Green Chemistry Blog

A continuous flow Barbier reaction was employed for the production of a key pharmaceutical intermediate (1) in the synthesis of edivoxetine·HCl (a highly selective norepinephrine re-uptake inhibitor).

US scientists from Eli Lilly and Company and D&M Continuous Solutions, led by Michael Kopach, report the development of a continuous Barbier reaction which preserves chirality and the product obtained in >99% ee.  The team ran the process in a series of continuous stirred tank reactors, where residence time, solvent composition, stoichiometry and operations temperature were optimised to produce 12 g per hour of the ketone precursor to 1 with 98% ee and 88% in situ yield for 47 hours total flow time.  Continuous salt formation and isolation of 1 could then be achieved from the ketone solution with >99% purity.

This process offers up several significant advantages over a traditional Grignard batch process.  This continuous flow method gave greater than 30% reduced process mass intensity and magnesium usage relative to the batch method.  Equally, the flow process resulted in >100 x less excess magnesium to quench and >100 x less diisobutylaluminum hydride to initiate giving significant safety benefits.  The authors expect that the maximum long-term scale of the process is 50 L which would replace 4000-6000 L batch reactors.

This article is free to access until the 11th May 2012! Click on the link below to find out more…

The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?, Michael E. Kopach, Dilwyn J. Roberts, Martin D. Johnson, Jennifer McClary Groh, Jonathan J. Adler, John P. Schafer, Michael E. Kobierski and William G. Trankle, Green Chem., 2012, DOI: 10.1039/C2GC35050E

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Development of safe and scalable continuous-flow methods for palladium-catalyzed aerobic oxidation reactions, Xuan Ye, Martin D. Johnson, Tianning Diao, Matthew H. Yates and Shannon S. Stahl, Green Chem., 2010, 12, 1180-1186

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