Process for improved opioid synthesis

Abstract

Compounds and compositions for use as starting materials or intermediate materials in the preparation of opioids including, e.g., oxymorphone base and/or an oxymorphone salt; processes for preparing these compounds and compositions; uses of these compounds and compositions in the preparation of APIs and pharmaceutical dosage forms; and uses of said APIs and pharma ceutical dosage forms in the treatment of medical conditions.

1 - 242 . (canceled) 
     
     
         243 . A compound having formula V or a solvate thereof 
       
         
           
           
               
               
           
         
         wherein R 1  is H, aralkyl, (C 2 -C 6 )alkenyl, SiR 3   3,  (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkyl-(C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkenyl, (C 1 -C 7 )alkyl-(C 3 -C 7 )cycloalkenyl, CR 4   2 O(C 1-6 )alkyl, C(halo) 3 , CH 2 (halo), CH(halo) 2 , SO 2 R 5 , or an O-protecting group, 
         R 2  is H, CH 3 , (C 2 -C 7 )alkyl, (C 2 -C 4 )alkenyl, benzyl, (C 1 -C 7 )alkyl-(C 3 -C 7 )cycloalkyl, CN, or an N-protecting group, and 
         X n  is SO 4   2 ; and n is 2. 
       
     
     
         244 . The compound of  claim 243 , wherein R 1  in each instance is —H. 
     
     
         245 . The compound of  claim 243 , wherein R 2  in each instance is —CH 3 . 
     
     
         246 . The compound of  claim 243 , wherein R 2  in each instance is —H. 
     
     
         247 . The compound of  claim 243 , wherein the compound having formula V is 
       
         
           
           
               
               
           
         
         or a hydrate thereof. 
       
     
     
         248 . The compound of  claim 243 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a hydrate thereof. 
       
     
     
         249 . The compound of  claim 243 , wherein the compound is a hydrate of 14-hydroxymorphinone sulfate having a formula of 
       
         
           
           
               
               
           
         
       
     
     
         250 . The compound of  claim 243 , which comprises a hydrate of the compound of formula V. 
     
     
         251 . The compound of  claim 250 , wherein the hydrate is a hydrate containing from 0.1 to 6.9 water molecules per molecule of the compound of formula V. 
     
     
         252 . The compound of  claim 250 , which is a monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, or hexahydrate. 
     
     
         253 . The compound of  claim 252 , which is a monohydrate or a pentahydrate. 
     
     
         254 . An isolated reaction product comprising a solid precipitate of a compound of  claim 243 , and a compound of formula III: 
       
         
           
           
               
               
           
         
         wherein R 1  is H, aralkyl, (C 2 -C 6 )alkenyl, SiR 3   3,  (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkyl-(C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkenyl, (C 1 -C 7 )alkyl-(C 3 -C 7 )cycloalkenyl, CR 4   2 O(C 1-6 )alkyl, C(halo) 3 , CH 2 (halo), CH(halo) 2 , SO 2 R 5 , or an O-protecting group, and 
         R 2  is H, CH 3 , (C 2 -C 7 )alkyl, (C 2 -C 4 )alkenyl, benzyl, (C 1 -C 7 )alkyl-(C 3 -C 7 )cycloalkyl, CN, or an N-protecting group, or a salt or solvate thereof; 
         wherein R 1  is H, aralkyl, (C 2 -C 6 )alkenyl, SiR 3   3 , (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkyl-(C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkenyl, (C 1 -C 7 )alkyl(C 3 -C 7 )cycloalkenyl, CR 4   2 O(C 1 -C 6 )alkyl, C(halo) 3 , CH 2 (halo), CH(halo) 2 , SO 2 R 5 , or an O-protecting group, and R 2  is H, CH 3 , (C 2 -C 7 )alkyl, (C 2 -C 4 )alkenyl, benzyl, (C 1 -C 7 )alkyl(C 3 -C 7 )cycloalkyl, CN, or an N-protecting group, or a salt or solvate thereof. 
         wherein the amount of compound of formula III in the reaction product is less than about 100 ppm of the compound of formula V (HPLC peak area ratio). 
       
     
     
         255 . The isolated reaction product of  claim 254 , wherein the amount of the compound of formula III in the composition is less than about 10 ppm, of the compound of formula V (HPLC peak area ratio). 
     
     
         256 . The isolated reaction product of  claim 255  , wherein the amount of the compound of formula III in the composition is less than about 1 ppm of the compound of formula V (HPLC peak area ratio). 
     
     
         257 . An isolated reaction product, which is a solid precipitate of a compound having formula V or a solvate thereof 
       
         
           
           
               
               
           
         
         wherein R 1  is H, aralkyl, (C 2 -C 6 )alkenyl, SiR 3   3,  (C 3 -C 7 )cycloalkyl, (C 1 -C 7 )alkyl-(C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkenyl, (C 1 -C 7 )alkyl-(C 3 -C 7 )cycloalkenyl, CR 4   2 O(C 1-6 )alkyl, C(halo) 3 , CH 2 (halo), CH(halo) 2 , SO 2 R 5 , or an O-protecting group, 
         R 2  is H, CH 3 , (C 2 -C 7 )alkyl, (C 2 -C 4 )alkenyl, benzyl, (C 1 -C 7 )alkyl-(C 3 -C 7 )cycloalkyl, CN, or an N-protecting group, and 
         X n  is SO 4   2 ; and n is 2, 
         prepared by a process comprising: 
       
       
         
           
           
               
               
           
         
         (a) oxidizing the compound of formula I in a reaction mixture; and 
         (b) adding an acid H +   n X n−  to the reaction mixture before or during the oxidation reaction, or both before and during the oxidation reaction, wherein the acid H +   n X n−  is added in an amount of from about 0.4 to about 0.6 molar equivalents per molar equivalent of the compound of formula I; 
         (c) precipitating the compound of formula V; and 
         (d) isolating the precipitate from the reaction mixture. 
       
     
     
         258 . Oxymorphone sulfate or a pharmaceutically acceptable salt thereof.