[(2R,3R)-3-[(1R)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxoazetidin-2-yl] acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cooled solution of 50g (0.174 mole) of (3R, 4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxyethyl]-2 -azetidinone and 24.69 (0.244 mole) of triethylamine in 500 ml of tetrahydrofuran were added 26.5g (0.244 mole) of trimethylchlorosilane under a nitrogen stream. The reaction temperature was allowed to rise to room temperature and the reaction mixture was stirred for 2 hours. The precipitate was filtered off using a Celite (trade mark) filter aid. After the precipitate had been washed with ether twice, the filtrate and the washings were combined, and the solvent was evaporated. The residue was washed with ether to filter off the insoluble materials, Evaporation of the solvent from the filtrate gave 6.23 g (yield 100%) of the title compound as a semi-solid. to rise to room temperature The precipitate was filtered off filter aid After the precipitate had been washed with ether twice the solvent was evaporated The residue was washed with ether to filter off the insoluble materials, Evaporation of the solvent from the filtrate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Imidazole (0.1 g) and tert-butyldimethylsilyl chloride (0.08 g) are added to a solution of the object compound (0.036 g) of Example 6 in DMF (5 ml) at 40° C. and the mixture is stirred at the same temperature for 2 hours and then poured into a mixture of ethyl acetate (50 ml) and water (30 ml). The organic layer is separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in a mixture of tetrahydrofuran (7 ml) and water (2 ml), and stirred at 25° C. for 4 hours in the presence of a trace of concentrated sulfuric acid. The reaction mixture is poured into a mixture of ethyl acetate (50 ml) and water (30 ml) and the organic layer is separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Thus obtained residue is dissolved in ethyl acetate (12 ml) and m-chloroperbenzoic acid (0.3 g) is added thereto. The mixture is stirred at room temperature for 2 days and then poured into a mixture of ethyl acetate (50 ml), saturated sodium bicarbonate solution (20 ml) and dimethyl sulfide (0.15 ml) followed by stirring. The organic layer is separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: 15% ethyl acetate-85% hexane) to give 0.012 g of (3R,4R)-4-acetoxy-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone. The organic layer is separated washed with brine dried over magnesium sulfate concentrated under reduced pressure The residue is dissolved in a mixture of tetrahydrofuran (7 ml) and water (2 ml) stirred at 25° C. for 4 hours in the presence of a trace of concentrated sulfuric acid The reaction mixture is poured into a mixture of ethyl acetate (50 ml) and water (30 ml) the organic layer is separated washed with brine dried over magnesium sulfate concentrated under reduced pressure Thus obtained residue is dissolved in ethyl acetate (12 ml) m-chloroperbenzoic acid (0.3 g) is added The mixture is stirred at room temperature for 2 days poured into a mixture of ethyl acetate (50 ml), saturated sodium bicarbonate solution (20 ml) and dimethyl sulfide (0.15 ml) by stirring The organic layer is separated washed with brine dried over magnesium sulfate concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-allyloxycarbonyl-2-(2-methyl-3-oxo-1-butenyl)piperidine (9.9 g), (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (17.0 g) and triethylamine (16.5 ml) in dichloromethane (100 ml) was added trimethylsilyl trifluoromethanesulfonate (28.6 ml at -15° C. After stirring at 0° C. for 2 hours, the reaction mixture was taken up into a mixture of ethyl acetate (200 ml) and water (200 ml). The mixture was stirred for 2 hours at ambient temperature. After addition of sodium chloride (40 g), the organic layer was separated, washed with saturated sodium hydrogen carbonate and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (300 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1-7:3, V/V) to give (3S,4R)-4-[4-(1-allyloxycarbonylpiperidin-2-yl)-3-methyl-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (13.48 g). The mixture was stirred for 2 hours at ambient temperature the organic layer was separated washed with saturated sodium hydrogen carbonate and brine dried over magnesium sulfate evaporated The residue was chromatographed on silica gel (300 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1-7:3, V/V)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (1.48 g) and N-ethylpiperidine (0.69 ml) in dichloromethane (10 ml) was added trimethylsilyl trifluoromethanesulfonate (1.0 ml) at -20° C., and the resulting mixture was stirred at 0° C. for 1 hour (Solution A). To a solution of (2S,4R)-1-allyloxycarbonyl-4-(methylcarbamoyloxy)-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (1.60 g) and N-ethylpiperidine (1.50 ml) in dichloromethane (20 ml) was added trimethylsilyl trifluoromethanesulfonate (2.5 ml) at -20° C. and the resulting mixture was stirred at 0° C. for 1 hour. To this mixture was added dropwise the above obtained Solution A at 0° C. and the resulting mixture was stirred for another 1 hour at 0° C. The resulting mixture was taken up into a mixture of ethyl acetate (150 ml) and water (150 ml) and the mixture was stirred at ambient temperature for 2 hours. After adjusting pH to around 6.5 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (75 ml) eluting with a mixture of n-hexane and ethyl acetate (7:3-0.10 V/V) to give (3S,4R)-4-[4-{(2S,4R)-1-allyloxycarbonyl-4-(methylcarbamoyloxy)pyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (2.00 g). the resulting mixture was stirred for another 1 hour at 0° C the mixture was stirred at ambient temperature for 2 hours the organic layer was separated washed with brine dried over magnesium sulfate evaporated in vacuo The residue was chromatographed on silica gel (75 ml) eluting with a mixture of n-hexane and ethyl acetate (7:3-0.10 V/V)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (2.90 g) and N-ethylpiperidine (1.35 ml) in dichloromethane (15 ml) and added trimethylsilyl trifluoromethanesulfonate (1.95 ml) at -20° C., and the resulting mixture was stirred at 0° C. for 1 hour (Solution A). To a solution of (2S,4R)-1-allyloxycarbonyl-4-methoxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (2.70 g) and N-ethylpiperidine (1.48 ml) in dichloromethane (50 ml) was added trimethylsilyl trifluoromethanesulfonate (2.93 ml) at -20° C. and the resulting mixture was stirred at 0° C. for 1 hour. To this mixture was added dropwise the above obtained Solution A at 0° C. and the resulting mixture was stirred for another 1 hour at 0° C. The reaction mixture was taken up into a mixture of ethyl acetate (300 ml) and water (300 ml) and the mixture was stirred at ambient temperature for 2 hours. After adjusting pH to around 6.5 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (120 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1 V/V) to give (3S,4R)-4-[4-{(2S,4R)-1-allyloxycarbonyl-4-methoxypyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (3.24 g). the resulting mixture was stirred for another 1 hour at 0° C the mixture was stirred at ambient temperature for 2 hours the organic layer was separated washed with brine dried over magnesium sulfate evaporated in vacuo The residue was chromatographed on silica gel (120 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1 V/V)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2S)-1-allyloxycarbonyl-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (9.00 g) and triethylamine (6.3 ml) in dichloromethane (200 ml) was added trimethylsilyl trifluoromethanesulfonate (11.7 ml) at -20° C. After stirring at 0° C. for 1 hour, a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-azetidinone (10.9 g) and zinc bromide (11.9 g) in ethyl acetate (70 ml) was added to the mixture and the resultant mixture was stirred at 0° C. for 45 minutes. The reaction mixture was taken up into a mixture of ethyl acetate (600 ml) and water (600 ml). After adjusting pH to 4 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-5:5 V/V) to give (3 S,4R)-4- [(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (9.96 g). the organic layer was separated washed with brine dried over magnesium sulfate evaporated The residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-5:5 V/V)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 300 ml of acetone were dissolved 3 g (7.5 mmole) of the product containing as a main component (3R, 4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)azetidin-2-one, which had been obtained in Preparation 5. To the solution was added a solution of 6.43 g (30.1 mmole) of sodium metaperiodate and 120 mg of potassium permanganate in a mixture of 150 ml of water and 150 ml of a 0.1 M phosphate buffer solution (pH 7.02) at about 18° C. over 30 minutes, and then the mixture was stirred at that temperature for 4 hours. After completion of the reaction, the precipitate produced was filtered off and about 25 ml of the above buffer solution was added to the filtrate to adjust its pH to a value of 6.8. The acetone was distilled off at a lower temperature under reduced pressure and the residue was extracted with benzene. The benzene layers were collected and dried. The solvent was distilled off to give a crystalline solid, which was recrystallized from hexane to afford 0.934 g (43.3%) of the desired product as needles melting at 104°-106° C. had been obtained in Preparation 5 After completion of the reaction the precipitate produced was filtered off about 25 ml of the above buffer solution was added to the filtrate The acetone was distilled off at a lower temperature under reduced pressure the residue was extracted with benzene The benzene layers were collected dried The solvent was distilled off to give a crystalline solid, which was recrystallized from hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of sodium (518 mg, 22.5 mmole) in methanol (100 ml) was added at -10° C. (R)-1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethanethiol (6.61 g, 23.1 mmole). The mixture was stirred for 5 minutes, and then carbon disulphide (1.76 g, 23.1 mmole) was added and stirring was continued for a further 10 minutes. (3R, 4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxyethyl]azetidin-2-one (6.46 g, 22.5 mmole) was then added at the same temperature, after which the bath temperature was raised to 0° C. over about 1 hour. About 300 mg of acetic acid was then added, and the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. After the solution had been dried, the solvent was distilled off under reduced pressure and the residue was purified through column chromatography (200 g of silica gel), eluted with a 10% v/v solution of ethyl acetate in benzene, affording the desired compound (10.8 g, 84%) in the form of a yellow oil. stirring was continued for a further 10 minutes washed with a saturated aqueous solution of sodium chloride After the solution had been dried the solvent was distilled off under reduced pressure the residue was purified through column chromatography (200 g of silica gel) eluted with a 10% v/v solution of ethyl acetate in benzene

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of sodium (518 mg, 22.5 mmole) in methanol (100 ml) was added at -10° C. (R)-1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethanethiol (6.61 g, 23.1 mmole). The mixture was stirred for 5 minutes, and then carbon disulphide (1.76 g, 23.1 mmole) was added and stirring was continued for a further 10 minutes. (3R, 4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxyethyl]azetidin-2-one (6.46 g, 22.5 mmole) was then added at the same temperature, after which the bath temperature was raised to 0° C. over about 1 hour. About 300 mg of acetic acid was then added, and the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. After the solution had been dried, the solvent was distilled off under reduced pressure and the residue was purified through column chromatography (200 g of silica gel), eluted with a 10% v/v solution of ethyl acetate in benzene, affording the desired compound (10.8 g, 84%) in the form of a yellow oil. stirring was continued for a further 10 minutes washed with a saturated aqueous solution of sodium chloride After the solution had been dried the solvent was distilled off under reduced pressure the residue was purified through column chromatography (200 g of silica gel) eluted with a 10% v/v solution of ethyl acetate in benzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 168 mg (0.59 mmole) of 1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethanethiol were added to a solution of 12.5 mg (0.57 mmole) of metallic sodium in 4 ml of methanol at -10° C., and then the mixture was stirred for 5 minutes. 45 mg (0.59 mmole) of carbon disulphide were added to the resulting solution at the same temperature, followed by stirring for 10 minutes. Then 154 mg (0.54 mmole) of (3R, 4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxyethyl]azetidin-2-one were added to the solution at the same temperature. The bath temperature was slowly elevated to 0° C. over a period of about 1 hour. After completion of the reaction, the reaction solution was made slightly acidic by the addition of a drop of acetic acid, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried. After evaporation of the solvent, the resulting residue was subjected to column chromatography through 10 g of silica gel eluted with a 10-15% v/v solution of ethyl acetate in benzene, to give 237 mg (yield 77%) of the desired product as a yellow oil. by stirring for 10 minutes The bath temperature was slowly elevated to 0° C. over a period of about 1 hour After completion of the reaction washed with a saturated aqueous solution of sodium chloride dried After evaporation of the solvent eluted with a 10-15% v/v solution of ethyl acetate in benzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (3.96 g) and triethylamine (2.03 ml) in dichloromethane (60 ml) was added dropwise trimethylsilyl trifluoromethanesulfonate (3.5 ml) at -70° C. under nitrogen atmosphere. To this solution was added dropwise at -70° C. a reaction mixture, which had been prepared by stirring a solution of 4-acetyl-1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridine (3.268 g), triethylamine (1.94 ml) and trimethylsilyl trifluoromethanesulfonate (2.6 ml) in dichloromethane at -70° C. under nitrogen atmosphere. After the mixture was warmed to ambient temperature, the mixture was stirred for 2 hours. The reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (100 ml), and the solution was stirred for 30 minutes. The organic layer was separated, washed with brine (100 ml), dried over magnesium sulfate and concentrated to give an oil, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (2:1-1:5, V/V) to give (3S,4R)-4-[2-(1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-oxoethyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (4.65 g). To this solution was added dropwise at -70° C. a reaction mixture, which had been prepared the solution was stirred for 30 minutes The organic layer was separated washed with brine (100 ml) dried over magnesium sulfate concentrated to give an oil, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (2:1-1:5, V/V)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-acetyl-1-allyloxycarbonyl-1,2,3,6-tetrahydropyridine (1.33 g) and triethylamine (1.06 ml) in dichloromethane (50 ml) was added trimethylsilyl trifluoromethanesulfonate (2.2 ml) at 0° C. After stirring for 4 hours, a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (1.82 g) and zinc bromide (1.86 g) in ethyl acetate (10 ml) was added to the mixture, and the resultant mixture was stirred for 1 hour at 0° C. The reaction mixture was taken up into a mixture of ethyl acetate (200 ml) and water (200 ml). After adjusting pH to 4 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (40 g) eluting with a mixture of n-hexane and ethyl acetate (9:1-3:7, V/V) to give (3S,4R)-4-[2-(1-allyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-oxoethyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (1.80 g). the organic layer was separated washed with brine dried over magnesium sulfate Evaporation of the solvent gave a residue, which was chromatographed on silica gel (40 g) eluting with a mixture of n-hexane and ethyl acetate (9:1-3:7, V/V)