Quinoxalinyl-piperazinamide methods of use

Abstract

The disclosed subject matter provides methods using and kits comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

1 . A method of preparing a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof on a commercial scale, comprising:
 (a) reacting 3-amino-6-fluoro-2-methoxyquinoxaline with ethyl chloroformate in an organic solvent in the presence of a base to form a mixture; 
 (b) distilling the mixture while adding ethyl acetate to form a suspension; 
 (c) filtering the suspension to isolate ethyl-N-(6-fluoro-2-methoxyquinoxaline-3-yl) carbonate; and 
 (d) reacting the ethyl-N-(6-fluoro-2-methoxyquinoxaline-3-yl) carbonate with 1-(3,5-dimethoxyphenyl) piperazine hydrochloride in a second organic solvent in the presence of a second base. 
 
     
     
         2 . The method of  claim 1 , further comprising:
 (e) reacting 3-amino-2-chloro-6-fluoroquinoxaline with sodium methoxide in an organic solvent in the presence of a base to form a mixture;   (f) adding water to the mixture of step (e) to form a solution;   (g) cooling the solution to a temperature of about 15-20° C. to form a suspension; and   (h) filtering the suspension of step (g) to isolate 3-amino-6-fluoro-2-methoxyquinoxaline.   
     
     
         3 . The method of  claim 1 , wherein in step (a), the organic solvent is dichloromethane and the base is pyridine. 
     
     
         4 . The method of  claim 1 , wherein the distilling step (b) is conducted under atmospheric pressure. 
     
     
         5 . The method of  claim 1 , wherein step (c) comprises vacuum filtration. 
     
     
         6 . The method of  claim 1 , wherein in step (d), the second organic solvent is tetrahydrofuran and the second base is 1,8-diazabicycloundec-7-ene. 
     
     
         7 . The method of  claim 1 , wherein the steps are performed in one or more fixed reactors. 
     
     
         8 . The method of  claim 1 , further comprising reducing the particle size of the compound of formula (I), or pharmaceutically acceptable salt thereof, under conditions sufficient to provide a suspension. 
     
     
         9 . The method of  claim 8 , wherein the suspension is made by a milling process. 
     
     
         10 . The method of  claim 9 , wherein the milling process is high-energy agitator milling or roller milling. 
     
     
         11 . The method of  claim 10 , wherein the milling process is high-energy agitator milling. 
     
     
         12 . The method of  claim 11 , wherein the suspension has a D50 particle size of about 200 nm or less. 
     
     
         13 . The method of  claim 8 , further comprising spray drying or lyophilizing the suspension to form a powder. 
     
     
         14 . A product prepared by a method according to  claim 1 . 
     
     
         15 . A product prepared by a method according to  claim 8 . 
     
     
         16 . A product prepared by a method according to  claim 13 .