title: Batch- and Continuous-Flow Aerobic Oxidation of 14-Hydroxy Opioids to 1,3-Oxazolidines-A Concise Synthesis of Noroxymorphone.
abstract: 14-Hydroxymorphinone is converted to noroxymorphone, the immediate precursor of important opioid antagonists, such as naltrexone and naloxone, in a three-step reaction sequence. The initial oxidation of the N-methyl group in 14-hydroxymorphinone with in situ generated colloidal palladium(0) as the catalyst and molecular oxygen as the terminal oxidant constitutes the key transformation in this new route. This oxidation results in the formation of an unexpected oxazolidine ring structure. Subsequent hydrolysis of the oxazolidine under reduced pressure followed by hydrogenation in a packed-bed flow reactor using palladium(0) as the catalyst provides noroxymorphone in high purity and good overall yield. To overcome challenges associated with gas-liquid reactions with molecular oxygen, the key oxidation reaction was translated to a continuous-flow process.
authors.affiliation: Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010, Graz, Austria.|Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010, Graz, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gutmann
authors.affiliation: Cilag AG, Hochstrasse 201, 8200, Schaffhausen, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Weigl
authors.affiliation: Noramco Inc., 503 Carr Rd, Suite 200, Wilmington, DE, 19809, USA.
authors.forename: D Phillip
authors.initials: DP
authors.lastname: Cox
authors.affiliation: Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010, Graz, Austria. oliver.kappe@uni-graz.at.|Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010, Graz, Austria. oliver.kappe@uni-graz.at.
authors.forename: C Oliver
authors.identifier: http://orcid.org/0000-0003-2983-6007
authors.initials: CO
authors.lastname: Kappe
mesh_terms: D002384:Catalysis; D003102:Colloids; D006865:Hydrogenation; D009019:Morphinans / Q000138:chemical synthesis*; D010080:Oxazoles / Q000138:chemical synthesis*; D016877:Oxidants / Q000737:chemistry; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D010165:Palladium; D013499:Surface Properties
chemical_list: D003102:Colloids; D009019:Morphinans; D010080:Oxazoles; D016877:Oxidants; C064210:oxazolidine; D010165:Palladium; C526569:noroxymorphone; D010100:Oxygen
keywords: N-demethylation; aerobic oxidation; flow chemistry; naloxone; naltrexone