(2S)-1-(2,4-difluorophenyl)-2-(oxan-2-yloxy)propan-1-one

反応条件: temp:8.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mechanically stirred mixture of methyl triphenylphosphonium bromide (169.2 g, 0.474 moles) in 350 ml of dry tetrahydrofuran was cooled to 8° C. A solution of lithium bis (trimethylsilyl) amide (84.8 g, 0.507 moles) in 500 ml tetrahydrofuran was added to the above mixture at a rate so that the temperature of the mixture remained at 23° C. After stirring for 1 hour at room temperature the contents were cooled to 31 70° C. and stirred for 1/2 hour. Then a solution of compound 4a, (2S)-2',4'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone, (100 g, 0.370 moles) in 250 ml of tetrahydrofuran was added slowly to maintain the temperature of the mixture below -70° C. The resulting mixture was stirred at 7° C. for 17 hours. Added 65 ml of ethyl acetate to the above mixture followed by the addition of 3.9 L of hexane and allowed to stand for 15 minutes. The solid was removed by suction-filtration and washed thoroughly with 650 ml of hexane. The filtrate was washed with 1:1 mixture of methanol: water (2×1300 ml) and brine (1300 ml) then dried over MgSO4. The solvent was evaporated to give the title compound 5a as an oil (91.5 g, 92%). remained at 23° C were cooled to 31 70° C. stirred for 1/2 hour to maintain the temperature of the mixture below -70° C The resulting mixture was stirred at 7° C. for 17 hours to stand for 15 minutes The solid was removed by suction-filtration washed thoroughly with 650 ml of hexane The filtrate was washed with 1:1 mixture of methanol water (2×1300 ml) and brine (1300 ml) then dried over MgSO4 The solvent was evaporated

反応条件: temp:8.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mechanically stirred mixture of methyl triphenylphosphonium bromide (169.2 g, 0.474 moles) in 350 ml of dry tetrahydrofuran was cooled to 8° C. A solution of lithium bis (trimethylsilyl) amide (84.8 g, 0.507 moles) in 500 ml tetrahydrofuran was added to the above mixture at a rate so that the temperature of the mixture remained at 23° C. After stirring for 1 hour at room temperature the contents were cooled to 31 70° C. and stirred for 1/2 hour. Then a solution of compound 4a, (2S)-2',4'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone, (100 g, 0.370 moles) in 250 ml of tetrahydrofuran was added slowly to maintain the temperature of the mixture below -70° C. The resulting mixture was stirred at 7° C. for 17 hours. Added 65 ml of ethyl acetate to the above mixture followed by the addition of 3.9 L of hexane and allowed to stand for 15 minutes. The solid was removed by suction-filtration and washed thoroughly with 650 ml of hexane. The filtrate was washed with 1:1 mixture of methanol: water (2×1300 ml) and brine (1300 ml) then dried over MgSO4. The solvent was evaporated to give the title compound 5a as an oil (91.5 g, 92%). remained at 23° C were cooled to 31 70° C. stirred for 1/2 hour to maintain the temperature of the mixture below -70° C The resulting mixture was stirred at 7° C. for 17 hours to stand for 15 minutes The solid was removed by suction-filtration washed thoroughly with 650 ml of hexane The filtrate was washed with 1:1 mixture of methanol water (2×1300 ml) and brine (1300 ml) then dried over MgSO4 The solvent was evaporated

反応条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To dimethyl sulfoxide (5 ml) was added 60% sodium hydride in oil (85 mg), to which was added trimethyl sulfoxonium iodide (0.49 g) with stirring at about 15° C., and the mixture was stirred for 15 minutes at room temperature. The reaction mixture was cooled with ice, to which was added a dimethyl sulfoxide solution (1.2 ml) of (2S)-2',4'-difluoro-2-(3,4,5,6-tetrahydro- 2H-pyran-2-yloxy)propiophenone (0.50 g), and the mixture was stirred for two hours at room temperature. To the reaction mixture were added water (10 ml) and ethyl acetate (50 ml), and the resultant mixture was shaken. The organic layer was washed with a saturated aqueous sodium chloride solution (10 ml) twice, which was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel chromatography (eluent, hexane:ethyl acetate=10:1) to afford 2-[(1S)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]-2-(2,4-difluorophenyl)oxirane (0.40 g) as a pale yellow oily product. the mixture was stirred for 15 minutes at room temperature The reaction mixture was cooled with ice, to which the mixture was stirred for two hours at room temperature The organic layer was washed with a saturated aqueous sodium chloride solution (10 ml) twice which was dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the residue was purified by means of a silica gel chromatography (eluent, hexane:ethyl acetate=10:1)

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In ethanol (3 ml) was dissolved (2S)-2',4'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (95 mg), to which was added pyridinium p-toluenesulfonate (21 mg), followed by stirring for one hour at 55° C. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml), which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel chromatography (eluent, hexane:ethyl acetate=5:1) to give (2S)-2',4'-difluoro-2-hydroxypropiophenone (40 mg) as a pale yellow oily product. The solvent was distilled off under reduced pressure the residue was dissolved in ethyl acetate (20 ml) which was dried over anhydrous magnesium sulfate by distilling off the solvent The residue was purified by means of a silica gel chromatography (eluent, hexane:ethyl acetate=5:1)

反応条件: temp:8.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mechanically stirred mixture of methyl triphenylphosphonium bromide (169.2 g, 0.474 moles) in 350 ml of dry tetrahydrofuran was cooled to 8° C. A solution of lithium bis (trimethylsilyl) amide (84.8 g, 0.507 moles) in 500 ml tetrahydrofuran was added to the above mixture at a rate so that the temperature of the mixture remained at 23° C. After stirring for 1 hour at room temperature the contents were cooled to 31 70° C. and stirred for 1/2 hour. Then a solution of compound 4a, (2S)-2',4'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone, (100 g, 0.370 moles) in 250 ml of tetrahydrofuran was added slowly to maintain the temperature of the mixture below -70° C. The resulting mixture was stirred at 7° C. for 17 hours. Added 65 ml of ethyl acetate to the above mixture followed by the addition of 3.9 L of hexane and allowed to stand for 15 minutes. The solid was removed by suction-filtration and washed thoroughly with 650 ml of hexane. The filtrate was washed with 1:1 mixture of methanol: water (2×1300 ml) and brine (1300 ml) then dried over MgSO4. The solvent was evaporated to give the title compound 5a as an oil (91.5 g, 92%). remained at 23° C were cooled to 31 70° C. stirred for 1/2 hour to maintain the temperature of the mixture below -70° C The resulting mixture was stirred at 7° C. for 17 hours to stand for 15 minutes The solid was removed by suction-filtration washed thoroughly with 650 ml of hexane The filtrate was washed with 1:1 mixture of methanol water (2×1300 ml) and brine (1300 ml) then dried over MgSO4 The solvent was evaporated