反应详情

温度

55 °C

Potassium carbonate powder (2.28 kg, 16.5 mol, 325 mesh) and milled (2R)-2-methylpyrrolidine tartrate (1.78 kg, 7.48 mol) were combined in acetonitrile (37.4 kg) and heated at 55° C. with agitation for 36 hours. The mixture was chilled to about 25° C., and the product from Example 1C (2.07 kg, 4.98 mol) was added to the mixture in portions. The reaction mixture was heated at 65° C. with -agitation for about 48 hours. The mixture was cooled to about 25° C., filtered, and the filtrate was concentrated to a volume of about 10 L. The mixture was partitioned between toluene (32.3 kg) and 5% NaHCO3 solution (23.7 kg). The organic phase was separated and washed with 5% NaHCO3 solution (23.7 kg). The organic phase was then extracted with a mixture of CH3SO3H:N-methylpyrrolidinone:H2O (10:20:70 v/v/v) (32 kg, 8.0 kg respectively). The extract was treated with isopropyl acetate (32.5 kg) and the pH adjusted to about 12 with 50% NaOH solution (about. 4.9 kg) at about 30° C. After stirring, the organic phase was separated and the aqueous phase was extracted with isopropyl acetate (IPAC) (6.0 kg). The organic phases were combined, washed with 5% NaHCO3 (33 kg×3), distilled water (33 kg×2), distilled to a volume of about 10 L, and chased with IPAC (15.6 kg) to about 10 L. The mixture was diluted with isopropyl alcohol (14.5 kg) and concentrated to 10 L. Additional 14.5 kg of isopropyl alcohol was added and the solution concentrated to a volume of 10 L. The solution was treated with active carbon (Darco KB-B, 0.125 kg) and heated at 30° C. with stirring for 1 hour. The mixture was filtered through a pad of Celite® and the Celite® washed with isopropyl alcohol (6.3 kg). The filtrate (about 13 kg) was used directly in the next step (1.17 kg).

1. temperatureThe mixture was chilled to about 25° C.
2. temperatureThe reaction mixture was heated at 65° C. with -agitation for about 48 hours
3. temperatureThe mixture was cooled to about 25° C.
4. filtrationfiltered
5. concentrationthe filtrate was concentrated to a volume of about 10 L
6. customThe mixture was partitioned between toluene (32.3 kg) and 5% NaHCO3 solution (23.7 kg)
7. customThe organic phase was separated
8. washwashed with 5% NaHCO3 solution (23.7 kg)
9. extractionThe organic phase was then extracted with a mixture of CH3SO3H:N-methylpyrrolidinone:H2O (10:20:70 v/v/v) (32 kg, 8.0 kg respectively)
10. additionThe extract was treated with isopropyl acetate (32.5 kg)
11. customadjusted to about 12 with 50% NaOH solution (about. 4.9 kg) at about 30° C
12. customthe organic phase was separated
13. extractionthe aqueous phase was extracted with isopropyl acetate (IPAC) (6.0 kg)
14. washwashed with 5% NaHCO3 (33 kg×3)
15. distillationdistilled water (33 kg×2)
16. distillationdistilled to a volume of about 10 L
17. additionThe mixture was diluted with isopropyl alcohol (14.5 kg)
18. concentrationconcentrated to 10 L
19. additionAdditional 14.5 kg of isopropyl alcohol was added
20. concentrationthe solution concentrated to a volume of 10 L
21. additionThe solution was treated with active carbon (Darco KB-B, 0.125 kg)
22. temperatureheated at 30° C.
23. stirringwith stirring for 1 hour
24. filtrationThe mixture was filtered through a pad of Celite®
25. washthe Celite® washed with isopropyl alcohol (6.3 kg)