反应详情

Trans-4-hydroxyproline (5.0 g, 38.1 mmoles) is suspended in a mixture of dioxane (75 mL) and water (75 mL), and stirred briskly at ambient temperature. Sodium bicarbonate (8.0 g, 95.2 mmoles) is added. And the mixture is stirred until all solids dissolve. A solution of 9-fluorenylmethyl chloroformate (11.4 g, 44.0 mmoles) in toluene (25 mL) is added slowly dropwise. The mixture is then stirred for 16 hours. Water (50 mL) and saturated aqueous sodium bicarbonate (50 mL) are added to the reaction mixture, which is then poured into a separatory funnel and washed with diethyl ether (100 mL). The layers are separated, and the aqueous layer is titrated to a pH of about 2 (as determined using pH paper) with concentrated aqueous hydrochloric acid. Ethyl acetate (150 mL) is added to the acidic solution; the mixture is shaken well, and then poured into a separatory funnel. The layers are separated and the aqueous layer extracted again with ethyl acetate (150 mL). The combined ethyl acetate extracts are dried over anhydrous sodium sulfate, filtered and evaporated to a white glassy foam. The crude product is purified on silica gel (400 mL bed volume) eluting with ethyl acetate:acetic acid (100:2 [v/v], 1800 mL), then ethyl acetate:methanol:acetic acid (95:5:2 [v/v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a clear colorless syrup. The syrup is co-evaporated three time with toluene (150 mL each) to remove residual acetic acid. The resulting amorphous white solid is dried well in vacuo. The yield is 12.0 g (89%).

1. stirringAnd the mixture is stirred until all solids
2. dissolutiondissolve
3. stirringThe mixture is then stirred for 16 hours
4. additionis then poured into a separatory funnel
5. washwashed with diethyl ether (100 mL)
6. customThe layers are separated
7. additionEthyl acetate (150 mL) is added to the acidic solution
8. stirringthe mixture is shaken well
9. additionpoured into a separatory funnel
10. customThe layers are separated
11. extractionthe aqueous layer extracted again with ethyl acetate (150 mL)
12. dry with materialThe combined ethyl acetate extracts are dried over anhydrous sodium sulfate
13. filtrationfiltered
14. customevaporated to a white glassy foam
15. customThe crude product is purified on silica gel (400 mL bed volume)
16. washeluting with ethyl acetate:acetic acid (100:2 [v/v], 1800 mL)
17. additionFractions containing pure product by thin layer chromatography
18. customevaporated to a clear colorless syrup
19. customto remove residual acetic acid
20. customThe resulting amorphous white solid is dried well in vacuo