1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone

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 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (6.67 g, 24.6 mmol, Intermediate 8, step a) in DMSO (6.2 mL) was treated with NaN3 (1.76 g, 27.0 mmol) and stirred under air (lightly capped) at 95° C. for 1 hour. The brownish-red opaque reaction was then cooled to room temperature on an ice bath, diluted with EtOAc (49 mL), treated with SnCl2-dihydrate (6.66 g, 29.5 mmol) in several portions over ˜30 sec followed by water (1.33 mL, 73.8 mmol), and the mixture was stirred at room temperature for 30 min. The reddish solution with heavy off-white particulates was then treated with anhydrous Na2SO4 (˜6 g; ˜40 mmol; ˜400 mmol water capacity) and stirred vigorously for a few minutes. The mixture was then filtered over a bed of Celite®, and the cloudy orange filtrate was dry load flash chromatographed (˜60 g silica gel) with a heptane to 50% DCM/heptane gradient to provide the title compound as an orange oil that crystallized upon standing. lightly capped) at 95° C. for 1 hour The brownish-red opaque reaction the mixture was stirred at room temperature for 30 min stirred vigorously for a few minutes The mixture was then filtered over a bed of Celite® the cloudy orange filtrate was dry load flash chromatographed (˜60 g silica gel) with a heptane to 50% DCM/heptane gradient

反応条件: temp:-68.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of diisopropylamine (22.1 mL, 157 mmol) in 140 mL THF was stirred under argon at −68° C. while n-BuLi (57.9 mL, 2.59 M in hexane, 150 mmol) was added in a fine stream in 2 portions over 6 min. The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath and stirred at ambient conditions for 9 min, and was then cooled back down to −68° C. and a solution of 1-bromo-4-fluorobenzene (15.6 mL, 143 mmol) in THF (30 mL) was added rapidly dropwise over 5 min. The reaction was then stirred in the cold bath for another 6 min, and the pale yellow reaction was then treated rapidly dropwise with a solution of ethyl trifluoroacetate (18.7 mL, 157 mmol) in THF (30 mL) over ˜8 min (internal temp rose to −47° C.). The pale yellow reaction was then stirred overnight as the acetone/dry ice bath expired (15 hrs). The resulting yellow homogeneous solution was washed with 5 M NH4Cl (2×50 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear dark yellow oil. was added in a fine stream in 2 portions over 6 min The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath The reaction was then stirred in the cold bath for another 6 min the pale yellow reaction The pale yellow reaction (15 hrs) The resulting yellow homogeneous solution was washed with 5 M NH4Cl (2×50 mL) the organic layer was dried (Na2SO4) filtered concentrated

反応条件: temp:-68.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of diisopropylamine (22.1 mL, 157 mmol) in 140 mL THF was stirred under argon at −68° C. while n-BuLi (57.9 mL, 2.59 M in hexane, 150 mmol) was added in a fine stream in 2 portions over 6 min. The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath and stirred at ambient conditions for 9 min, and was then cooled back down to −68° C. and a solution of 1-bromo-4-fluorobenzene (15.6 mL, 143 mmol) in THF (30 mL) was added rapidly dropwise over 5 min. The reaction was then stirred in the cold bath for another 6 min, and the pale yellow reaction was then treated rapidly dropwise with a solution of ethyl trifluoroacetate (18.7 mL, 157 mmol) in THF (30 mL) over ˜8 min (internal temp rose to −47° C.). The pale yellow reaction was then stirred overnight as the acetone/dry ice bath expired (15 hrs). The resulting yellow homogeneous solution was washed with 5 M NH4Cl (2×50 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear dark yellow oil. was added in a fine stream in 2 portions over 6 min The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath The reaction was then stirred in the cold bath for another 6 min the pale yellow reaction The pale yellow reaction (15 hrs) The resulting yellow homogeneous solution was washed with 5 M NH4Cl (2×50 mL) the organic layer was dried (Na2SO4) filtered concentrated

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

実験手順: A solution of 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (6.67 g, 24.6 mmol, Intermediate 7, step a) in DMSO (6.2 mL) was treated with NaN3 (1.76 g, 27.0 mmol) and stirred under air (lightly capped) at 95° C. for 1 hour. The brownish-red opaque reaction was then cooled to room temperature on an ice bath, diluted with EtOAc (49 mL), treated with SnCl2.dihydrate (6.66 g, 29.5 mmol) in several portions over ˜30 seconds followed by water (1.33 mL, 73.8 mmol), and the mixture was stirred at room temperature for 30 minutes. The reddish solution with heavy off-white particulates was then treated with anhydrous Na2SO4 (˜6 g) and stirred vigorously for a few minutes. The mixture was then filtered over a bed of Celite®, and the cloudy orange filtrate was dry load flash chromatographed (˜60 g silica gel) with a heptane to 50% DCM/heptane gradient to provide the title compound as an orange oil that crystallized upon standing. lightly capped) at 95° C. for 1 hour The brownish-red opaque reaction the mixture was stirred at room temperature for 30 minutes stirred vigorously for a few minutes The mixture was then filtered over a bed of Celite® the cloudy orange filtrate was dry load flash chromatographed (˜60 g silica gel) with a heptane to 50% DCM/heptane gradient

反応条件: temp:-68.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of diisopropylamine (22.1 mL, 157 mmol) in 140 mL THF was stirred under argon at −68° C. while n-BuLi (57.9 mL, 2.59 M in hexane, 150 mmol) was added in a fine stream in 2 portions over 6 minutes. The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath and stirred at ambient conditions for 9 minutes, and was then cooled back down to −68° C. and a solution of 1-bromo-4-fluorobenzene (15.6 mL, 143 mmol) in THF (30 mL) was added dropwise over 5 minutes. The reaction was then stirred in the cold bath for another 6 minutes, and the pale yellow reaction was then treated dropwise with a solution of ethyl trifluoroacetate (18.7 mL, 157 mmol) in THF (30 mL) over ˜8 minutes (internal temp rose to −47° C.). The pale yellow reaction was then stirred overnight as the acetone/dry ice bath expired (15 hours). The resulting yellow homogeneous solution was washed with 5 M aqueous NH4Cl (2×50 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear dark yellow oil. was added in a fine stream in 2 portions over 6 minutes The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath The reaction was then stirred in the cold bath for another 6 minutes the pale yellow reaction The pale yellow reaction (15 hours) The resulting yellow homogeneous solution was washed with 5 M aqueous NH4Cl (2×50 mL) the organic layer was dried (Na2SO4) filtered concentrated

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirring solution of diisopropylamine (56.4 g, 0.55 mol) in THF (500 mL) at −40° C., n-butyl lithium (200 mL, 2.66 M hexane solution) was added dropwise. The mixture was stirred at −40° C. for 1 hour and then cooled to −78° C. Then, a solution of 4-fluorobromobenzene (87.5 g, 0.50 mol) in THF (100 mL) was slowly added dropwise thereto such that the inner temperature of the reaction solution did not exceed −70° C. After the reaction solution was stirred at −78° C. for 1 hour, a solution of ethyl trifluoroacetate (65.4 mL, 0.55 mol) in THF (100 mL) was added thereto at the same temperature. After the temperature of the reaction solution was raised to 0° C. over 1 hour under stirring, a saturated aqueous ammonium chloride solution was added thereto, and the solution was diluted with ethyl acetate. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4), and the resulting yellow oily substance was purified again by distillation under reduced pressure (1 mmHg, 53° C.), whereby the objective compound (83.8 g, 61.8%) was obtained as a yellow oily substance. cooled to −78° C did not exceed −70° C After the reaction solution was stirred at −78° C. for 1 hour After the temperature of the reaction solution was raised to 0° C. over 1 hour under stirring The organic layer was separated washed with saturated brine dried over magnesium sulfate After the drying agent was removed by filtration the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) the resulting yellow oily substance was purified again by distillation under reduced pressure (1 mmHg, 53° C.), whereby the objective compound (83.8 g, 61.8%) was obtained as a yellow oily substance

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (2.20 g, 8.12 mmol) from Step 1, K2CO3 (1.68 g, 12.2 mmol), and 3-methyl-1H-pyrazole (1.33 g, 16.2 mmol) were stirred in toluene (10 mL). The reaction was then heated to 110° C. for 16 h. The reaction was cooled, and water and EtOAc were added. The toluene-EtOAc layer is removed in vacuo, and then the reaction is extracted with water and EtOAc, washed with brine, and dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-[5-bromo-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoroethanone. The reaction was cooled The toluene-EtOAc layer is removed in vacuo the reaction is extracted with water and EtOAc washed with brine dried over Na2SO4 filtered concentrated in vacuo Purification by normal phase silica gel column chromatography (EtOAc/heptane)

反応条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diisopropylamine (4.40 mL, 31.4 mmol) was dissolved in THF (28 mL) and cooled to −40° C. Then n-butyllithium (12.6 mL, 2.5 M in hexanes, 31.4 mmol) was added dropwise, and the reaction was stirred at −40° C. for 1 h, then cooled to −78° C. A solution of 1-bromo-4-fluorobenzene (5 g, 28.6 mmol) in THF (6.0 mL) was added, and the reaction was stirred at −78° C. for 1 h. Trifluoroacetic acid ethyl ester (3.73 mL, 31.4 mmol) in THF (6.0 mL) was then added, and the reaction was slowly warmed to 0° C. over an hour. The reaction was quenched with NH4Cl (aq. sat), and extracted with EtOAc, washed with brine, and dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone. cooled to −78° C the reaction was stirred at −78° C. for 1 h the reaction was slowly warmed to 0° C. over an hour The reaction was quenched with NH4Cl (aq. sat) extracted with EtOAc washed with brine dried over Na2SO4 filtered concentrated in vacuo Purification by normal phase silica gel column chromatography (EtOAc/heptane)

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

実験手順: A solution of 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (6.67 g, 24.6 mmol, Intermediate 8, step a) in DMSO (6.2 mL) was treated with NaN3 (1.76 g, 27.0 mmol) and stirred under air (lightly capped) at 95° C. for 1 hour. The brownish-red opaque reaction was then cooled to room temperature on an ice bath, diluted with EtOAc (49 mL), treated with SnCl2-dihydrate (6.66 g, 29.5 mmol) in several portions over ˜30 sec followed by water (1.33 mL, 73.8 mmol), and the mixture was stirred at room temperature for 30 min. The reddish solution with heavy off-white particulates was then treated with anhydrous Na2SO4 (˜6 g; ˜40 mmol; ˜400 mmol water capacity) and stirred vigorously for a few minutes. The mixture was then filtered over a bed of Celite®, and the cloudy orange filtrate was dry load flash chromatographed (˜60 g silica gel) with a heptane to 50% DCM/heptane gradient to provide the title compound as an orange oil that crystallized upon standing. lightly capped) at 95° C. for 1 hour The brownish-red opaque reaction the mixture was stirred at room temperature for 30 min stirred vigorously for a few minutes The mixture was then filtered over a bed of Celite® the cloudy orange filtrate was dry load flash chromatographed (˜60 g silica gel) with a heptane to 50% DCM/heptane gradient

反応条件: temp:-68.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of diisopropylamine (22.1 mL, 157 mmol) in 140 mL THF was stirred under argon at −68° C. while n-BuLi (57.9 mL, 2.59 M in hexane, 150 mmol) was added in a fine stream in 2 portions over 6 min. The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath and stirred at ambient conditions for 9 min, and was then cooled back down to −68° C. and a solution of 1-bromo-4-fluorobenzene (15.6 mL, 143 mmol) in THF (30 mL) was added rapidly dropwise over 5 min. The reaction was then stirred in the cold bath for another 6 min, and the pale yellow reaction was then treated rapidly dropwise with a solution of ethyl trifluoroacetate (18.7 mL, 157 mmol) in THF (30 mL) over ˜8 min (internal temp rose to −47° C.). The pale yellow reaction was then stirred overnight as the acetone/dry ice bath expired (15 hrs). The resulting yellow homogeneous solution was washed with 5 M NH4Cl (2×50 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the crude title compound as a clear dark yellow oil. was added in a fine stream in 2 portions over 6 min The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath The reaction was then stirred in the cold bath for another 6 min the pale yellow reaction The pale yellow reaction (15 hrs) The resulting yellow homogeneous solution was washed with 5 M NH4Cl (2×50 mL) the organic layer was dried (Na2SO4) filtered concentrated