反应详情

温度

95 °C

3-(4-(tert-butyldimethylsilyl)-5-chloro-3,6-difluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (132.7 g, 348 mmol) was dissolved in anhydrous THF (265 mL). Imidazol-1-yl(trimethyl)silane (254 mL) was added followed by (2R)-3-methyl-2-(piperazin-2-yl)butan-2-ol (90 g, 522 mmol). The mixture was divided into four glass pressure vessel's and the sealed containers heated and stirred at 95° C. for 48 hours. The crude mixtures were cooled, combined and diluted with ethyl acetate (1.7 L). The solution was washed with saturated sodium bicarbonate (2×500 ml). The combined aqueous layers were back-extracted with ethyl acetate (500 ml). The combined organics were washed with brine (500 ml), dried over MgSO4, filtered and concentrated in vacuo to give a viscous brown oil. The diastereoisomers were separated on silica gel (10-100% ethyl acetate containing 2% triethylamine in petroleum ether). This gave the required (S,R)-diastereoisomer as a yellow foam (125.3 g, 59%); 1H NMR (CDCl3) 0.01 (9H, s), 0.42 (6H, s), 0.78-0.89 (15H, m), 1.09-1.13 (3H, m), 1.74 (1H, m), 2.61 (1H, m), 2.80-2.99 (4H, m), 3.12 (1H, m), 3.45 (1H, d), 3.69 (1H, d), 7.12 (1H, m), 8.55 (1H, m), 8.81 (1H, m), 12.75 (1H, brs); 19F NMR (decoupled) −108.9; MS ES 605.2 (M+). The (R,R)-diastereoisomer was isolated as a yellow foam (27.5 g, 13%); 1H NMR (CDCl3) 0.00 (9H, s), 0.38 (6H, m), 0.76-0.80 (15H, m), 0.85 (3H, s), 1.85 (1H, m), 2.50 (1H, m), 2.90-3.13 (4H, m), 3.42 (1H, m), 3.56 (1H, m), 3.91 (1H, m), 7.08 (1H, m), 8.51 (1H, m), 8.76 (1H, m), 12.70 (1H, brs); 19F NMR (decoupled) −109.0; MS ES 605.2 (M+).

1. temperaturethe sealed containers heated
2. temperatureThe crude mixtures were cooled
3. washThe solution was washed with saturated sodium bicarbonate (2×500 ml)
4. extractionThe combined aqueous layers were back-extracted with ethyl acetate (500 ml)
5. washThe combined organics were washed with brine (500 ml)
6. dry with materialdried over MgSO4
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. customto give a viscous brown oil
10. customThe diastereoisomers were separated on silica gel (10-100% ethyl acetate containing 2% triethylamine in petroleum ether)