Process for improved oxycodone synthesis
Processes for preparing oxycodone are provided. Said processes encompass a step which is a hydrogenation of an 14-hydroxycodeinone salt in the presence of trifluoroacetic acid and/or a glycol.
1. A process for preparing oxycodone or a salt or solvate thereof from thebaine, the process comprising the steps of:
(a) oxidizing the thebaine to 14-hydroxycodeinone in the presence of an oxidizing agent formed in situ in a reaction mixture comprising a combination of sulfuric acid and hydrogen peroxide, or a combination of sulfuric acid, formic acid, and hydrogen peroxide;
(b) optionally precipitating the resulting 14-hydroxycodeinone from step (a) as 14-hydroxycodeinone sulfate or a solvate thereof;
(c) optionally isolating the precipitated 14-hydroxycodeinone sulfate or solvate thereof from step (b);
(d) providing a solution or suspension of the 14-hydroxycodeinone sulfate or solvate thereof;
(e) adding trifluoroacetic acid and/or a glycol to the solution or suspension obtained in step (d);
(f) after step (e), reducing the 14-hydroxycodeinone present in the solution or suspension to the oxycodone by hydrogenation; and
(g) optionally adding a base, thus raising the pH to a pH where the oxycodone precipitates as its free base, and isolating the oxycodone as its free base or a solvate thereof.
2. The process of claim 1 , wherein the molar ratio of trifluoroacetic acid to 14-hydroxycodeinone as the 14-hydroxycodeinone sulfate or solvate thereof is 99% or less.
3. The process of claim 2 , wherein the molar ratio of trifluoroacetic acid to 14-hydroxycodeinone as the 14-hydroxycodeinone sulfate or solvate thereof is from 30% to 50%.
4. The process of claim 1 , wherein the glycol is selected from the group consisting of ethylene glycol, propylene glycol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, neopentylglycol, and mixtures thereof.
5. The process of claim 4 , wherein the glycol is ethylene glycol, propylene glycol, or a mixture thereof.
6. The process of claim 1 , wherein the glycol added in step (e) is in the range of 1 to 8 volumes/weight calculated for the glycol volume in mL in relation to the weight in g of the 14-hydroxycodeinone sulfate.
7. The process of claim 1 , wherein the hydrogenation in step (f) is performed with H 2 and a hydrogenation catalyst.
8. The process of claim 1 , wherein a mixture of water and the glycol is used as solvent, wherein the mixture is in a range from 20:80 to 45:55 glycol:water.
9. The process of claim 1 , additionally comprising the step (g) of adding the base, thus raising the pH to a pH where the oxycodone precipitates as its free base, and isolating the oxycodone as its free base or a solvate thereof.
10. The process of claim 9 , wherein the base added is NaOH.
11. The process of claim 1 , wherein the 4-hydroxycodeinone sulfate or solvate thereof is precipitated and isolated in the steps (b) and (c).
12. The process of claim 1 , wherein the thebaine is oxidized in the step (a) in the presence of an oxidizing agent formed in situ in a reaction mixture comprising a combination of sulfuric acid, formic acid and hydrogen peroxide.