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Issue 5, 2012
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The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?

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Abstract

A key pharmaceutical intermediate (1) for production of edivoxetine·HCl was prepared in >99% ee via a continuous Barbier reaction, which improves the greenness of the process relative to a traditional Grignard batch process. The Barbier flow process was run optimally by Eli Lilly and Company in a series of continuous stirred tank reactors (CSTR) where residence times, solvent composition, stoichiometry, and operations temperature were optimized to produce 12 g h−1 crude ketone 6 with 98% ee and 88% in situ yield for 47 hours total flow time. Continuous salt formation and isolation of intermediate 1 from the ketone solution was demonstrated at 89% yield, >99% purity, and 22 g h−1 production rates using MSMPRs in series for 18 hours total flow time. Key benefits to this continuous approach include greater than 30% reduced process mass intensity and magnesium usage relative to a traditional batch process. In addition, the flow process imparts significant process safety benefits for Barbier/Grignard processes including >100× less excess magnesium to quench, >100× less diisobutylaluminum hydride to initiate, and in this system, maximum long-term scale is expected to be 50 L which replaces 4000–6000 L batch reactors.

Graphical abstract: The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?

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Publication details

The article was received on 11 Jan 2012, accepted on 06 Mar 2012 and first published on 06 Mar 2012


Article type: Paper
DOI: 10.1039/C2GC35050E
Citation: Green Chem., 2012,14, 1524-1536
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    The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?

    M. E. Kopach, D. J. Roberts, M. D. Johnson, J. McClary Groh, J. J. Adler, J. P. Schafer, M. E. Kobierski and W. G. Trankle, Green Chem., 2012, 14, 1524
    DOI: 10.1039/C2GC35050E

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