反应详情

温度

20 °C

Methyl (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)pyridin-2-yl]-2-[(tert-butoxycarbonyl)amino]-2-methylpent-4-ynoate (Intermediate 22, 1.23 Kg) was suspended in 6.2 L DCM at room temperature under inert atmosphere. The mixture was then heated to reflux (clear solution obtained at 30° C.). TFA (990 ml) was added dropwise over one hour. The resulting solution was stirred for at least 6 h at reflux and then was cooled to 20° C.±5° C. Water (6.15 L) was added and the biphasic mixture was stirred for 15 min. Layers were separated and the aqueous layer (top) was discarded. 6.1 L10% w/w aqueous potassium carbonate was added to the DCM layer and the biphasic mixture was stirred for 15 min. Layers were separated and the top layer (aqueous) was discarded. The DCM layer was dried over magnesium sulfate and was filtered. Acetonitrile (620 ml) was added to the above DCM solution and silver triflate (128.4 g,) was also charged to the vessel. The resulting mixture was then heated to reflux and stirred for 24 h. It was then cooled to 20° C. and quenched with 8.6 L. saturated ammonium chloride. The mixture was stirred for 1 h at 20° C. and was then cooled to 0° C. and stirred for 1 h. The silver chloride precipitate was then filtered cold and the resulting biphasic solution was allowed to warm to 20° C. Layers were separated. The top aqueous layer was discarded. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness under vacuum to give the title compound (1067.6 g).

1. temperatureThe mixture was then heated
2. temperatureto reflux
3. custom(clear solution obtained at 30° C.)
4. temperatureat reflux
5. temperaturewas cooled to 20° C.±5° C
6. stirringthe biphasic mixture was stirred for 15 min
7. customLayers were separated
8. addition6.1 L10% w/w aqueous potassium carbonate was added to the DCM layer
9. stirringthe biphasic mixture was stirred for 15 min
10. customLayers were separated
11. dry with materialThe DCM layer was dried over magnesium sulfate
12. filtrationwas filtered
13. additionAcetonitrile (620 ml) was added to the above DCM solution and silver triflate (128.4 g,)
14. additionwas also charged to the vessel
15. temperatureThe resulting mixture was then heated
16. temperatureto reflux
17. stirringstirred for 24 h
18. customquenched with 8.6 L
19. stirringThe mixture was stirred for 1 h at 20° C.
20. temperaturewas then cooled to 0° C.
21. stirringstirred for 1 h
22. filtrationThe silver chloride precipitate was then filtered cold
23. temperatureto warm to 20° C
24. customLayers were separated
25. dry with materialThe organic layer was dried over magnesium sulfate
26. filtrationfiltered
27. customevaporated to dryness under vacuum