4-chloro-6-fluoro-2,3-dihydroinden-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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl acetate (5.9 g, 0.07 mol) was added dropwise to a stirred, chilled (dry ice-acetone bath) solution of lithium diisopropylamide (prepared by dropwise addition of a 2.5M solution of n-butyllithium (26.8 ml, 0.07 mol) in hexane to a chilled (dry ice-acetone bath) solution of diisopropylamine (6.8 g, 0.07 mol) in tetrahydrofuran (35 ml) ). After 30 min, a solution of 4-chloro-6-fluoro-1-indanone (12.4 g, 0.07 mol) in tetrahydrofuran (100 ml) was added dropwise and the mixture was stirred for 1 h (dry ice-acetone bath). A solution of ammonium chloride (10.6 g, 0.20 mol) in water (80 ml) was added and the mixture was allowed to come to ambient temperature. The aqueous phase was separated and extracted with diethyl ether. The combined organic phase was dried (sodium sulphate), filtered and concentrated in vacuo to give 19.5 g of crude ethyl 2-(4-chloro-6-fluoro-1-hydroxy-1-indanyl)acetate. Chromatography on silica gel with hexanes:ethyl acetate (8:2) as eluent gave 15.2 g (83%) of a yellow oil; NMR (DMSO-d6): a 7.13-7.28 (m, 2H), 5.55 (s, 1H), 3.98 (m, 2H), 2.79 (2m's, 4H), 2.50 (m, 1H), 2.11 (m, 1H). 1.08 (t, 3H). to come to ambient temperature The aqueous phase was separated extracted with diethyl ether The combined organic phase was dried (sodium sulphate) filtered concentrated in vacuo

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

実験手順: To a mixture of 3-(2-chloro-4-fluorophenyl)propanoic acid (21.6 g, 0.11 mol) and dichloromethane at room temperature was added dropwise oxalyl chloride (19.2 ml). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-chloro-4-fluorophenyl)propionyl chloride. A solution of the 3-(2-chloro-4-fluorophenyl) propionyl chloride in dichloromethane (100 ml) was added dropwise to a mixture of aluminium chloride (17.3 g, 0.13 mol, Aldrich) in dichloromethane (100 ml) at room temperature. After the addition was completed, the mixture was refluxed for 2.5 h. The reaction mixture was poured into ice water (1.5 L). The two phases were separated and the dichloromethane phase was washed with 0.1N aqueous sodium hydroxide, dried (Na2SO4), and concentrated to give crude 4-chloro-6-fluoro-1-indanone. Chromatography on silica gel with hexanes:dichloromethane (1:1) as eluent gave 11.1 g (55%) of 4-chloro-6-fluoro-1-indanone as a white solid: mp 94°-96° C. After the addition the mixture was refluxed for 2.5 h The two phases were separated the dichloromethane phase was washed with 0.1N aqueous sodium hydroxide dried (Na2SO4) concentrated to give crude 4-chloro-6-fluoro-1-indanone

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

実験手順: To a mixture of 3-(2-chloro-4-fluorophenyl)propanoic acid (21.6 g, 0.11 mol) and dichloromethane at room temperature was added dropwise oxalyl chloride (19.2 ml). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-chloro-4-fluorophenyl)propionyl chloride. A solution of the 3-(2-chloro-4-fluorophenyl) propionyl chloride in dichloromethane (100 ml) was added dropwise to a mixture of aluminium chloride (17.3 g, 0.13 mol, Aldrich) in dichloromethane (100 ml) at room temperature. After the addition was completed, the mixture was refluxed for 2.5 h. The reaction mixture was poured into ice water (1.5 L). The two phases were separated and the dichloromethane phase was washed with 0.1N aqueous sodium hydroxide, dried (Na2SO4), and concentrated to give crude 4-chloro-6-fluoro-1-indanone. Chromatography on silica gel with hexanes:dichloromethane (1:1) as eluent gave 11.1 g (55%) of 4-chloro-6-fluoro-1-indanone as a white solid: mp 94°-96° C. After the addition the mixture was refluxed for 2.5 h The two phases were separated the dichloromethane phase was washed with 0.1N aqueous sodium hydroxide dried (Na2SO4) concentrated to give crude 4-chloro-6-fluoro-1-indanone

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

実験手順: Ethyl acetate (5.9 g, 0.07 mol) was added dropwise to a stirred, chilled (dry ice-acetone bath) solution of lithium diisopropylamide (prepared by dropwise addition of a 2.5M solution of n-butyllithium (26.8 ml, 0.07 mol) in hexane to a chilled (dry ice-acetone bath) solution of diisopropylamine (6.8 g, 0.07 mol) in tetrahydrofuran (35 ml) ). After 30 min, a solution of 4-chloro-6-fluoro-1-indanone (12.4 g, 0.07 mol) in tetrahydrofuran (100 ml) was added dropwise and the mixture was stirred for 1 h (dry ice-acetone bath). A solution of ammonium chloride (10.6 g, 0.20 mol) in water (80 ml) was added and the mixture was allowed to come to ambient temperature. The aqueous phase was separated and extracted with diethyl ether. The combined organic phase was dried (sodium sulphate), filtered and concentrated in vacuo to give 19.5 g of crude ethyl 2-(4-chloro-6-fluoro-1-hydroxy-1-indanyl)acetate. Chromatography on silica gel with hexanes:ethyl acetate (8:2) as eluent gave 15.2 g (83%) of a yellow oil; NMR (DMSO-d6): a 7.13-7.28 (m, 2H), 5.55 (s, 1H), 3.98 (m, 2H), 2.79 (2m's, 4H), 2.50 (m, 1H), 2.11 (m, 1H). 1.08 (t, 3H). to come to ambient temperature The aqueous phase was separated extracted with diethyl ether The combined organic phase was dried (sodium sulphate) filtered concentrated in vacuo

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

実験手順: To a mixture of 3-(2-chloro-4-fluorophenyl)propanoic acid (21.6 g, 0.11 mol) and dichloromethane at room temperature was added dropwise oxalyl chloride (19.2 ml). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-chloro-4-fluorophenyl)propionyl chloride. A solution of the 3-(2-chloro-4-fluorophenyl) propionyl chloride in dichloromethane (100 ml) was added dropwise to a mixture of aluminium chloride (17.3 g, 0.13 mol, Aldrich) in dichloromethane (100 ml) at room temperature. After the addition was completed, the mixture was refluxed for 2.5 h. The reaction mixture was poured into ice water (1.5 L). The two phases were separated and the dichloromethane phase was washed with 0.1N aqueous sodium hydroxide, dried (Na2SO4), and concentrated to give crude 4-chloro-6-fluoro-1-indanone. Chromatography on silica gel with hexanes:dichloromethane (1:1) as eluent gave 11.1 g (55%) of 4-chloro-6-fluoro-1-indanone as a white solid: mp 94°-96° C. After the addition the mixture was refluxed for 2.5 h The two phases were separated the dichloromethane phase was washed with 0.1N aqueous sodium hydroxide dried (Na2SO4) concentrated to give crude 4-chloro-6-fluoro-1-indanone