FI84716B - FOERFARANDE FOER FRAMSTAELLNING AV OPTISKT AKTIVA ACYLOXIAZETIDINONER. - Google Patents

Abstract

(4R)-3,4-trans-disubstituted azetidinones of the formula <IMAGE> in which R1 denotes hydrogen or lower alkyl, R2 denotes hydrogen or a hydroxyl-protecting group R, R3 denotes phenyl, substituted phenyl or lower alkyl and R4 denotes hydrogen or an amino-protecting group R, are valuable intermediates for the preparation of optically active penem or carbapenem compounds which act as antibiotics. The processes comprise the ring closure between carbon atoms 3 and 4 of the azetidinone ring.

Description

8471 6

Process for the preparation of optically active acyloxylacetones

The present invention relates to a process of formula I.

ff * T ϊ 8 R, 'pvji—: (R) °' c'R3 ui for the preparation of (4R) -3,4-trans-disubstituted azetidinones, in which formula represents hydrogen or lower alkyl, R2 represents hydrogen or a hydroxy-protecting group R2 ' , R 3 denotes phenyl or phenyl substituted by lower alkyl, lower alkoxy or halogen and R 4 denotes hydrogen or an amino-protecting group 1 * 4 ', and new compounds of the formula I in which the radicals R 1, R 2 and R 4 have the meanings given and R 3 is phenyl or em .phenyl substituted phenyl.

The compounds of formula I are novel. Compounds of formula I in which R 3 is methyl are known, for example, from Japanese Patent Application Sho 55-34077. Compared to previously known processes for the preparation of compounds of formula I in which R 3 is methyl, the process of this invention is superior in that the compounds of formula I are obtained in higher yield and in a more economical manner stereospecifically, and compared to other known starting groups such as tert. The benzoyloxy group optionally substituted with a.-butylsulfonyl or acetoxy group can be exchanged for a thiocarbonyl group in higher yield.

The general definitions used in the context of this invention preferably have the following meanings: 2,84716

The term "lower" as used in connection with groups or residues, e.g., lower alkyl, lower alkoxy, lower alkanoyl, etc., means that the groups thus marked contain at most 7, in particular at most 4, carbon atoms, unless expressly stated otherwise.

Lower alkyl is preferably methyl, further ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

is preferably methyl or also hydrogen.

R 2 is preferably hydrogen.

Hydroxy protecting groups R2 'and their attachment and cleavage are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, and "Protective Groups in Organic Chemistry", Wiley, New York 1974.

The hydroxy protecting group R2 'is, for example, an acyl group of a substituted carboxylic or sulfonic acid, e.g. a lower alkanoyl substituted by a halogen such as fluorine or chlorine, e.g. a 2,2-dichloro- or 2,2,2-trifluoroacetyl, lower alkyl or lower alkenyl carbonic acid half ester an acyl group optionally substituted, e.g. halogen, e.g. substituted by chlorine, phenyl or p-nitrophenyl, e.g. 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, optionally substituted by nitro, halo or lower aroyl, such as benzoyl, e.g. 4-nitro, 3,5-dinitro, 4-chloro or 4-methoxybenzoyl, lower alkanesulfonyl, such as methanesulfonyl, arylsulfonyl, such as toluenesulfonyl, 2-oxa or 2- thiacycloalkyl having 5 to 7 ring members, e.g. 2-tetrahydrofuryl or 2-tetrahydropyranyl 3,84716 or a thia analogue thereof, 1-lower alkoxy lower alkyl, e.g. methoxides yl or 1-ethoxyethyl, or a silyl group triple substituted by lower alkyl, aryl lower alkyl and / or aryloxy.

r 2 'is preferably a substituted acyl group of a carbonic acid half ester, e.g. 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, benzoyl once or twice substituted by nitro, e.g. 4-nitro or 3,5-dinitro -li, or a silyl group substituted by said groups, e.g. trialempkylsilyl such as trimethyl or triethylsilyl, dialempkyl-trialempalkylmethylsilyl, e.g. dimethyl or diethyl- (2-ethyl-2-propyl) silyl, dimethyl- ( tert-butyl) silyl or dimethyl- (2,3-dimethylbut-2-yl) silyl, diaryl (lower alkyl) silyl, e.g. diphenyl- (tert-butyl) silyl, aryl- (dialkylalkyl) silyl, e.g. tert-butylmethyl-phenylsilyl and tri-lower alkylaryloxy- (dialkylalkyl) silyl, e.g. 2,4,6-tri- (tert-butyl) phenoxy (dimethyl) silyl.

Particularly preferred protecting groups R2 'are 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl and 3,5-dinitrobenzoyl due to their very easy cleavability.

Substituted phenyl R 3 is, for example, mono- or trisubstituted by lower alkoxy, e.g. nitro, lower alkyl, e.g. methyl and / or halogen, e.g. chlorine. R3 is preferably phenyl.

The amino-protecting group R4 'is preferably oxidatively cleavable arylmethyl or aryl, the aryl being preferably phenyl substituted by one or more, e.g. two lower alkoxy groups, e.g. niethoxy, and 4,84716 in particular represents 4-methoxybenzyl or 2,4-dimethoxybenzyl or resp. 4-methoxyphenyl or 3,4-dimethoxyphenyl.

The process according to the invention is characterized in that the formula II

ffn R'-m - | (sf-Rj <»> ✓ A compound of the formula wherein the radicals R 1, R 2, R 3 and R 4 have the meanings given in connection with formula I is subjected to a Bayer-Villiger reaction by treatment with peracid and, if desired, in the resulting compound of formula I , wherein r 2 represents hydrogen, the free hydroxy group is converted into a protected hydroxy group 0R 2 'and / or, if desired, the hydroxy compound protecting group R 2' and / or the amino protecting group R 4 'is cleaved from the resulting compound of formula I.

Preferably, in the starting material of formula II, R 1 is hydrogen or methyl, R 2 is hydrogen or one of said hydroxy protecting groups R 2 ', such as 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, 3,5-dinitrobenzoyl, dimethyl tert-butylsilyl or dimethyl -2,2-dimethylbut-2-ylsilyl, R 4 is hydrogen or an aryl group, especially p-methoxyphenyl and R 3 is phenyl.

Organic, inorganic peracids or iminopercarboxylic acids or their salts, such as alkali metal or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts, e.g. optionally halogenated lower alkanercercarboxylic acids, such as peracetic acid or trifluoroacetic acid, or trifluoroacetic acid, can be used for the reaction. and / or halogenated mono- or disubstituted aromatic peracids such as perbenzoic acid, p-nitro-per-benzoic acid, m-chloroperbenzoic acid, 3,5-dinitro-per-benzoic acid, monoperphthalic acid or a salt thereof, e.g. magnesium monoperft , peroxosulphuric acids, e.g. peroxysulphuric acid, trihalogeniminoacetic acid, e.g. trichloro- or trifluoroiminoacetic acid. Preference is given to peracetic acid, m-chloroperbenzoic acid and monoperphthalic acid.

Peracids can also be formed in situ, e.g. from the corresponding acid or a salt thereof and hydrogen peroxide. In particular, iminopercarboxylic acids are conventionally prepared in situ, e.g. from the corresponding nitriles and hydrogen peroxide, preferably in the presence of a weakly acidic buffer, e.g. potassium hydrogen phosphate. The reaction takes place in a conventional solvent, e.g. a halogenated hydrocarbon such as methylene chloride or chloroform, a liquid acid ester such as ethyl acetate, such as glacial acetic acid, or an alcohol such as a lower alkanol, e.g. ethanol, at a temperature of about 0e to about 100eC, optionally inert. in the atmosphere and possibly under pressure, e.g. at about 10 bar.

The hydroxy-protecting group R2 'can be attached in a manner known per se, e.g. by reacting a compound of formula I in which R2 is hydrogen and R4 is preferably an amino-protecting group R4' with a reactive derivative of an acid whose acyl group is a hydroxy-protecting group, e.g. by reacting an anhydride, e.g. trifluoroacetic acid. a mixed anhydride, e.g. an acid halide, e.g. 2,2,2-dichloroacetyl chloride, a carbonic acid half ester mixed anhydride, e.g.

With 2,2,2-trichloroethyl, allyl, phenyl or p-nitrophenyl chloroformate, by reacting with 1,2-dihydrofuran or 1,2-dihydropyran in the presence of an acid, e.g. p-toluenesulfonic acid, or by reacting a halosilane , e.g. with a trialkylalkylhalosilane, 6,84716 such as trimethylchloro or dimethyl-tert-butylchlorosilane.

In the obtained compound of the formula I, the cleavage of the protecting group R2 'takes place in a manner known per se, e.g. by solvolysis, e.g. by acidolysis, reduction or oxidation.

The acyl group R2 'may be saponified under acidic or temporal conditions, depending on the meaning of the residue R2', for example with acids such as formic or trifluoroacetic acid or bases such as alkali metal hydroxide or carbonate, e.g. sodium bicarbonate, bicyclic amidine [ .0] undec-5-ene, or an alkali metal halide. The 2-oxa or 2-thiacycloalkyl group is cleaved in the presence of acids.

Halogen-lower alkoxycarbonyl and optionally nitro-substituted benzyloxycarbonyl R 2 'can be cleaved and replaced by hydrogen, by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a suitable hydrogenation catalyst, e.g. platinum oxide or palladium, or by treatment with aqueous reducing agents such as

The silyl group R2 'substituted as shown may be cleaved in the presence of hydroxyl group-containing solvents neutrally, acidically or alkaline, or in particular by treatment with a fluoride anion-producing hydrofluoric acid salt such as alkali metal fluoride, sodium fluoride, such as tetra-lower alkylammonium fluoride, e.g. tetrabutylammonium fluoride.

The conversion of the lower alkynyloxycarbonyloxy group -OR2 'to hydroxy, in which the lower alkenyl denotes in particular allyl, occurs preferably with the acceptor of the lower alkenyl groups in the presence of tetrakis-triphenylphosphine palladium and optionally in the presence of triphenylphosphine. Suitable acceptors for lower alkenyl groups, such as in particular the allyl group, are, for example, amines, such as especially sterically hindered amines, e.g. tert-butylamine, further tri-lower alkylamines, e.g. triethylamine, morpholine or thiomorpholine, aliphatic or cyclic e.g. acetylacetone, acetic acid ethyl ester or dimedone, further also lower alkanecarboxylic acids, e.g. acetic acid or propionic acid. One preferred acceptor is dimedone. The reaction is carried out with 1.5 to 10 molar equivalents of a lower alkylene group acceptor in the presence of 2 to 10 mol%, in particular 5 to 8 mol% (relative to the starting compound of the formula) of a tetrakis-triphenylphosphine-palladium catalyst, optionally 50 molar equivalents of triphenylphosphine. in the presence of% in an inert solvent such as ether, e.g. dioxane or especially tetrahydrofuran, halohydrocarbon, e.g. methylene chloride, lower alkanol, e.g. ethanol, ester, e.g. ethyl acetate or a mixture thereof at room temperature or at slightly elevated or reduced temperature. e.g. at about 0 ° to 40 ° C, preferably from about 20 ° to about 25 ° C, if necessary in an atmosphere of an inert gas such as nitrogen or argon.

The arylmethyl group 1 * 4 ', e.g. 4-methoxy or 2,4-dimethoxybenzyl, is cleaved, e.g. by oxidation, e.g. by reacting with a strong oxidizing agent, e.g. an inorganic peroxo salt, e.g. sodium or potassium peroxodisulphate, an acid salt, e.g. in the presence of dipotassium hydrogen phosphate and optionally in the presence of a catalyst, e.g. a metal salt, e.g. an iron (II) and / or copper (II) salt, e.g. an iron (II) sulphate heptahydrate and / or a copper (II) acetate hydrate, or in particular by reacting cer ( IV) salt, e.g. cer (IV) iodate, cer (IV) nitrate (CeOH (NO 3) 3), s 84716 with cer (IV) sulphate or preferably diammonium cer (IV) hexanitrate, e.g. in aqueous-organic media, preferably aqueous acetonitrile.

The aryl group R4 ', e.g. 4-methoxyphenyl or 3,4-dimethoxyphenyl, is preferably cleaved by oxidation, e.g. ozonolytically in ethyl acetate and then decomposed to form ozonides by reduction with a reducing agent, e.g. sodium thiosulphate or by reaction with a cer (IV) salt. , e.g. with diammonium cer (IV) hexanitrate.

R4 'can be cleaved depending on the meaning of the residue R2' either selectively or together with the residue R2 '.

The cleavage reactions shown are carried out under conditions known per se, if necessary with cooling or heating and possibly in an atmosphere of an inert gas, e.g. nitrogen.

In particular, this invention relates to a process for the preparation of compounds of formula I, wherein R 1 represents hydrogen or methyl, R 2 represents hydrogen or a hydroxy protecting group R 2 ', e.g. a substituted acyl group of a carbonic acid half ester, e.g. 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, 4-nitro or 3,5-dinitrobenzoyl or trialamalkylsilyl, e.g. trimethylsilyl, dimethyl-tert-butylsilyl or dimethyl- (2,3-dimethylbut-2-yl) silyl, R 3 denotes phenyl and R 4 denotes hydrogen or the amino-protecting group R 4 ', e.g. 4-methoxybenzyl, 2,4-dimethoxybenzyl, 4-methoxyphenyl or 3,4-dimethoxyphenyl and in which the 11-C atom of the side chain has the R or S configuration , when R 1 represents lower alkyl.

The compounds of the formula I, in particular those in which R1 is hydrogen or methyl, R2 represents hydrogen or also the hydroxy-protecting group R2 ', and R4 is hydrogen, are valuable intermediates 9 84716 which can be further treated in a manner known per se to antibiotically active penems. or carbapenem compounds. The work-up is carried out in the same way as for the known azetidinone compounds of the formula I in which R3 is methyl, e.g. in T. Hayashi et al., Chem. Pharm. Bull. 29, 3158, 1981 or in European Patent Application Nos. 42026 (penems) or 78026 (carbapenems).

The invention likewise relates to the starting compounds of the formula II, in particular those in which the radicals R1 # R2, R3 and R4 have the preferred meanings.

The compounds of formula II can be prepared by:

(a) cyclization of formula III

R 1 -C 2 - (2R) j 2 H 2 -? - R 3 (HI) c / Nit

the α-carbanion of the compound of formula wherein R1f R3 and R41 have the meanings given in connection with formula I, and the 2-C atom has the R configuration and when R1 represents lower alkyl, the 3-C atom has the R or S configuration , or of formula IV

(CH-if ^ R) CH 2 -H-R 1 and X represents a nucleofugic starting group and the 2-C atom has the R configuration and when R 1 represents lower alkyl, the 3-C-atom 8 4 71 6

having the R or s configuration, or b) isomerizing Formula II

l'f2 f! f

A cis compound according to R 1 - p.jHyC-Ra (II ') (/, in which the radicals R 1, R 2, R 3 and R 4 have the meanings given in connection with the formula II and, if desired, cleaving the amino-protecting group R 4' a compound of formula II to another compound of formula II.

In the starting material of formula IV, under the conditions of the cyclization process, the uncleaved hydroxy protecting group R2 "is one of the acyl groups of the substituted carboxylic or sulfonic acid mentioned in connection with the residue R2 ', e.g. 2,2,2-trifluoroacetyl, a substituted acyl group of a carbonic acid half ester, e.g. p-nitrobenzoyl tetrahydrofuryl or pyranyl, or 1-lower alkoxy lower alkyl, e.g. methoxymethyl or 1-ethoxyethyl, or an optionally substituted aroyl, e.g. 4-nitrobenzoyl or 3,5-dinitrobenzoyl group, and a suitable nucleofugic starting group x is, for example, halogen, e.g. chlorine, bromine or iodine, lower alkanoyloxy, e.g. acetoxy, arylsulfonyloxy, e.g. phenylsulfonyloxy or tosyloxy, or lower alkylsulfonyloxy, e.g. mesyloxy.

By α-carbanion of a compound of formula III or IV is meant an anion in which the negative charge is in the α-position on the carbon atom relative to the -CO-R3 group, i.e. the corresponding compound of the sub-formula -N-CH9-CO-R3. Such carbanions are prepared in situ by treating a compound of formula III or IV in a suitable solvent with a base which forms such carbanions. Such bases 11 8471 6 are, for example, alkali metal bases, such as hydroxides or carbonates of sodium, potassium or lithium, or organic alkali metal compounds, e.g. lower alkyllithium compounds, such as n-butyl or tert-butyllithium, alkali metal amides, e.g. lithium diisopropyl amide. di-tert-butylamide and especially alkali metal amides in which two hydrogen atoms have been replaced by silyl groups, e.g. trimethylsilyl groups, e.g. lithium, sodium or potassium bis- (trimethylsilyl) amide.

Other bases include organic nitrogen bases, e.g., amidines such as 1,5-diazabicyclo [4.3.0] non-5-ene and 1,5-diazabicyclo [5.4.0] undec-5-ene, and reagents, which produce fluoride ions in an aprotic organic solvent and are particularly suitable for the preparation of carbanones of the compounds of the formula III.

The reagent which produces fluoride ions in the aprotic organic solvent is preferably tetra-lower alkyl ammonium fluoride, especially tetra-n-butylammonium fluoride.

Suitable solvents for the formation of the carbanion include, for example, hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as methylene chloride or chloroform, ethers such as dioxane, tetrahydrofuran or dimethoxyethane, amides such as dimethylformamide or hexamethyltriethulfides such as acetyltersulfide, alloys. The reaction may also be carried out under phase transfer conditions, e.g. in a system of methylene chloride and 50% sodium hydroxide in the presence of a phase transfer catalyst such as benzyltriethylammonium chloride or tetrabutylammonium hydrogen sulphate. The reaction temperature also depends on the base used and is about -80 ° to 80 ° C. It is preferable to work in an atmosphere of an inert gas, e.g. argon or nitrogen.

i2 8 4 71 6

In the process, the configuration of the 2-C atom of the starting material is inverted so that the 2R compound of formula III or IV forms a 3S compound of formula II. The configuration of the l'-C atom of the side chain (R 1 = lower alkyl) remains unchanged. For example, R-glycidic acid pyramides of formula (III) give 3S-acetyldinones of formula II or (2R, 3R) -2,3-epoxybutyric acid amides of formula III give (3S, 1'R) -3-hydroxyethylacetidinones of formula II .

The isomerization process b) takes place in a suitable solvent or solvent mixture in the presence of a base. Suitable solvents and bases as well as reaction conditions are the same which can be used for the cyclization process a). Preferably, aprotic dipolar solvents such as dimethylformamide, N-methylpyrrolidine, dimethyl sulfoxide or the like are used. Suitable bases are, in particular, potassium carbonate or 1,5-diazabicyclo [5.4.0] undec-5-ene, in which case it is also possible to work under the mentioned phase transfer conditions.

The cis compounds of the formula II 'can be formed as by-products of the cyclization reaction a). They can be separated in a conventional manner, e.g. by chromatography.

Compounds of formula III may be prepared in a manner known per se by reacting compounds of formula VII

S

With epoxy acids of formula Rj-qt —-- pC (viii) </ noh or their salts, in a manner similar to that described for the reaction of a carboxylic acid of formula VI with an amine of formula VII. The epoxy acids of the formula VIII are known or can be prepared in a manner known per se.

In a preferred embodiment of the process, the starting materials of formula III can be prepared in situ according to formula V

Rk 0; ch-Ct2S) CH2-fi-Ra

Rg'O I_I

✓ Of the compounds according to Su, in which the radicals, R3, R4 'and X have the meanings given, R2, M denote hydrogen or a hydroxy-protecting group which can be cleaved under epoxide formation conditions and in which the 3-C atom has the R or S configuration when R1 denotes lower alkyl , under said carbanion-forming conditions and by Walden inversion at 2-C.

In the compound of formula V, the hydroxy protecting group R 2 "'which is cleavable under epoxide formation conditions is a trialamylalkylsilyl group, e.g. dimethyl-tert-butylsilyl or trimethylsilyl. X preferably represents halogen, e.g. chlorine or bromine, lower alkanesulfonyloxy, e.g. mesyloxy, e.g. tosyloxy.

Cleavage of the group R 2 "'- X, wherein R 2'" is hydrogen, takes place with one of said carbanion-forming bases, e.g. sodium or potassium hydroxide or sodium or potassium carbonate, preferably an amidine, e.g. 1,5-diazabicyclo [5.4 .0] undec-5-ene, or also with tetra-lower alkylammonium fluoride, e.g. anhydrous tetra-n-butylammonium fluoride. When R2 "'represents a trialempkylsilyl group to be cleaved under epoxide formation conditions, tetra-loweralkylammonium fluoride is preferably used.

i4 8471 6

The reaction to the epoxy compound of formula III is preferably carried out in an inert, more preferably anhydrous solvent or solvent mixture, for example a carboxylic acid amide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. in tetrahydrofuran, an ester, e.g. ethyl acetate, or a nitrile, e.g. acetonitrile or a mixture thereof, optionally at a reduced or elevated temperature, e.g. about -40 ° to about + 100 ° C, preferably about -10 ° to about + 50 ° C and possibly in an atmosphere of an inert gas, e.g. nitrogen.

In the reaction according to this method, the configuration of the 2-C atom is reversed, while the configuration of the 3-C atom = Lower alkyl) is retained. The 2S-halo-3R-hydroxycarboxylic acid amides of formula v are formed from the (2R, 3R) compounds of formula III. The same applies to 2S-halo-3S-hydroxycarboxylic acid amides of the formula III.

The epoxide of formula III can also be isolated after its preparation by cleaving the group R 2 "'- X from the compound of formula V.

The conversion of a compound of formula V wherein R 2 "'is hydrogen to an epoxy compound of formula III and its isolation takes place in a manner known per se, e.g. from steroid chemistry, see C. Djerassi et al.," Steroid Reactions ", Holden Day, San Francisco 1963, p. 606-613, under known reaction conditions, in particular with one of said amidines, such as 1,5-diazabicyclo [5.4.0] undec-5-ene When a compound of formula III has to be isolated before further processing, it is preferable to use one of said amidines. approximately as an equimolar amount.

is 8471 6

The compounds of formulas IV and V are likewise the subject of this invention.

Compounds of formula V may be prepared, for example, by reacting compounds of formula VI

A compound of the formula 0r2 'Κ, · 3κϊ ··· χ J (2S) (VI) </ noh, wherein the radicals, R2 "' and x have the formula

The meanings mentioned in connection with V are reacted with the compounds of formula VII

With an amine of the formula R (NH-CH2-E-Ra (VII) in which the radicals R3 and R4 'have the meanings given in connection with the formula V.

The reaction of the amines of the formula VII with the acid of the formula VI takes place in a manner known per se under acylating conditions, for example by condensing the two compounds in the presence of a condensing agent, or by reacting a reactive functional derivative of the carboxylic acid of the formula VI with an amine of the formula VII. Suitable condensing agents are, for example, diimides, such as diethyl or dicyclohexylcarbodiimide, or di-N-heterocyclylcarbonyl compounds, such as carbonyldiimidazole, or a 1,2-oxazolium compound, such as 2-ethyl-5-phenyl-1,2-oxazolium -3-sulfonate or 2-tert-butyl-5-methyl-1,2-oxazolium perchlorate, used in the presence of an inert solvent at room temperature or at a slightly reduced or elevated temperature. Reactive functional derivatives of the carboxylic acid (VI) are in particular anhydrides, in particular mixed anhydrides, such as the corresponding carboxylic acid chloride or bromide, which optionally react with an amine of the formula VII in the presence of a base.

Compounds of formula VI and vi 'wherein X is halogen are known. They can be prepared, for example, in a manner known per se from L-serine or L-threonine or, inter alia, their D-isomers by diazotizing the amino group with a nitrite salt, e.g. potassium nitrite in the presence of hydrohalic acid.

When L-serine is used according to the methods described, starting from the compounds of formula VI, compounds of formula I in which the carbon in the 3-position of the azetidinone ring has the R-configuration can be obtained.

The use of L-threonine gives compounds of the formula I in which the C atom in the 3-position of the azetidinone ring has the R configuration and the 1'-C atom in the hydroxyethyl side chain has the R configuration. If it is desired to prepare compounds of formula I in which the 3-C atom has the R-configuration and the 1'-C atom of the hydroxyethyl side chain has the S-configuration, the starting material is allotreonine. In all the reactions shown, the configuration of the C atom corresponding to the 1'-C atom of the 3-lower alkyl-CH- (OR2) side chain is retained.

In a manner similar to the preparation of compounds of formula V, compounds of formula IV can be prepared starting from compounds of formula VII and

Vi · 17 8471 6 QRä Η, Χ

Rl’x-r (vr) </ noh.

The compounds of the formula VII are known or can be prepared in a manner known per se, provided that they are new.

The present invention also relates to embodiments of the process which start from a compound obtained in one of the preliminary steps of the process and carry out the related process steps.

The invention also relates to a combination of process steps starting from compounds of formulas VI, VI ', VII and Vili to compounds of formula I.

Preference is given to the new compounds and methods mentioned in the examples.

The following, for example, illustrate the invention. Temperatures are shown in degrees Celsius and IR values are shown in emi. For 1 H-NMR spectra, chemical shifts are shown (δ) in ppm and coupling constants J in Hertz (Hz). The specific rotation values [a] are [a] 20D values. Columns packed with Merck-Kieselgel 60 can be used in the preparative final steps for chromatographic separation. Rf values apply to thin layer chromatography finished plates (Merck 60 F 254).

Abbreviations: m = medium strong absorption bands Γ · .. sh = sharp absorption bands s = singlet ie 8 471 6 m = multiplet d = doublet dd = doublet of doublets AB = AB type signal group

Example 1: (2S, 3R) -2-Bromo-3-hydroxyvolic acid N-p-methoxy-phenylphenyl-N-phenacylamide

To a solution of 13.73 g of (2S, 3R) -2-bromo-3-hydroxybutyric acid and 18.08 g of phenacyl-p-anisidine in 70 ml of dry tetrahydrofuran is added 15.47 g of dicyclohexylcarbodiimide and stirred under argon for 48 hours at room temperature. The dicyclohexyl urea formed during the reaction is filtered off with suction and the filtrate is evaporated in a water-jet vacuum. The amorphous residue is chromatographed for purification on 60 times the weight of silica gel with toluene / ethyl acetate (9: 1). The title compound obtained [NMR spectrum (CDCl 3) signals 1.23 (d), 3.83 (s), 3.88 (s), 4.10 (m), 4.18 (d), 4.75 / 4 , 80 / 5.31 / 5.36 (AB) and 6.94 (dd)] can be used directly for the next cyclization.

Example 2: (2R, 3R) -2,3-Epoxybutyric acid N-p-methoxyphenyl-N-phenacylamide

To a solution of 406 mg (1 mmol) of (2S, 3R) -2-bromo-3-hydroxybutyric acid N-p-methoxyphenyl-N-phenacylamide in 7 ml of abs. tetrahydrofuran, 165 μΐ (169 mg; 1.1 mmol) of 1,5-diazabicyclo- [5.4.0] undec-5-ene are added under an argon atmosphere at -10e and the resulting reaction mixture is stirred for 5 hours at 0 ° and for a further 3 hours at room temperature. . To carry out the final steps, the reaction mixture is diluted with methylene chloride and washed successively with water, 5% aqueous citric acid solution and 8% aqueous sodium bicarbonate solution. The aqueous portions are extracted with methylene chloride. The combined organics are dried and evaporated in vacuo, after which the residue obtained is chromatographed on silica gel plates in toluene / ethyl acetate (1: 1). The title compound is obtained as a viscous oil, Rf (Merck Kieselgel pre-sheets, toluene / ethyl acetate 1: 1): 0.27; (IR CH 2 Cl 2): mm. lanes 1700, 1670, 1595, 1580, 1505, 1427, 1392, 1365, 1348, 1300, 1243, 1221, 1180, 1170, 1140, 1103, 1028, 982; NMR (CDCl 3): signals 1.50 (d), 3.08 (m), 3.36 (d), 3.82 (s), 4.86 (d), 5.42 (d), δ, 91 (m), 7.34 (m), 7.46 (m), 7.57 (m), 7.93 (m).

Example 3: (3S, 4S, 1'R) -Np-Methoxyphenyl-3- (11-hydroxyethyl) -4-benzoylazetidin-2-one a) With lithium bis- (trimethylsilyl) amide: To a solution cooled To -20 ° and containing 3.37 g of (2S, 3R) -2-bromo-3-hydroxybutyric acid Np-methoxyphenyl-N-phenacylamide in 20 ml of tetrahydrofuran are added with stirring under an argon atmosphere to 33 ml of tetrahydrofuran. A 5 molar solution of lithium bis- (trimethylsilyl) amide and stirring is continued with slow warming to -10 ° for 1 1/2 hours. The reaction mixture is poured into ice water and extracted with methylene chloride. The organic phase is washed successively with ice-cold 1N-sulfuric acid, water, ice-cold, saturated aqueous sodium hydrogen carbonate solution and water, dried and evaporated on a rotary evaporator. A toluene / acetic acid mixture (9: 1) gives (3S, 4S, 1'R) -Nβ-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one, melting from a mixture of methylene chloride and ether. after reconstitution at 111-1130. [α] = -95.1 ° (c = 1.121% in CHCl 3).

(b) Sodium hydroxide: A mixture of 950 mg of (2S, 3R) 2-bromo-3-hydroxy-butyric acid Np-methoxyphenyl-N-phenacylamide in 25 ml of methylene chloride and 8 ml of 50% aqueous sodium hydroxide solution. , is stirred vigorously by adding 75 mg of benzyltriethylammonium chloride for 5 1/2 hours at room temperature. Sodium hydroxide is separated off from the reaction mixture, the organic phase is washed twice with water, dried and evaporated in a water-jet vacuum. Chromatography on silica gel with toluene / acetic acid (9: 1) and crystallization of the uniform fractions gives the title compound in pure form.

c) Tetrabutylammonium fluoride: To a solution of 300 mg (0.95 mmol) of tetrabutylammonium fluoride trihydrate in 4 ml of tetrahydrofuran is added activated molecular sieves (4x10-10m) to remove water and allowed to stand under argon for 18 hours at 0 °. A solution of 206 mg (0.63 mmol) of (2R, 3R) -2,3-epoxybutyric acid N-p-methoxyphenyl-N-phenacylamide in 2 ml of abs. Is then added dropwise at 0 °. tetrahydrofuran, and the reaction mixture is further stirred at 0 ° for 2 hours. The molecular sieves are filtered off, the filtrate is washed with tetrahydrofuran, the combined filtrates are evaporated in vacuo and the residue dissolved in methylene chloride is washed successively with 1N H 2 SO 4 and water. The aqueous portions are extracted with methylene chloride. The combined organics, after drying and evaporation in vacuo, give a crude product which is chromatographed on silica gel plates with toluene / ethyl acetate (9: 1). This gives the title compound having the above values.

d) With potassium carbonate: To a solution of 13.0 g of (2R, 3R) -2,3-epoxybutyric acid Np-methoxyphenyl-N-phenacylamide in 74 ml of dimethyl sulfoxide is added 55.2 mg of potassium carbonate and stirred under argon for 6 hours 21 -24 ° C. The reaction mixture is poured into 1.6 liters of ice water and stirred for 2 hours. The precipitate is filtered off with suction, washed with water and taken up in methylene chloride. The organic phase is separated from water, washed with saturated aqueous brine, dried and evaporated. The crude product obtained is chromatographed on a silica gel column. Elution with hexane / ethyl acetate (7: 3) gives a small amount of chromatographically uniform (3S, 4R, iR) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4- benzoylazetidin-2-one, which melts after crystallization from methylene chloride diisopropyl ether 168-170 ·. Further elution with hexane / ethyl acetate (1: 1) gives a chromatographically uniform (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one which melts with methylene chloride. after crystallization from diisopropyl ether at 111-113 °.

e) 1,5-diazabicyclo5.4.0lundek-5-ene: The same compound is obtained according to d) when an equivalent amount of 1,5-diazabicyclo [5.4.0] undec-5-ene is otherwise used under the same conditions instead of potassium carbonate.

f) Isomerization of the cis isomer with K 2 CO 3: (2S, 4R) -isomer of the title compound (Example 3d) obtained as a by-product in the cyclization of (2R, 3R) -2,3-epoxy-butyric acid Np-methoxyphenyl-N-phenacylamide as a by-product as the title compound by stirring 3.9 g of this cis compound in 80 ml of dimethylformamide with potassium carbonate (6.6 g) for 2.5 hours at 60 ° (bath temperature). The inorganic salt is filtered off, the filtrate is evaporated under reduced pressure, the residue is taken up in methylene chloride, the solution thus formed is washed with water and brine, dried, evaporated in vacuo and the residue is chromatographed on a silica gel column. Hexane-ethyl acetate (2: 1) elutes first a small amount of the (3S, 4R) -isomer, then elutes with hexane-ethyl acetate (1: 1) the pure title compound, which melts after crystallization from methylene chloride / diisopropyl ether. -113 * C.

g) Isomerization of the cis isomer with NaOH: In a biphasic mixture of equal amounts of methylene chloride and 1N sodium hydroxide and in the presence of tetrabutylammonium hydrogen sulphate 22 8 4 71 6 (60 mg), 3.9 g (3S, 4R, 1'R) are stirred. -Np-methoxy-phenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one (cis-isomer) for 2 hours at 21 °. The sodium hydroxide is separated off and the organic phase is washed with water, dried and evaporated in vacuo. The residue, consisting of a mixture of (3S, 4S) and (3S, 4R) (7: 3), is chromatographed on toluene-ethyl acetate on silica gel to give the pure isomers. The (3S, 4S) -compounded and evaporated fractions are recrystallized to give the pure title compound, m.p. 111-113 °.

Example 4: (3R, 4R, 1'R) -N-p-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoyloxyazetidin-2-one:

To a solution of 416 mg of (3S, 4S, 1'R) -Nβ-methoxyphenyl-3- (11-hydroxyethyl) -4-benzoylazetidinone in 20 ml of methylene chloride is added 1.27 g of m-chloroperbenzoic acid and heated for 72 hours in a bomb tube 45 -50 ° C. The reaction mixture is poured into ice water and diluted with methylene chloride. The organic phase is washed successively with potassium iodide-sodium thiosulphate solution, ice-cold saturated sodium hydrogen carbonate solution and water, dried and evaporated on a rotary evaporator. Chromatograph on silica gel (eluent: toluene / ethyl acetate (9: 1)) to give pure (3R, 4R, 1'R) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoyloxyazetidin-2-one. . IR: bands e.g. 3600, 1765, 1725, 1600, 1515, 1450, 1240, 1180, 1070 and 1025. NMR: signals e.g. 1.42 (d), 3.38 (d), 3.7 (S), 4.30 (m), 6.52 / 7.42 (AA1BB ').

The same compound is also obtained under similar conditions using p-nitrobenzoic acid or peracetic acid using acetic acid or ethyl acetate as solvent.

23 8471 6

Example 5: (3R, 4R, 1'R) -3- (1'-Hydroxyethyl) -4-benzoyloxyacetyl-2-one

To a solution of 325 mg of (3R, 4R, 1'R) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoyloxyazetidinone in 15 ml of acetonitrile, cooled to 0 °, is added a solution. with 1.642 g of cer (IV) ammonium nitrate in 15 ml of water and stirred for 30 minutes at -5 to 0 °. The reaction mixture is diluted with 200 ml of water and extracted three times with methylene chloride. The organic phases are washed successively with dilute aqueous sodium hydrogen carbonate solution, 10% sodium sulphite solution, sodium hydrogen carbonate solution and water, dried and evaporated. The crude product obtained is obtained after filtration through 20 times the weight of silica gel (eluent: toluene / ethyl acetate 8: 2) and then crystallized by thin-layer chromatography from chloroform-petroleum ether, pure (3R, 4R, 11R) -3 ( 1'-hydroxyethyl) -4-benzoyloxyazetidin-2-one. Sp. 144.5 to 146 ° C. [α] = +67.6 + 2.4 ° (c = 0.414%, CHCl 3).

Example 6: (3S, 4S, 11R) -3- (1'-hydroxyethyl) -4-benzoyl-azetidin-2-one a) To a solution cooled to -18 ° containing 325 mg of (3S, 4S , 1'R) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one in 10 ml of acetonitrile, a solution of 2.2 g of cer (IV) ammonium nitrate in 5 ml is added water and stir for 35 minutes at -16 to -18 °. The reaction mixture is poured into ice water and extracted three times with ethyl acetate. The organic phases are washed with ice-cold sodium hydrogen carbonate solution, dried and evaporated. The crude product is recrystallized from methylene chloride / ether to give pure (3S, 4S, 1'R) -3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one, melting at 132-134 °.

24 8 471 6 (b) Isomerization of the C1-5 isomer with 1,5-dazabicyclo5.4.01-un-dec-5-ene:

To a solution of 660 mg of (3S, 4R, 1'R) -3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one in 14 ml of chloroform is added 0.05 ml of 1,5-diazabicyclo [5.4 .0] undec-5-ene, and heated to 75 ° within 15 hours. The reaction mixture is evaporated in vacuo and the residue is chromatographed on a silica gel column. Hexane-ethyl acetate (1: 1) first elutes a small amount of the (3S, 4R) -isomer, followed by the (3S, 4S) -isomer, which is crystallized from methylene chloride / diisopropyl ether, m.p. 131-135 °.

The starting material (3S, 4R, 1'R) - (1'-hydroxyethyl) -4-benzoylazetidin-2-one can be prepared as follows:

To a suspension cooled to -18 ° containing 9.7 g of (3S, 4R, 1'R) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one (Example 3d). cis isomer) in 225 ml of acetonitrile, a solution of 36.3 g of cer (IV) ammonium nitrate in 150 ml of water is added and stirred for 30 minutes at -15 to -5 °. The reaction mixture is diluted with 800 ml of ice water and extracted 3 times with 600 ml of ethyl acetate. The organic phases are washed successively with 1% sodium sulfite and brine solution, dried over sodium sulfate and evaporated. The crude product obtained, after crystallization from methylene chloride / diisopropyl ether, yields pure (3S, 4R, 1'R) -3- (11-hydroxyethyl) -4-benzoylazetidin-2-one, m.p. 145-147 °.

Example 7: (3R, 4R, 11R) -3- (1-Hydroxyethyl) -4-benzoyl-oxyazetidin-2-one a) with m-chloroperbenzoic acid: To a solution of 1.9 g of (3S, 4S, 1'R ) -3- (1'-hydroxyethyl) -4-benzoylazetidinone in 172 ml of methylene chloride, 10.1 g of 85% m-chloro-8 8 71 6 perbenzoic acid are added and the mixture is stirred for 165 minutes at approximately room temperature. The reaction mixture is poured into ice water and extracted twice with methylene chloride. The organic phases are washed successively with aqueous potassium iodide / sodium thiosulphate and sodium hydrogen carbonate solution and then with water, dried and evaporated. The resulting crude product is filtered through toluene / ethyl acetate (8: 2) through silica gel (300 g) and then the crystalline uniform fractions are crystallized from methylene chloride / ether to give pure (3R, 4R, 1'R) 3- (1-hydroxyethyl). -4-benzoyloxy-thiazetidin-2-one, m.p. 145-147 °. The compound is identical to the product shown in Example 5 in terms of IR and NMR spectra and optical rotation.

b) With peracetic acid: The title compound can also be prepared by adding 4.27 g of (3S, 4S, 1Ή) -3- (1-hydroxyethyl) -4-benzoylazetidin-2-one in 60 ml of methylene chloride. , 12.2 ml of a 30% solution of peracetic acid in acetic acid are added and the mixture is refluxed for 6 hours. The resulting reaction mixture is diluted with methylene chloride and washed successively with 5% aqueous NaHSO 3 solution, 8% aqueous NaHCO 3 solution and saturated aqueous brine. The aqueous portions are extracted with methylene chloride, the combined organics are dried over Na 2 SO 4 and evaporated. The crystalline crude product is recrystallized directly from methylene chloride / ether to give the pure title compound having the above values.

c) With magnesium monoperphthalate hexahydrate: To a solution of 5 g of (3S, 4S, 1'R) -3- (1'-hydroxyethyl) -4-benzoyl-azetidin-2-one in 200 ml of ethyl acetate is added a solution , containing 16.5 g of magnesium monoperphthalate hexahydrate in 60 ml of ethanol (96%), and the resulting reaction mixture is stirred for 5 hours at a bath temperature of 50 °. In this case, the crystalline precipitate differs. 26 84 71 6 of methylene chloride and 5% aqueous sodium sulphite solution are added to the suspension and the organic phase is then washed with a further 8% aqueous sodium lumbicarbonate solution. The aqueous portions are extracted with methylene chloride, the organic extracts are combined, evaporated and the residue is recrystallized from methylene chloride / pentane. A pure title compound having the above properties is obtained.

d) Hydrogen peroxide and trichloroacetonitrile: The title compound can also be prepared by reacting 11 g of (3S, 4S, 1'R) -3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one with 19 ml of 30%: hydrogen peroxide and with 21 ml of trichloroacetonitrile in the presence of potassium hydrogen phosphate (10 g) in 200 ml of chloroform according to Example 13c).

Example 8: (3S, 4S, 1 * R) -N-p-methoxyphenyl-3- [11- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4-benzoylacetyl-din-2-one:

To a solution cooled to 0 ° containing 325 mg of (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one in 5 ml methylene chloride, 0.18 ml of triethylamine, 0.18 ml of chloroformic acid 2,2,2-trichloroethyl ester and 130 mg of dimethylaminopyridine are added under an argon atmosphere and stirred at the same temperature for 7 hours. The reaction mixture is poured into ice water and extracted twice with methylene chloride. The organic phases are washed with 5% aqueous citric acid solution and ice-cold aqueous sodium hydrogen carbonate solution, dried and evaporated. Filtration of the residue through silica gel (toluene / ethyl acetate 9: 1) gives pure (3S, 4S, 1'R) -Nβ-methoxyphenyl-3- [1- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4 -benzoylazetidin-2-one as a colorless foam. IR: bands e.g. 1760, 1690, 1512, 1380, 1240 and 1183 cm; [α] = -9.5 ° (c = 0.980%, chloroform).

27 8 4 7 1 6

Example 9; (3S / 4S, L, R) -3-NL- (2/2/2-trikloorietoksikarbo nyylloksl) -etyyli1-4-bentsoyyllatsetldln-2-onl:

To a solution cooled to -18e containing 400 mg of (3S, 4S, 1'R) -Np-methoxyphenyl-3- [1 '- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4- benzoylazetidin-2-one in 10 ml of acetonitrile, a solution of 965 mg of cer (IV) ammonium nitrate in 5 ml of water is added and the mixture is warmed to -5 ° with stirring over 2 1/2 hours. The reaction mixture is poured into ice water and extracted twice with ethyl acetate. The organic phases are washed twice with ice-cold aqueous sodium hydrogen carbonate solution, dried and evaporated. The crude product formed from the crystallization from methylene chloride / ether / petroleum ether gives pure (3S, 4S, 1'R) -3- [1 '- (2,2,2-trichloroethoxycarbonyloxy) ethyl] melting at 106-108 °. -bentsoyyliatsetidin-2-one.

Example 10: (3R, 4R, 1'R) -3- [11- (2,2,2-Trichloroethoxycarbonylloxy) ethyl] -4-benzoyloxyazetidin-2-one

To a solution of 230 mg of (3S, 4S, 1'R) -3- [1 '- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4-benzoylazetidinone in 20 ml of methylene chloride is added 683 mg of 85% m-chloroperbenzoic acid and stirred for 3 1/2 hours at room temperature. The reaction mixture is poured into ice water and extracted twice with methylene chloride. The organic phases are washed successively with aqueous potassium iodide / sodium thiosulphate solution, water, ice-cold, aqueous sodium hydrogen carbonate solution and water, dried and evaporated.

The crude product thus obtained is filtered through silica gel (toluene and toluene / ethyl acetate-8: 2) and then uniform fractions are crystallized from methylene chloride / ether / petroleum ether to give pure (3R, 4R, 1'R) -3- [11- (2, 2,2-trichloroethoxycarbonyloxy) ethyl] -4-benzoylazetidin-2-one, m.p. 118-120 °. [α] = + 75 ° (c = 1.01%, chloroform).

28 8471 6

Example 11; (3S, 4S, 11R) -N-p-methoxyphenyl-3- (11-allyl-llokslkarbonyylloksletyyll) -4-bentsoyyllatsetldln-2-onl

To a solution of 325 mg of (3S, 4S, 1 · R) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidinone in 5 ml of methylene chloride is added to a solution cooled to 0 ° in an argon atmosphere. 0.18 ml of triethylamine, 0.16 ml of chloroformic acid allyl ester and 130 mg of dimethylaminopyridine and stirred for one hour at the same temperature. Re-add the amounts of triethylamine, chloroformic acid allyl ester and dimethylaminopyridine, followed by stirring for an additional 17 hours at 0 °, then adding a third portion of the same amounts of the three reagents and stirring for 24 hours at room temperature. The reaction mixture is poured into ice water and extracted twice with methylene chloride. The organic phases are washed with 5% aqueous citric acid solution and ice-cold aqueous sodium hydrogen carbonate solution, dried and evaporated. The residue is filtered through silica gel (40 g, toluene / ethyl acetate-9: 1) to give pure (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1'-allyloxycarbonyloxyethyl) -4-benzoylazetidine-2- oni, sp. 78-80 °.

Example 12: (3S, 4S, 1'R) -3- (11-Allyloxycarbonyloxy-ethyl) -4-benzoyl-azetidin-2-one

To a solution cooled to -18 ° containing 270 mg of (3S, 4S, 1'R) -Nβ-methoxyphenyl-3- (11-allyloxycarbonyloxyethyl) -4-benzoylazetidin-2-one in 10 ml acetone-tril, a solution of 800 mg of cer (IV) ammonium nitrate in 5 ml of water is added and the mixture is warmed to 0 ° with stirring over 3 hours. The reaction mixture is poured into ice water and extracted twice with ethyl acetate. The organic phases are washed twice with ice-cold aqueous sodium hydrogen carbonate solution, dried and evaporated. Filtration of the crude product formed through silica gel (20 g, toluene / 29 84 71 6 ethyl ester-8: 2) followed by crystallization of the pure fractions from methylene chloride / ether / petroleum ether gives pure, melting at 93-95® (3S, 4S, 1'R ) -3- (1'-allyylioksikar-bonyylioksietyyli) -4-bentsoyyliatsetidin-2-one.

Example 13: (3R, 4R, 1'R) -3- (11-Allyloxycarbonyloxy-ethyl) -4-benzoyloxy-acetyl-2-one a) with m-chloroperbenzoic acid: To a solution of 60 mg (3S, 4S, 1 * R ) - 3- (1 * -allyloxycarbonyloxyethyl) -4-benzoyl-azetidin-2-one in 5 ml of methylene chloride, 234 mg of 85% m-chloroperbenzoic acid are added and the mixture is stirred for 3 1/2 hours at room temperature. The reaction mixture is poured into ice-water and extracted twice with methylene chloride. The organic phases are washed successively with aqueous potassium iodide-sodium thiosulphate solution, water, ice-cold aqueous sodium hydrogen carbonate solution and water, dried and evaporated. The crude product thus obtained is filtered through silica gel (toluene and toluene / ethyl acetate-8: 2) and then uniform fractions are crystallized from methylene chloride / ether / petroleum ether to give pure (3R, 4R, 1'R) -3- (1 '- allyloxycarbonyloxyethyl) -4-benzoyloxyazetidin-2-one, m.p. 84-85®.

b) With peracetic acid: The title compound can also be prepared by adding to a solution of 91 mg of (3S, 4S, 1'R) -3- (1'-allyloxycarbonyloxyethyl) -4-benzoylazetidin-2-one in 5 ml of methylene chloride. , a total of 0.4 ml of 30% peracetic acid in acetic acid is added in three portions and stirred for 48 hours at room temperature. The resulting reaction mixture is washed successively with methylene chloride, 5% aqueous sodium sulfite, 8% aqueous sodium bicarbonate and aqueous brine. The aqueous portions are extracted with methylene chloride and the combined organic extracts are evaporated after drying over Na 2 SO 4. The residue obtained is chromatographed on silica gel plates with hexane / ethyl acetate (1: 1) to give the pure title compound having the above properties.

c) With hydrogen peroxide and trichloroacetonitrile: The title compound can be prepared in a similar manner by adding to a solution of 152 mg of (3S, 4S, 1'R) -3- (1'-allyloxycarbonyloxyethyl) -4-benzoylazetidine-2- in 3 ml of chloroform, 0.3 ml of trichloroacetonitrile, 1.2 ml of 30% aqueous hydrogen peroxide and 138 mg of potassium hydrogen phosphate are added at room temperature, and the resulting mixture is stirred for 21 hours at room temperature. Dilute with methylene chloride, then wash successively with 5% aqueous sodium bisulfite, 8% aqueous sodium bicarbonate and brine. The aqueous portions are extracted with methylene chloride and the combined organic extracts are evaporated after drying over Na 2 SO 4. Chromatograph on silica gel plates in hexane / ethyl acetate (1: 1) to give the pure title compound having the above properties.

Example 14: (3S, 4R, 1'R) -3- (11-Allyloxycarbonyloxy-ethyl) -4-N-allyloxycarbonylglycylthioazetidin-2-one 26.75 g (75 mmol) of N-allyloxycarbonylthioglycine-dicyclohexylamine in water and 75 ml of 1N NaOH and extracted three times with 100 ml of methylene chloride each time. The aqueous phase is cooled to 0e and adjusted in pH control (glass electrode) by adding 1N NaOH to pH 10. With vigorous stirring under an argon atmosphere, a solution of 8 g (25 mmol) (3R, 4S, 1'R) is added dropwise. -3- (1'-Allyloxycarbonyloxyethyl) -4-benzoyloxyazetidin-2-one in 275 ml of acetone, keeping the temperature at 4 °. After the addition is complete, the mixture is stirred for a further 15 minutes at 0-5 [deg.] C., the solution is concentrated on a rotary evaporator to 300 ml and extracted 4 times with 3,847,166 ml of methylene chloride each time. The combined organic phases are washed twice more with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride solution, dried over Na2SO4 and evaporated. The residue obtained is chromatographed on 500 g of Merck silica gel by the flash method (Flash Verfahren) with CHCl3 / acetone (9: 1). The title compound is obtained with an Rf value (Merck prepared plates CHCl3 / acetone 9: 1) of 0.20.

Example 15: (5R, 6S, 1'R) -6- (11-Allyloxycarbonyloxy-ethyl) -2-allyloxycarbonylaminomethyl-2-penem-3-carboxylic acid allyl ester

To a solution of 930 mg (2.5 mmol) of (3S, 4R, 1'R) -3- (1'-allyloxycarbonyloxyethyl) -4-N-allyloxycarbonyl-glycylthioazetidin-2-one in 15 ml of methylene chloride (fresh Alox -filtered), 557 mg (3.75 mmol; 1.5 equiv.) of oxalic acid allyl ester chloride and 0.64 ml (3.75 mmol, 1.5 equiv.) of Hdnig base are added successively with stirring under an argon atmosphere at -15e. , and further stirred for 30 minutes at -15e. To carry out the final steps, the reaction mixture is diluted with methylene chloride and washed successively with 0.1 N HCl and (twice) cold, saturated NaHCO 3 solution, shaking vigorously and briefly (final treatment to remove excess allyloxyoxyl chloride). The aqueous portions are extracted with methylene chloride and the combined organics are dried over Na 2 SO 4 and evaporated in vacuo. The crude product is taken up several times in toluene, evaporated and dried under high vacuum. A thick residue obtained containing 2 [(3S, 4R, 1'R) -3- (1'-allyloxycarbonyloxyethyl) -4-N-allyloxycarbonylglycylthio-2-oxo-1-azetidinyl] -2-oxoacetic acid allyl ester, dissolved take for cyclization to 25 ml abs. toluene, 1.044 ml (6 mmol) are added at room temperature with stirring (argon); 2.4 equiv.) Of distilled triethyl phosphite and the reaction mixture is rapidly immersed in a 100 ° C preheated oil bath and stirred under argon for 7 hours at the same temperature. The reaction mixture is evaporated in vacuo and the residue is chromatographed on 100 g of Merck silica gel (0.04-0.063 mm grain size) by the flash method. First take a 500 ml pre-fraction with toluene / ethyl acetate (9: 1) and then a 150 ml fraction with toluene / ethyl acetate (4: 1). The title compound is eluted in subsequent 25 ml fractions with toluene / ethyl acetate (4: 1) to allow a small amount of the more mobile component (corresponding cis isomer) to be separated in the first fractions. Sp. 58-59 ° (from ether-pentane);

Rf (Merck pre-plates, toluene / ethyl acetate 2: 1): 0.40; [α] = + 127.7 ° (1.05% in CH 2 Cl 2).

Example 16: (5R, 6S, 11R) -2-Aminomethyl-6- (1-hydroxy-ethyl-11) -2-penem-3-carboxylic acid

Through a solution of 100 mg (0.22 mmol) of (5R, 6S, 1'R) -2-allyloxycarbonylaminomethyl-6- (1-allyloxycarbonyloxyethyl) -2-penem-3-carboxylic acid allyl ester, 308 mg (2, 2 mmol) of dimedone and 30 mg (0.11 mmol) of triphenylphosphine in 4 ml of tetrahydrofuran are purged with argon for 5 minutes. 22 mg (0.019 mmol) of tetrakis-triphenylphosphine palladium are then added at room temperature. After 5 minutes, the precipitate begins to precipitate. The suspension is stirred for a total of one hour at room temperature under an argon atmosphere. The precipitated product is filtered off, washed with tetrahydrofuran, ethyl acetate and hexane and dried under high vacuum. Rf (H 2 O, OPTI UPC12): = 0.48.

50 mg of crude (5R, 6S, 1'R) -2-aminomethyl-6- (1-hydroxyethyl) -2-penem-3-carboxylic acid are dissolved in 0.5 ml of doubly distilled water at 30 °. The aqueous solution is cooled to 5 °, a small amount of activated carbon is added, stirred for 15 minutes and then filtered clearly. The clear filtrate is evaporated completely under high vacuum and the residue is suspended in 0.3 ml of ethanol (96%). The suspension is stirred vigorously at room temperature for 30 minutes. The white crystals (needles) are filtered off and washed with ethanol (96%). The product is dried at 20 ° under high vacuum. Sp. 165 “(dec.).

Example 17: (2R, 3R) -N-Acetonyl-N-p-methoxy-phenyl-2,3-epoxylic acid amide

To a solution of 73.2 g of N-acetonyl-p-anisidine hydrochloride in 1700 ml of toluene, cooled to -20 °, is added dropwise with stirring (at -15 ° C) successively over 15 minutes 70.2 g of N, N-dicyclohexylcarbodiimide dissolved in 170 ml of toluene and, over 60 minutes, 103 g of a solution of the dicyclohexylammonium salt of (2R, 3R) -epoxybutyric acid in 340 ml of dichloromethane. The reaction mixture is allowed to warm to 0e over 45 minutes and stirred for an additional 18 1/2 hours at 0-5 °. The suspension is filtered off with suction, the residue is washed thoroughly with toluene, the filtrate is washed twice with 1 liter of water, dried and evaporated in a water-jet vacuum. Crystals can be separated from the reddish-brown, oily crude product after cooling to about 4e. Flash chromatography of the mother liquor with hexane / ethyl acetate (1: 4) gives (2R, 3R) -N-acetonyl-N-p-methoxy-phenyl-2,3-epoxybutyramide as the main product in the form of a light brown oil in addition to the regenerated N-acetonyl-p-anisidine. The compound can be used directly for cyclization without further purification. IR: bands e.g. 2840, 1735, 1670, 1510, 1240, 1220, 1170 and 840.

Example 18: (3S, 4S, 1'R) -N-p-methoxyphenyl-3- (11-hydroxymethyl) -4-acetylazetidin-2-one

To a solution of 10.1 g of (2R, 3R) -N-acetonyl-N-p-2,3-epoxybutyric acid amide in 200 ml of dimethylformamide is added 19.1 g of potassium carbonate at 60 ° and stirred for 13 hours at the same temperature. The cooled reaction mixture is filtered off from insoluble potassium carbonate, 1 l of methylene chloride is added and the mixture is washed successively five times with dilute aqueous sodium chloride solution, dried and evaporated. Flash chromatograph on hexane / ethyl acetate (2: 3) 700 g of silica gel to give, after recrystallization from methylene chloride / ether, the major product is (3S, 4S, 11R) -Np-methoxyphenyl-3- (1 ') melting at 91-92 °. -hydroxyethyl) -4-acetyl-azetidin-2-one [α] = -119.9 ° (c = 0.853 in chloroform) and as a by-product (about 10%) (3S, 4R, 1'R) -Np-methoxyphenyl- 3- (1'-hydroxyethyl) -4-acetylazetidin-2-one (m.p. 165-168 °).

Example 19: (3S, 4S, 1'RJ-N-p-methoxyphenyl-1- (11-tert-butyl-dimethylsilyloxyethyl) -4-acetylazetidin-2-one

To a solution of 3.39 g of (3S, 4S, 1'R) -Nβ-methoxyphenyl-3- (1'-hydroxyethyl) -4-acetylazetidin-2-one and 1.58 g of imidazole in 20 ml of dimethylformamide, 2.33 g of tert-butyldimethylchlorosilane are added at room temperature and further stirred at room temperature for 5 hours. To carry out the final steps, the reaction mixture is poured into ice-sodium hydrogen carbonate solution, taken up in methylene chloride and the organic phase is washed successively with sodium hydrogen carbonate solution, 1% citric acid solution and once more with sodium hydrogen carbonate solution. Dry over sodium sulfate and evaporate under reduced pressure to give a crude product which is recrystallized from petroleum ether. The title compound is obtained as colorless crystals, m.p. 82-84 °. [α] = -116.3 ° (c = 0.374% in CHCl 3).

Example 20: (3S, 4S, 1'R) -3- (11-tert-butyldimethylsilyloxyethyl) -4-acetylacetidin-2-one

To a solution cooled to 0 ° containing 4.34 g of (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1'-tert-butyldimethyl-35 8 4 71 6 silyloxyethyl) -4- acetylazetidin-2-one in 140 ml of acetonitrile, 13.85 g of cerairanonium nitrate dissolved in 70 ml of water are added dropwise over 15 minutes in Oe. The reaction mixture is allowed to stir for 2 hours at room temperature, then poured into ice water, extracted with methylene chloride, the organic layer is washed twice with aqueous sodium hydrogen carbonate solution and saturated brine, dried and evaporated in a water-jet vacuum. Flash chromatography of the dark brown crude product in hexane / ethyl acetate (3: 2) on silica gel followed by crystallization of the uniform fractions from ether / petroleum ether gives pure (3S, 4S, 1'R) -3- (1'-tert-butyldimethylsilyloxyethyl) -4-acetyl 2-one, m.p. 74-75 °. [α] = -14.6 ° (c = 0.397%; CHCl 3).

Example 21: (3R, 4R, 11R) -3- (11-tert-Butyl-dimethyl-1-yloxy) -ethyl-4-acetoxy-azetidin-2-one

To a solution of 1.4 g of (3S, 4S, 11R) -3- (1'-tert-butyl-dimethylsilyloxyethyl) -4-acetylazetidin-2-one in 70 ml of methylene chloride is added 5.75 g of 85 % m-chloroperbenzoic acid and stirred for 2 hours at room temperature. The yellow reaction mixture is poured into ice water, extracted with methylene chloride, the organic phase is washed successively with aqueous potassium iodide / sodium thiosulphate solution, water, aqueous sodium hydrogen carbonate solution and water and evaporated. Flash chromatography of the crude product in hexane / ethyl acetate (4: 1) followed by crystallization of the uniform fractions from low boiling petroleum ether gives pure (3R, 4R, 11R) -3- (1 '- (tert-butyldimethylsilyloxyethyl) -4-acetoxyazetidine-2- oni, mp 108-110 ° [α] = + 50.1 ° (c = 0.838%; CHCl 3).

36 847 1 6

Example 22: (3S, 4S, 11R) -N-p-methoxyphenyl-3- [11- (dimethyl-2,3-dimethylbut-2-methylsilyloxy) ethyl] -4-benzoyl-acetyl-2-one

To a solution of 4.53 g of (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one in 40 ml of dimethylformamide is added 1.7 g of imidazole. and 3.3 ml of dimethyl- (2,3-dimethylbut-2-yl) -chlorosilane and stirred for 23 hours at 25 °. An additional 1.7 g of imidazole and 3.3 ml of dimethyl- (2,3-dimethylbut-2-yl) -chlorosilane are added, followed by stirring for a further 22 hours. The reaction mixture is poured into ice-cold aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic phase is washed successively with aqueous sodium hydrogen carbonate solution, 1% aqueous citric acid, aqueous sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated in vacuo. The crude product formed is flash chromatographed on toluene / ethyl acetate (9: 1) on 521 g of silica gel. The combined homogeneous fractions are recrystallized from ether / petroleum ether to give pure (3S, 4S, 1'R) -Np-methoxyphenyl-3- [11- (dimethyl-2,3-dimethyl) melting at 89-90 °. -thylbut-2-ylsilyloxy) ethyl] -4-benzoylazetidin-2-one. [α] = -65.4 ° (c = 0.506%; CHCl 3).

Example 23: (3S, 4S, 1'R) -3- [1- (Dimethyl-2,3-dimethyl-but-2-yl-yloxy) -ethyl] -4-benzoyl-azetidin-2-one

To a solution of 37.02 g of (3S, 4S, 1'R) -Np-methoxyphenyl-3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) cooled to 0 ° ) ethyl] -4-benzoylazetidin-2-one in 980 ml of acetonitrile, a solution of 95.4 ml of cer (IV) ammonium nitrate in 490 ml of water is added dropwise over 15 minutes under an argon atmosphere, and the reaction mixture is stirred for 1 hour. -5 ° C. The organic phase is separated and evaporated in vacuo at 30 °. The residue is combined with an aqueous phase containing 37,847,16 6 by adding ice, and the mixture is extracted with ethyl acetate. The extract is washed successively twice with aqueous sodium hydrogen carbonate solution, dried and evaporated. The brownish residue is crystallized from methylene chloride / ether in 5e. To 50 ml of a 3: 2 mixture of hexane and ether in the washed crystals, an additional 50 ml of this mixture is added at 20e and then stirred at 0®, suction filtered and washed with hexane / ether (3: 2) and dried at 50e. in high vacuum. The pure title compound is obtained, melting at 165-166 °. Flash chromatography of the mother liquor with hexane / ethyl acetate (80:20) on 750 g of silica gel gives more of the title compound. [α] = -20.4 ° (c = 0.499%, CHCl 3).

Example 24: (3R, 4R, 1'R) -3-R1- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl-4-benzoyloxyacetyl-2-one

To a solution of 15.14 g of (3R, 4R, 1'R) -3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-benzoyl-acetidine-2- in 500 ml of methylene chloride, 47.3 g of 85% m-chloroperbenzoic acid are added and the mixture is left to stand for 5 1/2 hours at room temperature. The reaction mixture is then poured into ice water, extracted with methylene chloride, the organic phase is washed successively with aqueous potassium iodide / sodium thiosulphate solution, water, aqueous sodium hydrogen carbonate solution and water, dried and evaporated. Ether is added to the crude product to crystallize about 1.5 g of 3-chlorobenzoyl peroxide. The crystals are filtered off with suction and the crude product crystallizes out of the filtrate after evaporation from hexane. The slightly impure title compound thus obtained is flash chromatographed with hexane / ethyl acetate (90:10). Uniform fractions, after recrystallization from hexane, afford pure (3R, 4R, 1'R) -3- [1 '- (dimethyl-2,3-dimethylbut-2-ynyloxy) ethyl] -4, melting at 83-84®. -bentsoyylioksiatsetidin-2-one. [α] = + 62.5 ° (c = 0.256%, CHCl 3).

38 8471 6

Example 25: (3S, 4R, 11R) -3- [11- (Dimethyl-2,3-dimethyl-but-2-methyl-hydroxy) -ethyl] -4-N-allyloxycarbonyl-methyl-acetyl] -2-one 2.67 g (7 , 5 moles) of N-allyloxycarbonylthioglycine-dicyclohexylammonium salt is dissolved in 7.5 ml of N NaOH and 20 ml of water. The resulting solution is extracted three times with methylene chloride, 10 ml of acetone are added to the aqueous portion and a solution of 944 mg (2.5 moles) of (3S, 4R, 1'R) 3- [1- (dimethyl-2,3) is added under stirring under an argon atmosphere. -dimethylbut-2-ylsilyloxy) ethyl] -4-N-allyloxycarbonylglycine thioazetidin-2-one in 20 ml of acetone. The reaction mixture is further stirred at pH 10.5-10.7 for 5 hours with cooling. The acetone is distilled off under reduced pressure, the aqueous residue is extracted with methylene chloride, the organic phase is evaporated after drying over Na2SO4 and the residue is chromatographed on silica gel plates in hexane / ethyl acetate (1: 1). The title compound is obtained as a colorless crystalline compound which is recrystallized from ether-hexane, m.p. 74-76 °. [α] = +110.7 + 1.3 ° (c = 0.76% in CHCl 3).

Example 26: (5R, 6S, 11R) -6- [11- (dimethyl-2,3-dimethyl-but-2-ylsilyloxy) ethyl) -2-allyloxycarbonylaminomethyl-2-penem-3-carboxylic acid allyl ester

To a solution of 692 mg (1.6 mmol) of (3S, 4R, 1'R) -3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-N-allyloxycarbonylglycylthioazetidine- 2-one in 9 ml of methylene chloride, 360 mg (ca. 2.41 mmol) of oxalic acid allyl ester chloride and 410 ml (ca. 2.41 mmol) of Hilnig's base and the resulting reaction mixture are stirred successively at -20 ° under an argon atmosphere. , 5 hours at -10 ° and then 80 minutes at 0 °. It is diluted with methylene chloride and washed successively with ice-cold 0.1N HCl solution and 8% NaHCO3 solution. The organic portion is dried 39 8 4 71 6

Over Na 2 SO 4 and evaporated. The residue obtained is dissolved in 3 ml of triethyl phosphite and the solution is heated to 60 ° for 2 hours under an argon atmosphere. The volatiles are removed first under reduced pressure, then under high vacuum, the residue is dissolved in 10 ml of abs. dioxane and the resulting solution are heated to 105e (bath temperature) under argon for 8 hours. The dioxane is evaporated under reduced pressure, after which the crude product obtained is chromatographed on a silica gel column with hexane / ethyl acetate (9: 1 and 4: 1). The title compound is obtained as a colorless oil.

[α] = +62 + 2.7 ° (C = 0.371% in CHCl 3), U.V .: λmax = 320 nm (ε = 6230; in ethanol).

Example 27: (5R, 6S, 11R) -2-Aminomethyl-6- [11- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -2-penem-3-carboxylic acid

To a solution of 367 mg (0.72 mmol) of (5R, 6S, 1'R) -6- [11-dimethyl- (2,3-dimethylbut-2-ylsilyloxy) -ethyl] -2-allyloxycarbonylaminomethyl-2- penem-3-carboxylic acid allyl ester in 7 ml of abs. tetrahydrofuran, 223 mg (1.59 mmol) of dimedone and 36 mg of tetrakis-triphenylphosphine palladium are added at room temperature and the resulting solution is further stirred at room temperature. The crystalline title compound soon begins to separate and this is virtually complete after an hour. The crystals are filtered and washed on the filter with a small amount of tetrahydrofuran. The obtained title compound forms colorless crystals,

Sp. 119 °; UV: (EtOH): 309, 268 nm.

Example 28: (3S, 4S, 11R) -N-p-methoxyphenyl-3-yl (3,5-dimethylbenzoyloxy) ethyl) -4-benzoylazetidin-2-one

To a solution of 6.16 g of 3,5-dinitrobenzoic acid in 83 ml of pyridine is added 10.07 g of p-toluenesulfonic acid chloride over 10 minutes at room temperature. It is then stirred for one hour. To the cooled reaction mixture 0-5e is added 9.01 g (27.7 mmol) of (3S, 4S, 1'R) Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidine-2- and stirred for 1 1/4 hours at the same temperature. The reaction mixture is poured into 500 ml of methylene chloride and extracted with 250 ml of ice-cold 4N hydrochloric acid. The organic phase is washed once with 100 ml of saturated aqueous sodium bicarbonate solution and once with 100 ml of saturated aqueous brine and dried over sodium sulfate. After evaporation, the red residue is purified on 250 g of silica gel with toluene / ethyl acetate (9: 1). The title compound having the following physical values is obtained in quantitative yield: IR (CH 2 Cl 2): bands e.g. 3100, 1765, 1735, 1550, 1515, 1345, 1250; Rf (Merck silica gel ready plates, ethyl acetate / toluene 1: 1): 0.65.

Example 29: (3S, 4S, 11R) -3-Fl '- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoylazetidin-2-one

To a solution of 14.88 g (27.8 mmol) of (3S, 4S, 1'R) -Np-methoxyphenyl-3- [1 '- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoylazetidine-2- on 290 ml of acetonitrile, a solution of 34.4 g (62.8 mmol) of cer (IV) ammonium nitrate in 146 ml of H 2 O is added dropwise over 15 minutes. After reacting for a further 30 minutes at the same temperature, 500 ml of ethyl acetate are added and the organic phase is washed once with ice-cold aqueous sodium bicarbonate solution and twice with half-saturated aqueous brine. Dry over sodium sulfate and evaporate, then the crude product is crystallized from methylene chloride / ether to give the title compound in pure form. Additional title compound can be obtained from the mother liquor by evaporation and digestion in toluene. Sp. 156-160®; Rf value (Merck silica gel ready plates, ethyl acetate / toluene 1: 1): 0.42.

i 4i 8471 6

Example 30: 13R, 4R, 1'B) -3-H '- (3,5-Dichloro-benzoyloxy) -ethyl--4-benzoyloxy-oxetazin-2-one

To a solution of 8.30 g (20 mmol) of (3S, 4S, 1'R) -3- [1 '- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoylazetidin-2-one in 151 mL of methylene chloride , 6.129 g (30 mmol) of m-chloroperbenzoic acid (85%) are added and the mixture is stirred for 1 hour at room temperature, then for 2 1/2 hours at 30e. To carry out the final steps, 250 ml of methylene chloride are added and the mixture is washed successively at 0 ° with 100 ml of 10% aqueous sodium bicarbonate solution, about 5% aqueous sodium bisulfite solution and 100 ml of saturated aqueous brine. After drying and evaporation, the crude product is crystallized from 50 ml of pentane. The title compound is obtained, m.p. 165-169® (dec.) - Rf (Merck silica gel ready plates, ethyl acetate / toluene 1: 1): 0.58.

Example 31: (3S, 4R, 1'R) -3-Fl1- (3,5-dinitrobenzovioxy) ethyl] -4-N-allyloxycarbonylglycylthio) azetidin-2-one 3.77 g (10.6 mmol) N-allyloxycarbonylthioglycine The dicyclohexylammonium salt is dissolved in 18.7 ml of H 2 O and 10.6 ml of aqueous 1N NaOH and extracted three times with 5 ml of CH2Cl2 each time. About 0.2 ml of 0.1 N aqueous HCl is adjusted to pH 7-8 and then added at 23® to a solution of 2.28 g (5.3 mmol) of 3R, 4R , 1 * R) -3- [1 '- (3,5-dinitrobenzoyloxyethyl) -4'-benzoyloxyazetidin-4-one in 50 ml of dioxane, stir for a further 1 1/2 hours at 23 ° and carry out the final steps 100 The organic phase is washed twice more with 20 ml of saturated aqueous brine, dried over sodium sulphate and freed from the solvent. The residue is purified by chromatography on 200 g of silica gel (9 8471 g of acetic acid / methylene chloride). ) to give the title compound as a foam Rf (Merck pre-sheets, toluene / ethyl acetate 1: 1): 0.38, [α] = + 25 ° (c = 0.72; CHCl 3).

This product still contains about 5% of the 3S, 4S-cis isomer.

Example 32: (5R, 6S, 1 * R) -6-R1- (3,5-dimethyl-benzoyl-ethyl) -ethyl] -2-allyloxycarbonylaminomethyl-2-penem-3-carboxylic acid allyl ester

To a solution of 241 mg (0.5 mmol) of (3S, 4R, 1'R) -3- [1 '- (3,5-dinitrobenzoyloxy) ethyl] -4-N-allyloxycarbonyl-lysylthioazetidin-2-one 3 in methylene chloride (freshly filtered through Alox), 84.5 [mu] l (0.69 mmol) of oxalic acid allyl ester chloride and 124.2 [mu] l (0.73 mmol) of HUnig base are added successively with stirring and exclusion of moisture at -20 [deg.] C. for a further 30 minutes at -10 °. The IR experiment shows a characteristic oxalimide-carbonyl absorption at 1820 cm-1. To carry out the final steps, the reaction mixture is diluted with 5 ml of CH 2 Cl 2 and the organic phase is washed successively with ice-cold aqueous 0.1N HCl, 5% NaHCO 3 solution and saturated aqueous brine, dried over Na 2 SO 4 and dried over Na 2 SO 4. . After drying under high vacuum, (3S, 4R, 1'R) -4-N-allyloxycarbonylglycylthio) -3- [1 '- (3,5-dinitrobenzoyloxy) ethyl] azetidin-2-on-1- yloxalic acid allyl ester as a beige foam. This is dissolved in 2.5 ml of dioxane (Merck, p.A.) and 312 [mu] l (1.49 mmol) of triethyl phosphite are added under N2 at room temperature. Stir for one hour at room temperature and 2 hours at 40 ° bath temperature until no more oxalimide signal can be detected in 1R (bands at 1820 cm-1). After evaporation, add about 1.5 ml of decane three times and evaporate again under high vacuum. The crude phosphorane obtained is dissolved directly in 12.5 ml of dioxane (Merck, p.A.) for cyclization and stirred for 17 hours at a temperature of 105 ° C. It is then evaporated on a rotary evaporator and the residue is chromatographed on 30 g of silica gel with toluene / ethyl acetate (4: 1). The title compound is isolated from the middle fractions, which in turn contains about 5% of the 5S, 6S-cis isomer as an impurity. Rf (Merck pre-plates, toluene / ethyl acetate 4: 1): 0.48 (cis product) and 0.38 (trans product).

Example 33: (5R, 6S, 1'R) -6- (11-Hydroxyethyl) -2-allyloxycarbonylaminomethyl-2-penem-3-carboxylic acid allyl ester a) (5R, 6S, 1'R) - From 6- [11- (3,5-dimethylbenzoyloxy) ethyl] -2-allyloxycarbonylamino-methyl-2-penem-3-carboxylic acid polyallyl ester:

To a solution of 1.28 g (2.27 mmol) of (5R, 6S, 1'R) -6- [1 '- (3,5-dinitrobenzoyloxy) ethyl] -2-allyloxycarbonylaminomethyl-2-penem- 3-Carboxylic acid allyl ester (trans: cis ca. 95: 5) in 100 ml of methanol and 20 ml of water, 5 ml of saturated aqueous sodium bicarbonate solution are added at 0 °. After reacting for 20 minutes at 0 ° C, the reaction mixture is poured into 300 ml of ethyl acetate and 50 ml of saturated aqueous brine, the organic phase is separated off and the aqueous phase is extracted once more with 100 ml of ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated in vacuo to a volume of about 30 ml. Dilute with 150 ml of methylene chloride, dry once more over Na2SO4 and then evaporate completely on a rotary evaporator. The residue is chromatographed on 80 g of silica gel with toluene / ethyl acetate 4: 1 to 3: 2 to give the title compound after crystallization from ether / hexane (3: 7), m.p. 141 to 141.5 °. Rf (Merck pre-sheets, toluene / acetic acid ethyl ester 1: 1): 0.20.

44 8471 6 b) from (5R / 6S, 1Ή) -6- [11- (dimethyl-2,3-dimethylbut-2-yl-slyloxy) -ethyl] -2-allyloxycarbonylaminomethyl-2-penem-3-carboxylic acid allyl ester:

To a solution of 50 mg of (5R, 6S, 11R) -6- [1- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -2-allyloxycarbonylaminomethyl-2-penem-3-carboxylic acid allyl- ester in 1 ml of 2,6-lutidine S, 60 mg (ca. 30 mmol) of 70% HF urea mixture are added and stirred for 2 hours at room temperature. An additional 5 drops (ca. 100 mg = ca. 50 mmol) of HF urea are then added to the reaction solution. The viscous mixture is diluted with 1 mL of methylene chloride, stirred overnight at room temperature, and 10 drops of HF urine (ca. 100 mmol) are added again. After reacting for a further 24 hours at room temperature, the reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase is then washed with 4N hydrochloric acid and saturated aqueous sodium chloride solution, dried and evaporated on a rotary evaporator. Recrystallization of the reconstituted crude product from ether / hexane gives the pure title compound, which is identical to the sample shown in a).

Example 34: (3S, 4R, 1'R) -3- (11-Hydroxyethyl) -4- (N-allyloxycarbonylglycylthio) -2-azetidinone

A solution of 14.2 g (40 mmol) of N-allyloxycarbonyl-lithioglycine-dicyclohexylammonium salt in 60 ml of water and 40 ml of 1N aqueous NaOH solution is extracted three times with 20 ml of methylene chloride each time and made up to about 1 ml with 0 ml. , 1N aqueous HCl to pH 7-8. The resulting aqueous thiolic acid solution is added at 30 ° over 5 minutes to a solution of 4.70 g (20 mmol) of (3R, 4R, 1'R) -3- (11-hydroxyethyl) -4-benzyloxy-2-azetidinone in 100 ml. acetonitrile. At an internal temperature of 25 °, 2 ml of 0.1 N aqueous NaOH solution are added and the mixture is stirred for a further 30 minutes. 25 ° C. To carry out the final steps, place 250 ml of ethyl acetate and 30 g of NaCl in a separatory funnel and add the reaction mixture. Shake well and separate the aqueous phase, then wash the organic phase once more with 50 ml of 5% aqueous NaHCO 3 solution and twice with 50 ml of brine and dry over sodium sulfate. The solvent is removed on a rotary evaporator to give the title compound as an amorphous powder. The crude product is purified by chromatography on silica gel (toluene / ethyl acetate 2: 3). Rf value 0.23 (Merck pre-plates, toluene / ethyl acetate = 1: 4, ninhydrin as developing reagent).

Example 35: (5R, 6S, 11R) - (11-Hydroxy-ethyl) -2-allyloxycarbonylaminomethyl-2-penem-3-carboxylic acid allyl ester

To a solution of 2.88 g (10.0 mmol) of (3S, 4R, 1'R) -3- (11-hydroxyethyl) -4- (N-allyloxycarbonylglycylthio) -2-azetidinone (crude product of Method 34) in 80 ml methylene chloride (freshly filtered through Alox), 3.86 ml (31.5 mmol) of freshly distilled oxalic acid allyl ester chloride and 7.69 ml (44 ml) are added successively with stirring and exclusion of moisture at -10 to -15 °. 8 mmol) of N-ethyl-diisopropylamine and further stirred for 30 minutes at -10 °. The IR experiment showed characteristic oxalimide-carbonyl absorption at 1820 cm-1.

To complete the final steps, the reaction mixture is diluted with 50 mL of CH 2 Cl 2, washed three times with ice-cold water and once with ice water, and with 5 mL of saturated aqueous NaHCO 3 solution. The aqueous portions are extracted once with CH2Cl2. The combined organic phases are dried over Na2SO4, evaporated in vacuo and the crude product is dried under high vacuum. The resulting thick residue containing (3S, 4R, 1'R) 2- [4- (N-allyloxycarbonylglycylthio) -3- (1'-allyloxalyloxyethyl) -2-oxo-1-azetidinyl] -2-oxoacetic acid allyl ester (IR (CH 2 Cl 2) 3440 (NH); 46 8 4 71 6 oo o

II II II

120 (N-C-C); 1720-1760 (C)), is dissolved in 30 ml of dioxanes and 7 ml (40.2 mmol) of triethyl phosphite are added under N2 at room temperature. After 15 hours at room temperature, no more oxalimide can be detected by IR (bands 1820 cm-1). The reaction mixture is evaporated in vacuo, 2 ml of toluene and 2 ml of decane are added to the residue three times and the distillates are distilled again to remove excess phosphite / phosphate in each case under high vacuum. The crude phosphorane obtained is dissolved in 250 ml of dioxane for cyclization and stirred for 5 hours at 105-110 °. Reaction mixture containing (5R, 6S, 1'R) -2-allyloxycarbonylaminomethyl-6- [1 '- (allyloxyloxy) ethyl] -2-penem-3-carboxylic acid allyl ester (for analytical purposes, purify a batch of crude cyclization product on silica gel with toluene / toluene). with ethyl acetate (4: 1): UV (EtOH) 315 nm, IR (CH 2 Cl 2) 3440 (NH), 1790, 1770,

O

II

1745, 1720 (C)), evaporated in vacuo to about 15 ml, 100 ml of methanol / H 2 O (8: 2) and 25 ml of saturated aqueous NaHCO 3 solution are added at 0 °. After 20 minutes, the reaction mixture is poured into 300 ml of ethyl acetate and 50 ml of H2O, the organic phase is separated off and the aqueous phase is extracted once more with 100 ml of ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated in vacuo to a volume of about 50 ml. Dilute with 200 ml of methylene chloride, then dry over Na2SO4 and evaporate completely in vacuo. The residue is chromatographed on 80 g of silica gel with toluene / acetic acid ethyl ester (3: 2) to give, after recrystallization from ether / hexane (3: 7), the title compound, m.p. 141-141.5 °, Rf value 0.20 (Merck pre-sheets, toluene / acetic acid ethyl ester 1: 1).

47 8471 6

Example 36; (5R, 6S, 1'R) -2-amlnometvvli-6- (1 ·-hydroxy-ethyl) -2-penem-3-carboxylic acid A

A solution of 313 mg (0.85 mmol) of (5R, 6S, 1'R) -2-allyloxycarbonylaminomethyl-6- (1'-hydroxyethyl) -2-penem-3-carboxylic acid allyl ester and 174.6 mg (1.24 mmol) of dimedone in 7.5 ml of tetrahydrofuran, purged with argon for 5 minutes and 27 mg (0.023 mmol) of tetrakistriphenylphosphine-palladium are added under argon at room temperature. After about 5 minutes, the precipitate begins to precipitate, which is filtered after stirring for 2 hours, washed with about 10 ml of tetrahydrofuran and then dissolved in 4 ml of H2O. To the beige solution, add a microstat tip of activated carbon and two microstat tip Tonsils, mix well for 5 minutes, and filter clear through Hyflo. Evaporate under high vacuum and add 3 ml of cold ethanol to the resulting thick crystalline mass and suction filter. The colorless crystals are washed with 2 ml of tetrahydrofuran and dried under high vacuum. The title compound is obtained, Rf value = 0.50 (DC: H 2 O, OPTI UPC12); [α] 20 D = + 176 ° (c = 0.5, H 2 O).

Claims (12)

48 8471 6 1. Method of formula I? F ’? for the preparation of (4R) -3,4-trans-disubstituted azetidinones according to T 1 (R) 0 'fi-R 3 (I) </ 1, wherein R 1 represents hydrogen or Lower palkyl, R 2 represents hydrogen or hydroxy-protecting group R2 '/ R3 denotes phenyl or phenyl substituted by lower alkyl, lower alkoxy or halogen and R4 denotes hydrogen or amino-protecting group R4', characterized in that the formula II <? r2 yv 9 R, TTsTj1-nisT '* 1 UI) </ V wherein the radicals R 1, R 2, R 3 and R 4 have the meanings given in connection with the formula I are subjected to a Bayer-Villiger reaction by treatment with peracid and, if desired, in the resulting compound of formula I in which R 2 represents hydrogen, the free hydroxy group is converted to the protected hydroxy group and / or, if desired, cleaving the hydroxy-protecting group R2 'and / or the amino-protecting group R4' from the resulting compound of the formula I. Process according to Claim 1, characterized in that the starting materials are compounds of the formula II in which R 1 is methyl, R 2 is hydrogen, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl or 3,5-dinitrobenzoyl, R 3 is phenyl and R 4 is hydrogen or p-methoxyphenyl, and these are treated with m-chloroperbenzoic acid, p-nitroperbenzoic acid, peracetic acid or trichloroacetonitrile and hydrogen peroxide. Process for the preparation of (3R, 4R, 1'R) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoyloxyazetidin-2-one according to Claim 1, characterized in that (3S, 4S, 1 'R) -Np-Methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one is treated with m-chloroperbenzoic acid. Process for the preparation of (3R, 4R, 1'R) -3- (11-hydroxyethyl) -4-benzoyloxyazetidin-2-one according to Claim 1, characterized in that (3S, 4S, 1'R) -Np-methoxyphenyl -3- (1'-Hydroxyethyl) -4-benzoylazetidin-2-one is treated with m-chloroperbenzoic acid and the resulting compound is treated with cer (IV) ammonium nitrate. Process for the preparation of (3R, 4R, 1'R) -3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-benzoyloxyazetidin-2-one according to claim 1, characterized in that that (3R, 4R, 1'R) -3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-benzoylazetidin-2-one is treated with m-chloroperbenzoic acid. Process for the preparation of (3R, 4R, 1'R) -3- (1'-allyloxycarbonyloxyethyl) -4-benzoyloxyazetidin-2-one according to Claim 1, characterized in that (3S, 4S, 1'R) - 3- (11-Allyloxycarbonyloxyethyl) -4-benzoylazetidin-2-one is treated with m-chloroperbenzoic acid. 7. Compounds of formula II ff! T · li R1 '| 7syi — ΠΜ * -11' »D </ so 8471 6 in which formula represents hydrogen or lower alkyl, R2 represents hydrogen or a hydroxy-protecting group r21, R3 represents phenyl or phenyl substituted by lower alkyl, lower alkoxy or halogen and R4 represents hydrogen or the amino protecting group R4 '. Compound of formula II according to Claim 7, characterized in that R 1 represents methyl, R 2 represents hydrogen, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, tert-butyldimethylsilyl, dimethyl-2,3-dimethylbut-2-ylsilyl or 3,5-dinitrobenzoyl, R3 is phenyl and R4 is hydrogen or p-methoxyphenyl. Compound according to Claim 7, characterized in that it is (3S, 4S, 1'R) -N-p-methoxyphenyl) -3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one. Compound according to Claim 7, characterized in that it is (3S, 4S, 1'R) -3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one, (3S, 4S, 1 ' R) -Np-methoxyphenyl-3- [1 '- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4-benzoylazetidin-2-one, (3S, 4S, 1'R) -3- [1' - (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4-benzoylacetidin-2-one, (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1'-allyloxycarbonyloxyethyl) -4 -benzoylazetidin-2-one or (3S, 4S, 1'R) - (1'-allyloxycarbonyloxyethyl) -4-benzoylazetidin-2-one. Compound according to Claim 7, characterized in that it is (3S, 4S, 11R) -Np-methoxyphenyl-3- [1 '- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoylazetidine-2- one, (3S, 4S, 1'R) -3- [1 '- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoylazetidin-2-one, or (3S, 4S, 1 * R) -Np-methoxyphenyl -3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-benzoylazetidin-2-one. si 8471 6 Compound according to Claim 7, characterized in that it is (3S, 4S, 1'R) -3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] - 4-benzoylazetidin-2-one.