Citric Acid → (2S)-N-(5-cyanopyridin-2-yl)-3-ethoxy-2-[1-[2-(trifluoromethyl)phenyl]pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanamide

Participants

Reaction Conditions

Reaction Steps

60% Sodium hydride (60.0 mg, 1.50 mmol) was added in one portion to (S)—N-(5-cyanopyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H4) (235 mg, 1.00 mmol) in anhydrous THF (5 mL) and the mixture was cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and 4-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate P1) (298.6 mg, 1.00 mmol) as suspension in dry THF (4 mL) was added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric acid (4 mL) was added and the mixture extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 20 to 100% ethyl acetate in isohexane to give the product (430 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 1.25 (3H, t), 3.62-3.70 (2H, m), 4.08-4.14 (2H, m), 6.04 (1H, t), 7.53-7.55 (1H, m), 7.68-7.77 (2H, m), 7.91 (1H, dd), 7.97 (1H, dd), 8.39 (1H, dd), 8.41 (1H, s), 8.56 (1H, s), 8.57-8.59 (1H, m), 9.02 (1H, s); m/z (ESI−) (M−H)−=496; HPLC tR=2.55 min.

Provenance & Evidence