High Enantiomeric Purity Carboxylic Acid Synthesis via Synergistic Electrocatalytic Oxidation Using Mn‐NiSe2 and Aminoxyl Radicals

The constructed 3D Mn-NiSe₂/GF (GF: graphite felt) and aminoxyl synergistic catalytic system facilitates the electrocatalytic oxidation of chiral alcohols under mild conditions, achieving chiral purity of up to 99.1%. The modular stacked electrolyzer enables variable-scale synthesis within 250 g, highlighting the significant potential of flow electrochemistry for the synthesis of high-value chiral pharmaceutical intermediates.

Abstract

Chiral drugs play an indispensable role in pharmaceutical and healthcare fields. However, large-scale synthesis is hindered by challenges such as low reaction rates, racemization, and difficulties in scaling up. In this study, an effective synergistic electrocatalytic strategy involving a 3D Mn-NiSe₂/GF electrocatalyst and aminoxyl is proposed and demonstrated for the multi-hundred-gram scale synthesis of the chiral drug intermediate Levetiracetam. The mild reaction conditions of electrocatalysis effectively preserves the stereochemical configuration adjacent to the oxidation site, achieving yields of up to 93.5% and enantiomeric excess retention of 99.1% through process intensification in a continuous flow electrolyzer. Surface reconstruction of the Mn-NiSe₂/GF and potential catalytic mechanisms are validated through a series of electrochemical and in situ characterizations. Additionally, theoretical calculations elucidate the critical role of Mn doping in the adsorption of intermediates. The electrode area is expanded from 10 to 1200 cm² in the modular stacked electrolyzer, with ee retention remaining above 97.6% across varying reaction scales from 7.8 to 250 g further validating the robustness and scalability of the process. This work offers an effective approach for preparing efficient electrocatalytic materials and synthesizing chiral pharmaceutical intermediates, providing valuable insights for the design and application of modular industrial-scale electrolyzers.