Sodium hydride → (2S)-N-(5-chloropyridin-2-yl)-3-ethoxy-2-(1-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide

Participants

Reaction Conditions

Reaction Steps

Sodium hydride (60% in oil) (29.2 mg, 0.73 mmol) was added to (S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H3) (149 mg, 0.61 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 1-(1-methyl-1H-imidazol-2-yl)-4-phenoxy-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AV1) (196 mg, 0.67 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was quenched with 1M citric (2 mL), extracted with EtOAc, the organic layer was washed with water ×2 and brine, dried (MgSO4), filtered and evaporated to afford orange oil. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents to afford the product (111 mg, 41.2%, 95% ee). 1H NMR (400 MHz, CDCl3) δ 1.22 (3H, t), 3.56-3.72 (5H, m), 4.03-4.15 (2H, m), 6.05 (1H, t), 7.02 (1H, d), 7.17 (1H, d), 7.65-7.71 (1H, m), 8.19-8.26 (2H, m), 8.43 (1H, s), 8.65 (1H, s), 8.78 (1H, s); m/z (ES+) (M+H)+=443.40; HPLC tR=1.92 min.

Provenance & Evidence