反应详情

A mixture of (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid ethyl ester (897 g, 1.93 mol) and 10% aqueous sodium hydroxide (980 mL, 2.72 mol) in isopropyl alcohol (9 L) was heated at reflux for 6 hours, cooled to ambient temperature, and stirred for 12 hours. The reaction mixture was diluted with water (13.5 L), hexanes (9 L), and isopropyl ether (4.5 L). The aqueous layer was separated and extracted with hexanes (9 L) and isopropyl ether (4.5 L), adjusted to pH 2 with 2 N aqueous hydrochloric acid, and extracted with ethyl acetate (8 L and 4 L). The combined ethyl acetate extracts were washed with water (6 L), dried over magnesium sulfate, and concentrated in vacuo to a dark amber oil which was diluted with toluene (2 L) and concentrated again to an oil. The oil was dissolved in toluene (4.2 L) at 60° C., and hexanes (8.8 L) were added at a rate to maintain a temperature of greater than 50° C. The tan solids which precipitated upon slowly cooling to ambient temperature over several hours were filtered and washed with 2:1 hexane/toluene (2 L). These solids were dissolved in toluene (5 L) at 60° C., treated with Darco®G-60, filtered, washed with toluene, and concentrated in vacuo to approximately 4.0 L. This mixture was heated to 50-60° C.,treated drop-wise with hexanes(8.6 L), cooled, and granulated at 5° C. for 1 to 2 hours. The resulting solids were filtered, washed with 2:1 hexanes/toluene (2 L), and the wet cake was stirred with hexanes (4 L) at reflux for 30 minutes. This mixture was cooled to ambient temperature, granulated for 1 hour, filtered, and the resulting solids were dried under vacuum overnight to provide 450 g (55%) of (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid as an off white solid: 1H NMR (400 MHz, CDCl3) δ7.99 (d, J=8.1 Hz, 1H), 7.66 (dd, J=1.1, 8.1 Hz, 1H), 7.63 (s, 1H), 7.15-7.32 (m, 6H), 6.89 (dd, J=1.7, 7.9 Hz, 1H), 6.85 (d, J=1.7 Hz, 1H), 6.1 (bs, 2H), 4.50 (d, J=4.3 Hz, 1H), 4.1 8 (dd, J=2.7, 11.2 Hz, 1H), 3.94 (dd, J=4.6, 11.0 Hz, 1H), 2.74 (dd, J=6.1, 13.8 Hz, 1H), 2.51 (dd, J=9.4, 13.9 Hz, 1H),2.22 (m,1H); IR 3454,3218 (br), 1699, 1431, 1337, 1299, 1275, 1258, 1191, 1178, 1135, 1123, 700 cm−1; mp 142° C.

1. temperaturewas heated
2. temperatureat reflux for 6 hours
3. customThe aqueous layer was separated
4. extractionextracted with hexanes (9 L) and isopropyl ether (4.5 L)
5. extractionextracted with ethyl acetate (8 L and 4 L)
6. washThe combined ethyl acetate extracts were washed with water (6 L)
7. dry with materialdried over magnesium sulfate
8. concentrationconcentrated in vacuo to a dark amber oil which
9. additionwas diluted with toluene (2 L)
10. concentrationconcentrated again to an oil
11. dissolutionThe oil was dissolved in toluene (4.2 L) at 60° C.
12. additionhexanes (8.8 L) were added at a rate
13. temperatureto maintain a temperature of greater than 50° C
14. customThe tan solids which precipitated
15. temperatureupon slowly cooling to ambient temperature over several hours
16. filtrationwere filtered
17. washwashed with 2:1 hexane/toluene (2 L)
18. dissolutionThese solids were dissolved in toluene (5 L) at 60° C.
19. additiontreated with Darco®G-60
20. filtrationfiltered
21. washwashed with toluene
22. concentrationconcentrated in vacuo to approximately 4.0 L
23. temperatureThis mixture was heated to 50-60° C.
24. additiontreated drop-wise with hexanes(8.6 L)
25. temperaturecooled
26. waitgranulated at 5° C. for 1 to 2 hours
27. filtrationThe resulting solids were filtered
28. washwashed with 2:1 hexanes/toluene (2 L)
29. stirringthe wet cake was stirred with hexanes (4 L)
30. temperatureat reflux for 30 minutes
31. temperatureThis mixture was cooled to ambient temperature
32. waitgranulated for 1 hour
33. filtrationfiltered
34. customthe resulting solids were dried under vacuum overnight