Antiepileptic Drug Levetiracetam Synthesis And Process Research

Levetiracetam is a pyrrolidone derivative with unique anti-epileptic mechanism and good pharmacokinetic characteristics. It is a new antiepileptic drug which is not only mainly used for epilepsy patients with partial seizures, but also has a broad application prospect in the field of non-epilepsy.This paper describes the status of anti-epileptic drugs and the significance of synthesising levetiracetam. After reviewing a large number of literatures, we determined the best synthetic method in order to improve the optical purity of the target product and optimize reaction conditions by comparing with the various methods. The racemic a-ethyl-(2-oxo-l-pyrrolidinyl) acetic acid was obtained via the salt forming reaction, N-alkylation and hydrolysis of 2-pyrrolidone, and then, levetiracetan was got through chemical resolution with an optically active (R)-a-methyl-benzylamine, esterification and ammonolys. Furthermore, (R,S)-a-ethyl-(2-oxo-l-pyrrolidinyl) acetic acid could be recycled by the racemization of (R)-a-ethyl-(2-oxo-l-pyrrolidinyl) acetic acid with the strong alkaline. This synthetic route was quite feasible because of common raw materials and mild reaction conditions. Besides,each intermediate was solid and was convenient to purified and dealt with, which is beneficial to industrial production. While we did more experiments about the intermediate (S)-a-ethyl-(2-oxo-l-pyrrolidinyl) acetic acid by a crystallization-induced dynamic resolution which reducing reaction time, improving yielding, but reaction conditions was not easy to control of.Single factor experiments were carried to determine the most effective conditions such as reaction time, temperature, material ratio and catalyzer dose. A few steps were carried out to determine schemes that meet different requirments. Products were characterized by the melting point determination, infrared spectroscopy(IR), mass(MS),1H nuclear magnetic resonance(HNMR), the results showed that they were in line with the target products.The rourte of synthesizing levetiracetam was verified to be efficient.