Reaction Steps
A mixture of 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 27] (0.098 g, 0.268 mmol), 5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 33] (0.144 g, 0.349 mmol), Cs2CO3 (0.175 g, 0.537 mmol), and dioxane (1.6 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with PdCl2(dppf) DCM adduct (0.013 g, 0.016 mmol) and subjected to two more evacuate-fill cycles with nitrogen. The mixture was heated at 52° C. overnight. The cooled mixture was diluted with EtOAc, washed sequentially with water and brine, and dried and concentrated. The residue was purified by reverse-phase preparative HPLC. The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated. The residue was partitioned between EtOAc and water, and the organic layer was washed with brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified twice by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 50%, 65% and 75%) to give 4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a yellow solid (0.013 g, 8% yield). Mass spectrum m/z 571, 573 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 11.39 (d, J=5.3 Hz, 1H), 8.30-8.24 (m, 1H), 8.21 (br. s., 1H), 7.95 (dd, J=10.5, 1.7 Hz, 1H), 7.84 (s, 1H), 7.60 (d, J=7.2 Hz, 2H), 7.55-7.47 (m, 2H), 7.42-7.39 (m, 1H), 7.04-6.99 (m, 1H), 6.93 (d, J=8.6 Hz, 0.6H), 6.84 (d, J=8.6 Hz, 0.4H), 6.57 (td, J=7.3, 3.5 Hz, 1H), 6.00 (d, J=8.6 Hz, 1H), 4.98 (s, 1H), 1.78 (d, J=1.9 Hz, 3H), and 1.45 (d, J=3.9 Hz, 6H).
