Process for preparing pyrrolotriazine kinase inhibitors

Abstract

An improved process for the preparation of certain pyrrolotriazine compounds is disclosed. The compounds exhibit utility as kinase inhibitors.

1 - 4 . (canceled)  
     
     
         5 . A process for the preparation of a pyrrolotriazine carboxylic acid comprising the step of: 
 (a) reacting compound II of the formula                          wherein    R 4  is hydrogen, alkyl, aryl, or heteroaryl, and    R 5  is hydrogen, alkyl, aryl, or heteroaryl,    with compound III of the formula                          wherein    X is a leaving group, and    R 6  is hydrogen, alkyl, aryl, or heteroaryl,    to afford compound IV of the formula                          wherein    R 4 , R 5  and R 6  are as defined above;    (b) reacting compound IV with an alcohol in the presence of a coupling reagent to form an ester V of the formula                          wherein    R is alkyl, aryl or heteroaryl, and    R 4 , R 5  and R 6  are as defined above    (c) reacting the ester V with a chlorinating reagent in the presence of a base to give a Compound VI of the formula                          wherein R, R 4 —R 6  are as defined in step (b);    (d) reacting the Compound VI with an aniline Compound VII of the formula                          wherein    R 1  and R 2  are independently selected from hydrogen and alkyl, and    R 3  is attached to any available carbon atom of the phenyl ring and at each occurrence is independently selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, nitro, amino, hydroxy, alkoxy, and substituted alkoxyl,    to give compound VIII of the formula                          wherein    R and R 1 —R 6  are as defined above,    n is 0, 1, 2 or 3; and    (e) reacting compound VIII with an amine NHR 7 R 8  to afford pyrrolotriazine carboxamides and benzamides compounds of the formula                          wherein R 1 —R 6  and n are as defined above, and    R 7  and R 8  are    (i) independently selected from hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, and heterocyclic or substituted heterocyclic; or    (ii) R 7  and R 8  can be taken together with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic group or a heteroaryl or substituted heteroaryl group; said group formed optionally containing an additional 1 or 2 heteroatoms.    
     
     
         6 . The process as defined in  claim 5  wherein the coupling reagent in step (b) is hydrogen chloride or sulfuric acid.  
     
     
         7 . The process as defined in  claim 6  wherein the coupling reagent is hydrogen chloride.  
     
     
         8 . The process as defined in  claim 6  wherein the alcohol in step (b) is a C 1 -C 6  alkanol.  
     
     
         9 . The process as defined in  claim 8  wherein the alcohol is ethanol or methanol.  
     
     
         10 . The process as defined in  claim 6  wherein step (a) is conducted in a solvent, wherein the solvent is a hydrocarbon, an ether, or an alcohol.  
     
     
         11 . The process as defined in  claim 10  wherein the solvent is an alcohol.  
     
     
         12 . The process as defined in  claim 11  wherein the alcohol is ethanol.  
     
     
         13 . The process as defined in  claim 6  wherein the chlorinating reagent in step (c) is thionyl chloride, POCl 3 , or PCl 5 .  
     
     
         14 . The process as defined in  claim 13  wherein the chlorinating agent is POCl 3 .  
     
     
         15 . The process as defined in  claim 6  wherein the aniline Compound VII in step (d) is N-alkoxy-3-amino-alkylbenzamide.  
     
     
         16 . The process as defined in  claim 6  wherein the aniline Compound VII in step (d) is N-methoxy-3-amino-4-methylbenzamide.  
     
     
         17 . The process as defined in  claim 6  wherein step (e) is conducted in a solvent or solvent mixture, wherein the solvent is a hydrocarbon, a halogenated hydrocarbon, an ether, an amide, or mixture thereof.  
     
     
         18 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or prodrug thereof prepared by the process as defined in  claim 5 .  
     
     
         19 . The compound of  claim 18  wherein the compound has the formula  
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 19  wherein the pharmaceutically acceptable salt is a methanesulfonic acid salt.