반응 #156724

반응 방정식

Water

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

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

TFA

→

title compound

수율 100.4%

methyl (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)pyridin-2-yl]-2-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate

수율 100.4%

용매

DCM

반응 조건

후처리

1. 1
   온도The mixture was then heated
2. 2
   온도to reflux
3. 3
   기타(clear solution obtained at 30° C.)
4. 4
   온도at reflux
5. 5
   온도was cooled to 20° C.±5° C
6. 6
   workup.STIRRINGthe biphasic mixture was stirred for 15 min
7. 7
   기타Layers were separated
8. 8
   workup.ADDITION6.1 L10% w/w aqueous potassium carbonate was added to the DCM layer
9. 9
   workup.STIRRINGthe biphasic mixture was stirred for 15 min
10. 10
    기타Layers were separated
11. 11
    건조The DCM layer was dried over magnesium sulfate
12. 12
    여과was filtered
13. 13
    workup.ADDITIONAcetonitrile (620 ml) was added to the above DCM solution and silver triflate (128.4 g,)
14. 14
    workup.ADDITIONwas also charged to the vessel
15. 15
    온도The resulting mixture was then heated
16. 16
    온도to reflux
17. 17
    workup.STIRRINGstirred for 24 h
18. 18
    기타quenched with 8.6 L
19. 19
    workup.STIRRINGThe mixture was stirred for 1 h at 20° C.
20. 20
    온도was then cooled to 0° C.
21. 21
    workup.STIRRINGstirred for 1 h
22. 22
    여과The silver chloride precipitate was then filtered cold
23. 23
    온도to warm to 20° C
24. 24
    기타Layers were separated
25. 25
    건조The organic layer was dried over magnesium sulfate
26. 26
    여과filtered
27. 27
    기타evaporated to dryness under vacuum

실험 절차

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).

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