Application of the Polonovski Reaction: Scale-up of an Efficient and Environmentally Benign Opioid Demethylation
Antonio M. Ruda, Sofia Papadouli, Vargini Thangavadivale, Jonathan D. Moseley
Abstract
An environmentally benign iron-catalyzed nonclassical Polonovski reaction has been developed and scaled up to accomplish the challenging N-demethylation of MCL-509 Methyl to secondary amine MCL-509 Amine.HCl, key intermediates on the route to potential Parkinson’s treatment, MCL-509. The optimized reaction proceeded via the N-oxide in 2 h at room temperature in methanol/water using a mild stoichiometric oxidant and iron catalysis to yield the crystalline amine as its HCl salt directly from the reaction solution in typically 84% yield and 96% purity, after requiring only a screening filtration and facile solvent swap. This reaction was a great improvement in every aspect over the chloroformate-mediated and classical von Braun reactions utilized previously, especially for environmental, health, safety, and operability reasons. Robustness on scale was proven by the minimal technical transfer support required and the lack of any issues with all manufacturing batches produced in reproducible yields and consistent quality.