ethyl 4-methylpiperidine-4-carboxylate

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: A mixture of 4-chlorophenyl isothiocyanate (2.36 g, 13.98 mmol), and ethyl 4-methylpiperidine-4-carboxylate (US 2002/0086887, example 532C) (2.17 g, 12.71 mmol) in dichloromethane (50 mL) was stirred at room temperature for 30 minutes. The mixture was partitioned between dichloromethane and brine, and the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:ethyl acetate (100:0 to 90:10) to provide the title compound as a white solid, 3.46 g. The mixture was partitioned between dichloromethane and brine the layers were separated The organic phase was dried over MgSO4 evaporated under reduced pressure The crude product was purified by column chromatography on silica gel

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

実験手順: A solution of 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (500 mg, 1.6 mmol), AcOH (288 mg, 4.8 mmol, 3.0 eq) and ethyl 4-methylpiperidine-4-carboxylate (410 mg, 2.4 mmol, 1.5 eq) in DCM (5 mL) was stirred at room temperature for 10 min. Then NaBH3CN (300 mg, 4.8 mmol, 3.0 eq) was added. The reaction mixture was stirred at room temperature for 12 h, quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether:ethyl acetate=3:1) to give ethyl 1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-methylpiperidine-4-carboxylate (480 mg, yield: 30%) as a yellow oil. ESI-MS (M+1)+: 466.2. 1HNMR (400 MHz, CDCl3) δ: 7.75˜7.73 (m, 3H), 7.48 (d, 1H), 7.18˜7.15 (m, 2H), 4.28˜4.26 (m, 1H), 4.19˜4.12 (q, 2H), 4.01 (s, 2H), 3.17˜3.15 (m, 2H), 2.59 (br, 2H), 2.29˜2.17 (m, 4H), 1.91˜1.82 (m, 4H), 1.46˜1.43 (m, 3H), 1.30˜1.18 (m, 8H), 0.88 (s, 9H). quenched with water (5 mL) extracted with DCM (3×10 mL) The combined organic layers were washed with brine (10 mL) dried over Na2SO4 concentrated The residue was purified by silica gel column chromatography (Petroleum ether:ethyl acetate=3:1)

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

実験手順: A solution of 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (500 mg, 1.6 mmol), AcOH (288 mg, 4.8 mmol, 3.0 eq) and ethyl 4-methylpiperidine-4-carboxylate (410 mg, 2.4 mmol, 1.5 eq) in DCM (5 mL) was stirred at room temperature for 10 min. Then NaBH3CN (300 mg, 4.8 mmol, 3.0 eq) was added. The reaction mixture was stirred at room temperature for 12 h, quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether:ethyl acetate=3:1) to give ethyl 1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-methylpiperidine-4-carboxylate (480 mg, yield: 30%) as a yellow oil. ESI-MS (M+1)+: 466.2. 1HNMR (400 MHz, CDCl3) δ: 7.75˜7.73 (m, 3H), 7.48 (d, 1H), 7.18˜7.15 (m, 2H), 4.28˜4.26 (m, 1H), 4.19˜4.12 (q, 2H), 4.01 (s, 2H), 3.17˜3.15 (m, 2H), 2.59 (br, 2H), 2.29˜2.17 (m, 4H), 1.91˜1.82 (m, 4H), 1.46˜1.43 (m, 3H), 1.30˜1.18 (m, 8H), 0.88 (s, 9H). quenched with water (5 mL) extracted with DCM (3×10 mL) The combined organic layers were washed with brine (10 mL) dried over Na2SO4 concentrated The residue was purified by silica gel column chromatography (Petroleum ether:ethyl acetate=3:1)

反応条件: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-benzyl-6-chloro-4,5-dimethyl-pyridazine (1.0 g, 4.3 mmol) in NMP (10 mL) is added 4-methyl-piperidine-4-carboxylic acid ethyl ester (2.0 g, 8.6 mmol) and DIPEA (3.7 mL, 21.6 mmol). The mixture is heated in microwave at 210° C. for 1.5 h. The mixture is concentrated at 80° C. by rotovaporation. The crude product is purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-4-methyl-piperidine-4-carboxylic acid ethyl ester (0.64 g, 41%). The mixture is concentrated at 80° C. by rotovaporation The crude product is purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA)

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

実験手順: A mixture of 4-chlorophenyl isothiocyanate (2.36 g, 13.98 mmol), and ethyl 4-methylpiperidine-4-carboxylate (US 2002/0086887, example 532C) (2.17 g, 12.71 mmol) in dichloromethane (50 mL) was stirred at room temperature for 30 minutes. The mixture was partitioned between dichloromethane and brine, and the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:ethyl acetate (100:0 to 90:10) to provide the title compound as a white solid, 3.46 g. The mixture was partitioned between dichloromethane and brine the layers were separated The organic phase was dried over MgSO4 evaporated under reduced pressure The crude product was purified by column chromatography on silica gel

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

実験手順: A mixture of 4-chlorophenyl isothiocyanate (2.36 g, 13.98 mmol), and ethyl 4-methylpiperidine-4-carboxylate (US 2002/0086887, example 532C) (2.17 g, 12.71 mmol) in dichloromethane (50 mL) was stirred at room temperature for 30 minutes. The mixture was partitioned between dichloromethane and brine, and the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:ethyl acetate (100:0 to 90:10) to provide the title compound as a white solid, 3.46 g. The mixture was partitioned between dichloromethane and brine the layers were separated The organic phase was dried over MgSO4 evaporated under reduced pressure The crude product was purified by column chromatography on silica gel

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

実験手順: A mixture of 4-chlorophenyl isothiocyanate (2.36 g, 13.98 mmol), and ethyl 4-methylpiperidine-4-carboxylate (U.S. 2002/0086887, example 532C) (2.17 g, 12.71 mmol) in dichloromethane (50 mL) was stirred at room temperature for 30 minutes. The mixture was partitioned between dichloromethane and brine, and the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:ethyl acetate (100:0 to 90:10) to provide the title compound as a white solid, 3.46 g. The mixture was partitioned between dichloromethane and brine the layers were separated The organic phase was dried over MgSO4 evaporated under reduced pressure The crude product was purified by column chromatography on silica gel

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 mixture of 4-chlorophenyl isothiocyanate (2.36 g, 13.98 mmol), and ethyl 4-methylpiperidine-4-carboxylate (U.S. 2002/0086887, example 532C) (2.17 g, 12.71 mmol) in dichloromethane (50 mL) was stirred at room temperature for 30 minutes. The mixture was partitioned between dichloromethane and brine, and the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:ethyl acetate (100:0 to 90:10) to provide the title compound as a white solid, 3.46 g. The mixture was partitioned between dichloromethane and brine the layers were separated The organic phase was dried over MgSO4 evaporated under reduced pressure The crude product was purified by column chromatography on silica gel

反応条件: temp:0.00; pressure:0.00; stir: