A small footprint oxycodone generator based on continuous flow technology and real-time analytics

• Florian Sommer^a,b
• David Cantillo^a,b
• C. Oliver Kappe^a,b

• ^aInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010, Graz, Austria
• ^bCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010, Graz, Austria

A scalable continuous flow setup for the preparation of the opioid medication oxycodone is presented. The process is based on a two-step synthetic sequence consisting of C14 hydroxylation of thebaine with performic acid, followed by catalytic hydrogenation of the ensuing 14-hydroxycodeinone intermediate. Safe and efficient oxidation with performic acid has been achieved by generating the reagent in situ in the presence of the starting material using a micromixer. Catalytic hydrogenation has been carried out in a scalable shell-and-tube reactor equipped with palladium-electroplated catalytic static mixers. Acquisition of real-time process data has been enabled by integrating online UHPLC analysis at the reactor output. The continuous process features safe operation, high atom economy, simple workup and production of 7 g/h of high purity oxycodone in a small footprint setup.

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