GB2144419A

GB2144419A - Azetidinones

Info

Publication number: GB2144419A
Application number: GB08419149A
Authority: GB
Inventors: Paolo Lombardi; Maristella Colombo; Angelo Crugnola; Giovanni Franceschi
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1983-08-04
Filing date: 1984-07-27
Publication date: 1985-03-06
Also published as: JPS6054358A; BE900275A; DE3428049A1; GB8419149D0; DE3428049C2; JPH0557980B2; GB2144419B; GB8321004D0

Abstract

<IMAGE> Azetidinones of the above formula (R1=H or a group which can be replaced by H in a single step reaction proceeding under mild conditions, R2=H or a hydroxy protecting group, R3= substituted or unsubstituted alkyl or aryl, R4=H, lower alkyl, phenyl, or substituted phenyl) are useful intermediates in the preparation of penems. Their preparation is also described.

Description

SPECIFICATION Azetidinones The invention relates to chiral azetidinones and to a stereoselective process for their preparation. The azetidinones according to the invention are useful as intermediates for the preparation and known and new p-lactam compounds, including 8R,6S,5R penems having the general formula I

wherein R represents an organic group as described in British Patent Specifications Nos. 2043639 and 2013674 and in German Patent Specification No. 2819655. Such penems have shown high antibacterial activity.

In this Specification, the term "lower alkyl" means a straight or branched chain alkyl group having from 1 to 4 carbon atoms. Functionalized terms, such as "lower alkoxy" and "lower haloalkyl" are to be interpreted correspondingly.

The term "hydroxy protecting group" means any group conventionally used for the protection of a hydroxy function during chemical reactions. Such groups include, but are not limited to, lower alkoxycarbonyl groups such as t-butoxycarbonyl; lower haloalkoxycarbonyl groups such as 2 iodethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl; optionally substituted aralkoxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl and p-nitrobenzyloxycarbonyl; tri-(lower alkyl)-silyl groups such as t-butyldimethylsilyl ortrimethylsilyl; tertiary alkyl groups having from 4 to 10 carbon atoms such as t-butyl; substituted or unsubstituted mono-, di- or tri-phenylmethyl groups such as benzyl, p-methoxybenzyl, diphenylmethyl, di-(p-methoxyphenyl)-methyl, p-methoxyphenyl, zx,4- dimethoxybenzyl and trityl groups; and substituted or unsubstituted phenyl groups such asp- methoxyphenyl.

The term "a carboxy protecting group" means any group conventionally used for the protection of a carboxy funtion during chemical reactions. Such groups include, but are not limited to, lower alkyl groups such as methyl, ethyl, isopropyl and t-butyl; lower haloalkyl groups such as 2-iodoethyl and 2,2,2trichloroethyl; lower alkoxymethyl groups such as methoxymethyl, ethoxymethyl and isobutoxymethyl; lower alkoxycarbonyloxy methyl groups such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl; 1- (lower alkoxycarbonyloxy)-ethyl groups such as 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl; optionally substituted arylmethyl groups such as benzyl,p-methoxybenzyl, o-nitrobenzyl and p-nitrobenzyl; benzhydryl; phthalidyl; and tri-(lower alkyl)-silyl groups such as trimethylsilyl and t-butyldimethylsilyl.

The invention provides chiral azetidinones having the general formula Il

1'R*,3R*,4R* 1' R*,3R*, 4S* wherein R1 represents a hydrogen atom or a group which can be replaced by a hydrogen atom in a single step reaction proceeding under mild conditions, R2 represents a hydrogen atom or a hydroxy protecting n, R3 represents a substituted or unsubstituted alkyl or aryl group and R4 represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted phenyl group.

Groups which R1 represent include (i) unsubstituted or substituted phenyl groups, especially those of-the formulae

(ii) unsubstituted or substituted benzyl groups, especially those of the formulae

(iii) unsubstituted or substituted benzyloxy groups, especially benzyloxy and p-nitrobenzyloxy groups, (iv) trisubstituted being alkyl, aryl or aralkyl groups, especiallytrimethylsilyl, dimethyl-t-butyl-silyl and diphenyl-t-butyl-silyl groups, and (v) groups of the formulae

wherein each R5 independently represents a hydrogen atom, a trialkylsilyl group, a lower alkyl group (especially methyl or ethyl) or an acyl group (especially acetyl or trifluoroacetyl).

Groups which R2 may represent include alkoxycarbonyl groups, for example t-butoxycarbonyl; halogen substituted lower alkoxycarbonyl groups, for example 2-iodoethoxycarbonyl or 2,2,2 trichioroethoxycarbonyl; optionally substituted aralkoxycarbonyl groups, for example benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl or p-nitrobenzyloxycarbonyl; a tri-(lower alkyl) silyl group, for example t-butyl-dimethylsilyl or trimethylsilyl; a tertiary alkyl group having from 4 to 10 carbon atoms, for example t-butyl; a substituted or unsubstituted mono-, di- ortriphenylmethyl group, for example benzyl, p-methoxybenzyl, diphenylmethyl, di-(p-methoxyphenyl)-methyl, p-methoxyphenyl, or,4- dimethoxybenzyl or trityl; or a substituted or unsubstituted phenyl group, for example p-methoxyphenyl.

R3 preferably represents a methyl group. The preferred lower alkyl groups which R4 may represent are methyl and ethyl; the preferred substituted phenyl groups which R4 may represent arep-nitrophenyl and p-chlorophenyl.

The compounds according to the invention contain asymmetrical carbon atoms in their structures and, therefore, may exist in optical isomers as well as steric isomers. It is a purpose of the present invention to disclose a process to make preferentially one steric isomer only, which may exist as a single enantiomer or as a racemic mixture.

Such enantiomers are represented herein by a single chemical structure for simplicity, but the present invention includes within its scope each anantiomer as well as a racemic mixture thereof. The prefixes R* and S* (said R star and S star) are used in this Specification to designate a chiral compound with an univocally determined relative configuration (steric isomer) in one and/or the other mirror image (enantiomer) singularly described by the relative sequence of the prefixes. However, the enantiometers having the-R configuration at C-1' are preferred.

The chiral azetidinones II may be prepared by simple chemical manipulations of chiral compounds having the general formula lil

1'R*,3R*,4S* wherein R1, R2 and R3 are as above defined, X represents a halogen atom and A represents an organic group.

The preferred halogen atoms which X may represent are chlorine, bromine and iodine. The preferred organic groups which A may represent include (i) a carboxy group, (ii) a group of the general formula COOR6wherein R6 represents a carboxy protecting group, (iii) a group of the general formula COR4 wherein R4 is as above defined, and (iv) a group of the general formula R7 wherein R7 represents a straight or branched chain substituted or unsubstituted alkyl group; a substituted or unsubstituted mono-, di- ortriphenylmethyl group, for example benzyl; an alkoxy or aryloxy group; an alkylthio or arylthio group; a protected acyl group, for example phenyl-ethylidene or substituted phenylethylidene; and a group of the general formula

wherein R4 is as above defined.

We have surprisingly found that the compounds lil may be obtained by the stereospecific cycloaddition of a chiral a-haloalkylketene having the general formula IV (or a suitable precursor thereof)

R,S wherein R2 represents a hydroxy protecting group and P3 and X are as above defined, to a Schiff base or imine derivative having the general formula V

wherein A represents a group COOR6, COR4 or R7 as above defined and wherein R, represents a group which can be replaced by a hydrogen atom in a single step reaction proceeding under mild conditions.

The cycloaddition proceeds such that the compounds Ill have the two chiral centres at C-3 and C-4 univocally commanded by the configuration of the starting chiral ketene IV. If the starting chiral ketene IV is a racemic mixture, described by the prefix (R,S), only one diastereoisomeric azetidinone is formed, therefore the cycloaddition is said to be diastereoselective and the product is designated by the prefixes R* and S*. If the starting chiral ketene IV is an enantiomer, described by either the prefix R or S, only one enantiomeric azetidinone is formed, therefore the cyloaddition is said to be enantioselective and the product is designated by the prefixes R or S.

Since pharmacologically active 8R,6S,5R penems I may be obtained from azetidinones II having the 1 'R,3R,4RS configuration, by known reactions and methods as described, inter alia, in our German Patent Specification No. 3245270, the process of the invention is very useful in providing optically active azetidinones which are key intermediates in the synthesis of biologically active penems. Although a number of similar cycloadditions to give azetidinones have been reported, none leads to total aymmetric induction, therefore the cycloaddition process of the invention is surprisingly advantageous.In accordance with the process of the invention a starting chiral ketene IV having the R configuration will lead univocallyto azetidinones II having either the 1'R,3R,4R configuration or the 1'R,3R,4S configuration, so providing a novel and practical route to pharmacologically active penems. Moreover, the compounds Ill and some compounds II are new.

The process of the invention is illustrated by the following reaction scheme.

Step (a) of the process comprises reacting a chiral ketene IV with a Schiff base or imine V. The chiral ketene IV is best generated from a suitable chiral acyl derivative of the general formula IVa, wherein X, R2 and R3 have the meanings given above for the ketenes IV and Y represents a halogen atom, preferably a chlorine or bromine atom, or a conventional carboxy activating group. Suitable carboxy activating groups include groups such as acetoxy, trifluoroacetoxy and pivaloyloxy; alkoxy-groups; and groups having the formulae

The chiral acyl derivatives IVa may be prepared from the corresponding free carboxylic acids by methods well known to the skilled chemist.

The Schiff bases or imine derivatives V may be prepared from an aldehyde derivative and a primary amine in a conventional manner, or by other methods well known to the skilled chemist, according to the substitution pattern on the compounds V.

The first step of the process is a 2 + 2 cycloaddition reaction between the a-haloalkyl ketene IV and the imine V to form the azetidinone III wherein, at this stage A, R1, R2 and P3 have the meanings given above for the compounds IV and V. The reaction conditions for the cycloaddition may vary in accordance with the substitution pattern in the acyl derivative IVa. The cycloaddition is carried out in presence of a base such as triethylamine, pyridine, lutidine, N,N-dimethyl-pyridine or DBU in an inert organic solvent such as a hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ether, dimethylsulphoxide, dimethylformamide or a mixture thereof. The reaction temperature may be from -30"C to 100 C and the reaction may take from 30 minutes to 24 hours.

Step (b) of the process comprises the reductive dehalogenation of the compound Ill to give a compound having the general formula VI. This is done such that the proton replacing the halogen X occupies the spatial position occupied by the halogen in the compound lil, thus maintaining the same configuration at C-3 of the compound VI, albeit the description of this chiral centre will change from R* to S+, as well as the description of the chiral centre at C-4 from S* to R*, due to the change in the priority sequence according to the universally accepted Cahn, Ingold and Prelog rules.

The reductive dehalogenation may be carried out by catalytic hydrogenation, reduction with metal hydrides, or reduction with an active metal or alloy in a protic medium. The reductive dehalogenation may be performed on the compound III for any of the meanings previously defined for R1, R2 and A. In particular, when R1 is hydrogen, R2 is hydrogen or A is a carboxy group, extra steps are necessary to have these groups before proceeding to step (b). Such transformations are easily performed by resorting to simple chemical reactions well known to the skilled in the art.The preferred method for conducting step (b) of the process is to stir a solution or a suspension of the compound III in an organic solvent such as benzene, toluene or dimethylsulphoxide with tributyltinhydride at a temperature ranging from 0 C to 1 OO"C, for from 10 minutes to 24 hours.

Step (c) of the process comprises transforming the compound VI into the azetidinyl carboxylate II, and this may be performed on the compound VI for any of the meanings previously defined for R1 and R2. Since this step comprises an oxidative degradation of the group A, A should only represent a carboxy group or the group COR4. If such meanings have not been previously introduced in the compound III prior to step (b), extra steps are needed to have these groups before proceeding to step (c). Such transformations are easily performed by resorting to simple chemical reactions well known to the skilled chemist.

Particularly, when A represents a carboxy group, the oxidative degradation is carried out in the form of an oxidative decarboxylation, preferably with lead tetraacetate. The oxidative decarboxylation can be performed by treating the compound VI with an amount of not less than 1 mole of lead tetraacetate, preferably 1 to 3 mole per mole of the compound VI in an inert solvent in the presence or absence of a base, such as pyridine or lutidine, or a salt, such as sodium acetate or potassium acetate. Examples of suitable inert solvent are hydrocarbons, aromatic hydrocarbons, acetic acid, dimethylformamide, dimethylsulphoxide, pyridine, HMPA, diethyl ether, tetrahydrofuran, dioxan, or a mixture thereof. The reaction temperature can be from 00C to 100 C, and the reaction time from 10 minutes to 24 hours. In this case, one obtains inversion of configuration at C-4, therefore the compound II, wherein R4 is methyl, is described as 1 'R*,3R*, 4R*.

When A represents the group COR4, the oxidative degradation is carried out in the form of the Baeyer-Villiger reaction. This conversion can be performed by treating the compound VI with an oxidant agent such as a solution of peracetic acid in acetic acid containing sulphuric acid orp-toluenesulphonic acid as a catalyst, solutions of peroxytrifluoroacetic, monopermaleic, monoperphthalic or perbenzoic acids in methylene dichloride, chloroform or ethyl acetate, peroxymonosulphuric acid or mixture of hydrogen peroxide with an acid or a base or hydrogen peroxide-hexafluoroacetone adduct, inorganic oxidant salt such as ceric ammonium nitrate in acetonitrile and water. The reaction may be carried out at from- 100C to 100 C, for a period of from 30 minutes to 72 hours.In this case one obtains retention of configuration at 0-4, therefore the compound of general formula (II) is described as 1 'R*,3R*,4S*.

The steps (d) and (e) constitute an alternative route to the compound II where the oxidative degradation at C-4, as described in the step (c) is performed prior to the reductive dehalogenation at C-3, as described in the step (b). In this case the intermediate compound of the general formula VII has the configuration 1'tri, 'R*,3S*, 4S* or 1 'R*,3S,4R* according to the meaning of A, that is the form of oxidative degradation adopted.

The following Examples illustrate the invention.

EXAMPLE1 1-p-methoxyphenylJ-{3R*J-3-bromo-31, 1'-[(1 'R*)-t-butyldimethylsllyloxy]-ethyJ}-(4S*)-4-methoxycarbonyl- azetidin-2-one

A solution of 15 mmol of (2R*)-2-bromo-(3R*)-3-(t-butyidimethylsilyloxy)-butyryl chloride in 20 ml of dry benzene was added over a period of 3 hours under nitrogen at 0 C to a stirred solution of 1.93 g (10 mmol) of p-methoxycarbonylmethyleneamino-anisole and 3.5 ml (25 mmol) of triethyiamine in 25 ml of dry benzene.

The reaction mixture was stirred for a further 1 hour and was then washed with an aqueous solution of sodium chloride, 1 N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride in that order. The washed reaction mixture was then dried over anhydrous sodium sulphate and filtered. The benzene was evaporated off in vacuo to give 4 g of an oily residue which was purified by column chromatography over 150 g of silica gel. Elution with hexane:ethyl acetate 93.7 by volume gave the title compound as an oil (2.4 g, 50% yield).

I.R. (CHCI3,cm-1): 1765,1510 N.M.R. (CDC13, 6): 0.10 (3H, s) 0.13 (3H, s) 0.81 (9H,s) 1.50 (3H, d, J = 6 Hz) 3.77 (3H, s) 3.82 (3H, s) 4.30 (1H, q, J = 6 Hz) 4.85 (1 H, s) 6.8-7.3 (4H, ABq, J = 10 Hz) EXAMPLE 2 1-(p-methoxyphenyl)-(3R*)-3-{ 1'-[(1'R*J-t-butyl-dimethylsilyloxyl-ethyls-(4R*J-4methoxycarbonyl-azetidin- 2-one

A mixture of 950 mg (2 mmol) of the compound prepared in Example 1,0.64 ml (2.4 mmol) oftributyltin hydride and 10 mg of AIBN was refluxed for 1 hour in 80 ml of dry benzene.The cooled reaction mixture was thoroughly washed with water and an aqueous solution of sodium chloride, dried over anhydrous sodium sulphate, filtered off and evaporated to dryness in vacuo to give the crude title compound as a fairly pure oil (755 mg. 96%).

I.R. (CHC13, cam~1): 1755, 1510 N.M.R. (CDCI3, S):0.02 (3H, s) 0.10 (3H, s) 0.87 (9H, s) 1.40 (3H, d, J = 6 Hz) 3.56 (1 H, collapsed dd, J = 6 Hz) 3.78 (6H, s) 4.20-4.60 (1 H, m, J = 6 Hz) 4.60(1H,d,J = 6 Hz) 6.80-7.30 (4H, ABq, J = 10 Hz) EXAMPLE 3 1-(p-methoxyphenyl)-(3R*)-34 1'-[(1'R*)-t-butyldimethyl-silyloxyl-ethyl}-(4R*)-4-carboxy-azetidin-2-one

A mixture of 755 mg of the crude compound prepared in Example 2,2 ml of pyridine and 4 ml of 0.5 N aqueous sodium hydroxide solution was stirred at ambient temperature for 24 hours. The reaction mixture was then cooled, carefully acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 20 ml).The combined extracts were washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulphate and evaporated in vacuo to give the crude title compound as a gum (585 mg, 82%).

I.R. (CHCl3,cm-1). 3600-2400.1755,1725,1510 N.M.R. (CDCI3,8):0.06 (6H, s) 0.83 (9H, s) 1.37 (3H, d, J = 6 Hz) 3.60 (lH,dd,J = 6 Hz) 3.74 (3H, s) 4.20-4.60 (1 H, m, J = 6 Hz) 4.60 (1h, d,J = 6 Hz) 6.80-7.30 (4H, ABq, J = 10 Hz) 9.80 (1 H, br s) EXAMPLE 4 1-(p-methoxyphenyl)-(3R*)-3{ 1'-[(1'R*]-t-butyldimethyl-silyloxy}-(4R*)-4-acetoxy-azetidin-2-one

A mixture of 240 mg (0.63 mmol) of the compound prepared in Example 3,017 ml (1.9 mmol) of anhydrous pyridine and 620 mg (1.26 mmol) of 90% lead tetraacetate was stirred in 10 ml of dry benzene at 50 C for 30 minutes. The cooled reaction mixture was filtered through 2 g of florisil, washing with an additional 30 ml of benzene.The combined benzene solutions were washed with 1N hydrochloric acid and with an aqueous solution of sodium sulphate, dried over an hydros sodium sulphate and filtered. Evaporating off the benzene in vacuo gave the crude title compound as a fairly pure oil (210 mg, 85%).

I.R. (CHCI3, cm-5): 1755, 1510 N.M.R. (CDCl3, b) :0.07 (6H, s) 0.75 (6H, s) 1.31 (3H, d, J = 6 Hz) 2.10 (3H,s) 3.18(1H,d,J = 3 Hz) 3.75 (3H, s) 4.10-4.40(1H,m,J = 3Hz, 6Hz) 6.60 (1 H, s) 6.78-7.35 (4H, ABq, J = 10 Hz) EXAMPLE 5 (3R*)-3{ 1'[1'R*)-t-butydimethylsilyloxy]-ethyl}-(4R*)-4-acetoxy-azetidin-2-one

A solution of 3.84 g (7 mmol) of ceric ammonium nitrate in 25 ml of water was added over a period of 2 hours at -10 C to a solution of 920 mg (2.3 mmol) of the compound prepared in Example 4 in 25 ml of acetonitrile. The reaction mixture was stirred for a further 1 hour at - 1 00C and then diluted with 50 ml of water.It was then extracted 3 times with 30 ml aliquots of ethyl acetate, and the combined extracts were washed with a saturated aqueous solution of sodium bicarbonate, five times with 30 ml aliquots of a 10% aqueous solution of sodium sulphite, with 30 ml of saturated aqueous sodium bicarbonate and with an aqueous solution of sodium chloride in that order. The washed solution was dried over anhydrous sodium sulphate and filtered. The solvent was evaporated off in vacuo to give the crude title compound as a fairly pure white solid (560 mg,85%).

I.R. (CHCI3, cm-1): 3420, 1780, 1745 N.M.R. (CDCl3, b):0.06 (6H, s) 0.84 (9H, s) 1.25 (3H, d, J = 6 Hz) 2.10 (3H, s) 3.15(lH,d,J = 3 Hz) 4.08-4.33 (1 H, m, J = 3 Hz, 6 Hz) 5.82 (1 H, s) 6.78 (1 H, br s) EXAMPLE 6 1-(p-methoxyphenyl)-(3R*)-3-bromo-{1'-[1'R*)-t-butyl-dimethyilsilsyloxy)-ethyt}-(4S*)-4-p-chlorobenzoyl)azetidin-2-one

A solution of 7 mmol of (2R*)-2 bromo-(3R*)-3-(t-butyl-dimethylsilyloxy)-butyryl chloride in 10 ml of methylene dichloride was added over a period of 2 hours under nitrogen at 0 C to a stirred solution of 1.38 g (5 mmol) of 4-(p-chlorobenzoylmethyleneamino)-anisole and 1.75 ml (12.5 mmol) oftriethylamine in 15 ml of dry, methanol free methylene dichloride. The reaction mixture was then washed with water, IN hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water in that order. The washed reaction mixture was then dried over anhydrous sodium sulphate and filtered. The methylene dichloride was evaporated off in vacuo to give 3.16 g of an oily residue which was purified by column chromatography over 120 g of silica gel. Elution with hexane:ethyl acetate 93:7 by volume gave the title compound as a foam (2.35 g, 85% yield).

i.R. (CHCI3, cm-1): 1765, 1690,1590,1510.

N.M.R. (CDCI3, b):0.17 (6H, s) 0.88 (9H, s) 1.50 (3H, d, J = 6 Hz) 3.73 (3H, s) 4.48(1H,q,J =6Hz) 5.72 (1 H, s) 6.70-8.10 (8H, 2ABq,J = 9 Hz,9 Hz) EXAMPLE 7 l-(p-methoxyphenyi)-(3S*)-3 1'-[(1'R*)-t-butyldimethyl-silyloxy]-ethyl}-(4r*)-4-(p-chlorobenzoyl)-azetidin- 2-one

A mixture of 553 mg (1 mmol) of the compound prepared in Example 6,0.32 ml (1.2 mmol) oftributyltin hydride and 5 mg of AIBN was refluxed for 4 hours in 40 ml of dry benzene. The cooled reaction mixture was worked up as described in the Example 2 to give a residue which was purified by column chromatography on 20 g of silica gel. Elution with benzene:ethyl acetate 95:5 by volume gave the title compound as a yellow solid (415 mg, 88%).

I.R. (CHCl3, cmi): 1750, 1690, 1590, 1510 N.M.R. (CDCI3, ):-0.35 (3H, s) -0.18 (3H, s) 0.66 (9H, s) 1.28 (3H, d, J = 6 Hz) 3.67 (1H, m,J = 6 Hz) 3.73 (3H, s) 4.15-4.55 (1H, m,J = 6Hz) 5.48(1H,d,J = 6 Hz) 6.70-8.10 (8H, 2 ABq, J = 9Hz, 9 Hz)

Claims

CLAIMS 1. Achiral axetidinone having the general formula

1'R*,3R*,4R* 1'R*,3R*,4S* wherein R1 represents a hydrogen atom or a group which can be replaced by a hydrogen atom in a single step reaction proceeding under mild conditions, R2 represents a hydrogen atom or a hydroxy protecting group, P3 represents a substituted or unsubstituted alkyl or aryl group and R4 represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted phenyl group.

2. 1-(p-Methoxyphenyl)-(3R*)-3-{ 1'-[(1'R*)-t-butyldimethyl-silyloxy]-ethyl} -(4R*)-4-acetoxy-azetidine-2-one.

3. (3R*)-3-{ 1'-[(1'R*)-t-Butyidimethyisilyloxy]-ethyl }-(4R*)-4-acetoxy-azetidin-2-one.

4. ' A chiral azetidinone having the general formula Ill

1'R*,3R*,4S* wherein R1, R2 and P3 are as defined in claim 1, X represents a halogen atom and A represents an organic group.

5. A chiral azetidinone according to claim 4wherein A represents: (i) a carboxy group, (ii) a group of the general formula COOR6 wherein P6 represents a carboxy protecting group, (iii) a group of the general formula COR4 wherein R4 is as defined in claim 1, or (iv) a group of the general formula R7 wherein R7 represents a straight or branched chain substituted or unsubstituted alkyl group, a substituted or unsubstituted mono-, di- ortriphenylmethyl group, an alkoxy or aryloxy group; and alkylthio or arylthio group; a protected acyl group, for example phenyl-ethylidene or substituted phenylethylidene; and a group of the general formula

wherein R4 is as above defined.

6. 1 -(p-methoxyphenyl)-(3R*)-3-bromo-3-{1 '-[(1 R*)-t-butyldimethylsilyloxy]-ethyl} -(4S*)-4- methoxycarbonyl-azetidin-2-one.

7. 1-(p-methoxyphenyl)-(3R*)-bromo-3-{ 1 '-[(1 'R*)-t-butyl-dimethylsilyloxy]-ethyl}-(4S*)-4-p- chlorobenzoyl)-azetidin-2-one.

8. A chiral azetidinone having the general formula VI

1'R*,3S*,4R* wherein R1, R2 and P3 are as defined in claim 1 and A is as defined in claim 4.

9. A chiral azetidinone according to claim 8 wherein A represents a carboxy group or a group of the general formula COR4 wherein R4 is as defined in claim 1.

10. 1 -(p-methoxyphenyl)-(3P*)-3-f 1 '-[(1 'R*)-t-butyidimethylsilyloxy]-ethyl } -(4R*)-4-methoxy-carbonyl- azetidin-2-one.

11. 1 -(p-methoxyphenyl)-(3R+)-3-( 1 '-[(1 'R*)-t-butydimethylsilyloxy]-ethyl} -(4R*)-4-carboxy-azetidin-2- one.

12. 1 -(p-methoxyphenyl )-(3S*)-3-{1 '-[(1 'R*)-t-butyldimethylsilyloxy[-ethyl}-(4R*)-4-(p-chlorobenzoyl)- azetidin-2-one.

13. Achiral azetidinone having the general formula VII

lsR*,3st,4st 1'R*,3S*,4R* wherein P1, R2, R3 and R4 are as defined in claim 1 and X is as defined in claim 4.

14. A process for the preparation of a chiral azetidinone according to claim 1, the process comprising reacting in an organic solvent in the presence of a base a chiral a-haloketene having the general formula IV

R,S wherein R2 represents a hydroxy protecting group, P3 represents a substituted or unsubstituted alkyl or aryl group and X represents a halogen atom, or a precursor thereof having the general formula IVa

2R*,3R* wherein R2, P3 and X are as defined in this claim and Y represents a halogen atom or a carboxy activating group, with a Schiff base or imine having the general formula V

wherein A represents a group of the formula COOP6, COR4 or R7 as defined in claim 5 and R1 represents a group which can be replaced by a hydrogen atom in a single step reaction proceeding under mild conditions to obtain a compound of the general formula Ill

1'R*,3R*,4S* wherein R1, R2, R3, X and A are as defined in this claim, and submitting the compound Ill to the following steps:: (i) if A does not represent a group of the formula COR4 then converting it to such a group or to a carboxy group, (ii) oxidatively degrading the group A, (iii) reductively dehalogenating the compound to remove the 3-halo substituent X, (iv) optionally converting the group R1 to a hydrogen atom, and (v) optionally converting the group R2 to a hydrogen atom, the reactions being carried out in any order save that if step (i) is necessary then it must be carried out before step (ii).

15. A process according to claim 14 in which step (ii) is carried out on a compound in which A represents a carboxy group by reacting the compound with at least one mole equivalent of lead tetracetate in an inert solvent.

16. A process according to claim 14 in which step (ii) is carried out on a compound in which A represents a group of the formula COR4 by a Baeyer-Villiger reaction.

17. A process according to claim 14, the process being substantially as described herein with reference to Examples 1 to 4 or Examples 1 to 5.