Chemoenzymatic Synthesis in Flow Reactors: A Rapid and Convenient Preparation of Captopril

Abstract

The chemoenzymatic flow synthesis of enantiomerically pure captopril, a widely used antihypertensive drug, is accomplished starting from simple, inexpensive, and readily available reagents. The first step is a heterogeneous biocatalyzed regio‐ and stereoselective oxidation of cheap prochiral 2‐methyl‐1,3‐propandiol, performed in flow using immobilized whole cells of Acetobacter aceti MIM 2000/28, thus avoiding the use of aggressive and environmentally harmful chemical oxidants. The isolation of the highly hydrophilic intermediate (R)‐3‐hydroxy‐2‐methylpropanoic acid is achieved in‐line by using a catch‐and‐release strategy. Then, three sequential high‐throughput chemical steps lead to the isolation of captopril in only 75 min. In‐line quenching and liquid–liquid separation enable breaks in the workflow and other manipulations to be avoided.

Rapid, Heterogeneous Biocatalytic Hydrogenation and Deuteration in a Continuous Flow Reactor

“…As a result, there is an increasing number of examples of immobilised biocatalysts operated in flow, [20] with cofactor recycling provided by traditional methods. [21][22][23] However, there is currently no standard method for handling immobilised redox biocatalysts in flow, and so wider adoption outside the biotechnology community is limited. Therefore, a biocatalytic approach that more closely resembles the heterogeneous chemical methods already in widespread use in flow reactors could facilitate uptake of redox biocatalysis in flow.…”

An Enzymatic Flow-Based Preparative Route to Vidarabine

“…However, low productivity and difficult product downstream are still the most often encountered bottlenecks in biocatalysis, which limit the implementation of enzymatic processes in industry [3]. Continuous flow technology is emerging as a key enabling tool for biocatalytic process intensification [4][5][6][7][8]. Flow processing has the potential to accelerate heterogeneous biotransformations due to biocatalyst high local concentration and enhanced mass transfer, making large-scale production more economically feasible in small equipment, with a substantial decrease in reaction time and improvement in space-time yield.…”

The Promises and the Challenges of Biotransformations in Microflow

“…Four-step chemoenzymatic synthesis of enantiomerically pure captopril from 2-methyl-1, 3-propanediol (enzymatic step not yet inline with 3 chemical steps) [62] Closed-loop series of two mesoscale glass packed-bed reactors coupled with inline liquid-liquid extraction and adsorption [63] Series of two mesoscale PTFE packed-bed tubular reactors CaLB immobilized in acrylic resin beads (Novozym 435)…”