Development of a Commercial Flow Barbier Process for a Pharmaceutical Intermediate

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.

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

“…Copyright 2012 American Chemical Society), ( b ) 2 L and 1 L CSTRs-in-series used for continuous Barbier Grinard, quench, and neutralization (Reprinted with permission from Ref. [ 67 ]. Copyright 2017 American Chemical Society), ( c ) process flow diagram of a continuous reactive crystallization system (R: reactor; C: crystallizer; TT: temperature transmitter; TC: temperature controller; LT: Level transmitter; LC: level controller; HE: heat exchanger; M: motor; P: pump.…”

“…Braden et al [ 67 ] reported a Barbier Grignard formation and coupling, along with quench and neutralization. The authors used three CSTRs-in-series (see Fig.…”

What Elements Contribute to a High-Quality Continuous Processing Submission for OPR&D?

“…Continuous processes exhibit reduced momentary in-process volumes, which translates to a smaller potential magnitude for catastrophic safety events in addition to the reduction in total material at risk at any given time. Substantial experience has been gained with Grignard reagent formations run in continuous mode . These processes inspire less concern over initiation exotherm risks and afford high utilization of magnesium metal, avoiding large amounts of hydrogen liberation during the terminal quench.…”

Synthesis of Organometallic Compounds in Flow

“…For production purpose, Continuous Stirred Tank Reactors (CSTR) have been shown to better handle high exothermic reactions in which one or more of the reagents is a solid, as in the synthesis of Grignard reagents …”

“…[56] For production purpose, Continuous Stirred Tank Reactors (CSTR) have been shown to better handle high exothermic reactions in which one or more of the reagents is a solid, as in the synthesis of Grignard reagents. [57,58] Other processes are based on the use of thermostated columns containing some rotating blades where granulated magnesium (diam. 1-3 mm) was inserted from the top and the halide pumped from the bottom.…”