反应详情

温度

0 °C

Trimethylaluminium (2M in toluene) (0.472 mL, 0.94 mmol) was added to a solution of 5-methylpyridin-2-amine (102 mg, 0.94 mmol) in toluene (10 mL) at 0° C. under nitrogen in a microwave vial. The reaction mixture was stirred at 0° C. for 20 mins and then (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(5-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AM7) (300 mg, 0.47 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated in the microwave at 120° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and the concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water and DCM (50 mL). The organic layer was separated and the aqueous layer re-extracted with DCM (30 mL). The combined organics were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% Et2O in isohexane to afford the product (125 mg, 37.2%). 1H NMR (400 MHz, CDCl3) 0.99 (9H, s), 2.27 (3H, s), 2.29 (3H, s), 3.69-3.72 (2H, m), 3.81 (2H, t), 4.16-4.24 (2H, m), 6.07-6.09 (1H, m), 7.16-7.41 (6H, m), 7.51 (1H, s), 7.53 (1H, s), 7.63-7.65 (4H, m), 7.68-7.72 (2H, m), 8.08-8.08 (1H, m), 8.14 (1H, d), 8.37 (1H, s), 8.57 (1H, s), 8.67 (1H, s); m/z (ES+) (M+H)+=712.6; HPLC tR=3.65 min.

1. temperatureto warm to room temperature
2. temperatureheated in the microwave at 120° C. for 2 hours
3. temperatureto cool to room temperature
4. concentrationthe concentrated in vacuo
5. additiondiluted with water and DCM (50 mL)
6. customThe organic layer was separated
7. extractionthe aqueous layer re-extracted with DCM (30 mL)
8. dry with materialThe combined organics were dried (MgSO4)
9. filtrationfiltered
10. customevaporated in vacuo
11. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 50% Et2O in isohexane