Electrochemical N-Demethylation of 14-Hydroxy Morphinans – Sustainable Access towards Opioid Antagonists
2020-06-11T12:57:03Z (GMT) by
The growing demand for opioid antagonists necessitates the development of more efficient and affordable synthetic routes. The most challenging step in the preparation of these essential medicines is the selective N-demethylation of a 14-hydroxy opioid precursor to the corresponding nor-opioid, which is followed by N-alkylation of the resulting secondary amine. This process is carried out on large scales using stoichiometric amounts of hazardous chemicals like cyanogen bromide or chloroformates. We have developed a mild, reagent- and catalyst-free procedure for the N-demethylation step, based on the anodic oxidation of the tertiary amine. The ensuing iminium cation rapidly undergoes cyclization with the 14-hydroxy group, or acyl transfer from its acetylated derivative, resulting in intermediates that can be readily hydrolyzed to the target nor-opioids. The electrochemical method provides excellent yields and has successfully been transferred to a flow electrolysis cell, thus enabling the potential scale-up of this synthetic strategy.