Trifluoroacetic acid → 2-(6-(N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)benzamide

Participants

Reaction Steps

A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO; 0.085 g, 0.179 mmol), (2-cyano-4-(trifluoromethyl)phenyl)boronic acid (0.058 g, 0.268 mmol), Pd(PPh3)4 (0.021 g, 0.018 mmol), and potassium carbonate (0.123 g, 0.893 mmol). Dioxane (0.893 ml) and water (0.298 ml) were added, the vial was flushed with argon and sealed, and microwaved at 90° C. for 30 minutes. A small amount of 1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide was observed; however the predominant product was observed as the coupling product with hydrolysis of the nitrile. 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 1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide and 2-(6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)benzamide. The protected nitrile 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 2-(6-(N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)benzamide (0.049 g, 0.102 mmol, 57.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.89 (br. s., 1H), 8.61 (d, J=5.7 Hz, 1H), 8.54 (s, 1H), 8.10-8.03 (m, 3H), 7.98 (d, J=8.4 Hz, 1H), 7.87-7.81 (m, 1H), 7.79-7.68 (m, 2H), 7.34 (br. s., 1H), 7.27 (d, J=4.5 Hz, 1H), 6.86 (d, J=4.5 Hz, 1H). m/z (ESI) 479.2 (M+H)+.

Provenance & Evidence