Acetic Acid → Pregabalin

Participants

Reaction Conditions

Reaction Steps

An argon-purged 600 mL pressure reactor is charged tert-butyl ammonium 3-cyano-5-methylhex-3-enoate (prepared as described in Example 1A 36 g, 159.1 mmol) and [(R,R)MeDUPHOS]Rh(COD)BF4 (0.054 g, 0.0894 mmol). The reactor is pressure purged with argon (3×50 psi). To a 1000 mL reactor is charged 360 mL of methanol. The methanol is pressure purged with argon (3×50 psi). The methanol is then charged to the reactor containing the substrate and catalyst. The solution is pressure purged with argon (3×50 psi), and then the reactor is pressurized to 50 psi with hydrogen and stirred overnight at 27° C. to 33° C. The hydrogen pressure is released, and the solution purged with argon. The solution is transferred into a vessel containing a solution of potassium hydroxide (91%, 10.3 g, 167 mmol) in 90 mL of water. The solution is concentrated to about 180 mL in vacuo. The concentrated solution is transferred to a 600 mL pressure reactor containing sponge nickel A-7000 (12.0 g, 50% water wet). The solution is purged with argon (3×50 psi), and then the reactor is pressured to 50 psi with hydrogen and stirred overnight. The hydrogen pressure is released. The solution is purged with argon and filtered. The filter cake is washed with 90 mL of methanol. The filtrate is concentrated in vacuo to remove the methanol, and 72 mL of isopropyl alcohol is charged. The solution is heated to 65° C. Glacial acetic acid (9.4 mL, 171 mmol) is charged, and the solution is heated to 73° C. The solution is quickly cooled to 50° C., then slowly cooled to room temperature. The slurry is cooled to 0° C. to 5° C. for 3.5 hours. The slurry is filtered, and the cake is washed with isopropyl alcohol. The solid is dried under vacuum at 45° C. to give 18.4 g (73%) of pregabalin as a white solid (99.89% S).

Provenance & Evidence