IE45983B1 - Azido-, amino- and protected aminoazetidinylacetic acid derivatives - Google Patents

Description

This invention relates to certain azido-, amino- and protected aminoacetidinylacetic acid derivatives and to a process for their preparation.

Our Patent Specification No. 2287/77 from which the subject 5 matter of the present application is divided discloses and claims inter alia certain acyl aminoazetidinylacetic acid derivatives which have antibacterial activity. The compounds of this invention are useful as intermediates for preparing these antibacterially active compounds.

Accordingly the present invention provides compounds of formula (I) (I) N COOH and salts and protected esters thereof where A is azido, amino or protected amino; X is dig-halogen, CHgOSOg or CHgOSOgR in which Q is hydrogen, lower alkyl or halogen and R is lower alkyl; Y is hydroxy or II — SCE in which E is hydrogen, lower alkyl, trifluoromethyl or phenyl optionally substituted with one or two substituents selected from lower alkoxy, lower alkyl, halogen and nitro.

When used herein lower alkyl and lower alkoxy mean such groups containing 1-6 carbon atoms.

Preferably X is chloromethyl, bromomethyl or iodomethyl and E is methyl or phenyl.

Preferably Q is hydrogen, methyl or bromo.

One class of compounds within the scope of this invention is that where A is a protected amino group. The term protected amino group used herein means derivatives of the amino group where amino groups has been masked by another group which protects it during subsequent chemical reaction and then can be removed to generate the amino group.

Examples of protected amino groups are t-butoxycarbonylami no, tri chioroethoxycarbonylami no, benzyloxycarbonylami no, £-methoxybenzyloxycarbonylami no, ja-nitrobenzyloxycarbonylamino, isobornyloxycarbonylami no, trityl ami no, 1-methoxycarbonyl-2propenylamino, phthalimido, succinimido, maleimido and 59 8 3 4,5- diphenyl-4-oxazolin-2-onyl. The use of the 4,5-diphenyl-4oxazolin-2-onyl group is described in J. Org. Chem., 1973, 38, 3034.

Examples of protecting ester-forming groups include lower alkyl for example methyl, 2,2,2-trichloroethyl, β-iodoethyl, C^-Cg-tert-alkyl for example t-butyl, Cg-Cy-tert-alkenyl, Cg-Cy-tert-alkynyl, C^-Cg-alkanoylmethyl, phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, methylbenzoylmethyl, methanesulfonylbenzoylmethyl, phenylbenzoylmethyl, benzyl, £-nitrobenzyl, jo-methoxybenzyl, benzhydryl, trityl, trimethylsilyl, and triethylsilyl.

Particular ester-forming groups are 2,2,2-trichloroethyl, benzyl, benzhydryl, t-butyl and methyl.

Preferably the ester-forming group, is one of those which can be removed by hydrogenation or by zinc dust and acetic acid.

The above list of protected amino groups and ester-forming groups is not intended to be exhaustive. Many articles and books have been devoted to the subject. One standard work is J.F. McOmie Protective Groups in Organic Chemistry 1973 Plenum Press.

Particular compounds of this invention where A is a protected amino group are:a-(ci£-3-isobornyloxycarbonylamino-2-iodomethyl-4-oxo-l-azetidinyl)α-thiolacetoxyacetic acid, a-(cis-3-isoborn.yToxy-carbon.ylamino-2-bromomethyl-4-oxo-l-azetidinylα-thiolacetoxyacetic acid, a-(cis-3-isobornyloxycarbonylamino-2-chloromethyl-4-oxo-l-azeti di nyl)4 43983 a-thiolacetoxyacetic acid and their benzyl, benzhydryl, t-butyl, and methyl esters. Particular compounds of this invention where A is amino are:a-(cis-3-amino-2-iodomethy!-4-oxo-l-azeti di nyl)5 α-thiolacetoxyacetic acid, “-(cis-3-amino-2-bromomethyl-4-oxo-l-azeti di nylία-thiol acetoxyaceti c acid and a-(cis-3-amino-2-chioromethyl-4-oxo-l-azetidinyl)α-thiolacetoxyacetic acid.

The compounds of this invention can be prepared by a process which comprises condensing a compound of formula (II):'X (II) NH where A is azido or a protected amino group and X is as defined with reference to formula (I) with a protected ester of glyoxylic acid; optionally reacting the condensation product with a halogenation reagent and an alkali metal salt of a thiol acid of formula HSCOE where E is as defined with reference to formula (I) and optionally hydrogenating the azido group or converting the protected amino group into amino or removing the protected ester-forming group. 9 8 3 By way of example in the above process A in the compound of formula (II) is t-butoxycarbonylamino, trichloroethyloxycarbonylamino, benzyloxycarbonylamino, £-methoxybenzylcarbonyl amino, £-nitrobenzyloxycarbonylamino, or isobornyloxycarbonylamino and X is -Ci^halogen; the ester forming group in the glyoxylic acid ester is 2,2,2-trichloroethyl, benzyl, benzhydryl, t-butyl or methyl and the condensation product is converted into a compound of formula (I) where E is methyl or phenyl.

Preferably in the above process X in the compound of formula (II)is CH2Br and the condensation product is converted into a compound of formula (I) where Y is SCOE in which E is methyl.

In particular benzhydryl, benzyl and t-butyl a-cis-3-t-butoxycarbonylamino-2-bromomethyl-4-oxo-l-azetidinyl)-a-thiolacetoxyacetate can be prepared by condensing a-cis-3-t-butoxycarbonylamino-4-oxo-2-azetidinylmethyl bromide with benzyl, benzhydryl or t-butyl glyoxylate and reacting the condensation product with thionyl chloride and an alkali metal salt of thiolacetic acid. Removal of the t-butoxycarbonyl group and the benzyl, benzhydryl or t-butyl group gives 3-amino-2-bromomethyl-4-oxo-l-azetidinyl)thiol-acetic acid.

The following Examples where temperatures are Centigrade illustrate the invention.

PREPARATION 1 Methyl N-(2,4-dimethoxybenzyl)iminoacetate To a mixture containing 16.82 g (0.101 mol) of 2,4-dimethoxybenzylamine and anhydrous magnesium sulfate in 150 ml of methylene chloride at 25° is added a solution of 10.05 g (0.114 mol) of methyl glyoxylate 1n 20 ml of methylene chloride. The reaction mixture is stirred at room temperature overnight (15 hours) and then is filtered and the solvents are removed in vacuo to afford the imine as a dark orange gum.

PREPARATION 2 Isobornyl chloroformate Into an argon flushed flask is placed 82 ml (100 mmol) of a 12.5% phosgene in benzene solution and 100 ml of ether. The solution is cooled to 0° under argon and treated dropwise over a one-hour period with a solution of 11.7 g (75 mmol) dl-isoborneol and 6.7 ml (83.7 mmol) pyridine in 50 ml ether. The solution is allowed to warm at room temperature, stirred for 2.5 hours, and then filtered. The solid is washed with ether and the filtrate is evaporated in vacuo to give 15.25 g of product.

PREPARATION 3 Methyl cis-3-azido-l-(2,4-dimethoxybenzyl)-4-oxoazetidine-2carboxylate (1) Method A: To a solution of 15.1 g (0.149 mol) of azidoacetic acid in 130 ml of anhydrous methylene chloride at 0° (ice bath) is added dropwise 21.0 ml (0.15 mol) of trifluoroacetic anhydride. This mixture is stirred at 0° for 15 minutes and then 20.8 ml (0.15 mol) of triethylamine is added dropwise. Stirring is continued for an additional 45 minutes and then the entire reaction mixture is transferred under argon into an additional funnel which is cooled externally by dry ice.

The addition funnel is attached to a flask containing the imine from Preparation 1, anhydrous methylene chloride (200 ml), and triethylamine (20.8 ml, 0.15 mole). The solution of the mixed anhydride is added dropwise from the additional funnel to the solution of imine at 0°.

Stirring is continued at 0° for 1 hour and then the dark reaction mixture is transferred to a separatory funnel and washed with water, aqueous NaHCOg and brine and then dried over anhydrous magnesium sulfate. The solvents are removed in vacuo and the residue is chromatographed on 300 g of silica gel (70-230 mesh) affording an off-white solid which is further purified by trituration with ether to give 14.45 g (45%) of the title product as. a white solid; tlc:benzene:ethyl acetate (1:1), silica gel GF, Rf = 0.64. Recrystallization from ethyl acetate-hexane affords an analytical sample, mp 82-84°, Method B: A solution of 1.6 g (9.55 mmol) 2,4-dimethoxybenzylamine in 5 ml of methylene chloride is rapidly added at 0° to a solution of 1.06 g (10 mmol) freshly distilled methyl glyoxylate in 15 ml CHgClg. A slight exotherm occurred and water droplets appeared. Magnesium sulfate (5 g) is added and the mixture stirred at 0° for 2 hours. Fresh magnesium sulfate (1.0 g) is added, the magnesium sulfate removed by filtration under argon and washed with a minimum of methylene chloride.

To a solution of 3.8 g (36 mmol) of azidoacetic acid (pumped in high vacuum. 3 hr) in 125 ml of methylene chloride is added 10.6 ml (76 mmol) of triethylamine with cooling. Magnesium sulfate (3 g) is added, the mixture stirred 10 minutes at room temperature, filtered under argon and washed with 25 ml methylene chloride. -45983 The azldoacetic acid solution is added at 0° to the imine, sufficient methylene chloride is added to bring the total volume to 200 ml, the solution is cooled to 0° under argon and 5.3 ml (38 mmol) trifluoroacetie anhydride added slowly over 30 minutes with vigorous stirring and cooling.

The mixture is stirred for 1 hour at 0°, allowed to warm to room temperature; transferred to a separatory funnel; washed with water, % NaHCOg, 25» phosphoric acid and 5% NaHCOg; dried over magnesium sulfate-charcoal; filtered and the filtrate is decolourised twice with charcoal and evaporated to dryness. The residue is dissolved in a minimum of ether and stored at -20° to allow crystallization. The crystalline mass is isolated and washed with cold ether to give 1.9 g (64%) product, mp 79°-80.5°.

Method C: A solution of 1.6 g of 2,4-dimethoxybenzylamine in 15 ml of methylene chloride is shaken with an excess of magnesium sulfate then reacted with 1.05 g of methyl glyoxylate in 2 ml of methylene chloride at 25° (room temperature) overnight. The mixture is filtered, stripped and degassed with argon.

A solution of 1.5 g of azldoacetic acid in 25 ml of methylene chloride is cooled to 0° then reacted with 1.3 ml of oxalyl chloride with 1.2 ml of pyridine in 3 ml of methylene chloride at 0°. Argon is passed through the mixture which is stirred for one hour.

The imine from above is taken into 20 ml of methylene chloride with 4.15 ml of triethylamine. The solution of azidoacetyl chloride is added dropwise at 0°. After one hour at 0° the mixture is washed with water, sodium bicarbonate solution, and brine, dried and stripped. 9 8 3 After passing over a silica gel column with methylene chloride the yield is 1.31 g of the desired compound.

PREPARATION 4 cis-3-Azido-4-oxo-2-azetidinylmethyl tosyl ate 5 Methyl £isy3-azido-l-(2,4-dimethoxybenzyl)-4-oxoacetidine-2carboxylate is reacted with potassium persulfate and sodium monohydrogen phosphate according to the procedure of Example 4 to give methyl cis-3-azido-4-axoazetidine-2-carboxylate. The methyl ester of this product is reduced by treatment with sodium borohydride according to the procedure of Example 5 to give the methyl alcohol derivative. The alcohol is converted into the title compound by treatment with £-toluenesulfonyl chloride according to the procedure of Example 6; rap 77-78°.

EXAMPLE 1 Methyl cis-1-(2,4-Dimethoxybenzyl)-3-amino-4-oxoazetidine-2-carboxylate A mixture containing 10.0 g (0.312 mol) of methyl cis-l-(2,4-dimethoxybenzyl)-3-azido-4-oxoazetidine-2-carboxyalte, 1.0 g of 10% palladium on carbon, and 200 ml of ethanol is hydrogenated for 2 hours at 40-45° at 60 psi of hydrogen. The reaction mixture is allowed to cool to 25° and is filtered through a filter-aid. After removing the solvents in vacuo a clear, yellow gum of the title product is obtained. 9 8 3 EXAMPLE 2 Methyl cis-3-t-Butoxycarbonylamino-2-(2,4-dimethoxybenzyl)-4oxoazetidine-2-carboxylate A solution of 5.5 g (18.8 mmol) of methyl cis-3-amino-l-(2,4-dimethoxybenzyl)-4- oxoazetidine-2-carboxylate in 100 ml of dry toluene is cooled to -78°; 2.5 ml (18.8 mmol) of triethylamine is added followed by rapid addition of 35 ml (42 mmol) of a 12% solution of phosgene in benzene. The mixture is stirred for 15 minutes at -78°, 3 hours at -45° (acetonitrile-dry ice), then warmed to room temperature and concentrated to half volume in .vacuo. To the resulting solution is added 50 ml of _t-butanol and the mixture is stirred at room temperature overnight. The solvents are removed in vacuo, the residue is diluted with ethyl acetate and filtered. The filtrate is transferred to a separatory funnel and washed with 5% NaHCOg, 5% HC1 and brine; dried over magnesium sulfate and evaporated to dryness. Recrystallization of the crude, crystalline product affords 3.8 g (52%) of the title compound. Recrystallization from ether gives an analytical sample.

EXAMPLE 3 Methyl cis-3-isobornyloxycarbonylami no-1-(2,4-dimethoxybenzyl)-4oxoazetidine-2-carboxylate A solution of 11.5 g (53.7 mmol) of isobornyl chloroformate in 75 ml methylene chloride, is cooled to -78° in an argon flushed flask.

To this solution is added dropwise a mixture of 7.75 g (26.3 mmol) of the 3-amino product from Example 1 and 3,4 g (26.3 mmol) of N,N-diisopropyl-N-ethyl amine in 150 ml methylene over a 1.5 hour period with cooling to -78°. The reaction is stirred at -78° for 1-3 hours and then allowed to stand overnight at -25°. To the solution is added 10 ml of cold IN HgSO^ and the organic solvent is removed.

The residue is dissolved in ethyl acetate which is then washed with two portions of cold IN HgSO^, two portions aqueous NaHCOg and saturated NaCl. The dried solution is evaporated and the residue is chromatographed on silica gel with a gradient of 0% to 15% ethyl acetate in methylene chloride as eluant to give 9.7 g of product.

EXAMPLE 4 Methyl ci s-3-Isobornyloxycarbonylami no-4-oxoazeti di ne-2-carboxylate A degassed solution of 4.75 g (10 mmol) of the product from Example 3 in 128 ml acetonitrile is heated to reflux. To the refluxing solution is added in six portions over a period of one hour a degassed solution of 10.81 (40 mmol) KgSgOg and 5.35 g (20 mmol) Na2HP04'7H20 in 200 ml water. When tic analysis indicates the reaction is complete, the solution is cooled, the organic solvents are evaporated in vacuo and, after the addition of water, the aqueous phase is extracted with ethyl acetate. The dried extracts are concentrated and the residue is chromatographed on silica gel with a gradient of 0% to 50% ethyl acetate in benzene as eluant to give 2.57 g (79%) of the title compound.

EXAMPLE 5 cis-3-Isobornyloxycarbonylami no-4-oxo-2-azetidi nyImethy1 alcohol A solution of 2.5 g (7.7 mmol) of the product from Example 4 in 154 ml of tetrahydrofuran and 17 ml water under argon is cooled to 0° and treated with a solution of 582 mg (15.4 mmol) of FiaBH^ in ml cold water. The reaction is stirred for 1-2 hours at 0° and then at -25° overnight. Excess reagent is destroyed by the addition of 2 ml glacial acetic acid. The organic solvent is removed, additional water is added and the aqueous solution is extracted with ethyl acetate. The extracts are washed with saline solution, dried and evaporated to a residue which is recrystallized from ethyl acetate/ether/hexane; 1.42 g (63%) mp 152.5-154°.

EXAMPLE 6 cis-3-Isobornyloxycarbonylamino-4-oxo-2-azetidinylmethyl tosylate A solution of 1.185 g (4 mmol) of the alcohol product of Example 5 in 7.0 ml pyridine under argon is cooled to 0° and then 1.525 g (8 mmol) j)-toluenesulfonyl chloride in 2.4 ml pyridine is added. The reaction is stirred at 0° until tic analysis indicates that the reaction is completed. To the mixture is added 0.38 ml 85% lactic acid.

After stirring 1 hour at 0°, the reaction is poured into ethyl acetate and the resulting solution is washed twice with water, and each of the following: IN H^SO^, saturated NaHCQj and saturated NaCl. The dried solution is evaporated to give the title product; 2.0 g (100%), EXAMPLE 7 ci s-3-Isobornyloxycarbonylami no-4-oxo-2-azeti di nylmethyl bromi de To a mixture of 326 mg (3.75 mmol) LiBr in 4.5 ml dry dimethylformamide is added 338 mg (0.75 mmol) of the tosylate of Example 6. The mixture is degassed with argon and heated to 60° for 4 hours. The reaction mixture is poured into ethyl acetate and washed well with water and saturated NaCl. The dried solution is evaporated to give 75% yield of the title compound. 9 8 3 EXAMPLE 8 Benzhydryl g-(ci s-3- Isobornyl oxycarbony! ami no-2-bromoinethy 1 -4-oxo -1-azeti di nyl)-a-hydroxyacetate The bromo compound of Example 7 (800 mg, 2.23 mmol) is dissolved in ml tetrahydrofuran, cooled to -78° under argon, and treated with 1.22 ml (2.4 mmol) of 1.97M butyllithium in hexane. After stirring for 30 minutes at -78°, a solution of 577 mg (2.4 mmol) benzhydryl glyoxylate in 5 ml tetrahydrofuran is added. The reaction is stirred for 2 hours at -78°, quenched with a cold NaHgPO^ solution, and extracted with ethyl acetate. The extracts are washed with saline, dried and evaporated to give the title product.

EXAMPLE 9 Benzhydryl a-(cis-3-Isobornyloxycarbonylamino-2-bromomethyl-4-oxo-l-azetidinyl)a-thiolacetoxvacetate To a cold (-10° with CCl^/dry ice) solution of 943 mg (1.57 mmol) of product from Example 8 in 20 ml dry tetrahydrofuran under argon is added 151 ul (2.0 mmol) pyridine and then 144 yl (2.0 mmol) of thionyl chloride. The solution is stirred at -10° for 15 minutes and then a solution of 228 mg (2.0 mmol) potassium thiolacetate in ml dimethylformamide is added. After stirring 2 hours at -10°, the tetrahydrofuran is removed in vacuo and the residue is poured into ethyl acetate. The solution is washed with water and sodium chloride, dried, and evaporated. The residue is chromatographed on 25 g silica gel with an eluant gradient of 0-25% ethyl acetate in methylene chloride to give the product, 44% yield. ίΛΗπ L —— α-(cis^3-Amino-2-bromomethy1-4-οχο-1-azetidiny1)-αthiolacetoxyacetic acid The product from Example 9 (195 mg, 0.3 mmol) and 160 μΐ (1.48 mmol) anisole are combined, cooled to 0°, and then treated with 6 ml trifluoroacetic acid. The reaction mixture is stirred and cooled for 1 hour and the trifluoroacetic acid is removed in vacuo.

Ether is added to the residue and the precipitated tri fluoroacetate salt of the title compound is collected and dried under vacuum.

EXAMPLE 11 When the t-butoxycarbonylamino derivative of Example 2 is substituted for the isobornyloxycarbonylamino derivatives in Examples 4-9, the corresponding t-butoxycarbonylamino derivatives are obtained.

Treating benzhydryl a-(cis-3-t-butoxycarbony1amino-2-bromomethyl-4oxo-1-azetidinyl)-a-thiolacetoxyacetate with trifluoroacetic acid and anisole according to the procedure of Example 10 also gives the tri fluoroacetate salt a-(ci s-3-ami no-2-bromomethyl-4-oxo-lazeti di ny1)-a-thi olacetoxyaceti c aci d.

EXAMPLE 12 A solution of 3.5 g (7.74 mmol) of the tosylate from Example 6 in 10 ml dimethylformamide (DMF) is added to a solution 3.32 g (78.5 mmol) LiCl in 30 ml DMF. The resulting solution is degassed for 15 minutes with argon and then heated for 3 hours at 73° under argon. After cooling to room temperature, the mixture is taken up in saline solution and extracted with ethyl acetate. The extracts are washed with saline solution, dried and evaporated to give cis-3-isobornyloxycarbonylamino-4-oxo-2-azetidinylmethyl chloride. 9 a Similarly when the tosylate derivative is heated with a 10 mole excess of sodium iodide in acetone at 55-60° for 6-7 hours, cis-3isoborny 1oxycarbonylamino-4-oxo-2-azetidinylmethyl iodide is obtained.

When the above chloro and iodo derivatives are carried through 5 the reaction sequence of Examples 8, 9 and 10, the tri fluoroacetate salts of a-(cis-3-amino-2-chloromethyl-4-oxo-l-azeti di nyl)thi ol-α-acetoxyaceti c aci d and a-(cis-3-amino-2-iodomethyl-4-oxo-l-azetidinyl)-a-thiolacetoxyacetic acid are obtained.

EXAMPLE 13 Benzhydryl a-(ci s-3-Azi do-4-oxo-2-bromomethy1-1-azeti di nyl-g-hydroxyacetate A solution of 4.17 g (174 mmol) benzhydryl glyoxylate in 80 ml toluene is heated to reflux under an argon atmosphere and 12 ml of toluene-water mixture is removed by distillation. The remaining solution is cooled to ca. 50° and 2.02 g (9.85 mmol) of _cis-3-azido-4-ozo-2-azetidinemethyl bromide is added. The mixture is heated at 90° for 5 hours and then allowed to cool to 25°, The toluene is removed in vacuo to afford 6.05 g of orange gum which is chromatographed on 182 g of silica gel and with 20% ethyl acetate in cyclohexane to give 3.22 g (73%) of product as a mixture of diastereoisomers; tic: 20% ethyl acetate in cyclohexane; silica gel GF; Rf = 0.37 and 0.29. The lower Rf diastereoisomer was obtained as a crystalline solid, mp 114-116° (ether).

EXAMPLE 14 Benzhydryl a-(cis-3-Azido-4-oxo-2-bromomethyl-l-azetidinylΙα- thi olacetoxyacetate To a cold solution (-20°) of 0.840 g (1.89 mmol) of the product from Example 13 in 22 ml of anhydrous tetrahydrofuran under argon is added 193 μΐ (2.39 mmol) of anhydrous pyridine followed by 172 μΐ (2.39 mmol) of thionyl chloride. The reaction mixture is stirred at -20° for one hour and then a solution of 0.315 g (2.76 mmol) of potassium thiolacetate in 22 ml of anhydrous dimethylformamide is added. The reaction is stirred at -20° for 30 minutes and then allowed to stand at -23° overnight. The solution is poured into ethyl acetate and extracted copiously with water and then once with 0.1 N boric acid, NaHCOg solution and brine. The ethyl acetate layer is dried and evaporated to give 1.0 g of clear, light-yellow gum. This gum is crystallized from ether-hexane first at 25° and then at -23° overnight to give 0.807 g (85.%) of the title thiolacetate, mp 114-115.5°. Nuclear magnetic resonance analysis indicated that this material was a 2.6 : 1 mixture of diastereoisomers.

EXAMPLE 15 Benzhydryl g-(cis-3-Amino-2-bromomethyl-4-oxo-l-azetidinyl)a-thiolacetoxyacetate A solution of 0.044 g (0.088 mmol) of benzhydryl ester from Example 14, 0.084 g of platinum oxide, 0.018 g of j)-toluenesulfonic acid monohydrate, 3.5 ml of ethyl acetate, and 3.5 ml of ethanol is hydrogenated at ambient temperature and atmospheric pressure for one hour. The mixture is filtered and the solvents are removed in vacuo. The residue contains the title compound.

Claims (20)

1. A compound of formula (1):- N IX (I) COOH and salts and protected esters thereof where A is azido, amino or protected amino; X is CH 2 -halogen,· ch 2 oso 2 // or CHgOSOgR in which Q is hydrogen, loweralkyl or halogen and R is lower alkyl; Y is hydroxy or i| -SC-E 10 in which E is hydrogen,, loweralkyl, tri fluoromethyl or phenyl optionally substituted with one or two substituents selected from lower alkoxy, loweralkyl, halogen and nitro.

2. A compound as claimed in claim 1 where X is chloromethyl, bromomethyl, or iodomethyl and E is methyl or phenyl.

3. A compound as claimed in claim 2 where Q is hydrogen, methyl or bromo.

4. A compound as claimed in any one of claims 1 to 3 where A is a protected amino group.

5. A compound as claimed in claim 4 where A is t-butoxycarbonylamino, tri ch1oroethoxycarbonylami no, benzyloxycarbonylami no, j)-methoxybenzyl oxycarbonyl ami no, £-ni trobenzy 1 oxycarbonyl ami no, isobornyloxycarbonylamino, phthalimido, succinimido, maleimido or 4,5-diphenyl-4-oxoazolin-2-onyl.

6. A compound as claimed in any one of claims 1 to 3 where A is amino.

7. A compound as claimed in any one of claims 1 to 6 where the esterforming group is 2,2,2-trichloroethyl, benzyl, benzhydryl, t-butyl or methyl.

8. a-(cis-3-Isobornyloxycarbonylami no-2-i odomethyl-4-oxo-1 azetidinyl)-g-thiolacetoxyacetic acid and its benzyl, benzhydryl, t-butyl, and methyl esters.

9. a2ici£-3-Isobornyloxycarbonylamino-2-bromomethyl-4-oxo-l-azetidinyl) -g-thiolacetoxyacetic acid and its benzyl, benzhydryl, t-butyl, and methyl esters.

10. a2(cis-3-Isobornyloxycarbonylamino-2-chloroniethyl-4-oxo-l-azetidinyl) -g-thiolacetoxyacetic acid and its benzyl, benzhydryl, t-butyl, and methyl esters.

11. g-(cis-3-Amino-2-i odomethyl-4-oxo-l-azeti di ny1)-g-th i olacetoxyaceti c acid. zj 5 9 8 3

12. g- (ci s-3-Ami no-2-bromomethyl -4-oxo-l -azeti di nyl )-gthiolacetoxyacetic acid.

13. a-(cis-3-Amino-2-chloromethyl-4-oxo-l-azetidinyl)-gthiolacetoxyacetic acid. 5

14. A process for preparing a compound as claimed in claim 1 which comprises condensing a compound of formula (II):- (II) where A is azido or a protected amino group and X is as defined in the reference to formula (I) with a protected ester of glyoxylic acid 10 optionally reacting the condensation product with a halogenation reagent and an alkali metal salt of a thiol acid of formula HSCOE where E is as defined with reference to formula (I) and optionally hydrogenating the azido group or converting the protected amino group into amino or removing the protected ester-forming group.

15. 15. A process as claimed in claim 14 wherein in the compound of formula (II) A is t-butoxycarbonylamino, tri chloroethoxycarbonyl amino benzyl oxycarbonyl ami no, jj-methoxybenzy 1 oxycarbonyl ami no, £-ni trobenzyloxycarbonylami no, or isobornyloxycarbonylamino; X is CHg-halogen; the ester forming group in the glyoxylic acid 4 5 9 8 3 ester is 2,2,2-trichloroethyl, benzyl, benzhydryl, t-butyl or methyl and the condensation product is converted into a compound of formula (I) where E is methyl or phenyl.

16. A process as claimed in claim 15 where in the compound of 5 formula (II) X is CHgBr, and the condensation product is converted into a compound of formula (I) where Y is SCOE, and E is methyl.

17. A process for preparing benzyl, benzhydryl or t-butyl a-(cis-3-t-butoxycarbonylami no-2-bromomethyl-4-oxo-l-azeti di nyl)a-thiolacetoxyacetate which comprises condensing g-cis-3-t10 butoxycarbonyl amino-4-oxo-2-azetidinylmethyl bromide with benzyl, benzhydryl, or t-butyl glyoxylate and reacting the condensation product with thionyl chloride and an alkali metal salt of thiolacetic acid.

18. A process for preparing g-cis-3-amino-2-bromomethyl-4-oxo1-azetidinyl)-g-thiolacetic acid which comprises condensing 15 cr£is-3-t-butoxycarbonylamino-4-oxo-2-azetidinylmethyl bromide with benzyl, benzhydryl or t-butyl glyoxylate; reacting the condensation product with thionyl chloride and an alkali metal salt of thiolacetic acid; and removing the t-butoxycarbonyl and benzyl, benzhydryl or t-butyl group.

19. 20 19. A process for preparing a compound as claimed in claim 1 substantially as described in any of Examples 8 to 15 herein.

20. A compound as claimed in claim 1 whenever prepared by a process as claimed in anyone of claims 14 to 19.