Synthesis And Purification Of Levetiracetam And Its Scale-up Process

As a new anti-epileptic drug,Levoethiracetam is a kind of pyrrolidones with an S-configuration ethyl group.It has multiple advantages such as the unique anti-epileptic mechanism,good anti-epileptic efficiency,excellent safety,good pharmacokinetic profile and less drug-interaction.Levoethiracetam has been applied in the treatment of epilepsy patients in clinical applications,especially for adults and children above four years old with remittent seizures or secondary systemic seizures,due to the satisfied clinical effecton epilepsy,good drug tolerance and no serious aftereffects.As an important drug for clinical therapeutics of epilepsy,Levoethiracetam has received intensive attentions in clinical markets.Therefore,it is of great importance to investigate the effective synthesis approaches,the separation and purification methods,as well as the scale-up strategies towards the effective synthesis and industrial production of Levoethiracetam.In this thesis,the synthetic and purificiation of Levoethiracetam were studied experimentally.In the laboratory scale,the effects of several key factors including the mole ratio of two basic raw materials,the selection and dosage of reaction solvents and catalysts,the reaction temperature,the solvents and their volume ratios in crystallization,on the yield and purity of Levoethiracetam were investigated.The optimum conditions and parameters regarding the synthetic route were determined.Then,the influence of synthesis parameters on the chemical reaction for the preparation of this target drug was investigated in the small-scale-test stage and the results showed that the purity and yield of the target product obtained agreed well with the requirements.Furthermore,the pilot-scale test was conducted and the yield and purity of product also agreed with those obtained in the small scale-test.Finally,the production of Levoethiracetam was verified in the industrial scale test and the product quality was ensured and the expected yield and purity to the standard requirements were achieved by increasing the reaction time,the centrifugation time during the separation and the drying time together with nitrogen protection in the drying process.The obtained yield and purity were close to those observed in the small-scale and pilot-scale tests,indicating that the present synthesis and purification approaches were stable and thus suitable to be applied in large-scale production.The samples of Levoethiracetam produced were characterized by infrared spectrometry,mass spectrometry,nuclear magnetic resonance and elemental analysis.The products obtained in three runs were analyzed by X-ray diffraction and differential thermal analyse and the crystalline types were same.Based on these results regarding the laboratory scale,small-scale and pilot-scale tests,the efficient synthesis and purification process for the industrial production of Levoethiracetam was suggested and the process was applied successfully in large-scale production.The synthesis and purification process has advantages for the product Levoethiracetam with the high yield,good quality and stable crystal type,and thus could be interesting in the large-scale industrial production of this active pharmaceutical ingredient in application areas.