反应详情

温度

0 °C

60% Sodium hydride in mineral oil (48.8 mg, 1.22 mmol) was added in one portion to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (205 mg, 0.81 mmol) in anhydrous THF (5 mL) cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate M1) (200 mg, 0.81 mmol) as suspension in dry THF (4 mL) 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 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric combined organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 10% MeOH in ethyl acetate to give the product (360 mg, 96%). 1H NMR (400 (2H, m), 2.35 (3H, s), 2.54 (3H, s), 3.97-4.10 (3H, m), 6.05 (1H, t), 7.49 (1H, d), 8.12 (1H, d), 8.44 (1H, s), 8.61 (1H, s), 8.62-8.65 (2H, m), 8.69 (1H, s), 9.44 (1H, d); m/z (ESI+) (M+H)+=461; HPLC tR=1.67 min.

1. stirringThe mixture was stirred at 0° C. for 15 mins
2. temperatureto warm slowly to ambient temperature
3. stirringstirred for 2 hours
4. temperatureto warm slowly to ambient temperature
5. stirringstirred for 2 hours
6. washwere washed with water (15 mL) and brine (15 mL)
7. dry with materialdried (MgSO4)
8. customevaporated
9. customThe residue was purified by flash silica chromatography
10. washeluting (MgSO4)
11. customevaporated
12. customThe residue was purified by flash silica chromatography
13. washeluting with 0 to 10% MeOH in ethyl acetate