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 pharmaceutical dosage form comprising buprenorphine or a therapeutically acceptable salt thereof, and at least one excipient, wherein the buprenorphine or a therapeutically acceptable salt thereof is prepared by a method 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;   wherein the excipient comprises one or more of a carrier vehicle, a stabilizing agent, a solubilizing agent, a lubricating agent, a flow agent, a bulking agent, a control release agent, a disintegrating agent, a binding agent, a pigment, a flavoring agent, or a coating agent; and   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.   
     
     
         2 . The pharmaceutical dosage form of  claim 1  wherein the starting material comprises a concentrated poppy straw having oripavine as the main alkaloid. 
     
     
         3 . The pharmaceutical dosage form of  claim 1  wherein the starting material comprises greater than about 50% by weight oripavine. 
     
     
         4 . The pharmaceutical dosage form of  claim 1  wherein the inorganic halide salt comprises an inorganic iodide salt. 
     
     
         5 . The pharmaceutical dosage form of  claim 4  wherein the alkylating agent comprises a halomethylcyclopropane or tosylmethylcyclopropane. 
     
     
         6 . The pharmaceutical dosage form of  claim 5  wherein the metal carbonate comprises sodium carbonate or potassium bicarbonate. 
     
     
         7 . The pharmaceutical dosage form of  claim 6 , wherein the heating comprises heating the reaction mixture at a temperature not exceeding the boiling point of the reaction mixture. 
     
     
         8 . The pharmaceutical dosage form of  claim 7  wherein the organic solvent comprises an alcohol. 
     
     
         9 . The pharmaceutical dosage form of  claim 8  further comprising purifying the buprenorphine or therapeutically acceptable salt thereof. 
     
     
         10 . The pharmaceutical dosage form of  claim 9  wherein the further processing comprises obtaining buprenorphine hydrochloride. 
     
     
         11 . The pharmaceutical dosage form of  claim 4  wherein the inorganic iodide salt comprises potassium iodide. 
     
     
         12 . The pharmaceutical dosage form of  claim 1  wherein the alkylating agent comprises a haloalkane or a tosylalkane. 
     
     
         13 . The pharmaceutical dosage form of  claim 12  wherein the alkylating agent comprises a halomethylcyclopropane or tosylmethylcyclopropane. 
     
     
         14 . The pharmaceutical dosage form of  claim 13  wherein the inorganic halide salt comprises an inorganic iodide salt. 
     
     
         15 . The pharmaceutical dosage form of  claim 14 , wherein the heating comprises heating the reaction mixture at a temperature not exceeding the boiling point of the reaction mixture. 
     
     
         16 . The pharmaceutical dosage form of  claim 15  wherein the metal carbonate comprises sodium carbonate or potassium bicarbonate. 
     
     
         17 . The pharmaceutical dosage form of  claim 12  wherein the alkylating agent comprises a halomethylcyclopropane. 
     
     
         18 . The pharmaceutical dosage form of  claim 17  wherein the halomethylcyclopropane comprises (chloromethyl)cyclopropane. 
     
     
         19 . The pharmaceutical dosage form of  claim 12  wherein the alkylating agent comprises tosylmethylcyclopropane. 
     
     
         20 . The pharmaceutical dosage form of  claim 1  wherein the metal carbonate comprises sodium carbonate or potassium bicarbonate. 
     
     
         21 . The pharmaceutical dosage form of  claim 20  wherein the metal carbonate comprises sodium carbonate. 
     
     
         22 . The pharmaceutical dosage form of  claim 1  wherein the organic solvent comprises an alcohol. 
     
     
         23 . The pharmaceutical dosage form of  claim 22  wherein the alcohol comprises ethanol. 
     
     
         24 . The pharmaceutical dosage form of  claim 1 , wherein the heating comprises heating the reaction mixture at a temperature not exceeding the boiling point of the reaction mixture. 
     
     
         25 . The pharmaceutical dosage form of  claim 24  wherein the heating comprises heating under reflux. 
     
     
         26 . The pharmaceutical dosage form of  claim 1  further comprising purifying the buprenorphine or therapeutically acceptable salt thereof. 
     
     
         27 . The pharmaceutical dosage form of  claim 1  comprising buprenorphine hydrochloride.