Combining incompatible processes for deracemization of a Praziquantel derivative under flow conditions

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DOI http://dx.doi.org/10.1002/anie.202013502
Reference G. Valenti, P. Tinnemans, I. Baglai, W.L. Noorduin, B. Kaptein, M. Leeman, J.H. ter Horst and R.M. Kellogg, Combining incompatible processes for deracemization of a Praziquantel derivative under flow conditions, Angew. Chem. Int. Ed. 60, 10: 5279-5282 (2021)
Group Self-Organizing Matter

An efficient deracemization method for conversion of the racemate to the desirable ( R )‐enantiomer has been developed by coupling incompatible racemization and crystallization processes. By a library approach a derivative that crystallizes as a conglomerate in the solid phase has been identified. Racemization occurs via reversible hydrogenation over a palladium on carbon (Pd/C) packed column at 130 °C, whereas deracemization is achieved by alternating crystal growth/dissolution steps with temperature cycling between 5‐15 °C. These incompatible processes are combined by means of a flow system. Complete deracemization of the solid phase to the desired ( R )‐enantiomer (98% ee) takes place. Such an unprecedented deracemization by a decoupled crystallization/racemization approach can readily be turned into a practical process, and opens new opportunities for the development of essential enantiomerically pure building blocks that require harsh methods for racemization.