Donor Amine Salt‐Based Continuous in situ‐Product Crystallization in Amine Transaminase‐Catalyzed Reactions

Abstract

The unfavorable reaction equilibrium of transaminase-catalyzed reactions is a major challenge for the efficient biocatalytic synthesis of chiral amines. In this study the synthetic utilization of a salt-based, continuous in situ-product crystallization is described to overcome the thermodynamic limit in amine transaminase-reactions using only the commonly used amine donor isopropylamine. The simultaneous dissolution of isopropylammonium 3,3-diphenylpropionate (donor salt) in combination with the crystallization of the product salt facilitates a thermodynamic shift of the continuous amine transaminase-catalyzed reaction. The main process necessity is a lower product salt solubility in comparison to the applied donor salt. This concept facilitates a stoichiometric use of isopropylamine in combination with a significantly lowered concentration of the amines in solution.

Concept Study for an Integrated Reactor-Crystallizer Process for the Continuous Biocatalytic Synthesis of (S)-1-(3-Methoxyphenyl)ethylamine

“…5 mM, depending on the chosen pH in solution (Figure 3A). These results are comparable with the model product amine salt 1phenylethylammonium 3,3-diphenylpropionate in an earlier study [30]. Please note that the shown concentrations may be altered by the presence of other salts such as other buffer components, impurities and especially the additionally used isopropylamine.…”

“…These chemically-driven options offer higher yields but require often a complex process control, additional (bio)catalytic reaction systems, additional chemicals and eventually lead to lower atom efficiencies [29]. As a crystallization-based alternative we apply our recently developed in situ-product crystallization approach in the amine-transaminase-catalyzed reaction [16,30]. This reactive crystallization approach removes the product amine 3MPEA from solution by forming an ammonium salt with a suitable carboxylate anion that exhibits a very low solubility.…”

In situreactive extraction with oleic acid for process intensification in amine transaminase catalyzed reactions

“…[19][20][21] Still to further increase conversions, an equilibrium shift is required. This equilibrium shift is predominantly realized by in situ product removal (ISPR) strategies such as reactive crystallization 22 and supported liquid membrane product extraction. 23 Also, a two-phase system for a similar case has already been studied, but with less success than the approach shown in this present work.…”

Jochen Block Prize: J. von Langermann / DECHEMA Prize: H. Tüysüz / State Natural Science Award: Q.‐L. Zhou

“…His research focuses on the direct integration of separation techniques into biocatalytic processes in order to overcome common limitations, such as undesired side reactions, inhibitions, and thermodynamically unfavorable reaction equilibria. In a Minireview in Chemistry—A European Journal , von Langermann discussed applications of in situ product crystallization and related techniques in biocatalytic processes, and in Advanced Synthesis & Catalysis , he gave an Update on continuous in situ product crystallization in amine transaminase‐catalyzed reactions …”