The sustainable synthesis of levetiracetam by an enzymatic dynamic kinetic resolution and an anodic oxidation

• Published in: Green chemistry : an international journal and green chemistry resource : GC 2021-01, Vol.23 (1), p.388-395
• Main Authors: Arndt, Sebastian, Grill, Birgit, Schwab, Helmut, Steinkellner, Georg, Pogorev nik, Urška, Weis, Dominik, Nauth, Alexander M, Gruber, Karl, Opatz, Till, Donsbach, Kai, Waldvogel, Siegfried R, Winkler, Margit
• Format: Article
• ISSN: 1463-9262; 1463-9270
• DOI: 10.1039/d0gc03358h

Levetiracetam is an active pharmaceutical ingredient widely used to treat epilepsy. We describe a new synthesis of levetiracetam by a dynamic kinetic resolution and a ruthenium-catalysed ex-cell anodic oxidation. For the enzymatic resolution, we tailored a high throughput screening method to identify Comamonas testosteroni nitrile hydratase variants with high ( S )-selectivity and activity. Racemic nitrile was applied in a fed-batch reaction and was hydrated to ( S )-(pyrrolidine-1-yl)butaneamide. For the subsequent oxidation to levetiracetam, we developed a ligand-free ruthenium-catalysed method at a low catalyst loading. The oxidant was electrochemically generated in 86% yield. This route provides a significantly more sustainable access to levetiracetam than existing routes. Levetiracetam is an active pharmaceutical ingredient widely used to treat epilepsy.