4-bromo-2,5-difluorophenol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of tert-butyl 3-bromo-2-oxo-1,4′-bipiperidine-1′carboxylate (723 mg, 2.00 mmol) in DMF (5 mL) was added K2CO3 (553 mg, 4.00 mmol) and 4-bromo-2,5-difluorophenol (460 mg, 2.20 mmol). The reaction was heated at 60° C. overnight. The reaction was cooled and diluted with water and EtOAc. The organic layer was separated and the aqueous washed with EtOAc. The combined organic layers were dried with MgSO4 and concentrated. The crude residue was purified over silica gel (2:1 hexanes/EtOAc) to give tert-butyl 3-(4-bromo-2,5-difluorophenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (710 mg, 73%) as a white solid. The reaction was cooled The organic layer was separated the aqueous washed with EtOAc The combined organic layers were dried with MgSO4 concentrated The crude residue was purified over silica gel (2:1 hexanes/EtOAc)

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

実験手順: To 4-bromo-2,5-difluoro-phenol (41, 0.90 g, 0.0043 mol, prepared as described in Example 15, Scheme 3) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (47, 0.84 g, 65.0%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (47, 0.84 g, 65.0%)

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

実験手順: To 2,5-difluorophenol (40, 5.50 g, 0.0423 mol) in chloroform (110.0 mL), bromine (2.18 mL, 0.0423 mol) was added slowly. After 3 hours, the reaction was poured into a solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (41, 6.20 g, 70.2%). extracted with ethyl acetate The organic layer was dried over sodium sulfate concentrated purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (41, 6.20 g, 70.2%)

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

実験手順: To 2,5-difluorophenol (40, 5.50 g, 0.0423 mol) in chloroform (110.0 mL), bromine (2.18 mL, 0.0423 mol) was added slowly. After 3 hours, the reaction was poured into a solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (41, 6.20 g, 70.2%). extracted with ethyl acetate The organic layer was dried over sodium sulfate concentrated purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (41, 6.20 g, 70.2%)

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

実験手順: To 4-bromo-2,5-difluoro-phenol (595, 0.90 g, 0.0043 mol, prepared as described in Example 34, Scheme 61) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%)

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

実験手順: To 4-bromo-2,5-difluoro-phenol (595, 0.90 g, 0.0043 mol, prepared as described in Example 34, Scheme 61) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%)

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

実験手順: To 2,5-difluorophenol (594, 5.50 g, 0.0423 mol) in chloroform (110.0 mL), bromine (2.18 mL, 0.0423 mol) was added slowly. After 3 hours, the reaction was poured into a solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (595, 6.20 g, 70.2%). extracted with ethyl acetate The organic layer was dried over sodium sulfate concentrated purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (595, 6.20 g, 70.2%)

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

実験手順: To 2,5-difluorophenol (594, 5.50 g, 0.0423 mol) in chloroform (110.0 mL), bromine (2.18 mL, 0.0423 mol) was added slowly. After 3 hours, the reaction was poured into a solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (595, 6.20 g, 70.2%). extracted with ethyl acetate The organic layer was dried over sodium sulfate concentrated purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (595, 6.20 g, 70.2%)

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

実験手順: To 4-bromo-2,5-difluoro-phenol (595, 0.90 g, 0.0043 mol, prepared as described in Example 34, Scheme 61) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%)

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

実験手順: To 2,5-difluorophenol (594, 5.50 g, 0.0423 mol) in chloroform (110.0 mL), bromine (2.18 mL, 0.0423 mol) was added slowly. After 3 hours, the reaction was poured into a solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (595, 6.20 g, 70.2%). extracted with ethyl acetate The organic layer was dried over sodium sulfate concentrated purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (595, 6.20 g, 70.2%)

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 100 mL RB flask fitted with magnetic stirrer was charged with 20 mL of DMF. To the stirred solvent were added 4-Bromo-2,5-difluorophenol (2.0 g, 9.6 mmol), K2CO3 (3.98 g, 28.8 mmol) and methyl iodide (1.63 g, 11.53 mmol), stirred at 45° C. for 15 minutes under nitrogen atmosphere. The RM was quenched with water, extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as white color solid (1.2 g, yield: 56.07%). To a 100 mL RB flask fitted with magnetic stirrer The RM was quenched with water extracted with ethyl acetate (100 mL) The organic layer was washed with water (50 mL) and saturated brine solution (50 mL) The organic layer was dried over anhydrous Na2SO4 the solvent was removed under reduced pressure