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Issue 30, 2012
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Improved synthesis of 14-hydroxy opioid pharmaceuticals and intermediates

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Abstract

Significantly improved reaction conditions for the synthesis of oxycodone (1), via the conventional two-step process involving oxidation of thebaine (3) into 14-hydroxycodeinone (5) and the subsequent reduction of 5via catalytic hydrogenation, are reported. Employing the hydrochloride salt of thebaine (3) in the oxidation step, in place of the more traditionally used free base form of this opiate, now provides 5 in high yield and purity. For the reduction step, aqueous acetic acid has typically been employed as the solvent. However, this was found to generate varying amounts of 14-hydroxydihydrocodeine (16) as the dominant by-product. Instead, using 5% Pd/BaSO4 as the catalyst and MeOH as the solvent completely eliminated the formation of 16, giving oxycodone (1) in high yield and purity, without the need to purify the intermediates. These improved conditions have also proved effective in the synthesis of other 14-hydroxyopiates, such as oxymorphone (2) and N-noroxymorphone (9). In the latter case, a high overall yield was achieved by starting from N-nororipavine (10), without the need to employ protecting groups.

Graphical abstract: Improved synthesis of 14-hydroxy opioid pharmaceuticals and intermediates

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Publication details

The article was received on 06 Aug 2012, accepted on 23 Sep 2012 and first published on 25 Sep 2012


Article type: Paper
DOI: 10.1039/C2RA21693K
RSC Adv., 2012,2, 11318-11325

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    Improved synthesis of 14-hydroxy opioid pharmaceuticals and intermediates

    G. B. Kok and P. J. Scammells, RSC Adv., 2012, 2, 11318
    DOI: 10.1039/C2RA21693K

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