Reaction Steps
5-(1-(2-Methoxypyridin-4-yl)ethyl)-N-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine. 1-(2-Methoxypyridin-4-yl)-1-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)ethanol (0.348 g, 0.810 mmol), methanesulfonic anhydride (0.353 g, 2.026 mmol), N,N-diisopropylethylamine (0.565 mL, 3.24 mmol), and N,N-dimethylformamide (9 mL) were combined in a sealable vessel with a stirbar. Nitrogen gas was blown in to blow out air. The resulting mixture was sealed, stirred vigorously, and heated at 100° C. for 24 h. A very large excess of both methanesulfonic anhydride and N,N-diisopropylethylamine were added in order to push the reaction to completion. The resulting mixture was sealed, stirred vigorously, and heated at 100° C. for another 1 h. The resulting mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate, and water and shaken in a reparatory funnel. The layers were separated. The water layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate and purified using flash chromatography (Biotage) (20-80% ethyl acetate in hexane) to give an impure tan solid. MS (ESI) m/z 412.0 [M+1]+. The tan solids were dissolved in 1-methyl-2-pyrrolidinone (3 mL) with stirring at room temperature and then diluted with ethanol (3 mL). A combination vacuum/nitrogen/hydrogen manifold was attached. The atmosphere in the flask was removed and replaced with nitrogen three times. Palladium (10 wt. % on activated carbon) (0.122 g, 0.115 mmol) was added and the atmosphere in the flask was removed and replaced with hydrogen three times. The resulting mixture was stirred vigorously under a hydrogen balloon at room temperature for 2.5 h. The atmosphere in the flask was removed and replaced with hydrogen three times. The resulting mixture was stirred vigorously under a hydrogen balloon at 50° C. for 1.5 h. The atmosphere in the flask was removed and replaced with hydrogen three times. The resulting mixture was stirred vigorously under a hydrogen balloon at 60° C. for 27 h. The resulting black mixture was filtered through Celite and purified using reverse-phase preparatory HPLC (30-100% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 35 min). Fractions containing the desired product were loaded onto a Strata X—C ion exchange column from Phenomenex. The column was washed successively with water, acetonitrile, methanol, and then 5% ammonium hydroxide in methanol. The product came off with the 5% ammonium hydroxide in methanol eluent and was concentrated on a rotary evaporator and dried under high vacuum to give the desired product (0.172 g, 0.416 mmol, 51% yield over two steps) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.08 (s, 1H), 8.08 (d, J=4.69 Hz, 1H), 7.77 (d, J=8.59 Hz, 2H), 7.64-7.71 (m, J=7.42, 8.98 Hz, 1H), 7.54-7.64 (m, 3H), 7.16 (d, J=7.03 Hz, 1H), 6.92 (dd, J=1.37, 5.27 Hz, 1H), 6.80 (s, 1H), 4.84 (q, J=7.03 Hz, 1H), 3.80 (s, 3H), 1.72 (d, 3H); 19F NMR (376 MHz, DMSO-d6) δ (ppm)-60.10 (s, 3F); MS (ESI) m/z 414.4 [M+1]+.
