Opioids like oxymorphone and its hydrochloride salt have long been used as analgesics.
Oxymorphone base is conventionally prepared by O-demethylation of oxycodone. Oxymorphone base can also be prepared by oxidation of oripavine to 14-hydroxymorphinone, and reducing the 14-hydroxymorphinone to oxymorphone base. A route for the preparation of oxymorphone via oxidation of oripavine to 14-hydroxymorphinone is illustrated in Scheme 1:

Once the oxymorphone base has been prepared, it is usually reacted with an acid to produce an oxymorphone salt, typically oxymorphone hydrochloride, as shown below in Scheme 2:

The oxidation step in the synthetic route illustrated in Scheme 1 can yield by-products which may be converted into other by-products during further conversion of the oxidation product (e.g., during the reaction shown in Scheme 2) or may be carried over into the final opioid compound, final pharmaceutical composition or final dosage form. These by-products may be undesired in the final pharmaceutical composition or final dosage form. Separation of these by-products from the final opioid may often be difficult, time-consuming and not volume efficient (e.g., if a separation by HPLC is required).
For example, during oxidation of oripavine to 14-hydroxymorphinone, certain by-products can be formed, e.g., 8-hydroxyoxymorphone. These by-products can be converted to 14-hydroxymorphinone when HCl is added, as illustrated in Scheme 3:

Thus, the 14-hydroxymorphinone intermediate shown in Scheme 1 is not only the immediate precursor to oxymorphone, it is also often found in the final oxymorphone salt used in pharmaceutical compositions, e.g., in oxymorphone hydrochloride. 14-hydroxymorphinone belongs to a class of compounds known as α,β-unsaturated ketones (ABUKs). These compounds contain a substructural component (the α,β-unsaturated ketone component) which produces a structure-activity relationship alert for genotoxicity. Their presence may be undesired in a pharmaceutical composition. Some regulatory authorities do not approve a pharmaceutical composition or dosage form for use and sale to the public if the amount of ABUKs in the pharmaceutical composition or dosage form exceeds the amount set by these authorities.
The conventional oxymorphone hydrochloride compositions would thus have to be subjected to one or more additional processing steps (e.g., hydrogenation, multiple recrystallizations, etc.) to reduce the amount of 14-hydroxymorphinone or its hydrochloride salt in the oxymorphone hydrochloride compositions below the limit set by the FDA or another regulatory authority, before these compositions could be incorporated into pharmaceutical dosage forms and/or administered to humans. These additional processing steps typically increase the production costs of pharmaceutical dosage forms, and have the potential to form new compounds and/or increase amounts of certain compounds above the limits set by the regulatory authorities for these compounds.
The conventional processes for preparing oxymorphone or oxymorphone salts from oxycodone or from oripavine are also often not very volume and cost efficient in their oxidation step, or they are complicated (e.g., the O-demethylation of oxycodone) and require specific equipment.
There is a continuing need for oxymorphone compositions and oxymorphone salt compositions which may directly be incorporated into pharmaceutical dosage forms without or with a reduced number of additional processing steps, processes for preparing these compositions, and starting and intermediary compounds or compositions used in and/or produced by these processes.
There is also a continuing need for processes which allow for an increase in volume efficiency, comprise a reduced number of processing steps and/or reduce manufacturing costs of processes for preparation of pharmaceutical compositions and dosage forms containing opioids, as compared to the conventional processes.
There is also a continuing need for processes for preparing opioids which exhibit a reduced amount of by-products in the process intermediates (e.g., of 8-hydroxyoxymorphone in the intermediate 14-hydroxymorphinone) and/or in the final opioid product (e.g., of 14-hydroxymorphinone in oxymorphone hydrochloride).