Processes for making hydrocodone, hydromorphone and their derivatives
View Patent ↗Improved processes for making hydrocodone and hydromorphone as well as their 8,14-dihydrothebaine and 8,14-dihydrooripavine derivatives and salts are disclosed.
1. A process for preparing 8,14-dihydrooripavine, the process comprising the steps of:
a. dissolving oripavine in an alkoxy solvent and, optionally, at least one first co-solvent to form an oripavine mixture;
b. heating the oripavine mixture;
c. separately dissolving a sulfonic acid hydrazide in an organic base and, optionally, a second co-solvent to form a hydrazide base solution; and
d. adding the hydrazide base solution and the oripavine mixture at such a rate to maintain the temperature of the mixture to form a reaction mixture comprising 8,14-dihydrooripavine.
2. The process of claim 1 , further comprising the step of cooling the reaction mixture to precipitate the 8,14-dihydrooripavine.
3. The process of claim 1 , further comprising the step of adding water to the reaction mixture.
4. The process of claim 1 , further comprising the step of triturating the 8,14-dihydrooripavine.
5. The process of claim 1 , wherein the alkoxy solvent is an alkoxy alkanol or an alkoxy alkandiol.
6. The process of claim 5 , wherein the alkoxy solvent is selected from the group consisting of 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, 1-methoxy-2-propanol, 1-methoxy-2-butanol, 3-methoxy-1-butanol, 3-methoxy-3-methyl-1-butanol and 3-methoxy-1,2-propandiol.
7. The process of claim 1 , wherein the first co-solvent is selected from the group consisting of ethanolamine, morpholine, ethylenediamine, and 1,3-propanediamine.
8. The process of claim 1 , wherein the sulfonic acid hydrazide is p-toluenesulfonylhydrazide.
9. The process of claim 1 , wherein the organic base is selected from the group consisting of ethanoamine, morpholine, ethylenediamine, and 1,3-propanediamine.
10. The process of claim 1 , wherein the second co-solvent is an alkoxy alkanol or an alkoxy alkandiol.
11. The process of claim 1 , wherein the oripavine mixture is heated to about 108±2° C.
12. The process of claim 1 , wherein the amount of the sulfonic acid hydrazide is about 2 equivalents relative to the oripavine.
13. The process of claim 1 , wherein the amount of the organic base is about 12 equivalents relative to the oripavine.
14. The process of claim 1 , wherein the reaction mixture pH is at least 9.5.
15. The process of claim 1 , wherein the hydrazide base solution is continuously combined with the oripavine mixture.
16. The process of claim 1 , wherein the hydrazide base solution is combined with the oripavine mixture at a steady rate.
17. A 8,14-dihydrooripavine composition wherein the composition is at least 97 area % pure, by HPLC, 8,14-dihydrooripavine.
18. The product of claim 17 , wherein the product comprises less than about 0.1%, by HPLC, oripavine.
19. The product of claim 17 , wherein the product has no detectable, by HPLC, sulfonic acid hydrazide impurities.
20. A process for making hydromorphone comprising the steps of:
a. preparing 8,14-dihydrooripavine by the process of claim 1 ; and
b. hydrolyzing the 8,14-dihydrooripavine to form hydromorphone.
21. A process for making a hydromorphone salt comprising the steps of:
a. preparing 8,14-dihydrooripavine by the process of claim 1 ;
b. hydrolyzing the 8,14-dihydrooripavine to form hydromorphone; and
c. combining the hydromorphone with an acid to form a hydromorphone salt.
22. A hydromorphone composition wherein the composition is at least 99.8 area % pure, by HPLC, hydromorphone base.