反应详情

A mixture of 48.8 g (146 mmol) (3R,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic acid and 15.6 mL sulfuric acid in 400 mL methanol was heated to reflux for 21 h and evaporated. the residue was diluted with ice-water and extracted with ethyl acetate. the combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with ethyl acetate and heptane. The intermediate was dissolved in 500 mL methanol and 4.06 mL sodium methoxide (5.4N in methanol) was added and stirred at room temperature overnight. Another 31.3 mL sodium methoxide (5.4N in methanol) was added and stirred for 1 h at room temperature. Water was added and the mixture was stirred for 2 h at room temperature. After evaporation of methanol, water was added and the pH was adjusted to 6-7 with acetic acid. The product precipitated and the mixture was decanted. The organic layer from the extraction with THF and ethyl acetate was washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was washed with hexane and diethyl ether and filtered to yield after drying 44 g (49%) of the title compound as colorless solid. MS m/e: 334.3 [M+H]+.

1. temperaturewas heated
2. temperatureto reflux for 21 h
3. customevaporated
4. additionthe residue was diluted with ice-water
5. extractionextracted with ethyl acetate
6. washthe combined organic layers were washed with brine
7. dry with materialdried with Na2SO4
8. filtrationfiltered
9. customevaporated to dryness
10. customThe residue was purified by column chromatography on silica eluting with ethyl acetate and heptane
11. dissolutionThe intermediate was dissolved in 500 mL methanol
12. addition4.06 mL sodium methoxide (5.4N in methanol) was added
13. additionAnother 31.3 mL sodium methoxide (5.4N in methanol) was added
14. stirringstirred for 1 h at room temperature
15. additionWater was added
16. stirringthe mixture was stirred for 2 h at room temperature
17. customAfter evaporation of methanol, water
18. additionwas added
19. customThe product precipitated
20. customthe mixture was decanted
21. extractionThe organic layer from the extraction with THF and ethyl acetate
22. washwas washed with brine
23. dry with materialdried with Na2SO4
24. filtrationfiltered
25. customevaporated to dryness
26. washThe residue was washed with hexane and diethyl ether
27. filtrationfiltered
28. customto yield
29. dry with materialafter drying 44 g (49%) of the title compound as colorless solid