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

Abstract

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.

Design of a Mesoscale Continuous‐Flow Route toward Lithiated Methoxyallene

“…This corresponded to a throughput of 28.5 g h −1 . Two industrial research groups demonstrated the challenges for continuous‐flow lithiation scale‐up . Similar to our observations, the main issues involved guaranteeing isothermal conditions, even in microstructured reactors, the feedstock quality and exclusion of moisture, and operational problems, such as pressure build‐up in pumps, valves or precoolers and flow pulsations due to the formation of gaseous phases.…”

“…Many common pump types are incompatible with alkyllithium solutions. Despite the limited injection volume, in general syringe pumps or sample loops are preferred for safety and chemical resistance reasons . At the outlet of the reactor, the mixture was quenched at room temperature by using D 2 O.…”

“…A regular T‐connector and helical static mixing elements, inserted in a tubular reactor, were used (Table ). These static mixers were successfully used previously for pilot‐scale lithiations . Performing the lithiation at room temperature, however, led to strong flow irregularities and a prominent presence of gaseous phases, resulting from insufficient heat and reaction control.…”

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.…”