methyl 2-chloro-6-fluorobenzoate

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: A solution of methyl 2-chloro-6-fluorobenzoate (40.0 g) in ether was added to a solution of methyl magnesium iodide in ether (prepared from methyl iodide (120.0 g) and magnesium turnings (20.6 g) in ether). The resulting solution was stirred and heated at reflux for 5 hours, poured onto a mixture of ice and concentrated sulphuric acid and the layers separated. The organic layer was washed with water, saturated aqueous sodium bisulphite, water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 2-(2-chloro-6-fluorophenyl)-propan-2-ol (36.8 g) as an orange oil, NMR (CDCl3) 1.8(d,6H), 3.5-3.7(bs,1H), 6.9-7.05(m,1H), 7.1-7.25(m,2H). heated at reflux for 5 hours the layers separated The organic layer was washed with water, saturated aqueous sodium bisulphite, water dried (anhydrous magnesium sulphate) filtered The filtrate was evaporated to dryness

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

実験手順: A solution of methyl 2-chloro-6-fluorobenzoate (40.0 g) in ether was added to a solution of methyl magnesium iodide in ether (prepared from methyl iodide (120.0 g) and magnesium turnings (20.6 g) in ether). The resulting solution was stirred and heated at reflux for 5 hours, poured onto a mixture of ice and concentrated sulphuric acid and the layers separated. The organic layer was washed with water, saturated aqueous sodium bisulphite, water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 2-(2-chloro-6-fluorophenyl)-propan-2-ol (36.8 g) as an orange oil, NMR (CDCl3) 1.8(d,6H), 3.5-3.7(bs, 1H), 6.9-7.05(m,1H), 7.1-7.25(m,2H). heated at reflux for 5 hours the layers separated The organic layer was washed with water, saturated aqueous sodium bisulphite, water dried (anhydrous magnesium sulphate) filtered The filtrate was evaporated to dryness

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

実験手順: A solution of methyl 2-chloro-6-fluorobenzoate (40.0 g) in ether was added to a solution of methyl magnesium iodide in ether (prepared from methyl iodide (120.0 g) and magnesium turnings (20.6 g) in ether). The resulting solution was stirred and heated at reflux for 5 hours, poured onto a mixture of ice and concentrated sulphuric acid and the layers separated. The organic layer was washed with water, saturated aqueous sodium bisulphite, water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 2-(2-chloro-6-fluorophenyl)-propan-2-ol (36.8 g) as an orange oil, NMR (CDCl3) 1.8(d,6H), 3.5-3.7(bs, 1H), 6.9-7.05(m,1H), 7.1-7.25(m,2H). heated at reflux for 5 hours the layers separated The organic layer was washed with water, saturated aqueous sodium bisulphite, water dried (anhydrous magnesium sulphate) filtered The filtrate was evaporated to dryness

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

実験手順: An oven-dried round bottom flask successively evacuated and purged with N2 gas was charged with drisolv THF (13.3 ml), and diisopropyl amine (6.6 ml, 46 mmol). The mixture was placed in a −78° C. dry ice/acetone bath before n-butyllithium (2.5 M in hexanes) (17 ml, 43 mmol) was added. The LDA solution was then placed in a 0° C. bath for 10 minutes, then recooling to −78° C. A solution of methyl 2-chloro-6-fluorobenzoate (3.50 g, 19 mmol) in THF (56 ml) was added to the mixture dropwise over 30 minutes. The resulting mixture was stirred at −78° C. for 2.5 hrs, warmed to −50° C. over 30 min, and stirred for 30 minutes at −50° C. The mixture was then recooled to −78° C. and drisolv dimethylformamide (14 ml, 186 mmol) was added. The resulting mixture was stirred for 30 minutes at −78° C. and then gradually warmed to RT over 1 h (note: do not stir very long after reaching RT). The reaction was quenched with 10% aqueous acetic acid, diluted with EtOAc and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water, brine, and dried over Na2SO4, filtered and concentrated to a yellow oil, which was purified by silica gel chromatography using 12:1 hexanes/ethyl acetate to give the title compound as a light yellow oil, which solidified upon evacuation. An oven-dried round bottom flask successively evacuated purged with N2 gas was placed in a −78° C. was added was then placed in a 0° C. for 10 minutes recooling to −78° C warmed to −50° C. over 30 min stirred for 30 minutes at −50° C was then recooled to −78° C. The resulting mixture was stirred for 30 minutes at −78° C. gradually warmed to RT over 1 h (note do not stir very long after reaching RT The reaction was quenched with 10% aqueous acetic acid diluted with EtOAc the layers were separated The aqueous layer was extracted three times with EtOAc The combined organic layers were washed with water, brine dried over Na2SO4 filtered concentrated to a yellow oil, which was purified by silica gel chromatography

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

実験手順: An oven-dried round bottom flask successively evacuated and purged with N2 gas was charged with drisolv THF (13.3 ml), and diisopropyl amine (6.6 ml, 46 mmol). The mixture was placed in a −78° C. dry ice/acetone bath before n-butyllithium (2.5 M in hexanes) (17 ml, 43 mmol) was added. The LDA solution was then placed in a 0° C. bath for 10 minutes, then recooling to −78° C. A solution of methyl 2-chloro-6-fluorobenzoate (3.50 g, 19 mmol) in THF (56 ml) was added to the mixture dropwise over 30 minutes. The resulting mixture was stirred at −78° C. for 2.5 hrs, warmed to −50° C. over 30 min, and stirred for 30 minutes at −50° C. The mixture was then recooled to −78° C. and drisolv dimethylformamide (14 ml, 186 mmol) was added. The resulting mixture was stirred for 30 minutes at −78° C. and then gradually warmed to RT over 1 h (note: do not stir very long after reaching RT). The reaction was quenched with 10% aqueous acetic acid, diluted with EtOAc and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water, brine, and dried over Na2SO4, filtered and concentrated to a yellow oil, which was purified by silica gel chromatography using 12:1 hexanes/ethyl acetate to give the title compound as a light yellow oil, which solidified upon evacuation. An oven-dried round bottom flask successively evacuated purged with N2 gas was placed in a −78° C. was added was then placed in a 0° C. for 10 minutes recooling to −78° C warmed to −50° C. over 30 min stirred for 30 minutes at −50° C was then recooled to −78° C. The resulting mixture was stirred for 30 minutes at −78° C. gradually warmed to RT over 1 h (note do not stir very long after reaching RT The reaction was quenched with 10% aqueous acetic acid diluted with EtOAc the layers were separated The aqueous layer was extracted three times with EtOAc The combined organic layers were washed with water, brine dried over Na2SO4 filtered concentrated to a yellow oil, which was purified by silica gel chromatography

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

実験手順: An oven-dried round bottom flask successively evacuated and purged with N2 gas was charged with drisolv THF (84 ml) and placed in a −78° C. dry ice/acetone bath. To this was added n-butyllithium (2.5 M in hexanes) (18 ml, 46 mmol) and the mixture was stirred for 10 min before adding neat 1-chloro-3-fluorobenzene (5.48 g, 42.0 mmol). The solution was stirred for 2 hrs before adding neat methyl chloroformate (4.0 ml, 50 mmol). The resultant solution was stirred at −78° C. for 3 hrs and then allowed to warm to RT. Water was added to the mixture followed by EtOAc. The layers were separated and the aqueous layer was extracted 3× EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a clear liquid. An oven-dried round bottom flask successively evacuated purged with N2 gas was charged with drisolv THF (84 ml) placed in a −78° C. The solution was stirred for 2 hrs The layers were separated the aqueous layer was extracted 3× EtOAc The combined organics were washed with brine dried over MgSO4 filtered concentrated

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

実験手順: An oven-dried round bottom flask successively evacuated and purged with N2 gas was charged with drisolv THF (84 ml) and placed in a −78° C. dry ice/acetone bath. To this was added n-butyllithium (2.5 M in hexanes) (18 ml, 46 mmol) and the mixture was stirred for 10 min before adding neat 1-chloro-3-fluorobenzene (5.48 g, 42.0 mmol). The solution was stirred for 2 hrs before adding neat methyl chloroformate (4.0 ml, 50 mmol). The resultant solution was stirred at −78° C. for 3 hrs and then allowed to warm to RT. Water was added to the mixture followed by EtOAc. The layers were separated and the aqueous layer was extracted 3× EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a clear liquid. An oven-dried round bottom flask successively evacuated purged with N2 gas was charged with drisolv THF (84 ml) placed in a −78° C. The solution was stirred for 2 hrs The layers were separated the aqueous layer was extracted 3× EtOAc The combined organics were washed with brine dried over MgSO4 filtered concentrated

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

実験手順: A solution of methyl 2-chloro-6-fluorobenzoate (40.0 g) in ether was added to a solution of methyl magnesium iodide in ether (prepared from methyl iodide (120.0 g) and magnesium turnings (20.6 g) in ether). The resulting solution was stirred and heated at reflux for 5 hours, poured onto a mixture of ice and concentrated sulphuric acid and the layers separated. The organic layer was washed with water, saturated aqueous sodium bisulphite, water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 2-(2-chloro-6-fluorophenyl)-propan-2-ol (36.8 g) as an orange oil, NMR (CDCl3) 1.8(d,6H), 3.5-3.7(bs,1H), 6.9-7.05(m,1H), 7.1-7.25(m,2H). heated at reflux for 5 hours the layers separated The organic layer was washed with water, saturated aqueous sodium bisulphite, water dried (anhydrous magnesium sulphate) filtered The filtrate was evaporated to dryness

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

実験手順: A solution of methyl 2-chloro-6-fluorobenzoate (40.0 g) in ether was added to a solution of methyl magnesium iodide in ether (prepared from methyl iodide (120.0 g) and magnesium turnings (20.6 g) in ether). The resulting solution was stirred and heated at reflux for 5 hours, poured onto a mixture of ice and concentrated sulphuric acid and the layers separated. The organic layer was washed with water, saturated aqueous sodium bisulphite, water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 2-(2-chloro-6-fluorophenyl)-propan-2-ol (36.8 g) as an orange oil, NMR (CDCl3) 1.8(d,6H), 3.5-3.7(bs,1H), 6.9-7.05(m,1H), 7.1-7.25(m,2H). heated at reflux for 5 hours the layers separated The organic layer was washed with water, saturated aqueous sodium bisulphite, water dried (anhydrous magnesium sulphate) filtered The filtrate was evaporated to dryness

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

実験手順: A solution of methyl 2-chloro-6-fluorobenzoate (40.0 g) in ether was added to a solution of methyl magnesium iodide in ether (prepared from methyl iodide (120.0 g) and magnesium turnings (20.6 g) in ether). The resulting solution was stirred and heated at reflux for 5 hours, poured onto a mixture of ice and concentrated sulphuric acid and the layers separated. The organic layer was washed with water, saturated aqueous sodium bisulphite, water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 2-(2-chloro-6-fluorophenyl)-propan-2-ol (36.8 g) as an orange oil, NMR (CDCl3) 1.8(d,6H), 3.5-3.7(bs, 1H), 6.9-7.05(m,1H), 7.1-7.25(m,2H). heated at reflux for 5 hours the layers separated The organic layer was washed with water, saturated aqueous sodium bisulphite, water dried (anhydrous magnesium sulphate) filtered The filtrate was evaporated to dryness

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

実験手順: An oven-dried round bottom flask successively evacuated and purged with N2 gas was charged with drisolv THF (13.3 ml), and diisopropyl amine (6.6 ml, 46 mmol). The mixture was placed in a −78° C. dry ice/acetone bath before n-butyllithium (2.5 M in hexanes) (17 ml, 43 mmol) was added. The LDA solution was then placed in a 0° C. bath for 10 minutes, then recooling to −78° C. A solution of methyl 2-chloro-6-fluorobenzoate (3.50 g, 19 mmol) in THF (56 ml) was added to the mixture dropwise over 30 minutes. The resulting mixture was stirred at −78° C. for 2.5 hrs, warmed to −50° C. over 30 min, and stirred for 30 minutes at −50° C. The mixture was then recooled to −78° C. and drisolv dimethylformamide (14 ml, 186 mmol) was added. The resulting mixture was stirred for 30 minutes at −78° C. and then gradually warmed to RT over 1 h (note: do not stir very long after reaching RT). The reaction was quenched with 10% aqueous acetic acid, diluted with EtOAc and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water, brine, and dried over Na2SO4, filtered and concentrated to a yellow oil, which was purified by silica gel chromatography using 12:1 hexanes/ethyl acetate to give the title compound as a light yellow oil, which solidified upon evacuation. An oven-dried round bottom flask successively evacuated purged with N2 gas was placed in a −78° C. was added was then placed in a 0° C. for 10 minutes recooling to −78° C warmed to −50° C. over 30 min stirred for 30 minutes at −50° C was then recooled to −78° C. The resulting mixture was stirred for 30 minutes at −78° C. gradually warmed to RT over 1 h (note do not stir very long after reaching RT The reaction was quenched with 10% aqueous acetic acid diluted with EtOAc the layers were separated The aqueous layer was extracted three times with EtOAc The combined organic layers were washed with water, brine dried over Na2SO4 filtered concentrated to a yellow oil, which was purified by silica gel chromatography