(S)-3-Isopropyl-2,5-piperazinedione

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

実験手順: To a solution of methyl (methylthio)acetate (14.8 ml, 115 mmol) in dichloromethane (400 ml) was added sulfuryl chloride (9.64 ml, 120 mmol) at −78° C. and stirred for 15 minutes. To the mixture was added dropwise a solution of 4-methoxy-2,5-dimethylaniline (15.1 g, 100 mmol) and proton sponge (22.5 g, 105 mmol) in dichloromethane (100 ml) over 1 hour and the mixture was stirred at the same temperature for 1 hour. Then, triethylamine (15.3 ml, 110 mmol) was added, and the mixture was allowed to warm to room temperature slowly. After stirring at room temperature for 1 hour, water was added and the precipitated crystals were collected by filtration and washed with dichloromethane and water to obtain 18.3 g of the title compound. the mixture was stirred at the same temperature for 1 hour After stirring at room temperature for 1 hour the precipitated crystals were collected by filtration washed with dichloromethane and water

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a three-necked flask equipped with a stirring bar, thermometer and 2 addition funnels was added a solution of 4-trifluoromethylaniline (0.088 mol, 11.05 mL) in dichloromethane (300 mL). The solution was cooled to −70° C. and a solution of t-butyl hypochlorite (0.088 mol, 9.95 mL) in dichloromethane (20 mL) was added dropwise over a period of 30 minutes maintaining the temperature at −60° C. The mixture was then stirred at −70° C. for 1 h and a solution of methylsulfanyl-acetic acid methyl ester (0.088 mol, 9.52 mL) in dichloromethane (20 mL) was added over a period of 30 minutes maintaining the temperature at −65° C. The reaction mixture was stirred for 1 hour at −70° C. Triethylamine (0.088 mol, 12.3 mL) was added dropwise and stirring at −70° C. continued for 30 minutes before allowing the mixture to warm to room temperature. After 1 hour at ambient temperature the dichloromethane was evaporated under vacuum and ether (200 mL) was added to the residue followed by water (150 mL). The ether layer was separated, 1N hydrochloric acid (50 mL) added and the mixture was stirred for 16 hr at room temperature. The organic layer was separated, dried over anhydrous sodium sulfate and the solvent removed under vacuum. The residue was purified by chromatography on silica gel eluting with dichloromethane followed by 19:1 dichloromethane-ethyl acetate then 9:1 dichloromethane-ethyl acetate to give 3-methylsulfanyl-5-trifluoromethyl-1,3-dihydro-indol-2-one as a yellow solid (12.9 g, 59%). N-Chlorosuccimide (1.5 eq, 4.87 g, 36.46 mmol) was added to a solution of 3-methylsulfanyl-5-trifluoromethyl-1,3-dihydro-indol-2-one (6 g, 24.29 mmol) in chloroform (100 mL). After stirring for 2 hours at room temperature the precipitate was removed by filtration through a pad of Celite® and the solvent was removed under vacuum. The residue was dissolved in tetrahydrofuran (30 mL) and added to a solution prepared from red mercury (II) oxide (1.0 eq., 5.26 g, 24.29 mmol) in a mixture of tetrahydrofuran (80 mL) and water (20 mL) to which was added boron trifluoride etherate (1.0 eq, 2.99 mL). The solution was stirred overnight at room temperature then filtered through a pad of Celite®, rinsing through with tetrahydrofuran. The solution was extracted with dichloromethane (4×100 mL) and the combined organic layers dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel eluting with 10% ethyl acetate-dichloromethane to give 5-trifluoromethyl-1H-indole-2,3-dione as a yellow solid (2.79 g, 53%). To a solution of 5-trifluoromethyl-1H-indole-2,3-dione (0.93 mmol, 200 mg) in ethanol (30 mL) was added 1M sodium hydroxide (15 mL) and the mixture was stirred for 30 min. 4-Acetylpyridine (1.02 mmol, 0.072 mL) was added and the solution was heated under reflux for 16 hr. After cooling the mixture was extracted with diethyl ether and the organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The residue was purified by chromatography on a 4 mm silica gel rotor eluting with 9:1 dichloromethane-methanol to give the title compound (300 mg, 100%). To a three-necked flask equipped with a stirring bar thermometer and 2 addition funnels maintaining the temperature at −60° C maintaining the temperature at −65° C The reaction mixture was stirred for 1 hour at −70° C stirring at −70° C. continued for 30 minutes to warm to room temperature After 1 hour at ambient temperature the dichloromethane was evaporated under vacuum and ether (200 mL) was added to the residue The ether layer was separated 1N hydrochloric acid (50 mL) added the mixture was stirred for 16 hr at room temperature The organic layer was separated dried over anhydrous sodium sulfate the solvent removed under vacuum The residue was purified by chromatography on silica gel eluting with dichloromethane

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

実験手順: To a suspension of 21.4 g (535 mmol) of sodium hydride (60% in oil) in 200 ml of DMF was added dropwise a mixture of 25.8 g (214 mmol) of methyl 2-(methylthio)acetate and 26.5 g (428 mmol) of methyl formate under ice cooling and stirred at room temperature overnight. To the reaction mixture was added portionwise 27.0 g (141 mmol) of p-toluenesulfonyl chloride under ice cooling and stirred at room temperature for 1 hour. After dilution with tert-butyl methyl ether, the solution was washed sequentially with water and saturated NaCl solution, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 9.72 g of methyl 2-(methylthio)-3-(p-toluenesulfonyloxy)-2-propenoate and 1.88 g of methyl 3-chloro-2-(methylthio)-2-propenoate. was added dropwise stirred at room temperature for 1 hour After dilution with tert-butyl methyl ether, the solution was washed sequentially with water and saturated NaCl solution dried over anhydrous MgSO4 concentrated The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1)

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

実験手順: To a solution of methyl (methylthio)acetate (40.8 mL, 317 mmol) in dichloromethane (1100 mL) was added sulfuryl chloride (26.6 mL, 331 mmol) at −78° C., and the mixture was stirred for 15 minutes. Further, a solution of 4-methoxy-2,3-dimethylaniline (41.7 g, 276 mmol) and proton sponge (62.1 g, 290 mmol) in dichloromethane (200 mL) was added dropwise over 1 hour and mixture was stirred at the same temperature for 1 hour. Triethylamine (43 mL, 380 mmol) was added, and the temperature was gradually raised to room temperature. After stirring at room temperature for 2 hours, water was added, the organic layer was washed with an aqueous saturated solution of sodium bicarbonate and saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. To the residue was added toluene (300 mL), and the mixture was stirred at reflux for 1 hour. The solvent was distilled off under reduced pressure, which was recrystallized from ethyl acetate to obtain 30.0 g of the title compound. mixture was stirred at the same temperature for 1 hour After stirring at room temperature for 2 hours the organic layer was washed with an aqueous saturated solution of sodium bicarbonate and saturated brine dried over sodium sulfate the solvent was distilled off under reduced pressure To the residue was added toluene (300 mL) the mixture was stirred at reflux for 1 hour The solvent was distilled off under reduced pressure, which was recrystallized from ethyl acetate

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

実験手順: To a solution of methyl (methylthio)acetate (14.8 ml, 115 mmol) in dichloromethane (400 ml) was added sulfuryl chloride (9.64 ml, 120 mmol) at −78° C. and stirred for 15 minutes. To the mixture was added dropwise a solution of 4-methoxy-2,5-dimethylaniline (15.1 g, 100 mmol) and proton sponge (22.5 g, 105 mmol) in dichloromethane (100 ml) over 1 hour and the mixture was stirred at the same temperature for 1 hour. Then, triethylamine (15.3 ml, 110 mmol) was added, and the mixture was allowed to warm to room temperature slowly. After stirring at room temperature for 1 hour, water was added and the precipitated crystals were collected by filtration and washed with dichloromethane and water to obtain 18.3 g of the title compound. the mixture was stirred at the same temperature for 1 hour After stirring at room temperature for 1 hour the precipitated crystals were collected by filtration washed with dichloromethane and water

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a three-necked flask equipped with a stirring bar, thermometer and 2 addition funnels was added a solution of 4-trifluoromethylaniline (0.088 mol, 11.05 mL) in dichloromethane (300 mL). The solution was cooled to −70° C. and a solution of t-butyl hypochlorite (0.088 mol, 9.95 mL) in dichloromethane (20 mL) was added dropwise over a period of 30 minutes maintaining the temperature at −60° C. The mixture was then stirred at −70° C. for 1 h and a solution of methylsulfanyl-acetic acid methyl ester (0.088 mol, 9.52 mL) in dichloromethane (20 mL) was added over a period of 30 minutes maintaining the temperature at −65° C. The reaction mixture was stirred for 1 hour at −70° C. Triethylamine (0.088 mol, 12.3 mL) was added dropwise and stirring at −70° C. continued for 30 minutes before allowing the mixture to warm to room temperature. After 1 hour at ambient temperature the dichloromethane was evaporated under vacuum and ether (200 mL) was added to the residue followed by water (150 mL). The ether layer was separated, 1N hydrochloric acid (50 mL) added and the mixture was stirred for 16 hr at room temperature. The organic layer was separated, dried over anhydrous sodium sulfate and the solvent removed under vacuum. The residue was purified by chromatography on silica gel eluting with dichloromethane followed by 19:1 dichloromethane-ethyl acetate then 9:1 dichloromethane-ethyl acetate to give 3-methylsulfanyl-5-trifluoromethyl-1,3-dihydro-indol-2-one as a yellow solid (12.9 g, 59%). N-Chlorosuccimide (1.5 eq, 4.87 g, 36.46 mmol) was added to a solution of 3-methylsulfanyl-5-trifluoromethyl-1,3-dihydro-indol-2-one (6 g, 24.29 mmol) in chloroform (100 mL). After stirring for 2 hours at room temperature the precipitate was removed by filtration through a pad of Celite® and the solvent was removed under vacuum. The residue was dissolved in tetrahydrofuran (30 mL) and added to a solution prepared from red mercury (II) oxide (1.0 eq., 5.26 g, 24.29 mmol) in a mixture of tetrahydrofuran (80 mL) and water (20 mL) to which was added boron trifluoride etherate (1.0 eq, 2.99 mL). The solution was stirred overnight at room temperature then filtered through a pad of Celite®, rinsing through with tetrahydrofuran. The solution was extracted with dichloromethane (4×100 mL) and the combined organic layers dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel eluting with 10% ethyl acetate-dichloromethane to give 5-trifluoromethyl-1H-indole-2,3-dione as a yellow solid (2.79 g, 53%). To a solution of 5-trifluoromethyl-1H-indole-2,3-dione (0.93 mmol, 200 mg) in ethanol (30 mL) was added 1M sodium hydroxide (15 mL) and the mixture was stirred for 30 min. 4-Acetylpyridine (1.02 mmol, 0.072 mL) was added and the solution was heated under reflux for 16 hr. After cooling the mixture was extracted with diethyl ether and the organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The residue was purified by chromatography on a 4 mm silica gel rotor eluting with 9:1 dichloromethane-methanol to give the title compound (300 mg, 100%). To a three-necked flask equipped with a stirring bar thermometer and 2 addition funnels maintaining the temperature at −60° C maintaining the temperature at −65° C The reaction mixture was stirred for 1 hour at −70° C stirring at −70° C. continued for 30 minutes to warm to room temperature After 1 hour at ambient temperature the dichloromethane was evaporated under vacuum and ether (200 mL) was added to the residue The ether layer was separated 1N hydrochloric acid (50 mL) added the mixture was stirred for 16 hr at room temperature The organic layer was separated dried over anhydrous sodium sulfate the solvent removed under vacuum The residue was purified by chromatography on silica gel eluting with dichloromethane