Functional-Group Compatible Electrooxidation Synthesis of Key Antibiotic Intermediate Rifamycin O

Rifamycin O (RO), a key intermediate in the antibiotic drug rifaximin synthesis, faces several production challenges including low yield, purity issues, and environmental concerns. Here, we report an electrochemical synthesis strategy achieving RO production via electrooxidation of rifamycin B (RB) resulting in a 92% high yield. Trace water addition improves the functional-group compatibility during RB electrooxidation, substantially elevating the RO yield by 10%. Mechanistic studies reveal that trace water regulates methanol's hydrogen bond network, facilitates the dissociation of the hydroxyl group in the carboxylic acid, and enriches RB at the electrode/electrolyte interface, thereby achieving thermodynamic and kinetic synergistic optimization of RB electrooxidation. Systematic optimization of flow electrolyzer parameters further improves performance. The scale-up experiment with an electrode area of 400 cm² electrode demonstrates high yield and space time yield. The present work establishes the electrochemical synthesis of RO, providing a sustainable paradigm for pharmaceutical electrosynthesis.