NZ206831A

NZ206831A - The manufacture of beta-lactams

Info

Publication number: NZ206831A
Application number: NZ206831A
Authority: NZ
Inventors: G Schmid
Original assignee: Hoffmann La Roche
Priority date: 1983-01-20
Filing date: 1984-01-13
Publication date: 1987-04-30
Also published as: EP0116854A2; DE3474549D1; EP0116854A3; DK24084D0; ZA84292B; IE840114L; CA1251454A; DK24084A; KR840007230A; AU566914B2; IL70685A0; JPS59137479A; PH19214A; EP0116854B1; ATE37879T1; AU2328884A; IE56572B1; IL70685A

Abstract

1. A process for the manufacture of optically uniform beta -lactams of the general formula see diagramm : EP0116854,P10,F1 wherein R**1 signifies lower alkanoyl, lower alkoxycarbonyl or benzoyl, R**2 signifies hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or cyano, R**3 signifies hydrogen or lower alkyl, B signifies lower alkylidene, lower cycloalkylidene or carbonyl and Z signifies lower 2-alkenyl or 2,4-di(lower alkoxy)benzyl, whereby the residues denoted as lower have a maximum of 7 carbon atoms, and their corresponding optical antipodes, characterized by reacting a salt of a carboxylic acid of the general formula see diagramm : EP0116854,P10,F2 wherein R**1, R**3 have the above significance, in the presence of a reactive derivative of an organic sulphonic acid and a base with an optically uniform compound of the general formula see diagramm : EP0116854,P11,F3 wherein B and Z have the above significance, or the optical antipode thereof.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £06831 No.: Date: Priority Date(s): -2o /- Complete Specification Filed: /"?*. Class: Publication Date: P.O. Journal, No: ., NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION. PROCESS FOR THE MANUFACTURE OF B-LACTAMS 23^We, F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss Company, hereby declare the invention for whichXK/ we pray that a patent may be granted to to/us, and the method by which it is to be to be particularly described in and by the following statement: - 1 - (followed by la) - lex- - 2068c RAN 4410/175 vw 10 The present invention is concerned with a process for the manufacture of novel, optically uniform /3-lactams of the general formula 15 20 I I HH r2^|^VL-| wherein R signifies lower alkanoyl, 2 lower alkoxycarbonyl or benzoyl, R- signifies hydrogen, lower alkyl, lower 25 alkanoyl, lower alkoxycarbonyl or cyano, R3 signifies hydrogen or lower alkyl, B signifies lower alkylidene, lower cycloalkylidene or carbonyl and Z signifies lower 2-alkenyl or 2,4-di(lower 30 alkoxy)benzyl, and their corresponding optical antipodes, which process comprises reacting a salt of a carboxylic acid of the general formula 35 Nt/14.12.83 306831 1 - 2 - COOH II 1 2 3 wherein R , R and R have the above 10 significance, in the presence of a reactive derivative of an organic sulphonic acid and a base with an optically uniform compound of the general formula 15 20 III 25 wherein B and Z have the above significance, or the optical antipode thereof. The term "lower" denotes groups and compounds containing at most 7, preferably at most 4, carbon atoms. The term "alkyl" denotes straight-chain or branched-chain 30 saturated hydrocarbon groups such as methyl, ethyl and iso-propyl. The term "alkoxy" denotes alkyl ether groups such as methoxy and ethoxy. The term "alkanoyl" denotes straight-chailn or branched-chain saturated fatty acid groups such as formyl and acetyl. The term "2-alkenyl" denotes straight-:hain or branched-chain hydrocarbon groups containing at iast 3 carbon atoms which have a double bond in the 2,3- ANV#7l 206831 position such as allyl. The term "alkylidene" denotes groups such as methylene and isopropylidene. The term "cyclo-alkylidene" denotes cyclic hydrocarbon groups containing at least 3 carbon atoms such as cyclohexylidene. The term "aryl" used below signifies phenyl optionally substituted by halogen or lower alkyl. The tern "haloalkyl" used below denotes alkyl groups substituted by halogen such as trifluoromethyl. The term "halogen" signifies fluorine, chlorine, bromine or iodine. In a particular embodiment the present invention embraces the manufacture of compounds of formula I in which 1 2 R signifies lower alkoxycarbcnyl, R signifies hydrogen, B signifies lower alkylidene and Z signifies lower 2-alkenyl. The compounds listed hereinafter are representative compounds falling within formula I above: Methyl (Z)-3-[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]-2-butenoate, (3S,4S)-l-allyl-3-[[(Z)-2-benzoyl-l-methylvinyl]-amino]-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-azetidi-none, diethyl [[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]methylene]malonate, methyl (Z)-3-[[(2S,3S)-1-(2,4-dimethoxybenzyl)-2-[ (R) -2,2-dimethyl-l,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]-amino]-2-butenoate and (3S,4S)-3-[[(Z)-2-benzoyl-l-methylvinyl]amino]-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-azetidinone. The reaction in accordance with the invention is a cycloaddition which is familiar to the person skilled in the art. There is obtained a compound of formula I above or the optical antipode thereof in which the substituents in the 3- and 4-position of the azetidinone ring stand in cis-relationship to one another as expected. However, it has surprisingly been found that the use of an optically active compound of formula III (or the optical antipode thereof) in the above cycloaddition induces two new optical centres in high optical yield. In the products obtained the second possible cis-cycloaddition product, which would be diastereoisomeric to the product actually obtained, could not be detected. As reactive organic sulphonic acid derivatives there come into consideration for the present purpose primarily compounds of the general formula r4-so2-x IV wherein X signifies halogen or the group 4 4 -0S02-R and R signifies aryl, lower alkyl or lower haloalkyl. The preferred sulphonic acid derivatives are the compounds of formula IV in which X signifies halogen, especially 4 chlorine, and R signifies phenyl optionally substituted by halogen or lower alkyl, such as p-toluenesulphonyl chloride, p-chlorobenzenesulphonyl chloride and benzenesulphonyl chloride. As bases there are preferably used tertiary amines, with tertiary aliphatic amines such as diisopropylethylamine and triethylamine being especially suitable. The carboxylic acid of formula II is introduced into the reaction in the form of a carboxylic acid salt. Salts which come into consideration are primarily alkali metal 5 206B31 salts and ammonium salts derived from tertiary amines. In an especially preferred embodiment an alkali metal salt, especially the potassium salt, of carboxylic acids of formula II are used. accordance with the invention are, for example, ethers such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dioxan, ethylene glycol dimethyl ether or the like, halo-genated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane or the like, acetonitrile, dimethyl-formamide or the like. Halogenated hydrocarbons such as methylene chloride are especially suitable solvents. The above cycloaddition is carried out in a temperature range of about -30°C to about 50°C. The reaction temperature preferably lies in a range of about 0°C to room temperature. The compounds of formula III or their optical antipodes used as starting materials can be prepared by reacting an aldehyde of the general formula Suitable inert organic solvents for the process in V wherein B has the above significance, or its optical antipode with an amine of the general formula H2N-Z VI wherein Z has the above significance. The reaction is preferably carried out in an inert organic solvent, for example in a halogenated hydrocarbon such as methylene chloride, chloroform, 1,2-dichloroethane and the like or in a hydrocarbon such as benzene, toluene and the like. The water formed during the reaction is preferably removed continuously during the reaction, for example by azeotropic distillation or by working in the presence of a water-entraining agent, for example in the presence of a suitable molecular sieve, or of other customary drying agents such as potassium carbonate, magnesium sulphate and the like. When the water formed during the reaction is removed azeotropically the reaction is carried out at the boiling point of the chosen solvent; when a water-entraining agent is used the reaction is preferably carried out at room temperature. The compounds of formula III and their corresponding optical antipodes, which surprisingly yield optically uniform products in the cycloaddition described above, need not necessarily be isolated, but can be subjected directly to the cycloaddition in accordance with the invention. The compounds of formula I obtainable in accordance with the invention are novel and can be used for the manufacture of antimicrobially active, optically uniform substances which contain a 0-lactam ring. Such antimicrobially active substances can be manufactured from the compounds of formula I obtainable in accordance with the invention according to methods known per se, whereby the choice of reagents and reaction conditions, depending on the desired target compound, present no difficulties to the person skilled in the art. , - vmsmmWir-irfcity 206831» The compounds of formula I can be used, in particular, for the manufacture of antimicrobially active compounds of the general formula 5 ry-cJ. u i H2N \ _ 5 4 OR 5 wherein R signifies hydrogen, lower 6 alkyl or carboxy-lower alkyl and R signifies carbamoyl or carbamoyloxy-methyl, and their pharmaceutical^ acceptable salts. The use of the cycloaddition in accordance with the invention for the manufacture of antimicrobially active, optically uniform substances containing a 0-lactam ring such as the aforementioned compounds of formula VII is likewise an object of the present invention. 25 The compounds of formula VII can be manufactured, for example, in accordance with the following Reaction Scheme and the following description relating thereto. The 1 2 3 5 6 symbols R , R , R , R , R , B and Z used in the Reaction Scheme have the above significance and Z* signifies a readily 30 cleavable N-protecting group, preferably a readily cleavable acyl group such as t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl and the like. H I H H — > □ VII 0 SO3H 15 20 - 8 - 20683 REACTION SCHEME LJ *--&> vxi&r HO,H OH ■2H nls^ J—N IX H H H '•- ^CH_OCONH„ 7 H H „ • ? H H r.-^N^ 2 2 „,^N ^7 J^>OH " \ ^CHO ^ S- 0^ "\j d^~">S Z*"' XVII XIV XIII XII . s® V* B'.J:ooce3 ? iN H H| *, COOB ° V -XVIII JL / y>CH«NOH v~s XXI *—N II O H II I H H 6 — C — N- i *» ~ h2N 5 n0R so3H 20683t A compound of formula VIII is obtained by the mild acidic hydrolysis of a compound of formula I. The hydrolysis of a compound of formula I can be carried out, for 5 example* by treating the compound of formula I with an acid in the presence of water and optionally a water-miscible solvent such as acetone, tetrahydrofuran, dioxan, dimethyl sulphoxide, dimethylformamide or the like. As acids there come into consideration, for example, mineral acids such as 10 hydrochloric acid and sulphuric acid, or organic acids such as p-toluenesulphonic acid/ pyridinium p-toluenesulphonate or the like, or sulphuric acidic ion exchangers. Depending on the conditions used the dioxolan ring is also cleaved ~ during this reaction, there being obtained a compound of 15 formula IX. By treating a compound of formula VIII or IX with an agent yielding the group Z* there is obtained a compound of formula X or XI. Suitable agents yielding the group Z' 20 are, for example, chlorformic acid esters such as benzyl chloroformate, t-butyl chloroformate, 2,2,2-trichloroethyl chloroformate and the like. This reaction is conveniently carried out in an inert organic solvent, for example in a halogenated hydrocarbon such as methylene chloride, chloro-25 form and the like, and conveniently in the presence of an acid-binding agent such as butylene oxide, triethylamine, quinuclidine etc. The reaction is conveniently carried out at room temperature. 30 The hydrolysis of a compound of formula X to give a compound of formula XI is preferably carried out under mild acidic conditions. In a preferred embodiment the desired reaction is carried out by trans-acetalization in a lower alcohol such as methanol or ethanol and in the 35 presence of a suitable acidic catalyst. Suitable catalysts are, for example, sulphuric acidic ion exchangers, pyridinium ^ 15 20 25 30 p-toluenesulphonate, p-toluenesulphonic acid and the like. In this case the hydrolysis is preferably carried out at room temperature. The hydrolysis can, however, also be carried out readily in the presence of water and a water-miscible solvent such as tetrahydrofuran, dioxan, dimethyl sulphoxide,dimethylformamide or the like. The cleavage of the diol grouping in a compound of formula XI is carried out according to methods which are known per se and which are familiar to any person skilled in the art, and can be accomplished, for example, using sodium periodate in water. If desired, this reaction can be carried out in the presence of a solubilizer such as tetrahydrofuran, dioxan, methanol, ethanol or the like. This reaction yields an aldehyde of formula XII. The reduction of an aldehyde of formula XII to give a primary alcohol of formula XIII is also carried out according to methods which are known per se and which are familiar to any person skilled in the art, for example by treatment with sodium borohydride in a lower alcohol such as ethanol, isopropanol or the like. By reacting a compound of formula XIII with chloro-sulphonyl isocyanate in an inert organic solvent there is obtained a compound of formula XIV. Suitable solvents are, for example, ethers such as diethyl ether, t-butyl methyl ether and ethylene glycol dimethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, acetonitrile, dimethylformamide, dimethyl sulphoxide, acetone and the like. The reaction is preferably carried out in a temperature range of about 0°C to about room temperature. By cleaving the protecting group denoted by Z from a compound of formula XIV there is obtained a corresponding 206831 - 11 - compound of formula XV. The cleavage of a 2,4-di(lower alkoxy)benzyl group is conveniently carried out by mild oxidation. Suitable oxidation agents are, for example, potassium peroxydisulphate or ammonium peroxydisulphate, the oxidation being carried out in water at a pH of 6-8. A suitable buffer is, for example, disodium hydrogen phosphate . A lower 2-alkenyl group is cleaved by isomerization thereof to a 1-alkenyl group and subsequent oxidative cleavage of the latter. The isomerization of the double bond is preferably carried out with the aid of an isomerization catalyst, for example with a palladium dihalide such as palladium dichloride or with a tris(triphenylphosphine)-rhodium (I) halide (e.g. with the corresponding chloride) or also with palladium-on-carbon in the presence of a protonic acid such as hydrochloric acid or phosphoric acid. As the solvent there is conveniently used ethanol, methylene chloride or a mixture thereof with water. The reaction temperature conveniently lies in a range of about 50°C to the boiling point of the reaction mixture. The oxidative cleavage of the lower 1-alkenyl group can be carried out, for example, by treatment with an alkali metal permanganate, for example potassium permanganate, there being preferably used an aqueous potassium permanganate solution. If desired, the oxidation can be carried out with the aid of an alkali metal periodate (e.g. potassium periodate) in the presence of a catalytic amount of the mentioned alkali metal permanganate. The reaction is preferably carried out in an aqueous, buffered medium, especially an aqueous medium buffered to pH 7-8, but it can also be carried out in a water-miscible organic solvent, for example in acetone, dimethoxyethane, dioxan or tetrahydrofuran, with the addition of a weak organic base such as pyridine or in a mixture of one of these solvents with the mentioned aqueous buffer. The reaction can, however, also be carried out in a two-phase system using a phase transfer catalyst. Methylene chloride or benzene, for example, can be used as the organic phase which is not miscible with water. Conventional phase transfer catalysts can be used, especially organic quaternary ammonium halides such as benzyltriethylammonium chloride, tetra-n-butylammonium bromide and cetyltrimethylammonium bromide. The oxidative cleavage is preferably carried out at a temperature between about 0°C and 25°C. g The compounds of formula XV in which R signifies carbamoyl can be obtained by oxidizing an aldehyde of formula XII according to methods known per se to give a carboxylic acid of formula XVIII, esterifying the carboxylic acid of formula XVIII, for example with methyl iodide in the presence of potassium carbonate, cleaving off the protecting group denoted by Z in the manner described above from the resulting compound of formula XIX and treating the compound of formula XX obtained with hydroxylamine. The compounds of formula XV in which R6 signifies carbamoyl can, however, also be obtained by treating a compound of formula XII with hydroxylamine, converting the resulting oxime of formula XXI in a manner known per se into the nitrile of formula XXII, cleaving off therefrom the protecting group denoted by Z as described above and saponifying the nitrile group in the resulting compound of formula XXIII in a manner known per se to the carbamoyl group. By treating a compound of formula XV with sulphur trioxide or a suitable complex of sulphur trioxide there is obtained a compound of formula XVI. Suitable sulphur tri- - 13 - 20 oxide complexes are, for example, complexes with pyridine, trimethylamine, picoline, dimethylformamide and the like. An ether such as dioxan, pyridine, acetonitrile, dimethylformamide or the like is conveniently used as the solvent. The preferred solvent is acetonitrile. The reaction is preferably carried out at a temperature between about 0°C and 80°C. By cleaving off the protecting group denoted by Z' from a compound of formula XVI there is obtained a compound of formula XVII. A benzyloxycarbonyl group can be cleaved off, for example, hydrogenolytically, for example by treatment with elemental hydrogen in the presence of palladium-on-carbon. A t-butoxycarbonyl group can be cleaved off, for example, by treatment with trifluoroacetic acid or formic acid. A trichloroethoxycarbonyl group can be cleaved off, for example, by treatment with zinc in the presence of an acid such as acetic acid or hydrochloric acid. By acylating a compound of formula XVII with a reactive functional derivative of a carboxylic acid of the general formula T V-C-COOH XXIV N u » 5 "0R wherein R^ has the above significance, there is finally obtained the desired target compound of formula VII. It will be appreciated that the compound of formula XXIV must be suitably protected when R5 signifies hydrogen or carboxy-lower alkyl? the protecting group is removed after the acylation has been carried out. As reactive functional derivatives of compounds of formula xxiv there can be used, for example, corresponding acid anhydrides, mixed anhydrides, benzthiazolyl thioesters and the like. - 15 - The following Examples illustrate the present inven-. tion in more detail; they are, however, not intended to be limiting in any manner. All temperatures are given in 5 degrees Celsius. Example 1 a) 12 g (92.16 mmol) of isopropylidene-L-glyceralde- 10 hyde are dissolved in 200 ml of methylene chloride, treated firstly with 60 g of magnesium sulphate and then dropwise over a period of 10 minutes with 5.26 g (92.16 mmol) of 3-amino-l-propene in 50 ml of methylene chloride and the suspension is stirred at room temperature for 5 hours. 15 The magnesium sulphate is filtered off and the clear colourless solution is evaporated on a rotary evaporator. 14.6 g (86.3 mmol; 93.6%) of pure isopropylidene-L-glyceraldehyde allylimine are obtained. 20 b) 8.64 g (51.1 mmol) of isopropylidene-L-glyceralde hyde allylimine are dissolved in 400 ml of methylene chloride, treated firstly with 10.32 g (102.2 mmol) of tri-ethylamine and then with 10.79 g (51.1 mmol) of potassium N- (l-methyl-2-methoxycarbonylvinyl) aminoacetate, the sus-25 pension is cooled to O® and treated dropwise within 5 minutes with 9.74 g (51.1 mmol) of p-toluenesulphonyl chloride in 50 ml of methylene chloride. The cooling bath is removed, the mixture is stirred at room temperature for 8 hours, treated with 200 ml of water, the organic phase is 30 separated and evaporated. The crude product is chromato-graphed on silica gel while eluting with hexane/ethyl acetate (8:2). There are obtained 13.0 g (40.0 mmol; 78%) of methyl (Z)-3-[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]-2-butenoate as 35 an oil which solidifies slowly upon standing. A product of melting point 98° is obtained by crystallization from ether/hexane. Example 2 1.7 g (10 mmol) of isopropylidene-L-glyceralde-hyde allylimine are dissolved in 80 ml of methylene chloride, treated firstly with 3.03 g (30 mmol) of triethyl-amine and then with 2.6 g (10 mmol) of potassium N-(l-methyl-2-benzoylvinyl)aminoacetate and the suspension is cooled to 0°. 2.85 g (15 mmol) of p-toluenesulphonyl chloride in 10 ml of methylene chloride are added dropwise thereto, the mixture is stirred at room temperature for 5 hours, washed with 100 ml of water and evaporated. The crude product is purified on silica gel using hexane/ethyl acetate (7:3) for the elution. There are obtained 1.5 g (4.04 mmol; 40%) of (3S,4S)-l-allyl-3-[[(Z)-2-benzoyl-l-methylvinyl] amino]-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl] -2-azetidinone as a pure oil which crystallizes out from a mixture of ether and hexane and then has a melting point of 154-156°. Example 3 1.7 g (10 mmol) of isopropylidene-L-glyceraldehyde allylimine are dissolved in 80 ml of methylene chloride and treated firstly with 3.03 g (30 mmol) of triethylamine and then with 2.8 g (10 mmol) of potassium N-(2,2-diethoxy-carbonylvinyl)aminoacetate. 2.85 g (15 mmol) of p-toluenesulphonyl chloride in 20 ml of methylene chloride are then added dropwise to the solution which is cooled in ice and the mixture is stirred at room temperature for 5 hours. The mixture is subsequently washed with 100 ml of water, the organic phase is evaporated and the crude product obtained is chromatographed on silica gel while eluting with hexane/ ethyl acetate (7:3). There are obtained 1.15 g (2.9 mmol; 29%) of pure diethyl [[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl- €1 - 17 - 20683 1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]methylene]-malonate as an oil. IR spectrum (film): bands, inter alia, at 1755, 1740, 1700, 5 1660 and 1600 cm \ Example 4 _ 3.75 g (13.44 mmol) of isopropylidene-L-glyceralde- ^ 10 hyde (2,4-dimethoxybenzyl)imine [obtained from isopropyl-idene-L-glyceraldehyde and 2,4-dimethoxybenzylamine in a manner analogous to that described in Example la)] are dissolved in 150 ml of methylene chloride and treated with 3.25 g (32.25 mmol) of triethylamine. 3.40 g (16.12 mmol) V 15 of potassium N-(1-methy1-2-methoxycarbonylvinyl)aminoacetate are added and the suspension is cooled to 0°. 3.40 g (16.12 mmol) of p-toluenesulphonyl chloride in 50 ml of methylene chloride are added dropwise thereto within 5 minutes and the mixture is stirred at room temperature for 20 15 hours. After washing with 100 ml of water and evaporating the organic phase, the residue is purified by chromatography on silica gel using hexane/ethyl acetate (7:3) as the eluting agent. There are obtained 3.45 g (7.94 mmol; 59%) of pure methyl (Z)-3-[[(2S,3S)-1-(2,4-dimethoxybenzyl)-25 2-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]-amino]-2-butenoate as an oil which solidifies slowly. After crystallization from ether/hexane, the product has a melting point of 121°. ly 30 Example 5 / 2.8 g (10 mmol) of isopropylidene-L-glyceraldehyde (2,4-dimethoxybenzyl)imine are dissolved in 125 ml of methylene chloride and treated with 3.03 g (30 mmol) of 35 triethylamine. 2.6 g (10 mmol) of potassium N-(l-methyl-1-benzoyl-vinyl)aminoacetate are then added and the suspension is stirred strongly at 0°. 2.85 g (15 mmol) of p- </div>

Claims

<div class="application article clearfix printTableText" id="claims"> toluenesulphonyl chloride in 50 ml of methylene chloride are slowly added dropwise thereto and the mixture is stirred at room temperature for 5 hours. The mixture is then treated with 100 ml of water, the organic phase is separated and evaporated. The residue is chromatographed on silica gel using hexane/ethyl acetate (7:3) as the eluting agent. There are obtained 1.4 g (2.91 mmol; 29%) of pure (3S,4S)-3-[[(Z)-2-benzoyl-l-methylvinyl]amino]-1-(2,4-dimethoxy-benzyl)-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-azetidi-none which crystallizes out from ether/hexane and then has a melting point of 177-179°. Example 6 6.48 g (20 mmol) of methyl (Z)-3-[[(2S,3S)-1-allyl-2-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]-amino]-2-butenoate are dissolved in 40 ml of acetone and treated with 3.80 g (20 mmol) of p-toluenesulphonic acid monohydrate in 20 ml of acetone. The clear solution is stirred at room temperature for 15 minutes and then treated slowly with 120 ml of ether. The precipitated product is filtered off and dried. There are obtained 6.4 g (15.3 mmol; 77%) of pure (3S,4S)-cis-3-amino-l-allyl-4-[ (R)^^-dimethyl-l/S-dioxolan^-yl] -2-azetidinone p-toluenesulphonate of melting point 165°. Identical products are obtained when (3S,4S)-1-allyl-3-[t(Z)-2-benzoyl-l-methylvinyl]amino]-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-azetidinone and diethyl [[[(2S, 3S)-l-allyl-2-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]methylene]malonate are subjected to the same reaction conditions. The yields lie between 75% and 80%. ^juti^uirat56* - 19 - 20883.1 WHAT WE CLAIM IS; 1. A process for the manufacture of optically uniform 5 0-lactams of the general formula 10 H OK 1 H H 15 wherein R signifies lower alkanoyl, 2 lower alkoxycarbonyl or benzoyl, R signifies hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or 3 cyano, R signifies hydrogen or lover 20 alkyl, B signifies lower alkylidene, lower cycloalkylidene or carbonyl and Z signifies lower 2-alkenyl or 2,4-di(lower alkoxy)benzyl, and their corresponding optical antipodes, which process 25 comprises reacting a isalt of a carboxylic acid of the general formula 30 COOH II 35 1 2 3 wherein R , R and R have the above significance, 5 10 30 - 20 - 206831 in the presence of a reactive derivative of an organic sulphonic acid and a base with an optically uniform compound of the general formula III wherein B and Z have the above sig-15 nificance, or the optical antipode thereof. 2. A process according to claim 1, wherein R1 signifies 2 lower alkoxycarbonyl and'R signifies hydrogen. 20 3. A process according to claim 1 or 2, wherein B signifies lower alkylidene. 4. A process according to any one of claims 1 to 3, 25 wherein Z signifies lower 2-alkenyl. 5. A process according to claim 1, wherein methyl (Z) —3- [ [ (2S,3S)-l-allyl-2-[ (R) -2,2-dimethyl-l, 3-dioxolan-4-yl]-4-oxo—3-azetidinyl]amino] -2-butenoate is manufactured. 6. A process according to claim 1, wherein (3S,4S)-1-allyl-3-[ [ (Z)-2-benzoyl-l-methylvinyl]amino]-4-[ (R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone is manufactured. 7. A process according to claim 1, wherein diethyl [[(2S,3S)-l-allyl-2-[ (R)-2,2-dimethyl-l,3-dioxolan-4-yl]- <4^oxo-3-azetidinyl] amino]methylene]malonate is manufactured, ■7 JAN 1987 to - 21 - 20683: 8. A process according to claim 1, wherein methyl (Z)-3-[[(2S,3S)-1-(2,4-dimethoxybenzyl)-2-[(R)-2,2-dimethyl-1,3-dioxolan-4-ylJ-4-oxo-3-azetidinyl]amino]-2-butenoate is manufactured. 9. A process according to claim 1, wherein (3S,4S)-3- [[(Z)-2-benzoyl-l-methylvinyl]amino]-1-(2,4-dimethoxybenzyl) 4—[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-azetidinone is manufactured. 10. A process according to any one of claims 1 to 9, wherein the reactive derivative of an organic sulphonic acid is a compound of the general formula r4-so2-x IV wherein X signifies halogen or the group 4 4 -OSO2-R and R signifies aryl, lower alkyl or lower haloalkyl. 11. A process according to claim 10, wherein X signifies 4 halogen and R signifies phenyl optionally substituted by halogen or lower alkyl. 12. A process according to claim 11, wherein X signifies chlorine. . .' i ■'2? 13. A process according to any one of claims 1 to 12, wherein the base is a tertiary amine. 14. A process according to any one of claims 1 to 13, ^ wherein an alkali metal salt of a carboxylic acid of formula II is used. A process according to any one of claims 1 to 13, ein the potassium salt of a carboxylic acid of formula r*"7JANI95^is used- ■ -'P ?} v ' - 22 206831 16. The use of a process according to any one of claims 1 to 15 in the manufacture of antimicrobially active, optically uniform substances containing a 0-lactam ring. 17. The use of a process according to any one of claims 1 to 15 in the manufacture of antimicrobially active substances of the general formula A II I H H , \>—c — C —N _ - ^ r6 h2n VII S N\ o SO3H 5 wherein R signifies hydrogen, lower alkyl or carboxy-lower alkyl and R® signifies carbamoyl or carbamoyloxy-methyl, and their pharmaceutically acceptable salts. 18. A process according to claim 1, for the manufacture of optically uniform ^-lactams of-the formula I defined in claim 1, and their corresponding optical antipodes, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 5. 19. Optically uniform B-lactams of the formula I defined in claim 1, and their corresponding optical antipodes , whenever manufactured according to the process claimed in any one of claims 1 to 15 and 18. DATED THIS 2-^ DAY OF 3^ I* i A. J. PARK & SON AGENTS FOR THE APPLICANTS * </div>