2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl → 1-(2-methoxy-4-neopentylphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide

Participants

Reaction Conditions

Reaction Steps

A vial was charged with 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (EXAMPLE 160; 67 mg, 0.157 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (6.44 mg, 0.016 mmol), and Pd2(dba)3 (7.19 mg, 7.85 mmol). The vial was flushed with Ar (g), then neopentylzinc(II) iodide (0.5 M in THF) (1570 μl, 0.785 mmol) was added. The mixture was sonicated for 30 s to give a suspension. The sealed vial was heated to 70° C. for 2 h then 90° C. overnight. The mixture was diluted with MeOH, filtered through Celite, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7.5% MeOH/DCM) to give a yellow foam. The material was dissolved in MeOH/DCM and loaded onto a 2-g SCX-2 ion exchange column. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (25-g Interchim 15 micron column, 3.5% MeOH/DCM) to give 1-(2-methoxy-4-neopentylphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (23.65 mg, 0.051 mmol, 32.6% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.07 (br. s, 1H), 8.70-8.61 (m, 2H), 8.57 (s, 1H), 8.24 (br. s., 1H), 8.06 (d, J=5.8 Hz, 1H), 7.94 (dd, J=1.7, 8.9 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.03 (br. s., 1H), 6.96 (s, 1H), 6.89 (d, J=7.6 Hz, 1H), 3.62 (s, 3H), 2.60 (s, 2H), 0.97 (s, 9H). m/z (ESI) 463.2 (M+H)+.

Provenance & Evidence