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.