4,4-difluorocyclohexane-1-carboxamide

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

実験手順: 4,4-difluorocyclohexanecarboxamide (1.32 g, 8.10 mmol) was stirred in the solution of lithium borohydrate (1M, 30 ml) under nitrogen overnight. Then, the reaction mixture was refluxed for 4 hours. After cooled to room temperature, it was poured into ice-water slowly. After filtration, the product was extracted with dichloromethane from filtrate. Combined organic layers were water, brine, dried over anhydrous sodium sulphate, filtered and condensed to provide a 934 mg of colorless oil (82%). δ 2.53 (d, 2H), 1.98-2.09 (m, 2H), 1.73-1.82 (m, 6H), 1.17-1.29 (m, 3H). Then, the reaction mixture was refluxed for 4 hours After filtration the product was extracted with dichloromethane from filtrate dried over anhydrous sodium sulphate filtered condensed

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

実験手順: 4,4-difluorocyclohexanecarboxamide (1.32 g, 8.10 mmol) was stirred in the solution of lithium borohydrate (1M, 30 ml) under nitrogen overnight. Then, the reaction mixture was refluxed for 4 hours. After cooled to room temperature, it was poured into ice-water slowly. After filtration, the product was extracted with dichloromethane from filtrate. Combined organic layers were water, brine, dried over anhydrous sodium sulphate, filtered and condensed to provide a 934 mg of colorless oil (82%). δ 2.53 (d, 2H), 1.98-2.09 (m, 2H), 1.73-1.82 (m, 6H), 1.17-1.29 (m, 3H). Then, the reaction mixture was refluxed for 4 hours After filtration the product was extracted with dichloromethane from filtrate dried over anhydrous sodium sulphate filtered condensed

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

実験手順: A solution of 4,4-difluorocyclohexanecarboxylic acid (0.217 g, 1.322 mmol) in DCM (4 mL) was treated with oxalyl chloride (0.174 mL, 1.983 mmol) followed by catalytic DMF (1 drop) and the mixture stirred at RT for 1.5 h. The mixture was concentrated to dryness, co-evaporated with DCM (1×) and the resulting residue dissolved in THF (2 mL), added to a stirring solution of NH4OH (˜14M, 2 mL, 28.0 mmol) in THF (2 mL) and stirred for 30 minutes. The mixture was diluted with brine, extracted with EtOAc (3×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford 4,4-difluorocyclohexanecarboxamide (167 mg, 77%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.28 (s, 1H), 6.79 (s, 1H), 2.20 (m, 1H), 2.00 (m, 2H), 1.86-1.67 (m, 4H), 1.57 (m, 2H). The mixture was concentrated to dryness, co-evaporated with DCM (1×) the resulting residue dissolved in THF (2 mL) stirred for 30 minutes extracted with EtOAc (3×) the combined organics were dried over MgSO4 concentrated to dryness

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

実験手順: 4,4-difluorocyclohexanecarboxamide (1.32 g, 8.10 mmol) was stirred in the solution of lithium borohydrate (1M, 30 ml) under nitrogen overnight. Then, the reaction mixture was refluxed for 4 hours. After cooled to room temperature, it was poured into ice-water slowly. After filtration, the product was extracted with dichloromethane from filtrate. Combined organic layers were water, brine, dried over anhydrous sodium sulphate, filtered and condensed to provide a 934 mg of colorless oil (82%). δ 2.53 (d, 2H), 1.98-2.09 (m, 2H), 1.73-1.82 (m, 6H), 1.17-1.29 (m, 3H). Then, the reaction mixture was refluxed for 4 hours After filtration the product was extracted with dichloromethane from filtrate dried over anhydrous sodium sulphate filtered condensed

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

実験手順: To a solution of compound 4,4-difluorocyclohexanecarboxamide (1.8 g, 13 mmol) in 100 mL THF was added LiBH4 (1.1 g, 50 mmol) under N2 stirred for overnight. Then the reaction mixture was refluxed for 4 h. After cooled to r.t, it was poured into ice-water slowly. After filtration, the product was extracted with DCM from filtrate. Combined organic layers washed with water, brine, dried over Na2SO4, filtered and condensed to afford compound (4,4-difluorocyclohexyl)methanamine (0.8 g, crude) as a colorless oil. Then the reaction mixture was refluxed for 4 h After cooled After filtration the product was extracted with DCM from filtrate Combined organic layers washed with water, brine dried over Na2SO4 filtered condensed

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of compound 4,4-difluorocyclohexanecarboxylic acid (3.5 g, 21 mmol) in 80 mL THF, 4-methylmorpholine (2.51 g, 21 mmol) was added at −70° C., followed by isobutyl chloridocarbonate (2.85 g, 21 mmol). 30 min later, 10 mL ammonium hydroxide was added. The resulting mixture was allowed to warm up to 0° C. After removal of all solvents, the residue was washed with water, PE to afford the compound 4,4-difluorocyclohexanecarboxamide (1.82 g, 40%) as a white solid. After removal of all solvents the residue was washed with water, PE

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

実験手順: A solution of 4,4-difluorocyclohexanecarboxylic acid (0.217 g, 1.322 mmol) in DCM (4 mL) was treated with oxalyl chloride (0.174 mL, 1.983 mmol) followed by catalytic DMF (1 drop) and the mixture stirred at RT for 1.5 h. The mixture was concentrated to dryness, co-evaporated with DCM (1×) and the resulting residue dissolved in THF (2 mL), added to a stirring solution of NH4OH (˜14M, 2 mL, 28.0 mmol) in THF (2 mL) and stirred for 30 minutes. The mixture was diluted with brine, extracted with EtOAc (3×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford 4,4-difluorocyclohexanecarboxamide (167 mg, 77%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.28 (s, 1H), 6.79 (s, 1H), 2.20 (m, 1H), 2.00 (m, 2H), 1.86-1.67 (m, 4H), 1.57 (m, 2H). The mixture was concentrated to dryness, co-evaporated with DCM (1×) the resulting residue dissolved in THF (2 mL) stirred for 30 minutes extracted with EtOAc (3×) the combined organics were dried over MgSO4 concentrated to dryness

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

実験手順: 4,4-difluorocyclohexanecarboxamide (1.32 g, 8.10 mmol) was stirred in the solution of lithium borohydrate (1M, 30 ml) under nitrogen overnight. Then, the reaction mixture was refluxed for 4 hours. After cooled to room temperature, it was poured into ice-water slowly. After filtration, the product was extracted with dichloromethane from filtrate. Combined organic layers were water, brine, dried over anhydrous sodium sulphate, filtered and condensed to provide a 934 mg of colorless oil (82%). δ 2.53 (d, 2H), 1.98-2.09 (m, 2H), 1.73-1.82 (m, 6H), 1.17-1.29 (m, 3H). Then, the reaction mixture was refluxed for 4 hours After filtration the product was extracted with dichloromethane from filtrate dried over anhydrous sodium sulphate filtered condensed