反应详情

Example 1, Alternative Preparation, Step 8: To a mixture of acetamide 11 (28.5 g, HCl salt, 73.6% free base assay), acetonitrile (100 mL), N,N,-di-isopropyl-N-ethylamine (61 mL) at room temperature was added a solution of 13 (˜21.2 g) in MeCN (˜450 mL). The homogeneous mixture was held overnight. Upon reaction completion (HPLC), the mixture was concentrated in vacuo to approx. 125 mL. A 9.5% aqueous solution of acetic acid (240 mL) was added and the aqueous phase was extracted with methylene chloride. The aqueous phase was separated and methyl tert-butyl ether (450 mL) was added, followed by 2N aqueous lithium hydroxide solution to adjust to pH>11.5. The organic layer was separated, washed with water and filtered. Approx. half of the ether phase was diluted with methyl tert-butyl ether (˜250 mL) and concentrated in vacuo. Heptane (45 mL) was added slowly below 60° C., followed by seed crystals of Example 1 (0.4 g). Additional heptane (125 mL) was added and the mixture was slowly cooled to room temperature and the resulting slurry was held overnight. The product was isolated by filtration, the cake was washed with heptane and dried in vacuo to constant weight to give N-((1R,2S,5R)-5-(isopropylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)-quin-azolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide 14 (15.0 g, 85% yield).

1. customExample 1, Alternative Preparation, Step 8
2. customUpon reaction completion (HPLC)
3. concentrationthe mixture was concentrated in vacuo to approx. 125 mL
4. additionA 9.5% aqueous solution of acetic acid (240 mL) was added
5. extractionthe aqueous phase was extracted with methylene chloride
6. customThe aqueous phase was separated
7. additionmethyl tert-butyl ether (450 mL) was added
8. customThe organic layer was separated
9. washwashed with water
10. filtrationfiltered
11. additionApprox. half of the ether phase was diluted with methyl tert-butyl ether (˜250 mL)
12. concentrationconcentrated in vacuo
13. additionHeptane (45 mL) was added slowly below 60° C.
14. additionAdditional heptane (125 mL) was added
15. waitthe resulting slurry was held overnight
16. customThe product was isolated by filtration
17. washthe cake was washed with heptane
18. customdried in vacuo to constant weight