Potassium Phosphate, Tribasic → 1-(2-cyano-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide

Participants

Reaction Conditions

Reaction Steps

A vial was charged with 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (Example 337, 55.6 mg, 0.121 mmol) (3-fluorophenyl)boronic acid (34.0 mg, 0.243 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.492 mg, 6.07 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (9.20 mg, 0.012 mmol), and potassium phosphate (129 mg, 0.607 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (552 μl) and water (55.2 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. The mixture was extracted with EtOAc (2×) and 10% MeOH/EtOAc (2×) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7.5% MeOH/DCM, a few colored fractions were discarded). The resulting tan solid was taken up in DCM and filtered. The collected solid was washed with DCM (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(2-cyano-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (30.69 mg, 0.059 mmol, 48.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=14.49 (br. s., 1H), 8.79 (s, 1H), 8.73 (d, J=5.7 Hz, 1H), 8.59 (d, J=1.7 Hz, 1H), 8.17 (d, J=5.8 Hz, 1H), 7.96 (s, 1H), 7.90 (dd, J=1.9, 8.9 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.68-7.57 (m, 3H), 7.45 (s, 1H), 7.41 (dt, J=1.7, 8.5 Hz, 1H), 3.82 (s, 3H). m/z (ESI) 518.2 (M+H)+.

Provenance & Evidence