Composition and methods for modulating a kinase cascade

Abstract

The invention relates to compounds and methods for modulating one or more components of a kinase cascade. The invention also relats to substantially pure compound 1 and substantially pure compound 1 salt (e.g., compound 1 hydrochloride salt and compound 1 benzenesulfonate salt). The invention further relates to methods of preparing substantially pure compound 1 and compound 1 salts.

1 . A benzenesulfonate salt of compound 1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, prepared by a process comprising Step 3: 
         converting compound 12 to compound 1: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The benzenesulfonate salt of  claim 1 , wherein the process further comprises Step 2:
 converting compound 11 to compound 12:   
       
         
           
           
               
               
           
         
       
     
     
         3 . The benzenesulfonate salt of  claim 2 , wherein Step 2 comprises reacting compound 11 with trimethylsilylchloride in a polar protic solvent. 
     
     
         4 . The benzenesulfonate salt of  claim 3 , wherein the polar protic solvent is selected from methanol, ethanol, and isopropanol. 
     
     
         5 . The benzenesulfonate salt of  claim 2 , wherein the reaction is carried out at a temperature from about 40° C. to about 60° C. 
     
     
         6 . The benzenesulfonate salt of  claim 2 , wherein the process further comprises Step 1:
 converting compound 10 to compound 11:   
       
         
           
           
               
               
           
         
       
     
     
         7 . The benzenesulfonate salt of  claim 6 , wherein in Step 1 compound 10 is reacted with a base and acetonitrile in a polar aprotic solvent to form compound 11. 
     
     
         8 . The benzenesulfonate salt of  claim 7 , wherein the polar aprotic solvent is selected from tetrahydrofuran, ethyl acetate, acetone, and dimethylsulfoxide. 
     
     
         9 . The benzenesulfonate salt of  claim 7 , wherein the base is potassium bis(trimethylsilyl)amide. 
     
     
         10 . The benzenesulfonate salt of  claim 6 , wherein the reaction is carried out at a temperature less than about 10° C. 
     
     
         11 . The benzenesulfonate salt of  claim 1 , wherein in Step 3 compound 12 is reacted with reagent A in an ether solvent to form compound 1. 
     
     
         12 . The benzenesulfonate salt of  claim 11 , wherein the ether solvent is selected from anisole and diethyl ether. 
     
     
         13 . The benzenesulfonate salt of  claim 1 , wherein the reaction is carried at a temperature from about 120° C. to about 160° C. 
     
     
         14 . The benzenesulfonate salt of  claim 1 , wherein the process further comprises reacting compound 1 with benzenesulfonic acid in the presence of a polar aprotic solvent and an ether solvent. 
     
     
         15 . A benzenesulfonate salt of compound 1: 
       
         
           
           
               
               
           
         
         prepared by a process comprising:
 converting compound 12 to compound 1: 
 
       
       
         
           
           
               
               
           
         
         
           wherein compound 12 is formed by reacting compound 11: 
         
       
       
         
           
           
               
               
           
         
         
           with trimethylsilylchloride in a polar protic solvent, and 
           reacting compound 1 with benzenesulfonic acid in the presence of a polar aprotic solvent and an ether solvent. 
         
       
     
     
         16 . The benzenesulfonate salt of  claim 15 , wherein the polar aprotic solvent is selected from acetonitrile, ethyl acetate, and tetrahydrofuran. 
     
     
         17 . The benzenesulfonate salt of  claim 15 , wherein the ether solvent is selected from anisole and diethyl ether, preferably wherein the ether solvent is anisole.