1,3-dichloro-5-fluorobenzene

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

実験手順: Bromine (0.6 mol) is added to a mixture of 1,3-dichloro-5-fluorobenzene (0.6 mol) and ferrous powder within 2 hours. The brown reaction mixture is stirred 16 hours at room temperature and subsequently washed with dichloromethane and water. The organic layer is separated, washed with sodium hydrogen carbonate solution and dried with anhydrous sodium sulphate. The solvent is evaporated under reduced pressure. The raw product is recrystallized in ethanol to yield 61 g of the product as a white powder having a melting point of 83° C. subsequently washed with dichloromethane and water The organic layer is separated washed with sodium hydrogen carbonate solution dried with anhydrous sodium sulphate The solvent is evaporated under reduced pressure The raw product is recrystallized in ethanol

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of n-BuLi (4.8 mL, 12 mmol, 2.5 M solution in hexane) was added to THF (50 mL) at −78° C. under nitrogen, followed by the addition of 1.0 M KOtBu in THF (12 mL, 12 mmol). The mixture was stirred at −78° C. for 30 min, then 3,5-dichlorofluorobenzene (1.65 g, 10.0 mmol) in THF (5 mL) was added slowly, and the resulting mixture was stirred at this temperature for 30 min. Then a solution of acetaldehyde (0.88 g, 20 mmol) in THF (5 mL) was added. The mixture was slowly warmed to rt. The mixture was quenched with water (10 mL), and diluted with EtOAc (50 mL). The organic phase was separated, washed with brine (10 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (Hex:EtOAc=95:5→90:10) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ=1.62 (d, J=6.8 Hz, 3H), 2.30 (br s, 1H, —OH), 5.35 (q, J=6.8 Hz, 1H), 7.05 (dd, J=10.6, 2.0 Hz, 1H), 7.20 (m, 1H). the resulting mixture was stirred at this temperature for 30 min The mixture was slowly warmed to rt The mixture was quenched with water (10 mL) diluted with EtOAc (50 mL) The organic phase was separated washed with brine (10 mL) dried over anhydrous sodium sulfate The crude material was purified by silica gel chromatography (Hex:EtOAc=95:5→90:10)

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

実験手順: (R)-3-(S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (2.0 g, 7.2 mmol) was dissolved in anhydrous DMF (10 mL, 100 mmol). Lithium hydride (86 mg, 11 mmol) was added in 3 separate portions. The mixture was stirred at room temperature for 15 minutes. Into the mixture was added 3,5-dichlorofluorobenzene (1.7 mL, 14 mmol), and the resultant mixture stirred at room temperature for 15 minutes. The mixture was then stirred at 70° C. overnight. The mixture was cooled to room temperature, and EtOAc (80 mL) and 1M HCl (50 mL) were added. After mixing, the phases were separated and the organic layer was washed with diluted aqueous NaCl (1×50 mL), dried over Na2SO4, and concentrated to dryness to yield 3.5 g of crude product. Into the crude product was added 25 mL cold HCl in an EtOH/EtOAc solution and stirred at room temperature for 3 hours. Most of the solvent was removed by rotary evaporation, EtOAc was added (50 mL) and most of the solvent was removed again. Recrystallization and reslurry from EtOAc (20 mL) gave (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine as an HCl salt (2 g, ˜99% purity). separate portions The mixture was then stirred at 70° C. overnight The mixture was cooled to room temperature After mixing the phases were separated the organic layer was washed with diluted aqueous NaCl (1×50 mL) dried over Na2SO4 concentrated to dryness to yield 3.5 g of crude product stirred at room temperature for 3 hours Most of the solvent was removed by rotary evaporation, EtOAc was added (50 mL) most of the solvent was removed again Recrystallization

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

実験手順: (R)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 g, 36.0 mmol) was dissolved in anhydrous DMF (65 mL, 840 mmol). Washed and dried sodium hydride (1.0 g, 43 mmol) was added, and the mixture stirred at room temperature for 15 minutes. 3,5-Dichlorofluorobenzene (10 mL, 80 mmol) was then added, and the mixture stirred at 70° C. for 3 hours. The mixture was cooled to room temperature. EtOAc (200 mL) and 1M HCl (200 mL) was added, mixed, and the phases separated. The organic layer was washed with 2×200 mL of diluted aqueous NaCl, dried over Na2SO4, and concentrated to dryness to yield 19 g of crude product. The crude product was purified on a 300 g SiG column to yield (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester as a white sticky foam (14.1 g, 91.67% purity). Washed the mixture stirred at 70° C. for 3 hours The mixture was cooled to room temperature mixed the phases separated The organic layer was washed with 2×200 mL of diluted aqueous NaCl dried over Na2SO4 concentrated to dryness to yield 19 g of crude product The crude product was purified on a 300 g SiG column

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

実験手順: (R)-3-(S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (2.0 g, 7.2 mmol) was dissolved in anhydrous DMF (10 mL, 100 mmol). Lithium hydride (86 mg, 11 mmol) was added in 3 separate portions. The mixture was stirred at room temperature for 15 minutes. Into the mixture was added 3,5-dichlorofluorobenzene (1.7 mL, 14 mmol), and the resultant mixture stirred at room temperature for 15 minutes. The mixture was then stirred at 70° C. overnight. The mixture was cooled to room temperature, and EtOAc (80 mL) and 1M HCl (50 mL) were added. After mixing, the phases were separated and the organic layer was washed with diluted aqueous NaCl (1×50 mL), dried over Na2SO4, and concentrated to dryness to yield 3.5 g of crude product. Into the crude product was added 25 mL cold HCl in an EtOH/EtOAc solution and stirred at room temperature for 3 hours. Most of the solvent was removed by rotary evaporation, EtOAc was added (50 mL) and most of the solvent was removed again. Recrystallization and reslurry from EtOAc (20 mL) gave (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine as an HCl salt (2 g, ˜99% purity). separate portions The mixture was then stirred at 70° C. overnight The mixture was cooled to room temperature After mixing the phases were separated the organic layer was washed with diluted aqueous NaCl (1×50 mL) dried over Na2SO4 concentrated to dryness to yield 3.5 g of crude product stirred at room temperature for 3 hours Most of the solvent was removed by rotary evaporation, EtOAc was added (50 mL) most of the solvent was removed again Recrystallization

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

実験手順: (R)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 g, 36.0 mmol) was dissolved in anhydrous DMF (65 mL, 840 mmol). Washed and dried sodium hydride (1.0 g, 43 mmol) was added, and the mixture stirred at room temperature for 15 minutes. 3,5-Dichlorofluorobenzene (10 mL, 80 mmol) was then added, and the mixture stirred at 70° C. for 3 hours. The mixture was cooled to room temperature. EtOAc (200 mL) and 1M HCl (200 mL) was added, mixed, and the phases separated. The organic layer was washed with 2×200 mL of diluted aqueous NaCl, dried over Na2SO4, and concentrated to dryness to yield 19 g of crude product. The crude product was purified on a 300 g SiG column to yield (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester as a white sticky foam (14.1 g, 91.67% purity). Washed the mixture stirred at 70° C. for 3 hours The mixture was cooled to room temperature mixed the phases separated The organic layer was washed with 2×200 mL of diluted aqueous NaCl dried over Na2SO4 concentrated to dryness to yield 19 g of crude product The crude product was purified on a 300 g SiG column

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

実験手順: (R)-3-(S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (2.0 g, 7.2 mmol) was dissolved in anhydrous DMF (10 mL, 100 mmol). Lithium hydride (86 mg, 11 mmol) was added in 3 separate portions. The mixture was stirred at room temperature for 15 minutes. Into the mixture was added 3,5-dichlorofluorobenzene (1.7 mL, 14 mmol), and the resultant mixture stirred at room temperature for 15 minutes. The mixture was then stirred at 70° C. overnight. The mixture was cooled to room temperature, and EtOAc (80 mL) and 1M HCl (50 mL) were added. After mixing, the phases were separated and the organic layer was washed with diluted aqueous NaCl (1×50 mL), dried over Na2SO4, and concentrated to dryness to yield 3.5 g of crude product. Into the crude product was added 25 mL cold HCl in an EtOH/EtOAc solution and stirred at room temperature for 3 hours. Most of the solvent was removed by rotary evaporation, EtOAc was added (50 mL) and most of the solvent was removed again. Recrystallization and reslurry from EtOAc (20 mL) gave (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine as an HCl salt (2 g, ˜99% purity). separate portions The mixture was then stirred at 70° C. overnight The mixture was cooled to room temperature After mixing the phases were separated the organic layer was washed with diluted aqueous NaCl (1×50 mL) dried over Na2SO4 concentrated to dryness to yield 3.5 g of crude product stirred at room temperature for 3 hours Most of the solvent was removed by rotary evaporation, EtOAc was added (50 mL) most of the solvent was removed again Recrystallization

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

実験手順: (R)-3-((S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 g, 36.0 mmol) was dissolved in anhydrous DMF (65 mL, 840 mmol). Washed and dried sodium hydride (1.0 g, 43 mmol) was added, and the mixture stirred at room temperature for 15 minutes. 3,5-Dichlorofluorobenzene (10 mL, 80 mmol) was then added, and the mixture stirred at 70° C. for 3 hours. The mixture was cooled to room temperature. EtOAc (200 mL) and 1M HCl (200 mL) was added, mixed, and the phases separated. The organic layer was washed with 2×200 mL of diluted aqueous NaCl, dried over Na2SO4, and concentrated to dryness to yield 19 g of crude product. The crude product was purified on a 300 g SiG column to yield (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester as a white sticky foam (14.1 g, 91.67% purity). Washed the mixture stirred at 70° C. for 3 hours The mixture was cooled to room temperature mixed the phases separated The organic layer was washed with 2×200 mL of diluted aqueous NaCl dried over Na2SO4 concentrated to dryness to yield 19 g of crude product The crude product was purified on a 300 g SiG column

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

実験手順: A solution of 2.5 M n-butyllithium in hexane (8.72 mL, 21.8 mmol) was added to anhydrous THF (100 mL) at −78° C. under nitrogen with stirring, followed by the addition of 1.0 M potassium t-butyloxide in THF (21.81 mL, 21.8 mmol). The reaction mixture was stirred at −78° C. for 30 min, then 3,5-dichlorofluorobenzene (3.0 g, 18.2 mmol) was added over 10 min and the mixture was stirred at −78° C. for 40 minutes. Carbon dioxide gas was then bubbled into the reaction mixture for 10 min The reaction mixture was allowed to come to RT, diluted with ether (100 mL), extracted with a solution of aqueous 1.0 M sodium hydroxide (2×50 mL). The combined sodium hydroxide extract was washed with ether (100 mL). The sodium hydroxide layer was then acidified to pH 3 with a solution of aqueous concentrated HCl, extracted with ethyl acetate (2×50 mL). The combined ethyl acetate layers were dried over sodium sulfate and concentrated. The crude product was purified by ISCO flash chromatography (silica gel/hexane-ethyl acetate 100:0 to 0:100 gradient) to afford the title compound as a brown solid (1.34 g, 35% yield). The reaction mixture was stirred at −78° C. for 30 min the mixture was stirred at −78° C. for 40 minutes Carbon dioxide gas was then bubbled into the reaction mixture for 10 min The reaction mixture to come to RT diluted with ether (100 mL) extracted with a solution of aqueous 1.0 M sodium hydroxide (2×50 mL) The combined sodium hydroxide extract was washed with ether (100 mL) extracted with ethyl acetate (2×50 mL) The combined ethyl acetate layers were dried over sodium sulfate concentrated The crude product was purified by ISCO flash chromatography (silica gel/hexane-ethyl acetate 100:0 to 0:100 gradient)

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

実験手順: Bromine (0.6 mol) is added to a mixture of 1,3-dichloro-5-fluorobenzene (0.6 mol) and ferrous powder within 2 hours. The brown reaction mixture is stirred 16 hours at room temperature and subsequently washed with dichloromethane and water. The organic layer is separated, washed with sodium hydrogen carbonate solution and dried with anhydrous sodium sulphate. The solvent is evaporated under reduced pressure. The raw product is recrystallized in ethanol to yield 61 g of the product as a white powder having a melting point of 83° C. subsequently washed with dichloromethane and water The organic layer is separated washed with sodium hydrogen carbonate solution dried with anhydrous sodium sulphate The solvent is evaporated under reduced pressure The raw product is recrystallized in ethanol

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of n-BuLi (4.8 mL, 12 mmol, 2.5 M solution in hexane) was added to THF (50 mL) at −78° C. under nitrogen, followed by the addition of 1.0 M KOtBu in THF (12 mL, 12 mmol). The mixture was stirred at −78° C. for 30 min, then 3,5-dichlorofluorobenzene (1.65 g, 10.0 mmol) in THF (5 mL) was added slowly, and the resulting mixture was stirred at this temperature for 30 min. Then a solution of acetaldehyde (0.88 g, 20 mmol) in THF (5 mL) was added. The mixture was slowly warmed to rt. The mixture was quenched with water (10 mL), and diluted with EtOAc (50 mL). The organic phase was separated, washed with brine (10 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (Hex:EtOAc=95:5→90:10) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ=1.62 (d, J=6.8 Hz, 3H), 2.30 (br s, 1H, —OH), 5.35 (q, J=6.8 Hz, 1H), 7.05 (dd, J=10.6, 2.0 Hz, 1H), 7.20 (m, 1H). the resulting mixture was stirred at this temperature for 30 min The mixture was slowly warmed to rt The mixture was quenched with water (10 mL) diluted with EtOAc (50 mL) The organic phase was separated washed with brine (10 mL) dried over anhydrous sodium sulfate The crude material was purified by silica gel chromatography (Hex:EtOAc=95:5→90:10)

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

実験手順: (R)-3-(S)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (2.0 g, 7.2 mmol) was dissolved in anhydrous DMF (10 mL, 100 mmol). Lithium hydride (86 mg, 11 mmol) was added in 3 separate portions. The mixture was stirred at room temperature for 15 minutes. Into the mixture was added 3,5-dichlorofluorobenzene (1.7 mL, 14 mmol), and the resultant mixture stirred at room temperature for 15 minutes. The mixture was then stirred at 70° C. overnight. The mixture was cooled to room temperature, and EtOAc (80 mL) and 1M HCl (50 mL) were added. After mixing, the phases were separated and the organic layer was washed with diluted aqueous NaCl (1×50 mL), dried over Na2SO4, and concentrated to dryness to yield 3.5 g of crude product. Into the crude product was added 25 mL cold HCl in an EtOH/EtOAc solution and stirred at room temperature for 3 hours. Most of the solvent was removed by rotary evaporation, EtOAc was added (50 mL) and most of the solvent was removed again. Recrystallization and reslurry from EtOAc (20 mL) gave (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine as an HCl salt (2 g, ˜99% purity). separate portions The mixture was then stirred at 70° C. overnight The mixture was cooled to room temperature After mixing the phases were separated the organic layer was washed with diluted aqueous NaCl (1×50 mL) dried over Na2SO4 concentrated to dryness to yield 3.5 g of crude product stirred at room temperature for 3 hours Most of the solvent was removed by rotary evaporation, EtOAc was added (50 mL) most of the solvent was removed again Recrystallization