4-Aminopyrimidine → 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide

Participants

Reaction Steps

A round-bottom flask was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 72.97 mg, 0.120 mmol) pyrimidin-4-amine (Alfa Aesar, Ward Hill, Mass., 12.52 mg, 0.132 mmol), and THF (598 μl) to give a clear, lightly-colored solution. The flask was cooled in an ice-bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (251 μl, 0.251 mmol) was added drop wise over 30 s to give a yellow suspension. After 30 min, the mixture was purified directly by chromatography on silica gel (12-g Redi-Sep Gold column, 3.5 MeOH/DCM, then 3.5-10% MeOH/DCM). A few mixed fractions were discarded, and the remainder of fractions containing product were combined and concentrated to give 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (40.83 mg, 0.078 mmol, 65.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.12 (br. s., 1H), 8.71 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.24 (d, J=6.6 Hz, 1H), 8.14 (d, J=5.8 Hz, 1H), 7.99 (dd, J=1.8, 8.9 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.58 (dt, J=6.3, 8.0 Hz, 1H), 7.54 (s, 1H), 7.49-7.40 (m, 2H), 7.35-7.29 (m, 1H), 7.27 (s, 1H), 7.02 (d, J=6.6 Hz, 1H), 3.70 (s, 3H). m/z (ESI) 521.2 (M+H)+.

Provenance & Evidence