tert-butyl N-[(2S,3S)-2-methyl-4-oxoazetidin-3-yl]carbamate

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

Procedure: A solution of 3.3 g of (3S-trans)-3-t-butoxycarbonylamino-4-methylazetidinone in 10 ml each of dichloromethane and anisole is cooled to 0° C. and 112 ml of trifluoroacetic acid is added. The solution is stirred for 90 minutes and evaporated in vacuo (benzene added and evaporated three times). The residue is dissolved in 70 ml of acetone and the solution is adjusted to pH 7 with 5% sodium bicarbonate solution. A total of 5.33 g of benzyl chloroformate is added over 1 hour at pH 6.5-7.5. The mixture is stirred for 30 minutes at pH 7, diluted with 100 ml of saturated salt, and extracted with ethyl acetate (three 400 ml portions). The residue obtained by evaporation is chromatographed on a 1 liter silica gel column. Elution with chloroform-ethyl acetate (4:1) gives 2.19 g of compound. Crystallization from ether-hexane yields 1.125 g of the title compound. evaporated in vacuo (benzene added and evaporated three times) The residue is dissolved in 70 ml of acetone A total of 5.33 g of benzyl chloroformate is added over 1 hour at pH 6.5-7.5 The mixture is stirred for 30 minutes at pH 7 diluted with 100 ml of saturated salt extracted with ethyl acetate (three 400 ml portions) The residue obtained by evaporation is chromatographed on a 1 liter silica gel column Elution with chloroform-ethyl acetate (4:1)

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

Procedure: A solution of 4.98 of (3S-trans)-3-t-butoxycarbonylamino-1-hydroxy-4-methylazetidinone in 200 ml of methanol is treated with 132 ml of 4.5M ammonium acetate and then 66 ml of 1.5M titanium trichloride and stirred for 4.5 hours. The aqueous solution is diluted with an equal volume of 8% sodium chloride and extracted with ethyl acetate to give 3.48 g of crude product. Recrystallization from ether-hexane yields 3.3 g of the title compound. extracted with ethyl acetate to give 3.48 g of crude product Recrystallization from ether-hexane

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

Procedure: A solution of 4.98 g of (3S-trans)-3-t-butoxycarbonylamino-1-hydroxy-4-methylazetidinone in 200 ml of methanol was treated with 132 ml of 4.5 M ammonium acetate and then 66 ml of 1.5 titanium trichloride and stirred for 4.5 hours. The aqueous solution was diluted with an equal volume of 8% sodium chloride and extracted with ethyl acetate to give 3.48 g of crude product. Recrystallization from ether-hexane yielded 3.3 g of the title compound. extracted with ethyl acetate to give 3.48 g of crude product Recrystallization from ether-hexane

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

Procedure: A solution of 4.98 g of (3S-trans)-3-t-butoxycarbonylamino-1-hydroxy-4-methylazetidinone in 200 ml of methanol was treated with 132 ml of 4.5 M ammonium acetate and then 66 ml of 1.5 titanium trichloride and stirred for 4.5 hours. The aqueous solution was diluted with an equal volume of 8% sodium chloride and extracted with ethyl acetate to give 3.48 g of crude product. Recrystallization from ether-hexane yielded 3.3 g of the title compound. extracted with ethyl acetate to give 3.48 g of crude product Recrystallization from ether-hexane

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

Procedure: A solution of 3.3 g of (3S-trans)-3-t-butoxycarbonylamino-4-methylazetidinone in 10 ml each of dichloromethane and anisole is cooled to 0° C. and 112 ml of trifluoroacetic acid is added. The solution is stirred for 90 minutes and evaporated in vacuo (benzene added and evaporated three times). The residue is dissolved in 70 ml of acetone and the solution is adjusted to pH 7 with 5% sodium bicarbonate solution. A total of 5.33 g of benzyl chloroformate is added over 1 hour at pH 6.5-7.5. The mixture is stirred for 30 minutes at pH 7, diluted with 100 ml of saturated salt, and extracted with ethyl acetate (three 400 ml portions). The residue obtained by evaporation is chromatographed on a 1 liter silica gel column. Elution with chloroform-ethyl acetate (4:1) gives 2.19 g of compound. Crystallization from ether-hexane yields 1.125 g of the title compound. evaporated in vacuo (benzene added and evaporated three times) The residue is dissolved in 70 ml of acetone A total of 5.33 g of benzyl chloroformate is added over 1 hour at pH 6.5-7.5 The mixture is stirred for 30 minutes at pH 7 diluted with 100 ml of saturated salt extracted with ethyl acetate (three 400 ml portions) The residue obtained by evaporation is chromatographed on a 1 liter silica gel column Elution with chloroform-ethyl acetate (4:1)

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

Procedure: A solution of 3.3 g of (3S-trans)-3-t-butoxycarbonylamino-4-methylazetidinone in 10 ml each of dichloromethane and anisole is cooled to 0° C. and 112 ml of trifluoroacetic acid is added. The solution is stirred for 90 minutes and evaporated in vacuo (benzene added and evaporated three times). The residue is dissolved in 70 ml of acetone and the solution is adjusted to pH 7 with 5% sodium bicarbonate solution. A total of 5.33 g of benzyl chloroformate is added over 1 hour at pH 6.5-7.5. The mixture is stirred for 30 minutes at pH 7, diluted with 100 ml of saturated salt, and extracted with ethyl acetate (three 400 ml portions). The residue obtained by evaporation is chromatographed on a 1 liter silica gel column. Elution with chloroform-ethyl acetate (4:1) gives 2.19 g of compound. Crystallization from ether-hexane yields 1.125 g of the title compound. evaporated in vacuo (benzene added and evaporated three times) The residue is dissolved in 70 ml of acetone A total of 5.33 g of benzyl chloroformate is added over 1 hour at pH 6.5-7.5 The mixture is stirred for 30 minutes at pH 7 diluted with 100 ml of saturated salt extracted with ethyl acetate (three 400 ml portions) The residue obtained by evaporation is chromatographed on a 1 liter silica gel column Elution with chloroform-ethyl acetate (4:1)

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

Procedure: A solution of 4.98 of (3S-trans)-3-t-butoxycarbonylamino-1-hydroxy-4-methylazetidinone in 200 ml of methanol is treated with 132 ml of 4.5M ammonium acetate and then 66 ml of 1.5M titanium trichloride and stirred for 4.5 hours. The aqueous solution is diluted with an equal volume of 8% sodium chloride and extracted with ethyl acetate to give 3.48 g of crude product. Recrystallization from ether-hexane yields 3.3 g of the title compound. extracted with ethyl acetate to give 3.48 g of crude product Recrystallization from ether-hexane

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

Procedure: To 664 mg (4.0 mmol) of benzyl glycolate was added 5.8 ml of 12.5% phosgene (in toluene) at 0° C. To this solution at 0° C. was added pyridine (0.372 ml, 4.6 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 hours and was then filtered under argon. Most of the volatiles were removed under vacuum without external heating, and the residual chloroformate was dissolved in methylene chloride (8 ml). Approximately half of this solution was added to (3S-trans)-3-[[(t-butyloxy)carbonyl]amino]-4-methyl-2-azetidinone (440 mg, 2.0 mmol), and the resulting solution was cooled to -20° C. Triethylamine (0.293 ml, 2.1 mmol) was then added dropwise. After 2 hours at -20° C., the remaining chloroformate was added to the azetidinone reaction mixture followed by 0.293 ml of triethylamine. After 3 hours at -20° C., the product was extracted from aqueous KH2PO4 with three portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, and the volatiles were removed. The residue was subjected to column chromatography on silica gel (eluting with 35% ethyl acetate-hexane) to yield 488 mg of the title compound. was then filtered under argon Most of the volatiles were removed under vacuum without external heating the residual chloroformate was dissolved in methylene chloride (8 ml) the resulting solution was cooled to -20° C After 2 hours at -20° C. After 3 hours at -20° C. the product was extracted from aqueous KH2PO4 with three portions of ethyl acetate The combined organic layers were dried over sodium sulfate the volatiles were removed

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

Procedure: To 664 mg (4.0 mmol) of benzyl glycolate was added 5.8 ml of 12.5% phosgene (in toluene) at 0° C. To this solution at 0° C. was added pyridine (0.372 ml, 4.6 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 hours and was then filtered under argon. Most of the volatiles were removed under vacuum without external heating, and the residual chloroformate was dissolved in methylene chloride (8 ml). Approximately half of this solution was added to (3S-trans)-3-[[(t-butyloxy)carbonyl]amino]-4-methyl-2-azetidinone (440 mg, 2.0 mmol), and the resulting solution was cooled to -20° C. Triethylamine (0.293 ml, 2.1 mmol) was then added dropwise. After 2 hours at -20° C., the remaining chloroformate was added to the azetidinone reaction mixture followed by 0.293 ml of triethylamine. After 3 hours at -20° C., the product was extracted from aqueous KH2PO4 with three portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, and the volatiles were removed. The residue was subjected to column chromatography on silica gel (eluting with 35% ethyl acetate-hexane) to yield 488 mg of the title compound. was then filtered under argon Most of the volatiles were removed under vacuum without external heating the residual chloroformate was dissolved in methylene chloride (8 ml) the resulting solution was cooled to -20° C After 2 hours at -20° C. After 3 hours at -20° C. the product was extracted from aqueous KH2PO4 with three portions of ethyl acetate The combined organic layers were dried over sodium sulfate the volatiles were removed

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

Procedure: A solution of phosgene in toluene (1.35 ml of a 20% solution, 2.698 mmol) was cooled to -25° C. under an argon atmosphere. A solution of N-methylglycine, t-butyl ester (218 mg, 1.498 mmol) and triethylamine (251 μl, 1.798 mmol) in dichloromethane (2 ml) was added dropwise over 5 minutes. The reaction was stirred for 1 hour at -25° C. (after 15 minutes an additional 0.2 ml of dichloromethane was added to facilitate stirring). The volatiles were removed starting at -25° C. and slowly by warming to room temperature. The residue was dissolved in methylene chloride (5 ml), cooled to 0° C. and treated with (3S-trans)-3-[[t-butoxycarbonyl]amino]-4-methyl-2-azetidinone (300 mg, 1.498 mmol; pre-dried over P2O5 at 25° C. under high vacuum), 4-dimethylaminiopyridine (18 mg, 0.149 mmol), and triethylamine (251 μl, 1.798 mmol). The resulting mixture was warmed to room temperature, stirred for 36 hours, treated with additional triethylamine (502 μl), and refluxed for 5 hours. The reaction was cooled, diluted with ethyl acetate, washed with pH 4.5 KH2PO4, and with brine, and then dried over sodium sulfate. Filtration and concentration in vacuo produced 525 mg of an oil which was chromatographed on 21 g of silica gel (230-400 mesh). Elution with 40% ethyl acetate-hexane gave 356 mg of the title compound as a white solid. was added The volatiles were removed starting at -25° C. The residue was dissolved in methylene chloride (5 ml) cooled to 0° C. The resulting mixture was warmed to room temperature stirred for 36 hours refluxed for 5 hours The reaction was cooled washed with pH 4.5 KH2PO4 with brine, and then dried over sodium sulfate Filtration and concentration in vacuo

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of potassium cyanate (186 mg, 2.3 mmol) in 2 ml of dimethylformamide was added t-butyl bromoacetate (0.356 ml, 2.2 mmol). The mixture was heated to 100° C. for 1 hour and cooled to room temperature. (3S-trans)-3-[[(t-Butyloxy)carbonyl]amino]-4-methyl-2-azetidinone (400 mg, 2.0 mmol) was then added, and the mixture was heated to 140° C. for 1 hour. Upon cooling to room temperature, the crude product was extracted from ice cold 5% HCl with three portions of ethyl acetate. The combined organic layers were extracted twice with water, once with aqueous potassium bicarbonate, and dried over sodium sulfate. The volatiles were removed, and the residue was subjected to chromatography on silica gel (eluting with 40% ethyl acetate-hexane) yielding 149 mg of the title compound. cooled to room temperature the mixture was heated to 140° C. for 1 hour Upon cooling to room temperature the crude product was extracted from ice cold 5% HCl with three portions of ethyl acetate The combined organic layers were extracted twice with water, once with aqueous potassium bicarbonate dried over sodium sulfate The volatiles were removed

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

Procedure: A solution of 3.3 g of (3S-trans)-3-t-butoxycarbonylamino-4-methylazetidinone in 10 ml each of dichloromethane and anisole is cooled to 0° C. and 112 ml of trifluoroacetic acid is added. The solution is stirred for 90 minutes and evaporated in vacuo (benzene added and evaporated three times). The residue is dissolved in 70 ml of acetone and the solution is adjusted to pH 7 with 5% sodium bicarbonate solution. A total of 5.33 g of benzyl chloroformate is added over 1 hour at pH 6.5-7.5. The mixture is stirred for 30 minutes at pH 7, diluted with 100 ml of saturated salt, and extracted with ethyl acetate (three 400 ml portions). The residue obtained by evaporation is chromatographed on a 1 liter silica gel column. Elution with chloroform-ethyl acetate (4:1) gives 2.19 g of compound. Crystallization from ether-hexane yields 1.125 g of the title compound. evaporated in vacuo (benzene added and evaporated three times) The residue is dissolved in 70 ml of acetone A total of 5.33 g of benzyl chloroformate is added over 1 hour at pH 6.5-7.5 The mixture is stirred for 30 minutes at pH 7 diluted with 100 ml of saturated salt extracted with ethyl acetate (three 400 ml portions) The residue obtained by evaporation is chromatographed on a 1 liter silica gel column Elution with chloroform-ethyl acetate (4:1)