Development of a Safe and Environmentally Benign Manufacturing Process for Esomeprazole using an Iron Catalyst and Hydrogen Peroxide

The development of sustainable manufacturing processes for active pharmaceutical ingredients must address safety and environmental concerns. We successfully developed an environmentally benign process for the production of esomeprazole via asymmetric sulfoxidation using hydrogen peroxide as an oxidant in combination with an iron salt, a chiral Schiff base, and a carboxylate. This process uses 2.1 equiv of hydrogen peroxide as the oxidant, which poses safety issues for plant production owing to concerns surrounding the generation of oxygen and the hazards posed by the heat generated during the oxidation reaction. These issues can be mitigated by regulating the oxygen concentration with the nitrogen flow and maintaining the reaction temperature below the flash point of the solvent. Therefore, we evaluated the correlation between the addition rate of hydrogen peroxide, oxygen and heat flow profiles, and the heat accumulation properties. Based on this knowledge, we achieved the successful and safe manufacturing of esomeprazole at the kilo-lab and pilot production scales by optimizing the addition rate of hydrogen peroxide and nitrogen flow according to the reactor used.