Add time:07/15/2019         Source:sciencedirect.com

Levetiracetam, a novel antiepileptic drug, is administered as the S-enantiomer of etiracetam according to the predominant pharmacodynamic advantage compared to its R-enantiomer. Thus, the content of enantiomer is restricted explicitly, which creates a hotspot focused on the stereochemistry of levetiracetam during synthesis. However, unexpected racemization was observed during our practice. It's important to understand the racemization mechanism for levetiracetam. In this article, the racemization process for levetiracetam is comprehensively explored by means of widely used density functional theory. Firstly, basic structural movements were determined for further description of racemization process. Then, five plausible pathways for isolated levetiracetam were identified with detailed elucidation of structural movements during racemization. Significant energy barriers were observed corresponding to the proton transfer process, which demonstrated the chiral stability of levetiracetam in neutral environment. Further, hydroxide ion was introduced to elucidate the character of it in racemization process. The result indicated that hydroxide ion could facilitate the racemization by dramatically reducing the barriers for proton transfer, which was further confirmed by the experiment. Additionally, several suggestions were proposed according to the theoretical mechanism and experimental observation, resulting in the efficient control of racemization extent during synthesis. Finally, qualified levetiracetam could be prepared in kg-scale.

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