Method for catalytic preparation of hydromorphone, hydrocodone, and other opiates

Abstract

Methods are provided for efficient preparation of hydromorphone or hydrocodone by redox isomerization of morphine or codeine allylic alcohols, respectively, using transition metal aminophosphine catalysts formed in situ.

1 - 42 . (canceled) 
     
     
         43 . A method for preparing a pharmaceutically acceptable salt of hydrocodone or a solvate thereof, or a pharmaceutically acceptable salt of hydromorphone or a solvate thereof, comprising
 catalytically converting codeine into hydrocodone or morphine into hydromorphone comprising exposing the codeine or morphine to at least one transition metal complex catalyst to form a reaction mixture comprising the hydrocodone or hydromorphone;   removing the transition metal catalyst or a degradant thereof from the reaction mixture to provide hydrocodone base or hydromorphone base;   dissolving or diluting the hydrocodone base or hydromorphone base in a first water miscible solvent and adding a pharmaceutically acceptable acid to form a solution;   adding to the solution a first slurry of a pharmaceutically acceptable salt of hydrocodone or a pharmaceutically acceptable salt of hydromorphone, respectively, in a solvent system comprising a second water miscible solvent and water to form a second slurry; and   isolating a precipitate of the pharmaceutically acceptable salt of the hydrocodone or solvate thereof, or pharmaceutically acceptable salt of the hydromorphone or a solvate thereof, from the second slurry.   
     
     
         44 . The method of  claim 43 , wherein the isolated pharmaceutically acceptable salt of hydrocodone or a solvate thereof, or the pharmaceutically acceptable salt of hydromorphone or a solvate thereof exhibits not more than 3 ppm, not more than 2 ppm, or not more than 1 ppm of the transition metal. 
     
     
         45 . The method of  claim 43 , wherein the isolating comprises
 drying the crystalline precipitate of the pharmaceutically acceptable salt of the hydrocodone or solvate thereof, or the pharmaceutically acceptable salt of the hydromorphone or solvate thereof, under humidified compressed air, humidified nitrogen, or humidified argon.   
     
     
         46 . The method of  claim 45 , wherein the dried crystalline precipitate exhibits not more than 5000 ppm, not more than 4000 ppm, or not more than 3000 ppm of the first and/or second residual water miscible solvents. 
     
     
         47 . The method of  claim 43 , wherein the transition metal of the transition metal complex catalyst is selected from the group consisting of rhodium and iridium. 
     
     
         48 . The method of  claim 47 , wherein the transition metal complex catalyst is a transition metal amino phosphine complex catalyst. 
     
     
         49 . The method of  claim 48 , wherein the transition metal complex catalyst is a compound according to formula (III) 
       
         
           
           
               
               
           
         
       
       wherein
 M is selected from Rh or Ir; 
 each X is independently H, —OH, halo, alkoxy, aryloxide, an anion or a solvent molecule; 
 R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10  and R 11  are independently selected from H and optionally substituted aryl, heterocyclic, or cycloalkyl; 
 n is 0 or 1; and 
 m is 0 or 1. 
 
     
     
         50 . The method of  claim 43 , wherein the removing comprises exposing the reaction mixture to a metal scavenger. 
     
     
         51 . The method of  claim 50 , wherein the reaction mixture is exposed to a stationary phase metal scavenger for a period of 15 to 90 min at a temperature of from about 20 to 60° C., then filtered to provide a hydrocodone base or hydromorphone base as a filtrate. 
     
     
         52 . The method of  claim 43 , wherein the first or second water miscible solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, and acetone. 
     
     
         53 . The method of  claim 43 , wherein the pharmaceutically acceptable acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. 
     
     
         54 . The method of  claim 43 , wherein 0.05-0.3 mol % of the at least one transition metal complex catalyst is added to the codeine or morphine to form the reaction mixture. 
     
     
         55 . The method of  claim 43 , wherein the catalytically converting comprises dissolving the morphine or codeine in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, n-propanol, methylene chloride/methanol, tetrahydrofuran, and acetone prior to the exposing step. 
     
     
         56 . The method of  claim 55 , wherein the reaction mixture is heated to a temperature selected from within the range of 35° C. to 100° C. 
     
     
         57 . The method of  claim 56 , wherein the reaction mixture is heated for a period of 0.5 to 48 hours. 
     
     
         58 . The method of  claim 57 , wherein the reaction mixture is heated under increased pressure in a reactor for a period of about 0.5 to about 4 hours. 
     
     
         59 . The method of  claim 57 , wherein the transformation of compound (II) into the compound of formula (I) is greater than 97% by HPLC. 
     
     
         60 . The method of  claim 43 , wherein the pharmaceutically acceptable salt of the hydrocodone or solvate thereof, or pharmaceutically acceptable salt of the hydromorphone or a solvate thereof is isolated in greater than 80%, greater than 85%, or greater than 90% yield compared to the codeine or morphine. 
     
     
         61 . The method of  claim 60 , wherein the purity of the isolated pharmaceutically acceptable salt of the compound of formula (I) or the solvate thereof is greater than 99%, greater than 99.5%, or greater than 99.8%, optionally wherein the salt is a crystalline salt. 
     
     
         62 . The method of  claim 43 , wherein the codeine is concentrated poppy straw-codeine (CPS-C) used without purification. 
     
     
         63 . Isolated hydrocodone bitartrate hemipentahydrate prepared according to the method of  claim 43 . 
     
     
         64 . A method for preparing a pharmaceutically acceptable salt of hydrocodone or a solvate thereof, or a pharmaceutically acceptable salt of hydromorphone or a solvate thereof, comprising
 catalytically converting codeine into hydrocodone or morphine into hydromorphone comprising exposing the codeine or morphine to at least one transition metal complex catalyst to form a reaction mixture comprising the hydrocodone or hydromorphone;   removing the transition metal catalyst or a degradant thereof from the reaction mixture to provide hydrocodone base or hydromorphone base;   adding a pharmaceutically acceptable acid to the hydrocodone base or hydromorphone base to provide a pharmaceutically acceptable salt of the hydrocodone, or pharmaceutically acceptable salt of the hydromorphone;   isolating a precipitate of the pharmaceutically acceptable salt of the hydrocodone or solvate thereof, or pharmaceutically acceptable salt of the hydromorphone or a solvate thereof; and   drying the precipitate of the pharmaceutically acceptable salt of the hydrocodone or solvate thereof, or the pharmaceutically acceptable salt of the hydromorphone or solvate thereof, under humidified compressed air, humidified nitrogen, or humidified argon.   
     
     
         65 . A method for decreasing the residual solvent in a pharmaceutically acceptable salt of hydrocodone or a solvate thereof, or a pharmaceutically acceptable salt of hydromorphone or a solvate thereof, comprising
 drying the pharmaceutically acceptable salt of the hydrocodone or solvate thereof, or the pharmaceutically acceptable salt of the hydromorphone or solvate thereof, under humidified compressed air, humidified nitrogen, or humidified argon.