Design and Development of Pd‐Catalyzed Aerobic N‐Demethylation Strategies for the Synthesis of Noroxymorphone in Continuous Flow Mode

Abstract

Strategies for the generation of noroxymorphone from 14‐hydroxymorphinone are presented. Noroxymorphone is the key intermediate in the synthesis of various opioid antagonists, including naloxone, naltrexone, and nalmefene, as well as mixed agonists‐antagonists such as nalbuphine. The transformation requires removal of the N‐methyl group from the naturally occurring opiates and double‐bond hydrogenation. The pivotal reaction step thereby is an N‐methyl oxidation with colloidal palladium(0) as catalyst and pure oxygen as terminal oxidant. The reaction produces a 1,3‐oxazolidine intermediate, which can be readily hydrolyzed to the corresponding secondary amine. Different reaction sequences and the use of various phenol protecting groups were explored. The most direct route consumes only H2, O2, and H2O as stoichiometric reagents and produces only H2O as a byproduct. Challenges inherent to gas/liquid reactions with oxygen as oxidant have been addressed by developing a continuous flow process.

Fabrication of High‐Performance Palladium Supported on Activated Charcoal Nanocatalyst for Synthesis of Morphine Opioid Analgesics

“…Therefore, MeOH is the unfavorable (more difficult oxidation) for oxidation in comparison with the other mentioned alcohols . For the CH reaction of 14‐hydroxynormorphinone to noroxymorphone in present Pd/AC HEG nanocatalyst, the catalytic activity under these conditions is very suitable in this reaction …”

Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges

“…It is a medication typically used for blocking the effects of opioids especially in case of overdose. In a series of seminal papers, Kappe and colleagues reported on the preparation of various opioids , . The procedures produced a common advanced intermediate (noroxymorphone, 141 ) for the preparation of naloxone ( 142 , Figure ) and relied on pivotal alkene hydrogenation and N ‐demethylation reactions.…”

“…Hydrocodone is listed as a Schedule II substance by the DEA. In a series of papers dealing with the continuous flow preparation of opioids, Kappe and co‐workers described a continuous flow process for the preparation of hydrocodone ( 252 ) from thebaine ( 250 ) (Figure ) . Selective olefin reduction formed 8,14‐dihydrothebaine ( 251 ), which was next hydrolyzed to yield 252 .…”

An Integrated Continuous‐Flow Synthesis of a Key Oxazolidine Intermediate to Noroxymorphone from Naturally Occurring Opioids

“…Recently, our group has developed a series of strategies for the generation of noroxymorphone ( 4 ) from 14‐hydroxymorphinone under continuous‐flow conditions . The crucial reaction step towards the generation of 4 was an unprecedented aerobic N ‐methyl oxidation using palladium(0) as catalyst, which generates oxazolidine 5 as intermediate (Scheme ).…”

“…Palladium(0) particles of high catalytic activity were generated by heating Pd(OAc) 2 in DMA/AcOH. With the 14‐ N ‐hydroxy opioids dissolved in this solution, a rapid and selective methyl oxidation to 1,3‐oxazolidines ensued in the presence of O 2 . The reaction, based on the original method developed by Hudlicky et al in 2008, consumes only O 2 as stoichiometric reagent and produces H 2 O as the only byproduct.…”