反应详情

温度

80 °C

A mixture of (R)-7-(2-fluoro-phenyl)-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (3.05 g, 6.88 mmol) and paraformaldehyde (2.066 g, 68.8 mmol) in MeOH (60 mL) and AcOH (6 mL) was stirred at 80° C. for 16 h. Then, sodium cyanotrihydroborate (0.865 g, 13.76 mmol) was added and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on basified silica gel (eluting with 10% MeOH in DCM) to give (R)-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (1.15 g, 40%) as a white solid. The white solid was stirred in HCl/EtOAc (4 M, 50 mL) for 30 min and the reaction mixture was concentrated in vacuo to give (R)-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (1.215 g, 39%) as a white solid. 1H NMR (400 MHz, MeOD) δ 7.44 (m, 1H), 7.32-7.16 (m, 3H), 6.90 (m, 1H), 6.84 (s, 1H), 4.68-4.57 (d, J=13.2 Hz, 2H), 3.57 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H), 2.86 (m, 1H), 2.79 (s, 3H), 2.50 (m, 1H), 1.91 (m, 2H), 1.48 (d, J=6.8 Hz, 3H), 0.91 (m, 3H). LC/MS (Table 1, Method 5) Rt=2.275 min.; MS m/z: 423 [M+H]+. SFC (Table 1, Method 47), Rt=1.145 min.

1. stirringthe reaction mixture was stirred at ambient temperature for 0.5 h
2. concentrationThe reaction mixture was concentrated in vacuo
3. customthe residue was purified by column chromatography on basified silica gel (eluting with 10% MeOH in DCM)