Synthesis Research Of Chiral Drug Levetiracetam

As a second class of acetylcholine agonists, Levetiracetam can be used in the treatment of limited, systemic, primary and secondary epilepsy. Because of its excellent drug efficacy and high tolerance in clinical testing. Levetiracetam has become the most widely used one of the new generation of anti-epileptic drugs.In this paper, 2-chlorobutytric acid was initially synthesized from butytricacid and methyl esterification, ammonolysis reaction and amination was taken place to prepare racemic 2-aminobutanamide, then after chemical resolution of 2-aminobutanamide,(S)-2-aminobutanamide which was the key intermediate compound in producing levetiracetam was obtained. Finally, the cyclization reaction between(S)-2-aminobutanamide and 4-chrobutyryl chloride was operated to synthesize the target compound levetiracetam.In the first place, the thionyl chloride which is low-cost and common used in industrial production was put into the system, together with the radical scavenger to induce the chlorination of butytric acid with chlorine. The optimized conditions including 120 ℃, n(butytric acid):n(thionyl chloride)=10:1, n(Cl2):n(O2)=40:20(ml/min) and 28 h, the yield of 2-chlorobutytric acid was up to 96.5% and the selectivity was 99.7% after processing. Next with methnol as solvent, the experiment was under atmospheric ammonia for 4 hours. Hereafter, the reflux reaction was happened after increasing the ammonia pressure to 0.4MPa at-10℃ to prepare racemic 2-aminobutanamide. The yield was 89.6%; Then chemical resolution was happened to the racemate to obtain pure(S)-2-aminobutanamide and split liquor which through racemization to give the secondary racemic 2-aminobutanamide in a recycling way. The single resolution yield was proved to be 33.5%, while the racemization rate was up to 87.2%; Finally, the cyclization reaction between(S)-2-aminobutanamide and 4-chrobutyryl chloride was taken under the unhydrous of alkali to synthesize the levetiracetam, the yield of which was up to be 67.6%. The optimized temperature were tested to be at-10℃, while the material ratio was n((S)-2-aminobutanamide):n(4-chrobutyryl chloride)=1:1.2. The overall yield of this route was up to 19.6%.(not including the racemization and secondary resolution)In this synthesis route, the materials are low-priced, the reaction conditions are mild and the yield is pretty high, which make it more suitable for industrial applications.All the spectrums of the key compounds and product such as IR, 1H-NMR, GC, LC are corresponding to their standard data.