Processes for preparing morphinan-6-one products with low levels of α, β-unsaturated ketone compounds
The present invention generally relates to processes for preparing highly pure morphinan-6-one products. The processes involve reducing the concentration of alpha, beta 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.
1 . A process for preparing oxymorphone HCl having a reduced concentration of 14-hydroxymorphinone, comprising:
a. forming a reaction mixture comprising oxymorphone HCl and 14-hydroxymorphinone;
b. treating the reaction mixture with a non-thiol sulfur-containing compound to reduce the concentration of the 14-hydroxymorphinone in the reaction mixture; and
c. recovering oxymorphone base to produce the oxymorphone HCl.
2 . The process of claim 1 , wherein at least one of the following conditions are present:
(i) the molar ratio of non-thiol sulfur-containing compound to oxymorphone in the reaction mixture is from about 0.5:1 to about 3.0:1;
(ii) the reaction mixture is treated with the non-thiol sulfur-containing compound for at least about 1 hour;
(iii) the reaction mixture is treated with the non-thiol sulfur-containing compound at a temperature greater than room temperature; or
(iv) the oxymorphone is recovered from the reaction mixture without the use of an organic solvent.
3 . The process of claim 1 , wherein the non-thiol sulfur-containing compound is a sulfur-containing nucleophile.
4 . The process of claim 1 , wherein the non-thiol sulfur-containing compound is a sulfur-containing inorganic acid or salt thereof.
5 . The process of claim 1 , wherein the non-thiol sulfur-containing inorganic acid is selected from the group consisting of hydrosulfuric acid (H 2 S); sulfurous acid (H 2 SO 3 ); persulfuric acid (H 2 SO 5 ); thiosulfurous acid (H 2 S 2 O 2 ); dithionous acid (H 2 S 2 O 4 ); disulfurous acid (H 2 S 2 O 5 ); dithioic acid (H 2 S 2 O 6 ); pyrosulfuric acid (H 2 S 2 O 7 ); peroxydisulfuric acid (H 2 S 2 O 8 ); trithionic acid (H 2 S 3 O 6 ); tetrathionic acid (H 2 S 4 O 6 ); pentathionic acid (H 2 S 5 O 6 ); chlorosulfonic acid (HSO 3 Cl); furosulfonic acid (HSO 3 F); sulfamic acid (HSO 3 NH 2 ); salts thereof; and combinations thereof.
6 . The process of claim 4 , wherein the salt is selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salt (NH4+), and quaternary ammonium salts.
7 . The process of claim 1 , wherein the reaction mixture further comprises a media material.
8 . The process of claim 7 , wherein the weight ratio of media material to oxymorphone in the reaction mixture is from about 1:1 to about 50:1.
9 . The process of claim 7 , wherein the media material is an aqueous media or an aqueous/organic solvent biphasic media.
10 . The process of claim 9 , wherein the aqueous media is water.
11 . The process of claim 1 , wherein after recovery the oxymorphone HCl comprises less than 0.001% of 14-hydroxymorphinone as determined by HPLC with MS.
12 . The process of claim 1 , wherein after recovery the oxymorphone HCl comprises less than 0.0005% of 14-hydroxymorphinone as determined by HPLC with MS.