An improved process for the preparation of pregabalin
A compound, lipase technology, applied in the field of improvement for the preparation of pregabalin, which can solve the problems of low yield, economical and environmental infeasibility, etc.
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Embodiment 1
[0086] Embodiment 1: prepare 2-isobutylsuccinonitrile
[0087] To a reaction mixture containing methyl cyanoacetate (500 g, 1.0 eq) and isovaleraldehyde (273 g, 1.0 eq) and TBAB (10 g) was slowly added sodium cyanide (250 g, 1.0 eq) at 10°C to 50°C Solution in water (950ml, 1.9V). The reaction mixture was heated to 70-80°C for 2-3 hours (h). After the reaction was completed, the solvent was removed and further maintained at 90°C to 100°C for 5 hours. The reaction mixture was cooled to room temperature and extracted with toluene (1000ml). The solvent was removed under reduced pressure to obtain the crude compound, which was subjected to high vacuum distillation or thin film evaporation to provide 2-isobutylsuccinonitrile with 98% GC purity and 79% yield.
Embodiment 2
[0088] Example 2: Preparation of 3-cyano-5-methyl-hexanoic acid.
[0089] To compound 2-isobutylsuccinonitrile (350 g, 1.0 equiv) was added water (4550 ml, 13V) at room temperature. The pH of the reaction mixture was maintained using sodium bicarbonate solution and heated to 30°C to 40°C. Nitrilase (30.24 g) was added to the reaction mixture and stirred for 20 to 24 hours. After the reaction was complete, the reaction mixture was filtered, cooled to 0°C to 5°C, and further acidified with concentrated sulfuric acid. The precipitated compound was filtered to obtain racemic 3-cyano-5-methyl-hexanoic acid compound (378 g).
Embodiment 3
[0090] Example 3: Preparation of methyl 3-cyano-5-methyl-hexanoate.
[0091] To racemic 3-cyano-5-methyl-hexanoic acid compound (400 g, 1.0 eq) was added methanol (1500 ml, 5.0 V) and concentrated sulfuric acid (60 mL, 0.2 V) at room temperature. The reaction mixture was heated to reflux temperature for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature and neutralized with sodium bicarbonate. The reaction mass was concentrated under vacuum and water (1500ml) was added and stirred for 15 minutes. The aqueous layer was extracted with toluene (600 ml), and the organic layer was concentrated under reduced pressure to obtain a residue. The residue was subjected to high vacuum distillation to obtain the racemic compound 3-cyano-5-methyl-hexanoic acid methyl ester compound with a GC purity of 99.83% in a yield of 78.90% and a succinimide impurity of 0.01% (294.1g).
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