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Synthesis of noroxymorphone hydrochloride

Noroxymorphone has previously been synthesized from other opiates, such as morphine (1),

codeine (2), or thebaine (3) in good overall yields. However, several synthetic steps are required

and, as previously stated by Iijima et al. (4), noroxymorphone is difficult to purify. Although

noroxymorphone is used in the manufacturing of naloxone, it is not commercially readily available

for research purposes. Naloxone, however, is readily available and differs from noroxymorphone

only by having an allyl group in the nitrogen. We reasoned that direct N-deallylation of naloxone

would provide an easy access to a small-scale synthesis of pure noroxymorphone for research

purposes.



A practical method for the N-deallylation of naloxone hydrochloride to afford noroxymorphone

hydrochloride is presented. The N-deallylation was accomplished by rhodium-catalyzed

(Wilkinson’s catalyst) isomerization of N-allyl to enamine, followed by hydrolysis of the enamine

under the reaction conditions. The catalyst is not soluble in water under normal conditions and

therefore such deallylations are typically done in a mixture of water and an organic solvent such as

acetonitrile. However, the catalyst seems to be soluble in water, to some extent, at very high

temperatures because when a heterogeneous mixture of naloxone in water and 5 to 10 mole percent

of the catalyst was stirred at 200 °C for 30-60 min, a complete N-deallylation was observed (as

determined by the complete disappearance of the olefinic protons between 5.50 and 6.00 ppm in the
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    H NMR spectrum). When the reaction was performed at 150 °C or without the catalyst, no N-

deallylation was observed at all. The developed microwave-assisted and rhodium-catalyzed N-

deallylation method for preparing noroxymorphone is facile and robust.




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Experimental

Naloxone hydrochloride dihydrate (56 mg, 0.14 mmol) was dissolved in ion-exchanged water (2

mL) in a microwave reactor vial. Wilkinson’s catalyst (RhCl(PPh3)3) (10 mol-%) was added and

the vial was sealed. Argon was bubbled through the heterogeneous mixture for 30 min to remove

any dissolved oxygen. The mixture was heated to 200 °C for 60 min, cooled to room temperature

and filtered through C18 column to remove the catalyst and a small amount of triphenylphosphine

oxide formed in the reaction. The column was further eluted with water (10 mL). The water was

evaporated in vacuo to afford pure noroxymorphone hydrochloride in quantitative yield. The

structural and analytical data are in accordance with those previously published (1). 1H and 13C

NMR spectra of the product are shown in Figures 1a and 1b, respectively.




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References

1.    Ninan A, Sainsbury M. An improved synthesis of noroxymorphone.

      Tetrahedron 1992;48:6709-16.

2.    Schwartz MA, Wallace RA. Efficient synthesis of 14-hydroxymorphinans

      from codeine. J Med Chem 1981;24:1525-8.

3.    Blumberg H, Patcher IJ, Metossian Z, Dayton HB. 14-

      hydroxydihydronormorphinone derivatives. U.S. Patent, 1967 3 332 950.

4.    Iijima I, Minamikawa J, Jacobson AE, Brossi A, Rice KC. Studies in the (+)-

      morphinan series. 5. Synthesis and biological properties of (+)-naloxone. J

      Med Chem 1978;21:398-400.




Supplement figure legends

Fig 1a. 1H NMR Spectrum of Noroxymorphone hydrochloride (300 MHz, d6-DMSO)

Fig 1b. 13C NMR Spectrum of Noroxymorphone hydrochloride (75 MHz, d6-DMSO)




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