Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material

Efficient continuous Grignard and lithiation processes were developed to produce one of the key regulatory starting materials for the production of edivoxetine hydrochoride. For the Grignard process, organometallic reagent formation, Bouveault formylation, reduction, and workup steps were run in continuous stirred tank reactors (CSTRs). The lithiation utilized a hybrid approach where plug flow reactors (PFRs) were used for the metal halogen exchange and Bouveault formylation steps, while the reduction and workup steps were performed in CSTRs. Relative to traditional batch processing, both approaches offer significant advantages. Both processes were high-yielding and produced the product in high purity. The two main processes were directly compared from a number of perspectives including reagent and operational safety, fouling potential, process footprint, need for manual operation, and product yield and purity.

Michael E. Kopach^*†, Kevin P. Cole^†, Patrick M. Pollock^†, Martin D. Johnson^†, Timothy M. Braden^†, Luke P. Webster^†, Jennifer McClary Groh^†, Adam D. McFarland^†, John P. Schafer^‡, Jonathan J. Adler^‡, and Morgan Rosemeyer^‡

^† Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States

^‡ D&M Continuous Solutions, LLC, Greenwood, Indiana 46143, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00131, http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00131

*E-mail: kopach_michael@lilly.com.

//////////Flow Grignard,  Lithiation, Screening Tools,  Development, Continuous Processes,  Benzyl Alcohol, Starting Material

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