1-(4,4-difluorocyclohexyl)ethanone

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

実験手順: 0.361 g meta-chloro-perbenzoic acid were added into a solution of 0.262 g 1-(4,4-difluoro-cyclohexyl)-ethanone in 5 ml chloroform. The reaction was stirred at rt for 2 hours when TLC indicated consumption of the 1-(4,4-difluoro-cyclohexyl)-ethanone. The solution was poured into saturated sodium hydrogencarbonate solution and extracted with chloroform (3×50 ml). The combined organic phases were passed through a phase separator concentrated in vacuo. The crude product was resuspended in methanol (5 ml) and 10% aq. potassium carbonate solution. (5 ml) and stirred at rt over a weekend. The solution was diluted with chloroform (25 ml) and sat. sodium hydrogencarbonate solution. The organic phases were separated and the aqueous phase was extracted with methylene chloride (3×25 ml). The combined organic phases were passed through a phase-separator, concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 100%→1:1 petroleum ether/diethylether). consumption of the 1-(4,4-difluoro-cyclohexyl)-ethanone The solution was poured into saturated sodium hydrogencarbonate solution extracted with chloroform (3×50 ml) concentrated in vacuo (5 ml) and stirred at rt over a weekend The solution was diluted with chloroform (25 ml) and sat. sodium hydrogencarbonate solution The organic phases were separated the aqueous phase was extracted with methylene chloride (3×25 ml) concentrated in vacuo Purification

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

実験手順: 2 ml methyl lithium (1 M in diethylether) were added into a solution of 0.593 g 4,4-difluoro-cyclohexanecarboxylic acid methoxy-methyl-amide in anhydrous 5 ml THF at 0° C. The reaction was allowed to warm to rt overnight. The reaction was quenched with sat. ammonium chloride solution (˜50 ml) and diluted with sat. sodium hydrogencarbonate solution (25 ml). The aqueous layer was extracted with diethylether (3×50 ml) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 5:1→1:1 petroleum/ether (40-60). The reaction was quenched with sat. ammonium chloride solution (˜50 ml) diluted with sat. sodium hydrogencarbonate solution (25 ml) The aqueous layer was extracted with diethylether (3×50 ml) the combined organic phases were dried over sodium sulfate filtered concentrated in vacuo Purification

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

実験手順: 0.361 g meta-chloro-perbenzoic acid were added into a solution of 0.262 g 1-(4,4-difluoro-cyclohexyl)-ethanone in 5 ml chloroform. The reaction was stirred at rt for 2 hours when TLC indicated consumption of the 1-(4,4-difluoro-cyclohexyl)-ethanone. The solution was poured into saturated sodium hydrogencarbonate solution and extracted with chloroform (3×50 ml). The combined organic phases were passed through a phase separator concentrated in vacuo. The crude product was resuspended in methanol (5 ml) and 10% aq. potassium carbonate solution. (5 ml) and stirred at rt over a weekend. The solution was diluted with chloroform (25 ml) and sat. sodium hydrogencarbonate solution. The organic phases were separated and the aqueous phase was extracted with methylene chloride (3×25 ml). The combined organic phases were passed through a phase-separator, concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 100%→1:1 petroleum ether/diethylether). consumption of the 1-(4,4-difluoro-cyclohexyl)-ethanone The solution was poured into saturated sodium hydrogencarbonate solution extracted with chloroform (3×50 ml) concentrated in vacuo (5 ml) and stirred at rt over a weekend The solution was diluted with chloroform (25 ml) and sat. sodium hydrogencarbonate solution The organic phases were separated the aqueous phase was extracted with methylene chloride (3×25 ml) concentrated in vacuo Purification

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

実験手順: 2 ml methyl lithium (1 M in diethylether) were added into a solution of 0.593 g 4,4-difluoro-cyclohexanecarboxylic acid methoxy-methyl-amide in anhydrous 5 ml THF at 0° C. The reaction was allowed to warm to rt overnight. The reaction was quenched with sat. ammonium chloride solution (˜50 ml) and diluted with sat. sodium hydrogencarbonate solution (25 ml). The aqueous layer was extracted with diethylether (3×50 ml) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 5:1→1:1 petroleum/ether (40-60). The reaction was quenched with sat. ammonium chloride solution (˜50 ml) diluted with sat. sodium hydrogencarbonate solution (25 ml) The aqueous layer was extracted with diethylether (3×50 ml) the combined organic phases were dried over sodium sulfate filtered concentrated in vacuo Purification

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

実験手順: 2 ml methyl lithium (1 M in diethylether) were added into a solution of 0.593 g 4,4-difluoro-cyclohexanecarboxylic acid methoxy-methyl-amide in anhydrous 5 ml THF at 0° C. The reaction was allowed to warm to rt overnight. The reaction was quenched with sat. ammonium chloride solution (˜50 ml) and diluted with sat. sodium hydrogencarbonate solution (25 ml). The aqueous layer was extracted with diethylether (3×50 ml) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 5:1→1:1 petroleum/ether (40-60). The reaction was quenched with sat. ammonium chloride solution (˜50 ml) diluted with sat. sodium hydrogencarbonate solution (25 ml) The aqueous layer was extracted with diethylether (3×50 ml) the combined organic phases were dried over sodium sulfate filtered concentrated in vacuo Purification

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

実験手順: To a solution of 1-(4,4-difluorocyclohexyl)ethanone (1 g, 6.17 mmol) in THF (5 mL) was added a solution of ammonium acetate (9.51 g, 123.4 mmol) and NaBH3CN (3.82 g, 61.7 mmol) in MeOH. The mixture was stirred for 48 hr. The reaction mixture was quenched with aqueous NaHCO3 and extracted with tert-Butyl-methyl ether (20 mL*3). The combined organic layers were washed with 1N HCl, and the organic and aqueous layer were separated. The aqueous layer was brought to above pH 8 with 2N NaOH and extracted with ethyl acetate (20 mL*3). The organic layer was washed with brine, dried over sodium sulfate. The organic layer was concentrated to give 1-(4,4-difluorocyclohexyl)ethanamine (545 mg, crude) for next step. The reaction mixture was quenched with aqueous NaHCO3 extracted with tert-Butyl-methyl ether (20 mL*3) The combined organic layers were washed with 1N HCl the organic and aqueous layer were separated extracted with ethyl acetate (20 mL*3) The organic layer was washed with brine dried over sodium sulfate The organic layer was concentrated

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

実験手順: To a solution of 4,4-difluoro-N-methyl cyclohexanecarboxamide (3 g, 14.5 mmol) in THF (20 mL) were added CH3MgBr (5.19 g, 43.5 mmol) in −78° C. The mixture was stirred at −78° C. for 5 hr. Water (10 mL) was added and the mixture was concentrated and extracted by CH2Cl2 (40 mL*3). The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated to give 1-(4,4-difluorocyclohexyl)ethanone (1.5 g, crude) for next step. the mixture was concentrated extracted by CH2Cl2 (40 mL*3) The organic layer was washed with brine dried over sodium sulfate The organic layer was concentrated

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

実験手順: To a solution of 4,4-difluoro-N-methyl cyclohexanecarboxamide (3 g, 14.5 mmol) in THF (20 mL) were added CH3MgBr (5.19 g, 43.5 mmol) in −78° C. The mixture was stirred at −78° C. for 5 hr. Water (10 mL) was added and the mixture was concentrated and extracted by CH2Cl2 (40 mL*3). The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated to give 1-(4,4-difluorocyclohexyl)ethanone (1.5 g, crude) for next step. the mixture was concentrated extracted by CH2Cl2 (40 mL*3) The organic layer was washed with brine dried over sodium sulfate The organic layer was concentrated

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

実験手順: To a solution of 1-(4,4-difluorocyclohexyl)ethanone (1 g, 6.17 mmol) in THF (5 mL) was added a solution of ammonium acetate (9.51 g, 123.4 mmol) and NaBH3CN (3.82 g, 61.7 mmol) in MeOH. The mixture was stirred for 48 hr. The reaction mixture was quenched with aqueous NaHCO3 and extracted with tert-Butyl-methyl ether (20 mL*3). The combined organic layers were washed with 1N HCl, and the organic and aqueous layer were separated. The aqueous layer was brought to above pH 8 with 2N NaOH and extracted with ethyl acetate (20 mL*3). The organic layer was washed with brine, dried over sodium sulfate. The organic layer was concentrated to give 1-(4,4-difluorocyclohexyl)ethanamine (545 mg, crude) for next step. The reaction mixture was quenched with aqueous NaHCO3 extracted with tert-Butyl-methyl ether (20 mL*3) The combined organic layers were washed with 1N HCl the organic and aqueous layer were separated extracted with ethyl acetate (20 mL*3) The organic layer was washed with brine dried over sodium sulfate The organic layer was concentrated

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

実験手順: To a solution of 4,4-difluoro-N-methyl cyclohexanecarboxamide (3 g, 14.5 mmol) in THF (20 mL) were added CH3MgBr (5.19 g, 43.5 mmol) in −78° C. The mixture was stirred at −78° C. for 5 hr. Water (10 mL) was added and the mixture was concentrated and extracted by CH2Cl2 (40 mL*3). The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated to give 1-(4,4-difluorocyclohexyl)ethanone (1.5 g, crude) for next step. the mixture was concentrated extracted by CH2Cl2 (40 mL*3) The organic layer was washed with brine dried over sodium sulfate The organic layer was concentrated

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

実験手順: To a clear solution of 4,4-difluorocyclohexanecarboxylic acid (2.00 g, 12.18 mmol) in 100 mL THF at 0° C. was added slowly dropwise methyllithium, 1.6M solution in diethyl ether (30.5 mL, 48.7 mmol) from an addition funnel. The resulting cloudy mixture was allowed to stir 2 h, then was treated with chlorotrimethyl silane (24.74 mL, 195 mmol) dropwise over 10 min. The bath was removed and the clear solution allowed to stir 1 h. 5 mL 1M HCl aq. Was added and the reaction mixture stirred an additional hour. The reaction mixture was then concentrated in vacuo to a small volume, diluted with Et2O, and the organic layer was washed with water, sat'd aq. NaHCO3, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give impure 1-(4,4-difluorocyclohexyl)-ethanone as a clear/colorless oil, which was used without further purification. The bath was removed to stir 1 h 5 mL 1M HCl aq. Was added the reaction mixture stirred an additional hour The reaction mixture was then concentrated in vacuo to a small volume diluted with Et2O the organic layer was washed with water dried over magnesium sulfate filtered concentrated in vacuo

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

実験手順: 0.361 g meta-chloro-perbenzoic acid were added into a solution of 0.262 g 1-(4,4-difluoro-cyclohexyl)-ethanone in 5 ml chloroform. The reaction was stirred at rt for 2 hours when TLC indicated consumption of the 1-(4,4-difluoro-cyclohexyl)-ethanone. The solution was poured into saturated sodium hydrogencarbonate solution and extracted with chloroform (3×50 ml). The combined organic phases were passed through a phase separator concentrated in vacuo. The crude product was resuspended in methanol (5 ml) and 10% aq. potassium carbonate solution. (5 ml) and stirred at rt over a weekend. The solution was diluted with chloroform (25 ml) and sat. sodium hydrogencarbonate solution. The organic phases were separated and the aqueous phase was extracted with methylene chloride (3×25 ml). The combined organic phases were passed through a phase-separator, concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 100%→1:1 petroleum ether/diethylether). consumption of the 1-(4,4-difluoro-cyclohexyl)-ethanone The solution was poured into saturated sodium hydrogencarbonate solution extracted with chloroform (3×50 ml) concentrated in vacuo (5 ml) and stirred at rt over a weekend The solution was diluted with chloroform (25 ml) and sat. sodium hydrogencarbonate solution The organic phases were separated the aqueous phase was extracted with methylene chloride (3×25 ml) concentrated in vacuo Purification