反应详情

温度

90 °C

A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (100 mg, 0.262 mmol), 8-fluoro-1-methyl-3-(RS)-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (161 mg, 0.393 mmol), tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) and 2 M aqueous K3PO4 (0.26 mL, 0.524 mmol) in THF (2 mL) in a pressure reaction vial was heated at 90° C. for 2.5 h. The cooled mixture was concentrated, and the residue was purified by column chromatography on silica gel (40 g), eluting with DCM-MeOH—NH4OH (gradient from 90:9:1-97:2.7:0.3). The resulting impure product was again purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 50-100%), to give 3-chloro-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl) -7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (110 mg, 68% yield). Mass spectrum m/z 567 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 8.17-8.10 (m, 1H), 7.76 (s, 1H), 7.69 (d, J=1.1 Hz, 1H), 7.59-7.53 (m, 1H), 7.48 (ddt, J=13.9, 8.1, 1.8 Hz, 1H), 7.39 (dd, J=12.4, 7.8 Hz, 2H), 7.28-7.19 (m, 2H), 6.97 (t, J=8.5 Hz, 1H), 3.87-3.93 (m, 3H), 1.87 (d, J=1.8 Hz, 3H), 1.65 (s, 3H), 1.65 (s, 3H).

1. customin a pressure reaction
2. concentrationThe cooled mixture was concentrated
3. customthe residue was purified by column chromatography on silica gel (40 g)
4. washeluting with DCM-MeOH—NH4OH (gradient from 90:9:1-97:2.7:0.3)
5. customThe resulting impure product was again purified by column chromatography on silica gel (40 g)
6. washeluting with EtOAc-hexanes (gradient from 50-100%)