反应详情

[4-[tert-butyl(dimethyl)silyl]-5-chloro-3,6-difluoro-2-pyridyl]-(2-fluoro-3-pyridyl)methanone (294.86 g, 762.2 mmol) was dissolved in dioxane (2.212 L) and calcium carbonate (152.5 g, 1.524 mol) was added. The reaction was cooled in an ice bath and hydrazine hydrate (190.8 g, 185.4 mL, 3.811 mol) was added dropwise over 15 minutes via cannula to the yellow suspension keeping the internal temperature below 10° C. During addition, the internal temperature dropped to 7.1° C. and the colour changed from light yellow to mango orange. The resulting mixture was allowed to warm to ambient overnight. Lc/Ms after this time indicated the reaction was complete. The reaction mixture was filtered through a pad of Celite, washing copiously with dichloromethane (ca 2.5 L). Water (400 ml) was added to the filtrate followed by a saturated solution of sodium bicarbonate (400 mL). The organic phase separated and washed again with a saturated aqueous sodium bicarbonate (350 mL). The combined aqueous layers were back-extracted with dichloromethane (2×400 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was slurried in petroleum ether, filtered and dried (81 g). The Celite was further washed with dichloromethane/methanol 7:1 (3×800 ml) and with 4 L of dichloromethane/methanol 4:1 until no remaining compound was observed on TLC. The filtrate was concentrated in vacuo. The residual solid was triturated with Petroleum ether as described above (185 g). The solids were combined and dried at 40° C. under vacuum. This gave the title compound as an off-white solid (260.5 g, 89%); 1H NMR (CDCl3) 0.63 (6H, d), 1.07 (9H, s), 7.44 (1H, m), 8.76 (1H, m), 9.07 (1H, m), 13.31 (1H, brs); 19F NMR (decoupled) −104.7, −73.8; MS ES (+) 381.1 (M+1).

1. temperatureThe reaction was cooled in an ice bath
2. customthe internal temperature below 10° C
3. additionDuring addition
4. additionthe internal temperature dropped to 7.1° C.
5. temperatureto warm to ambient overnight
6. filtrationThe reaction mixture was filtered through a pad of Celite
7. washwashing copiously with dichloromethane (ca 2.5 L)
8. additionWater (400 ml) was added to the filtrate
9. customThe organic phase separated
10. washwashed again with a saturated aqueous sodium bicarbonate (350 mL)
11. extractionThe combined aqueous layers were back-extracted with dichloromethane (2×400 ml)
12. dry with materialThe combined organics were dried over magnesium sulfate
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. filtrationfiltered
16. customdried (81 g)
17. washThe Celite was further washed with dichloromethane/methanol 7:1 (3×800 ml) and with 4 L of dichloromethane/methanol 4:1 until no remaining compound
18. concentrationThe filtrate was concentrated in vacuo
19. customThe residual solid was triturated with Petroleum ether
20. customdried at 40° C. under vacuum