Reaction Steps
To a three-necked flask were charged potassium thiocyanate (200.0 g, 2.03 mol), and tetrahydrofuran (6.78 L). 2-Fluoro-5-(trifluoromethyl)benzoyl chloride (471.0 g, 2.07 mol) was added into the flask slowly at room temperature. The reaction mixture was stirred at room temperature for 5 hours or until less than 1% of the acid chloride remains. The reaction mixture was filtered to remove potassium chloride by-product, and rinsed with tetrahydrofuran (about 0.5 L). The combined solution of 2-fluoro-5-(trifluoromethyl)benzoyl isothiocyanate was charged back to the three-necked flask, followed by addition of N-butyl-4-chloropyridin-3-amine (266.0 g, 1.44 mol). The reaction mixture was heated to approximately 50° C., and stirred vigorously overnight or until less than 1% of N-butyl-4-chloropyridin-3-amine remains. The product suspension was then cooled to room temperature, and the product collected by filtration. The wet cake was washed with tetrahydrofuran (1.0 L), and dried under vacuum at 60° C. to give the desired product (584.0 g, 93% isolated yield). MS-ESI: 398 (M+1); 1H-NMR (CDCl3-DMSO-d6) δ 0.96 (3H, t, J=7.4 Hz), 1.45 (2H, m), 1.84 (2H, m), 4.58 (2H, d, J=7.6 Hz), 7.49 (1H, t, J=9.0 Hz), 7.92 (1H, m), 8.42 (1H, d, J=5.8 Hz), 8.46 (1H, dd, J=6.6, 2.5 Hz), 8.65 (1H, d, J=6.6 Hz), 9.37 (1H, s); 13-NMR (CDCl3-DMSO-d6) δ 13.50, 19.47, 29.12, 46.08, 118.07 (d, J=23 Hz), 119.70, 122.90 (q, J=269 Hz, CF3), 123.96 (d, J=10 Hz), 124.84 (q, J=33 Hz, C—CF3), 128.21, 128.78, 130.70, 134.50, 137.03, 141.20, 162.78 (d, J=262 Hz, C—F), 165.79, 170.06 (d, J=4.0 Hz).
