Development of a Commercial Flow Barbier Process for a Pharmaceutical Intermediate

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.