反应详情

温度

60 °C

A mixture of 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 27] (40 mg, 0.110 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione [Intermediate 41] (47 mg, 0.110 mmol), Cs2CO3 (107 mg, 0.329 mmol), dioxane (8 mL) and water (2 mL) was bubbled with nitrogen for 10 min. The mixture was treated with PdCl2(dppf) DCM adduct (7.2 mg, 8.76 μmol), and heated at 60° C. overnight. The cooled mixture was partitioned between EtOAc and water. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with MeOH-DCM (gradient from 0-5%), to give 4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (20 mg, 31% yield). Mass spectrum m/z 569 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.66-7.61 (m, 1H), 7.59-7.54 (m, 1H), 7.51-7.46 (m, 2H), 7.27-7.17 (m, 2H), 7.06-6.88 (m, 1H), 3.88 (dd, J=11.6, 8.0 Hz, 3H), 1.64 (s, 6H). 19F NMR (400 MHz, chloroform-d) δ −121.34, −127.34.

1. customwas bubbled with nitrogen for 10 min
2. customThe cooled mixture was partitioned between EtOAc and water
3. customThe organic phase was dried
4. concentrationconcentrated
5. customThe residue was purified by column chromatography on silica gel
6. washeluting with MeOH-DCM (gradient from 0-5%)