Scalable Flow Electrochemical Alcohol Oxidation: Maintaining High Stereochemical Fidelity in the Synthesis of Levetiracetam
Xing Zhong, Md Asmaul Hoque, Matthew D. Graaf, Kaid C. Harper, Fei Wang, J. David Genders, Shannon S. Stahl
Abstract
An electrochemical flow process has been developed for an alcohol oxidation step in the synthesis of the generic epilepsy drug levetiracetam. A crucial metric in this process is the retention of high enantiomeric purity as the oxidation of the primary alcohol to the carboxylic acid proceeds via an epimerizable aldehyde intermediate. Here, three different reactor configurations are compared: undivided batch, undivided flow, and divided flow cells. The divided flow cell accesses the highest rate, throughput, and enantiomeric fidelity among the three configurations. This approach is showcased in a 200-gram scale process that retains ≥97% enantiomeric purity and highlights a unique advantage of flow electrolysis.