反应详情

温度

0 °C

A solution of diisopropylamine (52.41 g, 72.59 mL, 517.9 mmol) in THF (967.3 mL) was cooled to −20° C. n-BuLi (2.5M in hexane) (198.5 mL of 2.5 M, 496.3 mmol) was added dropwise over 15 minutes via cannula maintaining the internal temperature below −15° C. The solution was warmed to 0° C. then immediately re-cooled to −90° C. A solution of tert-butyl-(3-chloro-2,5-difluoro-4-pyridyl)-dimethyl-silane (113.84 g, 431.6 mmol) in THF (85.35 mL) was added dropwise over 20 min via cannula at such a rate that the internal temperature was kept below −85° C. During addition the solution first changed to bright yellow then slowly became an orange coloured suspension. The reaction mixture was stirred at −85° C. for 1 h. A solution of 2-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (91.40 g, 496.3 mmol) in THF (85.35 mL) was added dropwise over 15 minutes via cannula at such a rate that the internal temperature was kept below −80.7° C. (ideally below −85° C.). The mixture turned dark orange brown after the addition. The mixture was stirred at −85° C. for 90 minutes after which time Lc/Ms indicated the reaction was complete. The cooling bath was removed and the mixture warmed to −50° C. Saturated ammonium chloride solution (400 mL) was added and the mixture allowed to warm up to RT. The mixture was diluted with ethyl acetate (1.5 L). The aqueous phase was separated and extracted with more ethyl acetate (300 ml). The combined organics were washed with brine (300 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to a brown oil. The crude was purified on silica gel (CombiFlash Companion XL, 1.5 kg column, 0.5-10% ethyl acetate in petroleum ether, 0-50% ethyl acetate in petroleum ether). This gave the title compound as a yellow oil which solidified on standing (159.6 g, 95%); 1H NMR (CDCl3) 0.60 (6H, d), 1.07 (9H, s), 7.47 (1H, m), 8.33 (1H, m), 8.52 (1H, m); 19F NMR (decoupled) −107.2, −72.4, −61.8; MS ES (+) 387.04 (M+1).

1. additionwas added dropwise over 15 minutes via cannula
2. temperaturemaintaining the internal temperature below −15° C
3. temperaturethen immediately re-cooled to −90° C
4. customwas kept below −85° C
5. additionDuring addition the solution
6. customwas kept below −80.7° C.
7. customideally below −85° C.
8. additionafter the addition
9. stirringThe mixture was stirred at −85° C. for 90 minutes after which time Lc/Ms
10. customThe cooling bath was removed
11. temperaturethe mixture warmed to −50° C
12. additionSaturated ammonium chloride solution (400 mL) was added
13. temperatureto warm up to RT
14. additionThe mixture was diluted with ethyl acetate (1.5 L)
15. customThe aqueous phase was separated
16. extractionextracted with more ethyl acetate (300 ml)
17. washThe combined organics were washed with brine (300 ml)
18. dry with materialdried over magnesium sulfate
19. filtrationfiltered
20. concentrationconcentrated in vacuo to a brown oil
21. customThe crude was purified on silica gel (CombiFlash Companion XL, 1.5 kg column, 0.5-10% ethyl acetate in petroleum ether, 0-50% ethyl acetate in petroleum ether)