4,4-difluorocyclohexane-1-carbaldehyde

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 173 g (0.900 mol) of 4,4-difluorocyclohexanecarboxylic acid ethyl ester in 1.0 L toluene, 945 ml (0.945 mol) of 1.0 M diisobutyl aluminum hydride-toluene solution was added dropwise at −55° C. or lower temperatures and then the reaction solution was stirred at −65° C. for 30 minutes. After completion of the reaction, saturated ammonium chloride aqueous solution was added at −40° C. or lower temperatures to the reaction solution and then 1.0 L of 4 N hydrochloric acid was added at 0° C. or lower temperatures. The organic layer was separated and then the aqueous layer was extracted with toluene, and the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg) to provide 75.3 g of the title compound as a colorless oil (yield: 57%). was added at −40° C. The organic layer was separated the aqueous layer was extracted with toluene the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order dried with anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg)

反応条件: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 173 g (0.900 mol) of 4,4-difluorocyclohexanecarboxylic acid ethyl ester in 1.0 L toluene, 945 ml (0.945 mol) of 1.0 M diisobutyl aluminum hydride-toluene solution was added dropwise at −55° C. or lower temperatures and then the reaction solution was stirred at −65° C. for 30 minutes. After completion of the reaction, saturated ammonium chloride aqueous solution was added at −40° C. or lower temperatures to the reaction solution and then 1.0 L of 4 N hydrochloric acid was added at 0° C. or lower temperatures. The organic layer was separated and then the aqueous layer was extracted with toluene, and the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg) to provide 75.3 g of the title compound as a colorless oil (yield: 57%). was added at −40° C. The organic layer was separated the aqueous layer was extracted with toluene the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order dried with anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg)

反応条件: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 173 g (0.900 mol) of 4,4-difluorocyclohexanecarboxylic acid ethyl ester in 1.0 L toluene, 945 ml (0.945 mol) of 1.0 M diisobutyl aluminum hydride-toluene solution was added dropwise at −55° C. or lower temperatures and then the reaction solution was stirred at −65° C. for 30 minutes. After completion of the reaction, saturated ammonium chloride aqueous solution was added at −40° C. or lower temperatures to the reaction solution and then 1.0 L of 4 N hydrochloric acid was added at 0° C. or lower temperatures. The organic layer was separated and then the aqueous layer was extracted with toluene, and the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg) to provide 75.3 g of the title compound as a colorless oil (yield: 57%). was added at −40° C. The organic layer was separated the aqueous layer was extracted with toluene the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order dried with anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg)

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

実験手順: A mixture of the crude product of 4,4-difluorocyclohexane-1-carbaldehyde obtained in Example 2b (1.4 g) and tetrahydrofuran (100 ml) was cooled to 0° C., tert-butyl N-(piperidin-4-yl)carbamate (2.27 g, 11.3 mmol) was added thereto, followed by stirring for 20 minutes. Sodium triacetoxyborohydride (2.2 g, 10.4 mmol) was then added to the reaction mixture, which was stirred at mom temperature for eight hours. Brine 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). The resulting residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution, and the solvent was then distilled off to give the title compound (650 mg, yield 20.7%). was stirred at mom temperature for eight hours 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) The resulting residue was dissolved in ethyl acetate washed with a saturated aqueous sodium bicarbonate solution the solvent was then 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 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: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: Methyl(triphenylphosphoranylidene)acetate (8.827 g, 26 mmol, 1.1 eq) is added at room temperature to a solution of 4,4-difluorocyclohexanecarbaldehyde (3.55 g, 24 mmol, 1 eq) in dry THF (60 ml). The mixture is stirred for 6 h and the solvent is evaporated. Hexane (50 ml) is added to the crude, the mixture is put a few minutes in an ultrasonic bath, stirred for 1 h and filtered. The filtrate is concentrated under reduced pressure to afford 4.05 g of methyl 3-(4,4-difluorocyclohexyl)prop-2-enoate a1-16. the solvent is evaporated Hexane (50 ml) is added to the crude the mixture is put a few minutes in an ultrasonic bath stirred for 1 h filtered The filtrate is concentrated under reduced pressure

反応条件: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 173 g (0.900 mol) of 4,4-difluorocyclohexanecarboxylic acid ethyl ester in 1.0 L toluene, 945 ml (0.945 mol) of 1.0 M diisobutyl aluminum hydride-toluene solution was added dropwise at −55° C. or lower temperatures and then the reaction solution was stirred at −65° C. for 30 minutes. After completion of the reaction, saturated ammonium chloride aqueous solution was added at −40° C. or lower temperatures to the reaction solution and then 1.0 L of 4 N hydrochloric acid was added at 0° C. or lower temperatures. The organic layer was separated and then the aqueous layer was extracted with toluene, and the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg) to provide 75.3 g of the title compound as a colorless oil (yield: 57%). was added at −40° C. The organic layer was separated the aqueous layer was extracted with toluene the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order dried with anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg)

反応条件: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 173 g (0.900 mol) of 4,4-difluorocyclohexanecarboxylic acid ethyl ester in 1.0 L toluene, 945 ml (0.945 mol) of 1.0 M diisobutyl aluminum hydride-toluene solution was added dropwise at −55° C. or lower temperatures and then the reaction solution was stirred at −65° C. for 30 minutes. After completion of the reaction, saturated ammonium chloride aqueous solution was added at −40° C. or lower temperatures to the reaction solution and then 1.0 L of 4 N hydrochloric acid was added at 0° C. or lower temperatures. The organic layer was separated and then the aqueous layer was extracted with toluene, and the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg) to provide 75.3 g of the title compound as a colorless oil (yield: 57%). was added at −40° C. The organic layer was separated the aqueous layer was extracted with toluene the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order dried with anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg)

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

実験手順: A mixture of the crude product of 4,4-difluorocyclohexane-1-carbaldehyde obtained in Example 2b (1.4 g) and tetrahydrofuran (100 ml) was cooled to 0° C., tert-butyl N-(piperidin-4-yl)carbamate (2.27 g, 11.3 mmol) was added thereto, followed by stirring for 20 minutes. Sodium triacetoxyborohydride (2.2 g, 10.4 mmol) was then added to the reaction mixture, which was stirred at mom temperature for eight hours. Brine 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). The resulting residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution, and the solvent was then distilled off to give the title compound (650 mg, yield 20.7%). was stirred at mom temperature for eight hours 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) The resulting residue was dissolved in ethyl acetate washed with a saturated aqueous sodium bicarbonate solution the solvent was then distilled off