Citric Acid → (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)propanamide

Participants

Reaction Conditions

Reaction Steps

Sodium hydride (87 mg, 2.18 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate BB2) (400 mg, 1.09 mmol) in anhydrous tetrahydrofuran (15 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BA3) (360 mg, 1.20 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (30 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 40 to 80% ethyl acetate in isohexane, to afford the product (395 mg, 57.5%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.88 (9H, s), 2.54 (3H, s), 3.09-3.13 (2H, m), 3.16-3.21 (1H, m), 3.29-3.34 (1H, m), 3.87-3.92 (2H, m), 4.51 (1H, qn), 5.92-5.95 (1H, m), 7.43-7.47 (1H, m), 7.52-7.55 (2H, m), 8.14 (1H, d), 8.41 (1H, s), 8.59 (1H, s), 9.42 (1H, d), 9.96 (1H, s); m/z (ES+) (M+H)+=631; HPLC tR=2.94 min.

Provenance & Evidence