1. Enhanced flow synthesis of small molecules by in-line integration of sequential catalysis and benchtop twin-column continuous chromatography
- Author
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Alessandra Sivo, Tae Keun Kim, Vincenzo Ruta, Renzo Luisi, Jose Osorio-Tejada, Marc Escriba-Gelonch, Volker Hessel, Mattia Sponchioni, and Gianvito Vilé
- Subjects
Fluid Flow and Transfer Processes ,Chromatography ,Chemistry (miscellaneous) ,Process Chemistry and Technology ,Small molecules ,Chemical Engineering (miscellaneous) ,Flow synthesis ,Catalysis - Abstract
We report an improved approach for the integration of flow synthesis and continuous chromatography, for applications in the end-to-end preparation of pharmaceutically-relevant small molecules. It involves the combination of sequential microreactors and twin-column counter-current chromatography based on the often-used C18 columns. The column loading method ensures that the product breaking through a fully loaded first column is loaded onto the second one, avoiding waste of precious material and technological complexity associated with the use of four-to-six columns typical of simulated moving bed chromatography. The system was applied to synthesize biphenyl via Suzuki–Miyaura reaction, and was also demonstrated for other structurally-different compounds. Compared to the discontinuous and other traditional approaches, our method leads to higher isolated yields (ca. +60%), higher productivity (ca. +30%), and reduced solvent consumption (ca. −80%). A circularity and life-cycle analysis was also conducted to demonstrate the environmental benefits of the flow process. Funding from the European Commission (GV, grant agreement 101031710), Bracco Imaging (AS, VR, and GV), Fondazione Bracco (GV), and YMC Japan (TKK and MS) is gratefully acknowledged.
- Published
- 2022