2,2-difluoroethoxybenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under Ar protection, 5-bromo-2-chloro-benzoyl chloride 12n (37.7 g, 148.6 mmol) was dissolved in 350 mL dichloromethane and 2,2-difluoroethoxybenzene 12c (25 g, 158.6 mmol) was added and stirred until dissolved, and cooled to 0° C., followed by addition of AlCl3 (19.1 g, 142.4 mmol) in batch. The reaction mixture was stirred for 2 hours at 0° C., then poured into 300 mL ice water and stirred for 30 minutes and partitioned. The aqueous layer was extracted with dichloromethane (100 mL). The organic layer was combined and partitioned after methanol (50 mL), dichloromethane (100 mL) and water (200 mL) were added. The organic layer was washed with saturated NaCl solution (200 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5-bromo-2-chloro-phenyl)-[4-(2,2-difluoroethoxy)phenyl]methanone 12o (56 g, yellow grease), yield: 99.0%. until dissolved The reaction mixture was stirred for 2 hours at 0° C. stirred for 30 minutes partitioned The aqueous layer was extracted with dichloromethane (100 mL) partitioned after methanol (50 mL), dichloromethane (100 mL) and water (200 mL) were added The organic layer was washed with saturated NaCl solution (200 mL) dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under N2, 60% NaH (10.2 g, 254.27 mmol) and 40 mL DMF were added into a 500 mL reaction flask and cooled to 0° C. 2,2-difluoroethanol 12a (23 g, 280.3 mmol) was dissolved in 40 mL DMF and then dropwise added into the mixture within 4 hours at 0° C. The reaction mixture was then warmed to room temperature. After 30 minutes, a solution of bromobenzene (39.92 g, 254.25 mmol) in DMF (40 mL) and CuBr (0.35 g, 2.43 mmol) were added in turn before the reaction mixture was warmed and stirred for 16 hours at 160° C. Thereafter, the reaction mixture was cooled to room temperature and filtered. The filtrate was washed with n-hexane. 5% hydrochloric acid (160 mL) was added to the filtrate before the resulting residue was extracted with n-hexane (160 mL×3). The organic extract was washed with saturated sodium chloride solution (50 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 2,2-difluoroethoxybenzene 12c (32.97 g, yellow liquid), yield: 82.0%. dropwise added into the mixture within 4 hours at 0° C The reaction mixture was then warmed to room temperature was warmed Thereafter, the reaction mixture was cooled to room temperature filtered The filtrate was washed with n-hexane 5% hydrochloric acid (160 mL) was added to the filtrate before the resulting residue was extracted with n-hexane (160 mL×3) The organic extract was washed with saturated sodium chloride solution (50 mL) dried over anhydrous magnesium sulfate filtered The filtrate was concentrated under reduced pressure