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Multistep batch-flow hybrid synthesis of a terbinafine precursor

Multistep batch-flow hybrid synthesis of a terbinafine precursor A three-step batch-flow hybrid process has been developed for an expeditious synthesis of the enynol key intermediate of antifungal terbinafine. This procedure involves consecutive organometallic steps without the necessity of any in-line purification: after a metalation by n-butyllithium, a selective addition of the lithium salt was elaborated followed by a Grignard reaction resulting in a high yield of 6,6-dimethylhept-1-en-4-yn-3-ol. Moreover, as an alternative to tetrahydrofuran, cyclopentyl methyl ether was used as solvent implementing a safe, sustainable, yet selective synthetic process. Even on a laboratory-scale, the optimized batch-flow hybrid process had a theoretical throughput of 41 g/h. Furthermore, the newly developed process provides an efficient synthesis route to the key-intermediate, while making acrolein obsolete, minimizing side-products, and enabling safe and convenient scale-up. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Flow Chemistry Springer Journals

Multistep batch-flow hybrid synthesis of a terbinafine precursor

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Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2021
ISSN
2062-249X
eISSN
2063-0212
DOI
10.1007/s41981-021-00188-9
Publisher site
See Article on Publisher Site

Abstract

A three-step batch-flow hybrid process has been developed for an expeditious synthesis of the enynol key intermediate of antifungal terbinafine. This procedure involves consecutive organometallic steps without the necessity of any in-line purification: after a metalation by n-butyllithium, a selective addition of the lithium salt was elaborated followed by a Grignard reaction resulting in a high yield of 6,6-dimethylhept-1-en-4-yn-3-ol. Moreover, as an alternative to tetrahydrofuran, cyclopentyl methyl ether was used as solvent implementing a safe, sustainable, yet selective synthetic process. Even on a laboratory-scale, the optimized batch-flow hybrid process had a theoretical throughput of 41 g/h. Furthermore, the newly developed process provides an efficient synthesis route to the key-intermediate, while making acrolein obsolete, minimizing side-products, and enabling safe and convenient scale-up.

Journal

Journal of Flow ChemistrySpringer Journals

Published: Mar 1, 2022

Keywords: Multistep organometallic reaction; Batch-flow hybrid synthesis; Terbinafine; Enynol

References