Toward the Synthesis of Noroxymorphone via Aerobic Palladium-Catalyzed Continuous Flow N-Demethylation Strategies

Abstract

The palladium-catalyzed N-demethylation of the opioid alkaloids oxymorphone 3,14-diacetate and 14-hydroxymorphinone 3,14-diacetate to their nor-derivatives with oxygen as the terminal oxidant has been investigated. Palladium­(II) acetate forms colloidal palladium(0) particles upon heating in N,N-dimethylacetamide. The palladium(0) particles are effective catalysts for the aerobic N-demethylation of these opiate alkaloids. Demethylation of 14-hydroxymorphinone 3,14-diacetate with pure oxygen as oxidant in a continuous flow reactor provided the demethylated product with excellent selectivity after residence times of only 10–20 min with 2.5–5 mol % palladium acetate as catalyst on a laboratory scale. Scale-up of the oxidation in a 100 mL flow reactor (combination of FlowPlate A6 and coiled tube to enhance the gas–liquid mass transfer), hydrogenation in a packed bed reactor, and subsequent hydrolysis afforded the desired noroxymorphone in high quality and good yield on a kg scale. The reaction sequence consumes only oxygen, hydrogen, and water as stoichiometric reagents.

The Use of Molecular Oxygen for Liquid Phase Aerobic Oxidations in Continuous Flow

“…The N-methyl group is contained in naturally occurring alkaloids (e.g., morphine, codeine, thebaine or oripavine) and its removal is needed to gain access to potent N-alklyated opioid receptor antagonists. In particular, the Pd-catalyzed aerobic N-demethylation of 14-hydroxymorphinone 3,14-diacetate was achieved using pure O 2 in a 100 mL stainless steel flow reactor on a 1 kg scale (Scheme 3) [35]. Prior to scale-up, micro-calorimeter (μRC) experiments and differential scanning…”

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

“…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. For instance, the authors used 14‐hydroxymorphinone‐3,14‐diacetate ( 136 ) as a starting material (Figure ). They reported that colloidal Pd 0 particles were very effective catalysts for the aerobic N ‐demethylation of selected opiate alkaloids.…”

“…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.…”