4,4-difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide

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: 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: 2.78 g HATU were added to a solution of 1 g 4,4-difluoro-cyclohexanecarboxylic acid and 1.3 ml diisopropylethlyamine in 10 ml anhydrous DMF at 0° C. The reaction was stirred at 0° C. for 0.5 hours when 0.891 g O,N-Dimethyl-hydroxylamine hydrochloride were added. The reaction was allowed to warm to rt overnight. The solution was concentrated in vacuo by co-evaporation with toluene (3×) and filtered. The filtrate was concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 5:1→3:1 petroleum ether/EtOAc). were added The solution was concentrated in vacuo by co-evaporation with toluene (3×) filtered The filtrate was concentrated in vacuo Purification

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4,4-difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide obtained in Example 2a (1.7 g, 8.21 mmol) and tetrahydrofuran (60 ml) was cooled to −70° C., a 1.0 M diisobutylaluminum hydride/toluene solution (9.85 ml, 9.85 mmol) was added, and the reaction mixture was stirred at −60° C. for 35 minutes. A 1.0 M diisobutylaluminum hydride/toluene solution (5 ml, 5 mmol) was further added at −65° C., and the reaction mixture was stirred at −70° C. for two hours. A 2 N aqueous hydrochloric acid solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off to give a crude product of the title compound (1.4 g). the reaction mixture was stirred at −70° C. for two hours was extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was distilled off

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4,4-difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide obtained in Example 2a (1.7 g, 8.21 mmol) and tetrahydrofuran (60 ml) was cooled to −70° C., a 1.0 M diisobutylaluminum hydride/toluene solution (9.85 ml, 9.85 mmol) was added, and the reaction mixture was stirred at −60° C. for 35 minutes. A 1.0 M diisobutylaluminum hydride/toluene solution (5 ml, 5 mmol) was further added at −65° C., and the reaction mixture was stirred at −70° C. for two hours. A 2 N aqueous hydrochloric acid solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off to give a crude product of the title compound (1.4 g). the reaction mixture was stirred at −70° C. for two hours was extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was distilled off

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 4,4-difluorocyclohexane-1-carboxylate (1.9 g, 9.88 mmol) and tetrahydrofuran (60 ml) was cooled to −70° C., and N,O-dimethylhydroxyamine hydrochloride (1.44 g, 14.8 mmol) was added. Further, 1.05 M n-propylmagnesium bromide (24.2 ml, 25.2 mmol) was added dropwise to the reaction mixture at −55° C. over five minutes so that the internal temperature did not exceed −35° C., and the reaction mixture was stirred at 0° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane) to give the title compound (1.7 g, yield 83%). did not exceed −35° C. was extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was distilled off The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane)

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 4,4-difluorocyclohexane-1-carboxylate (1.9 g, 9.88 mmol) and tetrahydrofuran (60 ml) was cooled to −70° C., and N,O-dimethylhydroxyamine hydrochloride (1.44 g, 14.8 mmol) was added. Further, 1.05 M n-propylmagnesium bromide (24.2 ml, 25.2 mmol) was added dropwise to the reaction mixture at −55° C. over five minutes so that the internal temperature did not exceed −35° C., and the reaction mixture was stirred at 0° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane) to give the title compound (1.7 g, yield 83%). did not exceed −35° C. was extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was distilled off The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane)

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: 2.78 g HATU were added to a solution of 1 g 4,4-difluoro-cyclohexanecarboxylic acid and 1.3 ml diisopropylethlyamine in 10 ml anhydrous DMF at 0° C. The reaction was stirred at 0° C. for 0.5 hours when 0.891 g O,N-Dimethyl-hydroxylamine hydrochloride were added. The reaction was allowed to warm to rt overnight. The solution was concentrated in vacuo by co-evaporation with toluene (3×) and filtered. The filtrate was concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 5:1→3:1 petroleum ether/EtOAc). were added The solution was concentrated in vacuo by co-evaporation with toluene (3×) filtered The filtrate was 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