Development of a Sustainable One-Pot Process for Esomeprazole Production via Enantioselective Iron Catalysis

Abstract

For the production of active pharmaceutical ingredients through sustainable organic synthesis, the use of inexpensive and non-toxic catalysts is desirable. Recently, homogeneous chiral Fe catalysts have received considerable attention as tools for achieving this goal. However, chiral Fe catalysts often perform poorly when used to synthesize complex molecules, limiting their application to large-scale syntheses. In this study, we developed an asymmetric sulfoxidation reaction for the production of esomeprazole at a pilot-plant scale. The reaction uses a catalytic system generated in situ from an Fe salt, which is abundant, inexpensive, and environmentally friendly, combined with a chiral Schiff ligand and a carboxylate salt, and hydrogen peroxide as the oxidant. Subsequently, the obtained esomeprazole is converted from its K-salt form to an Mg-salt, thereby establishing a manufacturing process that yields high-purity active pharmaceutical ingredients with impurities controlled to less than 0.05%. The enantioselectivity and kinetic resolution of the asymmetric sulfoxidation reaction are dependent on the spatial relationship between the sp³-hybridization center and the sp² carbon adjacent to the substituent attached to the S atom of the substrate. We also speculate that the carboxylic acid additive plays a critical role in activating hydrogen peroxide through heterolytic cleavage and enabling the formation of both mono- and dinuclear iron oxidants. Furthermore, we propose a catalytic mechanism for this enantioselective oxidation reaction.