Citric Acid → (2S)-Methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate

Participants

Reaction Conditions

Reaction Steps

Sodium hydride (0.167 g, 4.17 mmol) was added to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (1.4 g, 3.48 mmol) in anhydrous THF (25 ml) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AR2) (1.432 g, 3.83 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% EtOAc in isohexane. Fractions containing the product were evaporated to dryness to afford crude product which unfortunately was contaminated with starting alcohol and Methyl glycidate. The crude product was repurified by flash silica chromatography, elution gradient 0 to 30% EtOAc in toluene to afford the product (0.860 g, 37.1%). 1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 3.80-3.69 (5H, m), 3.85 (2H, t), 4.15-4.08 (1H, m), 4.20 (1H, dd), 5.87 (1H, dd), 7.48-7.33 (8H, m), 7.75-7.60 (5H, m), 8.32 (1H, s), 8.54 (1H, s). m/z (ES+) (M+H)+=667; HPLC tR=3.8 min.

Provenance & Evidence