Methods of manufacturing benzoquinoline compounds

Abstract

The present invention relates to new methods of manufacturing benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), and intermediates thereof.

1 . The (cis)-d 6 -Tetrabenazine having a diastereomeric purity of at least 99% and having a deuterium enrichment of no less than about 10%. 
     
     
         2 . The (cis)-d 6 -Tetrabenazine of  claim 1  having a deuterium enrichment of no less than about 20%. 
     
     
         3 . The (cis)-d 6 -Tetrabenazine of  claim 1  having a deuterium enrichment of no less than about 50%. 
     
     
         4 . The (cis)-d 6 -Tetrabenazine of  claim 1  having a deuterium enrichment of no less than about 70%. 
     
     
         5 . The (cis)-d 6 -Tetrabenazine of  claim 1  having a deuterium enrichment of no less than about 80%. 
     
     
         6 . The (cis)-d 6 -Tetrabenazine of  claim 1  having a deuterium enrichment of no less than about 90%. 
     
     
         7 . The (cis)-d 6 -Tetrabenazine of  claim 1  having a deuterium enrichment of no less than about 98%. 
     
     
         8 . A pharmaceutical composition comprising the (cis)-d 6 -tetrabenazine of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 20%. 
     
     
         10 . The pharmaceutical composition of  claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 50%. 
     
     
         11 . The pharmaceutical composition of  claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 70%. 
     
     
         12 . The pharmaceutical composition of  claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 80%. 
     
     
         13 . The pharmaceutical composition of  claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 90%. 
     
     
         14 . The pharmaceutical composition of  claim 8 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 98%. 
     
     
         15 . A process of preparing a (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99% and having a deuterium enrichment of no less than about 10%, comprising:
 reacting d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline, or a salt thereof,   
       
         
           
           
               
               
           
         
       
       d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline with a salt of 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium: 
       
         
           
           
               
               
           
         
       
       2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium salt wherein X is halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, or alkyl carbonate;
 and an optional base; 
 in the presence of one or more solvents; 
 for a period of time and at a temperature sufficient to produce the (cis)-d 6 -tetrabenazine having a diastereomeric purity of at least 99%, based on high performance liquid chromatography. 
 
     
     
         16 . The process of  claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 20%. 
     
     
         17 . The process of  claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 50%. 
     
     
         18 . The process of  claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 70%. 
     
     
         19 . The process of  claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 80%. 
     
     
         20 . The process of  claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 90%. 
     
     
         21 . The process of  claim 15 , wherein the (cis)-d 6 -tetrabenazine has a deuterium enrichment of no less than about 98%. 
     
     
         22 . The process of  claim 15 , wherein the one or more solvents are selected from the group consisting of water, methanol, and ethanol. 
     
     
         23 . The process of  claim 15 , wherein the one or more solvents comprise water. 
     
     
         24 . The process of  claim 15 , wherein the one or more solvents comprise water, methanol, or ethanol. 
     
     
         25 . The process of  claim 15 , wherein the process is carried out in the presence of a base. 
     
     
         26 . The process of  claim 25 , wherein the base is K 2 CO 3 . 
     
     
         27 . The process of  claim 15 , wherein the salt form of d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline is d 6 -6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride. 
     
     
         28 . The process of  claim 27 , wherein the process is carried out in the presence of a base. 
     
     
         29 . The process of  claim 28 , wherein the base is K 2 CO 3 . 
     
     
         30 . The process of  claim 15 , wherein X is halogen. 
     
     
         31 . The process of  claim 15 , wherein X is iodide. 
     
     
         32 . The process of  claim 15 , wherein the diastereomeric purity of the (cis)-d 6 -tetrabenazine is at least 99.1%.