example 26
Treat 1 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -a- (triphenylphosphoranylidene) -acetic acid tert-butyl ester under nitrogen with 0.65 g isopropylglyoxal in 7 ml toluene and left at 90 for 8 days. The solvent and the excess of the isopropylglyoxal are removed under reduced pressure at 500 and the residue is chromatographed on 50 g of acid-washed silica gel; it is washed out with a 4: 1 mixture of hexane and ethyl acetate.

  With the first 150 ml the isomer A (trans) of a- (2-Carbo tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo- [3 , 2.0] heptyl) -α- (isobutyrylmethylene) -acetic acid tert-butyl ester of the formula
EMI17.1
 washed out, which after crystallization from a mixture of hexane and ethyl acetate melts at 133-134; Ultraviolet absorption spectrum: in ethanol imax 294 m; in potassium hydroxide / ethanol Man 330 me; and in hydrogen chloride / ethanol #max 330 m; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62 lt, 5.80 (shoulder); 5.84-5.94 L and 6.26.



   The isomer B (cis) of a- (2-Carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0 ] heptyl) a (isobutyrylmethylene) acetic acid tert-butyl ester is obtained on further washing with the same solvent mixture and, after crystallization from a mixture of hexane and ethyl acetate, melts at 146-1470; Ultraviolet spectrum: in # ethanol Ämax 289 with, in potassium hydroxide / ethanol> Rmax 328 with; and in hydrogen chloride / itthanol imax 328 mlt; Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 5.60-5.66, 5.75 (shoulder), 5.85 to 5.95, u ic and 6.31 lt.



   Example 27
A mixture of 0.05 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) α- (triphenylphosphoranylidene) -acetic acid tert-butyl ester and 0.0355 g of 4-nitrobenzyl-glyoxal in 0.6 ml of toluene are heated at 800 for 7 hours. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a thin-layer silica gel plate (20 X 20 X 0.15 cm), developing with a 2: 1 mixture of hexane and alkyl acetate.

  Two yellow bands are obtained, the upper one being the isomer A of a- (2-carbo tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo- [3 , 2.0] heptyl-a - [(4-nitro-phenylacetyl) -methylenej-acetic acid tert-butyl ester of the formula
EMI18.1
 with Rf value = 0.41; Ultraviolet absorption spectrum: A max 288 with (broad; in ethanol), and AmaX 505 with, 262 m, u (Kaliumhydroxyd / Äthanoi); Infrared absorption spectrum (in methylene chloride);

   characteristic bands at 5.63, 5.83 (shoulder), 5.88-5.92 lt, 5.97 lt (shoulder), 6.28-6.33 lt, 6.59 and 7.45, u; and the lower isomer B of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bi cyclo [3.2.0] heptyl ) - α - [(4-nitro-phenylacetyl) -methylene] -acetic acid tert-butyl ester of the formula
EMI18.2
 results in yellow, glass-like products. Isomer 13 crystallizes from hexane, mp 1730; Rf value: 0.29; Ultraviolet absorption spectrum in ethanol: Ämax 293 with, and in potassium hydroxide / ethanol: #max 335 m and 285 m;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62, 5.77 (shoulder), 5.83-5.92, 6.30-6.35, 6.59 lt and 7.45.



   The 4-nitro-benzylglyoxal used as starting material above can be prepared as follows: 6 g of 4-nitrophenyacetyl chloride in 80 ml of dry tetrahydrofuran are added dropwise to a solution of about 4 g of diazomethane in 200 ml of dry ether while stirring, using Stir in an ice water bath to keep the temperature at 0-5. The addition is complete after about 30 minutes; the reaction mixture is stirred for a further 15 minutes at 0-5 and then evaporated in a rotary evaporator. The solid residue is dissolved in a mixture of methylene chloride and ether, the small amount of solid material is filtered off and the filtrate is evaporated.

  This gives the 4-nitro-benzyl-diazomethyl-ketone, which, after crystallization from a mixture of ether and hexane, melts at 9092; Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.78, 6.10, 6.26, 6.58 and 7.45
A solution of 3 g of 4-nitrobenzyl diazomethyl ketone in 100 ml of a 1: 1 mixture of ether and methylene chloride is mixed with a solution of 4.22 g of triphenylphosphine in 100 ml of ether. After about 5 minutes, the 1- (4-nitrophenyl) -3 - (triphenylphosphoranylidene-hydrazo- no) -acetone crystallizes out at room temperature; the mother liquor is filtered and concentrated, from which a further amount of the desired product crystallizes.

  The crude product is crystallized from a mixture of 50 ml of methylene chloride and 250 ml of hexane, mp 160165c. Ultraviolet absorption spectrum (in ethanol): # max 320 m and 270-275 m (shoulder); Infrared absorption spectrum (in methylene chloride): characteristic bands at 6.10 (shoulder), 6.14-6.20, 6.32, 6.67 and 6.75.

 

   A suspension of 0.467 g of 1- (4-nitrophenyl) -3- (triphenylphosphoranylidene hydrazono) acetone in 3 ml of tetrahydrofuran is mixed with 0.21 g of powdered sodium nitrite and 1.2 ml of water. The mixture is cooled to 0-5 and added dropwise over 2 minutes with 2.2 ml of 2-n.



  Hydrochloric acid is added, forming an emulsion. After 60 minutes at 0-5, the aqueous layer is separated off and extracted four times with 100 ml of methylene chloride each time. The combined organic solutions are washed twice with 10 ml of saturated aqueous sodium chloride solution each time and evaporated; the residue is chromatographed on 20 g of acid-washed silica gel.

  The crystalline, enolized 4-nitrobenzylglyoxal is eluted with 600 ml of benzene; Ultraviolet absorption spectrum in ethanol: one 343 m, in potassium hydroxide / ethanol: 444 m1, and hydrochloric acid / = aithanol: max 343 with; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.02, 5.98, 6.06, 6.28, 6.60 and 7.47, and with 350 ml of a 9: 1 mixture of Benyol and ethyl acetate the hydrate of des 4-nitrobenzylglyoxal as a non-crystalline, syrupy material; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.01, 6.27, 6.61 and 7.47.



   Example 28
A mixture of 0.872 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heopyl ) -α- (triphenylphosphoranylidene) -acetic acid tert-butyl ester and 0.611 g of 4-nitrobenzyl glyoxal hydrate in 10.5 g of toluene are heated at 800 for 61/2 hours. The solvent is distilled off under reduced pressure and the residue is chromatographed on 50 g of acid-washed silica gel.

  With 1300 ml of benzene and 500 ml of a 98.5: 1.5 mixture of benzene and ethyl acetate, the isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia -2,6-diaza-6 bicyclo [3.2.0] heptyl) -a - [(4-nitro-phenylacetyl) -methylenej-acetic acid tert-butyl ester, with 200 ml of a 96: 4 mixture of benzene and ethyl acetate, a mixture of the two isomers A and B of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.50lheptyl) -a- [(4-nitro-phenylacetyl) -methylene] -acetic acid tert-butyl ester and with a further 400 ml of the 96:

  : 4 mixture of benzene and ethyl acetate, the isomer B of a- (2-carbo-tert-butyloxy 3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2 , 0] heptyl) -? [(4-nitro-phenylacetyl) -methylene] -acetic acid tert-butyl ester together with a small amount of the isomer A eluted.



  The mixture is separated by means of thin layer chromatography (4 silica gel plates; 20 × 20 × 0.15 cm), developing with a 2: 1 mixture of hexane and ethyl acetate; a further amount of isomer A is thus obtained; Rf = 0.41; and of isomer B; Rf = 0.29. The latter is combined with the almost pure isomer B from the chromatogram and crystallized from hexane, mp 1730.



   Example 29
A mixture of 0.714 g of a- (2-carbo-tert-butyloxy-3,3 dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -a - (Triphenylphosphoranylidene) -acetic acid tert-butyl ester and 0.67 g of 4-methoxybenzylglyoxal hydrate in 8.6 ml of toluene are heated for 31/2 hours at 800, then evaporated under reduced pressure. The residue is chromatographed on 50 g of acid-washed silica gel.

  The excess 4-methoxybenzyl-glyoxal is washed out in anhydrous form with 500 ml of benzene, while the almost pure isomer A of a- (2-carbo-tert-butyloxy) is obtained with 800 ml of a 99: 1 mixture of benzene and ethyl acetate -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-byciclo [3,2,0] heptyl) - α - [(4-methoxyphenylacetyl) - methylene] -acetic acid tert-butyl ester of the formula
EMI19.1
 F. 105-107] after recrystallization from a mixture of ethyl acetate and hexane; Ultraviolet absorption spectrum in ethanol: #max 298 with, 288 with (shoulder) and 225 with (shoulder), and in potassium hydroxide / ethanol: Ämax 340 mlt;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63, 5.82 lt (shoulder), 5.87 to 5.97, 6.23 (shoulder), 6.28, 6.63 and 6.77 , with a further 400 ml of the 99: 1 mixture of benzene and ethyl acetate a mixture of the isomers A and B and with 300 ml of a 98: 2 mixture of benzene and ethyl acetate the isomer B of * - (2-carbo-tert.- butyloxy-3,3-dimethyl-7 oxo-4-thia-2,6-diaza-6-byciclo [3,2,0] heptyl) α - [(4-methoxy-phe-nyacetyl) -methylene] -acetic acid tert-butyl ester of the formula
EMI20.1
 washes out;

   the pure isomer B obtained from the mixture fraction by recrystallization from hexane and the pure isomer B obtained in the same way from the fraction of the isomer B melts at 169-1700; Ultraviolet absorption spectrum in ethanol: Ämax 289 with (broad) and 227 m, u (shoulder), and in potassium hydroxide / ethanol: Ämas 343 m; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59 Ed, 5.75, u lt (shoulder), 5.80-5.93, u, 6.24 lt (shoulder), 6.30 and 6.60 lt .



   Using preparative thin-layer chromatography and developing with a 2: 1 mixture of hexane and ethyl acetate, further amounts of the two isomers A and B of a- (2-carbo-tert-butyloxy.3,3-dimethyl-7-oxo -4-thia-2,6-diaza-6-bicyclo [3.2.0] -heptyl) -a - [(4-methoxyphenylacetyl) -methylene] -acetic acid-tert-butyl ester.



   The 4-methoxybenzyl glyoxal hydrate used as starting material in the above example can be obtained as follows:
A solution of 7.43 g of 4-methoxyphenylacetyl chloride in 100 ml of dry ether is added dropwise to a solution, cooled to 0-50, of 6 g of diazomethane in 300 ml of ether. The reaction mixture is stirred for a further 30 minutes, finally without cooling. The excess of diazomethane and the solvent are removed under reduced pressure in a rotary evaporator and the residue is dissolved in 100 ml of ether and the small amount of waxy material is filtered off.

  After evaporating the filtrate, 4-methoxy-benzyl-diazomethyl ketone is obtained; Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.79, 6.10, 6.22 u (shoulder), 6.62 lt and 7.73-7.45 it which is further processed without purification.



   A solution of 7.52 g of 4-methoxybenzyl diazomethyl ketone in 300 ml of ether is mixed with 11.1 g of triphenylphosphine in 200 ml of ether. The reaction mixture is stirred at room temperature, a crystalline precipitate forming after a few minutes, which is filtered off after an hour and washed with cold ether. This gives 1- (4-methoxyphenyl) -3- (triphenylphosphoranylidene-hy- drazono) -acetone, which melts at 111-1120; Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.80 lu, 6.05 (shoulder), 6.14, 6.24 eg (shoulder) and 6.63-6.70; and is processed without further cleaning.



   A solution of 1.82 g of 1- (4-methoxyphenyl) -3-triphenyl-phosphoranylidene-hydrazono) -acetone in 12 ml of tetrahydrofuran is mixed with 0.84 g of powdered sodium nitrite and the mixture is diluted with 5 ml of water. The received
Suspension is cooled to 0-50, dropwise within 7 minutes with 8.8 ml of 2-n. Treated hydrochloric acid and then held at 0-50 for a further 30 minutes. The aqueous phase is washed twice with methylene chloride; the combined organic solutions are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.



  The oily residue is chromatographed on 40 g of acid-washed silica gel. A small amount of a by-product is washed out with benzene and with 1200 ml of a 95: 5 mixture of benzene and ethyl acetate the 4-methoxybenzylglyoxal is obtained mainly in the form of the hydrate, the oily product; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5.79 to 5.84, 6.23 and 6.63.

  The anhydrous product melts after recrystallization from a mixture of chloroform and hexane at 139140c; Ultraviolet absorption spectrum in ethanol or hydrochloric acid / ethanol: max 333 with, and in potassium hydroxide / ethanol: max 367 with; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 5.97, 6.24, 6.61, 7.15.



   Example 30
A solution of 0.8 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-byciclo [3.2.0 ]) - α- (triphenylphosphoranylidene) -acetic acid tert-butyl ester and 1.2 g of the crude 4-chlorobenzyl glyoxal hydrate in 12 ml of toluene are heated at 80 for 5 hours. The solvent is distilled off under reduced pressure and the syrupy residue is dissolved in about 4 ml of benzene. The resulting crystalline precipitate, consisting of the enol of 4-chlorobenzyl-glyoxal, is filtered off and the filtrate is chromatographed on a column of 50 g of acid-washed silica gel.

  A further amount of 4-chlorobenzyl-glyoxal is eluted with 500 ml of benzene and a mixture of the isomers of a- (2-carbo-tert-butyloxy-3, with 200 ml of benzene and 800 ml of a 97: 3 mixture of benzene and ethyl acetate) 3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -a - [(4-chlorophenylacetyl) -methylene] -acetic acid-tert. butyl ester washed out, the chromatographed on a further 50 g of acid-washed silica gel using benzene and benzene containing 5 o / o ethyl acetate and then by preparative thin-layer chromatography (system hexane: ethyl acetate
2: 1) is separated.

  The non-crystalline isomer A (trans) of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) -α - [(4-chlorophenylacetyl) -methylene] -acetic acid tert-butyl ester of the formula
EMI21.1
 which shows the following bands in the ultraviolet absorption spectrum: A max 300 with (in ethanol); Ämax 342 with (in potassium hydroxide / ethanol); and #max 338 m, u (when adding hydrogen chloride to the previous sample);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.60 (shoulder), 5.80-5.92 (broad), 6.26 and 6.70; and the crystalline isomer B (cis) of a- (2-Carbo tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo- [3.2.0 ] heptyl) -? - [(4-chlorophenylacetyl) -methylene] -acetic acid tert-butyl ester of the formula
EMI21.2
 which, after recrystallization from hexane, melts at 178-179; Ultraviolet absorption spectrum: A max 295 m (in ethanol); Ämax 337 m, (in potassium hydroxide / ethanol); and #max 337 mlt (when adding hydrogen chloride to the previous sample); Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 5.59, 5.75 (shoulder), 5.78 to 5.94; 6.07 (shoulder), 6.31 and 6.70. Isomer A is processed further without purification.



   The 4-chlorobenzylglyoxal hydrate can be prepared as follows:
A solution of 16.5 g of 4-chlorophenylacetyl chloride in 150 ml of dry ether is added dropwise with vigorous stirring and while cooling in an ice-water bath to about 11 g of diazomethane in 500 ml of ether. After allowing to react for 30 minutes at 5-10, the diazomethane and the solvent are distilled off under reduced pressure. The 4 chlorobenzyl diazo methyl ketone, available as a yellowish crystalline residue; Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.84, 6.22, 6.80 and 7.47; is processed further without cleaning.



   A solution of 17 g of 4-chlorobenzyl diazomethyl ketone in 150 ml of ether is added at room temperature to a solution of 23.5 g of triphenylphosphine in 300 ml of ether. The yellowish crystalline precipitate is filtered off after 20 minutes, washed with ether and recrystallized from a mixture of methylene chloride and ether; the 1- (4-chlorophenyl) -3- (triphenylphosphoranylidene hydrazono) acetone thus obtainable melts at 130-131; Ultraviolet absorption spectrum: A max 320 with (ethanol); Ämax 320 m (potassium hydroxide / ethanol); and Man 255-278 mlt (broad shoulder) (in hydrogen chloride / ethanol);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.76, 6.03 St (shoulder), 6.12, 6.28 (shoulder) and 6.56 - 6.75.



   A suspension of 8 g of 1- (4-chlorophenyl) -3- (triphenylphosphoranylidene-hydrazono) -acetone and 3.6 g of sodium nitrite in 51 ml of tetrahydrofuran and 22 ml of water is stirred and cooled in an ice-water bath (10-13 ) dropwise with 37 ml of 2-n. Hydrochloric acid is added, 2 phases being formed. The mixture is stirred for 30 minutes at room temperature, the organic layer is separated off and the aqueous phase is extracted several times with methylene chloride. The combined organic solutions are dried over sodium sulfate and evaporated under reduced pressure. A syrupy residue is obtained which is chromatorgraphed on 60 g of acid-washed silica gel.

  The crude 4-chlorobenzyl glyoxyl hydrate is extracted with benzene and a 95: 5 mixture of benzene and ethyl acetate; Ultraviolet absorption spectrum: A max 222 m (in ethanol); Ämax 365 m, xt (in potassium hydroxide / ethynol); and #max 316 m (in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.87-4.3 lt, 5.77 6.27 lt and 6.72 lt; and processed further without cleaning.

  The anhydrous 4-chlorobenzylglyoxal in the enol form melts after recrystallization from methylene chloride at 144-147; Ultraviolet Absorption Spectrum: #max 316 m (in ethanol); #max 364 m (in potassium hydroxide / ethanol); and #max 316 m (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.92, 5.97, 6.07 lt, 6.29 and 6.71 lt.



   Example 31
A solution of 2.5 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0 ] heptyl) a (triphenylphosphoranylidene) acetic acid tert-butyl ester and 1.3 g of cyclohexylmethyl glyoxal hydrate in 50 ml of toluene are heated to 800 for 4 hours and the solvent is evaporated off under reduced pressure. The syrupy residue is triturated with ether, the resulting triphenylphosphine oxide is filtered off and the filtrate is evaporated. The residue is chromatographed on 120 g of acid-washed silica gel, washing with a 98: 2 and a 9: 1 mixture of hexane and ethyl acetate.

  The isomer A (trans) of a- (2-carbo-tert-butyloxy-3,3 dimethyl-ethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) -α- (cyclohexylacetylmethylene) -acetic acid-tert. butyl ester of the formula
EMI22.1
 prepared by means of preparative thin layer chromatography (plates 20> (20 X 0.15 cm; silica gel; benzene system:

  acetone
20 98.2) purified and obtained in syrupy form [α] D20 = -451 # 1 (c = 0.87 in chloroform); Ultraviolet absorption spectrum: #max 297 m (in ethanol); #max 334 m (in potassium hydroxide / ethanol); and AmaX 334 with (when adding hydrogen chloride to the alkaline sample); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.45, 3.50, 5.61, 5.78 (shoulder), 5.80-5.95, 6.07 (shoulder) and 6.28.



   The isomer B (cis) of a- (2-Carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0 ] heptyl) -α- (cyclohexylacetyl-methylene) -acetic acid tert-butyl ester of the formula
EMI22.2
 is eluted as the second product and crystallized from hexane, mp 154-155; [α] D = -232 # 1 (c = 0.8 in chloroform); Ultraviolet absorption spectrum: #max 288 with (in ethanol), Ämax 333 with (in potassium hydroxide / ethanol) and Ämax 333 with (when adding hydrogen chloride to the above alkaline sample);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.44, 3.53, 5.60, 5.75 (shoulder), 5.80 -5.93, 6.05 (shoulder) and 6.31.



   The cyclohexylmethylglyoxal hydrate used as the starting material can be prepared as follows.



   A solution of 19.8 g of cyclohexyl acetyl chloride (boiling point 98 to 100/23 mm Hg) in 150 ml of dry ether is slowly cooled to 0-5 in a Bis water bath to a vigorously stirred solution of 11 g of diazomethane in 500 ml of ether given. The excess of the diazomethane and the ether are distilled off under reduced pressure and the residue obtained is cyclohexylmethyl diazomethyl ketone; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.45, 3.52, 4.75 and 6.12; that is processed further without cleaning.



   A solution of 32 g of triphenylphosphine in 450 ml of ether is mixed all at once with a solution of 20 g of cyclohexylmethyl diazomethyl ketone in 100 ml of ether while stirring. After stirring for 30 minutes at room temperature, the solvent is evaporated off under reduced pressure. The 1-cyclohexyl-3- (triphenyl-phosphoranylidene-hydrazono) -acetone, which is available as an oily residue, crystallizes in the cold from ether, mp 58-620; Ultraviolet absorption spectrum: A max 314 with, 2.62-2.75 with and 223 with (in ethanol and in potassium hydroxide / ethanol) and A max 257-275 with and 230 m, u (in hydrochloride / ethanol);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.43, 3.56, 4.76, 6.15 and 6.67.



      A mixture of 15 g of 1-cyclohexyl-3- (triphenylphosphoranylidene-hydrazono) -acetone and 7.37 g of sodium nitrite in 120 ml of tetrahydrofuran and 42 ml of water is slowly added with stirring and cooling to 10-13 (ice-water bath) 77 ml 2-n. Hydrochloric acid added. After a further 30 minutes at room temperature, the organic solution is separated off and the aqueous phase is extracted with methylene chloride. The combined organic solutions are dried over sodium sulfate and evaporated under reduced pressure. The syrupy residue is treated with ether, the resulting triphenylphosphine oxide is filtered off and the filtrate is evaporated.

  The residue is chromatographed on an acid-washed silica gel column (120 g), the cyclohexylmethyl glyoxal hydrate being eluted as a syrupy product with about 3000 ml of a 97: 3 mixture of hexane and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.904.1 Ec (broad); 3.47, 3.53 and 5.80; and processed without cleaning.



   Example 32
A solution of 1.5 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0 ] heptyl) -α- (triphenylphosphoranylidene) -acetic acid tert-butyl ester and 1.0 g of 2-phenylethyl glyoxal hydrate in 20 ml of toluene are heated at 80 for 2 hours and then stand for 16 hours at room temperature calmly. The toluene is removed under high vacuum and the residue separated by means of preparative thin-layer chromatography; silica gel plates (100 X 20 X 0.15 cm) are used and developed with a 4: 1 mixture of hexane and ethyl acetate.



  This gives the less polar isomer A (trans) of a- (2 carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bi cyclo [3, 2.0] heptyl) - α - [(3-phenyl-propionyl) -methylene] -acetic acid tert-butyl ester of the formula
EMI23.1
 which crystallizes spontaneously and after recrystallization from He
20 times the 100-102 dirt, [α] D = -420 # 1 (c = 1 in chloroform); Ultraviolet absorption spectrum (in ethanol): A max 292 mlt (E = 11,100);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62 lt, 5.80 (shoulder), 5.85-5.93 lt and 6.27 lt. A further amount can be obtained from the crystallization mother liquor.



   The more polar fraction, which also crystallizes spontaneously, is recrystallized from hexane and gives the isomer B (cis) of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2 , 6-diaza-6-bicyclo [3.2.0] heptyl) -a - [(3-phenyl-propionyl) -methylene] -acetic acid tert-butyl ester of the formula
EMI23.2
 M.p. 129-130: [α] D20 = -358 # 1 8c = 1.04 in chloroform); Ultraviolet Absorption Spectrum (in ethanol): A max 289 with # = 18,200);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62, 5.75 (shoulder), 5.82-5.94 and 6.27, a
The 2-phenylethylglyoxal hydrate used as the starting material can be prepared as follows:
A solution of 4.8 g of diazomethane in 240 ml of ether is added within 20 minutes and with vigorous stirring with a solution of 7.1 g of dihydrocinnamic acid chloride in 100 ml of ether, the reaction mixture being cooled to -5. The mixture is stirred for 15 minutes without cooling and the volatile components are distilled off under reduced pressure.

  The oily residue obtained is 2-phenylethyl diazomethyl ketone; Infrared absorption: ion spectrum (in methylene chloride): characteristic bands at 4.76 1 "6.11, 6.16 (shoulder) and 6.69.



   A solution of 7.45 g of the crude 2-phenylethyldiazomethyl ketone in 200 ml of ether is treated with a solution of 11 g of triphenylphosphine in 200 ml of ether at room temperature. The mixture is stirred for 2 hours, the crystalline 1-13 enzyl-3 (triphenylphosphoranylidene-hydrazono) -acetone is filtered off, which melts after recrystallization from ether at 105C; Ultraviolet absorption spectrum (in ethanol: A max 316 with, 265-280 with (shoulder) and 223 with; infrared absorption spectrum (in methylene chloride): characteristic bands at 6.10 and 6.63.



   4.16 g of powdered sodium nitrite are suspended in a solution of 8 g of 1-benzyl-3- (triphenylphosphoranylidene-hydrazono) -acetone in 60 ml of tetrahydrofuran and 30 ml of water and the suspension, with vigorous stirring, with 44 ml of 2-n. Hydrochloric acid added; the addition takes 15-20 minutes, cooling to 10-150. After a further 15 minutes at room temperature, extraction is carried out with ether; the ether extract is washed with a concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on 100 g of silica gel (column), eluting with 98: 2 and 95: 5 mixtures of benzene and ethyl acetate.

  The 2-phenylethyl glyoxal hydrate is thus obtained; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88, 3.00, 30 lt (broad and 5.77-5.86 lt.



   Example 33
A solution of 0.77 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl ) -a- (tri phenylphosphoranylidene) -acetic acid tert-butyl ester and 0.92 g of 3-chloropropyl glyoxal hydrate in 23 ml of toluene are left to stand for 6 hours at 50 °. The solvent is evaporated off under reduced pressure and the oily residue is purified by preparative thin layer chromatography (silica gel plates 100 x 20 x 0.15 cm; system: hexane / ethyl acetate 4: 1).

  The least polar fraction (Rf = 0.3S) is the isomer A (trans) of a- (2-Carbotert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza- 6-bicyclo [3.2.0] heptyl) -α- [(4-chlorobutyryl) -methylene] -acetic acid tert-butyl ester of the formula
EMI24.1
 represents, which is obtained as a colorless oil; Thin-layer chromatogram (system: hexane / ethyl acetate 2: 1): Rf = 0.48; Ultraviolet absorption spectrum: A max 295 with (in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.42, 5.62, 5.80-5.95 and 6.27.



   The isomer B (cis) of a- (2-Carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3,2,0] Heptyl-α- [(4 chlorobutyryl) -methylene] -acetic acid tert-butyl ester of the formula
EMI24.2
 is obtained in the form of a colorless oil as the more polar fraction (Rf = 0.23); Thin-layer chromatogram (system hexane / ethyl acetate 2: 1): Rf = 0.42; Ultraviolet absorption spectrum: A max 295 with (in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.42, u, 5.61, 5.78-5.94 lt and 6.31 ,.



   A mixture of 0.29 g of isomer B of a- (2-Carbotert-butyloyx-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0 ] heptyl) -? - [(4-chlorobutyryl) -methylene] -acetic acid tert-butyl ester in 130 ml of benzene is irradiated with a high pressure mercury vapor lamp in a Pyrex glass jacket at room temperature for 3 hours and then evaporated under reduced pressure. The crude mixture of the two isomers A and B of a- (2-carbo-tert-butyloxy-3,3 dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0 ] heptyl) -? - [(4-chlorobutyryl) -methylene] -acetic acid tert-butyl ester is determined by means of preparative thin-layer chromatography, e.g. B. as described above, and so a further amount of the desired isomer A (trans) is obtained.



   The 3-chloropropyl-glyoxal used in the above example can be prepared as follows:
A solution of 10 g of 4-chlorobutyryl chloride in 150 ml of dry ether is slowly added with stirring and cooling to 0 to 50 in an ice-methanol bath to a solution of 12.3 g of diazomethane in 500 ml of ether. After a further 5 minutes at 0 to 50, the solution with the 3-chloropropyl-diazomethyl ketone is concentrated under reduced pressure to a volume of 150 ml and immediately treated with a solution of 22.8 g of triphenylphosphine in 200 ml of ether.

  The 1- (3-chloropropyl) -3 - (triphenylphosphoranyliden-hydrazono) -acetone crystallizes out, mp 103-1040; Ultraviolet absorption spectrum: λmax 320 with and 228 mlt (in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 6.10 lt and 6.64, ez. Another amount of the desired product can be isolated from the mother liquor.



   A mixture of 6 g 1- (3-chloropropyl) -3- <triphenyl-phosphoranylidene-hydrazono) acetone and 3.1 g of sodium nitrite in 55 ml of tetrahydrofuran and 30 ml of water are slowly added to 22 ml of 2-n. Hydrochloric acid is added, the addition being carried out with cooling to 13-150 in an ice-water bath. After a further 15 minutes at room temperature, the mixture is extracted three times with 150 ml of ether each time; the combined ether extracts are washed five times with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.

  The oily yellow precipitate is chromatographed on 100 g of acid-washed silica gel (column); the pure 3-chloropropyl glyoxal hydrate is eluted with a 95: 5 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90-4.0 (broad), 3.45 and 5.81.



   Example 34
A solution of 0.3784 g of the isomer A (trans) of a (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-byciclo [3 , 2.0] heptyl-α- [(4-tert-butzl-phenyl) -acetylmethylene] -acetic acid tert-butyl ester in 3 ml of precooled trifluoroacetic acid is left to stand for 20 hours at -20.

  The trifluoroacetic acid is distilled off under reduced pressure and at room temperature and the residue, which is the 7-amino-4- (4-tert.-butyl-benzylidene) -8-oxo-5-thia 1-azabicyclo [4,2,0] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-amino-2- (4-tert.-butyl benzylidene) -n3-cephem-4-carboxylic acid is mixed with 4 ml of a solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride (preparation see Example 12), the temperature being kept at 100. After the addition, 2 ml of a solution of triethylamine and triethylammonium acetate in methylene chloride (preparation see Example 12) are added and the resulting reaction mixture is stirred without cooling for 21/2 hours.

  It is treated with 40 ml of ethyl acetate and the mixture is washed with dilute hydrochloric acid and a saturated aqueous sodium chloride solution. The organic solution is dried over sodium sulfate and evaporated. The residue is chromatographed on a column of 10 g of acid-washed silica gel; with a 95: 5 mixture of benzene and acetone, trichloroacetic acid, cyanoacetic acid and some neutral by-products are washed out.

  With a 2: 1 mixture of benzene and ethyl acetate, the crude 7-N cyanoacetylamino-4- (4-tert-butyl-benzylidene) -8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) or 7-N-cyanoacetyl-amino-2- (4 tert-butyl-benzylidene) -n3-cephem -4-cafboxylic acid of the formula
EMI25.1
 eluted as an amorphous product; Ultraviolet absorption spectrum: Ämax 361 m (in ethanol, Ämax 352 m, c (in ethanol / potassium hydroxide) and Äm.x 363 spleen with (in ethanol / hydrogen chloride); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90 - 4.35, 3.40, 5.60-5.68, 5.75-5.90, 6.05 (shoulder), 6.25 and 6.40-6.65.



   A solution of the material obtained in 2 ml of acetone is mixed with 1 ml of a 100% solution of the sodium salt of α-ethyl-acpronic acid in acetone and with ether. The dark colored product is discarded and the beige colored sodium salt of 7-N-cyanoacetyl-amino-4- (4-tert-butyl-benzylidene) -8-oxo-5-thia-1-azabicyclo [4.2.0 ] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-N-cyanoacetyl-amino-2- (4-tert-butyl-benzylidene) -A3-cephem-4-carboxylic acid is filtered off , M.p.> 2400; Ultraviolet absorption spectrum: #max 352 with (in ethanol), and Ämax 363 m, u (in ethanol / hydrogen chloride);

  Infrared absorption spectrum (potassium bromide): characteristic bands at 2.80 to 4.0, 3.40 lt '4.52, 5.65-5.70 lt' 5.90 (shoulder) and 6.03-6.55 lt.



   The α- (2-carbo-tert-butyloyx-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- [(4-tert-Butyl-phenyl) -acetylmethylene] -acetic acid-tert-butyl ester, which is used as starting material in the above process, can be prepared as follows: A solution of 1.5 g of a- (2 -Carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3,2,0] - hepzyl) - α- (triphenylphosphoranylidene) - tert-butyl acetate and 1.5 g of 4-tert-butyl-benzyl-glyoxal hydrate in 15 ml of toluene are heated for 90 minutes at 800 under a nitrogen atmosphere.

  The solvent is then evaporated off under reduced pressure and the residue is chromatographed (preparative thin layer chromatography; 3 silica gel plates 100 X 20 X 0.15 cm), using a 4: 1 mixture of hexane and ethyl acetate as the mobile phase. This gives the isomer A (trans) of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3.2.0] heptyl) -a - [(4-tert-butyl-phenyl) -acetylmethylene] -acetic acid-tert-butyl ester of the formula
EMI25.2
  as amorphous foam; Thin-layer chromatogram (silica gel; system hexane / ethyl acetate 4: 1):

  Rf = 0.58; Ultraviolet absorption spectrum: #max 298 with (in ethanol), #max 338 m (in ethanol / potassium hydroxide), and #max 338 m (when adding hydrogen chloride to the ethanol / potassium hydroxide sample); Infrared absorption spectrum (in methylene chloride); characteristic bands at 3.40, 5.62, 5.78 (shoulder), 5.82-5.92 and 5.27;

   and isomer B (cis) of α- (2.Carbo-tert-butyloyx-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0 ] heptyl) a- [(4-tert-butylphenyl) -acetyl methylene] -acetic acid-tert-butyl ester of the formula
EMI26.1
 which, after recrystallization from hexane, melts at 1530;
20 [α] D = -526 # 1 (c = 0.888 in chloroform); Thin-layer chromatogram (silica gel; system hexane / ethyl acetate 4: 1):

  Rf = 0.44; Ultraviolet absorption spectrum: #max 295 m (# = 18300) (in ethanol), #max 338 m (in ethanol / potassium hydroxide) and #max 338 m (when acidifying the ethanol / potassium hydroxide sample with hydrogen chloride); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.40, 5.60, 5.72 (shoulder), 5.80 to 5.92 and 6.28.



   The 4-tert-butylbenzyl-glyoxal hydrate used in the preparation of the starting material can be prepared as follows: A solution of 10.6 g of 4-tert-butyl-phenyl-acetic acid chloride (prepared by heating a mixture of 10 g of 4-tert-butylphenylacetic acid with 60 ml of thionyl chloride to 600 for 3 hours, removal of the excess of thionyl chloride under reduced pressure and repeated evaporation of a mixture of the residue in benzene to remove the last traces of thionyl chloride) in 100 ml of dry ether slowly added to a solution of 8.3 g of diazomethane in 300 ml of ether. After standing for 10 minutes at -50, the excess of the diazomethane and the ether is distilled off under reduced pressure and at room temperature.

  The yellow oily residue is 4-tert-butyl-benzyl-diazomethyl ketone; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.40, 3.50 (shoulder), 4.72, 6.10 and 7.38; and is processed further without cleaning.



   A solution of 10.9 g of 4-tert-butylbenzyl diazomethyl ketone in 200 ml of dry ether and a mixture of 13.2 g of triphenylphosphine in 200 ml of dry ether are combined and stirred at room temperature for about 30 minutes. The 1- (4-tert-butylphenyl) -3- (triphenylphosphoranylidene) acetone precipitates, mp 129-1300 after recrystallization from hexane; Ultraviolet absorption spectrum (in ethanol): λ max 314 with (e = 7900) and λ max 258 with (e = 16,600); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.40, 4.72, 6.00 (shoulder), 6.07 and 6.60. Another amount of the product can be obtained by concentrating the mother liquor.



   A solution of 9.6 g of 1- (4-tert-butylphenyl) -3- (triphenylphosphoranylidene) acetone in 60 ml of tetrahydrofuran and 44 ml of water is treated with 4.2 g of sodium nitrite; the suspension is stirred at 10-13, with 44 ml of 2-n.



  Hydrochloric acid is added dropwise. After a further 10 minutes at 100, the organic layer is separated and the aqueous solution is extracted with methylene chloride. The organic solutions are combined and evaporated; the residue is crystallized from ether, and the product obtainable from the mother liquor is chromatographed on 80 g of acid-washed silica gel.

  The non-crystalline 4-tert-butylbenzyl-glyoxal hydrate is eluted with benzene and a 96: 4 mixture of benzene and ethyl acetate; Ultraviolet absorption spectrum: A max 250-275 with (in ethanol), A max 364 with (in ethanol / potassium hydroxide), and Am 322 with <in ethanol / hydrogen chloride); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.85-4.20 lt, 3.40, 5.76, 6.60 and 7.30; Thin-layer chromatogram (silica gel; system benzene / ethyl acetate 1: 1): Rf = # 0.57 (smeared); and processed further without cleaning.



   The following compounds can be obtained in an analogous manner if the suitable starting materials are selected:
2-Ethylidene-7-phenylacetylamino-ceph-3-em-4-carboxylic acid, mp 95-980 after recrystallization from a mixture of benzene and acetone; Thin-layer chromatogram (silica gel): Rf = 0.33 (system: acetic acid / toluene / water 5: 5: 1); Ultraviolet absorption spectrum: λmax = 318 m (in ethanol, λmax = 300 with (in ethanol / potassium hydroxide) and λmax 322 m, u (in ethanol / hydrogen chloride); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90, 3.29, 5 , 58, 5.75 (shoulder9, 5.90, 6.12, 6.64 and 7.06.



   7-Phenylacetylamino-2- (1,1-propylidene) -ceph-3-em-4-carboxylic acid, m.p. 102-1050 after recrystallization from benzene; Thin-layer chromatogram (silica gel): Rf = 0.36 (system: acetic acid / toluene / water 5: 5: 1); Ultraviolet absorption spectrum: λ max = 318 with (in ethanol), λ max = 312 with <in ethanol / potassium hydroxide) and Ä, max = 318 with (ethanol / hydrogen chloride); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95, 3.30-3.50, 5.60, 5.66-5.76, 5.91, 6.22 and 6.64;
2-ethylidene-7-cyanoacetylamino-ceph-3-em-4-carboxylic acid, mp 222-225 after recrystallization from acetone; Thin-layer chromatogram (silica gel): Rf = 0.12 (system:

  Acetic acid / toluene / water 5: 5: 1); Ultraviolet absorption spectrum: #max = 319 m (in ethanol), #max = 310 (in ethanol / potassium hydroxide) and #max = 320 m (ethanol / hydrogen chloride); Infrared absorption spectrum (potassium bromide): characteristic bands at 3.10, u, 3.30, ce, 4.45, u, 5.60, u, 5.90, u, 6.00, x, 6.25 and 6, 40, tr; 7-cyanoacetylamino-2- (1,1-propylidene) -ceph-3-em-4-carboxylic acid, amorphous; Thin layer chromatogram (silica gel): Rf = 0.18 (system:

  Acetic acid / toluene / water 5: 5: 1); Ultraviolet absorption spectrum: #max = 317 m (in ethanol), #max = 311 m (ethanol / potassium hydroxide) and #max = 321 m (ethanol / hydrogen chloride); Infrared absorption spectrum (potassium bromide): characteristic bands at 3.10, ee, 3.30, u, 3.14, 4.45, 5.60, 5.86, 6.02, 6.25, 6.41;
2-ethylidene-7-bromoacetylamino-ceph-3-em-4-carbon amorphous; Thin-layer chromatogram (silica gel): Rf = 0.24 (system:

  Acetic acid / toluene / water 5: 5: 1); Ultraviolet absorption spectrum: #max 0 315 m (ethanol), #max = 314 m (ethanol / potassium hydroxide) and #max = 323 m (ethanol / hydrogen chloride); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.06 (broad), 5.58, ez, 5.67, 5.81, 6.23 and 6.42-6.62; and 2-ethylidene-7- (1-tetrazolylacetylamino) -ceph-3-em-4-carboxylic acid, melting point 238240 after recrystallization from acetone; Thin-layer chromatogram (silica gel):

  Rf = 0.19 (system: acetic acid / water / toluene 5: 5: 1); Ultraviolet absorption spectrum: #max = 318 m (ethanol), #max = 308 m (ethanol / potassium hydroxide) and #max = 319 m (ethanol / hydrogen chloride); Infrared absorption spectrum (potassium bromide): characteristic bands at 3.05, * e, 3.20-3.45 Ae, 5.66, ee, 5.85, z, 5.95, z, 6.24 and 6.48 u .



   The following compounds can be used as starting materials to produce the above compounds:
Isomer A of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α ;-( n-butyrylmethylene) -acetic acid tert-butyl ester, m.p. 109110 after recrystallization from hexane; [α] D20 = -511 # 2 (in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.62 (system:

  Hexane / ethyl acetate 2: 1); Ultraviolet absorption spectrum / ethanol): #max = 292 m (# = 9900); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.36, 5.60, 5.80 (shoulder), 5.84-5.93 and 6.25; the corresponding isomer B melts after recrystallization from hexane at 126-127; [α] 20 D = -424 # 2 (in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.56 (system:

  Hexane / ethyl acetate 2: 1); Ultraviolet Absorption Spectrum (ethanol): #max = 286 m (# = 17,700); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.38, 5.60, 5.76 (shoulder), 5.82-5.95 to and 6.27, u; and
Isomer A of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α ; -propionylmethylene-acetic acid tert-butyl ester, melting point 126127 after recrystallization from hexane; [α] D20 = -524 # 1 (chloro form); Thin-layer chromatogram (silica gel): Rf = 0.64 (system:

  Hexane / ethyl acetate 2: 1); Ultraviolet Absorption Spectrum (in ethanol): #max = 289 m (# = 9500); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.43, 5.62, u, 5.82 (shoulder), 5.85 to 5.95, u and 6.28 / r; the corresponding isomer B melts at 151-153 after recrystallization from hexane; [α] 20 D = -410 + 1 (chloroform); Thin-layer chromatogram (silica gel): Rf = 0n57 (system:

  Hexane / ethyl acetate; Ultraviolet Absorption Spectrum (ethanol): Al ,, aX = 286 m (e = 17 150); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.43, 5.61, 5.80 (shoulder), 5.85 to 5.95 and 6.29, and the like.

 

Claims (1)

PATENT CLAIM Process for the preparation of 7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acids and their esters of the formula EMI27.1 wherein R1 represents a hydrogen atom or the organic radical of an alcohol R1OH, and R represents a methylene radical substituted by one or two optionally substituted hydrocarbon radicals or optionally substituted heterocyclic radicals, as well as salts of such compounds, characterized in that a compound of the formula EMI27.2 in which R1 has the meaning given above, and R 2 is hydrogen or an acyl radical Ac which can be split off under the acidic conditions of the reaction, and in which R3 is an organic radical and R6 is a hydrogen atom when R2 is an acyl group Ac, or in which R5 and R4 together represent a disubstituted carbon atom, if o R 2 represents a hydrogen atom or an acyl group Ac, and Ro represents the radical HR which under acidic conditions ring-closes with formation of the 7-amino group. SUBCLAIMS 1. The method according to claim, characterized in that an esterified carboxyl group -COORr in a compound of formula I obtained, in which R1 is a polysubstituted methyl group, is liberated by treatment with an acid. 2. The method according to claim, characterized in that an esterified carboxyl group -COORl in a compound of formula I obtained, wherein R1 is a 2-halo-lower alkyl group, is released by treatment with nascent hydrogen. 3. The method according to claim, characterized in that a compound of the formula I is converted into a salt or a salt obtained is converted into the free compound or into another salt. 4. The method according to claim, characterized in that the ring closure is carried out by treatment with a strong inorganic or organic acid. 5. The method according to dependent claim 4, characterized in that the ring closure is carried out by treatment with a strong oxygen-containing inorganic or organic acid. 6. The method according to dependent claim 5, characterized in that the ring closure is carried out by treatment with a strong lower alkanecarboxylic acid optionally substituted by hetero radicals. 7. The method according to dependent claim 6, characterized in that the ring closure is carried out by treatment with a strong, halogen-substituted lower alkanecarboxylic acid. 8. The method according to dependent claim 7, characterized in that the ring closure is carried out by treatment with trifluoroacetic acid. 9. The method according to claim, characterized in that the ring closes with cooling. 10. The method according to claim, characterized in that starting materials are used in the form of a crude reaction mixture obtainable under the reaction conditions. 11. The method according to claim or one of the dependent claims 1-10, characterized in that compounds of the formula EMI28.1 where Rr is a hydrogen atom or a lower alkyl, halo-lower alkyl, cycloalkyl or phenyl-lower alkyl radical, and R 'is a methylene group substituted by lower alkyl or optionally substituted phenyl radicals, or salts of such compounds are produced. 12. The method according to claim or one of the dependent claims 1-10, characterized in that compounds of the formula Ia according to dependent claim 11 or salts of such compounds are prepared in which R'1 is a hydrogen atom or an easily cleavable lower alkyl, halogen-lower alkyl, Represents cycloalkyl or phenyl-lower alkyl radical and R 'represents a methylene group which is substituted by one or two lower alkyl radicals or by a phenyl group optionally containing lower alkyl, lower alkoxy or nitro groups or halogen atoms. 13. The method according to claim or one of the dependent claims 1-10, characterized in that 7-amino-8-oxo-4-methylene-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acids or lower alkyl esters thereof, as well as salts of compounds in which the methylene group in the 4-position is substituted by one or two lower alkyl radicals or by a phenyl radical optionally containing lower alkyl, lower alkoxy or nitro groups or halogen atoms, and the lower alkyl radical of the ester grouping is optionally substituted may have one or more halogen atoms in the 2-position. 14. The method according to claim or one of the dependent claims 1-10, characterized in that 7 amino-8-oxo-4-methylene-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 - Carboxylic acids or lower alkyl esters thereof, as well as salts of compounds in which the methylene group in the 4-position is substituted by one or two methyl radicals or by a phenyl radical optionally containing lower alkyl, lower alkoxy or nitro groups or halogen atoms, and the lower alkyl radical of the ester group for the tert-butyl or the 2,2,2-trichloroethyl radical. 15. The method according to claim or one of the dependent claims 1-10, characterized in that the 7-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid produces. 16. The method according to claim or one of the dependent claims 1-10, characterized in that the 7-amino-4- (4-nitrobenzylidene) -8-oxo-5-thia- l-azabicyclo- [4.2.0oct- 2-en-2-carboxylic acid produces. 17. The method according to claim or one of the dependent claims 1-10, characterized in that the 7-amino-4- (4-methoxy-benzylidene) -8-oxo-5-thia-1-azabicyclo [4.2 , 0] oct-2-ene-2-carboxylic acid. 18. The method according to claim or one of the dependent claims 1-10, characterized in that the 7-amino-4-isopropylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct2-ene-carboxylic acid is prepared