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.