Potassium Carbonate → N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide

Participants

Reaction Conditions

Reaction Steps

A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO; 0.250 g, 0.525 mmol), (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid (0.164 g, 0.788 mmol), Pd(PPh3)4 (0.061 g, 0.053 mmol), and potassium carbonate (0.363 g, 2.63 mmol). Dioxane (2.63 mL) and Water (0.875 mL) were added, the vial was flushed with argon and sealed, and heated in a microwave reactor at 90° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 50% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.271 g, 0.449 mmol, 85% yield) as a white solid. N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (35 mg, 0.058 mmol) was dissolved in 1 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, dissolved in methanol, and passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford 1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.92 (br. s., 1H), 8.77 (d, J=5.7 Hz, 1H), 8.62 (d, J=1.6 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H), 7.99-7.91 (m, 2H), 7.89-7.77 (m, 3H), 7.27 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H). m/z (ESI) 454.1 (M+H)+.

Provenance & Evidence