反应详情

温度

40 °C

The solution of (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate 6 from Step 3 was added to a 570 L glass-lined reactor and rinsed with methyl tert-butyl ether (MTBE) (312.4 kg, 13.9 kg). The contents were concentrated under vacuum at a maximum W/G temperature of 40° C. until distillation stopped. Acetonitrile (CH3CN) (116 kg, 3.0 parts) was charged to the reactor and the vacuum distillation repeated until distillation ended. Additional acetonitrile (CH3CN) (112 kg, 2.9 parts) was charged to the reactor and the temperature was adjusted to 40° C. (39-41° C.). Methanesulfonic acid (MeSO3H) (6.97 kg, 0.18 parts) was charged to the reactor while maintaining the temperature at 40° C. (35-45° C.). The pump and lines were rinsed forward with acetonitrile (CH3CN) (3.9 kg, 0.1 part). The reaction was complete after two hrs (2-6 hrs expected) at 40° C. (35-45° C.) as determined by high pressure liquid chromatography (HPLC). The temperature of the mixture was adjusted to 22° C. (19-25° C.) and agitated for 32 hrs. The crude product was collected by centrifugation, the reactor, lines, and filter cake rinsed forward with acetonitrile (CH3CN) (38.7 kg, 1 part) and spun as dry as possible to provide a wet filter cake (10.9 kg). A portion of the wet filter cake (8.0 kg) was transferred to a 570 L glass-lined reactor. Acetonitrile (CH3CN) (278 kg, 10 parts) was charged to the reactor, the contents agitated, and the temperature adjusted to reflux (80-82° C.). Water (2.8 kg, 0.1 parts) was charged to the reactor, maintaining the temperature at 80-82° C. The suspension became a clear solution. The mixture was agitated at 80-82° C. for ca. 30 minutes. The solution was then cooled over 6 hrs to 22° C. (19-25° C.) with a slurry forming at 60° C. The slurry was held at 22° C. (19-25° C.) for an additional 2 hrs. The product, (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate 1, was collected by centrifugation and the reactor, lines, and filter cake were rinsed with 3 portions of methyl tert-butyl ether (MTBE) (30 kg each) and spun dry. The product was dried at a maximum temperature of 55° C. until LOD was ≦0.5% and acetonitrile is ≦400 ppm as determined by gas chromatography (GC) to provide 5.4 kg of (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate 1.

1. washrinsed with methyl tert-butyl ether (MTBE) (312.4 kg, 13.9 kg)
2. concentrationThe contents were concentrated under vacuum at a maximum W/G temperature of 40° C. until distillation
3. additionAcetonitrile (CH3CN) (116 kg, 3.0 parts) was charged to the reactor
4. distillationthe vacuum distillation
5. distillationrepeated until distillation
6. additionAdditional acetonitrile (CH3CN) (112 kg, 2.9 parts) was charged to the reactor
7. customwas adjusted to 40° C.
8. custom(39-41° C.)
9. additionMethanesulfonic acid (MeSO3H) (6.97 kg, 0.18 parts) was charged to the reactor
10. washThe pump and lines were rinsed forward with acetonitrile (CH3CN) (3.9 kg, 0.1 part)
11. custom(2-6 hrs expected)
12. customat 40° C.
13. custom(35-45° C.)
14. customwas adjusted to 22° C.
15. custom(19-25° C.)
16. customThe crude product was collected by centrifugation
17. filtrationthe reactor, lines, and filter cake
18. washrinsed forward with acetonitrile (CH3CN) (38.7 kg, 1 part)
19. customas dry as possible
20. customto provide a wet filter cake (10.9 kg)
21. customA portion of the wet filter cake (8.0 kg) was transferred to a 570 L glass-lined reactor
22. stirringthe contents agitated
23. temperatureto reflux (80-82° C.)
24. temperaturemaintaining the temperature at 80-82° C
25. stirringThe mixture was agitated at 80-82° C. for ca. 30 minutes
26. temperatureThe solution was then cooled over 6 hrs to 22° C. (19-25° C.) with a slurry
27. customforming at 60° C
28. customwas held at 22° C.
29. custom(19-25° C.)
30. customfor an additional 2 hrs
31. customThe product, (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate, methanesulfonate 1, was collected by centrifugation
32. filtrationthe reactor, lines, and filter cake
33. washwere rinsed with 3 portions of methyl tert-butyl ether (MTBE) (30 kg each)
34. customspun dry
35. customThe product was dried at a maximum temperature of 55° C. until LOD