Process for preparing oxymorphone, naltrexone, and buprenorphine

Abstract

Methods are provided which include converting oripavine to other opiates, including converting oripavine to naltrexone, buprenorphine, 14-hydroxymorphinone and/or converting 14-hydroxymorphinone to oxymorphone. Purification and salt formation are optionally included.

1 . A method of converting a starting material comprising an opiate precursor, a poppy straw extract, or a derivative thereof into buprenorphine or a therapeutically acceptable salt thereof, comprising:
 obtaining a starting material which is an opiate precursor, a concentrated poppy straw, or a derivative thereof;   processing the starting material to form an intermediate with or without a protecting group, wherein the protecting group comprises any of a benzyl group, a substituted benzyl group, or an aceto group, said intermediate further comprising a secondary amine;   forming a reaction mixture by combining the intermediate with
 (i) an inorganic halide salt, 
 (ii) an alkylating agent, 
 (iii) a metal carbonate, and 
 (iv) an organic solvent; 
   heating the reaction mixture under conditions which allow the intermediate to be alkylated on the secondary amine;   forming an alkylated intermediate by allowing the reaction mixture to react, the alkylated intermediate being alkylated on the secondary amine; and   further processing the alkylated intermediate to obtain buprenorphine or a therapeutically acceptable salt thereof.   
     
     
         2 . The method of  claim 1  wherein the starting material comprises a concentrated poppy straw having oripavine as the main alkaloid. 
     
     
         3 . The method of  claim 1  wherein the starting material comprises greater than about 50% by weight oripavine. 
     
     
         4 . The method of  claim 1  wherein the inorganic halide salt comprises an inorganic iodide salt. 
     
     
         5 . The method of  claim 4  wherein the inorganic iodide salt comprises potassium iodide. 
     
     
         6 . The method of  claim 1  wherein the alkylating agent comprises a halo alkane or a tosylalkane. 
     
     
         7 . The method of  claim 6  wherein the alkylating agent comprises a halomethylcyclopropane or a to sylmethylcyclopropane. 
     
     
         8 . The method of  claim 7  wherein the inorganic halide salt comprises an inorganic iodide salt. 
     
     
         9 . The method of  claim 8  wherein the metal carbonate comprises sodium carbonate or potassium bicarbonate. 
     
     
         10 . The method of  claim 9 , wherein the heating comprises heating the reaction mixture at a temperature not exceeding the boiling point of the reaction mixture. 
     
     
         11 . The method of  claim 10  wherein the starting material comprises greater than about 50% by weight oripavine. 
     
     
         12 . The method of  claim 6  wherein the alkylating agent comprises a halomethylcyclopropane. 
     
     
         13 . The method of  claim 12  wherein the halomethylcyclopropane comprises (chloromethyl)cyclopropane. 
     
     
         14 . The method of  claim 6  wherein the alkylating agent comprises tosylmethylcyclopropane. 
     
     
         15 . The method of  claim 1  wherein the metal carbonate comprises sodium carbonate or potassium bicarbonate. 
     
     
         16 . The method of  claim 15  wherein the metal carbonate comprises sodium carbonate. 
     
     
         17 . The method of  claim 1  wherein the organic solvent comprises an alcohol. 
     
     
         18 . The method of  claim 17  wherein the alcohol comprises ethanol. 
     
     
         19 . The method of  claim 1 , wherein the heating comprises heating the reaction mixture at a temperature not exceeding the boiling point of the reaction mixture. 
     
     
         20 . The method of  claim 19  wherein the alkylating agent comprises a halo methylcyclopropane or a to sylmethylcyclopropane. 
     
     
         21 . The method of  claim 20  wherein the inorganic halide salt comprises an inorganic iodide salt. 
     
     
         22 . The method of  claim 21  wherein the metal carbonate comprises sodium carbonate or potassium bicarbonate. 
     
     
         23 . The method of  claim 19  wherein the heating comprises heating under reflux. 
     
     
         24 . The method of  claim 1  further comprising purifying the buprenorphine or therapeutically acceptable salt thereof. 
     
     
         25 . The method of  claim 1  wherein the further processing comprises obtaining buprenorphine hydrochloride. 
     
     
         26 . A method of manufacturing a pharmaceutical dosage form comprising combining buprenorphine or a therapeutically acceptable salt thereof obtained by the method of  claim 1  with an excipient. 
     
     
         27 . The method of  claim 26  wherein the pharmaceutical dosage form comprises at least one of a tablet, a pill, a capsule, a parenteral formulation, a suppository, a patch, or a powder. 
     
     
         28 . A pharmaceutical dosage form prepared by the method of  claim 26 . 
     
     
         29 . The method of  claim 4  wherein the alkylating agent comprises a halo methylcyclopropane or to sylmethylcyclopropane. 
     
     
         30 . The method of  claim 29  wherein the organic solvent comprises an alcohol. 
     
     
         31 . The method of  claim 30 , wherein the heating comprises heating the reaction mixture at a temperature not exceeding the boiling point of the reaction mixture. 
     
     
         32 . The method of  claim 31  wherein the metal carbonate comprises sodium carbonate or potassium bicarbonate. 
     
     
         33 . The method of  claim 32  further comprising purifying the buprenorphine or therapeutically acceptable salt thereof. 
     
     
         34 . The method of  claim 33  wherein the further processing comprises obtaining buprenorphine hydrochloride. 
     
     
         35 . The method of  claim 34  wherein the starting material comprises greater than about 50% by weight oripavine 
     
     
         36 . The method of  claim 4 , wherein the heating comprises heating the reaction mixture at a temperature not exceeding the boiling point of the reaction mixture. 
     
     
         37 . The method of  claim 36  wherein the alkylating agent comprises a halo methylcyclopropane or to sylmethylcyclopropane. 
     
     
         38 . The method of  claim 37  wherein the metal carbonate comprises sodium carbonate or potassium bicarbonate. 
     
     
         39 . The method of  claim 38  further comprising purifying the buprenorphine or therapeutically acceptable salt thereof. 
     
     
         40 . The method of  claim 39  wherein the further processing comprises obtaining buprenorphine hydrochloride. 
     
     
         41 . A method of manufacturing a pharmaceutical dosage form comprising combining buprenorphine or a therapeutically acceptable salt thereof obtained by the method of  claim 34  with an excipient. 
     
     
         42 . The method of  claim 41  wherein the pharmaceutical dosage form comprises at least one of a tablet, a pill, a capsule, a parenteral formulation, a suppository, a patch, or a powder. 
     
     
         43 . A pharmaceutical dosage form prepared by the method of  claim 42 .