IE44231B1 - 3-amino-4-oxazetidine derivatives - Google Patents

Description

This invention concerns cis-2-azidomethyl- and cis-2-aminomethyl-3amino-4-oxazetidines and derivatives thereof which can be used as intermediates in preparing 1,3-diazabicyclo/“3.2.07heptan-7-one penicillin analogues as described and claimed in our Patent Specification No. 1953/76.

According to the present invention there is provided a compound of the formula where R is hydrogen, - 2 44231 or R5; R2 is phenyl; phenoxymethyl; benzyl; Λ-ami nobenzyl; -hydroxybenzyl; « -carboxybenzyl; phenyl substituted with lower alkyl of from one to four carbon atoms, lower alkoxy of from one to four carbon atoms, trifluoromethyl, halo or hydroxy; or benzyl substituted on the phenyl ring with lower alkyl of from one to four carbon atoms, lower alkoxy of from one to four carbon atoms, trifluoromethyl, halo or hydroxy; R5 is an easily removable amine protecting group; and Y is azido, or amino when R is c R may be trityl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, £-methoxybenzyloxycarbonyl, isobenzyloxycarbonyl or 1-methoxycarbonyl-2-propenyl.

Scheme 1 hereinafter shows the preparation of compounds of formula I (a - d) according to the invention, the compounds of formula Id being of particular use in the series of steps described in Scheme 1 of our Patent Specification No. 1953/76 in preparing 1,3-diazabicyclo/3'.2.CL7heptan-7-one penicillin analogues described and claimed therein.

According to Scheme 1, when the imine resulting from the condensation of methyl glyoxalate and 2,4-dimethoxy-benzjrlamine is allowed to react with a mixed anhydride of azidoacetic acid, azetidinone II is obtained. Hydrogenation of this compound gives the corresponding amino derivative which can be protected with an amine protecting group by standard methods to give compound III. In c formula III, R can be phthaloyl or imine-forming group. The hydrogen atom shown attached to the adjacent nitrogen atom being absent. Treatment of III with potassium persulfate results in removal of the dimethoxybenzyl group to give compound IV which upon reduction, for example with sodium borohydride, gives V. Reaction of the tosylate derivative of V with an azide such as sodium azide gives the corresponding azidomethyl compound Ia in accordance with the invention. The - 3 4 4231 amine protective group is removed, for example by treatment of Ia with trifluoroacetic acid, and the resulting amino compound lb can be acylated according to standard procedures to give Ic. Reduction of Ic gives the aminomethyl compound Id.

When the amine protective group R is itself a group desired as a 6-substituent in a 1,3-diazabicyclo/~3.2.£7heptan-7-one penicillin analogue described and claimed in Patent Specification No. 1953/76, viz. one of the 2 2 formula R CO- where R is defined as above, the steps of deblocking of the amine function and subsequent acylation can be eliminated from the reaction sequence depicted in Scheme 1 (X being halogen).

The 3-azido-azetidinone II can alternatively be converted into a 3- amino-2-tosyl-oxymethyl derivative by cleavage of the 2,4-dimethoxybenzyl group, followed by reduction of the ester function, conversion of the product hydroxymethyl compound into the tosylate, and reduction of the azide moiety, all as described above.

Examples of compounds of the present invention are cis-2-azidomethyl 4- oxo-3-phenoxyacetyl-ami noazeti dine, cis-2-azidomethyl-3-mandeloylami no-4oxoazetidine, cis-2-aminomethyl-3-mandeloylamino-4-oxoazetidine and cis-3amino-2-azi domethy!-4-oxoa?eti dine.

The starting materials for the compounds of this invention are commercially available, can be prepared by known methods, or are prepared as described herein. - 4 44231 C02CH3 N„ ΐ Ϊ .CO„CH„ R5NH 44331 It is recognised that, due to asymmetric carbon atoms both in the bicyclic -lactam ring system and in some acyl side chains, stereoisomers will exist. All of these isomers, including separated isomers and mixtures thereof, are included within the scope of this invention.

The following Preparations and Examples illustrate the invention, but are not to be construed as limiting the scope thereof. All temperatures are in degrees Centigrade (°C) unless otherwise indicated.

PREPARATION 1.

Methyl cis-3-azido-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate To a mixture containing 16.82 g (0.101 mole) of 2,4-dimethoxybenzylamine and anhydrous magnesium sulfate in 150 ml of methylene chloride at 25° was added a solution of 10.05 g (0.114 mole) of methyl glyoxalate in 20 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight (15 hours) and then was filtered and the solvents were removed in vacuo to afford the imine of Scheme 1 as a dark orange gum.

To a solution of 15.1 g (0.149 mole) of azidoacetic acid in 130 ml of anhydrous methylene chloride at 0° (ice bath) was added dropwise 21.0 ml (0.15 mole) of trifluoroacetic anhydride. This mixture was stirred at 0° for 15 min and then 20.8 ml (0.15 mole) of triethylamine was added dropwise. Stirring was continued for an additional 45 min and then the entire reaction mixture was transferred under argon into an addition funnel which was cooled externally by dry ice. The addition funnel was attached to a flask containing the imine from above, 200 ml of anhydrous methylene chloride and 20.8 ml (0.15 mole) of triethylamine. The solution of the mixed anhydride obtained was added dropwise from the addition funnel to the solution of the imine at 0°. Stirring was continued at 0° for 1 hour and then the dark reaction mixture was transferred to a separatory funnel and washed with water, aqueous sodium bicarbonate and brine and dried over anhydrous magnesium sulfate.

The solvents were removed in vacuo and the residue was chromatographed on 300 g of silica gel (70-230 mesh), affording an off-white solid which was further purified by - 6 44331 trituration with ether to give the title compound as a white solid; tic; benzene: ethyl acetate (1.Ί), silica gel GF, Rf = 0.64; mp 82-84° (ethyl acetate-hexane).

PREPARATION 2.

Methyl cis-4-oxo-3-phenoxyacetylaminoazetidine-2-carboxylate A mixture containing 10.0 g (0.0312 mole) of methyl cis-3-azido-l(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, 1.0 g of 10% palladium on carbon and 200 ml of ethanol was hydrogenated at 60 psi of hydrogen at 40-45° for 2 hours. The reaction mixture was allowed to cool to 25° and was filtered through Celite (Registered Trade Mark). After removing the solvents in vacuo there remained a clear, yellow gum. The crude amine was taken up in 100 ml of anhydrous methylene dichloride and was cooled to 0° in an ice bath. To this solution was added 4.32 ml (0.0312 mole) of triethylamine followed by the slow addition of a solution of 5.32 g (0.0312 mole) of phenoxyacetyl chloride in 40 ml of methylene dichloride. The mixture was stirred at 0° for 1 hour, then extracted successively with water, aqueous hydrochloric acid, aqueous sodium bicarbonate and brine and was dried over anhydrous magnesium sulfate. Filtration, followed by removal of the solvent in vacuo afforded a yellow solid. This material was partially dissolved in ether, cooled to -25° and filtered to give methyl cis-l-(2,4-dimethoxybenzyl)-4-oxo-3-phenoxyacetylaminoazetidine-2-carboxylate as a white solid; tic: benzene: ethyl acetate (l_l), silica gel, Rf = 0.38; mp 115.5-116.0° (ethyl acetate-hexane).

To 900 ml of acetonitrile, which had been thoroughly degassed with argon, was added 30.0 g (0.070 mole) of methyl cis-1-(2,4-dimethoxybenzyl)-4-oxo25 3-phenoxyacetylaminoazetidine-2-carboxylate and the solid was rinsed into the reaction vessel with an additional 50 ml of degassed acetonitrile. This solution was heated to 78° under argon and to this was added a degassed solution of 75.6 g (0.28 mole) of potassium persulfate and 37.5 g (0.14 mole) of sodium monohydrogen phosphate in 1400 ml of water. Addition of the aqueous solution was made in six - 7 44231 portions of 250 ml over a period of 1 hour while maintaining the external temperature between 78° and 82°. After cooling the reaction mixture, the acetonitrile was removed by evaporation. Sodium chloride was added to the concentrated reaction mixture and it was extracted four times with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO^), filtered and concentrated in vacuo to approximately 100-200 ml. Addition of ether (ca. 300 ml), followed by low temperature (-25°C) crystallization, afforded the title compound; tic: silica gel GF, ethyl acetate, Rf = 0.44; ethyl acetate: benzene (1:1), RF = 0.21; mp 140-141° (ethyl acetate-hexane).

PREPARATION 3. ci s-2-Hydroxymethy1-4-oxo-3-phenoxyacetylami noazeti di ne To a solution of 13.5 g (0.049 mole) of methyl cis-4-oxo-3-phenoxyacetylaminoazetidine-2-carboxylate in 975 ml of tetrahydrofuran and 100 ml of water at 0° (ice bath) was added a cold solution of 3.75 g (0.099 mole) of sodium borohydride in 250 ml of water over a period of 10 min. The solution was stirred at 0° for 40 min and then glacial acid was added dropwise until hydrogen evolution ceased.

Solid sodium bicarbonate and sodium chloride were added and this mixture was extracted five times with 250 ml portions of ethyl acetate. After drying the combined extracts (MgSO^), the solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, clarified with Norit (Registered Trade Mark) and allowed to crystalize to give the title compound; tic: ethyl acetate, silica gel GF, Fr = 0.10; mp 153-154°C (ethyl acetate).

PREPARATION 4. ci£-3-Amino-4-oxo-2-£-toluenesulfonyloxymethylazetidine A degassed solution of 3.8 g (0.012 mole) of ethyl cis-3-azido-l-(2,4dimethoxybenzyl)-4-oxoazetidine-2-carboxylate was treated with potassium persulfate and sodium monohydrogen phosphate as described in Preparation 2 to give methyl cis3-azido-4-oxoazetidine-2-carboxylate which was purified by chromatography on silica gel with benzene-ethyl acetate as eluant. - 8 44231 Methyl c[s-3-azido-4-oxoazetidine-2-carboxy1ate was reduced with sodium borohydride as described in Preparation 3 and the product was chromatographed on silica gel with ethyl acetate as eluant to give c|s-3-azido-2-hydroxymethyl-4oxoazetidine. cis-3-Azido-4-oxo-2-p-toluenesulfonyloxymethyl-azetidine was prepared from cis-3-azido-2-hydroxymethyl-4-oxoazetidine according to the procedure of Example 1.

Zinc dust (2.0 g, 0.03 mole) was slowly added with cooling to a solution if 5.0 g (0.011 mole) of cis-3-azido-4-oxo-2-£-toluenesulfonyloxymethylazetidine in 50 ml of 50% aqueous acetic acid. The reaction mixture was stirred for 30 minutes and filtered. The solids wwre washed with water and the filtrate was saturated with hydrogen sulfide, filtered and concentrated to near dryness. The residue was dissolved in ethyl acetate-water and the pH was adjusted to 8.0 by addition of sodium carbonate and sodium hydroxide solutions. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The extracts were combined, dried (MgSO^) and evaporated to dryness to give the title compound.

EXAMPLE 1. cis-2-Azidomethy!-4-oxo-3-phenoxyacetyl ami noazeti di ne To a solution of 4.30 g (0.022 mole) of 98% o-toluenesulfonyl chloride in 24 ml of anhydrous pyridine at 0° (ice bath) were added 2.64 g (0.011 mole) of cis2-hydroxymethyl-4-oxo-3-phenoxyacetylaminoazetidine, prepared in Preparation 3, in one portion. The solution was stirred at 0° for 3 hours, then was stored at -25° overnight. After warming to 0°, 1.0 ml of 85% lactic acid was added and stirring was continued for 1 hour. The reaction mixture was poured into ethyl acetate and extracted successively with water, dilute aqueous hydrochloric acid, aqueous sodium bicarbonate and brine, and was dried (MgSO^). Filtration, followed by removal of the solvent in vacuo, resulted in a yellow solid. Clarification of a hot solution of this material in ethyl acetate (375 ml), followed by the addition of hexane (200 ml) . g . 44331 and restystallization afforded ci£-4-oxo-3-phenoxyacetylamino-2-£-toluenesulfonyloxymethyl-azetidine; tic: ethyl acetate, silica gel GF, Rf = 0.47; m 136° (dec.).

A mixture containing 1.131 g (2.8 mmole) ofcis-4-oxo-3-phenoxyacetylamino2-£-toluenesulfonyloxymethylrazetidine, 0.961 g (14.8 mmole) of sodium azide and 25 ml of anhydrous Ν,Ν-dimethylformamide was heated under argon at 40° for 6 hours, then at ambient temperature for 24 hours. The reaction mixture was poured into ethyl acetate and was washed with water. The combined aqueous washes were extracted once with ethyl acetate and the ethyl acetate fractions were combined and extracted with brine. After drying the ethyl acetate solution (MgSO^) and filtering, the solvent was removed in vacuo to afford a yellow semi-crystalline residue. This residue was slurried in methylene dichloride and chromatographed on 25 g of silica gel (70-230 mesh). The 1:1 ethyl acetate:methylene dichloride fractions afforded the title compound; tic: ethyl acetate, ethyl acetate, silica gel GF, Rf = 0.38; mp 142-143° (dec.) (ethyl acetate-hexane).

EXAMPLE 2. cis-2-Azidomethyl-3-t-butoxycarbonylamino-4-oxoazetidine A mixture containing 10.0 g (0.0312 mole) of methyl cis-3-azido-l-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, prepared as in Preparation 1, 1,0 g of 10% palladium on carbon and 200 ml of ethanol was hydrogenated for 2 hours at 40-50° and 60 psi of hydrogen. The reaction mixture was allowed to cool to 25° and was filtered through a filter-aid. After removing solvents in vacuo there remained methyl cis-3-amino-l-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate.

A solution of 5.5 g (18.8 mmole) of methyl cis-3-amino-1,2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate in 100 ml of dry toluene were cooled to -78° and 2.5 ml (18.8 mmole) of triethylamine was added, followed by rapid addition of 35 ml (42 mmole) of a 12% solution of phosgene in benzene. The mixture was stirred for 15 min at -78°, and 3 hours at 45° (acetonitrile-dry ice), then warmed to room temperature and concentrated to half volume in vacuo. To the resulting solution were added 50 ml of t-butanol and the mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue diluted with ethyl - 10 44031 acetate and filtered. The filtrate was transferred to a separatory funnel and washed with 5% aqueous sodium bicarbonate, 5% hydrochloric acid and brine, dried (MgSO^), and evaporated to dryness. Recrystallization of the crude, crystalline product from ether gave methyl cis-3-t-butoxycarbonylamino-l-(2,4-dimethoxybenzyl)-4oxoazetidine-2-carboxylate, mp 134-135°.

A solution of 10.5 g (26.7 mmole) of methyl 3-t-butoxycarbonylamino-l(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate in 500 ml of acetonitrile was degassed with argon and warmed to 80°. A degassed solution of 15 g (55.5 mmole) of potassium persulfate and 7.5 g (28 mmole) of sodium monohydrogen phosphate in 150 ml of water was added in five portions over 1 hour. The reaction mixture was stirred at 80-85° under argon for 2-3 hours until all starting material had disappeared (tic). The reaction mixture was cooled, concentrated in vacuo and shaken with ethylacetate water. The organic phase was washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution and brine; dried (MgSO^); and evaporated to dryness. The residue was chromatographed on silica gel with 1:1 benzene: ethyl acetate to afford pure product which crystallized from ethyl acetatehexane to give methyl cis-3-t-butoxycarbonylamino-4-oxoazetidine-2-carboxylate, mp 140-144°.

Sodium borohydride reduction of methyl cis-3-t-butoxycarbonylami no-4-oxoazetidine-2-carboxylate as described in Preparation 3, followed by conversion of the 2-hydroxymethylazetidine product to the ^-toluene-sulfonate derivative, mp 150-162° (d), and reaction of the derivative with sodium azide as described in Example 1 gives the title compound.

EXAMPLE 3. cis-3-Amino-2-azidomethyl-4-oxoazetidine cis.-2-Azid0methyl-3-t-butoxycarbonylanrino-4-oxoazetidine prepared as in Example 1 (ca, 1 g) is dissolved in 2 ml of methylene chloride and the solution is cooled to 0° and treated with 0.5 ml of trifluoroacetic acid for 30 minutes at 0°.

The solution is washed with 5% aqueous sodium bicarbonate and extracted with dilute hydrochloric acid. The aqueous phase is neutralized and extracted with ethyl acetate. - 11 44231 Evaporation of the solvent gives the title compound.

EXAMPLE 4. cis.-2-Aminomethyl-4-oxo-3-mandeloylaroinoazetidine When ci£-3-amino-4-oxo-2-|-toluenesu1fonyloxymethylazetidine is reacted with 0-benzylmandeloyl chloride according to the procedure described in Preparation 2 and the product is subsequently converted to the corresponding 2-azidomethyl compound which is subsequently reduced with zinc and acetic acid as described in Example 2, cis-2-aminomethyl-3-(ot -benzyloxyphenylacetylamino)-4-oxoazetidine is obtained.

A suspension of 14 mg of 10% palladium on carbon and 0.06 mole of cis-2aminomethyl-3-(ex -benzyloxyphenylacetylamino)-4-oxoazetidine in ca. 2 ml of anhydrous ethylacetate is hydrogenated at room temperature at atmospheric pressure. The reaction mixture is filtered and the filtrate is evaporated to dryness to give the title compound.

EXAMPLE 5.

Reaction of ci£-3-amino-4-oxo-2-£-toluenesulfonyloxymethylazetidine with a halide of an acid listed below, suitably protected as necessary: benzoic acid £-toluic acid 4-ethylbenzoic acid 4-t-butylbenzoic acid m-anisic acid 4-n-butoxybenzoic acid 2- chlorobenzoic acid 4-bromobenzoic acid 4-hydroxybenzoic acid 3- trifluoromethylbenzoic acid phenyiacetic acid « -aminophenyl acetic acid «-carboxyphenylacetic acid - 12 44231 4-fluorophenylacetic acid 3- hydroxyphenylacetic acid 4- trif1uoromethylphenylacetic acid according to the procedure described in Preparation 2, followed by conversion of the products thus formed to the corresponding 2-azidomethy! compounds as described in Example 1 gives the following azetidines after removal of any protective groups: cis-2-azi domethy1-3-benzoylami no-4-oxoazeti di ne ci£-2-azidomethyl-4-oxo-3-(p-toluoylamino)azetidine cis-2-azidomethy!-3-(4-ethylbenzoyl ami no)-4-oxoazeti di ne cis-2-azidomethy!-3-{4-t-butylbenzoyl ami no)-4-oxoazeti di ne ci_s-3-(m-anisoyl ami no)-2-azi domethy! -4-oxoazetidine cis-2-azidomethy1-3-(4-n-butoxybenzoylamino)-4-oxoazetidine cis-2-azidomethyl-3-(2-chlorobenzoylami no)-4-oxoazetidine cis,-2-azidomethyl-3-(4-bromobenzoyl ami no)-4-oxoazetidine £is-2-azidomethy!-3-(4-hydroxybenzoylamino)-4-oxoazetidine cis-2-azidomethy!-4-oxo-3-(3-trif1uoromethylbenzoyl amino)azetidine cis-2-azidomethy!-4-oxo-3-phenylacetyl aminoazetidine cis-3-( -ami nophenyl acetyl ami no)-2-azi domethy1-4-oxoazeti di ne cis-2-azidomethy!-3-(<* -carboxyphenyl acetyl ami no)-4-oxoazetid i ne cis-2-azidomethy!-3-(4-fluo ropheny1 acetyl ami no)-4-oxoazetidine cis-2-azidomethy1-3-(3-hydroxyphenylacety1 ami no)-4-oxoazetidine cis-2-azidomethy!-4-oxo-3-(4-tri f1uoromethylphenylacetyl ami no)azeti di ne.

EXAMPLE 6. cis-2-Ami nomethyl-4-oxo-3-phenoxyacetylami noazet idine A suspension of 0.499 g (1.81 mmole) of cis-2-azidoniethyl-4-oxo-3-phenoxyacetylaminoazetidine and 0.189 g of 10% palladium on carbon in 25 ml of absolute ethanol was hydrogenated at atmospheric pressure and at 40° for 1 hour. The solution was filtered through Celite and the solvent was removed in vacuo to afford the title compound as a colourless gum. - 13 44S31 EXAMPLE 7.

Reduction of a 2-azidomethyl-3-substituted-4-oxoazetidine listed in Example 5 according to the procedures described in Example 4 or Example 6 gives the following 2-aminomethyl compounds: cis-2-ann nomethyl-3-benzoylamino-4-oxoazetidine cis-2-aminomethyl-4-oxo-3-(p-toluoylami noJazetidine cis-2-aminomethyl-3-(4-ethyl benzoylami no)-4-oxoazeti di ne cis-2-ami nomethyl -3- (4-t-butyl benzoyl amino) -4-oxoazeti di ne cis-2-aminomethyl-3-(m-ani soylami no)-4-oxoazetidi ne jcis-2-aminomethyl-3-(4-£-butoxybenzoylamino)-4-oxoazetidine cis-2-aminomethyl-3-(2-chlorobenzoylami no)-4-oxoazeti di ne cis-2-aminomethyl-3-(4-bromobenzoylami no)-4-oxoazeti di ne cis-2-aminomethyl-3-(4-hydroxybenzoylamino)-4-oxoazetidine ci s-2-aitii nomethyl -4-oxo-3-(3-tri f 1 uoromethyl benzoyl ami no Jazetidi ne ci£-2-aminomethyl-4-oxo-3-pheny1acetylaminoazetidine cis-2-aminomethyl-3-( » -ami nophenylacetyl ami ne)-4-oxoazeti di ne cis-2-aminomethyl-3-(-carboxyphenyl acetylami no)-4-oxoazetidi ne cis-2-aminomethyl-3-(4-fluorophenylacetyl ami no)-4-oxoazeti di ne cis-2-aminomethyl-3-(3-hydroxyphenylacetylami no)-4-oxoazeti di ne cis-2-aminomethyl-4-oxo-3-(4-tri f1uoromethylphenyl acetyl ami no) aeetidi ne.

EXAMPLE 8. cis-2-Azidomethyl-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4-oxoazetidine To a mixture containing 16,82 g (0.101 mole) 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 mole) of methyl glyoxalate in 20 ml of methylene chloride. The reaction mixture is stirred at room temperature overnight (15 hours) and then is filtered. The solvents are removed in vacuo to afford methyl N-(2,4-dimethoxybenzyljiminoacetate as a dark orange gum. - 14 44231 A mixture of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid (2.1 g, 7.1 mmole) /~J. Org. Chem., 38, 3034 (1973/7, 5 ml of thionyl chloride and 20 ml of methylene chloride is refluxed for 2.5 hours. After cooling to room temperature the solvent is removed in vacuo and the resulting oil crystallizes on standing. The product is triturated with ether-hexane to give 4,5-dipheny1-2-oxo-4-oxazolin-3-ylacetic acid chloride, mp 104-112°.

Methyl N-(2,4-dimethoxybenzyl)iminoacetate (1.43 g) is dissolved in 13 ml of dry methylene chloride and 1 ml of triethylamine and cooled in an ice bath. A solution of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid chloride (2.0 g, 6.4 mmole) in 10 ml of methylene chloride is added over a 10 minute period. After one hour, the mixture is washed with water and 5% aqueous sodium bicarbonate, then dried and evaporated to give a red oil which is chromatographed on silica gel to give methyl cis-1-(2,4-dimethoxybenzyl)-3-(4,5-di phenyl-2-oxo-4-oxazolin-3-yl)-4-oxoazetidi ne2- carboxylate.

Methyl cis-1-(2,4-dimethoxybenzyl)-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-y1)4-oxoazetidine-2-carboxylate is treated with potassium persulfate and sodium monohydrogen phosphate as described in Example 2 to give methyl cis-3-(4,5-diphenyl-2oxo-4-oxazolin-3-yl)-4-oxoazetidine-2-carboxylate.

Sodium borohydride reduction of methyl c/s-3-(4,5-diphenyl-2-axo-4“Oxazolin3- yl)-oxoazetidine-2-carboxylate as described in Preparation 3, followed by conversion of the 2-hydroxymethylazetidine product to the p-toluenesulfonate derivative and reaction of this derivative with sodium azide as described in Example 1 gives the title compound.

EXAMPLE 9.

When £-methoxybenzyl alcohol, isoborneol, benzyl alcohol or 2,2,2-trichloroethanol is substituted for t-butanol in Example 2 in the reaction with methyl cis-3-anrino-1 -(2,4-dimethoxybenzy1)-4-oxoazetidine-2-carboxylate, methyl cis-1(2,4-dimethoxybenzyl)-3-(£-methoxybenzyloxycarbonylamino)-4-oxoazetidine-2-carboxylate, methyl cis-1-(2,4-dimethoxybenzyl)-3-isobornyloxycarbonylamino-4-oxoazetidine-2carboxylate, methyl cis-3-benzyloxycarbonylamino-l-(2,4-dimethoxybenzyl)-4-oxo- 15 4 42 31 3-(2,2,2-trichloroethoxycarbonylamino)-azetidine-2-carboxylate is obtained respectively.

Methyl 3-isobornyloxycarbonylamino-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate can also be prepared by treating the 3-amino compound with isobornyloxycarbonyl chloride in the presence of base according to standard procedures; Chem. Pharm. Bull., 20, 1017 (1972).

Treatment of the methyl ci£-l-(2,4-dimethoxybenzyl)-3-(substituted oxycarbonylamino)-4-oxoazetidine-2-carboxylates mentioned above with potassium persulfate and sodium monohydrogen phosphate as described in Example 2 gives the following compounds, respectively: methyl cis-3-(p-methoxybenzyloxycarbonylamino)-4-oxoazetidine-2-carboxy1ate methyl cis-3-isobornyloxycarbonylamino-4-oxoazetidine-2-carboxylate methyl cis-3-benzyloxycarbonylamino-4-oxoazetidine-2-carboxylate methyl cis-4-oxo-3-(2,2,2-tri chioroethoxycarbonylami no)azeti di ne-215 carboxylate.

Sodium borohydride reduction of a methyl cis-3-(substituted oxycarbonylamino)-4-oxoazetidine-2-carboxylate listed above as described in Preparation 3, followed by conversion of the 2-hydroxymethylazetidine product thus formed to the j3-toluenesulfonate derivative and reaction of this derivative with sodium azide as described in Example 1 gives the following compounds, respectively: cis-2-azidomethyl-3-(£-methoxybenzyloxycarbonylamino)-4-oxoazetidine cis-2-azidomethy!-3-i sobornyloxycarbonylami no-4-oxoazeti di ne cis-2-azidomethy!-3-benzyloxycarbonylami no-4-oxoazeti di ne cis-2-azidomethyl-4-oxo-3-(2,2,2-trichloroethoxycarbonylamino)azetidine.

Claims (16)

1. A compound of the formula: R — N CH 2— Y in which R is hydrogen, 2. 11 R - C or R 5 ; R is phenyl; phenoxymethyl; benzyl; ot -aminobenzyl; ot -hydroxybenzyl; carboxybenzyl; phenyl substituted with lower alkyl of from one to four carbon atoms, lower alkoxy of from one to four carbon atoms, trifluoromethyl, halo or hydroxy; or benzyl substituted on the phenyl ring with lower alkyl of from one to four carbon atoms, lower alkoxy of from one to four carbon atoms, trifluoromethy!, halo or hydroxy; ς R is an easily removable amine protecting group; and Y is azido or amino when R is 3. H R - C - . - 17 4

2. A compound as claimed in Claim 1, in which Y is azido.

3. A compound as claimed in Claim 2, in which R is R .

4. A compound as claimed in Claim 2, in which R is

55. A compound as claimed in Claim 2, in which R is hydrogen.

6. A compound as claimed in Claim 1, in which R is and Y is amino.

7. A compound as claimed in Claim 3, in which R is trityl, jt-butoxycarbonyl, 10 tri chloroethoxycarbony1, benzyloxycarbonyl, £-methoxybenzyloxycarbonyl, isobornyl oxycarbonyl, 1-methoxycarbonyl-2-propenyl, phthaloyl or an imine-forming group.

8. cis-2-Azidomethyl-4-oxo-3-phenoxyacetylami noazeti dine.

9. cis-2-Azidomethyl-3-mandeloylami no-4-oxoazeti dine.

10. ci s-2-Aminomethyl-4-oxo-3-phenoxyacety1ami noazeti di ne. 15

11. cis-2-Aminomethyl-3-mandeloylamino-4-oxoazetidine.

12. cis-2-Azidomethyl-3-t-butoxycarbonylamino-4-oxoazetidine.

13. A process for preparing a compound according to Claim 1 which comprises (a) (where R represents R and Y represents azido) reacting a compound of the formula - 18 44231 Π (where R is as defined in Claim 1) with an azide; (b) (where R represents H and Y represents azido) replacing the protecting group R 5 by H; (c) (where R represents R Z C0 and Y represents azido) reacting the compound 5. According to Claim 1 (where R represents H and Y represents azido) with a compound of formula R COX (where X is halogen); or 2 (d) (where R represents R CO and Y represents amino) reducing a compound according to Claim 1 (where R represents R CO and Y represents azido),

14. A process for preparing a compound according to Claim 1, the process being 10 substantially as herein described.

15. A process for preparing a compound acco-ding to Claim 1, the process being substantially as herein described in any of the Examples.

16. A compound according to Claim 1, when prepared by a process according to any one of Claims 13 to 15.