Process for preparing morphinan-6-one products with low levels of α,β-unsaturated ketone compounds
Inventors
Buehler, Henry J. • Dummitt, William E. • Mannino, Anthony • Aubuchon, Dennis C. • Gu, Hong
Assignees
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Publication Number
US-8871779-B2
Publication Date
2014-10-28
Expiration Date
Abstract
The present invention generally relates to processes for preparing highly pure morphinan-6-one products. The processes involve reducing the concentration of α,β-unsaturated ketone compounds present as impurities in morphinan 6 one products or reaction mixtures including morphinan 6 one compounds by treatment with a sulfur-containing compound. (A)
Core Innovation
The disclosed subject matter provides morphinan-6-one products with a low level of an α,β-unsaturated ketone impurity. Reaction mixtures containing a morphinan-6-one compound and an α,β-unsaturated ketone impurity are treated with a sulfur-containing compound to reduce the concentration of the impurity in the reaction mixture.
The disclosed content describes treating morphinan-6-one compounds and α,β-unsaturated ketone impurities with sulfur-containing compounds to form reversible 1,2- and 1,4-sulfonated/bisulfite addition products. The sulfur-containing compounds include inorganic sulfurous acids and bisulfite precursors, and thiols.
The formation of the addition products is pH-dependent, with reversible addition products being associated with a pH range of about 3 to 9. Unwanted α,β-unsaturated ketone addition products can be removed by shifting pH outside the stated range, and optional removal of residual sulfur species is described by converting sulfur species to SO2 at low pH and stripping/distillation.
Claims Coverage
The independent claims cover hydrochloride salt forms of morphinan-6-one compounds with strict quantitative limits on an α,β-unsaturated ketone impurity, measured by HPLC. Two independent claim variants are present, anchored to the same impurity control concept but differing in the impurity identity and structural framing.
Hydrochloride salt of oxymorphone with less than 0.001% 14-hydroxymorphinone
A hydrochloride salt of oxymorphone comprising less than 0.001% of 14-hydroxymorphinone.
Hydrochloride salt of morphinan-6-one compound of Formula (2) with less than 0.001% α,β-unsaturated ketone of Formula (3) measured by HPLC
A hydrochloride salt of a morphinan-6-one compound corresponding to Formula (2) comprising less than 0.001% measured by HPLC of an α,β-unsaturated ketone compound corresponding to Formula (3).
Overall, the claims emphasize producing hydrochloride salt forms of morphinan-6-one with a very low level of a specified α,β-unsaturated ketone impurity, either directly defined as 14-hydroxymorphinone or defined structurally by Formula (3) and quantified by HPLC.
Stated Advantages
Reduces α,β-unsaturated ketone impurity concentration, including reducing levels from about 0.5% or more to ≤0.1% and lower.
Provides highly pure morphinan-6-one products.
Facilitates impurity removal through formation of 1,2- and 1,4-sulfonated addition products or adducts associated with sulfur-containing compound treatment.
Documented Applications
Use in providing morphinan-6-one products applicable to multiple morphinan-6-one compounds, including oxycodone, oxymorphone, hydrocodone, naloxone, naltrexone, nalbuphone, and noroxymorphone.
Recovery and optional conversion of the morphinan-6-one product to salts such as hydrochlorides, including oxymorphone hydrochloride.
Pharmaceutical formulation context that includes the specified oxymorphone hydrochloride.
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