Continuous Flow Synthesis of Esomeprazole via Asymmetric Sulfoxidation

Abstract

In this paper, an expeditious and efficient continuous flow process for the synthesis of esomeprazole is described. The asymmetric sulfoxidation was achieved in optimized continuous reaction equipment under a mild condition to provide esomeprazole in 98% yield and 98% ee. For a more efficient reaction, an inert gas was introduced into the homogeneous reaction process, and the residence time in the flow system was markedly reduced (from 2 h in batch to 48 s in flow) because of an enhanced mixing effect. The effects of the reaction equipment, gas and liquid flow rate, reagent equivalents, reaction temperature, system concentration, solvent, and pressure have been investigated successively. To reveal the versatility and applicability of the reaction procedure, a scale-up strategy of continuous oxidation was employed to obtain nearly 20 g of product with a total productivity of 5.6 g/h. Ultimately, esomeprazole sodium was obtained with 99.8% purity and 99.6% ee following a simplified salt formation operation.