Chemoenzymatic synthesis in flow reactors: a rapid and convenient preparation of captopril

• Dr. Valerio De Vitis¹
• Dr. Federica Dall'Oglio¹
• Dr. Andrea Pinto²
• Prof. Carlo De Micheli²
• Prof. Francesco Molinari¹
• Prof. Paola Conti²
• Dr. Diego Romano¹
• Dr. Lucia Tamborini²

• ¹ Department of Food Environmental and Nutritional Science, University of Milan, Milan, Italy
• ² Department of Pharmaceutical Sciences, University of Milan, Milan, Italy

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.

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