Potassium Phosphate, Tribasic → 3-fluoro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido [1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

Participants

Reaction Steps

A mixture of 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 27] (6.00 g, 16.4 mmol), 5-fluoro-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 (single enantiomer) [Intermediate 38] (7.81 g, 19.7 mmol), 2 M aqueous K3PO4 (24.6 mL, 49.3 mmol), and THF (70 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with 1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (0.535 g, 0.821 mmol), and subjected to two more evacuate-fill cycles with nitrogen. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed sequentially with water and brine, and dried. The aqueous layer was filtered and the collected solid was added to the organic layer. The organic layer was concentrated, and the residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 50%, 62%, 75%, 85% and 100%), to provide 3-fluoro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of two atropisomers) as a yellow solid (8.55 g, 94% yield). A sample of this material (combined with other batches of the same material) was separated by chiral super-critical fluid chromatography as follows: column. CHIRALPAK® IC (3×25 cm, 5 μm); Mobile Phase: CO2-MeOH (50:50) at 165 mL/min, 45° C., 100 bar; sample preparation: 55 mg/mL in MeOH-THF-DMSO (2:1:1); injection: 3 mL. The first peak eluting from the column provided a single atropisomer of 3-fluoro-4-(R)-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Example 41].

Provenance & Evidence