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 Nand 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.

Catalytic Conversion of Caffeine into Molecules of Valuable Interest Via N‐Demethylation Reaction

“…[19][20][21][22] Disadvantages include the use of expensive and toxic reagents, the number of reaction steps under severe conditions, and hazardous by-products. Some recent reports use metal-catalyzed, [23] photocatalyst-free, [24] anodic oxidation [25] highlighting difficulties and revealing the search for new practical discoveries of Ndemethylation methods.…”

Photoinduced Nickel-Catalyzed Selective N-Demethylation of Trialkylamines Using C(sp2)–Bromides as HAT Reagents

“…Trialkylamines are important motifs in alkaloid natural products and pharmaceutical compounds . The removal or replacement of N -methyl substituents is a useful transformation that has been employed in drug synthesis and in the development of tools for pharmacological and drug metabolic studies. , The classical and frequently employed approaches for N -demethylation of tertiary amines include the von Braun reaction, the use of chloroformate reagents (Scheme A), and the Polonovski reaction, which are two-step protocols involving a cyanamide, carbamate, or N -oxide intermediate, respectively, and require harsh reaction conditions (high temperature, employment of toxic reagent such as cyanogen bromide, or a strong oxidant), with limited functional group tolerance and poor site-selectivity. , Other approaches such as biochemical, , photochemical, − electrochemical, , and transition-metal catalyzed , methods have also been reported, albeit being restricted to specific structures and lack broad applicability.…”