1-(4-bromo-2-fluorophenyl)-3-chloropropan-1-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of sodium chloride (333 g, 5.69 mol) and aluminum trichloride (1270 g, 9.52 mol) was added to 144c (210 g, 0.79 mol) in several portions at 130° C. See FIG. 3. The neat reaction mixture was then stirred at 180° C. After 5 h the reaction mixture was poured into a stirred solution of ice water (1000 mL) and concentrated HCl (100 mL). The quenched reaction was stirred for 40 min and then extracted with DCM (4000 mL×3). The combined organic phase was washed with saturated NaHCO3 solution (1000 mL), brine (2000 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=50/1, 10/1) to afford 55.0 g (30.4%) of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one 144d. 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.10-7.12 (d, J=8.4 Hz, 1H), 3.04-3.10 (m, 2H), 2.50-2.66 (m, 2H). The quenched reaction was stirred for 40 min extracted with DCM (4000 mL×3) The combined organic phase was washed with saturated NaHCO3 solution (1000 mL), brine (2000 mL×2) dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel chromatography (PE/EA=50/1, 10/1)

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

実験手順: To a stirred suspension of aluminum trichloride (153 g, 1.15 mol) in DCE (1000 mL) was added a solution of 144b (271 g, 1.14 mol) in DCE (1000 mL) at 0° C. See FIG. 3. Ethylene gas was bubbled through the dark suspension for 3 h until the acid chloride was consumed. The reaction mixture was then stirred at RT overnight, cooled to 0° C., and quenched with 4M HCl (500 mL). The organic phase was separated and washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by column chromatography (PE/EA=30 to 10:1) to give 1-(4-bromo-2-fluorophenyl)-3-chloropropan-1-one 144c (210 g, 68%). Ethylene gas was bubbled through the dark suspension for 3 h until the acid chloride was consumed cooled to 0° C. quenched with 4M HCl (500 mL) The organic phase was separated washed with brine (100 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The crude residue was purified by column chromatography (PE/EA=30 to 10:1)

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

実験手順: To a stirred suspension of aluminum trichloride (153 g, 1.15 mol) in DCE (1000 mL) was added a solution of 144b (271 g, 1.14 mol) in DCE (1000 mL) at 0° C. See FIG. 3. Ethylene gas was bubbled through the dark suspension for 3 h until the acid chloride was consumed. The reaction mixture was then stirred at RT overnight, cooled to 0° C., and quenched with 4M HCl (500 mL). The organic phase was separated and washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by column chromatography (PE/EA=30 to 10:1) to give 1-(4-bromo-2-fluorophenyl)-3-chloropropan-1-one 144c (210 g, 68%). Ethylene gas was bubbled through the dark suspension for 3 h until the acid chloride was consumed cooled to 0° C. quenched with 4M HCl (500 mL) The organic phase was separated washed with brine (100 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The crude residue was purified by column chromatography (PE/EA=30 to 10:1)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(4-Bromo-2-fluoro-phenyl)-3-chloro-propan-1-one (27.45 g, 103 mmol) was added to a slurry of aluminum chloride (164 g, 1.23 mol) and sodium chloride (43.19 g, 0.739 mol) at 130° C. The mixture was stirred with a mechanical stirrer and heated to 180° C. for 6 hours. The whole mixture was quenched with ice and concentrated hydrochloric solution (122 ml, 1.24 mol). The resulting mixture was extracted with dichloromethane. The organic phase was washed with water, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and filtered. After concentrating under reduced pressure, purification by silica gel chromatography afforded 5-Bromo-7-fluoro-indan-1-one (5 g, 21.8 mmol). The whole mixture was quenched with ice The resulting mixture was extracted with dichloromethane The organic phase was washed with water, saturated sodium bicarbonate solution and brine dried over sodium sulfate filtered After concentrating under reduced pressure, purification by silica gel chromatography

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

実験手順: A solution of 4-Bromo-2-fluoro-benzoyl chloride (26.79 g, 113 mmol) in dichloroethane was added to a stirred suspension of aluminum chloride (15 g, 113 mmol)in dichloroethane at room temperature. The suspension turned into a dark solution after adding the acid chloride. The temperature was maintained by an ice-bath. Ethylene gas was bubbled through the reaction mixture for 3 hours until the acid chloride was consumed. The reaction mixture was stirred over night at room temperature. The reaction mixture was cooled to 0° C. and quenched with a 4 M hydrochloric acid solution (34 ml, 134 mmol). The organic phase was separated and the water phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and filtered. After concentrating under reduced pressure, crude 1-(4-Bromo-2-fluoro-phenyl)-3-chloro-propan-1-one (27.45 g, 103 mmol) was obtained which was carried over to the next step. The temperature was maintained by an ice-bath Ethylene gas was bubbled through the reaction mixture for 3 hours until the acid chloride was consumed The reaction mixture was cooled to 0° C. The organic phase was separated the water phase was extracted with dichloromethane The combined organic phases were washed with water, saturated sodium bicarbonate solution and brine dried over sodium sulfate filtered After concentrating under reduced pressure

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of AlCl3 (37.5 g, 282.48 mmol) and NaCl (11 g, 188.32 mmol) was added 1-(4-bromo-2-fluoro-phenyl)-3-chloro-propan-1-one (5 g, 18.83 mmol) at 130° C. The reaction temperature was slowly increased to 180° C. and kept for 1 hour. It was cooled, the mixture was poured into ice and extracted twice with ethyl acetate (2×100 ml). The combined ethyl acetate phases were dried over Na2SO4 and evaporated to get the crude product which was purified by column chromatography (silica gel, 5-10% ethyl acetate/hexane) to give 2.4 g (55%) of the title compound as brown solid. MS: 229.2 (MH+, 1Br). It was cooled the mixture was poured into ice extracted twice with ethyl acetate (2×100 ml) The combined ethyl acetate phases were dried over Na2SO4 evaporated to get the crude product which was purified by column chromatography (silica gel, 5-10% ethyl acetate/hexane)

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

実験手順: To a suspension of 4-bromo-2-fluoro-benzoic acid (10 g, 45.65 mmol) in benzene (50 ml) was added thionyl chloride (7.8 ml, 12.79 g, 91.32 mmol) and the resulting mixture was heated to reflux for 12 hours. Thionyl chloride was evaporated, the reaction mixture was diluted with 1,2-dichloroethane (50 ml) and added to a slurry of aluminum chloride (5.7 g, 42.53 mmol) in 1,2 dichloroethane (50 ml) at room temperature. Ethylene was bubbled through the reaction mixture for 5 hours and the reaction mixture was stirred for another 2 hours at room temperature. It was then quenched with 2N HCl (50 ml). The layers were separated. The aqueous phase was extracted twice with 100 ml dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate solution (50 ml) followed by water (50 ml). It was then dried over Na2SO4 and evaporated under reduced pressure to get the crude product, which was purified subsequently by column chromatography (silica gel, 0-5% ethyl acetate/hexane) to afford 8.6 g (71%) of the title compound as reddish solid. the resulting mixture was heated to reflux for 12 hours Thionyl chloride was evaporated the reaction mixture was diluted with 1,2-dichloroethane (50 ml) Ethylene was bubbled through the reaction mixture for 5 hours It was then quenched with 2N HCl (50 ml) The layers were separated The aqueous phase was extracted twice with 100 ml dichloromethane The combined organic phases were washed with saturated sodium bicarbonate solution (50 ml) It was then dried over Na2SO4 evaporated under reduced pressure to get the crude product, which was purified subsequently by column chromatography (silica gel, 0-5% ethyl acetate/hexane)

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of sodium chloride (333 g, 5.69 mol) and aluminum trichloride (1270 g, 9.52 mol) was added to 144c (210 g, 0.79 mol) in several portions at 130° C. See FIG. 3. The neat reaction mixture was then stirred at 180° C. After 5 h the reaction mixture was poured into a stirred solution of ice water (1000 mL) and concentrated HCl (100 mL). The quenched reaction was stirred for 40 min and then extracted with DCM (4000 mL×3). The combined organic phase was washed with saturated NaHCO3 solution (1000 mL), brine (2000 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=50/1, 10/1) to afford 55.0 g (30.4%) of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one 144d. 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.10-7.12 (d, J=8.4 Hz, 1H), 3.04-3.10 (m, 2H), 2.50-2.66 (m, 2H). The quenched reaction was stirred for 40 min extracted with DCM (4000 mL×3) The combined organic phase was washed with saturated NaHCO3 solution (1000 mL), brine (2000 mL×2) dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel chromatography (PE/EA=50/1, 10/1)

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

実験手順: To a stirred suspension of aluminum trichloride (153 g, 1.15 mol) in DCE (1000 mL) was added a solution of 144b (271 g, 1.14 mol) in DCE (1000 mL) at 0° C. See FIG. 3. Ethylene gas was bubbled through the dark suspension for 3 h until the acid chloride was consumed. The reaction mixture was then stirred at RT overnight, cooled to 0° C., and quenched with 4M HCl (500 mL). The organic phase was separated and washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by column chromatography (PE/EA=30 to 10:1) to give 1-(4-bromo-2-fluorophenyl)-3-chloropropan-1-one 144c (210 g, 68%). Ethylene gas was bubbled through the dark suspension for 3 h until the acid chloride was consumed cooled to 0° C. quenched with 4M HCl (500 mL) The organic phase was separated washed with brine (100 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The crude residue was purified by column chromatography (PE/EA=30 to 10:1)