1-benzyl-4-methylpyrrolidin-3-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A solution of 31.7 g (0.168 mole) of 1-benzyl-4-methyl-3-pyrrolidone [prepared as described in Step (4) above] dissolved in 200 ml of ethanol was added dropwise to a solution of 59.4 g (0.79 mole) of hydroxylamine hydrochloride dissolved in 200 ml of water over a period of 1 hour, whilst keeping the temperature at 20° to 25° C. 62.1 g (0.45 mole) of potassium carbonate were then added, and the mixture was stirred at room temperature overnight, after which it was diluted with 100 ml of water. The aqueous solution was extracted with chloroform, and the chloroform extract was washed with water, dried and concentrated by evaporation under reduced pressure, to give 36.9 g of 1-benzyl-3-(hydroxyimino)-4-methylpyrrolidine as brown crystals. at 20° to 25° C The aqueous solution was extracted with chloroform the chloroform extract was washed with water dried concentrated by evaporation under reduced pressure

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

実験手順: A mixture of 48.0 g (0.184 mole) of 1-benzyl-4-ethoxycarbonyl-4-methyl-3-pyrrolidone [prepared as described in Step (3) above] and 80 ml of concentrated hydrochloric acid was heated under reflux for 24 hours. The reaction mixture was then filtered, and the filtrate was concentrated by evaporation under reduced pressure. The residue was diluted with water and made alkaline by adding a 50% w/v aqueous solution of sodium hydroxide to pH 10, after which it was extracted with diethyl ether. The diethyl ether extract was dried and the solvent was then distilled from the extract under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 2.5:7.5 by volume mixture of ethyl acetate and toluene, to give 31.7 g of 1-benzyl-4-methyl-3-pyrrolidone as a red oil. was heated under reflux for 24 hours The reaction mixture was then filtered the filtrate was concentrated by evaporation under reduced pressure The residue was diluted with water by adding a 50% w/v aqueous solution of sodium hydroxide to pH 10 after which it was extracted with diethyl ether The diethyl ether extract was dried the solvent was then distilled from the extract under reduced pressure The residue was purified by column chromatography through silica gel eluted with a 2.5:7.5 by volume mixture of ethyl acetate and toluene

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 15.58 g (82.3 mmol) sample of the ketone from step d was reduced to the alcohol by dissolving it in 32 mL of ethanol and adding the solution dropwise to a stirred suspension of sodium borohydride (3.11 g, 82.3 mmol) in 32 mL of ethanol at 0° C. The suspension was then stirred for 30 min at 0° C. and for 4 hours at room temperature. The solvent was then removed and the residue suspended in water. The product was extracted with methylene chloride and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under vacuum. The crude product was purified in a kugelrohr apparatus (160°-180° C. @ 1.0 Torr) to yield 1-benzyl-4-methyl-3-pyrrolidinol, MS M/Z 192 (M+H); NMR (CDCl3) d 1.04 (d, 3H, J=7.5 Hz), 1.90 (dd, 1H, J=7.5 Hz, J=9.0 Hz), 2.14 (m, 1H), 2.55 (dd, 1H, J=6.0 Hz, J=10.5 Hz), 2.82 (dd, 1H, J=3.0 Hz, J=10.5 Hz), 3.13 (dd, 1H, J=3.0 Hz, J=3.0 Hz), 3.82 (m, 2H), 3.95 (m, 1H), 7.33 (m, 5H). adding the solution The solvent was then removed The product was extracted with methylene chloride dried over anhydrous sodium sulfate the solvent was removed by evaporation under vacuum The crude product was purified in a kugelrohr apparatus (160°-180° C. @ 1.0 Torr)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 15.58 g (82.3 mmol) sample of the ketone from step d was reduced to the alcohol by dissolving it in 32 mL of ethanol and adding the solution dropwise to a stirred suspension of sodium borohydride (3.11 g, 82.3 mmol) in 32 mL of ethanol at 0° C. The suspension was then stirred for 30 min at 0° C. and for 4 hours at room temperature. The solvent was then removed and the residue suspended in water. The product was extracted with methylene chloride and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under vacuum. The crude product was purified in a kugelrohr apparatus (160°-180° C. @ 1.0 Torr) to yield 1-benzyl-4-methyl-3-pyrrolidinol, MS M/Z 192 (M+H); NMR (CDCl3) d 1.04 (d, 3H, J=7.5 Hz), 1.90 (dd, 1H, J=7.5 Hz, J=9.0 Hz), 2.14 (m, 1H), 2.55 (dd, 1H, J=6.0 Hz, J=10.5 Hz), 2.82 (dd, 1H, J=3.0 Hz, J=10.5 Hz), 3.13 (dd, 1H, J=3.0 Hz, J=3.0 Hz), 3.82 (m, 2H), 3.95 (m, 1H), 7.33 (m, 5H). adding the solution The solvent was then removed The product was extracted with methylene chloride dried over anhydrous sodium sulfate the solvent was removed by evaporation under vacuum The crude product was purified in a kugelrohr apparatus (160°-180° C. @ 1.0 Torr)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 30.15 g (115.4 mmol) sample of the ester from step c was hydrolyzed and decarboxylated by adding to 280 mL of 1M HCl and heating at 100° C. under reflux conditions for 12 hours. The mixture was then poured over ice and the impurities extracted into methylene chloride. The aqueous solution was then adjusted to pH 8 with potassium carbonate and the product extracted into methylene chloride, which was then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under vacuum, to yield 9.95 g of 1-benzyl-4-methylpyrrolidin-3-one, NMR (CDCl3) d 1.12 (d, 3H, J=7.5 Hz), 2.50 (m, 1H), 2.75 (m, 2H), 3.33 (m, 2H), 3.69 (d, 2H, J=7.5 Hz), 7.32 (m, 5H). The mixture was then poured over ice the impurities extracted into methylene chloride the product extracted into methylene chloride, which was then dried over anhydrous sodium sulfate The solvent was removed by evaporation under vacuum

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

実験手順: A solution of 31.7 g (0.168 mole) of 1-benzyl-4-methyl-3-pyrrolidone [prepared as described in Step (4) above] dissolved in 200 ml of ethanol was added dropwise to a solution of 59.4 g (0.79 mole) of hydroxylamine hydrochloride dissolved in 200 ml of water over a period of 1 hour, whilst keeping the temperature at 20° to 25° C. 62.1 g (0.45 mole) of potassium carbonate were then added, and the mixture was stirred at room temperature overnight, after which it was diluted with 100 ml of water. The aqueous solution was extracted with chloroform, and the chloroform extract was washed with water, dried and concentrated by evaporation under reduced pressure, to give 36.9 g of 1-benzyl-3-(hydroxyimino)-4-methylpyrrolidine as brown crystals. at 20° to 25° C The aqueous solution was extracted with chloroform the chloroform extract was washed with water dried concentrated by evaporation under reduced pressure

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

実験手順: A solution of 31.7 g (0.168 mole) of 1-benzyl-4-methyl-3-pyrrolidone [prepared as described in Step (4) above] dissolved in 200 ml of ethanol was added dropwise to a solution of 59.4 g (0.79 mole) of hydroxylamine hydrochloride dissolved in 200 ml of water over a period of 1 hour, whilst keeping the temperature at 20° to 25° C. 62.1 g (0.45 mole) of potassium carbonate were then added, and the mixture was stirred at room temperature overnight, after which it was diluted with 100 ml of water. The aqueous solution was extracted with chloroform, and the chloroform extract was washed with water, dried and concentrated by evaporation under reduced pressure, to give 36.9 g of 1-benzyl-3-(hydroxyimino)-4-methylpyrrolidine as brown crystals. at 20° to 25° C The aqueous solution was extracted with chloroform the chloroform extract was washed with water dried concentrated by evaporation under reduced pressure

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

実験手順: A mixture of 48.0 g (0.184 mole) of 1-benzyl-4-ethoxycarbonyl-4-methyl-3-pyrrolidone [prepared as described in Step (3) above] and 80 ml of concentrated hydrochloric acid was heated under reflux for 24 hours. The reaction mixture was then filtered, and the filtrate was concentrated by evaporation under reduced pressure. The residue was diluted with water and made alkaline by adding a 50% w/v aqueous solution of sodium hydroxide to pH 10, after which it was extracted with diethyl ether. The diethyl ether extract was dried and the solvent was then distilled from the extract under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 2.5:7.5 by volume mixture of ethyl acetate and toluene, to give 31.7 g of 1-benzyl-4-methyl-3-pyrrolidone as a red oil. was heated under reflux for 24 hours The reaction mixture was then filtered the filtrate was concentrated by evaporation under reduced pressure The residue was diluted with water by adding a 50% w/v aqueous solution of sodium hydroxide to pH 10 after which it was extracted with diethyl ether The diethyl ether extract was dried the solvent was then distilled from the extract under reduced pressure The residue was purified by column chromatography through silica gel eluted with a 2.5:7.5 by volume mixture of ethyl acetate and toluene

反応条件: temp:0.00; pressure:0.00; stir: