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Issue 18, 2016

From alcohol to 1,2,3-triazole via a multi-step continuous-flow synthesis of a rufinamide precursor

Author affiliations

Abstract

Rufinamide is an antiepileptic drug used to treat the Lennox–Gastaut syndrome. It comprises a relatively simple molecular structure. Rufinamide can be synthesized from an organohalide in three steps. Recently we have shown that microreactor flow networks have better sustainability profiles in terms of life-cycle assessment than the respective consecutive processing in a batch. The analysis was based on the results of a single step conversion from batch to continuous mode. An uninterrupted continuous process towards rufinamide was developed, starting from an alcohol precursor, which is converted to the corresponding chloride with hydrogen chloride gas. The chloride is then converted to the corresponding organoazide that yields the rufinamide precursor via cycloaddition to the greenest and cheapest dipolarophile available on the market. The current process demonstrates chemical and process-design intensification aspects encompassed by novel process windows. Single reaction steps are chemically intensified via a wide range of conditions available in a microreactor environment. Meanwhile, the connection of reaction steps and separations results in process-design intensification. With two in-line separations the process consists of five stages resulting in a total yield of 82% and productivity of 9 g h−1 (11.5 mol h−1 L−1). The process minimizes the isolation and handling of strong alkylating or energetic intermediates, while minimizing water and organic solvent consumption.

Graphical abstract: From alcohol to 1,2,3-triazole via a multi-step continuous-flow synthesis of a rufinamide precursor

Supplementary files

Article information


Submitted
21 Apr 2016
Accepted
27 May 2016
First published
27 May 2016

Green Chem., 2016,18, 4947-4953
Article type
Paper

From alcohol to 1,2,3-triazole via a multi-step continuous-flow synthesis of a rufinamide precursor

S. Borukhova, T. Noël, B. Metten, E. de Vos and V. Hessel, Green Chem., 2016, 18, 4947 DOI: 10.1039/C6GC01133K

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