Process for n-dealkylation of tertiary amines

Abstract

The present disclosure provides improved methods for N-dealkylation of tertiary amines, including methods for N-demethylation of alkaloids and opioids, in which the dealkylation reaction is carried out in a solvent comprising a tertiary alcohol. The present disclosure also provides improved processes for preparing semi-synthetic opioids that incorporate the disclosed methods for N-dealkylation of tertiary amines.

What is claimed is: 
     
         1 . A method for dealkylation of a tertiary amine of formula (1) 
       
         
           
           
               
               
           
         
         comprising 
         contacting the compound of formula (1) with compound of formula (2) 
       
       
         
           
           
               
               
           
         
         in a solvent to provide a compound of formula (3) 
       
       
         
           
           
               
               
           
         
         wherein
 the solvent comprises a tertiary alcohol; 
 R 3  is selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, aryl, and heteroaryl, each being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 5  groups; 
 R 1  and R 2  are taken together with the nitrogen atom to which they are bound to form a heterocyclic or heteroaryl ring of formula (4) 
 
       
       
         
           
           
               
               
           
         
         
           n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11; 
           the heterocyclic or heteroaryl ring of formula (4) is a monocyclic ring that is saturated, unsaturated non-heteroaryl, or heteroaryl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 20  groups, or is a subunit of a polycyclic ring system comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic, heterocyclic, aryl, or heteroaryl rings, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 20  groups; 
           each R 20  is independently selected from the group consisting of ═O, ═CH 2 , —OR 21 , —O(C 1 -C 6 )alkyl, —C(═O)(C 1 -C 6 ) alkyl, and —(C 1 -C 6 )alkyl, each alkyl independently being either unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected —OR 21  groups; 
           R 21  is H or an oxygen protecting group; 
           R 4  is selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, aryl, and heteroaryl, each being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 5  groups; 
           each R 5  is independently selected from the group consisting of —OH, —Cl, —Br, —I, —NH 2 , —CN, —O—(C 1 -C 6 ) alkyl, and phenyl; and 
           X is selected from the group consisting of —Cl, —Br, 'I, mesylate, and tosylate. 
         
       
     
     
         2 . The method of  claim 1 , wherein said contacting is carried out in the presence of an iodide salt. 
     
     
         3 . The method of  claim 2 , wherein the iodide salt is selected from the group consisting of NaI, KI, LiI, CsI, RuI, MgI 2 , CaI 2 , NH 4 I, tetrabutylammonium iodide, and combinations of two or more thereof. 
     
     
         4 . The method of  claim 3 , wherein the iodide salt is NaI. 
     
     
         5 . The method of  claim 1 , wherein R 3  is —CH 3 . 
     
     
         6 . The method of  claim 1 , wherein R 4  is —(C 1 -C 6 )alkyl, said alkyl being either unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 5  groups. 
     
     
         7 . The method of  claim 6 , wherein R 4  is ethyl. 
     
     
         8 . The method of  claim 1 , wherein
 the oxygen protecting group is selected from the group consisting of acetyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, p-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, triisopropylsilyl, —C(O)O—CH 2 —CH═CH 2 ), tert-butyl-diphenylsilyl, tert-butyl-dimethylsilyl, tri-iso-propylsilyl, [bis-(4-methoxyphenyl)phenylmethyl)], methoxymethyl, ethoxyethyl, triphenylmethyl, —C(O)(C 1 -C 6 )alkyl, —C(O)OR 18 , and —(C 1 -C 6 )alkyl, each said alkyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 50  groups;   each R 18  is independently selected from —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, and —(C 2 -C 6 )alkynyl, each said alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 50  groups; and   each R 50  is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.   
     
     
         9 . The method of  claim 1 , wherein the solvent consists essentially of a tertiary alcohol. 
     
     
         10 . The method of  claim 9 , wherein the tertiary alcohol is an alcohol of formula (5) 
       
         
           
           
               
               
           
         
         wherein R 6 , R 7 , and R 8  are each independently —(C 1 -C 6 )alkyl. 
       
     
     
         11 . The method of  claim 10 , wherein the tertiary alcohol is selected from the group consisting of tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-hexanol, and mixtures of two or more thereof. 
     
     
         12 . The method of  claim 11 , wherein said contacting is carried out in the presence of an iodide salt. 
     
     
         13 . The method of  claim 12 , wherein the iodide salt is selected from the group consisting of NaI, KI, LiI, CsI, RuI, MgI 2 , CaI 2 , NH 4 I, tetrabutylammonium iodide, and combinations of two or more thereof. 
     
     
         14 . The method of  claim 13 , wherein the iodide salt is NaI. 
     
     
         15 . The method of  claim 11 , wherein R 3  is —CH 3 . 
     
     
         16 . The method of  claim 11 , wherein R 4  is —(C 1 -C 6 )alkyl, said alkyl being either unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 5  groups. 
     
     
         17 . The method of  claim 16 , wherein R 4  is ethyl. 
     
     
         18 . The method of  claim 11 , wherein the tertiary alcohol is tent-amyl alcohol. 
     
     
         19 . The method of  claim 18 , wherein said contacting is carried out in the presence of an iodide salt. 
     
     
         20 . The method of  claim 19 , wherein the iodide salt is selected from the group consisting of NaI, KI, LH, CsI, RuI, MgI 2 , CaI 2 , NH 4 I, tetrabutylammonium iodide, and combinations of two or more thereof. 
     
     
         21 . The method of  claim 20 , wherein the iodide salt is NaI. 
     
     
         22 . The method of  claim 18 , wherein R 3  is —CH 3 . 
     
     
         23 . The method of  claim 18 , wherein R 4  is —(C 1 -C 6 )alkyl, said alkyl being either unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 5  groups. 
     
     
         24 . The method of  claim 23 , wherein R 4  is ethyl.