The continuous flow Barbier reaction: an improved environmental alternative to the Grignard reaction?

Abstract

A key pharmaceutical intermediate (1) for production of edivoxetine•HCl was prepared in >99% ee via a continuous Barbier reaction, which improves the greenness of the process relative to a traditional Grignard batch process. The Barbier flow process was run optimally by Eli Lilly and Company in a series of continuous stirred tank reactors (CSTR) where residence times, solvent composition, stoichiometry, and operations temperature were optimized to produce 12 g h −1 crude ketone 6 with 98% ee and 88% in situ yield for 47 hours total flow time. Continuous salt formation and isolation of intermediate 1 from the ketone solution was demonstrated at 89% yield, >99% purity, and 22 g h −1 production rates using MSMPRs in series for 18 hours total flow time. Key benefits to this continuous approach include greater than 30% reduced process mass intensity and magnesium usage relative to a traditional batch process. In addition, the flow process imparts significant process safety benefits for Barbier/Grignard processes including >100× less excess magnesium to quench, >100× less diisobutylaluminum hydride to initiate, and in this system, maximum long-term scale is expected to be 50 L which replaces 4000-6000 L batch reactors.

Continuous manufacturing – the Green Chemistry promise?

“…This can be realised through the use of a continuous stirred tank reactor (CSTR) and the slow addition of material to a continuous stream, as demonstrated by researchers in Eli Lilly. 134 The pumping of magnetically stirred slurries has been reported, however particle settling and potential clogging adds process risk. 135 The use of mechanical feeders, i.e., hoppers or screw feeders similar to equipment used for solid formulation, could also be implemented for solids addition.…”

The coupling of in-flow reaction with continuous flow seedless tubular crystallization

“…Organic synthesis reactions in continuous flow setups are nowadays widely described for several chemical compounds and Active Pharmaceutical Ingredients (APIs) [1][2][3][4][5][6][7] . Continuous flow reactions need to be extented into end-to-end flow processes, while accordingly scaling down the required buffering volumes and unit operations.…”

Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

“…The reaction control afforded by use of high surface-area-to-volume ratio tubular reactors, specifically with respect to dissipation of heat, offers a safety profile unique to flow chemistry. Continuous processing also provides the capacity to continuously generate hazardous reagents and intermediates in small quantities, in situ, and transferred directly into a reaction stage without operator handling [21–26]. As rapid heat transfer (steps 1 and 3) and greater reaction control (steps 2 and 3) were identified as the key challenges to be overcome, we envisaged that continuous processing could facilitate the preparation of large quantities of α-thio-β-chloroacrylamide with reduced purification requirements.…”