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-hydroxycodeihone. 
   
   
       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 the temperature is at least 60° C. 
   
   
       10 . The process of  claim 1 , wherein 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 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 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.   
   
   
       20 . The process of  claim 19 , further comprising, after step b), a step c) of filtering the solution at a temperature of about 56° C. 
   
   
       21 . The process of  claim 20 , wherein the prepared oxycodone or oxycodone salt contains approximately 0 ppm of 14-hydroxycodeinone. 
   
   
       22 . The process of  claim 19 , wherein the pH is less than 5. 
   
   
       23 . The process of  claim 19 , wherein the pH is less than 3. 
   
   
       24 . The process of  claim 19 , wherein the pH is less than or about 1. 
   
   
       25 . 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.   
   
   
       26 . The process of  claim 25 , wherein the prepared oxycodone or oxycodone salt contains approximately 0 ppm of 14-hydroxycodeinone. 
   
   
       27 . The process of  claim 1 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride. 
   
   
       28 . The process of  claim 19 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride. 
   
   
       29 . The process of  claim 25 , wherein said oxycodone or oxycodone salt comprises oxycodone hydrochloride. 
   
   
       30 . The process of  claim 1 , further comprising, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution. 
   
   
       31 . The process of  claim 1 , further comprising, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution. 
   
   
       32 . The process of  claim 31 , further comprising, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol. 
   
   
       33 . The process of  claim 19 , further comprising, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution. 
   
   
       34 . The process of  claim 19 , further comprising, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution. 
   
   
       35 . The process of  claim 34 , further comprising, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol. 
   
   
       36 . The process of  claim 25 , further comprising, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution. 
   
   
       37 . The process of  claim 25 , further comprising, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution. 
   
   
       38 . The process of  claim 37 , further comprising, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol. 
   
   
       39 . The process of  claim 31 , wherein the oxycodone or oxycodone salt is oxycodone hydrochloride, the pH is less than or about 1, and the maintaining is performed for at least 5 hours at a temperature from about 70° C. to 75° C. 
   
   
       40 . The process of  claim 39 , wherein step (b) is performed for about 6 hours from about 45° C. to 55° C. 
   
   
       41 . The process of  claim 39 , wherein the maintaining is performed for about 10 hours at a temperature of about 75° C. 
   
   
       42 . The process of  claim 1 , wherein the oxycodone or oxycodone salt is oxycodone hydrochloride, the pH is less than or about 1, and the maintaining is performed for at least 5 hours at a temperature from about 70° C. to 75° C. 
   
   
       43 . The process of  claim 42 , wherein step (b) is performed for about 6 hours from about 45° C. to 55° C. 
   
   
       44 . The process of  claim 42 , wherein the maintaining is performed for about 10 hours at a temperature of about 75° C. 
   
   
       45 . A process of purifying oxycodone or a salt thereof, comprising the steps of:
 a) preparing a solution comprising the oxycodone or salt thereof in a solvent, said solution having a pH less than 6, and;   b) maintaining the solution at a temperature of at least 55° C. for a period of at least 3 hours;   wherein the solution comprises, after the maintaining step, a level of 14-hydroxycodeinone that is higher than a level of 14-hydroxycodeinone before the maintaining step.   
   
   
       46 . The process of  claim 45 , wherein the oxycodone or salt thereof comprises oxycodone hydrochloride. 
   
   
       47 . The process of  claim 45 , wherein the pH is less than 5. 
   
   
       48 . The process of  claim 45 , wherein the pH is less than 3. 
   
   
       49 . The process of  claim 45 , wherein the temperature is at least 60° C. 
   
   
       50 . The process of  claim 45 , wherein the temperature is from about 70° C. to 75° C. 
   
   
       51 . The process of  claim 45 , wherein the period is at least 5 hours. 
   
   
       52 . The process of  claim 45 , wherein the period is from 5 to 10 hours. 
   
   
       53 . The process of  claim 45 , wherein the step of maintaining is performed in the absence of hydrogenation reagents. 
   
   
       54 . The process of  claim 45 , further comprising after step (b) the steps of:
 c) contacting the solution with hydrogenation reagents for a period of at least 1 hour; and   d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof.   
   
   
       55 . The process of  claim 54 , wherein the purified oxycodone or salt thereof is oxycodone hydrochloride. 
   
   
       56 . The process of  claim 54 , wherein the hydrogenation reagents comprise a hydrogenation catalyst and either hydrogen or a hydrogen transfer reagent. 
   
   
       57 . The process of  claim 54 , wherein the pH is less than or about 1. 
   
   
       58 . The process of  claim 45 , further comprising, prior to preparing the solution, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone or oxycodone salt that is used for preparing the solution. 
   
   
       59 . The process of  claim 45 , further comprising, prior to preparing the solution, the step of washing oxycodone with ethanol to form washed oxycodone and optionally forming a salt therefrom, wherein the washed oxycodone or salt formed therefrom is the oxycodone or oxycodone salt that is used to prepare the solution. 
   
   
       60 . The process of  claim 59 , further comprising, prior to the step of washing the oxycodone, the steps of washing 14-hydroxycodeinone with ethanol and subsequently converting the 14-hydroxycodeinone to a crude oxycodone, wherein the crude oxycodone is the oxycodone that is washed with ethanol. 
   
   
       61 . The process of  claim 59 , further comprising after step (b) the steps of:
 c) contacting the solution with hydrogenation reagents for a period of at least 1 hour; and   d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;   wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.   
   
   
       62 . The process of  claim 61 , wherein step (c) is performed for about 6 hours from about 45° C. to 55° C. 
   
   
       63 . The process of  claim 61 , wherein step (b) is performed at about 75° C. for about 10 hours. 
   
   
       64 . The process of  claim 45 , further comprising after step (b) the steps of:
 c) contacting the solution with hydrogenation reagents for a period of at least 1 hour; and   d) crystallizing the product of step (c) to form the purified oxycodone or salt thereof;   wherein the purified oxycodone or salt thereof is oxycodone hydrochloride, the pH is less than or about 1, and step (b) is carried out for at least 5 hours at a temperature from about 70° C. to 75° C.   
   
   
       65 . The process of  claim 64 , wherein step (c) is performed for about 6 hours from about 45° C. to 55° C. 
   
   
       66 . The process of  claim 64 , wherein step (b) is performed at about 75° C. for about 10 hours. 
   
   
       67 . The process of  claim 54  further comprising, after step (c), removing the hydrogenation catalysts by filtering to provide the product which is crystallized in step (d).