Sustainable Synthesis of Noroxymorphone via a Key Electrochemical N-Demethylation Step

Abstract

Noroxymorphone is a pivotal intermediate in the synthesis of important opioid antagonists such as naloxone and naltrexone. The preparation of noroxymorphone from thebaine, a naturally occurring opioate isolated from poppy extract, is a multistep sequence in which oxycodone is first generated and then N- and O-demethylated. Both demethylations are problematic from the safety and sustainability viewpoint, as they involve harmful reagents such as alkyl chloroformates or boron tribromide. Herein, we present a green, safe, and efficient process for the N- and O-demethylation of oxycodone. The method is based on the anodic oxidative intramolecular cyclization of the N-methyl tertiary amine with the 14-hydroxyl group of the morphinan, followed by hydrolysis with hydrobromic acid, which releases the carbon from both heteroatoms. The electrolysis process has been transferred to a scalable flow electrolysis cell, significantly improving the reaction throughput and increasing the space-time yield over 300-fold with respect to batch. The sustainability of the new methodology has been assessed by means of green metrics and qualitative indicators. The sustainability assessment has demonstrated that the new methodology is far superior to the conventional chloroformate process.