TERT-BUTYL METHYL(PIPERIDIN-4-YLMETHYL)-CARBAMATE

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

実験手順: A solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (0.2 g, 1.23 mmol), tert-butyl methyl(piperidin-4-ylmethyl)carbamate (0.29 g, 1.36 mmol) and DIPEA (1 mL, 5.7 mmol) in EtOH (3 mL) was heated at 130° C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (40% EtOAc/isohexane) to give tert-butyl (1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as a yellow oil (0.34 g, 80%). To a solution of this oil (0.15 mg, 0.44 mmol) in DMF (5 mL) cooled to 0° C. was added sodium hydride (27 mg, 0.66 mmol, 60% in mineral oil) and the mixture was stirred at 0° C. for 15 min. Iodomethane (0.03 mL, 0.53 mmol) was added and the mixture was stirred at 0° C. for 30 min. Additional sodium hydride (14 mg, 0.33 mmol) and iodomethane (0.02 mL, 0.78 mmol) were added, the reaction mixture was allowed to warm to 10° C. and stirred for 1 hr. Water (10 mL) was added and the mixture was extracted with EtOAc (60 mL). The organic layer was washed with water (7×10 mL), washed with brine (10 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification of the residue by silica gel column chromatography (30% EtOAc/isohexane) afforded tert-butyl methyl((1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methyl)carbamate as a yellow oil (148 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 3.74 (s, 3H), 3.38-3.26 (m, 2H), 3.25-3.15 (m, 2H), 3.12-2.95 (m, 2H), 2.89 (s, 3H), 1.90-1.71 (m, 3H), 1.60-1.32 (m, 2H), 1.47 (s, 9H). The solvent was removed under reduced pressure the residue was purified by silica gel column chromatography (40% EtOAc/isohexane)

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

実験手順: tert-Butyl methyl(piperidin-4-ylmethyl)carbamate (4.67 mmol, 1.0 eq) and 4-chloropyrimidine hydrochloride (14.0 mmol, 3.0 eq) were dissolved in 2-propanol (18 ml) and DIPEA (23.33 mmol. 5.0 eq) and refluxed for 16 hours. After monitoring by TLC, the reaction solution was diluted with ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was washed with ethyl acetate. The combined organic phases were washed 1× with sat. NaCl solution, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia solution). Yield: 78% the phases were separated The aqueous phase was washed with ethyl acetate The combined organic phases were washed 1× with sat. NaCl solution dried over magnesium sulfate concentrated under reduced pressure The crude product was purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia solution)

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

実験手順: tert-Butyl methyl(piperidin-4-ylmethyl)carbamate (1.4 mmol, 1.0 eq) and 4-chloropyridine (4.2 mmol, 3.0 eq) were dissolved in 2-propanol (5 ml) and DIPEA (7.0 mmol. 5.0 eq) and refluxed for 16 hours. After monitoring by TLC, the reaction solution was diluted with ethyl acetate and sat. sodium hydrogen carbonate solution and the phases were separated. The aqueous phase was washed with ethyl acetate. The combined organic phases were dried over magnesium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia solution). Yield: 51% the phases were separated The aqueous phase was washed with ethyl acetate The combined organic phases were dried over magnesium sulfate concentrated under reduced pressure purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia solution)