CH510013A - Alpha-hydroxy-2-oxo-1-azetidinemethane-carboxylic acids - inters for pharmaceuticals e.g. antibiotics - Google Patents

Abstract

New: Alpha-hydroxy-2-oxo-1-azetidinemethane-carboxylic acids of formula (where R1 is H or organic residue of alcohol, R2 is H or acyl, R3 is opt. substd. hydrocarbon residue and R4 is H if R2 is acyl, or R3 and R4 together stand for disubstituted carbon if R2 is H or acyl) and their salts. Produced by reacting 1-unsubstituted azetidine-2-one cpds. of formula (where R2A is acyl) with a cpd. of formula O=CH-COOR1A (where R1A is residue of alcohol) or with a reactive derivative thereof and opt. splitting off acyl groups R2A and opt. acylating free N-atom in cpd. obtained, and/or converting ester obtained to free carboxylic acid, opt. converting salt to free cpd. or different salt and/or separating isomers from mixture. Products useful intermediates in production of pharmaceuticals, such as antibiotics.

Description

  

  
 



  Process for the preparation of oxyacetic acid compounds
The present invention relates to a process for the preparation of os-hydroxy-2-oxo-1-azetidine-methane-carboxylic acid compounds of the formula
EMI1.1
 where R1 represents a hydrogen atom or the organic radical of an alcohol, R2 represents a hydrogen atom or an acyl radical, R3 represents an organic radical and R4 represents a hydrogen atom, or the two groups R3 and R together represent a disubstituted carbon atom, as well as salts of such compounds with salt-forming groups.



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



   An acyl radical R2 is primarily that of an organic carboxylic acid, in particular a carbonic acid half derivative or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid.



   An organic radical R3 is an optionally substituted hydrocarbon radical, primarily an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical which can be split off, is unsaturated in the linkage position or substituted by a hetero radical.



   Substituents of a disubstituted carbon atom, which is represented by the two radicals R3 and R4 together, are optionally substituted hydrocarbon radicals, such as optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals. The two substituents on the disubstituted carbon atom can also be taken together and e.g. represent an optionally substituted and / or interrupted by heteroatoms divalent, aliphatic hydrocarbon radical.



   An aliphatic hydrocarbon radical is an alkyl, alkenyl or alkynyl, especially a lower alkyl or lower alkenyl, as well as a lower alkynyl radical, e.g. can contain up to 7, preferably up to 4 carbon atoms. Such radicals can optionally be replaced by functional groups, e.g.

   by etherified or esterified hydroxy or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkyl mercapto groups or optionally substituted phenyl mercapto or phenyl-lower alkyl mercapto, lower alkoxycarbonyloxy or lower alkanoyloxy groups, and also halo-alkanoyloxy groups be mono-, di- or poly-substituted by nitro groups, substituted amino groups or functionally modified carboxy groups, such as carbo-lower alkoxy, optionally N-substituted carbamyl or cyano groups.



   Cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radicals are e.g. Cycloalkyl or cycloalkenyl groups, or cycloalkyl or cycloalkenyl-lower alkyl or -lower alkenyl groups, in which cycloalkyl radicals e.g. Contain 3-8, preferably 3-6 ring carbon atoms, while cycloalkenyl radicals e.g. 5-8, preferably 5 or 6 ring carbon atoms and 1 to 2 double bonds, and the aliphatic part of cycloaliphatic-aliphatic radicals e.g. can contain up to 7, preferably up to 4 carbon atoms.

  The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, e.g. by optionally substituted aliphatic hydrocarbon radicals, such as, for example, 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 araliphatic hydrocarbon radical is e.g.



  up to three, optionally substituted, mono- or bicyclic, aromatic hydrocarbon radicals, optionally substituted aliphatic hydrocarbon radical and primarily represents a phenyl-lower alkyl or phenyl-lower alkenyl and phenyl-lower alkynyl radical, such radicals containing 1-3 phenyl groups and optionally, e.g. as the above-mentioned aliphatic and cycloaliphatic radicals can be substituted in the aromatic and aliphatic part.



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



   The acyl radical of a carbonic acid half-derivative is preferably the acyl radical of a corresponding half-ester, such as an optionally substituted aliphatic half-ester, primarily an optionally substituted lower alkyl half-ester of carbonic acid, i. a carbo-lower alkoxy radical which is optionally substituted in the lower alkyl part. An aliphatic carboxylic acid is in particular an optionally, e.g. such as the abovementioned aliphatic hydrocarbon radicals, substituted alkane, as well as alkene or alkyne, primarily lower alkane, and also lower alkene or lower alkyne carboxylic acid, e.g. can contain up to 7, in particular up to 4 carbon atoms.

  A cycloaliphatic or cycloaliphatic-aliphatic carboxylic acid is an optionally, e.g. such as the above-mentioned cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radicals, substituted cycloalkanoic or cycloalkenecarboxylic acid, or



  Cycloalkyl or cycloalkenyl-lower alkanoic or lower alkenecarboxylic acid, where a cycloalkyl or cycloalkenyl radical, as well as the aliphatic part of cycloaliphatic-aliphatic carboxylic acids e.g. have the number of carbon atoms and / or double bonds indicated above for corresponding radicals and may optionally be substituted as indicated. An aromatic carboxylic acid is primarily a mono- or bicyclic aromatic carboxylic acid which may optionally, e.g. B.



  such as the above-mentioned cycloaliphatic radical, may be substituted. In an araliphatic carboxylic acid, the araliphatic part has e.g. the above meaning: an araliphatic carboxylic acid means primarily a phenyl-lower alkanoic or phenyl-lower alkene carboxylic acid, in which the phenyl radical and the aliphatic part optionally, e.g. such as the above-mentioned cycloaliphatic or aliphatic groups, may be substituted.



  A heterocyclic carboxylic acid is in particular one of aromatic character in which the heterocyclic radical can be mono- or bicyclic and primarily for an optionally, e.g. like the above-mentioned cycloaliphatic radical, substituted mono- or bicyclic. monoaza, monooxa or monothia, diaza, oxaza, or thiazacyclic radical, primarily a pyridyl, thienyl, furyl, quinolyl or isoquinolyl radical. In a heterocyclic-aliphatic carboxylic acid, the heterocyclic radical has the meaning given above, while the aliphatic part, e.g. in an araliphatic carboxylic acid represents an optionally substituted lower alkyl or lower alkenyl radical.



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



   A cycloalkyl group is e.g. a cyclopropyl, cyclo- butyl, cyclopentyl, cyclohexyl or cycloheptyl group, and a cycloalkenyl e.g. a 2- or 3-cyclopentenyl, 1-, 2 or 3-cyclohexenyl or 3-cycloheptenyl group. Cycloalkyl, lower alkyl or lower alkenyl is e.g. a cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, methyl, ethyl, propyl, vinyl or allyl group, while a cycloalkenyl, lower alkyl or lower alkenyl group is e.g. a 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl or 1-, 2- or 3-cycloheptenyl-methyl, -ethyl, -propyl, -vinyl or -allyl group represents.



   A phenyl lower alkyl or phenyl lower alkenyl.



  rest is e.g. a benzyl, 1. or 2-phenylethyl, 1-, 2 or 3-phenylethyl, diphenylmethyl or -ethyl, trityl, 1- or 2-naphthylmethyl, styryl or cinnamyl radical.



   A lower alkylene or lower alkenylene radical is e.g.



  by a 1,2-ethylene, 1,3-propylene, 2,2-dimethyl-1,3-propylene, 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-butene-1, 4-ylene or 2 or 3-penten-1,5-ylene group.



   A carbo-lower alkoxy radical is e.g. a carbomethoxy, carbethoxy, carbo-n-propyloxy, carboisopropyloxy or carbo-tert-butyloxy group.



   A lower alkanoic or lower alkene carboxylic acid is e.g. Acetic, propionic, butyric, isobutyric, valeric, pivalic or acrylic acid, while a cycloalkanoic or cycloalkenyl, or cycloalkyl or cycloalkerlyl-lower alkanoic or lower alkene carboxylic acid e.g. means a cyclopentane, cyclohexane or 3-cyclohexenecarboxylic acid, cyclopentylpropionic, cyclohexyl acetic, 3-cyclohexenyl acetic or cyclohexyl acrylic acid. A mono- or bicylic aromatic carboxylic acid is e.g. Benzoic acid or 1- or 2-naphthoic acid, and a phenyl-lower alkanoic or phenyl-lower alkene carboxylic acid e.g. a phenylacetic, phenylpropionic or cinnamic acid.



  As pyridine, thiophene, furan, quinoline or isoquinoline carboxylic acids are nicotinic or isonicotinic acid, 2-thiophene. 2-furan. 2- or 4-quinoline or 1-isoquinoline carboxylic acid, and as corresponding pyridyl, furyl, thienyl, quinolyl or isoquinolyl-lower alkanoic or lower alkene carboxylic acids e.g. the 2-, 3- or 4-pyridyl acetic, 2-thienyl acetic, 2-furyl acetic. or 2-furyl acrylic acid called.

 

   Optionally substituted aliphatic hydrocarbon radicals, especially lower alkyl groups, which i.a. can also substitute cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radicals. contain the above-mentioned substituents and are e.g. Halo-lower alkyl groups such as mono-, di- or tri-halogenated lower alkyl, e.g. 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.



   Other substituted aliphatic hydrocarbon radicals, such as the aliphatic hydrocarbon radicals R3 substituted in the linkage position by hetero radicals, are primarily lower alkyl groups containing ether or esterified hydroxy groups in the linkage position, such as lower alkoxy groups or lower alkanoyloxy groups or halogen atoms containing lower alkyl, such as methyl atoms -, ethyl, propyl or isopropyl radicals. These aliphatic hydrocarbon radicals R3, in particular the 2-propenyl radical, which are unsaturated in the linked position, can preferably be removed under acidic conditions, an alkanoyloxy group also under alkaline conditions, as well as by treatment with mercaptide-forming heavy metal salts, such as mercury or cadmium salts, e.g. the corresponding halides or lower alkanoyloxy compounds, split off.



   Among the etherified hydroxy and mercapto groups are lower alkoxy, e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy groups, lower alkenyloxy, e.g. Vinyloxy or allyloxy groups, lower alkylenedioxy, e.g. Methylene or ethylenedioxy groups, phenyl-lower alkoxy, e.g. Benzyloxy or 1- or 2-phenylethoxy groups, lower alkyl mercapto, e.g. Methyl mercapto or ethyl mercapto groups, phenyl mercapto groups, or phenyl-lower alkyl mercapto, e.g. Benzyl mercapto groups. Esterified hydroxy groups are primarily halogen, e.g. Fluorine, chlorine, bromine or iodine atoms, as well as lower alkanoyloxy, e.g. 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 radicals. Such amino groups are especially lower alkylamino or di-lower alkylamino, e.g. Methylamino, ethylamino, dimethylamino or diethylamino groups, or optionally by heteroatoms such as oxygen, sulfur or optionally, e.g. lower alkyleneamino groups interrupted by lower alkyl groups, substituted nitrogen atoms, such as pyrrolidino, piperidino, morpholino, thiamorpholino or 4-methylpiperazino groups.



   Optionally N-substituted carbamyl groups are e.g. N-lower alkyl or N, N-di-lower alkyl-carbamyl, such as N-methyl, N-ethyl, N, N-dimethyl or N, N-diet ethylcarbamyl 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 are novel intermediates which are suitable for the preparation of valuable compounds which primarily have pharmacological activity. So you can e.g.



  in compounds of the formula I in which R. preferably a reductively cleavable organic radical of an alcohol, such as a 2-halo-lower alkyl, e.g. the 2,2-trichloroethyl radical, or an organic radical of an alcohol that can be split off under acidic conditions, such as a methyl radical which is polysubstituted by aliphatic or aromatic, optionally substituted hydrocarbon radicals, e.g. denotes the benzhydryl, trityl or tert-butyl radical, and R2 represents an acyl radical that can preferably be split off under acidic conditions, such as the carbo-tert.-butyloxy radical. by treating with halogenating agents, e.g.

  Thionyl chloride, preferably in the presence of a base such as triethylamine, replace the hydroxy group with a halogen atom and convert the halogen compounds obtainable in this way with phosphine compounds of the formula P (Ra) (Rb) (Re), in which each of the radicals Ra, Rb and Re is one represents organic, in particular an aliphatic or aromatic radical, e.g. with triphenyl- or tributylphosphine, via the corresponding phosphonium salts, preferably with treatment with a basic agent to form phosphorane compounds of the formula
EMI3.1
 where R, "and R2a preferably represent the abovementioned removable radicals. These compounds represent versatile starting materials of the Wittig type.

  So you can e.g. by treatment with glyoxylic acid compounds, preferably at an elevated temperature tS0-150 C) and in an inert solvent such as dioxane, toluene, xylene or diethylene glycol dimethyl ether. optionally with the addition of a suitable carboxylic acid such as benzoic acid, an optionally functionally modified carboxymethylene radical can be introduced. The resulting double bond in a compound thus obtainable can be obtained by treating e.g. with catalytically activated hydrogen, e.g. in the presence of a noble metal such as palladium catalyst, nascent hydrogen, e.g. by treating with a suitable zinc compound such as zinc, zinc amalgam or zinc copper in the presence of a hydrogen donating agent such as a weak carboxylic acid, e.g.

  Acetic acid, or a lower alkanol such as methanol, ethanol or isopropanol, if desired, an aqueous mixture thereof, or with a homogeneous hydrogenation catalyst such as transition metal hydrides, e.g. corresponding chromium (III), manganese (II), iron (III), cobalt (II) or nickel (II) compounds or complexes, such as carbonyl, cyano or phosphine complexes thereof, are saturated.

  By treating with a strong, preferably oxygen-containing inorganic or organic acid, primarily trifluoroacetic acid, in the presence of an anhydride of a strong acid, such as trifluoroacetic anhydride, followed by a suitable acid anhydride, in particular acetic anhydride, a compound of the formula which can be obtained in this way can be obtained
EMI3.2
  wherein R, l represents a hydrogen atom or one of the removable organic radicals of alcohols mentioned for the group Rla, optionally after cleavage of an acyl group R 'and / or conversion of an intermediate of the formula B, in which Rd represents a hydrogen atom, into a reactive derivative, such as an acid halide, e.g. chloride (e.g. using thionyl chloride or oxalyl chloride) or a mixed anhydride, e.g.

   with a carbonic acid lower alkyl half ester, such as ethyl half ester (e.g. using a halo-enoformic acid lower alkyl ester) or a lower alkanecarboxylic acid, such as acetic acid (e.g. using an appropriate anhydride), with cleavage of the R1-S bond and the -N-R4 Bond, to a compound of the formula
EMI4.1
 close the ring. The latter, primarily those in which Rla is a hydrogen atom and R2a is an acyl group, are resistant to various microorganisms, e.g. against gram-positive and gram-negative bacteria such as Staph. aureus, Proteus vulgaris and Bacillus megatheriimi, have an antibiotic effect and can be used accordingly.



   You can also use compounds of the formula. A with carboxyaldehyde compounds of the formula
EMI4.2
 wherein R is a carbon atom which, in addition to at least one hydrogen atom, contains optionally substituted aromatic and aliphatic hydrocarbon radicals such as phenyl and lower alkyl groups, or tautomers or reactive derivatives thereof, such as e.g. React hydrates or enols thereof, wherein the reaction is preferably carried out like the addition reaction described above.

  The compounds of the formula thus obtained
EMI4.3
 in which R, Rla, R2a, R5 and R4 have the meanings given above, where R stands in particular for a carbon atom which, in addition to at least one hydrogen atom, preferably contains one or two lower alkyl groups or one optionally as indicated above, e.g. by hydrocarbon radicals, such as lower alkyl groups, or by functional groups, such as etherified or esterified hydroxyl groups, e.g. Lower alkoxy groups or halogen atoms, or phenyl groups substituted by nitro groups, optionally also together with a lower alkyl group, or an acyl, e.g. an optionally substituted benzoyl group, containing as substituents, by treatment with a suitable acidic agent, e.g. Trifluoroacetic acid, ring closure.

  In compounds of the formula
EMI4.4
 where R is an optionally substituted hydrocarbon radicals, optionally substituted heterocyclic or heterocyclic-aliphatic radicals in which heterocyclic groups have aromatic character, or functional groups mono- or disubstituted carbon atom, an organic group R1 can be replaced by hydrogen and / or a hydrogen R1 and / or Usually by an organic group Rl or an acyl radical R2, in particular by a suitable acyl radical, replaced.

 

   Compounds of type (E), especially those in which R1 represents a hydrogen atom and R2 represents a suitable acyl radical of an organic carboxylic acid, especially one occurring in pharmacologically active 6-acylamino-penicillanic or 7-acylamino-cephalosporanic acid derivatives, have excellent properties various microorganisms, especially against gram-positive bacteria such as Staph. aureus and Proteus vlllgaris have antibiotic effects and can be used accordingly.



   The invention relates primarily to compounds of the formula
EMI4.5
  and
EMI5.1
 wherein R ', for a lower alkyl, such as methyl, ethyl or tert. -Butyl radical, a halo-lower alkyl, primarily a 2-halo-lower alkyl, such as 2,2,2-trichloro-ethyl radical, or a phenyl-lower alkyl, especially diphenylmethyl radical, R'2 is an acyl radical, especially the Acyl radical of an organic carboxylic acid, which occurs in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid, such as phenylacetyl, phenyloxyacetyl, phenylglycyl, thienylacetyl, for example, which have a protected amino group

   2-thienylacetyl, chloroethylcarbamoyl or cyanoacetyl radical, or then an easily cleavable acyl radical, in particular the radical of a half-ester of carbonic acid, such as a carbo-lower alkoxy, e.g. Carbo-tert-butyloxy radical and represents a hydrogen atom, each of the radicals R and R6 represents a lower alkyl, in particular methyl radical, and R'3 represents a 2-propenyl or 2-lower alkanoyloxy-2-propyl group.



   The i .- (2-carbo-lower alkoxy-3,3-dimethyl-7-oxo-4-thia-2,6-di-aza-6-bicyclo [3,2-O] heptyl) are particularly valuable as intermediates -z-hydroxy-acetic acid-lower alkyl ester, in which the lower alkyl radical of the ester group can optionally have one or more halogen atoms, preferably in the 2-position, and primarily for the tert-butyl or 2,2,2-trichloroethyl radical stands, while the carbo-lower alkoxy radical in the 2-position is preferably the carbo-tert-butyloxy radical.



   The compounds of the present invention can be obtained in a surprising manner if a 1-unsubstituted azetidin-2-one compound of the formula
EMI5.2
 where R2 represents an acyl radical, reacted with a glyoxylic acid ester or a reactive derivative thereof.

  If desired, the acyl group R, and in an available compound can be split off. if desired, acylated the free nitrogen atom in the compound thus obtained, and / or converted the ester compound obtained into the corresponding free acid compound, and, if desired, converted a free carboxylic acid compound thus obtained into a corresponding ester, and / or, if desired, a The compound obtained having a salt-binding group is converted into a salt or a salt obtained is converted into the free compound or into another salt, and / or, if desired, a mixture of isomers obtained can be separated into the individual isomers.



   The above reaction, i.e. the addition of the glyoxylic acid compound to the nitrogen atom of the lactam ring takes place preferably at an elevated temperature, primarily from about 50 ° C. to about 1500 ° C., in the absence of a condensing agent and / or without the formation of a salt. Instead of the glyoxylic acid compound, it is also possible to use a reactive oxo derivative thereof, primarily a hydrate, the water formed when the hydrate is used, if necessary, by distillation, e.g. azeotropic, can remove.



   It is preferred to work in the presence of a suitable solvent, e.g. Dioxane or toluene, or solvent mixture, if desired or necessary, in a closed vessel under pressure and / or in the atmosphere of an inert gas such as nitrogen.



   In a compound obtained, an acyl group R. in the 3-position in acidic medium, a carbo-tert. -butyloxy group e.g. by treatment with trifluoroacetic acid, a carbo-2,2,2-trichloroethoxy group also by treatment with nasal hydrogen, e.g. with zinc or a chromium (II) compound, such as chloride or acetate, in the presence of acetic acid containing water.



   In a compound thus obtained, the unsubstituted nitrogen atom in the 3-position can be removed by methods known per se, e.g. by treatment with carboxylic or sulphonic acids or acid derivatives thereof such as halides, e.g. Chlorides or anhydrides (which also include the internal anhydrides of carboxylic acids, i.e. ketenes, or of carbamic or thiocarbamic acids, i.e. isocyanates or isothiocyanates) or activated esters are acylated. If necessary, suitable condensing agents such as carbodiimides, e.g. Dicyclohexylcarbodiimide is used.



   In a compound obtained, an ester moiety can be converted to the free carboxyl group, e.g. a Carbodiphenylmethoxy- or Carbo-tert. -butyloxy group by treatment with an acidic reagent. such as trifluoroacetic acid, a carboxy group esterified with a 2-halo-lower alkanol, especially 2,2,2-trichloroethanol, and 2 iodine ethanol, can be obtained by treating with chemical reducing agents such as nascent hydrogen. receive e.g. by the action of metals, metal alloys or amalgams on hydrogen-releasing agents such as zinc, zinc alloys, e.g. Zinc copper. or Zinzamalgam in the presence of acids. such as organic carboxylic acids, e.g. Acetic acid, or alcohols. such as lower alkanols, alkali metal, e.g.



  Sodium or potassium amalgam or aluminum amalgam, in the presence of moist ether, furthermore by treatment with strongly reducing metal salts, such as chromium-II compounds, e.g. Chromium (II) chloride or chromium (II) acetate, preferably in the presence of aqueous media, containing organic solvents which are miscible with water, such as lower alkanols, lower alkanecarboxylic acids or ethers, e.g. Methanol, ethanol, acetic acid, tetrahydrofuran. Dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether.



   A free carboxylic acid compound obtainable in this way can be converted into its salts in a manner known per se, such as e.g. Alkali or alkaline earth metal or ammonium salts, or converted into their esters. Free carboxy groups can e.g. by treating with a diazo compound such as a diazo lower alkane, e.g. Diazomethane or diazoethane, or a phenyl-diazo-lower alkane, e.g. Phenyldiazomethane or diphenyldiazomethane, or by reaction with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide. e.g.

  Dicyclohexylcarbodiimide, as well as carbonyldiimidazole, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid.



  Acid halides such as chlorides (prepared e.g. by treatment with oxalyl chloride) or activated esters, e.g. those with N-hydroxy nitrogen compounds, or e.g. mixed anhydrides formed with haloformic acid lower alkyl esters, such as chloroformic acid ethyl esters, can be converted into esters by reaction with alcohols, optionally in the presence of a base such as pyridine.



   Mixtures of isomers obtained can be prepared by methods known per se, e.g. by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation processes, can be separated into the individual isomers. Racemates obtained can be processed in a conventional manner, e.g.



  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 separated into the antipodes by fractional crystallization from optically active solvents.



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



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



   Starting materials used according to the procedure. in which R and R together represent a disubstituted carbon atom are known. Others in which R is a removable organic radical and R4 is a hydrogen atom can e.g. can be obtained if the carboxyl group in a 6-N-acylamino-penicillanic acid compound is converted into an isocyanato group in a manner known per se. the compound so obtained with a 2-halo-lower alkanol, e.g. 2,2,2-trichloroethanol or 2-iodoethanol, treated and in the 6-acylamino-2- (2-halogen-lower alkoxycarbonylamino) -3,3-dimethyl-4-thia- 1 -azabicyc) o [ 3,2,0iheptan- -7-one compound the substituents in the 2-position by treatment with a chemical reducing agent, for example



  Zinc in the presence of 90 oily acetic acid splits. The corresponding 6-acylamino-2-hydroxy-3,3-dimethyl-4-thia-1-azabicyclo [3.2.0] heptane-7-one compound is obtained in this way, which when treated with a heavy metallacid oxidizing agent . in particular a lead IV carboxylate such as lower alkanoate, e.g. Lead tetraacetate, usually under illumination, preferably with ultraviolet light, can be converted into a 3-acylamino-2- (2-acyloxy-2-propylmercapto) -l-formyl-azetidin-4-one compound. If desired, the acyloxy group can be cleaved off by heating with the introduction of a double bond in the 2-propyl mercapto group together with a hydrogen atom in the form of the corresponding acid.

  The formyl group attached to one of the nitrogen atoms can be removed by treatment with an unsuitable decarbonylating agent such as a tris (tri-organically substituted phosphine) rhodium halide, e.g. Tris- (tri-phenylphosphine> -rhodium chloride, in a suitable solvent, for example benzene, or with conversion into the carbinol group, for example by treating with catalytically activated hydrogen in the presence of an acidic reagent, such as with hydrogen in the presence of a palladium catalyst and glacial acetic acid or hydrochloric acid tetrahydrofuran be removed.

  If desired, in a compound obtainable by the above process, the 2-acyioxy-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 residue can be replaced.



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



   Example I.
A solution of 3 g of 2-carbo-tert-butyloxy-3,3-dimethyl-4-thia-2,6-diaza-bicyclo [3.2, ojheptan-7-one in 23.3 ml of dry dioxane is with 5.2 g of glyoxylic acid-2,2,2 -trichloroethyl ester hyd rat added; the reaction vessel is closed and heated at a bath temperature of 950 for 7 hours. The slightly yellowish, clear reaction solution is diluted with 150 ml of benzene and washed three times with 150 ml of water each time, and any emulsions that arise can be broken in a simple manner by adding 20 ml of a concentrated aqueous solution of sodium chloride. The combined aqueous solutions are washed with 150 ml of benzene; the combined organic solutions are dried with sodium sulfate and evaporated under reduced pressure.

  The viscous residue is dissolved in 60 ml of a 3: 1 mixture of pentane and ether, the higher melting isomer of -, - (2-carbo-tert-butyloxy- -3.3-dimethyl -7-oxo-rl-thia- 2,6-diaza-6-birllo [3 .2, olheptyl) - - hydroxy-acetic acid - 2,2,2-trichloroethyl ester of the formula
EMI6.1
  crystallized in prisms which are filtered off at the beginning of the appearance of needle-shaped crystals and melt at 141-1460; analytical preparation: F. 146
147; [x] D2 "= -3070 + ia (c = 0.938 in chloroform); infrared spectrum (in methylene chloride) bands at 2.7, 5.6, 5.68, 5.85, 7.32, 8.65 and 9 , 4 u.



   The clear filtrate is evaporated and the residue is recrystallized from 50 ml of a 5: 1 mixture of pentane and ether, the lower-melting isomer of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7 -oxo-4-thia -2,6-diaza-6-bicyclo [3.2.0] heptyl) -α-hydroxy-acetic acid-2,2,2-trichloroethyl ester, which is obtained in colorless needles at 125 -1290 melts: analytical preparation:
F. 126-1290; [x] 1} = - 187 + 20 (c = 0.625 in chloroform); Infrared absorption spectrum (in methylene chloride) bands at 2.8, 5.6, 5.84, 7.3 and 7.36 and the like.



   Further crystalline material is obtained from the mother liquor after 2 days, which after recrystallization from a 3: 1 mixture of pentane and ether in prisms melts at 140-145 and with the higher-boiling one
Isomers is identical. A further amount of the needle-shaped, low-melting point is obtained from the filtrate
Isomers, m.p. 127.1310.



   Example 2
A mixture of 5 g of 2-carbo-tert-butyloxy-3,3-dimethyl-4-thia-2,6-diaza-bicyclo [3.2.0] heptan-7-one and the like. 5.5 g of tert-butyl glyoxylate hydrate in 40 ml of dioxane are stirred in a closed vessel at 950 for 131 hours 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 x- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 is obtained in this way -bi- cyclo [3.2.0] heptyl) -s: - hydroxy-acetic acid tert-butyl ester of the formula
EMI7.1
 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. 134.1370, being obtained: [; c] = 365 + 1 (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): characteristic bands at 2.94. 5.62, 5.77 and 5.85 and the like



   Example 3
A mixture of 0.05 g of the lower-melting isomer of a (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxO- -4-thia-2,6-diaza -6-bicyclo [3, 2.0] heptyl) -a-hydroxy-acetic acid-2,2,2-trichloroethyl ester (Example 1) in trifluoroacetic acid is kept at 200 for 5 minutes and then evaporated together with toluene. The residue is dissolved in methylene chloride, the solution is washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate and evaporated.

  The residue is crystallized from hexane and the z - (3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -a-hydroxy- acetic acid 2s2s2-trichloroethyl ester of the formula
EMI7.2
 F. 125-127; Infrared absorption spectrum with a characteristic band at 2.7.



   Example 4
A solution of 0.05 g of the higher-melting isomer of z- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo -4-thia -2,6-diaza-6-bicyclo [3.2 , 0] heptyl) -x-hydroxy-acetic acid-2.2,2-trichloroethyl ester (Example 1) in 3 ml of distilled trifluoroacetic acid is stirred for 5 minutes. then evaporated under reduced pressure without heating. The residue is mixed with saturated aqueous sodium hydrogen carbonate solution until neutralization and extracted with 20 ml of methylene chloride.

  The organic extract is dried and evaporated: the residue is recrystallized from a mixture of methylene chloride, ether and hexane; the isomer of z- (3,3-dimethyl-7-oxo-4-thia -2,6-diaza-6-bicyclo [3.2.0] heptyl) -x-hydroxy-acetic acid -2 obtained in this way, 2,2-trichloroethyl ester melts at 107-1090C, analytical preparation: F. 108-1100; tD2O = - 1760 + 2 (c = 0.513 in chloroform): infrared absorption spectrum (in methylene chloride): characteristic bands at 2.87, 3.02. 5.68. 7.33 and 9.08 L'l.



   Example 5
A solution of 0.25 g of tert-butyl glyoxylate in 5 ml of toluene is concentrated to a volume of about 3 ml under normal pressure. After cooling to 900, 0.069 g of 2x-isopropylmercapto-3a-N-phenyloxyacetyl-aminoazetidin-4-one is added and the mixture is diluted after 2 hours with 20 ml of benzene and washed three times with 20 ml of water each time, the aqueous washing solutions are mixed with Backwashed 10 ml of benzene u. the combined benzene solutions dried and evaporated.

  The residue is degassed at a pressure of 0.05 mm Hg: the amorphous mixture of the two isomers of a-hydroxy-a- (2a-isopropylmercapto-4-oxo-3a-N-phenyloxyacetylamino-1) is obtained -azeti dinyl) -acetic acid tert-butyl ester of the formula
EMI8.1
 which still contains a small amount of the glyoxylic acid tert-butyl ester hydrate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.83, 2.98, 3.05, 5.65, 5.78, 5.93, 6.26, 6.60.6.71.7.31, 8 , 65 and 9.23.u.



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



   The reaction mixture is treated with a solution of 0.51 g of sodium azide in 5.1 ml of water, stirred for 30 minutes at 0 to 5 and diluted with 150 ml of ice water. It is extracted three times with methylene chloride; the organic extracts are washed with water, dried and evaporated at 250 ° and under reduced pressure. The amorphous penicillin V-azide is thus obtained as a slightly yellowish oil; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 4.70, 5.61, 5.82 (shoulder), 5.93, 6.26, 6.61, 6.71. 8.50 and 9.40 for
A solution of 2.468 g of penicillin V azide in 30 ml of benzene is heated to 700 for 30 minutes.



  The pure 2-isocyanato-3,3-dimethyl-6 - - phenyloxyacetylamino) -4-thia-1-azabicyclo [3.2.0] -heptan-7-one can be obtained by evaporating the solution under reduced pressure ; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 4.46, 5.59. 5.93, 6.26, 6.62, 6.70, 7.53, 8.28, 8.53, 9.24 and 9.40 Lt.



   The above solution of 2-isocyanato-3,3.dimethyl.6.



  - (N -phenyloxyacetyl-amino) -4-thia-azabicyclo [3.2.0] heptan-7-one is treated with 3.4 ml of a 10 ml solution of 2 ml of 2,2,2-trichloroethanol added in benzene and the reaction mixture kept at 700 for 95 minutes. The solvent is removed under reduced pressure and the residue is purified on 40 ml of acid-washed silica gel (column. By-products are washed with 300 ml of benzene and 300 ml of a 19: 1 mixture of benzene and ethyl acetate, and the pure 2- (N-Carbo -2,2,2-trichloroethoxy-amino) -3,3-dimethyl-6- - (N-phenyloxyacetyl-amino) -4-thia-1 -azabicyclo [3.2.0] -heptan-7-one formula
EMI8.2
 with 960 ml of a 9: 1 mixture of benzene and ethyl acetate.

  After recrystallization from a mixture of ether and pentane, the product melts at 169-1710 (with decomposition); 20 D = +830 (c = 1.015 in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.5 in a 1: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.62, 5.77, 5.93, 6.27, 6.62, 6.70, 8.30, 9.23 and 9.50.



   The last. Fractions eluted with a 9: 1 mixture of benzene and ethyl acetate contain a small amount of the product isomeric with the above compound in the 2-position.



   A solution of 3 g of crystalline 2- (N-carbo-2,2,2 -trichloroethoxy-amino) -3,3-dimethyl-6- (N-phenyloxy-acetyl-amino) -4.thia- 1 - azabicyclo [3.2.0] heptan-7-one in 65 ml of 90% strength aqueous acetic acid and 30 ml of dimethylformamide are admixed with 32.6 g of zinc dust over the course of 20 minutes while cooling with ice and stirred for 20 minutes. The excess zinc is filtered off and the filter residue is washed with benzene; the filtrate is diluted with 450 ml of benzene, washed with a saturated aqueous sodium chloride solution and water, dried and evaporated under reduced pressure. The residue is purified on a column of 45 g of acid-washed silica gel. It is eluted with 100 ml of benzene and 400 ml of a 9: 1 mixture of benzene and ethyl acetate apolar products.

  Starting material is washed out with 100 ml of a 4: 1 mixture of benzene and ethyl acetate and with a further 500 ml of the 4: 1 mixture of benzene and ethyl acetate. and with 200 ml of a 2: 1 mixture of benzene and ethyl acetate, 2-hydroxy -3,3-dimethyl-6 - (N-phenyloxyacetyl-amino) -4 -thia-1-azabicyclo [3.2.0 ] heptan-7-one of the formula
EMI8.3
 which crystallizes spontaneously as a hydrate and, after trituration with water-saturated ether, melts indistinctly in the range of 62,850.



   If chromatographed but non-crystalline starting material is used and reduced in dilute acetic acid without the addition of dimethylformamide, the pure product is obtained, which melts at 62-70; Thin-layer chromatogram (silica gel): Rf = 0.35 in 1: 1
Mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.93, 3.09, 5.65, 5.96, 6.29, 6.65, 6.75,
8.57, 9.27, 10.00 and 11.95 a.



   A solution of 0.065 g of 3,3-dimethyl-2-hydroxy-6 - (N-phenyloxyacetyl-amino) -4-thial-t-azabicyclo [3.2.0] -heptan-7-one in 5 ml of benzene becomes with 0.15 g of lead tetraacetate containing 10% acetic acid, and the yellow solution is illuminated with a high pressure mercury vapor lamp (80 watts) in a water-cooled Pyrex glass jacket. After 10 minutes the yellow color disappears and a partly flaky white, partly rubbery yellow precipitate forms. It is diluted with benzene, washed with water, dilute aqueous sodium hydrogen carbonate solution and water and evaporated under reduced pressure.

  The 1 -formyl-2- (2-acetyloxy-2-propyl-mercapto) -3 - (N-phenyl-oxyacetyl-amino) -azetidin-4-one of the formula is obtained in this way
EMI9.1
 as a slightly yellowish, rubbery product; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.56, 5.78, 5.90, 6.27, 6.62, 6.71, 7.33, 7.67. 8.92, 9.24 and 9.82 ..



   A solution of 0.051 g of l-formyl-2- (2-acetyloxy-2- propylmercapto) - 3- (N-phenyloxyacetyl-amino) -azetidin -4-one in 3 ml of anhydrous benzene is mixed with 0.13 g of Tris - treated triphenylphosphine-rhodium chloride and refluxed for 3 hours. The initially red solution turns brown, with a small amount of precipitate forming. After cooling, this is filtered off and the filtrate is evaporated under reduced pressure. The residue is chromatographed on 5 g of acid-washed silica gel, with fractions of 5 ml each being removed. It is eluted with 10 ml of benzene, 30 ml of a 9: 1, 25 ml of a 4: 1 and 10 ml of a 1: 1 mixture of benzene and ethyl acetate, then with 25 ml of ethyl acetate.

  Fractions 2-6 give a rhodium complex with a strong CO absorption at 5.18 a in the infrared spectrum. A small amount of the l-formyl- -2- isopropenylmercapto-3 - (N-phenyloxyacetyl-amino) -azetidin-4-one can be isolated from fractions 10-12, while the 2-isopropenylmercapto- 3- (N-phenyloxy acetyl-amino) -azetidin-4-one of the formula
EMI9.2
 as an amorphous product.



   The product can be obtained in crystalline form if the eluting solution is filtered through 0.5 g of acid-washed silica gel and the product is eluted with a 1: mixture of benzene and ethyl acetate, mp 156-1580; [a] D2 "= 700 + 20 (c = 0.665 in chloroform); infrared absorption spectrum (in methylene chloride): characteristic bands at 3.07, 5.65, 5.96, 6.29, 6.59, 6, 74, 8.19, 9.25 and 9.92 and the like



   A solution of 0.08 g of 2a-isopropenylmercapto-3 -N-phenyloxyacetyl-amino-azetidin-4-one in 10 ml of ethyl acetate is mixed with 0.1 g of a 10% palladium-on-carbon catalyst and the mixture during Stirred for 45 minutes in a hydrogen atmosphere, then filtered. The filtrate is evaporated and the crystalline residue is recrystallized from a mixture of methylene chloride and ether. The 2a-isopropylmercapto -3- N-phenyloxyacetylamino-azetitidin-4-one of the formula is obtained in this way
EMI9.3
 that melts at 128-1309 and 1430 (double melting point); [D '= -480 + 10 (c = 0.785 in chloroform): infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.63, 5.93, 6.26, 6.58, 6.70, 8 , 15, 9.21 and 9.41, and the like



   Example 6
The anhydrous compound is obtained by concentrating a solution of 0.414 g of tert-butyl gly oxylic acid hydrate in 5 ml of toluene to a volume of 3 ml: the solution is at 900 with 0.128 g of 2a-isopropenylmercapto - 3a - (N - phenyloxyacetyl -amino) - azetidin -4-one added. The mixture is kept at 900 for 3 hours, after cooling it is treated with methylene chloride, washed with water, dried and evaporated under reduced pressure. The residue is chromatographed on 10 g of acid-washed silica gel.

  With a 4: 1 mixture of benzene and ethyl acetate, the amorphous mixture of the two isomers of a- -hydroxy - - [2a - isopropenylmercapto-4-oxo-3a- (N-phenyloxyacetyl-amino) - 1 - azetidinyl] tert-butyl acetic acid ester of the formula
EMI9.4
  receive; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95, 3.03, 5.62, 5.78, 5.91, 6.24, 6.60, 6.70, 7.25, 8.62 and 9 , 22! J.



   The cerium bonds that can be produced by the above process can be further processed as follows:
Example 7
A solution of 1.84 g of the higher melting isomer of sc- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2,% heptyl) - a - hydroxy-acetic acid-2,2,2-trichloroethyl ester in 20 ml of a 14 mixture of dry dioxane and tetrahydrofuran is mixed with 12 ml of a freshly prepared 1-molar solution of triethylamine in dioxane . The mixture is cooled to −15 and, with exclusion of atmospheric moisture, treated dropwise with 8 ml of a freshly prepared imolar solution of thionyl chloride in dioxane, then stirred at −150 for 5 minutes.

  After warming to room temperature u. Stirring for 10 minutes at 200 is diluted with 60 ml of toluene and the mixture is filtered through a glass filter. The clear filtrate is evaporated under reduced pressure and with a bath temperature below 45. The residue is dried for 2 hours at 250 / 0.01 mm Hg, then triturated three times with 60 ml of boiling pentane each time; the solution is stirred for 10 minutes with 0.3 g of an activated charcoal preparation and filtered through a glass filter.

  After evaporation, the residue is crystallized from pentane; the s :-( 2-carbo-tert-butyloxy-3,3-dimethyl- -7-oxo-4-thia-2,6-diaza-6-bicydo [3.2.0] heptyl) - obtained in this way 2,2.2-trichloroethyl α-chloro-acetic acid of the formula
EMI10.1
 after repeated recrystallization from pentane, it melts at 131-1360; Analysis preparation 130-1310; [w'0 = 3070 + 10 (c = 0.991 in chloroform); Infrared spectrum (in methylene chloride), bands at 5.60, 5.64 and 5.85 and the like.



   Example 8
A mixture of 12 g of the so-called. Polystyrene Hünig base "(prepared by heating a mixture of 100 g of chloromethyl polystyrene [J. Am. Chem. Soc. 85, 2149 (1963)]. 500 ml of benzene, 200 ml of methanol and 100 ml of di Isopropylamine to 1500 with shaking, filtering, washing with 1000 ml of methanol, 1000 ml of a 3:

  I 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: mixture of dioxane and water) in 50 ml of a 1: 1 mixture of dioxane and tetrahydrofuran is stirred for 30 minutes, then with a solution of 1.84 g of the higher melting point Isomers of α- (2-carbo- -tert.-butyloxy-3,3-dimethyl-7-oxo -4-thia-2,6-diaza-6-bi.



  cyclo 3.2.0] heptyl) - - hydroxyacetic acid - 2.2.2 - trichloroethyl ester in 5 ml of a 1: l mixture of dioxane and tetrahydrofuran. After the mixture has cooled to 15 while stirring, 8 ml of a freshly prepared l-m. Solution of thionyl chloride in dioxane added dropwise; the mixture is stirred for 10 minutes at -15 ± and then for 9 () minutes at 25. After filtering, the filter residue is washed three times with 30 ml of dioxane each time: the combined filtrates are evaporated at a bath temperature below 45.

  The viscous residue obtained is Oc- (2-carbo-tert-butyloxy-3.3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - 2,2,2-trichloroethyl α-chloroacetic acid, which, after recrystallization from 30 ml of pentane, melts at 130-1310.



   Example 9
A mixture of 6 g of a 1: 1 mixture of the isomers of z- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza -6-bicyloxy-3 , 2.0] heptvl) -z.-hydroxy-acetic acid tert-butyl ester and 10.5 g of the so-called polystyrene Hünig base (see Example 6) in a 1: 1 mixture of dioxane and tetrahydrofuran is stirred for 20 minutes . After cooling, it is treated dropwise over the course of 20 minutes with a solution of 6 g of thionyl chloride in 50 ml of dioxane, and the mixture is stirred at 209 for 140 minutes. then filtered.

  The filtrate is evaporated. the residue was taken up in 200 ml of pentane and the solution was treated with 1 g of an activated charcoal preparation. then filtered. This gives an approximately 1: 1 mixture of the isomers of x- (2-carbo-tert-butyloxy--3,3-dimethyl-7-oxo-thia-2,6-diaxa-6-bicyclo [3, 2.0] heptyl) - -r.-chloro-acetic acid tert-butyl ester of the formula
EMI10.2
 that is processed further without cleaning.

 

   Example 10
A solution of 0.165 g of os- (2-carbo-tert-butyloxy- -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0gheptyl) -X-chloro-acetic acid-2,2,2-trichloroethyl ester in 30 ml of dry ether is mixed with 0.22 g of dry lithium bromide and the suspension is stirred at 25 for 150 minutes. The filtered solution is diluted with 20 ml of pentane, then filtered again and evaporated. The residue is triturated with 20 ml of a 9: I mixture of boiling pentane and ether and filtered, and the clear filtrate is evaporated.

  The a- (2-carbo-tert-butyloxy -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -a is obtained in this way - 2,2,2-trichloroethyl bromoacetic acid ester of the formula
EMI11.1
 which after crystallization from pentane melts at 119-1200 (with decomposition).



   Example 11
A solution of 0.115 g of the crude mixture of the isomers of a-hydroxy-a- (2a-isopropylmercapto-4-oxo- -3a-N-phenyloxyacetyl-amino -1-azetidinyl) -acetic acid tert-butyl ester (about 0, 1 g of the two epimers) in 2.4 ml of anhydrous dioxane are mixed with 0.1 g <(Polystyrene Hünig base is added and the mixture is cooled to 0 while stirring. 0.06 g of thionyl chloride in 0.5 ml of dioxane is added, stirring is continued for 21/4 hours at room temperature and filtered; the filter residue is washed with dioxane and the The filtrate was evaporated under reduced pressure.

  The residue contains the mixture of the isomers of a-chloro-a- (2a-isopropylmercapto4-oxo -3Ya - N-phenyloxyacetylamino-1-azetidinyl) -acetic acid tert-butyl ester of the formula
EMI11.2
 which shows the following characteristic bands in the infrared absorption spectrum (in methylene chloride): 3.05, 5.63, 5.75, 5.93, 6.25, 6.70, 7.30 and 8.70 u.



   Example 12
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) -α-chloro-acetic 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) y or diisopropylaminomethyl-polystyrene, while Stirred at 550 for 17 hours under a nitrogen atmosphere, 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, with a further 4000 ml of the 3: mixture of hexane and ethyl acetate, the a- (2- carbo-tert-butyloxy-3,3- dimethyl-7-oxo-4-thia-2,6-diaza-6-hicyclo [3.2.0] heptyl) -a - (triphenylphosphoranylden) -acetic acid tert-butyl ester of the formula
EMI11.3
 eluted; a further amount of the impure product can be obtained with 1500 ml of the same solvent mixture.

  In the thin-layer chromatogram (silica gel; system: 1: 1 mixture of benzene and ethyl acetate) the product has an Rf value of 0.5 and crystallizes from a mixture of ether and pentane, mp 121-1220; = = -2190 + 10 (c = 1.145 in chloroform), ultraviolet absorption spectrum (in ethanol): i.max = 225 m (e = 30000) and 260 mu (± = 5400);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.76'a, 5.80 FL (shoulder), 5.97 St, 6.05 r (shoulder) and 6.17>. A further amount of the product can be isolated from the mother liquor by crystallization in an ether-pentane mixture.



   Example 13
A solution of 0.1 g of a- (2-Carbo-tert-butyloxy-3,3- -dimethyl-7-oxo-4-thia-2, 6-diaza-6-bicyclo [3.2.0] heptyl) -ia- -chloro-acetic acid-2,2,2-trichloroethyl ester in 3 ml of dry benzene (after treatment with sodium and filtering through aluminum oxide, neutral, activity 1) is mixed with 0.072 g of freshly distilled tri-n-butyl-phosphine treated and the mixture stirred for 25 hours at room temperature.

  The product obtained is chromatographed on silica gel, using a 9: 1 mixture of benzene and ethyl acetate to give the a- (2-carbo-tert-butyloxy -3,3-dimethyl-7-oxo -4-thia-2, 6-diaza-6-bi cyclo [3.2.0] heptyl) -1a- (tri-n-butyl-phosphoranylidene) -acetic acid 2,2,2-trichloroethyl ester of the formula
EMI12.1
 that is processed further without cleaning.



   Example 14
A mixture of 0.735 g of polystyrene Hünig base)) in 10 ml of dioxane (treated with neutral aluminum oxide, activity I) is treated with 0.34 g of triphenylphosphine recrystallized from hexane, then with 0.5 g of a- (2-carbo-tert. -butyloxy -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicydo [3,2, O] heptyl) - chloroacetic acid-2,2,2-trichloroethyl - Treated ester and stirred for 17 hours at 600 under a nitrogen atmosphere. The mixture is filtered through a glass filter, and the filter residue is washed twice with 5 ml of methylene chloride each time and once with 5 ml of benzene. The filtrate is evaporated to dryness under reduced pressure and the residue is chromatographed on silica gel.

  Triphenylphosphine, starting material and dehalogenated starting material are washed out with benzene and a 19: 1 mixture of benzene and ethyl acetate. The desired a - (2 - carbo-tert-butyloxy -3,3-dimethyl-7-oxo-4-thia-2,6- -diaza-6-bicyclo [3.2.0] heptyl) -? - (triphenyl-phosphoranyliden) -acetic acid-2,2,2-trichloroethyl ester of the formula
EMI12.2
 obtained with a 9: 1 mixture of benzene and ethyl acetate in oily form, which, after crystallizing twice from a methylene chloride-pentane mixture, melts at 2050; [a] 20 D = - 1920 + 10 (c = 1.054 in chloroform); Thin-layer chromatogram (Sillcagel):

  Rf 0.54 in the benzene-ethyl acetate system (3: 1); Ultraviolet absorption spectrum (in ethanol): = = 225 ma (± = 30100) and 265 mp (e = 5760); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65, 5.85 and 6.10 p. More polar components are washed out using a 4: 1 mixture of benzene and ethyl acetate.



   Example 15
A mixture of 0.104 g of a- (2-carbo-tert-butyloxy- -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] hep- tyl) -a-bromo-acetic acid-2,2,2-trichloroethyl ester and triphenylphosphine (1.3 equivalents) in 0.2 ml of benzene at 250 gives a colorless precipitate within 20 minutes. After one hour, it is filtered off and the precipitate is washed four times with 0.5 ml of a 1: 1 mixture of benzene and hexane and dried.

  The a- (2-CarbO-tert-butvloxy-3,3-dimethyl-7-oxo-4-thia -2,6-diaza-6-bicyclo [3.2.0] heptyl) - α- (triphenylphosphonium) -acetic acid-2,2,2-trichloroethyl ester bromide, which after treatment with aqueous sodium carbonate solution gives the crude a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo -4-thia-2, u-diaza-6-bicyclo [3,2,0heptyl-a- (triphenylphosphoranylidene) -acetic acid-2,2,2-trichloroethyl ester, which after crystallization from hexane on 201-2020 melts.



   Example 16
A solution of 0.115 g of the crude mixture of the isomers of α-chloro-α (2α-isopropylmercapto-4-oxo-N-phenyloxyacetyl-amino-1-acetidinyl) -acetic acid.



   tert-butyl ester in 2 ml of dioxane is admixed with 0.12 g of triphenylphosphine and 0.11 g of polystyrene Hünig base and the mixture is stirred at 550 for 16 hours, then filtered. The filter residue is washed with benzene and the filtrate is evaporated to dryness under reduced pressure. The residue is chromatographed on 5 g of acid-washed silica gel.

  The excess triphenylphosphine is washed out with 40 ml of benzene, and with a 1: 1 mixture of benzene and ethyl acetate, as well as with ethyl ester, the desired a- (2a-isopropylmercapto-4-oxo-3 N-phenyloxyacetyl-amino - 1 - azetidinyl) - x-triphenylphosphoranylidene-acetic acid tert-butyl ester of the formula
EMI12.3
 as a colorless oil; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.71, 5.94, 6.17, 6.58, 6.72, 7.34, 8.60 and 9.03 p.

 

   Example 17
A solution of 0.301 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 - 2,2,2-trichloroethyl ester and 0.3 g of liquid tert-butyl glyoxylate (mainly in the form of the hydrate) is stirred for 22 hours at 500, then diluted with benzene and washed with water , dried and evaporated under reduced pressure. The crude product is taken up in benzene and filtered through a column of 3 g of acid-washed silica gel. With 90 ml of benzene, the pure mixture of the isomers of o- (2-carbo- tert -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) - 0s - (carbo-tert-butyloxymethylene) -acetic acid-2,2,2-trichloroethyl ester of the formula
EMI13.1
 receive.

  Crystallization from ether gives isomer A, which melts after renewed recrystallization in 1890; [µC] 20 D = -3290 + 20 (c = 0.558 in chloroform); Thin-layer chromatogram (silica gel): Ff 0.64 in a 3: 1 mixture of benzene and ethyl acetate; Ultraviolet absorption spectrum (in ethanol): max = 270 mz E =
17600);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.611, 5.68 (shoulder), 5.75 p (shoulder), 5.87, 6.17, 7.27, 7.37, 8.70 and
9.32 cis crystallization of the mother liquor residue from an ether-pentane mixture results in a crystalline mixture of isomers, from which isomer B is obtained
Wash out with cold ether can remove; from the
After evaporation and crystallization of the filtrate from an ether-pentane mixture, the isomer B is obtained in fine needles, F. 119-1200: [^ X] D20 = ¯ -3630 + 10 (c = 1.213 in chloroform);

  Thin-layer chromatogram (silica gel):
Rf to 0.64 in a 3:: 1 mixture of benzene and ethyl acetate; Ultraviolet absorption spectrum (in ethanol): Xrnax 279 mm, (= 8900); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62, 5.75, 5.87,
6.15, 7.31, 8.65, 9.05 and 9.30.



   The above reaction can also be carried out as follows: A mixture of 5.04 g of a- (2-carbo-tert-butyl-oxy -3,3-dimethyl-7-oxo-4-thia-2,6-diaza -6-bicyclo [3.2.0] - heptyl) - sc - (triphenyl-phosphoranylidene) -acetic acid -2,2,2- -trichloroethyl ester in 15 ml of absolute toluene (prepared at 600) is stirred and in a nitrogen atmosphere with a solution of 4.5 g of tert-butyl glyoxylate in 10 ml of absolute toluene and during
Heated at 600 for 15 hours. After the
Solvent under reduced pressure, the oily residue in benzene is passed through a column (diameter:
3 cm; Height: 32 cm) filtered by 100 g of acid-washed silica gel.

  The pure mixture of the isomers A and B of a- (2-carbo-tert-butyloxy-3.3-dimethyl-7-oxo-4-thia- -2,6-diaza-6-bicydo [3.2,0] heptyl) -a- (carbo-tert-butyloxy methylene) -acetic acid-2,2,2-trichloroethyl ester is with
500 ml of benzene and an impure mixture of isomers with a further 750 ml of benzene were obtained. The pure isomer A, F. 1910, is obtained from the pure product by crystallization according to the process described above, the pure isomer B (F. 120 1210) from the mother liquor; from the impure mixture a further amount of
Isomers B are obtained.



   Example 18
A mixture of 0.035 g of a- (2-carbo-tert-butyloxy- -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] hep- thyl) - - triphenylphosphoranylidene) - acetic acid-2,2,2-tri chloroethyl ester and 0.036 g glyoxylic acid-2,2,2-trichloroethyl ester hydrate in 0.5 ml toluene is heated for 5 hours and under a nitrogen atmosphere at 500.



   After dilution with benzene and washing with water, a residue is obtained from the organic solution, which can be filtered through 0.7 g of acid-washed
Silica gel is cleaned. The mixture of the isomers of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2 , 0] heptyl) -? - (carbo-2,
2,2-trichloroethoxymethylene) -acetic acid-2,2,2-trichloroethyl ester of the formula
EMI13.2
 by washing out with 20 ml of benzene; Thin-layer chromatogram (silica gel): Rf 0.7 in a 3: 1 mixture of benzene and ethyl acetate. Crystallization from an ether-pentane mixture gives an isomer as a crystalline product which melts at 176-1770 and very probably has the configuration of maleic acid.



   Example 19
A solution of 0.212 g of sc- (2-carbo-tert-butyloxy- -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] hep- tyl) - - (triphenylphosphoranylidene) - acetic acid -2,2,2-trichloroethyl ester in 0.5 g of ethylene glycol dimethyl ether is reacted in a closed glass tube for 17 hours at 600 with glyoxylic acid ethyl ester hemiethylacetal. It is then diluted with 1 ml of xylene and evaporated under reduced pressure. The residue is chromatographed on silica gel (column 1.8 cm in diameter and 20 cm in length), eluting with a 95: 5 mixture of benzene and ethyl acetate.

  This gives a 5: 1 mixture of the two isomers of o- (2- -Garlo-tert-butyloxy -3,3-dimethyl-7-oxo-4-thia -2,6-di aza-6-bicyclo [3,2,0] heptyl) -a - (carbethoxymethylene) acetic acid 2,2,2-trichloroethyl ester of the formula
EMI14.1
 which, after recrystallization from pentane, melts at 950;
Ultraviolet Absorption Spectrum (in ethanol): #max = 277 m (= 10500); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.64, 5.85, 5.90 and 6.20 y.



   Example 20
A solution of 0.5 g of x- (2-carbo-tert-butyloxy-3,3- -dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -x- (triphenylphosphoranylidene) -acetic acid-tert-butyl ester in 5 ml of dry dioxane is reacted with 0.6 g of glyoxylic acid -2,2,2-trichloroethyl ester hydrate under a nitrogen atmosphere at 600 for 1 and 4 hours. The solvent is then removed under reduced pressure; the residue is diluted with 10 ml of benzene, the excess of glyoxylic acid ester crystallized out and filtered off. The filtrate is used three times
Washed 10 ml of water, backwashed the washing liquids with benzene and poured the organic solutions over
Dried sodium sulfate and evaporated.

  The crude product is chromatographed on silica gel (column 1.8 cm diam water and 15 cm height), one with
150 ml of benzene, 100 ml of a 49: 1 mixture and 100 ml of a 19: 1 mixture of benzene and ethyl acetate eluted.

  This gives a 4: 1 mixture of the two isomers of x- (2-carbo tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) -α- (carbo-2,2,2-trichloroethoxymethylene) -acetic acid tert-butyl ester of the formula
EMI14.2
 From the fractions which contain the majority of isomer A, this is obtained by crystallization from pentane, mp 130-131; [α] 20 D = -371 + 10 (c = 1.061 in chloroform); Thin-layer chromatogram (silica gel): Rf 0.5 in a 3: 1 mixture of benzene and hexane; Ultraviolet absorption spectrum (in ethanol): man = 287 mF (± = 10950);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65, 5.83, 5.90 and 6.20. The other isomer shows an Rf value of 0.3 in the thin-layer chromatogram.



   Example 21
A mixture of 4 g - (2-carbo-tert-butyloxy-3,3-dimethyl 7-oxo - 4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -o- - (triphenylphosphoranylidene) acetic acid tert. -butyl ester u.



  0.9 g of glyoxylic acid hydrate in 80 ml of absolute dioxane is kept for 3 hours at room temperature under a nitrogen atmosphere and then evaporated at a bath temperature of 450 under reduced pressure. The residue is dissolved in 150 ml of ether and then mixed with 40 ml of l-n. extracted aqueous sodium carbonate. The aqueous extracts are washed with 150 ml of ether, treated with 20 ml of a concentrated phosphate buffer solution (pH 6) and with 63.2 ml of 2-n.



  aqueous sulfuric acid acidified to pH 6-5, then extracted four times with 150 ml of ether each time. The ether extracts are dried over sodium sulfate and evaporated; the mixture of the isomers of o- (2-carbo- -tert.-butyloxy -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bi cyclo [3.2.0] heptyl) - - (carboxymethylene) acetic acid tert. butyl ester of the formula
EMI14.3
 which consists of about 65% of isomer A and 35% of isomer B.

  Chromatography on acid-washed silica gel elutes first the isomer A with a 4: 1 mixture of hexane and ethyl acetate, which, after three recrystallization from pentane, melts at 1300; [α] 20 D = 4570 + 10 (c = 1 in chloroform); Thin-layer chromatogram (silica gel; system toluene: acetic acid: water 5: 4 1):

  Rf = 0.40; Ultraviolet absorption spectrum (in ethanol): Àmax = 277 mu (E = 8850); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.55, 5.80, 5.95 and 6.25 µ; then isomer B, which, after crystallizing three times from pentane, melts at 1770; [a] 20 D = 4310 + 10 (c = 1.041 in chloroform); Thin-layer chromatogram (silica gel; system toluene: acetic acid: water 5: 4: 1): Rf = 0.47; Ultraviolet absorption spectrum (in ethanol): Amax = 270 m, u (E = 17,000); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65, 5.80, 5.95 and 6.25 Xu (strong).



   Example 22
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) - α- (triphenylphosphoranylidene) -acetic acid tert-butyl ester and the like.



  0> 7 g of benzylglyoxal (in enol form) in 30 ml of dry toluene is heated under a nitrogen atmosphere for 23 hours at 800 (bath temperature), then a further amount of 0.2 g of benzylglyoxal is added; the mixture is heated at 80 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, 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) -? - (phenylacetylmethylene) -acetic acid-tert-butyl ester of the formula
EMI15.1
 and washed out a more 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, with off.

  Fraction I the isomer A; M.p. 109-1100; [OC] 20 D = 4520 + 10 (c = 1 in chloroform); Thin-layer chromatogram: Rf = 0.49 (silica gel; in the hexane system:

  Ethyl acetate 2: 1); Ultraviolet absorption spectrum: Ainax 297 m (= 11000) (in ethanol), 337 ms (in potassium hydroxide / ethanol) and 337 mu (when acidifying a basic solution in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63, 5.83 p (shoulder), 5.85-5.95 ss and 6.29 y: and from fractions II and III the isomer B; F. 157-1580; [aJ20 = 3630 + 0.70 (c = 1 in chloroform); Thin layer chromatogram:

  Rf = 0.42 (silica gel; in the system hexane: ethyl acetate 2: 1); Ultraviolet absorption spectrum: ismax 294 with (s = 19300) (in ethanol), 335 m (potassium hydroxide / ethanol) and 335 m (when acidifying a basic solution in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63, 5.80 e (shoulder), 5.84-5.96 and 6.34 tt; is obtained. Further amounts of the two isomers can be isolated from the mother liquors in the same way.



   Example 23
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-bicyclo [3, 2.0] heptyl) -a- - (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) -oc- (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) - (phenylacetylmethylene) -acetic acid tert-butyl ester can be converted in the same way into isomer mixtures containing isomer A and isomer B of α- (2-carbo-tert-butyloxy - 3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - 0 '- (phenylacetylmethylene) -acetic acid tert-butyl ester are isomerized.



   Example 24
Treat 1 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicydo [3.2.0] heptyl) -α ; - (triphenylphosphoranylidene) - acetic acid - tert. - butyl ester under nitrogen with 0.65 g isopropylglyoxal (in enol form) in 7 ml toluene and left to stand at 900 for 8 days. The solvent and the excess of isopropylglyoxal are removed under reduced pressure at 500 and the residue is chromatographed on 50 g of acid-washed silica gel; it is washed 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-di-aza -6-bicydo [3.2.0] heptyl) -α- (isobutyryl-methylene) -acetic acid tert-butyl ester of the formula
EMI15.2
 washed out, which melts after crystallization from a mixture of hexane and ethyl acetate at 133-1340; Ultraviolet absorption spectrum: lmax 294 m, 'u (in ethanol); one 330 m, u (in potassium hydroxide / ethanol) and lmax 330 mu (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62p, 5.80 (shoulder); 5.84-5.94 and 6.26 p.



   The isomer B (cis) des - (2-Carbo.tert.-buty1oxy- -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclol3,2,0] heptyl ) - - (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 absorption spectrum: i.max 289 m (in ethanol); lmax 328 m (in potassium hydroxide / ethanol) and max 328 m (in hydrogen chloride / ethanol);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.60-5.66 and 5.75 (shoulder), 5.85-5.95 and 6.31.



   Example 25
A mixture of 0.05 g of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -? - (triphenylphosphoranylidene) -acetic acid tert-butyl ester and the like.



  0.0355 g of 4-Nitrobenzyl.glyoxal in 0.6 ml of toluene is 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 × 20 × 0.15 cm), developing with a 2: 1 mixture of hexane and ethyl 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) - α - - [(4 - nitro-phenylacetyl) - methylene] -acetic acid-tert-butyl.



  esters of the formula
EMI16.1
 with Rf value = 0.41; Ultraviolet absorption spectrum: iWmax 288 my (broad; in ethanol), and iWmnX 505 m. and 262 m (potassium hydroxide / ethanol); Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 5.63, 5.83 11 (shoulder), 5.88, 5.92 and 5.97 u (shoulder), 6.28 - 6.33 ,. 6.59 and 7.45 u; and the lower isomer B of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0 ] heptyl) -a - [(4-nitro-phenylacetyl) -methylene] -acetic acid tert-butyl ester of the formula
EMI16.2
 as yellow, glass-like products.

  Isomer B crystallizes from hexane, mp 1730; Rf value: 0.29; Ultraviolet absorption spectrum in ethanol:) max 293 m, u, and in potassium hydroxide / ethanol: #max 335 mF and 285 to the infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62, 5.77 (shoulder), 5.83
5.92, 6.30-6.35, 6.59 and 7.45 and the like
The 4-nitrobenzylglyoxal used as starting material above can be prepared as follows:

  A solution of about 4 g of diazomethane in 200 ml of dry ether is added dropwise with stirring with 6 g of 4-nitrophenylacetyl chloride in 80 ml of dry tetrahydrofuran, the temperature being kept at 0-50 by stirring in an ice-water bath. The addition is complete after about 30 minutes; the reaction mixture is stirred for a further 15 minutes at 0-50 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 4-nitrobenzyl-diazomethyl-ketone which, after crystallization from a mixture of ether and hexane, melts at 90-920: 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-hydrazono) -acetone crystallizes out at room temperature; one filtered u. concentrates the mother liquor from which a further amount of the desired product crystallizes.



  The crude product is made from a mixture of 50 ml
Methylene chloride and 250 ml of hexane crystallized, mp 160 1650; Ultraviolet Absorption Spectrum (in ethanol): 320 mii and 270-275 my (shoulder); Infrared absorption spectrum (in methylene chloride): characteristic bands at 6.10 (shoulder), 6.14-6.20, 6.32, 6.67-6.74 and 7.45.



   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 0-50 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 10 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, mp 163-1640; Ultraviolet absorption spectrum in ethanol:) imax 343 m, in potassium hydroxide / ethanol: 444 mp, and in hydrochloric acid / ethanol: #max 343 m; 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 a 9:

  I mixture of benzene and ethyl acetate, the hydrate of 4-nitrobenzylglyoxal as a non-crystalline, syrupy material; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.01, 5.82. 6.27, 6.61 and 7.47.



   Example 26
A mixture of 0.872 g of z- (2-carbo-tert-butyloxy- -3.3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - - (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 6172 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 z- (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, 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 [3.2.0] heptyl) -? - -r (4-nitro-phenylacetyl) - methylene] -acetic acid tert-butyl ester and with another 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- -ú-bicyclo [3,2,0] heptyl) - z- [(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. F. 1730.



   Example 27
A mixture of 0.714 g of a- (2-Carbo-tert-butyl oxy - -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0 ] hep- tyl) -x - (triphenylphosphoranylidene) acetic acid tert. Butyl ester and 0.67 g of 4-methoxybenzylglyoxal hydrate in 8.6 ml of toluene are heated at 800 for 372 hours. then evaporated under reduced pressure. The residue is chromatographed on 50 g of acid-washed silica gel.

  The excess of 4-methoxybenzyl-glyoxal in anhydrous form is washed out with 500 ml of benzene, while the almost pure isomer A of α- (2-carbo-tert) is washed out with 800 ml of a 99: 1 mixture of benzene and ethyl acetate .-Butyloxy-3,3-dimethyl-7- -oxo-4-thia -2.6-diaza-6-bicyclo [3,2, O] heptyl) -a - [(4-methoxy-phenylacetyl) -methylene] - Acetic acid tert-butyl ester of the formula
EMI17.1
 F. 105-107 after recrystallization from a mixture of ethyl acetate and hexane;

  Ultraviolet absorption spectrum in ethanol: kIIIaX 298 m, 288 mlu (shoulder) and 225 m (shoulder), and in potassium hydroxide / ethanol: #max 340 mLt; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63, 5.82 it (shoulder), 5.87-5.97 and 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 the? - (2 - Carbo-tert-butyloxy-3.3-dimethyl-7-oxo-4-thia-2,6- -diaza-6-bicyclo [3.2.0] heptyl) -? - [(4- methoxyphenylacetyl) - -methylene] acetic acid tert-butyl ester of the formula
EMI17.2
 washes out; the pure isomer B obtained from the mixed fraction and the pure fraction of the isomer B by recrystallization from hexane melts at 169-1700; Ultraviolet absorption spectrum: #max 289 m (wide) and 227 with (shoulder) (in ethanol), and #max 343 m, u (in potassium hydroxide / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59, 5.75 (shoulder), 5.80-5.93 and 6.24 u (shoulder), 6.30 and 6.6011.

 

   From the combined mother liquors, additional amounts of the two isomers A and B of x- (2-carbo-tert-butyloxy -3,3-dimethyl-7-oxo can be obtained from the combined mother liquors by means of preparative thin layer chromatography and development with a 2: mixture of hexane and ethyl acetate -4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- [(4-methoxy-phenylacetyl) -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 1 ounce ml of dry ether is added dropwise to a solution, cooled to 0-5, of 6 g of diazomethane in 3ij ml of ether. The reaction mixture is stirred for a further 30 minutes. last 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, the 4-methoxy-benzyl-diazomethyl-ketone is obtained; Infrared absorption spectrum (in methylene chloride): characteristic
Bands at 4.79. 6.10 and 6.92 (shoulder), 6.62 and 7.73-7.45 that is processed further without cleaning.



   A solution of 7.52 g of 4-methoxybenzyl-diazome thylketone 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. after a few minutes a crystalline precipitate forms, which is filtered off after an hour and washed with cold ether. This gives 1- (4-methoxyphenyl) -3- (triphenylphosphoranylidene-hydrazono) -acetone. that melts at 111-112-:

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.80, 6.05 (shoulder). 6.14 p. 6.24 lt (shoulder) and 6.63-6.70 tt; and is processed without further cleaning.



   A solution of 1.82 g of 1- (4-methoxyphenyl) -3- (triphenylphosphoranylidene-hydrazono) -acetone in 12 nil tetrahydrofuran is mixed with () .84 o powdered sodium nitrite and the mixture is diluted with 5 ml of water . The suspension obtained is cooled to 05, dropwise with 8.8 ml of 2-n over the course of 7 minutes.



  Treated hydrochloric acid and kept dinn for a further 30 minutes at 0-5. 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. With benzene, a small amount of a by-product is washed out and with
1200 ml of a 45: 5 mixture of benzene and acetic acid ether is obtained n the 4-methoxybenzylglyoxal mainly in the form of the hydrate. of the oily product: Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 2.96. 5.79-5.84. 6,13 and 6,63 1. The anhydrous product melts after recrystallization from a mixture of chloroform and hexane at 139-140; Ultraviolet absorption spectrum in ethanol or hydrochloric acid / ethanol: #max 333 m. and in potassium hydroxide / ethanol:, 367 mn; Infrared absorption spectrum (in methylene chloride): characteristic
Bands at 3.01). 5.79. 6.09. 6.24. 6.61 and 7.15.



      Example 8
A solution of 0.8 g of α- (2-carbo-tert-butyloxy-3.3- -d imethyl -7-oxo-4-thia-2,6-diaza-6.bicyclo [3.2.0] heptyl) - - Z-rtriphenylph osphoranylidene) -acetic acid tert-butyl ester and 1.2 g of the crude 4-chlorobenzyl glyoxal hydrate in 12 ml of toluene are heated at 800 for 5 hours.



  The solvent is distilled off under reduced pressure and the syrupy residue in about 4 ml
Benzene dissolved. 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 α- (2-carbo-tert-butyloxy-3,3) with 200 ml of benzene and 800 ml of a 97: 3 mixture of benzene and ethyl acetate -dimethyl-7-oxo-4-thia-2.6-diaza-6-bicyclo [3.2.0] heptyl) -α- [(4-chlorophenyl-acetyl) -methylene] -acetic acid tert-butyl ester isomers washed out. which is chromatographed on a further 50 g of acid-washed silica gel using benzene and benzene containing 5% ethyl acetate and then separated by preparative thin layer chromatography (system hexane: ethyl acetate 2: 1).

  The non-crystalline isomer A (trans) of z- (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
EMI18.1
 which shows the following bands in the ultraviolet absorption spectrum: # max 300 ml (in ethanol); # max 342 mu (in potassium hydroxide / ethanol); and ,, 338 with (when adding hydrogen chloride to the previous sample);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.60, 5.75 u (shoulder). 5.80-5.92 lt (wide). 6.26 and 6.70 u; and the crystalline 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) -? - [(4-chlorophenylacetyl) -methylene] -acetic acid tert-butyl ester of the formula
EMI18.2
 which, after recrystallization from hexane, melts at 178-179; Ultraviolet Absorption Spectrum: #max 295 m, u (In ethanol); one 337 m, u (in potassium hydroxide / ethanol); and A x 337 m (when hydrogen chloride is added to the previous sample);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59 y, 5.75 p (shoulder), 5.78-5.94, 6.07 (shoulder), 6.31 and 6.70 .. The isomer A becomes further processed without cleaning.



   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 at 5-100 for 30 minutes, the diazomethane and the solvent are distilled off under reduced pressure. The 4-chlorobenzyl-diazomethyl 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-hyd razono) -acetone thus obtainable melts at 130 1310; Ultraviolet Absorption Spectrum: #max 320 mu (ethanol); #max 320 m (potassium hydroxide / ethanol); and Man 255-278 m, u (broad shoulder) (in hydrogen chloride / ethanol;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.76 u, 6.03 u (shoulder), 6.12, 6.28 y (shoulder) and 6.65-6.75, u.



   A suspension of 8 g of 1- (4-chlorophenyl) -3- (triphenyl-phosphoranylidene-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 (10-130) dropwise over about 10 minutes with 37 ml of 2-n. Hydrochloric acid added. whereby 2 phases are 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 chromatographed on 60 g of acid-washed silica gel.

  The crude 4-chlorobenzyl glyoxal hydrate is extracted with benzene and a 95: 5 mixture of benzene and ethyl acetate; Ultraviolet Absorption Spectrum: #max 222 met (in ethanol); liliax 365 m (in potassium hydroxide / ethanol); and liliax 316 m (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.87-4.3, 5.77, 6.27 and 6.72; 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: liliax 316 mu (in ethanol); #max 3 364 mSt (in potassium hydroxide / ethanolj; and lnlax 316 mu (in hydrogen chloride / ethanol); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.92, 5.97, 6.07, 6.29 and 6.71 11.



   Example 29
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-7-oxo -4-thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) -α- (cyclohexylacetyl-methylene) -acetic acid tert-butyl ester of the formula
EMI19.1
 which is purified by means of preparative thin layer chromatography (plates 20 X 20 X 0.15 cm; silica gel; system benzene: acetone 98: 2) and obtained in a syrupy form; [D20 = 4510 + 10 (c = 0.87 in chloroform); Ultraviolet absorption spectrum: lmax 297 mu (in ethanol); #max 334 m (in potassium hydroxide / ethanol); and #max 334 with (when adding hydrogen chloride to the alkaline sample);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.45, 3.50, 5.16 and 5.78 (shoulder), 5.80-5.95 and 6.07 (shoulder) and 6.28.



   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) - - (cyclohexylacetyl-methylene) -acetic acid-tert. butyl ester of the formula
EMI19.2
 is eluted as the second product and crystallized from hexane, F.154-155); [α] D = -232 # 1 (c = 0.8 in chloroform); Ultraviolet absorption spectrum: #max 288 m (in ethanol), h ,,,,,, 333 mu (in potassium hydroxide / ethanol) and lmax 333 mii (when hydrogen chloride is added to the above alkaline sample);

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



   The cyclohexylmethylglyoxal hydrate used as starting material can be prepared as follows: A solution of 19.8 g of cyclohexyl acetyl chloride (bp.



     98-1000 / 23 mm Hg) in 150 ml of dry ether is slowly added to a vigorously stirred solution of 11 g of diazomethane in 500 ml of ether, while cooling to 0-5 in an ice-water bath. 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- (triphenylphosphoranylidene-hydrazono) -acetone available as an oily residue crystallizes in the cold from ether, mp 58-620; Ultraviolet absorption spectrum:); max 314 mF, 2.62, 2.75 mu and 223 mZ (in ethanol and in potassium hydroxide / ethanol). and Amax 257-275 my (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.43, 3.56, 4.76, 6.15 and 6.67 u.



   A mixture of 15 g of l-cyclohexyl-3- (triphenyl phosphoranylidene-hydrazono) -acetone and 7.37 g of sodium nitrite in 120 ml of tetrahydrofuran and 42 ml of water is slowly added to 77 with stirring and cooling to 10-130 (ice-water bath) 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 2.90-4.1 LL (broad); 3.47, 3.53 and 5.80! 1; and processed further without cleaning.



   Example 30
A solution of 2.55 g of the mixture of the isomers of cc- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) -x- (carboxymethylene) -acetic acid tert-butyl ester in 80 ml of a 9: 1 mixture of acetic acid and water is added every 15 minutes with 0.5 g of zinc dust until the reduction is complete Room temperature and mixed with vigorous stirring.



  After an hour, only a small amount of starting material can be detected; the addition of zinc dust is interrupted and stirring is continued at room temperature for 2 hours and then 60 ml of water and 60 ml of methylene chloride are added. It is filtered through cotton wool and then extracted four times with 100 ml of methylene chloride each time. The combined methylene chloride solutions are dried over sodium sulphate and evaporated at 450 under reduced pressure. The residue is repeatedly mixed with benzene and this is evaporated in each case until the acetic acid is completely removed.

  The crude residue is filtered through acid-washed silica gel (diameter: 4 cm; height: 10 cm), eluting with a 2: 1 mixture of hexane and ethyl acetate; the 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) <- - (carboxymethyl) -acetic acid-tert-butyl ester of the formula
EMI20.1
 which can be largely separated by crystallization from ether and hexane. The isomer A is obtained first, which, in somewhat impure form, melts at 169-1710 after recrystallization from the ether-hexane mixture.

  Analysis preparation: F. 172-1730; [a] 20 D = 2950: 1:10 (c = 1.168 in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.35 (system toluene: acetic acid: water 5: 1): infrared absorption spectrum (in methylene chloride): characteristic bands at 5.68, 5.72 and 5.901 l.



   The first mother liquor mainly contains isomer B, which can be purified as follows: A solution of 0.1983 g of the mother liquor residue containing isomer B in 5 ml of methylene chloride is mixed with 2.26 ml of a solution of 1.9836 g of cyclohexylamine in 100 ml Ether added and the solution evaporated. The residue is taken up in methylene chloride and filtered, the filtrate is evaporated and the residue is crystallized from a mixture of methylene chloride and acetone. The crystalline material thus obtainable and that of the first work-up of the mother liquor are dissolved in 5 ml of methylene chloride with 5 ml of water containing 0.5 ml of 2-n. Sulfuric acid, shaken and the aqueous phase washed back with 10 ml of methylene chloride.



  The organic solutions are washed with 10 ml of water. dried over sodium sulfate and evaporated to give the pure isomer B of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2 , 0] heptyl) - (carboxymethyl) - acetic acid - tert-butyl ester. F. 116-1170; a] = - 2520 + 10 (c = 0.924 in chloroform); Thin-layer chromatogram: Rf = 0.35-0.33 (system toluene: acetic acid: water 5: 4: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.68, 5.78 and 5.85-5.90, and the like.

 

   Example 31
A solution of 0.065 g of the isomer mixture of sc - (2-carbo-tert-butyloxy -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) a (carbethoxymethylene) -es sigsäure-2.2,2-trichloroethyl ester in 2 ml of a 4: 1 mixture of hexane and methylene chloride is at room temperature for one hour in a carbon monoxide-nitrogen atmosphere with about 2 molar equivalents of cobalt hydrocarbonyl in hexane offset. The reducing agent is prepared as follows: a solution of 0.39 g of dicobalt octacarbonyl in 10 ml of dry hexane is mixed with 3 ml of dimethylformamide under a nitrogen atmosphere and stirred for half an hour. A two-phase system is obtained, the upper layer is colorless, the lower red.

  Then, while cooling in an ice bath, 8 ml of a 1: 1 mixture of concentrated hydrochloric acid and 2-n. Hydrochloric acid was added and the mixture was stirred at 0 for one hour.



  The blue acid layer is peeled off and the yellow hexane solution is washed three times with 1 ml of water. The hexane solution contains 1.47 mmol of cobalt hydrocarbonyl u.



  is used in this form.



   The reaction mixture is then filtered through a column (height: 7 cm; diameter: 2 cm) of silica gel and washed out with benzene (cobalt derivatives) and with 20 ml of a 3: I mixture of benzene and ethyl acetate. A crude product is obtained from the latter mixture, which is in turn chromatographed on silica gel and eluted with 49: 1, 19: 1 and 4: 1 mixtures 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 is obtained ) -a- (carbäthoxymethyl) -acetic acid-2,2,2-trichloroethyl ester of the formula
EMI21.1
 which melts after crystallization from pentane at 900, and a mixture of isomer B with some isomer A, and a small amount of 2-carbo-tert-butyloxy-3.3- dimethyl-4-thia-2,6-diaza-bicyclo [3.2,0] heptan-7-one.



   Example 32
A hexane solution of 1.47 mmol of cobalt hydroxycarbonyl is mixed with 0.2 g of z- (2-carbo-tert-butyloxy-3.3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3,2,0] heptyl) -a- (carbo-tert-butyloxy.methylene) -acetic acid-2,2,2-trichloroethyl ester in 2 ml of a 4: 1 mixture of hexane and methylene chloride ; the reaction mixture turns dark brown. After 30 minutes at room temperature, filter through silica gel.

  The cobalt compounds are washed out with benzene until the silica gel is colorless, then it is eluted with a 9: 1 mixture of benzene and ethyl acetate, a mixture of the isomers of - (2-carbo-tert-butyloxy-3,3- - dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -ac- (carbo-tert-butyloxymethyl) -acetic acid -222-trichloroethyl ester of the formula
EMI21.2
 and with a 3: 1 mixture of benzene and ethyl acetate the 2-carbo-tert. -butyloxy-3.3-dimethyl-4-thia- -2,6-diaza-bicyclo [3,2,4] heptan-7-one eluted.

  By crystallization from a mixture of methylene chloride and
Pentane gives a mixture of the two isomers,
F. 95-1050, after a further crystallization the isomer A, F. 1080; [a] D20 = 2400 + 10 (c = 0.452 in
Chloroform); Ultraviolet absorption spectrum (in Etha nol):) * max = 230 ml, U (weak); Infrared absorption spectrum (in methylene chloride): characteristic bands at
5.65, 5.70, 5.85 and 5.90!
Example 33
A mixture of 0.0414 g of a- (2-carbo-tert-butyloxy -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] hep .



   tyl) -oG- (carbo-tert-butyloxy-methylene) -acetic acid-2,2,2-trichloroethyl ester in 4 ml acetic acid ethyl ester is in the presence of 0.0524 g of a 100% palladium-on-carbon Catalyst hydrogenated at 300 for 45 minutes under atmospheric pressure. After filtering, the filtrate is evaporated and the residue is passed through
Filter through 1.2 g acid washed silica gel purified. Apolar material is eluted with 15 ml of benzene and the main part of the isomer mixture the - (2-Carbo- -tert.-butyloxy -3,3-dimethyl-7-oxo - 4 - thia-2,6-diaza-6-bi - cyclo [3.2.0] heptyl) a (carbo-tert-butyloxy-methyl) -acetic acid.



   2,2,2-trichloroethyl ester with 5 ml of a 9: 1 mixture of benzene and ethyl acetate which, after crystallization from pentane, melts at 90-960.



   Example 34
A solution of 1.98 g of dicobalt octacarbonyl in
25 ml of hexane are mixed with 6 ml of dimethylformamide while stirring in a nitrogen atmosphere. After 30 minutes, two phases form, an upper yellow and a lower red. The mixture is cooled to 0, below
Stir with 10 ml of a 1: 1 mixture of 2-n. Hydrochloric acid and concentrated hydrochloric acid were added and kept at about 0 for one hour. The blue acid layer is peeled off, the mixture that remains is washed three times with 5 ml of water and then dried with a little sodium sulfate.



   A solution of 1.039 g of a- (2-carbo-tert-butyloxy -3,3-dimethyl -7-oxo -4-thia-2, 6-diaza-6.bicyclo [3.2.0] hep.



      tyl) -a- (carbo-tert-butyloxy methylene) -acetic acid-2,2,2-trichloroethyl ester in 3 ml of methylene chloride and 4 ml u
Hexane is in a nitrogen atmosphere with the cobalt hydrocarbo produced by the above process.



   Nyllösung added and the mixture stirred for 15 minutes at room temperature. then filtered through acid-washed silica gel. The column (2 cm diameter, height: 25 cm) is washed colorless with benzene and then the 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) - - (carbo-tert-butyloxymethyl) -acetic acid -2,2,2-trichloroethyl ester eluted with a 19: 1 mixture of benzene and ethyl acetate. Repeated crystallization from pentane gives isomer A, which melts at 108-1100; the mother liquor contains mainly a 1: 1 mixture of the two isomers.

  The isomer A has the following configuration:
EMI22.1

Example 35
A solution of 0.205 g of a- (2-carbo-tert-butyloxy--3,3-dimethyl-7-oxo-4-thia-2.6-diaza-6-bicyclo [3.2.0] heptyl) -a - (Carbo-tert-butyloxymethylene) -acetic acid-2,2,2-trichloroethyl ester (mixture of the two isomers) in 6 ml of a 4: 1 mixture of hexane and methylene chloride is under a nitrogen atmosphere at room temperature with 3 equivalents of cobalt hydrocarbonyl in 10 ml of hexane are added, then filtered through a column of silica gel (2 cm in diameter and 8 cm in length), cobalt compounds being washed out with benzene and reduction products with a 3: 1 mixture of benzene and ethyl acetate.

  The crude product is again filtered on silica gel (diameter of the column: 1 cm; height: 25 cm), prewashing with 100 ml of benzene, eluting an isomer of the starting material with 150 ml of a 99: 1 mixture of benzene and ethyl acetate, with 200 ml of a 49: 1 mixture of benzene and ethyl acetate the isomer B of a- (2 -carbo - tert.-butyloxy - 3,3-dimethyl-7-oxo-4-thia-, 2,6-di-aza - 6 - bicyclo [3.2.0] heptyl) - a - (carbo-tert.-butyloxymethyl) -acetic acid-2,2,2-trichloroethyl ester, followed by a mixture of the two isomers and by pure isomer B, and then with 80 ml of a 4:

  : 1 mixture of benzene and ethyl acetate a small amount of the 2-carbo-tert. -butyloxy-3,3-dimethyl -4-thia-2.6-diaza-bicyclo [3.2.0] heptan-7-one. The isomer B has the following configuration:
EMI22.2
 and, after crystallization from pentane, melts at 92-930; [a] 20 D = -1970 + 10 (c = 0.555 in chloroform); Ultraviolet absorption spectrum (in ethanol): weak absorption at 230-240 m;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65, 5.725 and 5.85-5.95 u
Example 36
A mixture of 0.035 g of the isomer A of a- (2- -Garbo-tert-butyloxy-3.3-dimethyl-7-oxo-4-thia-2,6-; liaza- -6-bicyclo [3.2, 0] heptyl) a (carbo-tert-butyloxymethyl) acetic acid 2,2,2-trichloroethyl ester (Example 34) and 2 ml of precooled trifluoroacetic acid are left to stand at 0 for 25 minutes. then evaporated under high vacuum and treated with 3 ml of a saturated aqueous solution of sodium acetate. The reaction mixture is extracted with methylene chloride, the organic solution is dried over sodium sulfate and evaporated.

  The residue crystallizes from a mixture of ether and pentane and gives the 3,3-dimethyl-7-oxo-4-thia-2.6-diaza-6-bicyclo [3.2.0] heptyl-z- (carbo-tert.- - butyloxy-methyl) -acetic acid-2,2,2-trichloroethyl ester of the formula
EMI22.3
 which melts at 136-1380; [a] D20 = -1120 + 20 (c = 0.625 in chloroform); Thin layer chromatography (silica gel): Rf = 0.25 in a 3: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.12. 5.74, 5.84 and 7.34 ,.



   Example 37
A mixture of 0.75 g of the isomer mixture of a- (2-carbo-tert-butyloxy -3,3-dunethyl-7-oxo4-thia-2,6- -diaza-6-bicyclo [3.2.0 ] heptyl) -a-carboxymethylene) -acetic acid tert-butyl ester in 20 ml of a 9: l mixture of acetic acid and water is treated within 31/2 hours with small amounts of a total of 4 g of zinc at room temperature, then with 20 ml of water are added and the mixture is filtered through cotton wool. It is extracted three times with 30 ml of methylene chloride each time. The organic extracts are dried over sodium sulphate and evaporated, acetic acid residues being removed azeotropically together with benzene under reduced pressure; the latter operation is repeated five times.

  The residue is filtered through a silica gel column (1.8 cm in diameter; 5.5 cm in height), eluting with a 1: 1 mixture of hexane and ethyl acetate and finally with ethyl acetate. A 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] hepty]) -? - (carboxymethyl) acetic acid tert-butyl ester. Crystallization from a mixture of ether and hexane at room temperature from a mixture of ether and hexane at room temperature gives isomer A which, after recrystallization from hexane (00), melts at 169-173 (analpsen preparation: 172-1730); [ajr> o = -2950 + 10 (c = 1.168 in chloroform);

  Thin layer chromatogram (silica gel): Rf = 0.35 in a 5: 4: 1 mixture of toluene, acetic acid and water; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.68, 5.72 and 5.90 p.



   The mother liquor from the above crystallization of the isomer mixture is concentrated and left to stand at room temperature for 16 hours, after which a further amount of isomer A is obtained. The filtrate is evaporated and made from hexane (00); 7 days) recrystallized; isomer B, F. 116-1170; [a] n20 = - 2520 + 10 (c = 0.924 in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.35-0.33 in a 5: 4 I mixture of toluene, acetic acid and water; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.68, 5.78 and 5.85-5.90 it.



   The separation of 0.583 g of the 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- (carboxymethyl) - -acetic acid tert-butyl ester can also be performed chromatographically on acid-washed silica gel (column: 3 cm diameter; and 35 cm height), using 300 ml of a 49: 1, 300 ml of a 19: 1, 450 ml of a 9: 1, 300 ml of a 4: 1, 300 ml of a 3: 1, 300 ml of a 2: 1 and 300 ml of a 1: 1 mixture of hexane and Ethyl acetate and 400 ml of ethyl acetate are used as eluting liquids.

  Isomer A is washed out with the 3: 1 and 2: 1 mixture before isomer B and, after crystallization from hexane, melts at 172-1730.



   An extensive separation of the two isomers A and B of oc- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo- -4-thia 2,6-diaza-6-bicyclo [3.2, 0] heptyl) -a- (carboxymethyl) -acetic acid tert-butyl ester can, for example can also be carried out if 0.1 g of the 1: 1 isomer mixture in 3 ml of methylene chloride with 1.16 ml of a 100 ml solution of 1.9836 g of cyclohexylamine, 'in ether (1 equivalent). The main part of the isomer A precipitates as a gel and is mixed with 2 ml of methylene chloride and 1.2 ml of water containing 0.12 ml of 2-n. aqueous sulfuric acid, shaken.

  The organic phase is washed with 2.5 ml of water and the aqueous phase with 2.5 ml of methylene chloride; the organic extracts are combined, dried over sodium sulfate and evaporated; a 7: 1 mixture of isomers A and B is obtained.



   Example 38
A mixture of 0.027 g of the isomer A of a- (2 -Garbo-tert-butyloxy-3,3-dimethyl-7-oxo4-thia-2,6-diaza -6-bicyclo [3.2.0] heptyl) - &alpha; - (Carboxymethyl) - acetic acid tert-butyl ester and 1 ml of pre-cooled trifluoroacetic acid are kept at -100 for 30 minutes, then evaporated at -100 under high vacuum and mixed with 10 ml of ether. The solution is washed once with 4 ml and once with 1 ml of saturated aqueous sodium hydrogen carbonate solution, then 4 ml of a saturated phosphate buffer solution (pH 6) are added and 3.75 ml of 2-n. aqueous sulfuric acid adjusted to pH 5-6. It is extracted twice with 10 ml of ether each time, the organic phase is washed once with 2 ml of water, dried over sodium sulfate and evaporated.

  The non-crystalline isomer A of a- (3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -? - (carboxymethyl) acetic acid tert-butyl ester of the formula
EMI23.1
 which in the thin layer chromatogram (silica gel) has an Rf =. 0.31 in a 5: 5: 1 mixture of toluene, acetic acid and water.



   Example 39
A mixture of 0.105 g of isomer B of oc- (2- -carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza- - 6-bicyclo [3.2 , 0] heptyl) - a - (carboxymethyl) - acetic acid -tert. Butyl ester and 2.5 ml of trifluoroacetic acid pre-cooled to 80 is held at -100 for 35 minutes, then evaporated under high vacuum. 40 ml of a 1: 1 mixture of saturated aqueous sodium hydrogen carbonate solution and ether are added to the crude product at 0; the ether phase is washed with 5 ml of saturated aqueous sodium hydrogen carbonate solution and 5 ml of water. then treated with 3 ml of a concentrated phosphate buffer solution (pH 6) and treated with 2-n.

 

  aqueous sulfuric acid adjusted to pH 5-6. then extracted 3 times with 15 ml of ether each time. The combined ether solutions are washed with 5 ml of water, dried over sodium sulfate and evaporated. After recrystallization from a mixture of ether, methylene chloride and hexane, the isomer B of a- (3,3-dimethyl-7'-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.olheptyl) - a- - (carboxymethyl) -acetic acid tert-butyl ester, mp 137-1380; [C: 1D2O = -1070 + 10 (c = 0.7 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.70, 5.78, 7.30 and 8.70 p.



   Example 40
A mixture of 0.025 g of the isomer B of 3,3-dimethyl-7-oxo4-thia 2,6-diaza-6-bicyclo [3.2.0] heptyl) a - (carboxymethyl) -acetic acid tert-butyl ester (Example 27) and 1 ml of trifluoroacetic acid is kept at 0 for 18 hours. then evaporated under reduced pressure and 1 ml of dioxane is added to the residue and an ethereal solution of diazomethane is added to saturation.

  After a reaction time of 3 minutes, it is evaporated under reduced pressure, the residue is filtered through a silica gel column (diameter: 0.8 cm; height: 10 cm), eluting with a 2: mixture of hexane and ethyl acetate; the isomer B of 3,3-dimethyl-7-oxo-4-thia -2,6-diaza-6-bicyclo [3.2.0] heptyl) -oc- (carbomethoxymethyl) acetic acid obtained as the crude product tert-butyl ester of the formula
EMI24.1
   Schmelztmach recrystallization from a mixture of ether, methylene chloride and hexane at 136-137.



   Example 41
A solution of 0.1056 g of the isomer A of z- (2- -carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicydo [3.2.0 ] hepty - (carbo-tert-butyloxymethyl) acetic acid 2,2,2-trichloroethyl ester in 1.6 ml of an 84:16 mixture (parts by weight) of trifluoroacetic acid and trifluoroacetic anhydride is added to 12 ml after standing for two hours at room temperature Treated acetic anhydride and, after standing for one hour at room temperature, evaporated under high vacuum without heating.



  The residue is dissolved four times in a mixture of methylene chloride and benzene and each time taken to dryness. The residue crystallizes from chloroform and gives the 7O: -trifluoroacetylammo-4,8-dioxbo-1-aza-5-thia-2p-bicyclo [4.2.0] octanecarboxylic acid -2,2,2-trichloroethyl ester of the formula
EMI24.2
 F. 175-1760; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.07, 5.60, 5.69, 5.79, 5.94 and 6.56 p.



   Example 42
A solution of 0.017 g of 7a-trifluoroacetylamineO-4,8- -dioxo-1-aza-5-thia-2, -bicyclo [4.2.0] octanecarboxylic acid 2.2, 2-trichloethyl ester in 1 ml of 90% strength Aqueous acetic acid is treated with 0.17 g of activated zinc dust within 5 minutes. After 50 minutes, 10 ml of ethyl acetate are added, the mixture is filtered and the filter residue is washed with 10 ml of ethyl acetate. The organic filtrate is washed with 4 ml of a saturated aqueous sodium chloride solution. dried and evaporated under reduced pressure.



  The oily 7a-trifluoroacetylamino-4,8-dioxo-1-aza-5-thia-2-bicydo [4.2.0] octanecarboxylic acid of the formula is obtained in this way
EMI24.3
 which has characteristic bands in the infrared absorption spectrum (in potassium bromide) at 5.64, 5.83, 5.95, 6.47, 7.12, 8.12, 8.60, 9.60 and 10.00 µ.



   This compound shows the effects indicated in the description against gram-positive and gram-negative microorganisms, in particular against Staph. aureus, Proteus vulgaris and Bacillus megatherium.



   Example 43
A solution of 0.05 g of the isomer B of a- (2- -Garbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-: diaza- -6-bicyclo [ 3.2.0] heptyl) - x - (carbo-tert-butyloxy-methyl) -acetic acid-2,2,2-trichloroethyl ester in 0.8 ml of an 84:16 mixture (parts by weight) of trifluoroacetic acid and. Trifluoroacetic anhydride is left to stand for 2 hours at room temperature and then 2 ml of acetic anhydride are added. After one hour (room temperature) the volatile components are removed under high vacuum without heating and the residue is dissolved in methylene chloride and benzene. The solution is taken to dryness and this process is repeated three times.

  The residue is crystallized from chloroform, the 7a-N-trifluoroacetylamino-4,8-dioxo-5-thia-1-azabicyclo [4.2.0] octane -2p-carboxylic acid-2,2,2-tri - chloroethyl ester of the formula
EMI25.1
 receives. The mother liquor is chromatographed on acid-washed silica gel, a further amount of the desired product being eluted with a 9: mixture of benzene and ethyl acetate and recrystallized from chloroform, mp 183-187; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.08, 5.61, 5.71, 5.79, 5.94 and 6.56 it.



   Example 44
A solution of 0.1211 g of the isomer A of a- (2-carbo-tert-butyloxy-3.3-d imethyl-7-oxo-4-thia-2,6-diaza -6-bicyclo [3.2.0] heptyl) -? - (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) is mixed with a solution of 0.129 g of phenyloxyacetyl chloride in 1 ml of dioxane.



   After standing for 2 hours at room temperature, 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 it becomes phenyloxyacetic acid and a small amount of a neutral material and with a 2-1 mixture of benzene and acetone it becomes 4-benzvliden-7 - N - phenyloxyacetylamino-8-oxo-5-thia - 1-Azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amine-cephalosporanic acid) of the formula
EMI25.2
 eluted. which, after recrystallization from a mixture of acetone and benzene, melts in the form of yellowish crystals at 191-193 (decomposition); Thin-layer chromatogram: Rf 0.36 (silica gel; in the system toluene / acetic acid / water 5: 4: 1);

  Ultraviolet absorption spectrum: in ethanol. #max 349 m and 250-265 m (shoulder): in potassium hydroxide / ethanol. #max 345 m and 250-265 with (shoulder); and in hydrogen chloride / ethanol, A 357 mu and 250-265 with (shoulder): infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90 11 (shoulder), 3.20-4.15, 5.62, 5.70 (Shoulder), 5.82-5.95, 6.00 Ft (shoulder), 6.10-5.15 and 6.23-6.33 (infection).



   Example 45
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-bicyclo [3.2, 0] heptyl) -? - (Phenylacetylmethylene) -acetic acid tert-butyl ester in 4 ml of precooled trifluoroacetic acid 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-ene-2-carboxylic acid (configuration of 7-Amino-cephalosporanic acid), with a solution of 0.5 freshly distilled phenylacetic acid chloride in 5 ml of dioxane.

  The reaction mixture is left to stand for 3 hours at room temperature. then mixed with 2 ml of water; it is left to stand for one hour at room temperature, then cooled to -10 and the volatile components are 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-thia-1-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7- Amino-cephalosporanic acid) of the formula
EMI25.3
 which, after recrystallization from 90% aqueous ethanol, melts at 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,) aX 353 ma and 250-265 mu (shoulder); in potassium hydroxide / ethanol. #max 347 my. 250-265 ma and 240 ms (shoulder): and in hydrogen chloride / ethanol, #max 358 m and 250-265 ma; Infrared absorption spectrum (in potassium bromide):

   characteristic bands at 3.00> (shoulder), 3.10-4.10, 5.65, 5.75 it (shoulder), 5.80, (shoulder). 5.90-5.95. 6.00 it (shoulder), 6.15, 6.24 u (shoulder), 6.28, a (shoulder), 6.55, 6.65 and 6.73 a (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 an additional amount of 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. 223-225.



   Example 46
A solution of 0.0917 g of the isomer A of cc- (2- -carbo-tert-butyloxy-3.3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2 , 0] heptyl) - ob - (phenylacetylmethylene) -acetic acid tert-butyl ester in 1 ml of precooled trifluoroacetic acid is left to stand for 21 hours at -20 ° C., then diluted with 7 ml of dioxane. The mixture obtained, containing the 7-amino-4-benzylidene-8-oxo-5-thia- 1 -azabicyclo [4, r, 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 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 formula
EMI26.1
 crystallizes from, m.p. 160-164; Thin-layer chromatogram: Rf 0.16 (silica gel; in the system toluene / acetic acid / water 5: 4: 1); Ultraviolet absorption spectrum: in ethanol, i. ,,,; ,, 354 mu and 250-265 m (shoulder); in ethanol / potassium hydroxide,} aX 346 mp, 250-265 ml and 240 m (shoulder), and in ethanol / hydrogen chloride, i., 357 m and 250-260 m (shoulder);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90 it (shoulder), 3.15-4.20, 5.63-5.71, 5.75 y (shoulder), 5.80-5.94, (inflection) , 6.00 u (shoulder), 6.04
6.13 and 6.40-6.70 it (inflection).



   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-thi-1-azabicyclo [4.2.0] oct-2 is eluted with a 4: I mixture of benzene and acetone -en-2-carboxylic acid, together with a neutral product that is enriched in the first fractions.



   Example 47
A suspension, cooled in ice water, of 0.0198 g of 4-benzylidene-7-N-phenylacetyl-amino-8-oxo-5-thia-1-aza-bicyclo [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-phenylacetyl-amino-8-oxo- -5-thia- l -azabicyclo [4.2.0] oct-2-en-2-carboxylic acid methyl ester (configuration of the 7- Amino-cephalosporanic acid) of the formula
EMI26.2
 melts at 193-195.50; [α] 20 D = -325 # 1 (c = 1 in chloroform); Thin-layer chromatogram: Rf = 0.22 (silica gel; in the hexane system:

  Ethyl acetate 2: 1); Ultraviolet absorption spectrum (in ethanol): Amax 360 m (s = 24800) and 262 m (s = 8100); #max 362 mp and 250 with (shoulder) (in potassium hydroxide / ethanol); and A À ,, lx 362 m and 250-265 mu (shoulder) (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.06, 5.62, 5.82, 5.95, 6.00 u (shoulder). 6.24, 6.30 u (shoulder), 6.62 (shoulder) and 6.65-6.73 p.



   Example 48
A mixture of 0.1158 g of cc- (2-carbo-tert-butyloxy- -3,3-dimethyl-7-oxo-4-thia-2.6-diaza.6-bicyclo [3.2.0] hep- tyl) -Os- (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-4-isopropylidene-8-oxo-5-thia-1-azabicyclo [4,2, O] oct-2-en-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-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-enecarboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI26.3
 is washed out with a 2: 1 mixture of benzene and acetone.

  It melts after crystallizing from benzene. containing a small amount of acetone, at 216-219; Infrared absorption spectrum: in ethanol, x, ", x 326 m; in potassium hydroxide / ethanol,? X 317 mu; and in hydrogen chloride / ethanol, #max 332 mez; infrared absorption spectrum (in potassium bromide): characteristic bands at 3.00 1l (shoulder) , 3.15-4.35, 5.60, 5.65 u (shoulder), 5.90, 6.04, 6.25, 6.30> (shoulder) and 6.45-6.55 u.



   Example 49
A mixture of 0.128 g of the isomer A of cc- (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 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-azabicydo [4.20] - oct-2-ene-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, 0.5 ml of water is 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-amino-8-ozo-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
EMI27.1
 which, after recrystallization from a mixture of acetone and benzene, melts at 202-204; Ultraviolet absorption spectrum in ethanol: max. 390 m / y and 273 m, (weak); in potassium hydroxide / ethanol: lmax 398 m and about 275 m, (weak); and in hydrogen chloride / ethanol: nIax 392 mlu and about 275 with (weak);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.9-4.2 (broad), 5.60-5.65, 5.80-6.0, 6.05, 6.25, 6.60 and 7, 45.



   Example 50
A solution of 0.023 g of crude 4- (4-nitro-benzylidene) -7-N-phenylacetylamino-8-oxo-5-thia- 1 -azabicyclo [4.2.0] oct -2-en- - obtained from crystallization mother liquor 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 means of thin layer chromatography (silica gel plate: 20 × 10 × 0.15 cm).



  being developed with a 2: I mixture of hexane and ethyl acetate and ethyl acetate alone. The orange band is extracted with ethyl acetate and this gives 4- (4-nitrobenzylidene) -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) of the formula
EMI27.2
 which crystallizes after standing for a long time, F. 185-187 (with decomposition);

  Ultraviolet absorption spectrum in ethanol: lmax 382 ini and 278 mu (shoulder), in potassium hydroxide / ethanol: Man 380 ms and 278 mZ (shoulder), and in hydrogen chloride / ethanol: man 378 mu and 278 m (shoulder); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 5.60, 5.81, 5.95, 6.24-6.30, 6.60-6.65, 6.70 a (shoulder) and 7 , 46 p.



   Example 51
A solution of 0.12 g of the isomer A of z- (2- -Garbo - tert-butyloxy -3,3-dimethyl -7-oxo-4-thia-2,6-di aza-6-bicyclo [3 , 2.0] heptyl) - oc - [(4-methoxyphenylacetyl) -methylene] -acetic acid tert-butyl ester in 1 ml of pre-cooled 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, O] 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] O 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-phenylacetyl-amino-8-oxo-5-thia-1-aza bicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7- Amino-cephalosphoric acid) of the formula
EMI27.3
 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 ma (shoulder), in potassium hydroxide / ethanol : Amax 356 ma and 272 m, (shoulder), and in hydrogen chloride / ethanol:); max 372 mu and 277 mu (shoulder);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.95 (shoulder), 3.014.40, 5.64-5.70, 5.75 u (inflection), 6.04-6.40, 6.28 and 6.61 u .



   Example 52
A mixture of 0.0052 g of 4- (4-methoxybenzylidene) 7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid ( Configuration of 7-amino-cephalosporanic acid) in 2 ml of methanol is mixed with 2 ml of a 27% 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-phenyl acetylamino-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
EMI28.1
 melts at 210-211 ': ultraviolet absorption spectrum in ethanol: Amax 378 m and 278 m (shoulder), in potassium hydroxydl / ethanol): liliax 376 mu and 278 mu (shoulder), and in hydrogen chloride / ethanol: in au 374 with; Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 3.02, 5.60, 5.80, 5.91, 6.26, 6.60-6.65 and 7.12 tv.



   Example 53
A solution of 0.232 g of the isomer A des% - (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia- -2.6-diaza-6-bicyclo [3.2, 0] heptyl) -X - [(4-chlorophenylacetyl) -methylene] -acetic acid tert-butyl ester in 2 ml of trifluoroacetic acid for 21 hours at 20 °. 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 which contains the 7-amino-4- (4-chlorobenzylidene) -8-oxo-5-thia- 1 -azabicyclo- [4.2.0] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephaiosporanic acid) contains.

  The reaction solution is kept at room temperature for 3 hours. then mixed with 0.3 ml of water and left to stand for one hour at room temperature. 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-azabi cyclo [4.2.0] oct-2 -en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI28.2
 eluted, which crystallizes in the form of yellowish crystals on addition of a little benzene and ethyl acetate, F. 226-227; Ultraviolet Absorption Spectrum: Amax 359 mu (in ethanol); Amax 351 m (in potassium hydroxide / ethanol) and Amax 362 mu (in hydrogen chloride / ethanol);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.85-4.30 Ft (broad), 3.20, 5.62, 5.88, 6.15, 6.26, 6.55 and 6.70 it.



   Example 54
A solution of 0.3285 g of the isomer A (trans) of x- (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 200 for 161 / hours. The reaction mixture containing the 7-amino-4-cyclohexylmethylene-8-oxo-5-thia- 1 -azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic 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 neutral substances are removed with a 100: 5 mixture of benzene and acetone, and the 4-cyclohexylmethylene-7-N-phenylacetylamino-8-oxo-5 is eluted with a 2: 1 mixture of benzene and acetone -thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI28.3
 which, after crystallization from benzene, melts at 120-1210; Ultraviolet absorption spectrum:

  : man 317 with (in Ethanol). #max ax 309 mla (in potassium hydroxide / ethanol) and 323 323 mu (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 3.45, 3.53, 2.85-4.3 p (broad), 5.6, 5.705.85 u (broad), 5.94 , 6.05, u (shoulder), 6.24 and 6.60-6.70 p.



   Example 55
A mixture of 0.4 g 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 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-colored residue containing the 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) is mixed with 4 ml of a solution, cooled to - 150, of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride. (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 -50, to a solution of 1.45, kept at 150, while stirring g of trichloroacetyl chloride in 3 ml of methylene chloride.

  This gives a suspension which at -150 with methylene chloride to a volume of
14 ml and used in this form). The
The reaction mixture is mixed with 2 ml of a solution of 0.3 ml
Acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride are added. 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 hydrochloric acid) and with concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure
Pressure a. About 1 ml of ethyl acetate is added to the residue and the mixture is carefully diluted with ether and then left to stand.

  This gives the crystalline 4-benzylidene-7-N-cyanoacetylamino-8-oxo-5-thia- -1 -azabicycla [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) the formula
EMI29.1
 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 225-2270 (decomposition);

  Ultraviolet absorption spectrum: Xmax 353 mu and 240-265 mll (broad shoulder) (in ethanol). ); ml.x 346 mu and 248 mu (shoulder) (in potassium hydroxide / ethanol) and Xmax 356 mlF and 247 m, u (shoulder) (in hydrogen chloride / ethanol); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90-4.20, 4.42, 5.60, 5.85-5.90, 5.98, 6.22 and 6.45.



   Example 56
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 7th -Amino-cephalosporanic acid) in about 2 ml of methanol is treated with a large excess of a 2% 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-Benz.ylidene-7-N-cyano-acetylamino-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
EMI29.2
 is obtained in crystalline form, m.p. 232-2340; Ultraviolet absorption spectrum:, mx 356 mF and 247-265 myx (broad shoulder) (in ethanol), Ämax 364 mu and 253 m (in potassium hydroxide / ethanol) and Àmax 364 mF and 254 mlt (when acidifying 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 L (shoulder).



   Example 57
A mixture of 0.328 g of cc- (2-carbo-tert-butyloxy--3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl ) - oc - (4-nitrophenylacetyl-methylene) -acetic acid tert-butyl ester and 3 ml of trifluoroacetic acid are left to stand at -200 for 44 hours.

  The trifluoroacetic acid is removed under reduced pressure (oil pump) and the residue containing the 7-amino-4- (nitrobenzylidene) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid (configuration of 7-amino-cephalosporanic acid), with 3 ml of a solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride (preparation see Example 55), followed by 1.5 ml of a solution of 0.3 ml of acetic acid and 1 ml Treated 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 treated with concentrated aqueous sodium chloride solution containing hydrochloric acid (10 ml of sodium chloride solution contain 1 ml of l-n.

  Hydrochloric acid) and washed 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-colored neutral component and with a 2: 1 mixture of benzene and acetone the amorphous yellow-orange 7-N-cyanoacetylamino - 4 - (4- nitro-benzylidene) -5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI30.1
   eluted; Ultraviolet absorption spectrum: X aX 388 mu u.



  275 mu (in ethanol), A Lx 453 mF and 263 mu (in potassium hydroxide / ethanol) and tmax 420 mss and 263 mu (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.



   Pharmacologically active compounds of the above type are preferably used in the form of pharmaceutical preparations which contain them in admixture with a solid or liquid pharmaceutical carrier material and which are suitable for enteral or parenteral administration. Suitable carriers. which behave inert towards the active substances are e.g. Water, gelatin, saccharides such as lactose. Glucose or sucrose, starches such as corn, wheat or arrowroot starch, stearic acid or salts thereof such as magnesium or calcium stearate, talc, vegetable fats and oils, alginic acid, benzyl alcohols, glycols or other known carriers. The preparations can be in solid form, e.g. as tablets, dragees, capsules or suppositories, or in liquid form, e.g. as solutions.

 

  Suspensions or emulsions are present. They can be sterilized and / or auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizers. Contains salts to regulate the osmotic pressure and / or buffers. They can also contain other pharmacologically usable substances. The pharmaceutical preparations can be produced in a manner known per se.

 

Claims (1)

PATENT CLAIM Process for the preparation of α-hydroxy-2-oxo-1-azetidinemethane-carboxylic acid compounds of the formula EMI30.2 wherein R1 is the organic radical of an alcohol of the formula Rl-OH, R. is an acyl radical, R3 is an organic radical and Rg is a hydrogen atom, or the two groups RQ and R4 together represent a disubstituted methylene group, as well as salts of such compounds with salt-forming groups, characterized in that one is an l-unsubstituted azetidin-2-one compound of the formula EMI30.3 with a corresponding glyoxylic acid ester or a reactive aldehyde derivative thereof. SUBCLAIMS 1. The method according to claim, characterized in that the reaction is carried out at an elevated temperature, primarily at 50oC to 1500C. 2. The method according to claim, characterized in that the reaction is carried out in the absence of a condensing agent. 3. The method according to claim, characterized in that the reaction is carried out without the formation of a salt. 4. The method according to claim, characterized in that the hydrate of the glyoxylic acid ester is used as the reactive aldehyde derivative thereof. 5. The method according to dependent claim 4, characterized in that the water formed is removed by distillation. 6. The method according to claim, characterized in that the acyl group R2 is split off in a compound obtained. 7. The method according to claim, characterized in that the ester compound obtained is converted into the corresponding free acid compound. 8. The method according to claim, characterized in that a compound obtained with a salt-forming group is converted into a salt or a salt obtained is converted into the free compound or into another salt. 9. The method according to claim, characterized in that an isomer mixture obtained is separated into the individual isomers. 10. The method according to claim, characterized in that starting materials are used in the form of a raw reaction mixer obtainable under the reaction conditions. 11. The method according to claim or one of the dependent claims 1-5 and 8-10, characterized in that compounds of the formula EMI31.1 wherein R'1 is a lower alkyl, halo-lower alkyl or phenyl-lower alkyl radical, R'2 is an acyl radical, and each of the radicals R5 and R6 is lower alkyl. 12. The method according to claim or one of the dependent claims 1-5 and 8-10, characterized in that compounds of the formula (Ia) shown in dependent claim 11, wherein R'1 is a lower alkyl or 2-halo-lower alkyl radical, R '2 denotes the acyl radical of an organic carboxylic acid, which occurs in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid or denotes the acyl radical of a half-ester of carbonic acid, and each of the radicals R5 and Rs represents a lower alkyl radical, manufactures. 13. The method according to claim or one of the dependent claims 1-5 and 8-10, characterized in that compounds of the formula (Ia) shown in claim 11, wherein R'1 is the tert-butyl radical or 2,2.2-trichloroethyl radical R'2 is the acyl radical of an organic carboxylic acid, which occurs in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid, or a carbon-lower alkoxy radical, such as carbo-tert-butyloxy radical, and each of the radicals R5 and R6 represent the methyl radical, produces. 14. The method according to claim or one of the dependent claims 1-5 and 8-10, characterized in that x- (2-carbon-lower alkoxy-3,3-dimethyl-7-oxo-4- thia -2,6- diaza - 6-bicyclo [3.2.0] heptyl) -a-hydroxy-acetic acid lower alkyl ester, in which the lower alkyl radical of the ester grouping can optionally have one or more halogen atoms, preferably in the 2-position, and primarily for the tert. Butyl or 2,2,2-trichloroethyl radical, while the carbo-lower alkoxy radical in the 2 position preferably represents the carbo-tert-butyloxy radical. 15. The method according to claim or one of the dependent claims 1-5 and 8-10, characterized in that x- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia -2 , 6- diaza -6-bicyclo [3.2.0] heptyl) -a-hydroxy-acetic acid-2.2,2-trichloroethyl ester. 16. The method according to claim or one of the dependent claims 1-5 and 8-10, characterized in that z- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia 26-diaza -6-bicyclo [3.2.0] heptyl) <-hydroxy- -acetic acid tert-butyl ester. 17. The method according to claim or one of the dependent claims 1-6 and 8-10, characterized in that - (3,3-dimethyl-7-oxo-4-thia-2,6-diazai-6-bicyclic [ 3,2,0] he.ptyl) -x-hydroxy-acetic acid -2,2,2-trichloroethyl ester.