Reaction Steps
A vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE OOO) (71.96 mg, 0.151 mmol), (4-chloro-2-methoxyphenyl)boronic acid (31.0 mg, 0.166 mmol), Pd(AmPhos)2Cl2 (5.35 mg, 7.56 μmol), potassium phosphate (128 mg, 0.605 mmol), 1,4-dioxane (567 μl), and water (189 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 30 min h at 90° C. At this point, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62.9 mg, 0.302 mmol) and additional catalyst (about 3 mg) were added. The vial was resealed and heated in the microwave reactor for 1 h at 100° C. Additional portions of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62.9 mg, 0.302 mmol), potassium phosphate (128 mg, 0.605 mmol), and catalyst (about 3 mg) were added, and the vial was heated for 1 h at 100° C. in the microwave. The vial was heated for an additional 2 h at 110° C. The mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 35 min, the mixture was diluted with MeOH and filtered through diatomaceous earth. The filtrate was concentrated. The residue was purified by reverse-phase HPLC (25 to 70% CH3CN/H2O with 0.1% TFA). Fractions containing the desired product were combined in saturated aq. sodium bicarbonate solution with the aid of methanol. The mixture was extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give 1-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (8.5 mg, 0.018 mmol, 11.77% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.88 (br. s., 1H), 8.67 (d, J=5.7 Hz, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.29 (s, 1H), 8.06 (d, J=5.6 Hz, 1H), 8.01 (s, 1H), 7.89-7.74 (m, 2H), 7.38 (s, 1H), 7.34-7.24 (m, 3H), 6.87 (d, J=4.6 Hz, 1H), 3.91 (s, 3H), 3.71 (s, 3H); m/z (ESI) 478.2 (M+H)+.
