Development of a Continuously Operating Process for the Enantioselective Synthesis of a β-Amino Acid Ester via a Solvent-Free Chemoenzymatic Reaction Sequence

A sequential, chemoenzymatic process for a continuously operating production of the chiral β‐amino acid ester ethyl (S)‐3‐(benzylamino)butanoate was developed. The reactor set‐up combined a plug‐flow reactor for the thermal aza‐Michael addition of benzylamine to trans‐ethyl crotonate coupled to a subsequent packed‐bed reactor for the lipase (Novozym 435)‐catalyzed kinetic resolution of the racemic intermediate product, which was formed in the initial step. The coupled reactors were operated continuously for a time period of 4 days without significant loss of enzyme activity. The target β‐amino acid ester was obtained with 92% conversion in the plug‐flow reactor and 59% conversion in the packed bed reactor at high enantiomeric excess of >98%. A space‐time yield of 0.4 kg L−1 d−1 was calculated for the total reactor system and 1.8 kg L−1 d−1 based solely on the volume of the packed bed reactor. A total turnover number of 158,000 was calculated for the biocatalyst assuming the same deactivation rate as observed in batch experiments. The continuously operating, solvent‐free process thus represents an efficient method for the enantioselective production of a value added (S)‐β‐amino acid ester starting from cheap substrates. Abbreviations: CALB=Candida antarctica lipase B; CSTR=continuously stirred tank reactor; di=inner diameter [mm]; ee=enantiomeric excess; ε=porosity; kcat,obs=apparent turnover number [h−1]; kdeact=enzyme deactivation constant [h−1]; L=length of reactor [m]; m̄p=average mass of a single particle [g]; N435=Novozym 435 (Candida antarctica lipase B immobilized on acrylic resin); PBR=packed‐bed reactor; PFR=plug‐flow reactor; PTFE=polytetrafluoroethylene; ρbp=bulk particle density [kg m−3]; ρp=density of carrier material [kg m−3]; Q=productivity [kg ${{\rm kg}{{- 1\hfill \atop {\rm N435}\hfill}}}$ d−1]; R=channel radius of curvature [cm]; ttn=total turnover number [mol mol−1]; T=temperature [°C]; τ=residence time [h]; uf=fluid velocity [cm min−1]; $\dot \nu $=volumetric flow rate [mL min−1]; νι=flow rate of substance [mmol min−1]; V=volume [mL]; χi=mole fraction of compound i; Xi=conversion of compound i; STY=space‐time yield [kg L−1 d−1].