Preparation of oxycodone

Abstract

A process for preparing oxycodone or an oxycodone salt, wherein the oxycodone or oxycodone salt has low levels of impurities (especially 14-hydroxycodeinone) is disclosed. The process comprises the steps of: a) preparing a mixture comprising oxycodone and a solvent and adjusting the pH of the mixture to less than 6; and subsequently b) exposing the mixture to hydrogenation reagents for a period of at least 1 hour.

1 . A process for preparing oxycodone or an oxycodone salt having low levels of impurities, comprising the steps of: 
 a) preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining said solution at a temperature of at least 55° C. for at least 1 hour, said solution having a pH less than 6; and    b) subsequently exposing the solution to hydrogenation reagents for a period of at least 1 hour.    
   
   
       2 . The process of  claim 1 , wherein the impurities include α,β-unsaturated ketones.  
   
   
       3 . The process of  claim 1 , wherein the solution comprises, after the maintaining step but before the exposing step, a level of 14-hydroxycodeinone that is higher than a level of 14-hydroxycodeinone before the maintaining step.  
   
   
       4 . The process of  claim 3 , wherein the prepared oxycodone or oxycodone salt contains less than 15 ppm of 14-hydroxycodeinone.  
   
   
       5 . The process of  claim 3 , wherein the prepared oxycodone or oxycodone salt contains less than 5 ppm of 14-hydroxycodeinone.  
   
   
       6 . The process of  claim 1 , wherein the pH is less than 5.  
   
   
       7 . The process of  claim 1 , wherein the pH is less than 3.  
   
   
       8 . The process of  claim 1 , wherein the pH is less than or about 1.  
   
   
       9 . The process of  claim 1 , wherein in step a) the temperature is at least 60° C.  
   
   
       10 . The process of  claim 1 , wherein in step a) the temperature is about 70-75° C.  
   
   
       11 . The process of  claim 1 , wherein in step a) the period is at least 3 hours.  
   
   
       12 . The process of  claim 1 , wherein in step a) the period is 5-10 hours.  
   
   
       13 . The process of claims  1 , wherein step b) is carried out at or above about 40° C.  
   
   
       14 . The process of  claim 1 , wherein step b) is carried out at a temperature between 40° C. and 70° C.  
   
   
       15 . The process of  claim 1 , wherein in step b) the period is at least 2 hours.  
   
   
       16 . The process of  claim 1 , wherein in step b) the period is about 6 hours.  
   
   
       17 . The process of  claim 1 , wherein in step b) the hydrogenation reagents comprise a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent.  
   
   
       18 . The process of  claim 1 , wherein the process further comprises in sequence the subsequent steps of c) stirring the solution in contact with charcoal at a temperature of approximately 60-65° C. for 5-10 hours, d) filtering the solution to remove the charcoal, and e) cooling the solution.  
   
   
       19 . A process for preparing oxycodone or an oxycodone salt having low levels of impurities, comprising the steps of preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining, for a period of at least one hour, said solution at a temperature in a range from ambient to 70° C. while in contact with hydrogenation reagents, said solution having a pH less than 6.  
   
   
       20 . The process of  claim 19 , wherein the impurities include 14-hydroxycodeinone.  
   
   
       21 . The process of  claim 19 , wherein the pH is less than 5.  
   
   
       22 . The process of  claim 19 , wherein substantially all of the oxycodone or oxycodone salt in the solution is in solution during the step of maintaining.  
   
   
       23 . The process of  claim 19 , wherein in the period is at least 2 hours.  
   
   
       24 . The process of  claim 19 , wherein the period is at least 6 hours.  
   
   
       25 . The process of  claim 19 , wherein the process further comprises in sequence the subsequent steps of stirring the solution in contact with charcoal at a temperature of approximately 60-65° C. for 5-10 hours, filtering the solution to remove the charcoal, and cooling the solution.  
   
   
       26 . The process of  claim 19 , wherein the step of maintaining is performed at a temperature of at least 50° C.  
   
   
       27 . The process of  claim 26 , wherein the period is at least 5.5 hours.  
   
   
       28 . The process of  claim 19 , wherein the step of maintaining comprises maintaining at 50° C. for 1.5 hours and then further maintaining at 50-55° C. for at least 4 hours.  
   
   
       29 . The process of  claim 19 , wherein the prepared oxycodone or oxycodone salt contains approximately 12 ppm of 14-hydroxycodeinone.  
   
   
       30 . A process for preparing oxycodone or an oxycodone salt having low levels of 14-hydroxycodeinone, comprising the steps of: 
 a) preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining said solution at a temperature of about 75° C. for about 10-12 hours, said solution having a pH less than 6; and    b) subsequently exposing the solution to hydrogenation reagents at or above about 40° C. for about 6.5 hours.    
   
   
       31 . The process of  claim 30 , further comprising after step b) a step c) of filtering the solution at a temperature of about 56° C.  
   
   
       32 . The process of  claim 31 , wherein the prepared oxycodone or oxycodone salt contains approximately 0 ppm of 14-hydroxycodeinone.  
   
   
       33 . The process of  claim 30 , wherein the pH is less than 5.  
   
   
       34 . The process of  claim 30 , wherein the pH is less than 3.  
   
   
       35 . The process of  claim 30 , wherein the pH is less than or about 1.  
   
   
       36 . A process for preparing oxycodone or an oxycodone salt having low levels of 14-hydroxycodeinone, comprising the steps of: 
 a) preparing a solution comprising oxycodone or an oxycodone salt in a solvent and maintaining said solution at a temperature of about 75° C. for about 5 hours, said solution having a pH of about 1; and    b) subsequently exposing the solution to hydrogenation reagents at about 65° C. for about 6 hours.    
   
   
       37 . The process of  claim 36 , wherein the prepared oxycodone or oxycodone salt contains approximately 0 ppm of 14-hydroxycodeinone.  
   
   
       38 . The process of  claim 1 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride.  
   
   
       39 . The process of  claim 19 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride.  
   
   
       40 . The process of  claim 30 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride.  
   
   
       41 . The process of  claim 36 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride.