Processes for Making Opioids Including 14-Hydroxycodeinone and 14-hydroxymorphinone

Abstract

Improved processes for making opioid products having low impurity levels including making 14-hydroxycodeinone and 14-hydroxymorphinone from thebaine and oripavine, respectively.

1 . A method of making a 14-hydroxycodeinone composition comprising the steps of:
 a. dissolving thebaine in a carboxylic acid to form a reaction mixture;   b. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ; and   c. oxidizing the thebaine by reacting it with the peroxyacid to form the 14-hydroxycodeinone composition,   wherein the composition 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.   
     
     
         2 . The process of  claim 1 , wherein the carboxylic acid is selected from the group consisting of formic acid, acetic acid and propionic acid. 
     
     
         3 . A method of making a 14-hydroxycodeinone composition comprising the steps of:
 a. dissolving thebaine in a carboxylic acid to form a reaction mixture;   b. adding at least one strong acid to the reaction mixture;   c. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ; and   d. oxidizing the thebaine by reacting it with the peroxyacid to form the 14-hydroxycodeinone composition.   
     
     
         4 . The process of  claim 3 , wherein the strong acid is selected from hydrochloric acid, sulphuric acid, phosphoric acid, methanesulfonic acid, trifluroacetic acid or mixtures thereof. 
     
     
         5 . A method of making a 14-hydroxycodeinone composition comprising the steps of:
 a. dissolving thebaine in a carboxylic acid and a solvent to form a reaction mixture;   b. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ; and   c. oxidizing the thebaine by reacting it with the peroxyacid to form the 14-hydroxycodeinone composition.   
     
     
         6 . The process of  claim 5 , wherein the alcohol solvent is an alcohol. 
     
     
         7 . The process of  claim 6 , wherein the alcohol is selected from the group consisting of methanol, ethanol, and propanol. 
     
     
         8 . A method of making a 14-hydroxycodeinone composition comprising the steps of:
 a. dissolving thebaine in a carboxylic acid to form a reaction mixture;   b. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ;   c. oxidizing the thebaine by reacting it with the peroxyacid to form the 14-hydroxycodeinone composition; and   d. adding a solvent to the reaction mixture.   
     
     
         9 . The process of  claims 1 ,  3 ,  5  and  8  further comprising the step of purifying the 14-hydroxycodeinone composition. 
     
     
         10 . The process of  claim 9 , wherein the purification step comprises reducing an amount of at least one of 8β,14-dihydroxy-7,8-dihydrocodeinone and 8β,14-dihydroxy-7,8-dihydrocodeinone isomer in the composition. 
     
     
         11 . The process of  claim 10 , 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 composition. 
     
     
         12 . The process of  claim 10 , wherein the purification step comprises the steps of:
 a. dissolving the composition in a solvent to form a mixture;   b. distilling the mixture while adding a second solvent to the mixture; and   c. cooling the mixture to crystallize at least a portion of the 14-hydroxycodeinone.   
     
     
         13 . The process of  claim 12 , wherein the other solvent is dichloromethane. 
     
     
         14 . The process of  claim 13 , wherein the second solvent is an alcohol or acetonitrile. 
     
     
         15 . The process of  claim 14 , wherein the alcohol is ethanol or methanol. 
     
     
         16 . A 14-hydroxycodeinone composition wherein the composition is greater than 91 percent (area, HPLC) pure 14-hydroxycodeinone and wherein the composition comprises less than about 45 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone. 
     
     
         17 . A 14-hydroxymorphinone composition wherein the composition is greater than 95 percent (area, HPLC) pure 14-hydroxymorphinone. 
     
     
         18 . An oxycodone free base composition wherein the composition comprises less than about 200 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone and less than about 10 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone isomer. 
     
     
         19 . An oxycodone hydrochloride composition wherein the composition comprises less than about 25 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone and less than about 10 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone isomer. 
     
     
         20 . A method of making a 14-hydroxymorphinone composition comprising the steps of:
 a. dissolving oripavine in a carboxylic acid to form a reaction mixture;   b. adding at least one strong acid to the reaction mixture;   c. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ; and   d. oxidizing the oripavine by reacting it with the peroxyacid to form the 14-hydroxymorphinone composition.   
     
     
         21 . A method of making a 14-hydroxymorphinone composition comprising the steps of:
 a. dissolving oripavine in a carboxylic acid and a solvent to form a reaction mixture;   b. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ; and   c. oxidizing the oripavine by reacting it with the peroxyacid to form the 14-hydroxymorphinone composition.   
     
     
         22 . A method of making a 14-hydroxymorphinone composition comprising the steps of:
 a. dissolving oripavine in a carboxylic acid to form a reaction mixture;   b. adding hydrogen peroxide to the reaction mixture to form a peroxyacid in situ;   c. oxidizing the oripavine by reacting it with the peroxyacid to form the 14-hydroxymorphinone composition; and   d. adding a solvent to the reaction mixture.   
     
     
         23 . The process of any one of  claims 20 - 22  further comprising the step of purifying the 14-hydroxymorphinone composition. 
     
     
         24 . The process of  claim 23 , wherein the purification step comprises the steps of:
 a. dissolving the composition in a solvent to form a mixture;   b. distilling the mixture while adding a second solvent to the mixture; and   c. cooling the mixture to crystallize at least a portion of the 14-hydroxymorphinone.   
     
     
         25 . An oxymorphone free base composition having at least a 99.9 percent (area, HPLC) purity made by the process as recited in  claim 23  and further comprising the step of converting the 14-hydroxymorphinone to the free base composition. 
     
     
         26 . An oxymorphone hydrochloride composition having at least a 99.9 percent (area, HPLC) purity and comprising less than 5 ppm 14-hydroxymorphinone. 
     
     
         27 . The oxymorphone hydrochloride composition of  claim 26  made by the process as recited in  claim 23  and further comprising at least one step of converting the 14-hydroxymorphinone to the oxymorphone hydrochloride composition. 
     
     
         28 . (canceled) 
     
     
         29 . The composition of  claim 16 , wherein the composition comprises less than about 30 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone isomer. 
     
     
         30 . The composition of  claim 16 , wherein the composition is greater than 99 percent (area, HPLC) pure 14-hydroxycodeinone. 
     
     
         31 . The composition of  claim 30 , wherein the composition comprises less than about 45 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone and less than about 110 ppm 8β,14-dihydroxy-7,8-dihydrocodeinone isomer.