(S)-1-Benzyl 2-Methyl 4-Oxopyrrolidine-1,2-Dicarboxylate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Methyl 2-(phenylmethyl) (3S)-6,10-dioxa-2-azaspiro[4.5]decane-2,3-dicarboxylate (Intermediate 24) (1.02 g, yield 84%) was prepared from 2-methyl 1-(phenylmethyl) (2S)-4-oxo-1,2-pyrrolidinedicarboxylate (1.0 g, 3.61 mmol) and 1,3-propanediol (0.55 g, 7.21 mmol) following the similar procedure outlined in the preparation of Intermediate 14 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.05-7.61 (m, 5H) 4.91-5.25 (m, 2H) 4.29-4.68 (m, 1H) 3.75-4.07 (m, 5H) 3.38-3.75 (m, 4H) 2.25-2.67 (m, 2H) 1.51-2.00 (m, 1H). ES LC-MS m/z=336.6 (M+H)+.

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Potassium t-butoxide (1.41 g, 12.6 mmol) was suspended in diethyl ether (100 ml). To the suspension was added methyltriphenylphosphonium bromide (4.80 g, 13.4 mmol), and the resulting mixture was stirred at 5° C. for 15 minutes. To the mixture was added (S)-1-benzyloxycarbonyl-4-oxoproline methyl ester (2.50 g, 9.0 mmol) in diethyl ether (30 ml), and the resulting mixture was stirred at 35° C. for 3 hours. At the end of this time, the reaction mixture was added to a saturated solution of ammonium chloride (50 ml) under ice cooling, and then partitioned. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:hexane=1:3), to give the title compound (1.80 g) as a pale yellow oil (yield 72%). the resulting mixture was stirred at 35° C. for 3 hours partitioned The organic layer was washed with water dried over anhydrous magnesium sulfate the solvent was removed by distillation under reduced pressure The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:hexane=1:3)

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Potassium t-butoxide (1.41 g, 12.6 mmol) was suspended in diethyl ether (100 ml). To the suspension was added methyltriphenylphosphonium bromide (4.80 g, 13.4 mmol), and the resulting mixture was stirred at 5° C. for 15 minutes. To the mixture was added (S)-1-benzyloxycarbonyl-4-oxoproline methyl ester (2.50 g, 9.0 mmol) in diethyl ether (30 ml), and the resulting mixture was stirred at 35° C. for 3 hours. At the end of this time, the reaction mixture was added to a saturated solution of ammonium chloride (50 ml) under ice cooling, and then partitioned. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:hexane=1:3), to give the title compound (1.80 g) as a pale yellow oil (yield 72%). the resulting mixture was stirred at 35° C. for 3 hours partitioned The organic layer was washed with water dried over anhydrous magnesium sulfate the solvent was removed by distillation under reduced pressure The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:hexane=1:3)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve 7.0 g of 1-benzyloxycarbonyl-4-keto-(S)-proline methyl ester in 75 ml of glacial acetic acid. Add 0.7 g of p-toluenesulfonic acid and 2.8 g of 1,2-ethanedithiol and heat under reflux with stirring for eighteen hours. Add the reaction mixture to saturated sodium bicarbonate solution and extract with ethyl acetate. Dry the organic layer over magnesium sulfate and concentrate it. Place the residue on a column of silica gel (300 g, 60-200 mesh) and elute with hexane:ethyl acetate (1:1) to give 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro-[4.4]nonane-8(S)-carboxylic acid methylester, a yellow oil having [α]D26 -12.6° (dioxane). heat under reflux extract with ethyl acetate Dry the organic layer over magnesium sulfate concentrate it elute with hexane:ethyl acetate (1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve 7.0 g of 1-benzyloxycarbonyl-4-keto-(S)-proline methyl ester in 75 ml of glacial acetic acid. Add 0.7 g of p-toluenesulfonic acid and 2.8 g of 1,2-ethanedithiol and heat under reflux with stirring for eighteen hours. Add the reaction mixture to saturated sodium bicarbonate solution and extract with ethyl acetate. Dry the organic layer over magnesium sulfate and concentrate it. Place the residue on a column of silica gel (300 g, 60-200 mesh) and elute with hexane:ethyl acetate (1:1) to give 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro-[4.4]nonane-8(S)-carboxylic acid methylester, a yellow oil having [α]D26 -12.6° (dioxane). heat under reflux extract with ethyl acetate Dry the organic layer over magnesium sulfate concentrate it elute with hexane:ethyl acetate (1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To solution of methyl sulfoxide (23.90 ml, 337 mmol) in DCM (100 ml) at −78° C. was added oxalyl chloride (2 M in DCM, 84 ml, 168 mmol) dropwise. The formed solution was stirred at this temperature for 30 min. A solution of (2S,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (21.38 g, 77 mmol) in DCM (100 ml) was added dropwise at −78° C. The formed slurry was stirred at −78° C. for 2 hr before addition of N,N-Diisopropylethylamine (66.7 ml, 383 mmol) dropwise. The final solution was stirred at room temperature 3 h. The mixture was washed with iced 1M HCl, 5% citric acid, and then brine, dried over MgSO4, filtered, and evaporated. The residual light brown oil was purified by silica gel column chromatography, eluted with 4:1, 3:1, then 2:1 hexane-EtOAc to afford (S)-1-benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (14.8 g, 70% yield) as light brown viscous oil. The mixture was washed with iced 1M HCl, 5% citric acid brine, dried over MgSO4 filtered evaporated The residual light brown oil was purified by silica gel column chromatography eluted with 4:1, 3:1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To solution of methyl sulfoxide (23.90 ml, 337 mmol) in DCM (100 ml) at −78° C. was added oxalyl chloride (2 M in DCM, 84 ml, 168 mmol) dropwise. The formed solution was stirred at this temperature for 30 min. A solution of (2S,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (21.38 g, 77 mmol) in DCM (100 ml) was added dropwise at −78° C. The formed slurry was stirred at −78° C. for 2 hr before addition of N,N-Diisopropylethylamine (66.7 ml, 383 mmol) dropwise. The final solution was stirred at room temperature 3 h. The mixture was washed with iced 1M HCl, 5% citric acid, and then brine, dried over MgSO4, filtered, and evaporated. The residual light brown oil was purified by silica gel column chromatography, eluted with 4:1, 3:1, then 2:1 hexane-EtOAc to afford (S)-1-benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (14.8 g, 70% yield) as light brown viscous oil. The mixture was washed with iced 1M HCl, 5% citric acid brine, dried over MgSO4 filtered evaporated The residual light brown oil was purified by silica gel column chromatography eluted with 4:1, 3:1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-Methyl 4-oxopyrrolidine-2-carboxylate HCl salt (9.4 g, 52.6 mmol) was dissolved in 1,4-dioxane (210 mL) and a solution of potassiumbicarbonate (13.2 g, 131.5 mmol) in DI-water (70 mL) was added at 0° C., followed by slow addition of benzylchloroformate (15 mL, 105.2 mmol). The mixture was then let warm up to room temperature and it was stirred overnight. The resulting crude mixture was concentrated down as much as possible on the rotovap and it was diluted with EtOAc and washed twice with saturated NaHCO3 and 10% citric acid and once with saturated NaHCO3 again and then with brine. The organic layer was dried over Na2SO4 and after filtration it was concentrated down on rotovap. The crude product was then purified on normal phase column chromatography (15% EtOAc/Hexanes). (14.6 g, 100%) The resulting crude mixture was concentrated down as much as possible on the rotovap and it was diluted with EtOAc washed twice with saturated NaHCO3 and 10% citric acid and once with saturated NaHCO3 again The organic layer was dried over Na2SO4 after filtration it was concentrated down on rotovap The crude product was then purified on normal phase column chromatography (15% EtOAc/Hexanes)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Methyl 2-(phenylmethyl) (3S)-6,10-dioxa-2-azaspiro[4.5]decane-2,3-dicarboxylate (Intermediate 24) (1.02 g, yield 84%) was prepared from 2-methyl 1-(phenylmethyl) (2S)-4-oxo-1,2-pyrrolidinedicarboxylate (1.0 g, 3.61 mmol) and 1,3-propanediol (0.55 g, 7.21 mmol) following the similar procedure outlined in the preparation of Intermediate 14 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.05-7.61 (m, 5H) 4.91-5.25 (m, 2H) 4.29-4.68 (m, 1H) 3.75-4.07 (m, 5H) 3.38-3.75 (m, 4H) 2.25-2.67 (m, 2H) 1.51-2.00 (m, 1H). ES LC-MS m/z=336.6 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To solution of methyl sulfoxide (23.90 ml, 337 mmol) in DCM (100 ml) at −78° C. was added oxalyl chloride (2 M in DCM, 84 ml, 168 mmol) dropwise. The formed solution was stirred at this temperature for 30 min. A solution of (2S,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (21.38 g, 77 mmol) in DCM (100 ml) was added dropwise at −78° C. The formed slurry was stirred at −78° C. for 2 hr before addition of N,N-Diisopropylethylamine (66.7 ml, 383 mmol) dropwise. The final solution was stirred at room temperature 3 h. The mixture was washed with iced 1M HCl, 5% citric acid, and then brine, dried over MgSO4, filtered, and evaporated. The residual light brown oil was purified by silica gel column chromatography, eluted with 4:1, 3:1, then 2:1 hexane-EtOAc to afford (S)-1-benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (14.8 g, 70% yield) as light brown viscous oil. 1H NMR (CDCl3) δ 2.58-2.63 (m, 1H), 2.90-2.99 (m, 1H), 3.62, 3.77 (s, 3H, rotamers), 3.95-4.02 (m, 2H), 4.82-4.89 (m, 1H), 5.11-5.24 (m, 2H), 7.32-7.39 (m, 5H). The mixture was washed with iced 1M HCl, 5% citric acid brine, dried over MgSO4 filtered evaporated The residual light brown oil was purified by silica gel column chromatography eluted with 4:1, 3:1

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.80 g (13.4 mmol) of methyltriphenylphosphonium bromide were added to a suspension of 1.41 g (12.6 mmol) of potassium t-butoxide in 100 ml of diethyl ether, and the resulting mixture was stirred for 15 minutes at 5° C. At the end of this time, a solution of 2.50 g (9.0 mmol) of (S)-1-benzyloxycarbonyl-4-oxoproline methyl ester in 30 ml of diethyl ether was added to the mixture thus obtained, and the mixture was stirred for an additional 3 hours at 35° C. At the end of this time, 50 ml of a saturated aqueous solution of ammonium chloride were added to the reaction mixture with ice-cooling, and the resulting mixture was partitioned. The organic extract thus obtained was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography on a silica gel column using a 1:3 by volume mixture of ethyl acetate and hexane as the eluant to afford 1.80 g (yield: 72%) of the title compound as a pale yellow oil. thus obtained the mixture was stirred for an additional 3 hours at 35° C cooling the resulting mixture was partitioned The organic extract thus obtained was washed with water dried over anhydrous magnesium sulfate concentrated by evaporation under reduced pressure The residue was purified by chromatography on a silica gel column by volume mixture of ethyl acetate and hexane as the eluant

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Methyl 2-(phenylmethyl) (3S)-6,10-dioxa-2-azaspiro[4.5]decane-2,3-dicarboxylate (Intermediate 24) (1.02 g, yield 84%) was prepared from 2-methyl 1-(phenylmethyl) (2S)-4-oxo-1,2-pyrrolidinedicarboxylate (1.0 g, 3.61 mmol) and 1,3-propanediol (0.55 g, 7.21 mmol) following the similar procedure outlined in the preparation of Intermediate 14 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.05-7.61 (m, 5H) 4.91-5.25 (m, 2H) 4.29-4.68 (m, 1H) 3.75-4.07 (m, 5H) 3.38-3.75 (m, 4H) 2.25-2.67 (m, 2H) 1.51-2.00 (m, 1H). ES LC-MS m/z=336.6 (M+H)+.