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 preparing oxymorphone or a salt thereof comprising:
 oxidizing oripavine to obtain 14-hydroxymorphinone; and   reducing the 14-hydroxymorphinone to obtain oxymorphone.   
     
     
         2 . The method of  claim 1  wherein the oxidizing comprises combining oripavine and an oxidizing agent. 
     
     
         3 . The method of  claim 2  wherein the oxidizing agent comprises a peroxy acid. 
     
     
         4 . The method of  claim 2  wherein the oxidizing agent comprises performic acid. 
     
     
         5 . The method of  claim 2  wherein the oxidizing agent comprises m-chloroperoxybenzoic acid. 
     
     
         6 . The method of  claim 1  wherein the reducing includes catalytic hydrogenation. 
     
     
         7 . The method of  claim 1  wherein the reducing comprises palladium-catalyzed hydrogenation. 
     
     
         8 . The method of  claim 6  wherein the hydrogenation includes hydrogenation at low pressure. 
     
     
         9 . The method of  claim 1  further comprising converting the oxymorphone to an oxymorphone salt. 
     
     
         10 . The method of  claim 9  wherein the oxymorphone salt comprises oxymorphone hydrochloride. 
     
     
         11 . The method of  claim 1  further comprising purifying the oxymorphone or salt thereof. 
     
     
         12 . The method of  claim 11  comprising recrystallizing the oxymorphone or salt thereof. 
     
     
         13 . A method of preparing oxymorphone or a salt thereof comprising converting 14-hydroxymorphinone to oxymorphone or a salt thereof. 
     
     
         14 . The method of  claim 13  wherein the converting comprises hydrogenation. 
     
     
         15 . The method of  claim 14  wherein the hydrogenation comprises palladium-catalyzed hydrogenation. 
     
     
         16 . The method of  claim 14  wherein the hydrogenation includes hydrogenation at low pressure. 
     
     
         17 . A method of preparing oxymorphone or a salt thereof comprising converting oripavine to oxymorphone or a salt thereof. 
     
     
         18 . A method of preparing 14-hydroxymorphinone comprising converting oripavine to 14-hydroxymorphinone. 
     
     
         19 . The method of  claim 1  wherein the oripavine includes oripavine present in a concentrate of poppy straw comprising oripavine as the main alkaloid. 
     
     
         20 . The method of  claim 17  which includes converting oripavine in a concentrate of poppy straw comprising oripavine as the main alkaloid to oxymorphone or a salt thereof. 
     
     
         21 . A method of preparing naltrexone or a salt thereof comprising converting oripavine to naltrexone or a salt thereof. 
     
     
         22 . The method according to  claim 21 , comprising:
 protecting a hydroxyl group of oripavine with a benzyl group to 3-benzyloripavine;   reacting 3-benzyloripavine with 1-chloroethyl chloroformate and then reacting with methanol to obtain 3-benzyl-nororipavine;   alkylating the 3-benzyl-nororipavine with (chloromethyl)cyclopropane to produce 3-benzyl-17-cyclopropylmethylnororipavine;   oxidizing the 3-benzyl-17-cyclopropylmethylnororipavine with a peroxy acid to produce 3-benzyl-17-cyclopropylmethyl-14-hydroxynororipavine; and   reducing the 3-benzyl-17-cyclopropylmethyl-14-hydroxynororipavine with catalytic hydrogenation to produce naltrexone.   
     
     
         23 . A method of preparing buprenorphine or a salt thereof comprising converting oripavine to buprenorphine or a salt thereof. 
     
     
         24 . The method according to  claim 23 , comprising:
 reacting the oripavine with methyl vinyl ketone to produce 7α-acetyl-6,7,8,14-tetrahydro-6,14-endoethenooripavine;   protecting a hydroxyl group of 7α-acetyl-6,7,8,14-tetrahydro-6,14-endoethenooripavine with a benzyl group to 7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endoethenooripavine;   de-methylating the 7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endoethenooripavine with ACE-Cl to 7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endoethenonororipavine;   alkylating the 7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endoethenooripavine with (chloromethyl)cyclopropane to obtain 7α-acetyl-3-benzyl-17-cyclopropylmethyl-6,7,8,14-tetrahydro-6,14-endoethenonororipavine;   reacting the 7α-acetyl-3-benzyl-17-cyclopropylmethyl-6,7,8,14-tetrahydro-6,14-endoethenonororipavine with tert-butyl magnesium chloride or tert-butyl lithium to produce 3-benzyl-17-cyclopropylmethyl-6,14-endo-etheno-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,7,8,14-tetrahydronororipavine; and   reducing the 3-benzyl-17-cyclopropylmethyl-6,14-endo-etheno-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,7,8,14-tetrahydronororipavine by catalytic hydrogenation to produce buprenorphine.   
     
     
         25 . The method according to  claim 23 , comprising:
 protecting a hydroxyl group of oripavine with a benzyl group to 3-benzyloripavine;   reacting the 3-benzyloripavine with methyl vinyl ketone to produce 7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endoethenooripavine;   de-methylating the 7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endoethenooripavine with ACE-Cl to 7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endoethenonororipavine;   alkylating the 7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endoethenooripavine with (chloromethyl)cyclopropane to obtain 7α-acetyl-3-benzyl-17-cyclopropylmethyl-6,7,8,14-tetrahydro-6,14-endoethenonororipavine;   reacting the 7α-acetyl-3-benzyl-17-cyclopropylmethyl-6,7,8,14-tetrahydro-6,14-endoethenonororipavine with tert-butyl magnesium chloride or tert-butyl lithium to produce 3-benzyl-17-cyclopropylmethyl-6,14-endo-etheno-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,7,8,14-tetrahydronororipavine; and   reducing the 3-benzyl-17-cyclopropylmethyl-6,14-endo-etheno-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,7,8,14-tetrahydronororipavine with catalytic hydrogenation to produce buprenorphine.   
     
     
         26 . A compound useful for the synthesis of an opioid, the compound selected from the group consisting 3-benzylnororipavine, 3-benzyloripavine, 3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone, 3-benzyl-17-cyclopropylmethylnororipavine, a-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endo-ethenooripavine, 7α-acetyl-6,7,8,14-tetrahydro-6,14-endo-ethenooripavine, 7α-acetyl-3-benzyl-17-cyclopropylmethyl-6,7,8,14-tetrahydro-6,14-endo-ethenonororipavine, 7α-acetyl-3-benzyl-6,7,8,14-tetrahydro-6,14-endo-ethenonororipavine, and 3-benzyl-17-cyclopropylmethyl-6,14-endo-etheno-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,7,8,14-tetrahydronororipavine.