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Development of a Commercial Flow Barbier Process for a Pharmaceutical Intermediate

By Braden, Timothy M.; Johnson, Martin D.; Kopach, Michael E.; Groh, Jennifer McClary; Spencer, Richard D.; Lewis, Jeffrey; Heller, Michael R.; Schafer, John P.; Adler, Jonathan J.

Published on CMKC

Abstract

A flow Barbier process was developed to produce a key intermediate in the edivoxetine·HCl registered sequence. The control strategy was developed based on a critical understanding of integrated parameters and design space requirements for a continuous stirred tank reactor (CSTR) process. In this flow Barbier process, the Grignard reagent formation and reaction occurs in a single CSTR, with quenching of the resulting tetrahedral intermediate in a second CSTR. Real time Process Analytical Technology (PAT) monitoring was used to assist process development and understanding. The postquench liquid–liquid separation was continuous, and the quenched intermediate flowed directly into a neutralization CSTR to minimize the epimerization potential of the quenched intermediate. The optimized process was run for 80 consecutive hours in 2 L CSTRs where magnesium was recharged every 4 h for the first half of the continuous campaign and every 8 h for the second half with no quantifiable differences in performance. The Barbier process delivered in situ >99% ee which is sufficient for telescoping into the next step. The process development is intended to support a Quality by Design (Qbd) regulatory submission.

Journal

Organic Process Research & Development. Volume 21, 2017, 317–326

DOI

10.1021/acs.oprd.6b00373

Type of publication

Peer-reviewed journal

Affiliations

  • Eli Lilly and Company
  • Eli Lilly SA
  • D&M Continuous Solutions, LLC

Article Classification

Research Article

Classification Areas

  • Intermediate
  • Process Analytical Technologies

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