Potassium Phosphate, Tribasic → 3-chloro-4-(3-(6, 8-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

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Reaction Steps

A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (10 mg, 0.026 mmol), 6,8-difluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 16] (14.1 mg, 0.034 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (12.8 mg, 0.020 mmol) and THF (2 mL) in a reaction vial was treated with 2 M aqueous K3PO4 (0.039 mL, 0.079 mmol). The vial was sealed and subjected to three evacuate-fill cycles with nitrogen. The mixture was stirred at room temperature overnight. The phases of the mixture were separated, the aqueous phase was extracted twice with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc -hexanes (gradient from 80-100%). The isolated material was triturated with MeOH to give a solid after filtration. The filtrate was concentrated and subjected to column chromatography on silica (40 g), eluting with DCM-MeOH—NH4OH (gradient from 90:9:1-97:2.7:0.3) to give additional solid. The two solids were combined to provide 3-chloro-4-(3-(6,8-difluoro-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 pale yellow solid (164 mg, 71% yield). Mass spectrum m/z 571 (M+H—H2O)+. 1H NMR (500 MHz, MeOH-d4) δ 8.04 (d, J=2.0 Hz, 1H), 7.70-7.68 (m, 1H), 7.65 (dd, J=7.2, 3.2 Hz, 1H), 7.57-7.52 (m, 1H), 7.43-7.34 (m, 3H), 7.18-7.07 (m, 1H), 6.90 (dd, J=8.4, 3.0 Hz, 1H), 1.84 (s, 3H), 1.62-1.56 (m, 6H).

Provenance & Evidence