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 . (canceled) 
     
     
         3 . The process of  claim 1  wherein Y 1  is ethoxy and said base is sodium tert-butoxide. 
     
     
         4 - 9 . (canceled) 
     
     
         10 . 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. 
       
     
     
         11 . (canceled) 
     
     
         12 . The process of  claim 10  wherein Y 2  is iodide and said base is potassium carbonate. 
     
     
         13 - 16 . (canceled) 
     
     
         17 . The process of  claim 10  wherein said solvent is acetone. 
     
     
         18 . (canceled) 
     
     
         19 . The process of  claim 17  wherein the volume of said solvent is between about 6 to about 10 times the mass of the compound of Formula IV. 
     
     
         20 . (canceled) 
     
     
         21 . The process of  claim 10  wherein said reaction step is carried out in the presence of a phase transfer catalyst selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium iodide, and 18-crown-6. 
     
     
         22 . (canceled) 
     
     
         23 . The process of  claim 21  wherein said phase transfer catalyst is tetrabutylammonium bromide. 
     
     
         24 . A process of preparing a solid salt of a compound of Formula VII: 
       
         
           
           
               
               
           
         
         comprising: 
         a first step of reacting a compound of Formula VI: 
       
       
         
           
           
               
               
           
         
         with a dehydrating agent in a reaction solvent; 
         a second step of adding a quenching solvent and an antisolvent to the reaction mixture; and 
         a third step of isolating the salt of the compound of Formula VII from the reaction mixture; 
         wherein: 
         R 1 -R 12  and R 15  are independently selected from the group consisting of hydrogen and deuterium. 
       
     
     
         25 . The process of  claim 24  wherein said salt of the compound of Formula I is the hydrochloride salt. 
     
     
         26 . The process of  claim 25  wherein said dehydrating agent is phosphorous oxychloride. 
     
     
         27 . (canceled) 
     
     
         28 . The process of  claim 26  wherein the amount of said phosphorous oxychloride is between about 1.6 to about 2.0 molar equivalents relative to the compound of Formula VI. 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . The process of  claim 24  wherein said reaction solvent is acetonitrile. 
     
     
         32 . (canceled) 
     
     
         33 . The process of  claim 31  wherein the volume of said acetonitrile is between about 1.5 to about 2.5 times the mass of the compound of Formula VI. 
     
     
         34 - 36 . (canceled) 
     
     
         37 . The process of  claim 24  wherein said quenching solvent is 1-butanol. 
     
     
         38 - 39 . (canceled) 
     
     
         40 . The process of  claim 37  wherein the amount of said 1-butanol is between about 3.4 to about 4.2 molar equivalents relative to the compound of Formula VI. 
     
     
         41 - 43 . (canceled) 
     
     
         44 . The process of  claim 24  wherein said antisolvent is methyl tert-butyl ether. 
     
     
         45 . (canceled) 
     
     
         46 . The process of  claim 44  wherein the volume of said methyl tert-butyl ether is between about 3 to about 5 times the mass of the compound of Formula VI. 
     
     
         47 - 50 . (canceled) 
     
     
         51 . The process of  claim 24  wherein said first reaction step is held at a temperature of between about 80° C. to about 85° C. 
     
     
         52 - 55 . (canceled) 
     
     
         56 . The process of  claim 24  wherein said second reaction step is carried out at between about 25° C. to about 35° C. 
     
     
         57 - 58 . (canceled) 
     
     
         59 . A process of purifying a hydrochloride salt of a compound of Formula VII: 
       
         
           
           
               
               
           
         
         comprising: 
         a first step of mixing the compound of Formula VII with one or more solvents; and 
         a second step of filtering the salt of the compound of Formula VII from the mixture; 
         wherein: 
         R 1 -R 12  and R 15  are independently selected from the group consisting of hydrogen and deuterium. 
       
     
     
         60 . (canceled) 
     
     
         61 . The process of  claim 59  wherein said solvent is a mixture of ethanol and methyl tert-butyl ether. 
     
     
         62 . The process of  claim 61  wherein said solvent is a mixture of 10% ethanol and 90% methyl tert-butyl ether. 
     
     
         63 - 64 . (canceled) 
     
     
         65 . The process of  claim 59  wherein said first mixing step is carried out at between about 28° C. to about 32° C. 
     
     
         66 . A process of preparing a compound of Formula IX: 
       
         
           
           
               
               
           
         
         comprising: 
         a step of reacting a compound of Formula VII or a salt thereof with a compound of Formula VIII in one or more solvents: 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 1 -R 27  are independently selected from the group consisting of hydrogen and deuterium; and 
         X 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. 
       
     
     
         67 . (canceled) 
     
     
         68 . The process of  claim 66  wherein said solvent is a mixture of methanol and water. 
     
     
         69 . (canceled) 
     
     
         70 . The process of  claim 68  wherein said methanol and water mixture is between about four parts methanol to one part water and about two parts methanol to one part water. 
     
     
         71 . The process of  claim 70  wherein said methanol and water mixture is about three parts methanol to one part water. 
     
     
         72 . (canceled) 
     
     
         73 . The process of  claim 71  wherein the volume of said mixture of methanol and water is between about 4 and about 8 times the mass of the compound of Formula VII. 
     
     
         74 . (canceled) 
     
     
         75 . The process of  claim 66  wherein said solvent is a mixture of ethanol and water. 
     
     
         76 . (canceled) 
     
     
         77 . The process of  claim 75  wherein said ethanol and water mixture is between about four parts ethanol to one part water and about two parts ethanol to one part water. 
     
     
         78 . The process of  claim 77  wherein said ethanol and water mixture is about three parts ethanol to one part water. 
     
     
         79 . (canceled) 
     
     
         80 . The process of  claim 78  wherein the volume of said mixture of ethanol and water is between about 4 and about 8 times the mass of the compound of Formula VII. 
     
     
         81 - 83 . (canceled) 
     
     
         84 . The process of  claim 66  wherein said reaction step is held at a temperature of between about 40° C. to about 60° C. 
     
     
         85 - 86 . (canceled) 
     
     
         87 . The process of  claim 84  wherein said reaction step is carried out for about 24 to about 72 hours. 
     
     
         88 . (canceled) 
     
     
         89 . The process of  claim 66  wherein the compound of Formula VII is the hydrochloride salt and a base is added during the reaction step. 
     
     
         90 - 91 . (canceled) 
     
     
         92 . The process of  claim 89  wherein said base is potassium carbonate. 
     
     
         93 . A process of preparing a compound of Formula XI: 
       
         
           
           
               
               
           
         
         comprising: 
         a first step of reacting a compound of Formula X or a salt thereof with a base in one or more solvents: 
       
       
         
           
           
               
               
           
         
         a second step of adjusting the pH of the reaction mixture by addition of an acid; 
         a third step of adding dimethylamine or a salt thereof and a formaldehyde equivalent to the reaction mixture; 
         a fourth step of lowering the pH of the reaction mixture by addition of an acid; 
         a fifth step of raising the pH of the reaction mixture by addition of an base; 
         a sixth step of adding dimethylamine or a salt thereof to the reaction mixture; 
         wherein: 
         R 16 -R 27  are independently selected from the group consisting of hydrogen and deuterium. 
       
     
     
         94 . The process of  claim 93  wherein the base used in the first hydrolysis step or the fifth pH adjustment step is potassium hydroxide. 
     
     
         95 - 98 . (canceled) 
     
     
         99 . The process of  claim 93  wherein said formaldehyde equivalent is aqueous formaldehyde solution. 
     
     
         100 . The process of  claim 93  wherein the acid used in the second pH adjustment step or the fourth pH adjustment step is hydrochloric acid. 
     
     
         101 . (canceled) 
     
     
         102 . The process of  claim 93  wherein a phase transfer catalyst tetrabutylammonium bromide is added during the third reaction step. 
     
     
         103 - 104 . (canceled) 
     
     
         105 . The process of  claim 93  wherein said solvent is water. 
     
     
         106 . The process of  claim 93  wherein the first hydrolysis step is carried out by the addition of about 1 to about 2 molar equivalents of potassium hydroxide relative to said compound of Formula X. 
     
     
         107 - 109 . (canceled) 
     
     
         110 . The process of  claim 93  wherein the first hydrolysis step is carried out at a temperature of between about 20° C. to about 40° C. 
     
     
         111 . The process of  claim 93  wherein the second pH adjustment step results in a pH of about 6 to about 8. 
     
     
         112 - 114 . (canceled) 
     
     
         115 . The process of  claim 93  wherein the third addition step is carried out by the addition of about 1.25 to about 1.75 molar equivalents of dimethylamine and about 1.25 to about 1.75 molar equivalents of formaldehyde equivalents relative to said compound of Formula X. 
     
     
         116 - 117 . (canceled) 
     
     
         118 . The process of  claim 93  wherein the third addition step is carried out at a temperature of between about 25° C. to about 35° C. 
     
     
         119 . (canceled) 
     
     
         120 . The process of  claim 118  wherein the reaction temperature is maintained for about 9 to about 15 hours after third addition step. 
     
     
         121 - 122 . (canceled) 
     
     
         123 . The process of  claim 93  wherein the fourth pH adjustment step results in a pH of less than 1. 
     
     
         124 - 126 . (canceled) 
     
     
         127 . The process of  claim 93  wherein the fifth pH adjustment step results in a pH of about 12 to about 13. 
     
     
         128 - 130 . (canceled) 
     
     
         131 . The process of  claim 93  wherein the sixth addition step is carried out by the addition of about 1.25 to about 1.75 molar equivalents of dimethylamine relative to said compound of Formula X. 
     
     
         132 - 137 . (canceled)