Acetic Acid → Pregabalin

Temperature

50 °C

An argon-purged 170 L reactor is charged with tert-butyl ammonium 3-cyano-5-methylhex-3-enoate (10 kg, 44.2 mol prepared as described in Example 1A) and [(R,R)MeDUPHOS]Rh(COD)BF4 (0.015 kg, 0.0025 mol). The reactor is pressure purged with argon (3×50 psi). To a 170 L still is charged 100 L of methanol. The reactor is evacuated under vacuum, and then the vacuum is broken with argon. The still is pressurized to 50 psi with argon and then vented. This entire purge procedure is repeated twice more. The methanol is charged to the reactor containing the substrate and catalyst. The solution is pressure purged with argon (3×50 psi), and then the vessel is pressurized to 50 psi with hydrogen and stirred overnight at 27° C. to 33° C. The hydrogen pressure is released, and the solution is purged with nitrogen. The solution is filtered into a 170 L still containing a solution of potassium hydroxide (91%, 2.9 kg, 46.4 mol) in 25 L of water. A 5 L wash of methanol is used to clean the transfer line. The filtrate is concentrated to a volume of 50 to 60 L by vacuum distillation. This concentrated solution is transferred to a 170 L reactor containing sponge nickel A-7000 (5.0 kg, 50% water wet). The solution is purged with nitrogen (3×50 psi). Then, the reactor is pressurized to 50 psi with hydrogen and stirred overnight. The hydrogen pressure is released, and the solution is purged with nitrogen. The solution is filtered into a 170 L still, and the filter and lines are rinsed with 30 L of methanol. The filtrate is concentrate by vacuum distillation to a volume of 25 to 35 L, and then 30 L of isopropyl alcohol is charged. The solution is concentrated by vacuum distillation to about 18 L. Isopropyl alcohol (20 L) and water (5 L) are charged, and the solution is heated to 60° C. to 65° C. Glacial acetic acid (2.9 kg, 47.7 mol) is charged, and the solution is heated to reflux. Water (8 L) is charged to make a solution. The solution is quickly cooled to 50° C. and then cooled to −5° C.±5° C. over about 5.5 hours. The slurry is held at −5° C.±5° C. for about 10 hours and then filtered and washed with isopropyl alcohol (10 L). The solvent-wet filter cake is charged to a 170 L still followed by water (20 L) and isopropyl alcohol (40 L). The slurry is heated to reflux to make a clear solution, which is filtered into a 170 L reactor. The solution is quickly cooled to 50° C. and then cooled to −5° C.±5° C. over about 3.5 hours. The slurry is held a −5° C.±5° C. for about 16 hours. The solid is filtered and washed with isopropyl alcohol (10 L). The solid is dried under vacuum at 45° C. for 3 days to give 4.0 kg (57%) of pregabalin as a white solid (99.84% S).

1. customAn argon-purged 170 L reactor
2. custompurged with argon (3×50 psi)
3. additionTo a 170 L still is charged 100 L of methanol
4. customThe reactor is evacuated under vacuum
5. customThis entire purge procedure
6. additionThe methanol is charged to the reactor
7. additioncontaining the substrate and catalyst
8. custompurged with argon (3×50 psi)
9. customthe solution is purged with nitrogen
10. filtrationThe solution is filtered into a 170 L
11. washA 5 L wash of methanol
12. concentrationThe filtrate is concentrated to a volume of 50 to 60 L by vacuum distillation
13. customThis concentrated solution is transferred to a 170 L reactor
14. additioncontaining sponge nickel
15. customThe solution is purged with nitrogen (3×50 psi)
16. stirringstirred overnight
17. customthe solution is purged with nitrogen
18. filtrationThe solution is filtered into a 170 L still
19. filtrationthe filter
20. washlines are rinsed with 30 L of methanol
21. concentrationThe filtrate is concentrate by vacuum distillation to a volume of 25 to 35 L
22. addition30 L of isopropyl alcohol is charged
23. concentrationThe solution is concentrated by vacuum distillation to about 18 L
24. additionIsopropyl alcohol (20 L) and water (5 L) are charged
25. temperaturethe solution is heated to 60° C. to 65° C
26. temperaturethe solution is heated to reflux
27. temperaturecooled to −5° C.±5° C. over about 5.5 hours
28. waitThe slurry is held at −5° C.±5° C. for about 10 hours
29. filtrationfiltered
30. washwashed with isopropyl alcohol (10 L)
31. additionThe solvent-wet filter cake is charged to a 170 L
32. temperatureThe slurry is heated
33. temperatureto reflux
34. filtrationis filtered into a 170 L reactor
35. temperatureThe solution is quickly cooled to 50° C.
36. temperaturecooled to −5° C.±5° C. over about 3.5 hours
37. waitThe slurry is held a −5° C.±5° C. for about 16 hours
38. filtrationThe solid is filtered
39. washwashed with isopropyl alcohol (10 L)
40. customThe solid is dried under vacuum at 45° C. for 3 days

ORD record

ord-920f33ed87d944348d5676d9c712f0c3

Source dataset

uspto-grants-2005_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06891059B2