4-chloro-1-(2,5-difluorophenyl)butan-1-one

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Titanium (IV) ethoxide (54.77 g, 240.13 mmol) was added to a solution of 4-chloro-1-(2,5-difluorophenyl)butan-1-one (35 g, 160.09 mmol) and (S)-2-methylpropane-2-sulfinamide (29.1 g, 240.13 mmol) in THF (400 mL) with stirring. The mixture was stirred continuously at 70° C. for 16 h. Reaction mixture was then cooled to a temperature of 20-35° C., quenched with saturated aqueous NH4Cl solution, diluted with ethylacetate and filtered. The filtrate was washed with water followed by brine solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 44.5 g of the title compound as a colorless liquid. MS (ESI): m/z 322.3 (M+H). The mixture was stirred continuously at 70° C. for 16 h Reaction mixture quenched with saturated aqueous NH4Cl solution diluted with ethylacetate filtered The filtrate was washed with water The organic layer was separated dried over anhydrous sodium sulfate concentrated under reduced pressure

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

実験手順: 2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF (50 ml) was cooled to −50° C., to it was added isopropyl magnesium chloride (2M in THF) (133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added drop wise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.60-7.53 (1H, m), 7.26-7.09 (2H, m), 3.70 (2H, t), 3.22-3.14 (2H, m), 2.28-2.16 (2H, m). The reaction mixture thus obtained The reaction mixture was cooled again to −50° C with stirring the stirring was continued at 0° C. for 1 h The reaction mixture was quenched with saturated aqueous NH4Cl solution extracted with ethylacetate The organic layer collected was washed with water (500 mL) with brine solution, dried over anhydrous sodium sulfate concentrated under reduced pressure to afford a crude liquid residue The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent)

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Titanium (IV) ethoxide (54.77 g, 240.13 mmol) was added to a solution of 4-chloro-1-(2,5-difluorophenyl)butan-1-one (35 g, 160.09 mmol) and (S)-2-methylpropane-2-sulfinamide (29.1 g, 240.13 mmol) in THF (400 mL) with stirring. The mixture was stirred continuously at 70° C. for 16 h. Reaction mixture was then cooled to a temperature of 20-35° C., quenched with saturated aqueous NH4Cl solution, diluted with ethylacetate and filtered. The filtrate was washed with water followed by brine solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 44.5 g of the title compound as a colourless liquid. The mixture was stirred continuously at 70° C. for 16 h Reaction mixture quenched with saturated aqueous NH4Cl solution diluted with ethylacetate filtered The filtrate was washed with water The organic layer was separated dried over anhydrous sodium sulfate concentrated under reduced pressure

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

実験手順: 2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF)(133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. The reaction mixture thus obtained The reaction mixture was cooled again to −50° C with stirring the stirring was continued at 0° C. for 1 h The reaction mixture was quenched with saturated aqueous NH4Cl solution extracted with ethylacetate The organic layer collected was washed with water (500 mL) with brine solution, dried over anhydrous sodium sulfate concentrated under reduced pressure to afford a crude liquid residue The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent)

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

実験手順: 2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF)(133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. The reaction mixture thus obtained The reaction mixture was cooled again to −50° C with stirring the stirring was continued at 0° C. for 1 h The reaction mixture was quenched with saturated aqueous NH4Cl solution extracted with ethylacetate The organic layer collected was washed with water (500 mL) with brine solution, dried over anhydrous sodium sulfate concentrated under reduced pressure to afford a crude liquid residue The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent)

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Titanium (IV) ethoxide (54.77 g, 240.13 mmol) was added to a solution of 4-chloro-1-(2,5-difluorophenyl)butan-1-one (35 g, 160.09 mmol) and (S)-2-methylpropane-2-sulfinamide (29.1 g, 240.13 mmol) in THF (400 mL) with stirring. The mixture was stirred continuously at 70° C. for 16 h. Reaction mixture was then cooled to a temperature of 20-35° C., quenched with saturated aqueous NH4Cl solution, diluted with ethylacetate and filtered. The filtrate was washed with water followed by brine solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 44.5 g of the title compound as a colourless liquid. The mixture was stirred continuously at 70° C. for 16 h Reaction mixture quenched with saturated aqueous NH4Cl solution diluted with ethylacetate filtered The filtrate was washed with water The organic layer was separated dried over anhydrous sodium sulfate concentrated under reduced pressure

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

実験手順: 2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF)(133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. The reaction mixture thus obtained The reaction mixture was cooled again to −50° C with stirring the stirring was continued at 0° C. for 1 h The reaction mixture was quenched with saturated aqueous NH4Cl solution extracted with ethylacetate The organic layer collected was washed with water (500 mL) with brine solution, dried over anhydrous sodium sulfate concentrated under reduced pressure to afford a crude liquid residue The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent)

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Titanium (IV) ethoxide (54.77 g, 240.13 mmol) was added to a solution of 4-chloro-1-(2,5-difluorophenyl)butan-1-one (35 g, 160.09 mmol) and (S)-2-methylpropane-2-sulfinamide (29.1 g, 240.13 mmol) in THF (400 mL) with stirring. The mixture was stirred continuously at 70° C. for 16 h. Reaction mixture was then cooled to a temperature of 20-35° C., quenched with saturated aqueous NH4Cl solution, diluted with ethylacetate and filtered. The filtrate was washed with water followed by brine solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 44.5 g of the title compound as a colourless liquid. The mixture was stirred continuously at 70° C. for 16 h Reaction mixture quenched with saturated aqueous NH4Cl solution diluted with ethylacetate filtered The filtrate was washed with water The organic layer was separated dried over anhydrous sodium sulfate concentrated under reduced pressure

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

実験手順: 2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF) (133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. The reaction mixture thus obtained The reaction mixture was cooled again to −50° C with stirring the stirring was continued at 0° C. for 1 h The reaction mixture was quenched with saturated aqueous NH4Cl solution extracted with ethylacetate The organic layer collected was washed with water (500 mL) with brine solution, dried over anhydrous sodium sulfate concentrated under reduced pressure to afford a crude liquid residue The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent)

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Titanium (IV) ethoxide (54.77 g, 240.13 mmol) was added to a solution of 4-chloro-1-(2,5-difluorophenyl)butan-1-one (35 g, 160.09 mmol) and (S)-2-methylpropane-2-sulfinamide (29.1 g, 240.13 mmol) in THF (400 mL) with stirring. The mixture was stirred continuously at 70° C. for 16 h. Reaction mixture was then cooled to a temperature of 20-35° C., quenched with saturated aqueous NH4Cl solution, diluted with ethylacetate and filtered. The filtrate was washed with water followed by brine solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 44.5 g of the title compound as a colourless liquid. The mixture was stirred continuously at 70° C. for 16 h Reaction mixture quenched with saturated aqueous NH4Cl solution diluted with ethylacetate filtered The filtrate was washed with water The organic layer was separated dried over anhydrous sodium sulfate concentrated under reduced pressure

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

実験手順: 2-Bromo-1,4-difluorobenzene (53.6 g, 277.74 mmol) in THF cooled to −50° C. was added to isopropyl magnesium chloride (2M in THF) (133 mL, 266 mmol). The reaction mixture thus obtained was warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled again to −50° C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200 mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with ethylacetate. The organic layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent) to afford 35 g of the title compound as a colourless liquid. The reaction mixture thus obtained The reaction mixture was cooled again to −50° C with stirring the stirring was continued at 0° C. for 1 h The reaction mixture was quenched with saturated aqueous NH4Cl solution extracted with ethylacetate The organic layer collected was washed with water (500 mL) with brine solution, dried over anhydrous sodium sulfate concentrated under reduced pressure to afford a crude liquid residue The residue thus obtained was purified by column chromatography (using 60-120 silica gel and 5% EtOAc in Hexane as eluent)

反応条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Titanium (IV) ethoxide (54.77 g, 240.13 mmol) was added to a solution of 4-chloro-1-(2,5-difluorophenyl)butan-1-one (35 g, 160.09 mmol) and (S)-2-methylpropane-2-sulfinamide (29.1 g, 240.13 mmol) in THF (400 mL) with stirring. The mixture was stirred continuously at 70° C. for 16 h. Reaction mixture was then cooled to a temperature of 20-35° C., quenched with saturated aqueous NH4Cl solution, diluted with ethylacetate and filtered. The filtrate was washed with water followed by brine solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 44.5 g of the title compound as a colorless liquid. MS (ESI): m/z 322.3 (M+H). The mixture was stirred continuously at 70° C. for 16 h Reaction mixture quenched with saturated aqueous NH4Cl solution diluted with ethylacetate filtered The filtrate was washed with water The organic layer was separated dried over anhydrous sodium sulfate concentrated under reduced pressure