Three‐liquid‐phase Spinning Reactor for the Transaminase‐catalyzed Synthesis and Recovery of a Chiral Amine

Abstract

A device for the transaminase‐catalysed synthesis combined with continuous recovery of chiral amines was designed. The system enabled the separation of the reaction components in three liquid phases: a reaction phase, an organic solvent phase (where the poorly water soluble ketone substrate was supplied), and an aqueous extraction phase for continuous product recovery. The transaminase‐mediated asymmetric synthesis of (S)‐1‐methyl‐3‐phenylpropylamine was employed as model reaction. Factors influencing the performance of the system, such as reactor geometry, working volumes and operating parameters, were investigated. Specifically, reaction yield and product recovery were enhanced by i) reducing the thickness of the reaction phase, while continuously stirring and ii) reducing the volume of the extraction phase. Under the optimal condition tested, 85 % of the product formed was extracted and a product concentration value of 9 g/L was reached. However, co‐extraction of the unreacted amine donor (17 %) was observed. Advantages and drawbacks of this process compared to existing technologies, as well as possible optimization strategies are discussed.

Considerations for the Scale‐up of in vitro Transaminase‐Catalyzed Asymmetric Synthesis of Chiral Amines

“…[69] The amine donor used was the commercial Jeffamine® ED-600, and aliphatic polyether diamine chosen based on its high-molecular weight and resulted in a 2.6-fold improvement from conventional batch conversion. [69] However, difficulties with separation of the three phases after the end of conversion and poor extraction selectivity between substrates and products could limit the proposed set-up at larger scale unless additional optimization is done. This report highlights the difficulties with in situ product removal; the difference between the substrate and product in a transaminase catalyzed reaction is just a single functional group.…”

“…[200] Commonly, enzymes used at an industrial scale will simply be released from the cells by cell disruption and subsequent cell-debris removal, and thus used as cell-free extract,. Based on the presented pilot scale publications, this requirement was fulfilled for all publications except Savile-, [15] Matassa- [69] and Yasuda and co-workers, [140] where purified enzymes were used instead.…”

“…Another approach is in‐situ product removal, which was implemented in the study by Matassa and co‐workers (2020), [69] where a three‐liquid‐phase spinning reactor was used in the production of (S)‐1‐methyl‐3‐phenylpropylamine. Here, a 1.5 L double‐jacketed glass reactor with nitrogen head space sweep and a fixed inner tubular cylinder was used.…”

“…More details on the system itself can be found in the publication. The overall principle of separation was diffusion of the substrate through the reaction phase, with further diffusion to‐ and trapping in the extraction phase of the produced amine [69] . The amine donor used was the commercial Jeffamine® ED‐600, and aliphatic polyether diamine chosen based on its high‐molecular weight and resulted in a 2.6‐fold improvement from conventional batch conversion [69] .…”

“…The overall principle of separation was diffusion of the substrate through the reaction phase, with further diffusion to‐ and trapping in the extraction phase of the produced amine [69] . The amine donor used was the commercial Jeffamine® ED‐600, and aliphatic polyether diamine chosen based on its high‐molecular weight and resulted in a 2.6‐fold improvement from conventional batch conversion [69] . However, difficulties with separation of the three phases after the end of conversion and poor extraction selectivity between substrates and products could limit the proposed set‐up at larger scale unless additional optimization is done.…”