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

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Reaction Conditions

Reaction Steps

A vial was charged with 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (Example 337, 68.14 mg, 0.149 mmol) (3-fluorophenyl)boronic acid (62.5 mg, 0.446 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (3.05 mg, 7.44 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (11.27 mg, 0.015 mmol), and potassium phosphate (158 mg, 0.744 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (676 μl) and water (67.6 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. LCMS showed >95% conversion to the desired product. The mixture was extracted with EtOAc (3×), 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, 7.5% MeOH/DCM). The resulting material was taken up in DCM, sonicated, filtered, 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-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (58.22 mg, 0.112 mmol, 76% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.17 (d, J=5.8 Hz, 1H), 7.96 (s, 1H), 7.91 (dd, J=1.9, 8.9 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.69-7.58 (m, 3H), 7.45 (s, 1H), 7.41 (dt, J=1.6, 8.5 Hz, 1H), 3.82 (s, 3H). m/z (ESI) 518.2 (M+H)+.

Provenance & Evidence