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.
Reactions of 3-aryl-3-bromodiazirines (11) with molten tetrabutylammonium fluoride at 25 O C provide 65-74% isolated yields of the novel corresponding 3-aryl-3-fluorodiazirines (12). Related reactions of 11 with tetrabutylammonium azide afford high yields of aryl nitriles. The latter reactions are believed to proceed through unstable intermediate 3-aryl-3-azidodiazirines (7). These reactions involve rate-determining formation of 7 and display kinetics which are first order in azide ion and bromodiazirine. The likely intermediacy of an aryldiazirinium bromide ion pair between 11 and 7 is supported by a combination of salt effect, leaving group effect, and Hammett studies. Molecular orbital calculations are employed to characterize azidodiazirines as well as the mode of their decomposition to nitriles. In particular, we consider the possible intermediacy of a 3-nitrenodiazirine or an azidocarbene.3H-Diazirines, 1, are important precursors for the thermal or photolytic generation of carbenes.'Z2 There are three principal syntheses of these compounds:* the oxidation of 1,2-unsubstituted
The palladium-catalyzed N-demethylation of the
opioid alkaloids oxymorphone 3,14-diacetate and 14-hydroxymorphinone
3,14-diacetate to their nor-derivatives with oxygen as the terminal
oxidant has been investigated. Palladium(II) acetate forms colloidal
palladium(0) particles upon heating in N,N-dimethylacetamide.
The palladium(0) particles are effective catalysts for the aerobic N-demethylation of these opiate alkaloids. Demethylation
of 14-hydroxymorphinone 3,14-diacetate with pure oxygen as oxidant
in a continuous flow reactor provided the demethylated product with
excellent selectivity after residence times of only 10–20 min
with 2.5–5 mol % palladium acetate as catalyst on a laboratory
scale. Scale-up of the oxidation in a 100 mL flow reactor (combination
of FlowPlate A6 and coiled tube to enhance the gas–liquid mass
transfer), hydrogenation in a packed bed reactor, and subsequent hydrolysis
afforded the desired noroxymorphone in high quality and good yield
on a kg scale. The reaction sequence consumes only oxygen, hydrogen,
and water as stoichiometric reagents.
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