Electric-field-assisted in situ separation of mandelic acid in an enzymatic milli-reactor improves the control of reaction conversion and enhances the enantiomeric ratio

Abstract

Enantiopure or enantiomerically enriched chemicals are often used as active pharmaceutical ingredients (APIs). However, API synthesis and purification on a preparative scale is usually costly, time-consuming, and difficult to scale up in conventional batch reactors. To develop an alternative solution, we applied kinetic enantioselective synthesis with simultaneous product separation. More specifically, we constructed a continuously operated packed-bed milli-reactor (PBR) with an orthogonally applied electric field for in situ separation. We tested our concept in the enzymatic production of mandelic acid (MA) enantiomers from racemic methyl mandelate (rMM) by immobilised Aspergillus niger lipase. The electric field selectively extracted the product (mandelate anions) whilst leaving almost 100 % of the electroneutral substrate in the reaction mixture. Such selective product separation significantly enhanced MA formation by shifting the reaction toward product synthesis. The applied electric current efficiently controlled the overall rMM conversion, reaching more than 90 % compared to 30% without current. We identified the electric current providing the highest (R)-(-)-MA to (S)-(+)-MA enantiomeric ratio equals to 5.20. This ratio was above 3.86 achieved in an ordinary PBR, albeit subject to further optimization. Our PBR with in situ product separation provided superior process control and significantly enhanced enantiomerically enriched chemical synthesis.