Diisopropylethylamine → N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide

Participants

Reaction Steps

5-Cyano-3-methylpicolinic acid (232 mg, 1.432 mmol) (Prepared as described in Badiger, Sangamesh et al. PCT Int. Appl., 2012095469) was placed in a round bottom flask and dissolved in DMF (7 mL). HATU (669 mg, 1.760 mmol) was added and the reaction was stirred at room temperature for 5 min, N,N-diisopropylethylamine (0.7 mL, 4.1 mmol) was added. The reaction mixture was cooled to 0° C. and added dropwise to a solution of (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethyl-3,4,5,6-tetrahydropyridin-2-amine (470 mg, 1.63 mmol) in DMF (7 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min then at 30 min at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water. The phases were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified using a RediSep Automated flash system on 80 g silica gel (eluent: ethyl acetate/heptane). The product was further purified by the following procedure: The product was dissolved in ethyl acetate (50 mL) and washed with a solution of saturated aqueous NaHCO3/water (1/1). The organic phase was washed total of 15 times (using 10 mL each time). The organic phase was dried over MgSO4, filtered, and evaporated to give N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide (153 mg, 26% yield).

Provenance & Evidence