Study On The Process Optimization Of Levetiracetam

Levetiracetam is the only anti-epilepsy drug which can prevent epileptic seizure acording to the recent reports. Because of its special effects and low medicinal properties of side effects Its clinical application is increasingly wide in the global scope. The synthetic route is more and more important as well.The first step of synthesis route is N-alkylation reaction. Mixture with raw material of2-pyrrolidone and2-bromide butyric acid methyl ester gived raise to nucleophilic substitution reaction and produced (R, S)-a-ethyl-2-oxo-l-pyrrolidine methyl acetate(LV10) which is one of the key intermediates. Then We get the target product by the reaction of hydrolysis, resolution and amidation. Improve the LV10synthesis reaction conditions. With isopropyl sodium instead of sodium hydride which is higher risk, the yield can also reach82.4%. Determine the hydrolysis of the best dosage of alkali, and reaction temperature, time and other factors to optimize reaction conditions. As to the resolution process, by the use of alkali to deal with the residual liquid and mother liquor of recrystallization can recycle the racemic (R, S)-α-ethyl-2-oxo-1-pyrrolidine methyl acetate which can be reused further in the next batch. The method greatly reduced the cost. The final step was amidation process which took the methanesulfonyl chloride as activation reagent. The related impurity of product is very low and the reaction yield increased from80.0%to92.0%. Through condition optimization and process validation, the process was suitable for industrial production.Under the existing synthetic conditions, synthesize etiracetam by using chloride method, N-alkylation method and activation ester method and optimization of process conditions respectively. Then compare the advantages and disadvantages among the three methods to select the best one.