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.

What is claimed is: 
     
         1 . A process of preparing a compound of Formula IV: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, comprising:
 a step of reacting a compound of Formula II or a salt thereof with a compound of Formula III: 
 
       
         
           
           
               
               
           
         
         in the presence of a base; 
         wherein: 
         R 7 -R 12  and R 15  are independently selected from the group consisting of hydrogen and deuterium; and 
         Y 1  is selected from the group consisting of acetoxy, alkoxy, halogen, haloalkoxy, perhaloalkoxy, heteroalkoxy, and aryloxy, any of which may be optionally substituted. 
       
     
     
         2 . The process of  claim 1  wherein Y 1  is C 1 -C 4  alkoxy. 
     
     
         3 . The process of  claim 2  wherein Y 1  is ethoxy. 
     
     
         4 . The process of  claim 1  wherein Y 1  is acetoxy. 
     
     
         5 . The process of  claim 1  wherein Y 1  is selected from the group consisting of fluorine, chlorine, and bromine. 
     
     
         6 . The process of  claim 1  wherein said base is selected from the group consisting of alkali metal alkoxides, alkali metal hydroxides, alkali metal hydrides, alkali metal carbonates, and trialkylamines. 
     
     
         7 . The process of  claim 6  wherein said base is an alkali metal alkoxide. 
     
     
         8 . The process of  claim 7  wherein said base is sodium tert-butoxide. 
     
     
         9 . A process of preparing a compound of Formula VI: 
       
         
           
           
               
               
           
         
       
       comprising:
 a step of reacting a compound of Formula IV or a salt thereof with a compound of Formula V: 
 
       
         
           
           
               
               
           
         
         in a solvent and in the presence of a base; 
         wherein: 
         R 1 -R 12  and R 15  are independently selected from the group consisting of hydrogen and deuterium; and 
         Y 2  is selected from the group consisting of halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, and alkylcarbonate, any of which may be optionally substituted. 
       
     
     
         10 . The process of  claim 9  wherein Y 2  is iodide or methylsulfate. 
     
     
         11 . The process of  claim 10  wherein Y 2  is iodide. 
     
     
         12 . The process of  claim 9  wherein said base is selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides, alkali metal hydroxides, alkali metal hydrides, and trialkylamines. 
     
     
         13 . The process of  claim 12  wherein said base is an alkali metal carbonate. 
     
     
         14 . The process of  claim 13  wherein said base is potassium carbonate. 
     
     
         15 . The process of  claim 9  wherein said solvent is selected from the group consisting of acetone, acetonitrile, dimethyl formamide, 2-methyltetrahydrofuran, and tetrahydrofuran. 
     
     
         16 . The process of  claim 15  wherein said solvent is acetone. 
     
     
         17 . The process of  claim 15  wherein the volume of said solvent is between about 5 to about 15 times the mass of the compound of Formula IV. 
     
     
         18 . The process of  claim 15  wherein the volume of said solvent is about 8 times the mass of the compound of Formula IV. 
     
     
         19 . The process of  claim 9  wherein said reaction step is carried out in the presence of a phase transfer catalyst that is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium iodide, and 18-crown-6. 
     
     
         20 . The process of  claim 19  wherein said phase transfer catalyst is tetrabutylammonium bromide.