Continuous flow telescoped synthesis of Levetiracetam

Levetiracetam is an antiepileptic drug approved by the Food and Drug Administration in 1999. It is one of the best drugs sold, and many efforts are done for the development of new and more efficient synthesis providing this bioactive molecule. To develop innovative synthetic strategies based on renewable and environmentally friendly resources, photocatalysis and flow chemistry emerges as victorious strategies to introduce novel and intriguing synthetic methodologies with reduced environmental impact and increased efficiency. In this work, we report the development of a continuous flow telescoped process for the synthesis of Levetiracetam. The telescoped process is divided in three different stages, that are all merged in a single continuous process. In the first step the β-lactam moiety is added to a cheap and abundant starting aldehyde through a photocatalytic strategy that enables the direct stereoselective introduction of the lactam ring, via nitrogen radicals. To the best of our knowledge, in the literature no example of nitrogen radical localized on lactam rings is described [1]: the innovative strategy proposed in this work, that combines photocatalysis and organocatalysis, was developed in our research group [2] by taking inspiration from a work of MacMillan and coworkers [3]. The desired aldehyde is obtained in a good yield and excellent enantiomeric excess. In the second stage, the continuous stream resulting from the first reaction stage is purified, using an in-line separator. Finally, in the third stage, the obtained aldehyde is oxidized to the corresponding amide, that represents the target compound itself. Levetiracetam is achieved in a continuous telescoped process, with productivities and space-time yields improved respect to the corresponding conventional batch procedure, exploiting an innovative synthetic methodology not known in literature. [1] J. Davies, S.P. Morcillo, J.J. Douglas, and D. Leonori, Chem. Eur. J. 24 (2018) 12154-12163. [2] M.F. Boselli, N. Intini, A. Puglisi, L. Raimondi, S. Rossi, and M. Benaglia, Eur. J. Org. Chem. (2023) e202201309. [3] G. Cecere, C.M. König, J. L. Alleva, and D.W.C. MacMillan, JACS 135 (2013) 11521-11524.