反应详情

温度

-15 °C

Ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (199 g, for example, as prepared by Example 1) in water (800 ml) was added to toluene (2000 ml) and potassium carbonate (118 g) in water (800 ml) and rinsed in with water (400 ml). The mixture was stirred until a biphasic solution was obtained. The aqueous layer was separated and extracted with toluene (3000 ml). The combined organic layers were concentrated to 4000 ml by vacuum distillation. This solution was added to 0.5 M potassium hexamethyldisilazide in toluene (1700 ml) and toluene (2000 ml) at 40° C. Acetic acid (178 ml) was added, the mixture concentrated to 4000 ml by vacuum distillation and added to an 18% w/w aqueous potassium carbonate solution (2432 g). The layers were separated, the organic layer was concentrated to 3000 ml by vacuum distillation and toluene (1000 ml) added. The solution was cooled to −15° C. and 2M phenyl lithium in dibutyl ether (800 ml) added. Water (2000 ml) and n-butanol (700 ml) were added and the mixture heated to 75° C. The aqueous layer was removed and the organic layer washed with water (1000 ml). Toluene (1000 ml) was added and mixture distilled until 3000 ml of solvent had been removed, then cooled to 20° C. and stirred overnight. The product was filtered, washed with toluene (2×200 ml) and dried under vacuum at 40° C. to give a white solid (131 g, 57%). EI-MS m/z 294 (M+H+) Rt (3.6 min).

1. washrinsed in with water (400 ml)
2. customwas obtained
3. customThe aqueous layer was separated
4. extractionextracted with toluene (3000 ml)
5. concentrationThe combined organic layers were concentrated to 4000 ml by vacuum distillation
6. additionThis solution was added to 0.5 M potassium hexamethyldisilazide in toluene (1700 ml) and toluene (2000 ml) at 40° C
7. additionAcetic acid (178 ml) was added
8. concentrationthe mixture concentrated to 4000 ml by vacuum distillation
9. additionadded to an 18% w/w aqueous potassium carbonate solution (2432 g)
10. customThe layers were separated
11. concentrationthe organic layer was concentrated to 3000 ml by vacuum distillation and toluene (1000 ml)
12. additionadded
13. addition2M phenyl lithium in dibutyl ether (800 ml) added
14. additionWater (2000 ml) and n-butanol (700 ml) were added
15. temperaturethe mixture heated to 75° C
16. customThe aqueous layer was removed
17. washthe organic layer washed with water (1000 ml)
18. additionToluene (1000 ml) was added
19. distillationmixture distilled until 3000 ml of solvent
20. customhad been removed
21. temperaturecooled to 20° C.
22. stirringstirred overnight
23. filtrationThe product was filtered
24. washwashed with toluene (2×200 ml)
25. customdried under vacuum at 40° C.