Processes for making opioids including 14-hydroxycodeinone and 14-hydroxymorphinone

1. A method of making an oxymorphone free base comprising the steps of:

a. oxidizing oripavine with a peroxyacid to form 14-hydroxymorphinone;

b. adding an alcohol to the reaction mixture at or about upon completion of step a;

c. treating the reaction mixture of step b with a mixture of ammonium hydroxide solution and water to yield 14-hydroxymorphinone; and

d. converting the 14-hydroxymorphinone to the oxymorphone free base.

2. The method of claim 1 further comprising purifying the 14-hydroxymorphinone of step c before proceeding to step d.

3. The method of claim 1 , wherein step a is affected by

i. dissolving oripavine in a carboxylic acid to form a reaction mixture; and

ii. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ in the reaction mixture.

4. The method of claim 3 , further comprising adding to step a at least one strong acid to the reaction mixture.

5. The method of claim 3 , further comprising in step i an alcohol in addition to the carboxylic acid.

6. The method of claim 1 further comprising purifying the oxymorphone free base of step d.

7. The method of claim 1 further comprising converting the oxymorphone free base to oxymorphone hydrochloride.

8. The method of claim 2 , wherein the purifying comprises the steps of:

a. dissolving the 14-hydroxymorphinone of step c in dichloromethane to form a mixture;

b. distilling the mixture while adding an alcohol or acetonitrile to the mixture; and

c. cooling the mixture to crystallize at least a portion of the 14-hydroxymorphinone.

9. The method of claim 7 , wherein the oxymorphone hydrochloride has at least a 99.9% (area, HPLC) purity and comprises less than 5 ppm of 14-hydroxymorphinone.

10. The method of claim 6 wherein the purifying comprises:

a. mixing the oxymorphone free base of step d with an alcohol to form a slurry;

b. heating the slurry to reflux temperature; and

c. cooling the slurry to obtain the oxymorphone free base.

11. The method of claim 1 , wherein the converting the 14-hydroxymorphinone to the oxymorphone free base comprises the steps of:

a. dissolving the 14-hydroxymorphinone in a mixture of water and acid;

b. adding a quantity of 5% palladium on charcoal to the mixture;

c. hydrogenating the mixture;

d. cooling the hydrogenated mixture while adjusting the pH of the mixture to obtain a slurry yielding the oxymorphone free base.

12. The method of claim 10 , wherein the oxymorphone free base is at least 99.9% (area, HPLC) pure.

13. A method of making an oxycodone free base comprising the steps of:

a. oxidizing thebaine with a peroxyacid to form 14-hydroxycodeinone;

b. adding an alcohol to the reaction mixture at or about upon completion of step a;

c. treating the reaction mixture of step b with a mixture of ammonium hydroxide solution and water to yield 14-hydroxycodeinone; and

d. converting the 14-hydroxycodeinone to the oxycodone free base.

14. The method of claim 13 , wherein step a is affected by

i. dissolving thebaine in a carboxylic acid to form a reaction mixture; and

ii. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ in the reaction mixture.

15. The method of claim 13 , wherein the alcohol is selected from the group consisting of ethanol and methanol.

16. The method of claim 13 , wherein the 14-hydroxycodeinone contains less than about 1000 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone and less than about 1000 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone isomer.

17. The method of claim 14 , wherein the carboxylic acid is selected from the group consisting of formic acid, acetic acid and propionic acid.

18. The method of claim 14 , further comprising adding to step a at least one strong acid to the reaction mixture.

19. The method of claim 18 , wherein the strong acid is selected from the group consisting of hydrochloric acid, sulphuric acid, phosphoric acid, methanesulfonic acid, trifluoroacetic acid or mixtures thereof.

20. The method of claim 14 , further comprising in step i an alcohol in addition to the carboxylic acid.

21. The method of claim 20 , wherein the alcohol is selected from the group consisting of methanol, ethanol, and propanol.

22. The method of claim 13 , further comprising purifying the 14-hydroxycodeinone of step c before proceeding to step d.

23. The method of claim 22 , wherein the purifying comprises reducing an amount of at least one of 8β,14-dihydroxy-7,8-dihydrocodeinone and 8β,14-dihydroxy-7,8-dihydrocodeinone isomer of the 8,14-dihydroxy-7,8-dihydrocodeinone in the 14-hydroxycodeinone.

24. The method of claim 23 , wherein the amount of 8β,14-dihydroxy-7,8-dihydrocodeinone is less than about 50 ppm and the amount of 8β,14-dihydroxy-7,8-dihydrocodeinone isomer is less than about 125 ppm in the 14-hydroxycodeinone.

25. The method of claim 22 , wherein the purifying comprises the steps of:

a. dissolving the 14-hydroxycodeinone of step c in dichloromethane to form a mixture;

b. distilling the mixture while adding an alcohol or acetonitrile to the mixture; and

c. cooling the mixture to crystallize at least a portion of the 14-hydroxycodeinone.

26. The method of claim 25 , wherein the alcohol is ethanol or methanol.

27. The method of claim 13 further comprising purifying the oxycodone free base of step d.

28. The method of claim 13 , further comprising converting the oxycodone free base to oxycodone hydrochloride.

29. The method of claim 27 wherein the purifying comprises:

a. mixing the oxycodone free base of step d with an alcohol to form a slurry;

b. heating the slurry to reflux temperature; and

c. cooling the slurry to obtain the oxycodone free base.

30. The method of claim 13 , wherein, the converting the 14-hydroxycodeinone to the oxycodone free base comprises the steps of:

a. dissolving the 14-hydroxycodeinone in a mixture of water and acid;

b. adding a first quantity of 10% palladium on charcoal to the mixture of step a;

c. heating the mixture of step b followed by a first hydrogenation reaction to form a first hydrogenated mixture;

d. adding a hydrochloric acid solution to the first hydrogenated mixture of step c;

e. adding a second quantity of 10% palladium on charcoal to the mixture of step d;

f. heating the mixture of step e followed by a second hydrogenation reaction to form a second hydrogenated mixture;

g. adjusting the pH of the second hydrogenated mixture to obtain a slurry yielding the oxycodone free base.

31. The method of claim 29 , wherein the oxycodone free base is at least 99.6% (area, HPLC) pure.

32. The method of claim 28 , wherein the oxycodone hydrochloride has a purity of at least 99.9% (area, HPLC) and comprises less than 5 ppm of 14-hydroxycodeinone.