反应详情

温度

-45 °C

(4S)-4-Benzyl-1,3-oxazolidin-2-one (828 g, 4.67 moles) was dissolved in 6.8 L THF and cool to −40 to −50° C. To the solution of (4S)-4-benzyl-1,3-oxazolidin-2-one, 2.5 M BuLi in hexanes (1302 g, 1880 mL, 4.70 mole, 1.01 equivalents) was added while keeping the temperature at <−40° C. To the cold solution of the Li salt of (4S)-4-benzyl-1,3-oxazolidin-2-one, 4,4,4-trifluoro-3-methyl-2-butenoic acid chloride (887 g, 5.14 moles, 1.1 equivalents) was added over 10-30 minutes, allowing the temperature to rise and wash in with 0.4 L THF. The reaction was warmed to 20-25° C. and stirred for 2 h. 0.9 L water was added and stirred for 16 h. The THF was distilled off with a bath temperature of 35° C. and vacuum <40 mm Hg. Toluene (5.8 L) was added and the phases split. 4-L saturated NaHCO3 was used to wash (2×), the mixture was filtered through Celite and the phases split. 2.5-L water (2×) was used as a wash and the toluene layer was filtered through Celite. The remaining water was removed. The toluene was distilled off with a bath temperature of 40° C. and vacuum <40 mm Hg. At the end of the distillation the product started to crystallize with a pot temperature of 30° C. Distillation is continued to a pot temperature of 35° C. giving a solid mobile mass of 1456 g. The solid is dissolved in 2.9 L (2 vol) EtOH (99.5% EtOH:0.5% toluene). While stirring at 20-25° C., water (1.09 L, 0.75 vol) was added over 1 h forming crystals. Stirring is continued for 16 h at 15-25° C., followed by cooling to 0-5° C. and holding for 1 h. The crystals are filtered, washed with filtrate and dried at 50° C. for 16 h giving 1229 g, 84% of (4S)-4-benzyl-3-[(2E)-4,4,4-trifluoro-3-methyl-but-2-enoyl]-1,3-oxazolidin-2-one.

1. customat <−40° C
2. washwash in with 0.4 L THF
3. temperatureThe reaction was warmed to 20-25° C.
4. addition0.9 L water was added
5. stirringstirred for 16 h
6. distillationThe THF was distilled off with a bath temperature of 35° C. and vacuum <40 mm Hg
7. additionToluene (5.8 L) was added
8. customthe phases split
9. washto wash (2×)
10. filtrationthe mixture was filtered through Celite
11. customthe phases split
12. washa wash
13. filtrationthe toluene layer was filtered through Celite
14. customThe remaining water was removed
15. distillationThe toluene was distilled off with a bath temperature of 40° C. and vacuum <40 mm Hg
16. distillationAt the end of the distillation the product
17. customto crystallize with a pot temperature of 30° C
18. distillationDistillation
19. customis continued to a pot temperature of 35° C.
20. customgiving a solid mobile mass of 1456 g
21. stirringWhile stirring at 20-25° C.
22. customforming crystals
23. stirringStirring
24. waitis continued for 16 h at 15-25° C.
25. temperatureby cooling to 0-5° C.
26. waitholding for 1 h
27. filtrationThe crystals are filtered
28. washwashed with filtrate
29. customdried at 50° C. for 16 h