反应详情

温度

0 °C

Sodium hydride (64.3 mg, 1.61 mmol) was added to (S)-2-hydroxy-N-(5-methylpyridin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AU4) (300 mg, 0.73 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (212 mg, 0.73 mmol) added. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (50 mL) and EtOAc (100 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 (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane to afford the product (334 mg, 68.8%). 1H NMR (400 MHz, DMSO) δ 0.98-0.86 (21H, m), 1.09 (3H, d), 2.24 (3H, s), 3.58-3.47 (1H, m), 3.64 (1H, m), 3.81-3.71 (1H, m), 4.10 (2H, m), 5.92 (1H, s), 7.58 (1H, d), 7.89 (2H, t), 8.18 (3H, m), 8.59 (1H, s), 8.72 (1H, s), 10.88 (1H, s). m/z (ES+) (M+H)+=664; HPLC tR=3.99 min.

1. temperatureto warm to ambient temperature
2. stirringstirred for 2 hours
3. customThe organic layer was separated
4. extractionthe aqueous layer re-extracted with EtOAc (2×100 mL)
5. washThe combined organics were washed with saturated brine (50 mL)
6. dry with materialdried (MgSO4)
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane