CH512513A - 1-R2-2 Alpha-isopropenylmercapto-3-alpha-N-Ac-amino-azetidine-4-ones antibacterial agents - Google Patents

Abstract

Antibacterial 1-R2-2 alpha-isopropenylmercapto-3-alpha N-Ac-amino-azetidine-4-ones. G3A. are new cmpds. of formula (I) (where Ac = acyl residue of an organic acid and R2 = H or formyl) and are prepared from the corresp. 2-acyloxyprop-2-yl tiooethers by thermal cleavege in a hydrocarbon solvent at 50-150 degrees C pref. at 70-120 degrees. Cpds. I have valuable pharmacologicalproperties, at dilutions of up to 0.01% they are active against gram-positive bacteria, particularly Staphylococcus aureus. Cpds. I are also useful intermediates; when Ac= tert butoxycarbonyl, they can be cyclised with cold, strong oxyacids to obtain derivs. with structures analogous to that of 6-aminopenicillanic acid; or if the acyl group is removed, re-acylation with 6-aminopenicillanic acid or 7-aminocephalosporanic acid yields further valuable pharmaceuticals.

Description

  

  
 



  Process for the preparation of azetidinothiazolidine compounds
The present invention relates to a new process for the preparation of azetidinothiazolidine compounds, primarily 4,4-dimethyl-3-R-azetidino [3,2-d] thiazolidin-2-ones of the formula
EMI1.1
 wherein R represents a hydrogen atom or the acyl radical Ac of an organic acid.



   A group Ac primarily represents the acyl radical of an organic carboxylic acid, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid, and the acyl radical of a carbonic acid half derivative.



   The aliphatic radical of an aliphatic carboxylic acid, which term also includes formic acid, is an optionally substituted aliphatic hydrocarbon radical, such as an alkyl, alkenyl or alkynyl; in particular a lower alkyl or lower alkenyl, as well as a lower alkynyl radical, the z. B. can contain up to 7, preferably up to 4 carbon atoms. Such radicals can optionally be replaced by functional groups, e.g.

  B. by free, etherified or esterified hydroxy or mercapto groups, such as lower alkoxy, lower alkenyloxy, Niederalky lendioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylmercapto- or optionally substituted phenylmercapto- or phenyl-lower alkylmercapto-, lower alkoxycarbonyloxy or Lower alkanoyloxy groups and halogen atoms, furthermore mono-, di or poly-substituted by nitro groups, optionally substituted amino groups or optionally functionally modified carboxy groups, such as carbo-lower alkoxy, optionally N-substituted carbamyl or cyano groups.



   A cycloaliphatic or cycloaliphatic-aliphatic radical of a corresponding carboxylic acid is an optionally substituted cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, e.g. B. a mono-, bi- or polycylic cycloalkyl or cycloalkenyl group, or cycloalkyl or cycloalkenyl-lower alkyl or lower alkenyl group, wherein a cycloalkyl radical z. B.



  contains up to 12, such as 3-8, preferably 3-6 ring carbon atoms, while a cycloalkenyl radical z. B. have up to 12, such as 5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic radical z. B.



  can contain up to 7, preferably up to 4 carbon atoms. The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, e.g. B.



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



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



   The araliphatic radical in an araliphatic carboxylic acid is e.g. B. an optionally substituted araliphatic hydrocarbon radical, such as an optionally substituted, e.g. B. to three, optionally substituted mono-, bi- or polycyclic, aromatic hydrocarbon radicals aufelsender aliphatic hydrocarbon radical and is primarily a phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl radical, such radicals z. B. 1-3 phenyl groups and optionally, z. B. as the above-mentioned aliphatic and cycloaliphatic radicals, in the aromatic un dloder aliphatic part can be mono-, di- or polysubstituted.



   Heterocyclic radicals in heterocyclic or heterocyclic-aliphatic carboxylic acids are, in particular, monocyclic, as well as bi- or polycyclic, aza-, thia-, oxa-, thiaza-, oxaza- or diazacyclic radicals of aromatic character, which optionally, z. B. as the above cycloaliphatic radicals, mono; can be di- or polysubstituted. The aliphatic part in heterocyclic-aliphatic radicals has z. B. the meaning given for the corresponding cycloaliphatic-aliphatic or araliphatic radicals.



   The acyl radical of a carbonic acid half derivative is preferably the acyl radical of a corresponding half ester, in which the organic radical of the hydroxy part is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or a heterocylic-aliphatic radical, primarily the acyl radical of an optionally, preferably in a-position , substituted lower alkyl half-ester of carbonic acid (ie a carbo-lower alkoxy radical which is optionally substituted in the lower alkyl part, preferably in the a-position), and a lower alkenyl, cycloalkyl, phenyl group optionally substituted in the lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl part or phenyl-lower-alkyl-semiesters of carbonic acid (ie an optionally lower-alkenyl-, cycloalkyl-, phenyl- or

  Phenyl-lower alkyl part-substituted carbo-lower alkenyloxy, carbo-cycloalkoxy, carbo-phenyloxy or carbo-phenyl-lower alkoxy radical). Acyl radicals of a carbonic acid half ester are also corresponding radicals of lower alkyl half esters of carbonic acid, in which the lower alkyl part is a heterocyclic, e.g. B. contains one of the above-mentioned heterocyclic groups of aromatic character, both the lower alkyl radical and the heterocyclic group may optionally be substituted. Such acyl radicals are optionally substituted carbo-lower alkoxy groups in the lower alkyl part and in the heterocyclic group which contain a heterocyclic group of aromatic character in the lower alkyl radical.



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



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



   A naphthyl radical is a 1- or 2-naphthyl radical, while a biphenylyl group z. B. represents a 4-biphenylyl radical
A phenyl-lower alkyl or phenyl-lower alkenyl radical is e.g. B. a benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl, trityl, 1- or 2-naphthylmethyl, styryl or cinnamyl radical.



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



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



   Etherified hydroxyl groups are primarily lower alkoxy, e.g. B. methoxy, ethoxy, n-propyloxy,
Isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy or tert-pentyloxy groups, and substituted lower alkoxy, such as halo-lower alkoxy, in particular 2-halo-lower alkoxy -, e.g. B. 2,2,2-trichloro-ethoxy or 2-iodathoxy groups, also Niederalkeny loxy, z. B. vinyloxy or allyloxy groups, lower alkylenedioxy, z. B. methylene or ethylenedioxy groups, cycloalkoxy, z. B. cyclopentyloxy, cyclohexyloxy or adamantyloxy groups, phenyloxy groups, phenyl-lower alkoxy, z. B.

  Benzyloxy or 1- or 2-phenylethoxy groups, or by monocyclic, monoaza-, monooxa- or monot hiacyclic groups of aromatic character substituted lower alkoxy, such as pyridyl-lower alkoxy, z. B. 2-pyridylmethoxy, furyl-lower alkoxy, e.g. B. furfuryloxy, or thienyl-lower alkoxy, z. B. 2-thenyloxy groups to understand hen.



   As etherified mercapto groups, Niederalkylmer capto-, z. B. Methylmercapto- or Äthylmercaptogrup pen, phenylmercapto groups or phenyl-lower alkylmer capto, z. B. benzyl mercapto groups to mention.



   Esterified hydroxyl groups are primarily halogen, e.g. B. fluorine, chlorine, bromine or iodine atoms, and Niederalkanoyfoxy-, z. B. acetyloxy or propionyloxy groups.



   Substituted amino groups are mono- or disubstituted amino groups in which the substituents in the first line represent optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals. Such
Amino groups are in particular lower alkylamino or
Di-lower alkyl-amino, e.g. B. methylamino, ethylamino, di methylamino or diethylamino groups, or if appropriate by heteroatoms such as oxygen, sulfur or optionally, z.

  B. by lower alkyl groups, substituted nitrogen atoms interrupted lower alkyleneamino groups, such as pyrrolidino; Piperidino, morpholino, thio morpholino or 4-methyl-piperazino groups, as well as acylamino, especially lower alkanoylamino., Such as acetyla mino- or propionylamino groups.

 

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



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



   A carbo-lower alkenyl radical is z. B. the carbovinyloxy group, while carbo-cycloalkoxy and carbo-phenyl lower alkoxy groups, in which the cycloalkyl or



   Phenyl lower alkyl radical have the above meaning, e.g. B. represent Carboadamantyloxy- or Carbo-benzyloxy groups. Carbo-lower alkoxy groups in which the lower alkyl radical contains monocyclic, monoaza-, monooxa- or monothiacyclic groups are, for. B. Carbo-furylniederalkoxy-, such as carbofurfuryloxy-, or Carbo-thienylniederalkoxy-, z. B. Carbo-2-thenyloxy groups.



   The compounds of the formula obtainable according to the process are known, for. B. as valuable intermediates in the synthetic production of 7-N-acylamino-cephalosporanic acid compounds; see e.g. B. Austrian patents No. 263 768 and 264 537. With the new method of the present invention they can be made available more easily and in a cheaper way compared to the known method of manufacture.



   The process according to the invention is particularly suitable for the preparation of compounds of the formula
EMI3.1
 wherein R 'represents a hydrogen atom or represents the acyl radical Ac', which represents an acyl radical in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid, such as. B.



  the radical of the formula 57Y- (CmH2m) -CO-, in which m is an integer from 0 to 4, preferably 1, and a carbon atom of a preferably unbranched alkylene radical of the formula - (CmH2m) -, optionally by an optionally substituted amino group , a free, etherified or esterified hydroxy or mercapto group or a free or functionally modified carboxyl group, e.g. B. by one of the above groups of this type, can be substituted, and wherein Y is an optionally in the nucleus, z.

  B. as the above alkylene radical, as well as by sulfo or nitro groups, substituted aromatic or cycloaliphatic hydrocarbon radical or heterocyclic radical, preferably aromatic, or a hydroxy or mercapto group etherified by an aromatic or cycloaliphatic hydrocarbon radical or a heterocyclic radical, preferably aromatic, z.

  B. a 2,6-dimethoxy benzoyl, tetrahydronaphthoyl, 2-methoxy-naphthoyl, 2-ethoxy-naphthoyl, phenylacetyl, phenyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, a-phenylacetloxyphenyl α-Methoxy-phenylacetyl α-methoxy-3,4-dichlorophenylacetyl, α-cyano-phenylacetyl, phenylglycyl (optionally with protected amino group), benzyloxycarbonyl, benzylthioacetyl, benzylthiopropionyl, hexahydrobenzyloxycarbonyl, cyclo -Amino-cyclopentanoyl- or a-amino-cyclohexanoyl- (optionally with a protected amino group), 2-thienylacetyl-, a-cyano-2-thienylacetyl-, a-amino-2-thienylacetyl (optionally with a protected amino group), 3 -Thienylacetyl-, 2-furylacetyl-,

   2-phenyl-5-methyl-isoxazolyl-carbonyl or 2- (2-chloro-phenyl) -5-methyl-isoxazolyl-carbonyl group, or represents a radical of the formula C "HBI, + ICO- or CnH2n-1CO- where n is an integer up to 7 and the chain is straight or branched and optionally interrupted by an oxygen or sulfur atom or, for example, by halogen atoms, trifluoromethyl, free or functionally modified carboxyl, such as cyano, free or substituted Amino or nitro groups may be substituted, e.g.

  B. a propionyl, butyryl, hexanoyl, octanoyl, butyl mercapto-acetyl, acrylyl, crotonyl, 2-pentenoyl, allyl mercapto-acetyl, chloroacetyl, 3-chloro-propionyl, 3-bromopropionyl , Aminoacetyl, 2-carboxypropionyl, cy anacetyl or 2-cyano-3-dimethyl-acrylyl group, or a radical of the formula Z-NH-CO-, where Z is an optionally substituted aromatic or aliphatic hydrocarbon radical, in particular one by lower alkoxy groups and / or halogen atoms are substituted lower alkyl radical, but primarily an easily cleavable acyl radical, in particular the radical of a half ester of carbonic acid, such as a carbon lower alkoxy optionally substituted by halogen atoms, z. B. Carbotert.-butyloxy, Carbo-tert.-pentyloxy or Carbo2,2,2-trichloroethoxy, a Carbocyclolakoxy-, z. B.

  Carbo-adamantyloxy, a carbophenyl-lower alkoxy, e.g. B. Carbo-diphenylmethoxy, or a Carbo-furylniederalkoxy-, z. B. Carbofurfuryloxyest represents.



   According to the invention, the compounds of the formula I are produced by adding a 1-R2-2a-isopropenylmercapto-3α-N-aco-amino-azetidin-4-one compound of the formula
EMI3.2
 wherein Ac "represents an acyl radical which can be split off under acidic conditions, treated with a strong, oxygen-containing acid. If desired, the unsubstituted nitrogen atom in the 3-position in a compound obtained can be acylated.



   An acyl radical Ac "which can be split off under acidic conditions is primarily a suitable acyl radical of a carbonic acid half-ester, such as a carbo-lower alkoxy radical which is substituted, for example, branched in the a-position, preferably in the lower alkyl moiety, primarily the carbo-tert-butyloxy -, as well as the carbo-tert-pentyloxy radical, as well as an optionally substituted in the lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl moiety, preferably substituted, e.g. branched, carbo-lower alkenyloxy, e.g. carbo- vinyloxy, carbo-cycloalkoxy, e.g. carbo-adamantyloxy, carbo-phenyloxy or carbo-phenyl-lower alkoxy, e.g.

  Carbo-diphenylmethoxy or carbo-a-biphenylyl-isopropyloxy, also a carbo-lower alkoxy, preferably in the a-position, having a heterocyclic group of aromatic character, e.g. B. Carbo-furfuryloxy residue.



   The ring closure can be achieved by treatment with a strong inorganic or organic, oxygen-containing acid, such as organic carboxylic or sulfonic acid, in particular a strong lower alkanecarboxylic acid, optionally substituted by hetero radicals, preferably by halogen atoms, such as an α-haloacetic or α-halogen propionic acid, in which halogen is preferably fluorine and chlorine, primarily trifluoroacetic acid, are effected, in the absence or presence of an inert solvent such as dioxane or a mixture of diluents and, if necessary, with cooling, for. B. at temperatures of about -30 "C to about +10" C, and / or in an inert gas, e.g. B.



  Nitrogen atmosphere, works. At the same time, a group Ac ″ which can be split off under acidic conditions is split off.



   In a compound obtainable according to the above type, the hydrogen-bearing ring nitrogen atom can be in a conventional manner, for. Acylate as described below for the hydroxy group, e.g. B. by treating with a free organic acid, especially carboxylic acid, or a reactive functionally modified derivative thereof, e.g. B. with an acid chloride or anhydride, the free acid optionally in the presence of a suitable condensing agent such as a carbodiimide, e.g. B.



  Dicyclohexylcarbodiimide, and a functional derivative is used optionally in the presence of a base such as pyridine. The acyl group can also be introduced in stages; so you get at
Reacting a 3-unsubstituted compound of the formula I with phosgene first the chlorocarbonyl derivative, which when treated with an alcohol, such as lower alcohol, the corresponding N-acyl derivative with a
Carbonic acid half ester results.



   The starting materials used according to the process can be prepared using a compound of the formula
EMI4.1
 wherein Rt represents an organic radical and R represents a hydrogen atom or a formyl group, thermally decomposed, and in a compound obtained cleaving the formyl group and, if desired, in a compound obtained releasing protected functional groups in an acyl radical.



   The thermal decomposition of a compound of the formula III is preferably carried out in the presence of an inert solvent or solvent mixture, in particular a suitable hydrocarbon such as an aliphatic or aromatic hydrocarbon, e.g. B. high-boiling ePtrolether, benzene, toluene or xylene, at temperatures from about 50 ° C. to about 150 ° C., preferably from about 70 ° C. to about 120 ° C. If desired, you can work in an inert gas such as nitrogen atmosphere. The thermal decomposition can, under suitable conditions, take place simultaneously with the preparation of compounds of the formula III.



   In a starting material of the formula II obtainable in this way, a formyl group R2, e.g. B. by hydrolysis, alcoholysis, ammonolysis or aminolysis, and by treatment with an actual decarbonylating agent, can be replaced by hydrogen. The hydrolysis can e.g. By treating with a suitable inorganic base such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. B.



  Sodium, potassium, calcium or barium hydroxide or carbonate, and an alkali metal hydrogen carbonate, e.g. B. sodium or potassium hydrogen carbonate, be carried out in an aqueous medium. Alcoholysis with alcohols such as lower alkanols, e.g. B. methanol or ethanol, and mercaptans, is preferably in the presence of appropriate alcoholates or thiolates, such as alkali metal lower alkanolates, eg. B. sodium methylate or ethylate, and weakly basic acylates, such as alkali metal lower alkanolates, z. B. sodium acetate made.



  The ammonolysis with ammonia, as well as with quaternary ammonium hydroxides, z. B. Benzyltrimethylammoniumhydroxyd or Tetrabutylammoniumhydroxyd, also leads to the removal of a formyl group R2. When using ammonia one works z. B. in a two-phase system; the ammonia, which is preferably used in the form of an aqueous solution, enters the organic phase with the formyl compound in low concentration and thus causes the formyl group to be split off. Aminolysis can be carried out with amines, especially primary or secondary, primarily aliphatic or aromatic amines, e.g. B. ethyl amine, diethylamine, pyrrolidine or aniline. be performed.



   Real Carbo-furylniederalkoxy-, are z. B. complex transition metal compounds that are able to form a stable complex together with carbon monoxide, such as trisubstituted tris-phosphine-rhodium halides, z. B. Tris (triphenyl) -phosphine-rhodium chloride. They are preferably in a suitable inert solvent, for. B. benzene, or a mixed solvent used, if desired, in an inert gas, z. B. nitrogen atmosphere works.



   Furthermore, in a compound obtainable according to the process, protected functional groups in an acyl radical, e.g. B. as stated above, are released.



   Intermediate products of the formula in which R2 stands for a formyl group can, for. B. be prepared if a 2-I socyanato3,3-dimethvI-6-N-Ac, -amino4 thia-1 -azabicyclo [3, 2.0] heptane-7n (configuration of 6-aminopenicillanic acid) of the formula
EMI4.2
 wherein Aco has the meaning of an acyl radical Ac, in which any free functional groups present in the acyl radical are protected, with a 2-halo-lower alkanol of the formula Ro-OH, wherein Ro represents a 2-halo-lower alkyl radical, in which halogen has an atomic weight of over 19 has a compound of the formula which can be obtained in this way
EMI5.1
 (Configutarion of 6-amino-penicillanic acid) treated with a chemical reducing agent in the presence of water,

   a 2-hydroxy-3,3-dimethyl-6 N-AcO-amino-4-thia-1-azabicyclo [3,2,0] heptan-7-one (configuration of 6-amino-pennicillanic acid) of the formula which can be obtained in this way
EMI5.2
 with an oxidizing agent which donates an acyloxy group of the formula -OC (= O) -Rl, in which Rl represents an organic radical, and in a 1-formyl-2a- (2-Rl-carbonyloxy-2-propylmer-capto) obtainable in this way - 3a-N-AcOamino-azetidin4-one compound of the formula
EMI5.3
 if desired, releases these groups in an acyl radical having protected functional groups, and / or, if desired, breaks down a mixture of isomers obtained into the individual isomers.



   Free functional groups in the acyl residue Ac ,, which occur during the reaction, e.g. B. must be protected in a conventional manner, are primarily free hydroxyl, mercapto and amino, and carboxy groups. The latter can e.g. B. by transferring to a, z. B. under acidic conditions easily cleavable ester, such as an optionally substituted aliphatic or aromatic hydrocarbon radicals polysubstituted methyl ester, such as the tert; butyl ester, or reductively easily cleavable ester, such as a 2-halo-lower alkyl, especially the 2,2,2- Trichloroethyl ester, those z. B. by converting into an easily cleavable acyl derivative, such as a carbo-lower alkoxy derivative which can be cleaved under acidic conditions, in which the lower alkyl radical in the a-position is preferably branched or z.

  B. is substituted by optionally substituted aromatic hydrocarbon radicals, e.g. B.



  the carbo-tert-butyloxy derivative, or in a carbo-2-halogeno-lower alkoxy, such as carbo-2,2,2trichloroethoxy derivative, which can be easily split reductively.



   A 2-halo-lower alkanol of the formula R, -OH can contain one, two or more halogen atoms, where halogen is e.g. B stands for bromine or iodine, preferably for chlorine. The radical Ro is in particular a 2-polychloro lower alkyl, such as 2-polychloroethyl radical, primarily the 2,2,2-trichloroethyl radical, but can also be, for. B. a 2-iodine-lower alkyl, e.g. B. the 2-Jodäthylrest mean.



   The reaction with the 2-halo-lower alkanol, especially a 2-haloethanol, e.g. B. with 2,2,2-trichloroethanol, is optionally in an inert solvent, for. B. in a halogenated hydrocarbon such as carbon tetrachloride, chloroform or methylene chloride, or in an aromatic solvent such as benzene, toluene or chlorobenzene, preferably carried out with heating.



   It is possible to start from precursors of compounds of the formula IV, form the latter under the reaction conditions and thus arrive at the desired intermediates directly. If you use z. B. a corresponding 3,3-dimethyl-6-N-Ac, -amino-7-oxoi4-thia-
1-aza-2-bicyclo [3, 2.0] heptane-carboxylic acid azide (configuration of 6-amino-penicillanic acid), which can be used, for. B.



   by transferring a 3,3-dimethyl-6-N-AcO-amino-7-oxo-4-thia-1-aza-2-bicyclo [3.2.0] heptane-carboxylic acid (configuration of the 6-amino-penicillanic acid ), e.g. B. a 6-N-AcO-amino-penicillanic acid, or a suitable salt, especially an ammonium salt thereof, into a mixed anhydride (e.g. by treatment with a lower alkyl haloformate, such as ethyl chloroformate, in the presence of a basic agent, such as Triethylamine) and treating such with a metal azide, such as sodium azide, or an ammonium azide, e.g. B. Benzyltrimethylammoniumazid, this decomposes with evolution of nitrogen in the absence or presence of the 2-halo-lower alkanol under the reaction conditions, eg.

  B. on heating, into the desired isocyanato compound of the formula IV, which usually does not need to be isolated and can be converted directly into the desired intermediate in the presence of the 2-halo-lower alkanol.



   The treatment of an intermediate of the formula V with the chemical reducing agent is carried out under mild conditions, usually at room temperature or even with cooling.



   Suitable chemical reducing agents are in particular nascent hydrogen, obtained e.g. B. by the action of metals, metal alloys or amalgams on hydrogen-releasing agents such as zinc, zinc alloys, e.g. B. zinc copper, or zinc amalgam on acids such as organic carboxylic acids, primarily lower alkanecarboxylic acids, e.g. B. acetic acid, preferably with the addition of water, and alcohols such as lower alkanols, z. B.

  Methanol, ethanol or isopropanol, which can optionally be used together with an organic carboxylic acid and / or the addition of water, also through the action of alkali metal amalgams, such as sodium or
Potassium amalgam, or aluminum amalgam on moist
Solvents such as ethers or lower alkanols.



  Chromium-II compounds, e.g. B. chromium (II) chloride or chromium (I) acetate, preferably in the presence of aqueous media containing water-miscible organic solvents such as lower alkanols, lower alkanecarboxylic acids or ethers, e.g. B. methanol, ethanol, acetic acid, Tetrahy drofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, use as chemical reducing agents.



   In acyloxy groups of the formula -O-C (= O) -R1, an organic radical Rl is z. B. an optionally substituted hydrocarbon radical, primarily an optionally substituted aliphatic or aromatic
Hydrocarbon radical, such as one of the abovementioned corresponding radicals, in particular a lower alkyl, such as methyl radical, or a monocyclic aromatic radical
Hydrocarbon, especially an optionally, e.g. B. as indicated above, substituted phenyl radical.



   Heavy metal carboxylates, preferably lead IV carboxylates, such as lead IV alkanoates, in particular lower alkanoates and primarily lead tetraacetate, also lead tetrapropionate or lead tetrastearate, and optionally substituted lead trabenzoates, e.g. B. lead trabenzoate or lead tra-3-bromobenzoate, also thallium-III-carboxylates, z. B.



  Thallium-III-acetate, or mercury-II-carboxylate, like
Mercury-II-acetate. If desired, these oxidizing agents can be used in situ, e.g. B. by reaction of lead dioxide or mercury-II-oxide with an organic carbonic acid, such as acetic acid, are formed.



   The above heavy metal carboxylates, in particular the corresponding lead IV compounds, are advantageously used in the presence of a light source, preferably using ultraviolet and longer-wave, such as visible light, optionally with the addition of suitable sensitizers.



  UV light preferably has a main wavelength range of over 280 m, up to about 350 m, u; this can e.g. B. by suitable filtering of the ultraviolet light through an appropriate filter, e.g. B. glass filters, or by suitable solutions, such as salt solutions, or other, short-wave light absorbing liquids, such as benzene or toluene, can be achieved. The ultraviolet light is preferably generated by means of a high pressure mercury vapor lamp.



  leads to an intermediate of the formula VI with the necessary amount of the oxidizing agent donating an acyloxy group of the formula -OC (= O) -Rl, usually in the presence of a suitable diluent such as benzene, acetonitrile or acetic acid, if necessary, with cooling or treated with heating and / or in an inert gas atmosphere with illumination with ultraviolet light.



   In a compound of formula IIIA obtainable in this way, protected functional groups in an acyl radical, e.g. B. as described above, are released.



   Intermediate products of the formula III in which R2 stands for a hydrogen atom can, for. B. be prepared if you have a 2-hydroxy-3,3-dimethyl-6-N-AcO-amino-Sthia- 1-azabicyclo [3,2,0] heptane (configuration of 6-amino-penicillanic acid) of the formula VI treated with a hydride reducing agent which is inert towards amide groups, if desired, in a 2a- (2-hydroxy-methyl-2-propylmercaptof 3cc-amino-azetidin-2-one compound of the formula obtained
EMI6.1
 esterifying the hydroxy group and treating a compound of the formula VII or an O-ester thereof with an oxidizing agent which releases an acyloxy group of the formula -O-C (= O) -R, and, if desired, in a compound of the formula obtainable in this way
EMI6.2
 releases protected functional groups.



   An amide group non-reducing hydride reducing agents are primarily boron-containing hydrides, such as. B diborane and primarily alkali metal or Erdalka limetallborhydride, especially sodium borohydride. Complex organic aluminum hydrides, such as alkali metal tri-lower alkoxy aluminum hydrides, e.g. B. Lithium tritert-butyloxy aluminum hydride can also be used.



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



   In a compound obtainable in this way, the free hydroxyl group can, if desired, be acylated in a manner known per se. For this purpose, the usual acylating agents, such as acids or their reactive ceric derivatives, such. B. in the presence of a suitable condensing agent such as a carbodiimide, e.g. B. dicyclohexylcarbodiimide, and this, if necessary, in the presence of a basic agent such as an organic tertiary base, e.g. B. triethylamine or pyridine. Reactive derivatives of acids are anhydrides, including internal anhydrides, such as ketenes, isocyanates or isothiocyanates, or mixed, in particular with haloformic acid esters, e.g. B.

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

 

   The oxidizing agents which donate acyloxy groups of the formula -OC (= O) -R1 are primarily the above-mentioned oxidizing heavy metal carboxylates, in particular lead-IV-alkonoates and preferably lead tetraacetate, whereby, as stated, advantageously in the presence of a light source, in the first place Line of ultraviolet light and a suitable solvent or diluent works.



   Protected functional groups known per se can be used in a compound of the formula IIIb obtained
Way, e.g. B. as described above, are released.



   Mixtures of. Obtained by the above procedures
Isomers can be prepared by methods known per se, e.g. B.



  by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation processes, are separated into the individual isomers. Obtained racemates with salt-forming groups, which can be temporarily introduced in the usual manner with a view to the resolution by suitable substituents, can, as usual, for. B. by forming a mixture of diastereoisomeric salts with optically active salt-forming agents, separating the mixture into the diastereoisomeric salts and converting the separated salts into the free compounds or by fractional crystallization from optically active solvents into which antipodes are separated.



   The above processes also include those embodiments according to which starting materials are used in the form of crude mixtures obtainable under the reaction conditions.



   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.



   In the following examples the temperatures are given in degrees Celsius.



   Example 1:
A solution of 2a-isopropenylmercapto-30C- (N-carbo-tert-butyloxy-amino) -azetidin-4-one in 0.5 ml of cold trifluoroacetic acid is kept at 0 for 15 minutes; the solution turns slightly yellow in color and is then diluted with a solution of 1 g of crystalline sodium acetate in 2 ml of water. It is extracted three times with 10 ml of methylene chloride each time; the combined organic extracts are dried and evaporated under reduced pressure; the acetic acid is removed at 0.001 mm Hg.



  4,4-Dimethyl-azetidino [3,2-dlthiazolidin-2-one of the formula is obtained in this way as a colorless oil
EMI7.1
 which crystallizes on addition of benzene and, after recrystallization from benzene, melts at 114-116; lag020 = +8 +1 (c = 0.845 in chloroform); Thin-layer chromatography (silica gel; system: 1: 1 mixture of benzene and ethyl acetate): Rf = 0.13; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95u, 5.68po (potassium bromide) and 5.781l.



   Example 2:
A solution of 0.15 g of 4,4-dimethyl-azetidino [3,2-d] thiazolidin-2-one in 10 ml of dry tetrahydrofuran (freshly filtered through a column with aluminum oxide, activity 1) is cooled to 0. Phosgene is passed through the cold solution for 5 minutes and the reaction mixture is stirred for a further 30 minutes with exclusion of atmospheric moisture; the initially appearing precipitate dissolves again. It is then evaporated and the residue is chromatographed on 3 g of acid-washed silica gel. The desired 3-chlorocarbonyl4,4-dimethyl-azetidino [3,2-dl thiazolidin2-one of the formula
EMI7.2
 is eluted with benzene and a 9: 1 mixture of benzene and ethyl acetate and crystallizes spontaneously.

  It is recrystallized from a mixture of benzene and hexane and melts at 178-180 (transformation at 140-160); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, u, 5.62, 5.74, u, 7.48so, 8.28u and 11.84, u.



   A solution of 0.1 g of 3-chlorocarbonyl4,4-dimethyl azetidino 13,2-dlthiazolidin-2-one in 10 ml of tertiary butanol is mixed with 0.2 g of calcium carbonate and for 2'k days at 90 "bath temperature and Heated with stirring in a closed vessel After cooling, the mixture is filtered, the residue is washed with benzene and the filtrate is evaporated under reduced pressure.



  The residue is taken up in benzene; the organic solution is washed with water, dried and again evaporated. The residue is redissolved in benzene and chromatographed on 1 g of acid-washed silica gel. With 9: 1 and 4: 1 mixtures of benzene and ethyl acetate, 3-carbo-tert-butyloxy-4,4-diemethyl-azetidino [3,2-dlthiazolidin-2-one of the formula
EMI7.3
 eluted and recrystallized from a mixture of ether and pentane, F. 117-120 (analytical preparation:
120.5 [a] 20 D = -274 OC (c = 0.522 in chloroform); Thin-layer chromatogram (silica gel; system: 1: 1 mixture of benzene and ethyl acetate):

  Rf = 0.15; Infrared absorption spectrum (methylene chloride): characteristic bands at 2.95btu, 5.62ru, 5.90u, 7.25u, 7.35dgl, 7.75p, 198.65R, 9.36, 10.60A, 1 1.65 and 12.30 so .



   The starting material used in Example 1 can be prepared as follows:
Example 3:
A suspension of 0.5 g of crude 6-aminopenicillanic acid in 4 ml of chloroform (freshly distilled over phosphorus pentoxide) is treated with 1 ml of hexamethyldisilazane of the formula [(CHS) 3Si] 2NH and 1 ml of chloroform dried over phosphorus pentoxide; the reaction mixture is refluxed for 21/2 hours with exclusion of atmospheric moisture, then cooled to 0 and, after the addition of 1.7 ml of a 10 ml solution of 2 ml of triethylamine in chloroform, 0.385 g of distilled tert.-butyl fluoroformate treated.

  The mixture is kept at 0 for 30 minutes, then at room temperature for 90 minutes and diluted with cold methylene chloride. The organic solution is washed with cold aqueous 10% strength citric acid and water, the aqueous washing liquids being backwashed with cold methylene chloride. The combined organic extracts are extracted twice with a dilute aqueous sodium hydrogen carbonate solution and, immediately after separation, acidified in the presence of methylene chloride and at 0 with citric acid. The organic phase is separated off, dried and evaporated; the pure amorphous 6- (N-carbo-tert-butyloxy-amino) -penicillanic acid is obtained in this way.

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 5.63, t1, 5.82, 6.67, 7.32 and 8.60.



   The 6- (N-carbo-tert-butyloxy-amino) penicillanic acid obtained is dissolved in 10 ml of methylene chloride and treated with 0.43 ml of a 10 ml solution of 2 ml of triethylamine in methylene chloride. On evaporation, the 6- (N-carbo-tert-butyloxy-amino) -penicillanic acid triethylammonium salt is obtained as an amorphous precipitate; Infrared spectrum (in methylene chloride): characteristic bands at 3.05, 5.67, 5.86, 6.17y, 6.67, 7.32 and 8.53.



   0.26 ml of a 10 ml solution of 2 ml ethyl chloroformate in tetrahydrofuran is added to a solution of 0.218 g of 6- (N-carbo-tert-butyl-oxyamino) penicillanic acid triethylammonium salt in tetrahydrofuran 90 minutes of stirring at -5 "to -10" is treated with a solution of 0.04 g of sodium azide in 0.4 ml of water. The mixture is stirred for a further 30 minutes at -5 "to 0, then it is diluted with 20 ml of ice water and extracted with methylene chloride.

  The organic extract is dried and evaporated at a temperature below 250 under reduced pressure; the crude 6- (N-Carbotert.-butyloxy-amino) -penicillanic acid azide is obtained as residue; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 4.70H, 5.62u, 5.83, 6.16, 7.32F, 8.60u and 9.40u.



   The crude product obtained above is dissolved in 5 ml of benzene, stirred for 5 minutes at 70 and a small amount of the solvent is evaporated off; It. Infrared spectrum (in methylene chloride; characteristic bands at 3.03u, 4.48, 5.61, u, 5.83, u, 6.67u, 7.31, u, 7.55u and 8.62) is the rearrangement into 2-isocyanato-3,3-dimethyl-6- (N-carbo-tert-butyloxy-amino) 4thia-1-azabicyclo [3,2,01heptan-7-one (configuration of 6-amino-penicillanic acid) Completely.



  The warm benzene solution is mixed with 0.2 ml of 2,2,2-trichloroethanol; the reaction mixture is stirred for a further 90 minutes at 70 and then evaporated under reduced pressure. The 2AN-carbo-2,2,2-trichloroethoxy-amino) -3,3-dimethyl-6- (N-carbo-tert; butyloxy-amino) 4-thia-t-azabicy is obtained as a crystalline product - clo [3,2,0] heptan-7-one (configuration of 6-amino-penicillanic acid) of the formula
EMI8.1
 which, after recrystallization from a mixture of ether and pentane, melts at 165-167; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, u, 5.63u, 5.81, 5.84u, 6.69p, 7.34u, 8.6511, 9.16 and
9.5911-
The compounds obtainable according to the invention can, for.

  B. can be used as starting materials as follows:
Example 4:
A solution of 0.5 g of 2- (N-carbo-2; 2,2-trichloro-ethoxy-aminof3,3-dimethyl -6- (N-carbo-tert; -butyloxy-amino> 4-thia-1 - azabicyclo [3,2,01heptan-7-one (configuration of 6-amino-penicillanic acid) in 5 ml of tert-butanol is diluted with 4 ml of acetic acid and 1 ml of water. After cooling in an ice bath, the mixture is stirred for 15 minutes 5 g of zinc dust are added in small portions, the mixture is stirred for a further 30 minutes at 0 and then filtered into a 70 ml receiver of a saturated sodium chloride solution.

  The residue is washed with methylene chloride and the aqueous phase of the filtrate is extracted with the same solvent. The organic extracts are washed with saturated sodium chloride solution, dried and evaporated under reduced pressure. The crude product obtained in this way can be purified by chromatography on 10 g of acid-washed silica gel, first pre-washing with a 9: 1 mixture of benzene and ethyl acetate and then with the same solvent mixture and a 4: 1 mixture of benzene and ethyl acetate the 2nd -Hydroxy-3,3-dimethyl-6- (N-carbo-tert-butyloxy-amino) 4-thia-1-azabicyclo [3,2,0lheptan-7-one (configuration of 6-amino-penicillanic acid ) of the formula
EMI8.2
 eluted as a colorless oil.

  This crystallizes from a mixture of ether and pentane, mp 106-110 (sintering from 100); [alD20 = f1150 +10 (c = 0.858 in chloroform); Thin-layer chromatogram (silica gel): Rf 0.53 in a 1: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.91, 3.04, 5.64, u, 5.8411, 6.68, 7.33u and 8.60p.



   Example 5:
A solution of 0.3 g of 2-hydroxy-3,3-dimethyl-6- (N-car bo-tert-butyloxy-aminoS4-thia -1 -azabicyclo [3.2.0] heptan7-one (configuration of 6-amino-penicillanic acid) in 125 ml of anhydrous benzene is mixed with 1 g of vacuum-dried lead tetraacetate and 0.09 ml of pyridine and the mixture is illuminated at about 12-15 with a high-pressure mercury vapor lamp (Hanau; type Q 81; 80 watts) in a water-cooled Pyrex glass jacket Keeping it moving by passing an oxygen-free nitrogen atom through it, a white precipitate of lead diacetate forms; a small amount of a rubbery black product, very likely containing metallic lead, is deposited on the pyrex glass jacket and is scraped off from time to time.

  After one hour the entire amount of lead tetraacetate is used up; the mixture is filtered, the filtrate washed with dilute aqueous sodium hydrogen carbonate and water, dried and evaporated under reduced pressure.



  The crude 1-formyl-2a- (2-acetyloxy-2-propyl-mercapto) -3α- (N-carbo-tert-butyloxy-amino) -azetidin-4-one of the formula is obtained in this way
EMI9.1
 which is obtained as an amorphous product and processed further without cleaning; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 5.56> 1, 5.88.1, 6.70p, 7.33 and 8.7011o
Example 6:
The crude product obtainable by the process of Example 5, containing the 1-formyl-2a- (2-acetyloxy-2-propyl-mercapto) -3a- (N-carbo-tert-butyloxy-amino) -azetidine-4- on is dissolved in 15 ml of toluene and heated at 90O for 17 hours in a nitrogen atmosphere.

  It is evaporated under reduced pressure to give the crude 1-formyl-2α-isopropenylmercapto-2α (N-carbo-tert-butyloxy-amino) -azetidin-4-one of the formula
EMI9.2
 as an amorphous product which has the following characteristic bands in the infrared spectrum (in methylene chloride): 3.0311, 5.55, 5.85, 6.69 and 7.32.



   Example 7:
The crude 1-formyl-2α-isopropenylmercapto-3α- (N-carbo-tert-butyloxy-aminopazetidin-4-one obtainable by the procedure of Example 6 is dissolved in 10 ml of methylene chloride, the solution is mixed with 10 ml of water diluted and treated with 10 drops of concentrated aqueous ammonia. The reaction mixture is stirred vigorously at room temperature for 4 hours and then separated into the two layers; the aqueous phase is washed with methylene chloride, and the organic solutions are combined, dried and evaporated Chromatograph g of acid washed silica gel, eluting with chloroform.

  Fewer polar by-products are first eluted in the forerun, then the desired 2a-isopropenylmercapto-3a- (N-carbo-tert-butyloxy-amino) -azetidin-4-one of the formula is obtained
EMI9.3
 which after crystallization from cold ether melts at 141O and after sublimation (128-132 / 0.001 mm Hg) at 142-144; [alD = -26 "+1 (c = 0.883 in chloroform); Ultraviolet absorption spectrum (in ethanol): Xmax = 223 mW (8 = 4840);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.0311, 5.631l, 5.84) 1, 6.221l, 6.67u, 7.3211, 7.57, u, 8.6411, 9.45, and 11.65.



   Example 8:
A solution of 0.08 g of 2-hydroxy-3,3-dimethyl-6- (Ncarbo-tert-butyloxy-amino) -4-thia-1-azabicyclo [3.2.0] heptan-7- on (configuration of 6-amino-penicillanic acid) in 5 ml of tetrahydrofuran is added at 0 with 0.13 ml of a solution of 0.38 g of sodium borohydride in 5 ml of water. The reaction mixture is stirred for 20 minutes at room temperature, then acidified with 5 drops of acetic acid and diluted with methylene chloride. The organic phase is washed with a saturated aqueous common salt solution, dried and evaporated under reduced pressure.

  The residue is chromatographed on 0.5 g of acid-washed silica gel, washing off apolar by-products with 5 ml of benzene and 9: 1 and 4: 1 mixtures of benzene and ethyl acetate and 10 ml of a 1: 1 mixture of benzene and ethyl acetate and 5 ml of ethyl acetate are the amorphous 2a- (2-hydroxymethyl-2-propylmercapto) -3a- (N-carbo-tert-butyloxy-amino) -azetidin-4-one of the formula
EMI9.4
 eluted;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, u, 5.63, u, 5.83t, 1, 6.631l, 7.31, 8.60 and 9.4311-
If a mixture of the 2aX2-hydroxymethyl-2-propylmercapto) -3?

  ;-( N-carbo-tert-butyloxy-amino) azetidin4-one and lead tetraacetate in anhydrous benzene with a high-pressure mercury vapor lamp in a water-cooled pyrex glass jacket, the 202 (2-acetyloxy-2-propylmercaptop3a4N-carbo-tert. -buty loxy-aminocazetidin4-one, which can be converted into 2a-isoprope nylmercapto-3a- (N-carbo-tert-butyloxy-amino) -azetidin-4-one when heated to about 100 "in an inert solvent.



   PATENT CLAIM 1:
1. Process for the preparation of compounds of the formula
EMI10.1
 characterized in that a compound of the formula
EMI10.2
 where Ac "represents an acyl radical that can be split off under acidic conditions, treated with a strong, oxygen-containing acid
SUBCLAIMS:
Process according to claim 1, characterized in that an acyl radical AcO which can be split off under acidic conditions represents a suitable acyl radical of a carbonic acid half-ester.



   2. The method according to dependent claim 1, characterized in that a carbo-lower alkoxy radical substituted in the a-position in the lower alkyl part is the acyl radical of a carbonic acid half-ester
3. The method according to dependent claim 2, characterized in that the carbo-tert-butyloxy radical is the acyl radical of a carbonic acid half-ester
4. The method according to claim 1, characterized in that a carbo-lower-alkenyloxy, carbo-cycloalkoxy, carbo-phenyloxy or carbophenyl-lower alkoxy radical which is optionally substituted in the lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl moiety is the acyl radical of a carbonic acid half-ester represents
5.

  Process according to dependent claim 1, characterized in that a carbon-lower alkoxy radical having a heterocyclic group of aromatic character in the lower alkyl part represents the acyl radical of a carbonic acid half-ester
6. The method according to claim 1, characterized in that a strong inorganic or organic, oxygen-containing acid is used.



   7. The method according to dependent claim 6, characterized in that a strong organic carboxylic or sulfonic acid is used.



   8. The method according to dependent claim 7, characterized in that a strong, optionally substituted by hetero radicals lower alkanecarboxylic acid is used.



   9. The method according to dependent claim 8, characterized in that an α-halo-acetic acid or α-halo propionic acid is used, in which halogen is fluorine or chlorine
10. The method according to dependent claim 9, characterized in that trifluoroacetic acid is used.

 

   11. The method according to claim I, characterized in that one works with cooling.



   12. The method according to dependent claim 11, characterized in that one works at temperatures of -30 "C to +10 OC.



   13. The method according to claim I, characterized in that starting materials are used in the form of a crude mixture obtainable under the reaction conditions.



      PATENT CLAIM II:
Use of the compound obtained by the process of claim I for the preparation of compounds of the formula
EMI10.3
 wherein R represents the acyl radical Ac of an organic acid, characterized in that the compound obtained is acylated accordingly.

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



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. 202 (2-Acetyloxy-2-propylmercaptop3a4N-carbo-tert-butyloxy-aminocazetidin4-one, which when heated to about 100 "in an inert solvent in the 2a-isoprope nylmercapto-3a- (N-carbo- tert.- butyloxy-amino) -azetidin-4-one can be converted. PATENT CLAIM 1: 1. Process for the preparation of compounds of the formula EMI10.1 characterized in that a compound of the formula EMI10.2 where Ac "represents an acyl radical that can be split off under acidic conditions, treated with a strong, oxygen-containing acid SUBCLAIMS: Process according to claim 1, characterized in that an acyl radical AcO which can be split off under acidic conditions represents a suitable acyl radical of a carbonic acid half-ester. 2. The method according to dependent claim 1, characterized in that a carbo-lower alkoxy radical substituted in the a-position in the lower alkyl part is the acyl radical of a carbonic acid half-ester 3. The method according to dependent claim 2, characterized in that the carbo-tert-butyloxy radical is the acyl radical of a carbonic acid half-ester 4. The method according to claim 1, characterized in that a carbo-lower-alkenyloxy, carbo-cycloalkoxy, carbo-phenyloxy or carbophenyl-lower alkoxy radical which is optionally substituted in the lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl moiety is the acyl radical of a carbonic acid half-ester represents 5. Process according to dependent claim 1, characterized in that a carbon-lower alkoxy radical having a heterocyclic group of aromatic character in the lower alkyl part represents the acyl radical of a carbonic acid half-ester 6. The method according to claim 1, characterized in that a strong inorganic or organic, oxygen-containing acid is used. 7. The method according to dependent claim 6, characterized in that a strong organic carboxylic or sulfonic acid is used. 8. The method according to dependent claim 7, characterized in that a strong, optionally substituted by hetero radicals lower alkanecarboxylic acid is used. 9. The method according to dependent claim 8, characterized in that an α-halo-acetic acid or α-halo propionic acid is used, in which halogen is fluorine or chlorine 10. The method according to dependent claim 9, characterized in that trifluoroacetic acid is used. 11. The method according to claim I, characterized in that one works with cooling. 12. The method according to dependent claim 11, characterized in that one works at temperatures of -30 "C to +10 OC. 13. The method according to claim I, characterized in that starting materials are used in the form of a crude mixture obtainable under the reaction conditions. PATENT CLAIM II: Use of the compound obtained by the process of claim I for the preparation of compounds of the formula EMI10.3 wherein R represents the acyl radical Ac of an organic acid, characterized in that the compound obtained is acylated accordingly.