CH511833A - 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 M-halo-2-oxo "1-azetichinmethanecarbonsäureestern
The present invention relates to a process for the preparation of esters of cc-hydroxy-2-oxo-1-azetidine methanecarboxylic acid esters of the formula I.
EMI1.1
 where R1 represents an optionally substituted aliphatic or araliphatic hydrocarbon radical, R represents an acyl radical, R3 represents an organic radical and R4 represents a hydrogen atom, or the two groups R3 and R4 together represent a disubstituted carbon atom and represents halogen.



   The group R1 can mean the organic radical of any alkanol, 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 and which 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 R 1 and R 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 hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkyl or optionally substituted phenyl mercapto or phenyl-lower alkyl mercapto, lower alkoxycarbonyloxy or lower alkanoyloxy groups, as well as halo be mono-, di- or poly-substituted by nitro groups, substituted amino groups, or functionally modified carboxyl 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, e.g. 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, as well as 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. like the abovementioned aliphatic hydrocarbon radicals, substituted Al, as well as alkene or alkyne, primarily lower alkanoic, as well as 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 cyclo aliphatic-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 monocyclic or bicyclic aromatic carboxylic acid which may optionally, e.g. 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. as the above-mentioned cycloaliphatic or aliphatic groups can 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. such as 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, cyclobutyl, 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 cycloheptylmethyl, ethyl, propyl, vinyl or allyl group, while a cycloalkenyl lower alkyl or lower alkenyl group is e.g. represents a 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl or 1-, 2- or 3-cycloheptenyl-methyl, -ethyl, -propyl, -vinyl or -allyl group.



   A phenyl-lower alkyl or phenyl-lower alkenyl radical 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 shown.



   A carbo-lower alkoxy radical is e.g. a carbomethoxy, carbethoxy, carbo-n-propyloxy, carbo-isopropyloxy 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 cycloalkenyl-lower alkanoic or lower alkene carboxylic acid e.g. denotes a cyclopentane, cyclohexane or 3-cyclohexenecarboxylic acid, cyclopentylpropionic, cyclohexyl acetic, 3-cyclohexenyl acetic or cyclohexyl acrylic acid. A mono- or bicyclic 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, fu ran-. Quinoline or isoquinoline carboxylic acids are nicotinic or isonicotinic acid, 2-thiophene, 2-fluorine, 2- or 4-quinoline or 1-isoquinoline carboxylic acid, and the corresponding pyridyl, furyl, thienyl, quinolyl or isoquinolyl lower alkane or lower alkene carboxylic acids, for example

 

  called 2-, 3- or 4-pyridyl acetic, 2-thienyl acetic, 2-furyl acetic or 2-furylacrylic acid.



   Optionally substituted aliphatic hydrocarbon radicals, especially lower alkyl groups, soft 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 trihalogenated 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 R ..



   5
Other substituted aliphatic hydrocarbon radicals, such as the aliphatic hydrocarbon radicals R5 substituted by hetero radicals in the linkage position, are primarily etherified or esterified hydroxyl groups in the linkage position
Lower alkyl groups, as in the corresponding position
Lower alkoxy or lower alkanoyloxy groups or lower alkyl groups containing halogen atoms, such as methyl, ethyl, propyl or isopropyl groups.

  These, as well as aliphatic hydrocarbon radicals R3 which are unsaturated in the linkage position, in particular the 2-propenyl radical, can preferably be removed under acidic conditions, an alkanoyl oxy group also under alkaline conditions, as well as by treatment with mercaptide-forming heavy metal, 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 (halogen atoms X are primarily chlorine, bromine and 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.



   Optionally substituted alkylsulfonyloxy groups are e.g. Methylsulfonyloxy-, ethylsulfonyloxy- or.



  2-hydroxyethylsulfonyloxy groups, optionally substituted phenylsulfonyloxy groups, e.g. 4-methylphenylsulfonyloxy, 4-bromophenylsulfonyloxy or 3-nitrophenylsulfonyloxy 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 can be used to produce valuable, primarily pharmacological, active substances
6 511 833 connections with a high quality. For example, starting from compounds of the formula I in which R1 is preferably a reductively cleavable organic radical of an alcohol, such as a 2-halo-lower alkyl, e.g. the 2,2,2-trichloroethyl radical, or then an organic radical of an alcohol which can be split off under acidic conditions, such as a methyl radical substituted 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 reaction with phosphine compounds of the formula P (Ra) (Rb) (R,), wherein each of the radicals Ra, Rb and Re represents an organic, in particular an aliphatic or aromatic radical, for example with triphenylphosphine or tributylphosphine, via the corresponding phosphonium salts, optionally with treatment with a basic agent, to form phosphorane compounds of the formula
EMI3.1
 arrive, in which R1a and R2a preferably represent the abovementioned removable radicals. These compounds are versatile starting materials of the Wittig type.

  So you can e.g. introduce an optionally functionally modified carboxymethylene radical by treating with glyoxylic acid compounds, preferably at elevated temperature (50-1500C) 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.

  The resulting double bond in a compound obtainable in this way can be treated 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 (II), 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 the 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
EMI4.1
 wherein Rd represents a hydrogen atom or one of the removable organic radicals of alcohols mentioned for the group R3a, optionally after cleavage of an acyl group RPa and / or conversion of an intermediate of the formula B, wherein 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 haloformic acid lower alkyl ester), or a lower alkanecarboxylic acid such as acetic acid (e.g. using a corresponding anhydride), with cleavage of the Rs-S bond and the -N-R4- Bond, to a compound of the formula
EMI4.2
 close the ring.

  The latter, primarily those in which R1 "stands for a hydrogen atom and R2a for an acyl group, are antibiotically effective against various types of microorganisms, for example against Gram-positive and Gram-negative bacteria such as Staph. AUreluS, Proteus vulgaris and Bacillus megatfteriunt and can be used accordingly.



   In addition, compounds of the formula A can be mixed with carboxyaldehyde compounds of the formula
EMI4.3
 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
EMI4.4
 wherein R, R1 ", R.a, Rs 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 stated 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 as a substituent can be obtained by treatment with a suitable acidic agent, e.g. Trifluoroacetic acid. close the ring.

  In compounds of the formula obtainable in this way
EMI4.5
 where R "is an optionally substituted hydrocarbon radical, 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 R, by hydrogen and / or a hydrogen R1 and / or R can be replaced by an organic group Rl or an acyl radical R-, in particular by a suitable acyl radical.

 

   Compounds of type (E), especially those.



  in which R 1 represents a hydrogen atom and R 2 represents a suitable acyl radical of an organic carboxylic acid, in particular one occurring in pharmacologically active 6-acylamino-penicillan or 7-acylamino-cephalo-sporanoic acid derivatives.



  against various types of microorganisms, in particular against gram-positive bacteria such as Staph. aureus and Proteus vulgaris have antibiotic effects and can be used accordingly.



   The invention relates primarily to compounds of the formula one in an α-hydroxy-2-oxo-l-azetidine methanecarboxylic acid ester of the formula II
EMI5.1
 converts the hydroxy group to a halogen atom X by treatment with a halogenating agent.



  If desired, a reactive esterified hydroxyl group in a compound obtained can be converted into another reactive esterified hydroxyl group and / or, if desired, a mixture of isomers obtained can be separated into the individual isomers.



   The above reaction is carried out by treating the starting material with a suitable halogenating agent such as a thionyl halide, e.g. chloride, a phosphorus oxyhalide, especially chloride, or a halophosphorus compound such as triphenylphosphonium dibromide or iodide, preferably in the presence of a basic, primarily an organic basic agent such as an aliphatic tertiary amine, e.g. Triethylamine or diisopropylethylamine, or a heterocyclic base of the pyridine type, e.g. Pyridine or collidine.



   It is preferred to operate in the presence of a suitable solvent, e.g. Dioxane or tetrahydrofuran, or a solvent mixture, if necessary, with cooling and / or in the atmosphere of an inert gas such as nitrogen.



   In a compound obtained according to the process, a halogen atom X can be added in a manner known per se, e.g. a chlorine atom by treating the corresponding chlorine with a bromine or iodine compound, in particular with an inorganic bromide or iodide salt such as lithium bromide, preferably in the presence of a suitable solvent such as ether, by another halogen, e.g. a bromine or iodine atom, can be exchanged.



   Mixtures of isomers obtained can be prepared by methods known per se, e.g. through fractional crystallization, adsorption chromatography (column or



  Thin-layer chromatography) or other suitable separation method, 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 by fractional crystallization from optically active solvents into the antipodes.



   The process also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the rest
EMI5.2
 and
EMI5.3
 wherein R1 is 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-trichloroethyl radical. or a phenyl-lower alkyl-.

   especially diphenylmethyl, R. ' an acyl radical, in particular 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-, an optionally substituted phenylglycyl-, lhienylacetyl-, eg 2-thienylacetyl, also the chlorine äthylcarbamoyl-, or cyanoacetyl, or then an easily cleavable acyl radical, especially the radical of a half ester of carbonic acid, such as a carbo-lower alkoxy, for example

  Carbo-tert.butyloxy radical represents. each of R. and Rf; is a lower alkyl, especially a methyl radical, R, 'is a 2-propenyl or 2-lower alkanoyloxy-2-propyl group and Hal is a chlorine or bromine atom.



   The z - (2 - carbo-lower alkoxy-3.3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) - oc - Hal are particularly valuable as intermediate products -Lower alkyl acetic acid ester, in which Hal has the meaning given above, and the lower alkyl radical of the ester grouping optionally, preferably in the 2-position. may have one or more halogen atoms. and primarily represents 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.



   The compounds of the present invention can be obtained in a surprising manner if union process steps are carried out with them, or the process is terminated at any stage: furthermore, starting materials can be used in the form of derivatives or formed during the reaction.



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



   The starting materials used according to the process are obtained by using a compound of the formula
EMI6.1
 with a glyoxylic acid ester or a reactive derivative, e.g. a hydrate, of which at increased
Temperature, primarily at about 500C to about
150 C, in the absence of a condensation agent and / or without the formation of a salt, which is produced when the hydrate is used
Water, if necessary, by distillation, e.g. azeo trop, can remove.



   The intermediates of the formula III used in the preparation of the starting materials, in which R.



   and R together represent a disubstituted carbon atom. are known. Others in which R3 is a removable organic radical and R4 is a hydrogen atom. can e.g. 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 thus obtained with a 2-halo-lower alkanol, e.g.

   2,2,2-trichloroethanol or 2-iodoethanol, treated, and in the 6-acylamino-2- (2-halogenniederalkoxycarbonylamino) -3, 3-dimethyl-4-thia- 1 -azabicyclo [3, 2, O] heptane -7- -one compound the substituent in the 2-position by treatment with a chemical reducing agent, for example



  Zinc in the presence of 90% acetic acid cleaves.



  The corresponding 6-acylamino-2-hydroxy-3,3-dimethyl-4-thia-1-azabicyclo [3.2.0] heptan-7-one compound is obtained in this way, which when treated with a heavy metal acylate oxidizing agent , especially 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-propylmereapto) -1-formyl-azetidin-4-one compound. If desired, the acyloxy group can be cleaved off 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 by heating.

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

  If desired, in a compound obtainable by the above process, the 2-acyloxy-2-propyl radical by treatment 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 1.84 g of the higher melting isomer of x- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo- -4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) oc-hydroxy-acetic acid-2,2,2-trichloroethyl ester in 20 ml of a 1: 4 mixture of dry dioxane and tetrahydrofuran is mixed with 12 mol of a freshly prepared 1 molar solution of triethylamine in dioxane offset. The mixture is cooled to -150 and treated dropwise with 8 ml of a freshly prepared 1 molar solution of thionyl chloride in dioxane with exclusion of atmospheric moisture, then stirred at -150 for 5 minutes.

  After warming to room temperature and stirring at 200 for 10 minutes, it 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 450. The residue is dried for 2 hours at 25 "/ 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 carbon preparation and filtered through a glass filter.

  After evaporation, the residue is crystallized from pentane: the resulting cc- (2- -Carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) - x-chloro-acetic acid-2,2,2-trichloroethyl ester of the formula
EMI6.2
 after repeated recrystallization from pentane, it melts at 131-1360; Analysis preparation 130-1310; [a] 20 = 3070 + 10 (c = 0.991 in chloroform); Infrared spectrum (in methylene chloride), bands at 5.60, 5.64 and 5.85.



   Example 2
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 diisopropylamine to 1500 with shaking, filtering, washing with 1000 ml of methanol, 1000 ml of a 3: 1 mixture of dioxane and triethylamine, 100 ml of methanol, 1000 ml of dioxane and 1000 ml of methanol and drying for 16 hours at 1000/10 mm Hg; the product neutralizes 1.55 Milliequivalents of hydrochloric acid per gram in a 2: 1 mixture of dioxane and water) in 50 ml of a 1:

   1-mixture of dioxane and terahydrofuran is stirred for 30 minutes, then with a solution of 1.84 g of the higher 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-hydroxyacetic acid -2,2,2-trichloroethyl ester in 5 ml of a 1: 1 mixture of dioxane and tetrahydrofuran. After the mixture has cooled to -150 while stirring, 8 ml of a freshly prepared 1-m solution of thionyl chloride in dioxane are added dropwise; the mixture is stirred for 10 minutes at -150 and then for 90 minutes at 250.

  After filtering, the filter residue is washed three times with 30 ml of dioxane each time; the combined filtrates are at one
Bath temperature below 450 evaporated. The viscous residue obtained is - (2-Carbo-tert.butyloxy-3,3-dimethyí - 7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -z- -chloro-acetic acid-2,2,2-trichloroethyl ester, which melts at 130-1310 after recrystallization from 30 ml of pentane.



   Example 3
A mixture of 6 g of a 1: 1 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) -α-hydroxy-acetic acid tert-butyl ester and 10.5 g of the so-called <ePolystyrene-Hünig base>) (see Example 2) in a 1: 1 mixture of dioxane and tetrahydrofuran is stirred for 20 minutes. After cooling, it is treated dropwise over 20 minutes with a solution of 6 g of thionyl chloride in 50 ml of dioxane and the mixture is stirred at 200 for 140 minutes, then filtered. The filtrate is evaporated, the residue is taken up in 200 ml of pentane and the solution is treated with 1 g of an activated charcoal preparation, then filtered.

  An approximately 1: mixture of the isomers of z- (2- -carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2b6-diaza-6-bicyclo [3.2, 0] heptyl) -α-chloroacetic acid tert-butyl ester of the formula
EMI7.1
 that is processed further without cleaning.



   Example 4
A solution of 0.165 g of α- (2-carbo-tert-butyloxy--3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl ) -? -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 250 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: 1 mixture of boiling pentane and ether and filtered, and the clear filtrate is evaporated. The α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6- - diaza-6-bicyclo [3.2.0] heptyl) -? -bromo-acetic acid-2,2,2-trichloroethyl ester of the formula
EMI7.2
 which, after crystallization from pentane, melts at 119-120 (with decomposition).



   Example 5
A solution of 0.115 g of the crude mixture of the isomers of α-hydroxy-α- (2α-isopropylmercapto-4-oxo-3a-N-phenyloxyacetyl-amino-1-acetidinyl) -acetic acid -tert.butyl ester (approx 0.1 g of the two epimers) in 2.4 ml of anhydrous dioxane are mixed with 0.1 g of <(polystyrene Hünig base)> and 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 the mixture is filtered; the filter residue is washed with dioxane and the filtrate is evaporated under reduced pressure.

  The residue contains the mixture of the isomers of the α-chloro-α- (2α-isopropylmercapto-4-oxo-α-N-phenyloxyacetyl-amino-1-acetidinyl) -acetic acid-tert-butyl ester of the formula
EMI7.3
 which shows the following characteristic bands in the infrared absorption spectrum (in methylene chloride): 3.05, 5.6311 ", 5.75, 5.93, 6.25, 6.70, 7.30 and 8.70.



   The starting materials used in the above examples can be prepared as follows:
Example 6
A solution of 3 g of 2-carbo-tert-butyloxy-3,3-dimethyl-4-thia-2,6-diaza-bicyclo [3.2.0] heptan-7-one in 23.3 ml of dry dioxane 5.2 g of glyoxylic acid-2,2,2-trichloroethyl ester hydrate are 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 occur 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.butyl-oxy - 3,3-dimethyl-7-oxo-thia-2 , 6-diaza-6-bicydo [3 2.0] - heptyl) - hydroxy-acetic acid-2,2,2-trichloroethyl ester of the formula
EMI8.1
 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. 1461470; X] D20 = 3070 1 10 (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 p .



   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 sc- (2-C: arbo-tert-butyloxy-3,3-dimethyl-7 -oxo- -4-thia-2,6-diaza-6-bicyclo [3,2,0] heptyl) hydroxy-acetic acid-2,2,2-trichloroethyl ester, which melts in colorless needles at 125-1290 ; analytical preparation: F.



  126-1290; [] D20 = -1870 + 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 y.



   After 2 days, further crystalline material is obtained from the mother liquor which, after recrystallization from a 3: 1 mixture of pentane and ether in prisms, melts at 140-1450 and is identical to the higher-boiling isomer. A further amount of the needle-shaped, low-melting isomer, mp 127-1310C, is obtained from the filtrate.



   Example 7
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 5.5 g of glyoxylic acid tert-butyl ester hydrate in 40 ml of DiS oxane is stirred in a closed vessel for 13/2 hours at 950 and then evaporated. The residue is dissolved in 1000 ml of pentane, washed three times with 500 ml of water and once with 200 ml of a saturated aqueous sodium chloride solution, dried over dry sodium sulfate and evaporated.

  This gives 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- bicyclo [3.2.0] heptyl) -a-hydroxy-acetic acid-tert-butyl ester of the formula
EMI8.2
 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, mp 134-1370, being obtained; [D50 = -3650 + 10 (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 p.



   Example 8
A solution of 0.25 g of the glyoxylic acid tert-butyl ester hydrate 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-phenyloxyacetylamino-azetidin-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 backwashed with 10 ml of benzene and the combined benzene solutions are dried and evaporated.

  The residue is degassed at a pressure of 0.05 mm Hg; the amorphous mixture of the two isomers of the x-hydroxy-, x- (2a-isopropylmercapto-4-oxo-3a-N-phenyloxyacetylamino-1-acetidinyl) -acetic acid tert-butyl ester of the formula is obtained
EMI8.3
  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 g, 5.78, 5.93, 6.26, 6.60, 6.71, 7.31 and 8, 65, and 9.23.



   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 ethyl chloroformate in tetrahydrofuran are slowly added at -10 and, after the addition is complete, the mixture is stirred at -10 to -5 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 00 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, 430, 5.61, 5.82, u (shoulder), 5.93, 6.26, 6.61, 6.71, 8.50 and 9 , 40.



   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 - (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan-7-one can be obtained by evaporating the solution under reduced pressure receive; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 4.46, 5.59, 5.93, 6.26, 6.62, 6.70, 7.53y, 8.28, u, 8.53, 9.24 y and 9.40, u-
The above solution of 2-isocyanato-3,3-dimethyl-6 - (N-phenyloxyacetyl-amino) -4-thia-azabicyclo [3.2.0] heptan-7-one is mixed with 3.4 ml of a 10 ml solution of 2 ml 2,2,2-trichloroethanol in benzene was added and the reaction mixture was 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). It is washed with 300 ml of benzene and 300 ml of a 19: 1 mixture of benzene and ethyl acetate by-products and the pure 2 - (N-carbo-2,2,2-trichloroethoxy-amino) -3,3-dimethyl-6- - (N - phenyloxyacetyl-amino) -4-thia-1 -azabicyclo [3,2,0] - heptan-7-one of the formula
EMI9.1
 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); [a] 0 = +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, 5.77p, 5.93, 6.27, 6.62 lt 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] heptane) -7-one in 65 ml of 90% strength aqueous acetic acid and 30 ml of dimethylformamide are mixed 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 a further 500 ml of the 4: 1 mixture of benzene and ethyl acetate and 200 ml of a 2: 1 mixture of benzene and ethyl acetate are obtained the 2 - hydroxy-3,3-dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan-7-one of the formula
EMI9.2
 which crystallizes spontaneously as a hydrate and, after trituration with water-saturated ether, melts 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 62-700; Thin-layer chromatogram (silica gel): Rf = 0.35 in a 1: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.93, 3.09>, 5.65 y, 5.96, 6.29, 6.65 lt 6.75, 8.57 lt 9.27, 10.00 lt and 11.95.



   A solution of 0.065 g of 3,3-dimethyl-2-hydroxy-6 - (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [3.2.0] -heptan-7-one in 5 mol 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-phenyloxyacetyl-amino) -azetidin-4-one of the formula is obtained in this way
EMI10.1
 as a slightly yellowish, rubbery product; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05 u, 5.56, 5.78, 5.90 u, 6.27, 6.62 u, 6.71, 7.33 u, 7.67 u, 8.92>, 9.24> and 9.82.



   A solution of 0.051 g of 1-formyl-2- (2-acetyloxy -2-propylrnercapto) -3 - (N-phenyloxyacetyl-amino) -azetidin-4-one in 3 ml of anhydrous benzene is mixed with 0.13 g of tris-triphenylphosphine treated rhodium chloride and refluxed for 3 hours. The initial 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, fractions of 5 ml each being taken. 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 u in the infrared spectrum. A small amount of 1-formyl-2-isopropenylmercapto-3- (N-phenyloxy-acetyl-amino) -azetidin-4-one can be isolated from fractions 10-12, while 2-isopropenylmercapto is isolated from fractions 15-17 -3- (N-phenyloxyacetyl-amino) -azetidin-4-one of the formula
EMI10.2
 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: 1 mixture of benzene and ethyl acetate, F.



     156 1580; [zjo = 700 +20 (c = 0.665 in chloro form); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.07, 5.65 u, 5.96 lt, 6.29 u, 6.59, 6.74, 8.19, 9.25 p and 9.92 u
A solution of 0.08 g of .2ee-isopropenylnnercapto-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 for 45 minutes stirred in a hydrogen atmosphere, then filtered.

  The filtrate is evaporated and the crystalline residue is recrystallized from a mixture of methylene chloride and ether. This gives the 2-isoprnpyimereapto-3 - N - phenyloxyacetylaminoazetidin-4-one of the formula
EMI10.3
 that melts at 128-1300 and 1430 (double melting point): [: C] D20 = -48 t 10 (c = 0.785 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05 u, 5.63, 5.93, 6.26, 6.58, 6.70 Lt, 8.15 u, 9.21 St and 9.41 Lt.



   The compounds obtainable by the process illustrated above can be e.g. process as follows:
Example 9
A solution of 11.3 g of a crude mixture of the isomers of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3? , 0] heptyl) - - chloroacetic acid tert-butyl ester in 150 ml of absolute dioxane is mixed with 11.4 g of triphenylphosphine and 10.8 g of polystyrene Hünig base or diisopropylaminomethyl-polystyrene, stirred for 17 hours under a nitrogen atmosphere at 55 ", then cooled and filtered through a glass filter.

  It is washed with 100 ml of benzene; the filtrate is evaporated under a water jet vacuum; the residue is dried under high vacuum, dissolved in 100 ml of a 9: 1 mixture of hexane and ethyl acetate and chromatographed on a column (height 48 cm; diameter 6 cm) with acid-washed silica gel.

  With 2000 ml of a 3: 1 mixture of hexane and ethyl acetate, triphenylphosphine and a little triphenylphosphine sulfide are converted into α- (2-carbo-tert-butyloxy-3,3 with a further 4000 ml of the 3: 1 mixture of hexane and ethyl acetate -dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3,2,0j heptyl) -oc- (triphenylphosphoranylidene) -acetic acid tert. butyl ester of the formula
EMI10.4
 eluted; a further amount of the impure product can be obtained with 1500 ml of the same solvent mixture.

  The product has an Rf value of 0.5 in a thin layer chromatogram (silica gel; system: 1: 1 mixture of benzene and ethyl acetate) and crystallizes from a mixture of ether and pentane, mp 121-1220; [] 20 D = -2190 + 10 (c = 1.145 in chloroform); Ultraviolet absorption spectrum (in ethanol): = = 225 mSt (s = 30,000) and 260 mm (e = 5,400); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.7611, 5.80 a (shoulder), 5.97 u, 6.05 (shoulder) and 6.17 p. A further amount of the product can be isolated from the mother liquor by crystallization in an ether-pentane mixture.



   Example 10
A solution of 0.19 g of sc- (2-carbo-tert-butyloxy-3,3- -dimethyl-7-oxo-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - 2,2,2-trichloroethyl chloroacetate in 3 ml of dry benzene (after treatment with sodium and filtering through aluminum oxide, neutral, activity I) is treated with 0.072 g of freshly distilled tri-n-butyl-phosphine and the mixture for 25 Stirred for hours at room temperature.

  The product obtained is chromatographed on silica gel, using a 9: 1 mixture of benzene and ethyl acetate to give z- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6 -di aza-6-bicyclo [3, 2.0] heptyl) - x - (tri-n-butyl-phosphoranylidene) -acetic acid-2,2,2-trichloroethyl ester of the formula
EMI11.1
 that is processed further without cleaning.



   Example 11
A mixture of 0.735 g of polystyrene Hünig base) y 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 x- (2-carbo-tert. - butylox y-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo- [3.2.0] heptyl) - - chloro - acetic acid-22,2-trichloroethyl ester treated 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 x - (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo -4-thia - 2,6 - diaza-6-bicyclo [3,2,0] heptyl) - - (triphenyl - phosphoranylidene) acetic acid 2,2,2-trichloroethyl ester of the formula
EMI11.2
 is 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; [5GID2 "= - 1920 + 10 (c = 1.054 in chloroform); thin layer chromatogram (silica gel):

  Rf - 0.54 in the benzene-ethyl acetate system (3: 1); Ultraviolet absorption spectrum (in ethanol): Xrnax = 225 with (s = 30,100) and 265 m (# = 5760); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65, 5.85 and 6.10. More polar components are washed out using a 4: 1 mixture of benzene and ethyl acetate.



   Example 12
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] heptyl ) -x-bromo-acetic acid-2,2,2-trichloroethyl ester and triphenylphosphine (1.3 equivalents) in 0.2ml benzene at 25 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-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -? - (triphenyl- phosphonium) - acetic acid -2,2,2-trichloroethyl ester bromide, which after treatment with aqueous sodium carbonate solution gives the crude x- (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, which after crystallization from hexane at 201-2020 melts.



   Example 13
A solution of 0.115 g of the crude mixture of the isomers of α-chloro-α- (2-isopropylmercapto-4-oxo - - N - phenyloxyacetyl-amino-1-azetidinyl) -acetic acid tert-butyl ester in 2 ml of dioxane 0.12 g of triphenylphosphine and 0.11 g of polystyrene Hünig base are added 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 - (2a-isopropylmercapto-4-oxo- -3a - N - phenyloxyacetyl-amino- 1 -azetidinyl) -a-triphenyl-phosphoranylidene-acetic acid tert-butyl ester of the formula togramm (silica gel): Rf ¯ 0.64 in a 3: 1 mixture of benzene and ethyl acetate; Ultraviolet absorption spectrum (in ethanol):) max 279 mlt = 8900): Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62, 5.75, 5.87, 6.15, 7.31, 8.65, 9 , 05 y and 9.30.



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

  The pure mixture of the isomers A and B of z- (2-Carbo-tert-butyloxy-3, 3- -dimethyl -7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0 ] heptyl) - - α- (carbo-tert-butyloxymethylene) - acetic acid -2,2,2 - trichloroethyl ester is obtained with 500 ml of benzene and an impure mixture of isomers with a further 750 ml of benzene. The pure isomer A, F. 1910, is obtained from the pure product by crystallization according to the process described above, the pure isomer B (M. 120-1210) from the mother liquor; A further amount of isomer B can be obtained from the impure mixture.



   Example 15
A solution of 2 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - a - (triphenylphosphoranylidene) -acetic acid tert-butyl ester u.



  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 800 for 22 hours.



  The solvent is removed under reduced pressure and the viscous residue is chromatographed on a column containing 60 g of acid-washed silica gel. With 450 ml of benzene, the excess benzylglyoxal, with 250 ml (10 fractions) of a 95: 5 mixture of benzene and ethyl acetate, a mixture of the isomers of a - (2 - carbo-tert-butyloxy-3,3-dimethyl-7-oxo- 4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - a.- (phenylacetylmethylene) -acetic acid tert-butyl ester of the formula
EMI12.1

EMI12.2
 as a colorless oil; Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 3.05 t ±, 5.71, 5.94 u, 6.17 iu, 6.58, 6.72, 7.34 y, 8.60 y and 9,03.



   Example 14
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] hep tyl) - - (triphenylphosphoranylidene) -acetic acid-2,2,2-trichloroethyl ester and 0.3 g liquid glyoxylic acid tert-butyl ester (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.

  The pure 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 - (carbo-tert.butyloxyme thylen) -acetic acid-2,2,2-trichloroethyl ester of the formula
EMI12.3
 receive.

  Crystallization from ether gives isomer A, which melts after renewed recrystallization in 1890; [a] n20 = -3290 + 20 (c = 0.558 in chloroform): Thin-layer chromatogram (silica gel): Rf ¯ 0.64 in a 3: l mixture of benzene and ethyl acetate: Ultraviolet absorption spectrum (in ethanol): #max = 270r e ( 5 = 17,600); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.61.

 

  5.68 (shoulder), 5.75 (shoulder), 5.87 tt, 6.17, 7.27 e, 7.37 + ,, 8.70 p and 9.32. Crystallization of the mother liquor residue from an ether-pentane mixture results in a crystalline isomer mixture from which isomer B can be removed by washing with cold ether; after evaporation and crystallization from an ether-pentane mixture, the isomer Bin fine needles is obtained from the filtrate, mp 119-1200; [µC] .D20 = 3630 + 10 (c = 1.213 in chloroform); Thin layer chrome and washed out a more polar material with another amount of the same solvent mixture.



   The above isomer mixture 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 III consisting mainly of isomer B .

  The above three fractions are recrystallized from hexane, from fraction I the isomer A; F. 109-1100; [a] 20 D = 4520 + 10 (c = 1 in chloroform); Thin-layer chromatogram: Rf = 0.49 (silica gel; in the system hexane: ethyl acetate 2: 1); Ultraviolet absorption spectrum: Smax 297 ma (B = 11,000) (in ethanol), 337 m (in potassium hydroxide / ethanol) and 337 mIt (when acidifying a basic solution in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63 lF, 5.83 lt (shoulder), 5.85-5.95 p and 6.29 and from fractions II and III the isomer B;

  F. 157-1580; [, a] 20 D = -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: one 294 mIt (s = 19,300) (in ethanol), 335 m (potassium hydroxide / ethanol) and 335 mlu (when acidifying a basic solution in ethanol); Infrared absorption spectrum (in methylene chloride); characteristic bands at 5.63, 5.80 lt (shoulder), 5.84, 5.96 lt and 6.34 '; is obtained. Further amounts of the two isomers can be isolated from the mother liquors in the same way.



   Example 16
A solution of 1.98 g of dicobalt octacarbonyl in 25 ml of hexane is 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 00, 10 ml of a 1: 1 mixture of 2N hydrochloric acid and concentrated hydrochloric acid are added while stirring and the mixture is kept at about 0 for one hour. The blue acid layer is peeled off, the mixture which 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] heptyl ) va- (carbo-tert.butyloxymethylene) -acetic acid-2,2,2-trichloroethyl ester in 3 ml of methylene chloride and 4 ml of n hexane is added in a nitrogen atmosphere with the cobalt hydrocarbonyl solution prepared by the above process and the mixture during 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-bicy- clo [3.2.0] heptyl) - a - (carbo-tert-butyloxymethyl) -acetic acid-2,2,2-trichloroethyl ester with a 19: 1 mixture of benzene and acetic acid ethyl ester eluted. Repeated crystallization from pentane gives isomer A, which melts at 108-1100: the mother liquor mainly contains a 1: 1 mixture of the two isomers.

  The isomer A has the following configuration:
EMI13.1

Example 17
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, 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, an isomer of the starting material with 150 ml of a 99: 1 mixture of benzene and ethyl acetate, eluted with 200 ml of a 49: 1 mixture of benzene and ethyl acetate, the isomer B of M- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia- -2,6-diaza-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 pure isomers B, and then with 80 ml of one 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 13.2, - 0] heptan-7-one . The isomer B has the following configuration:
EMI13.2
 and, after crystallization from pentane, melts at 92 to 930; [: C] 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 lot 5.725 Lt and 5.85-5.95 u
Example 18
A solution of 0.1056 g of isomer A of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) -α- (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 after two hours Standing at room temperature treated with 12 mol of 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 7sc-trifluoroacetylamino -4,8-dioxo-1-aza-5-thia-2ss-bicyclo [4.2.0] octanecarboxylic acid 22,2-trichloroethyl ester of the formula
EMI14.1
 F. 175-1760; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.07, 5.60 e, 5.69 u, 5.79 Lt, 5.94 u and 6.56 a.



   Example 19
A solution of 0.017 g of 7x-trifluoroacetylamino-4,8- dioxo-1-aza-5-thia-2-bicyclo [4.2.0] octanecarboxylic acid -2,2,2-trichloroethanol ester-trichloroethyl ester in 1 ml 90 % 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 7x-trifluoroacetylamino-4,8-dioxo-1-a2a-5-thia-2p-bicyclo [4.2.0] octanecarboxylic acid of the formula is obtained in this way
EMI14.2
 the bands characteristic of the infrared absorption spectrum (in potassium bromide) at 5.64Cl. 5.83, 5.95, u, 6.47 a, 7.12 Lt '8.121, w, 8.60, 9.60 iu and 10.00 Cl.



   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 20
A solution of 0.05 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) -α- (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 added for 2 hours Let stand room temperature and then mixed with 2 ml of acetic anhydride. 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 7α-N-trifluoroacetylamino-4,8-dioxo-5-thia-1-azabicyclo [4.2.0] octane-25-carboxylic acid-2,2,2- trichloroethyl ester of the formula
EMI14.3
 receives. The mother liquor is chromatographed on acid-washed silica gel, a further amount of the desired product being eluted with a 9: 1 mixture of benzene and ethyl acetate and recrystallized from chloroform, F. 183-1870:

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.08 u, 5.61 Lt, 5.71), 5.79, 5.94 Lt and 6.56 Lt
Example 21
A solution of 0.1211 g of the isomer A of x- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2 , 0] heptyl) - z - (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-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid ) a solution of 0.129 g of phenyloxyacetyl chloride in 1 ml of dioxane is added.

  After standing at room temperature for 2¸ hours, the reaction mixture is treated with 1 ml of water and left to stand for a further hour.



  The volatile components are removed by lyophilization under high vacuum and the residue is chromatographed on 9 g of acid-washed silica gel. With a 100: 5 mixture of benzene and acetone, phenyloxyacetic acid and a small amount of a neutral material, and with a 2: 1 mixture of benzene and acetone, the 4-benzylidene-7-N-phenyloxyacetylamino-8-oxo- 5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI15.1
 eluted which, after recrystallization from a mixture of acetone and benzene, melts in the form of yellowish crystals at 191-1930 (decomposition); Thin layer chromatogram:

  Rf 0.36 (silica gel; in the system toluene / acetic acid / water 5: 4:: 1); Ultraviolet absorption spectrum: in ethanol,?, A 349 mp and 250 - 265 m (shoulder); in potassium hydroxide / ethanol, v nY 345 with and 250 to 265 m (shoulder): and in hydrogen chloride / ethanol.



     #max 357 mIt and 250 - 265 m (shoulder); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90 (shoulder), 3.20-4.15, 5.62, 5.70 (shoulder), 5.82-5.95 *, 6.00 (shoulder) , 6.10-6.151x and 6.23 - 6.33 Lt (inflection).



   Example 22
A solution of 0.5625 g of the isomer A of: t- (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 -200 and for one hour at room temperature. It is diluted with 30 ml of dry dioxane and the mixture, containing the 7-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid ( Configuration of 7-amino-cephalosporanic acid), with a solution of 0.5 g of freshly distilled phenylacetic acid chloride in 5 ml of dioxane.

  The reaction mixture is left to stand for 3 hours at room temperature, then 2 ml of water are added; it is left to stand for one hour at room temperature, then cooled to -100 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-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino cephalosporanic acid) of the formula
EMI15.2
 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, #max 353 m and 250-265 mIt (shoulder); in potassium hydroxide / ethanol,) * max 347 m, 250 - 265 mp and 240 mu (shoulder); and in hydrogen chloride / ethanol, one 358 mIt and 250-265 m;

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 3.00 (shoulder), 3.10-4.10, 5.65, 5.75 y (shoulder), 5.80 (shoulder), 5.90-5.95 , 6.00 (shoulder), 6.15, 6.24 (shoulder), 6.28 Lt (shoulder), 6.55, 6.65 tt and 6.73 Lt (shoulder).



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



   Example 23
A suspension, cooled in ice water, of 0.0198 g of 4-benzylidene-7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 1.5 ml of methanol is treated in portions with an excess of the above solution of diazomethane in ether; the development of nitrogen begins immediately and the solid material dissolves. The addition of diazomethane is stopped as soon as the yellow discoloration persists for 2-3 minutes. The volatile components are removed in a rotary evaporator and the residue is crystallized by adding a few drops of methanol.

  The 4-benzylidene-7-N-phenylacetylamino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid methyl ester (configuration of the 7-amino-cephalosporanic acid ) of the formula
EMI15.3
 melts at 193-195.50; [α] 20 D = 3250 + 10 (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): #max 360 with (E = 24,800) and 262 m (e = 8100); #max 362 mFt and 250 mIt (shoulder) (in potassium hydroxide / ethanol); and one 362 m and 250 - 265 mtt (shoulder) (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.06, 5.62 u, 5.82 Lt, 5.95 Lt, 6.00 (shoulder). 6.24, 6.30 (shoulder), 6.62 (shoulder) and 6.65 - 6.73.



   Example 24
A mixture of 0.4 g of 1- (2-carbo-tert-butyloxy-3, 3- -dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl ) Kc- (phenylacetylmethylene) -acetic acid tert-butyl ester in 4 ml trifluoroacetic acid is left to stand for 20 hours at -200; the trifluoroacetic acid is removed under reduced pressure (oil pump) and the orange residue, containing the 7-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2-en - 2 -carboxylic acid (configuration of 7-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:

  A mixture of 1.45 g of cyanoacetic acid in 3 ml of methylene chloride is mixed with 1.1 ml of triethylamine and the resulting solution, cooled to 50%, is added with stirring to a solution of 1.45 g of trichloroacetyl chloride in 3 ml of methylene chloride which is kept at - 150. A suspension is thus obtained which is brought to a volume of 14 mol with methylene chloride at 150 and is used in this form). The reaction mixture is mixed with 2 ml of a solution of 0.3 ml of acetic acid and 1 mol of triethylamine in 6 ml of methylene chloride, stirred for 2 hours at room temperature and then diluted with 30 mol of ethyl acetate.

  It is washed with a concentrated sodium chloride solution containing hydrochloric acid in water (15 ml of the sodium chloride solution contains 1.5 ml of 1N hydrochloric acid) and with concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. About 1 ml of ethyl acetate is added to the residue and the mixture is carefully diluted with ether and then left to stand.

  The crystalline 4-benzylidene-7-N-cyanoacetylamino-8-oxo-5-thia-1-azabicyclo [4,2.0] oct-2-en-2-carboxylic acid is obtained Amino-cephalosporanic acid) of the formula
EMI16.1
 The residue from the mother liquor is chromatographed on 20 g of acid-washed silica gel, with a 100: 5 mixture of benzene and acetone neutral components, cyanoacetic acid and trichloroacetic acid and a further amount of the desired product with a 2: 1 mixture of benzene and acetone eluted, which, after crystallization from ethyl acetate and ether, melts at 225-2270 (decomposition);

  Ultraviolet absorption spectrum: Xmax 353 mm and 240-265mju (broad shoulder) (in ethanol), Amax 346 with and 248 with (shoulder) (in potassium hydroxide / ethanol) and) max 356 mu and 247 mu (shoulder) (in hydrogen chloride / etha nol ); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90-4.20 to 4.42, 5.60 U, 5.85-5.90, 5.98, 6.22 p and 6.45 X

 

Claims (1)

PATENT CLAIM Process for the preparation of α-halo-2-oxo-1-azetidine methanecarboxylic acid esters of the formula I. EMI16.2 where R1 represents an optionally substituted aliphatic or araliphatic hydrocarbon radical, R2 represents an acyl radical, R3 represents an organic radical and R, represents a hydrogen atom, or the two groups R3 and R4 together represent a disubstituted methylene group and X represents a halogen atom, characterized in that that in a z - hydroxy-2-oxo- 1 -azetidinemethanecarboxylic acid ester of the formula II EMI16.3 converts the hydroxy group to a halogen atom X by treatment with a halogenating agent. SUBCLAIMS 1. The method according to claim, characterized in that a thionyl halide, phosphorus oxyhalide or a halophosphorus compound is used as the halogenating agent. 2. The method according to claim, characterized in that the reaction is carried out in the presence of an organic basic agent. 3. The method according to claim, characterized in that a chlorine atom X in a compound obtained by treatment with a bromine or iodine compound, in particular with an inorganic bromide or iodide salt, such as lithium bromide, preferably in the presence of a suitable solvent such as ether a bromine or iodine atom X exchanges. 4. The method according to claim, characterized in that an isomer mixture obtained is separated into the individual isomers. 5. The method according to claim, characterized in that starting materials are used in the form of a crude reaction mixture obtainable under the reaction conditions. 6. The method according to claim or one of the dependent claims 1-5, characterized in that compounds of the formula EMI17.1 wherein R1 is a lower alkyl, halo-lower alkyl or phenyl-lower alkyl radical, R2 is an acyl radical, each of the radicals R and R6 is a lower alkyl radical and Hal is a chlorine or bromine atom. 7. The method according to claim or one of the dependent claims 1-5, characterized in that compounds of the formula Ia shown in dependent claim 6, wherein R1 'is the tert-butyl or 2,2,2-trichloro methyl radical, R2 the acyl radical an organic carboxylic acid, which occurs in pharmacologically active N acyl derivatives of 6-amino-penicillic acid or 7-amino-cephalosporanic acid or the remainder of a half-ester of carbonic acid, such as a carbo-lower alkoxy, e.g. Carbo-tert-butyloxy radical, means that each of the radicals R5 and R6 stands for the methyl radical and Hal means a chlorine or bromine atom, produces. 8. The method according to claim or one of the dependent claims 1-5, characterized in that a - (2 - carbo-lower alkoxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3,2,0] heptyl) - - Hal-acetic acid-lower alkyl ester, in which Hal denotes a chlorine or bromine atom, 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, and the carbon-lower alkoxy radical in the 2-position is preferably the carbo-tert-butyloxy radical. 9. The method according to claim or one of the dependent claims 1, 2, 4 and 5, 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-chloro-acetic acid -2,2,2-trichloroethyl ester. 10. The method according to claim, or one of the dependent claims 1, 2, 4 and 5, characterized in that manix- (2-carbo-tert.butyloxy-3,3-dimethyl-7-oXo-4-thia-2, 6-diaza-6-bicyclo [3.2.0] heptyl) -x-chloro-acetic acid- tert-butyl ester. 11. The method according to claim or one of the dependent claims 1-5, characterized in that x - (2 - carbo-tert.butyloxy-3,3-dimethyl-7-oxo-4-thia - 2,6- -diaza- 6-bicyclo [3.2.0] heptyl) -lx-bromo-acetic acid-2,2,2-trichloroethyl ester.