(2R)-1-(2,4-二氟苯基)-2-((四氢-2H-吡喃-2-基)氧基)丙-1-酮

反应条件: temp:8.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mechanically stirred mixture of methyl triphenylphosphonium bromide (84.6 g, 0.237 moles) in 175 ml of dry tetrahydrofuran was cooled to 8° C. A solution of lithium bis (trimethylsilyl)amide (42.4 g, 0.253 moles) in 250 ml tetrahydrofuran was added to the above mixture at a rate so that the temperature of the mixture remained 23° C. After stirring for 1 hour at room temperature the contents were cooled to -70° C. and stirred for 1/2 hour. Added a solution of compound 4b, (2R)-2',4'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (50 g, 0.185 moles) in 125 ml of tetrahydrofuran slowly to maintain the temperature of the mixture below -70° C. The resulting mixture was stirred at 7° C. for 60 hours. Added 33 ml of ethyl acetate to the above mixture followed by the addition of 2 L of hexane and allowed to stand for 15 minutes. The solid was removed by suction-filtration and washed thoroughly with 325 ml of hexane. The filtrate was washed with 1:1 mixture of methanol : water (2×650 ml) and brine (650 ml) and dried over MgSO4. The solvent was evaporated to give the title compound 5b as an oil (47.7 g, 96%). remained 23° C were cooled to -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 60 hours to stand for 15 minutes The solid was removed by suction-filtration washed thoroughly with 325 ml of hexane The filtrate was washed with 1:1 mixture of methanol water (2×650 ml) and brine (650 ml) and dried over MgSO4 The solvent was evaporated

反应条件: temp:8.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mechanically stirred mixture of methyl triphenylphosphonium bromide (84.6 g, 0.237 moles) in 175 ml of dry tetrahydrofuran was cooled to 8° C. A solution of lithium bis (trimethylsilyl)amide (42.4 g, 0.253 moles) in 250 ml tetrahydrofuran was added to the above mixture at a rate so that the temperature of the mixture remained 23° C. After stirring for 1 hour at room temperature the contents were cooled to -70° C. and stirred for 1/2 hour. Added a solution of compound 4b, (2R)-2',4'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (50 g, 0.185 moles) in 125 ml of tetrahydrofuran slowly to maintain the temperature of the mixture below -70° C. The resulting mixture was stirred at 7° C. for 60 hours. Added 33 ml of ethyl acetate to the above mixture followed by the addition of 2 L of hexane and allowed to stand for 15 minutes. The solid was removed by suction-filtration and washed thoroughly with 325 ml of hexane. The filtrate was washed with 1:1 mixture of methanol : water (2×650 ml) and brine (650 ml) and dried over MgSO4. The solvent was evaporated to give the title compound 5b as an oil (47.7 g, 96%). remained 23° C were cooled to -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 60 hours to stand for 15 minutes The solid was removed by suction-filtration washed thoroughly with 325 ml of hexane The filtrate was washed with 1:1 mixture of methanol water (2×650 ml) and brine (650 ml) and dried over MgSO4 The solvent was evaporated

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (2R)-2′,4′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (9.62 g, 35.6 mmol, synthesized according to the description in Chem. Pharm. Bull., Vol. 41(6), 1035-1042 (1993)) was dissolved in ethanol (99.5%, 50 mL), and pyridinium p-toluenesulfonate (0.89 g, 3.6 mmol) was added. The mixture was stirred at 50-60° C. for 1 hr. After cooling, the reaction mixture was concentrated under reduced pressure to about 10 mL. Water (20 mL) was flown in and the mixture was extracted twice with ethyl acetate (50 mL). The layers extracted with ethyl acetate were mixed, washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. After filtration, the filtrate (ethyl acetate solution) was concentrated. The obtained concentrate (about 9.5 g) was subjected to silica gel column chromatography (SiO2, 30 g) and eluted with n-heptane—ethyl acetate (10:1→5:1). The objective fraction was concentrated to give the title compound as a pale-yellow oil (6.00 g, yield: 91%). After cooling the reaction mixture was concentrated under reduced pressure to about 10 mL was extracted twice with ethyl acetate (50 mL) The layers extracted with ethyl acetate were mixed washed with saturated brine (20 mL) dried over anhydrous magnesium sulfate After filtration the filtrate (ethyl acetate solution) was concentrated The obtained concentrate (about 9.5 g) eluted with n-heptane—ethyl acetate (10:1→5:1) The objective fraction was concentrated

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To dimethyl sulfoxide (50 ml) was added 60% sodium hydride (0.833 g) in mineral oil. While stirring the mixture at about 15° C., trimethylsulfoxonium iodide (4.80 g) was added thereto, which was stirred for 15 minutes at room temperature. The reaction mixture was cooled with ice, to which was added a dimethyl sulfoxide solution (10 ml) of (2R)-2',4'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (4.90 g). The resultant mixture was stirred for two hours at room temperature. The reaction mixture was poured into ice-water (120 ml), followed by extraction with ethyl acetate (150 ml, 100 ml, 100ml). Ethyl acetate layers were combined and washed with water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml), followed by drying 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-[(1R)-1-(3,4,5,6 -tetrahydro-2H-pyran-2-yloxy)ethyl]-2-(2,4-difluorophenyl)oxirane (4.70 g) as a pale yellow oily product. which was stirred for 15 minutes at room temperature The reaction mixture was cooled with ice, to which followed by extraction with ethyl acetate (150 ml, 100 ml, 100ml) washed with water (50 ml) by drying 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)

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In ethanol (3 ml) was dissolved (2R)-2',4'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (121 mg), to which was added pyridinium p-toluenesulfonate (25 mg), and the mixture was stirred for one hour at 55° C. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml). The solution was washed with water and 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 (2R)-2',4'-difluoro-2-hydroxypropiophenone (62 mg) as a pale yellow oily product. [α]D +68.7 (c=1.8 in chloroform) The solvent was distilled off under reduced pressure the residue was dissolved in ethyl acetate (20 ml) The solution was washed with water 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)

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (2R)-2′,4′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (9.62 g, 35.6 mmol, synthesized according to the description in Chem. Pharm. Bull., Vol. 41(6), 1035-1042 (1993)) was dissolved in ethanol (99.5%, 50 mL), and pyridinium p-toluenesulfonate (0.89 g, 3.6 mmol) was added. The mixture was stirred at 50-60° C. for 1 hr. After cooling, the reaction mixture was concentrated under reduced pressure to about 10 mL. Water (20 mL) was flown in and the mixture was extracted twice with ethyl acetate (50 mL). The layers extracted with ethyl acetate were mixed, washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. After filtration, the filtrate (ethyl acetate solution) was concentrated. The obtained concentrate (about 9.5 g) was subjected to silica gel column chromatography (SiO2, 30 g) and eluted with n-heptane-ethyl acetate (10:1→5:1). The objective fraction was concentrated to give the title compound as a pale-yellow oil (6.00 g, yield: 91%). After cooling the reaction mixture was concentrated under reduced pressure to about 10 mL was extracted twice with ethyl acetate (50 mL) The layers extracted with ethyl acetate were mixed washed with saturated brine (20 mL) dried over anhydrous magnesium sulfate After filtration the filtrate (ethyl acetate solution) was concentrated The obtained concentrate (about 9.5 g) eluted with n-heptane-ethyl acetate (10:1→5:1) The objective fraction was concentrated

反应条件: temp:8.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mechanically stirred mixture of methyl triphenylphosphonium bromide (84.6 g, 0.237 moles) in 175 ml of dry tetrahydrofuran was cooled to 8° C. A solution of lithium bis (trimethylsilyl)amide (42.4 g, 0.253 moles) in 250 ml tetrahydrofuran was added to the above mixture at a rate so that the temperature of the mixture remained 23° C. After stirring for 1 hour at room temperature the contents were cooled to -70° C. and stirred for 1/2 hour. Added a solution of compound 4b, (2R)-2',4'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (50 g, 0.185 moles) in 125 ml of tetrahydrofuran slowly to maintain the temperature of the mixture below -70° C. The resulting mixture was stirred at 7° C. for 60 hours. Added 33 ml of ethyl acetate to the above mixture followed by the addition of 2 L of hexane and allowed to stand for 15 minutes. The solid was removed by suction-filtration and washed thoroughly with 325 ml of hexane. The filtrate was washed with 1:1 mixture of methanol : water (2×650 ml) and brine (650 ml) and dried over MgSO4. The solvent was evaporated to give the title compound 5b as an oil (47.7 g, 96%). remained 23° C were cooled to -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 60 hours to stand for 15 minutes The solid was removed by suction-filtration washed thoroughly with 325 ml of hexane The filtrate was washed with 1:1 mixture of methanol water (2×650 ml) and brine (650 ml) and dried over MgSO4 The solvent was evaporated