2-Chloroethanol → 1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol

Temperature

100 °C

Ethyl isonipecotate (600 g) and DBU (600 ml) were dissolved in toluene (3000 ml) and heated to 100° C. 2-Chloroethanol (330 ml) was added over 2 hours and the mixture stirred at 109° C. for a further 4.5 hours. The temperature was adjusted to 55-65° C. and thionyl chloride (378 ml) added. After stirring for 1 hour the mixture was cooled to 30° C. and water (1800 ml) and 40% w/w aqueous potassium carbonate (3350 g) were added. The layers were separated and the aqueous layer extracted with toluene (3000 ml). The combined organic layers were washed with water (600 ml) and dried by addition of toluene (2000 ml) and concentration to 6000 ml by vacuum distillation. A solution assay showed 94% conversion from ethyl isonipecotate. 0.5M Potassium hexamethyldisilazide in toluene (8400 ml) was added at 45-50° C. and the mixture stirred for 2 hours. Further 0.5M potassium hexamethyldisilazide in toluene (1260 ml) was added and the mixture stirred for 30 minutes. Ethanol (390 ml) was added and the mixture concentrated to 8400 ml by vacuum distillation. Acetic acid (850 ml) was added and the mixture stirred at 45° C. for 15 hours. A 26% w/w aqueous potassium carbonate solution (8110 g) was added and the layers separated. The aqueous layer was extracted with toluene (4800 ml). The combined organic layers were split in two halves and filtered using filter aid (38 g of Celite or Harborlite), recombined and concentrated to 6000 ml by vacuum distillation. The solution was cooled to 0-5° C. and 2M phenyl lithium in dibutyl ether (3840 ml) added. After one hour, water (3000 ml) and n-butanol (3960 ml) were added and the mixture heated to 83° C. The aqueous layer was removed and the organic layer washed with water (3000 ml). The organic phase was concentrated to 12000 ml by distillation with addition of toluene, then cooled to 20° C. and stirred overnight. The product was filtered, washed with toluene (2×1200 ml) and dried under vacuum at 70° C. to give a white solid (561 g, 50%). EI-MS m/z 294 (M+H+) Rt (3.7 min).

1. customwas adjusted to 55-65° C.
2. stirringAfter stirring for 1 hour the mixture
3. temperaturewas cooled to 30° C.
4. customThe layers were separated
5. extractionthe aqueous layer extracted with toluene (3000 ml)
6. washThe combined organic layers were washed with water (600 ml)
7. dry with materialdried by addition of toluene (2000 ml) and concentration to 6000 ml by vacuum distillation
8. addition0.5M Potassium hexamethyldisilazide in toluene (8400 ml) was added at 45-50° C.
9. stirringthe mixture stirred for 2 hours
10. additionFurther 0.5M potassium hexamethyldisilazide in toluene (1260 ml) was added
11. stirringthe mixture stirred for 30 minutes
12. additionEthanol (390 ml) was added
13. concentrationthe mixture concentrated to 8400 ml by vacuum distillation
14. additionAcetic acid (850 ml) was added
15. stirringthe mixture stirred at 45° C. for 15 hours
16. additionA 26% w/w aqueous potassium carbonate solution (8110 g) was added
17. customthe layers separated
18. extractionThe aqueous layer was extracted with toluene (4800 ml)
19. customThe combined organic layers were split in two halves
20. filtrationfiltered
21. filtrationusing filter aid (38 g of Celite or Harborlite)
22. concentrationconcentrated to 6000 ml by vacuum distillation
23. temperatureThe solution was cooled to 0-5° C.
24. addition2M phenyl lithium in dibutyl ether (3840 ml) added
25. waitAfter one hour
26. additionwater (3000 ml) and n-butanol (3960 ml) were added
27. temperaturethe mixture heated to 83° C
28. customThe aqueous layer was removed
29. washthe organic layer washed with water (3000 ml)
30. concentrationThe organic phase was concentrated to 12000 ml by distillation with addition of toluene
31. temperaturecooled to 20° C.
32. stirringstirred overnight
33. filtrationThe product was filtered
34. washwashed with toluene (2×1200 ml)
35. customdried under vacuum at 70° C.

ORD record

ord-0b19fd5aca4c42978228b7bf2bc93931

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09273001B2