반응 단계
A solution of 3,5-dichloropyridazine (4.47 g, 30 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (5.59 g, 30 mmol) and triethylamine (8.1 g, 80 mmol) in THF (50 mL) was stirred at ambient temperature for 20 hrs. The solvent was removed under reduced pressure and the residue was purified by column chromatography to afford the desired product (5.4 g, 60%) as a colorless solid. LC-MS: m/z=299.2 [M+H+]+. (R)-tert-butyl-1-(6-chloropyridazin-4-yl)pyrrolidin-3-yl(methyl)carbamate. A solution of (R)-tert-butyl 1-(6-chloropyridazin-4-yl)pyrrolidin-3-ylcarbamate (3.6 g, 12.05 mmol) in N,N-dimethylformamide (DMF, 40 mL) was added into a suspension of 60% sodium hydride (0.58 g, 14.5 mmol) in DMF (40 mL) at 0° C. The mixture was stirred at 0° C. for further 30 min then Iodomethane (2.06 g, 14.5 mmol) was added into the mixture and the resulting reaction was stirred for further 3 h at ambient temperature. Water (100 mL) was added and the mixture was extracted with dichloromethane. The combined organic layer was dried over Na2SO4, filtered and concentrated. The solvent was removed under reduced pressure and the residue was purified by column chromatography to afford the desired product (2.5 g, 66%) as a brown solid. 1H NMR (300 MHz, CDCl3): 8.47 (d, J=2.4 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 4.89 (br s, 1H), 3.58-3.52 (m, 2H), 3.42-3.36 (m, 1H), 3.29-3.23 (m, 1H), 2.82 (s, 3H), 2.27-2.14 (m, 2H), 1.47 (s, 9H). (R)-tert-butyl methyl(1-(6-(1-adamantylamino)pyridazin-4-yl)pyrrolidin-3-yl)carbamate. A mixture of (R)-tert-butyl 1-(6-chloropyridazin-4-yl)pyrrolidin-3-yl(methyl)carbamate (78 mg, 0.25 mmol), 1-adamantylamine (76 mg, 0.5 mmol), BINAP (10.9 mg, 0.0175 mmol), palladium acetate (3.9 mg, 0.0175 mmol) and t-BuONa (72.1 mg, 0.75 mmol) in 1,2-dimethoxyethane (2 mL) was charged with N2. The reaction mixture was stirred at 80° C. for 1.5 hours. The solution was diluted with ethyl acetate (5 mL) and washed with 5% NaHCO3 solution. The solvent was removed under reduced pressure and the residue was purified by column chromatography 0˜3.5% NH3 MeOH/DCM to afford the desired product (64 mg, 60%) as a colorless solid. LC-MS: m/z=428.3 [M+H]+. (R)-5-(3-(methylamino)pyrrolidin-1-yl)-N-(1-adamantyl)pyridazin-3-amine dihydrochloride. (R)-tert-butyl methyl(1-(6-(1-adamantylamino)pyridazin-4-yl)pyrrolidin-3-yl)carbamate (120 mg, 0.28 mmol) was dissolved in MeOH (4 mL) and 7N HCl/Et2O solution (20 mL) was added. The resulting solution was stirred at ambient temperature for 18 hrs. The solvent was concentrated to give the desired product as a light yellow solid (73 mg, 60%). MS (ESI): mass calcd. for C19H29N5, 327.48 m/z found, 328.3 [M+H]+. 1H NMR (300 MHz, CD3OD): 8.15 (s, 1H), 6.12 (s, 1H), 4.08-3.60 (m, 5H), 2.84 (s, 3H), 2.61-2.56 (m, 1H), 2.42-2.38 (m, 1H), 2.20 (s, 3H), 2.10 (s, 6H), 1.87-1.77 (m, 6H). The compounds in Examples 414 through 416 were made analogously to Example 413.
