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Design and Development of Pd‐Catalyzed Aerobic N ‐Demethylation Strategies for the Synthesis of Noroxymorphone in Continuous Flow Mode
Author(s) -
Gutmann Bernhard,
Cantillo David,
Weigl Ulrich,
Cox D. Phillip,
Kappe C. Oliver
Publication year - 2017
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201601453
Subject(s) - chemistry , catalysis , combinatorial chemistry , demethylation , reagent , amine gas treating , phenol , organic chemistry , biochemistry , gene expression , dna methylation , gene
Strategies for the generation of noroxymorphone from 14‐hydroxymorphinone are presented. Noroxymorphone is the key intermediate in the synthesis of various opioid antagonists, including naloxone, naltrexone, and nalmefene, as well as mixed agonists‐antagonists such as nalbuphine. The transformation requires removal of the N ‐methyl group from the naturally occurring opiates and double‐bond hydrogenation. The pivotal reaction step thereby is an N ‐methyl oxidation with colloidal palladium(0) as catalyst and pure oxygen as terminal oxidant. The reaction produces a 1,3‐oxazolidine intermediate, which can be readily hydrolyzed to the corresponding secondary amine. Different reaction sequences and the use of various phenol protecting groups were explored. The most direct route consumes only H 2 , O 2 , and H 2 O as stoichiometric reagents and produces only H 2 O as a byproduct. Challenges inherent to gas/liquid reactions with oxygen as oxidant have been addressed by developing a continuous flow process.