The general procedure for the synthesis of N-(2-(1-piperidinyl)-5-(trifluoromethyl)phenyl)isonicotinamide from 2-piperidin-1-yl-5-(trifluoromethyl)aniline and isocyanidinium chloride is as follows: isonicotinic acid chloride hydrochloride (6.48 g, 36.4 mmol, commercially available) and triethylamine (5.57 ml, 54.6 mmol) are sequentially added at 0°C to the 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (4.45 g, 18.2 mmol, prepared as described in Reference Examples 1-2B) to a solution of methylene chloride (10 ml). The reaction mixture was stirred for 30 minutes. Subsequently, water was added to the mixture and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (200 g silica gel, eluent ratio hexane/ethyl acetate = 1/1) and recrystallized. The final N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (SRPIN-1, GIF-0340) (5.49 g, 86.3% yield) was obtained as a colorless solid.
