Toward the Synthesis of Noroxymorphone via Aerobic Palladium-Catalyzed Continuous Flow <i>N</i>‑Demethylation Strategies

The palladium-catalyzed <i>N</i>-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 <i>N,N</i>-dimethylacetamide. The palladium(0) particles are effective catalysts for the aerobic <i>N</i>-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