Process for improved oxycodone synthesis

1. A process for preparing oxycodone or a salt or solvate thereof from thebaine, the process comprising or consisting of the steps

(a) oxidizing the thebaine to 14-hydroxycodeinone;

(b) adding an acid H + n X n− to the reaction mixture of step (a) before, during and/or after the oxidation reaction;

(c) optionally precipitating the resulting 14-hydroxycodeinone as 14-hydroxycodeinone salt or a solvate thereof;

(d) optionally isolating the precipitated 14-hydroxycodeinone salt or solvate thereof;

(e) providing a solution or suspension of the 14-hydroxycodeinone salt or solvate thereof;

(f) adding trifluoroacetic acid and/or a glycol to the solution or suspension obtained in step (e);

(g) after step (f), reducing the 14-hydroxycodeinone present in the solution or suspension to the oxycodone by hydrogenation; and

(h) 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,

wherein

X n− is an anion selected from the group consisting of Cl − , HSO 4 − , SO 4 2− , methanesulfonate, tosylate, trifluoroacetate, H 2 PO 4 − , HPO 4 2− , PO 4 3− , oxalate, perchlorate, and any mixtures thereof; and

n is 1, 2, or 3.

2. The process of claim 1 , wherein trifluoroacetic acid and a glycol are added in step (f).

3. The process of claim 1 , wherein n is 2 and X n− is SO 4 2− .

4. The process of claim 1 , wherein the amount of trifluoroacetic acid is 99 mol % or less as compared to the molar amount of 14-hydroxycodeinone contained in the 14-hydroxycodeinone salt.

5. The process of claim 4 , wherein the amount of trifluoroacetic acid is from 30 mol % to 50 mol % as compared to the molar amount of 14-hydroxycodeinone contained in the 14-hydroxycodeinone salt.

6. 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.

7. The process of claim 6 , wherein the glycol is ethylene glycol, propylene glycol, or a mixture thereof.

8. The process of claim 1 , wherein the glycol added in step (f) 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 salt.

9. The process of claim 1 , wherein the hydrogenation in step (g) is performed with H 2 and a hydrogenation catalyst.

10. 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.

11. The process of claim 1 , additionally comprising the step (h) 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.

12. The process of claim 1 , wherein the 14-hydroxycodeinone salt or a solvate thereof is 14-hydroxycodeinone sulfate or a solvate thereof.

13. The process of claim 1 , wherein the 14-hydroxycodeinone salt or solvate thereof is precipitated and isolated in the steps (c) and (d).

14. 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 formic acid and hydrogen peroxide.

15. The process of claim 1 , wherein the acid is added to the reaction mixture in the step (b) before or during the oxidation reaction.

16. The process of claim 11 , wherein the base added is NaOH.