**1. Introduction**

In recent years, biocatalytic synthesis reactions have made a significant impact in the scientific community and have even replaced existing chemical pathways in industrial processes. The main advantages are often higher stereo-, regio- and chemoselectivities, while mild reaction conditions and environmentally friendly solvents such as water can be applied. The high selectivity of biocatalysts results also frequently in less or even no side reactions, which itself yields higher process and atom efficiencies. In addition, recent scientific and technological advances in enzyme engineering allow the relatively fast design and production of tailor-made biocatalysts for a specific process [1–7]. Furthermore, downstream-processing from biocatalyst-based reaction systems remains an issue and is a major economic factor in the overall process. This problem originates mostly from the presence of water-soluble proteins, buffer salts, biocatalyst-based cofactors, remaining unreacted substrates and co-substrates, which have to be removed efficiently to ensure high product purities. The purification from such complex mixtures is typically achieved by multiple extractions and further purification steps [8].

In contrast, selective crystallization techniques provide a more selective product isolation approach from complex mixtures, especially aqueous solutions and was integrated in this study directly into the biocatalytic synthesis process [9]. In the presented study this is utilized at the synthesis of (*S*)-1-(3-methoxyphenyl)ethylamine, which is a valuable intermediate for the synthesis of rivastigmine, a highly potent drug for the treatment of early stage Alzheimer's disease (Scheme 1). Studies have shown that the (*S*)-enantiomer is more potent as the (*R*)-enantiomer and preferably the enantiomerically pure (*S*)-form should be administered to avoid complications [10–13].

**Scheme 1.** Investigated biocatalytic transamination reaction and the inclusion of a reactive crystallization step for the synthesis of rivastigmine; R = –CH2–CHPh2.

The applied amine transaminase from *Ruegeria pomeroyi* catalyzes the transfer of the amine group from the donor amine isopropylamine (IPA) to the carbonyl compound 3-methoxyacetophenone (3MAP), forming (*S*)-1-(3-methoxyphenyl)ethylamine (3MPEA) and acetone (Ac) as a co-product [14,15]. The biocatalytic transformation forming 3MPEA itself is very enantioselective but suffers from an unfavorable reaction equilibrium [16]. These limitations in amine transaminase-catalyzed reactions are often overcome by classical (bio)chemical solutions to remove the co-product from the equilibrium or using specifically tailor-made donor amines to shift the reaction to the product side [17–28]. 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. Additional chemical reactants or (bio)catalysts are not required and a simplified downstream-processing approach via filtration is possible.
