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submitted on 10.06.2020 and posted on 11.06.2020by Gabriel Glotz, C. Oliver Kappe, David Cantillo
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.