Selective Olefin Reduction in Thebaine Using Hydrazine Hydrate and O₂ under Intensified Continuous Flow Conditions

Hydrocodone, a high value active pharmaceutical ingredient (API), is usually produced in a semisynthetic pathway from morphine, codeine or thebaine. The latter alkaloid is an attractive precursor as it is not used as a remedy itself. The key step in this production route is a selective olefin reduction forming 8,14-dihydrothebaine which can be subsequently hydrolyzed to yield hydrocodone. Unfortunately, standard hydrogenation procedures cannot be applied due to severe selectivity problems. A transfer hydrogenation using in situ generated diimide is the only known alternative to achieve a selective transformation. The most (atom) economic generation of this highly unstable reducing agent is by oxidizing hydrazine hydrate (N₂H₄·H₂O) with O₂. In the past, this route was “forbidden” on an industrial scale due to its enormous explosion potential in batch. A continuous high-temperature/high-pressure methodology allows an efficient, safe, and scalable processing of the hazardous reaction mixture. The industrially relevant reduction was achieved by using four consecutive liquid feeds (of N₂H₄·H₂O) and residence time units, resulting in a highly selective reduction within less than 1 h

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

Heteroatom Analogues of Hydrocodone: Synthesis and Biological Activity

Heteroatom analogues of hydrocodone, in which the <i>N</i>-methyl functionality was replaced with oxygen, sulfur, sulfoxide, and sulfone, were prepared by a short sequence from the ethylene glycol ketal of hydrocodone; a carbocyclic analogue of bisnorhydrocodone was also prepared. The compounds were tested for receptor binding and revealed moderate levels of activity for the sulfone analogue of hydrocodone