Processes for preparing ask1 inhibitors

Abstract

The present disclosure provides processes for the preparation of a compound of formula:which exhibits apoptosis signal-regulating kinase (“ASK1”) inhibitory activity and is thus useful in the treatment of diseases such as kidney disease, diabetic nephropathy and kidney fibrosis. The disclosure also provides compounds that are synthetic intermediates.

What is claimed is: 
     
         1 . A method for preparing a compound of formula (A): 
       
         
           
           
               
               
           
         
         or a salt or solvate thereof, 
         comprising the steps of: 
         (a) formylating a compound of formula (G): 
       
       
         
           
           
               
               
           
         
         under reaction conditions sufficient to form a compound of formula (F): 
       
       
         
           
           
               
               
           
         
         (b) cyclizing a compound of formula (F) under reaction conditions sufficient to form a compound of formula (E) or a salt thereof: 
       
       
         
           
           
               
               
           
         
         (c) carboxylating a compound of formula (E) or a salt thereof under reaction conditions sufficient to form a compound of formula (D) or a hydrate, solvate or salt thereof: 
       
       
         
           
           
               
               
           
         
         (d) chlorinating a compound of formula (D) or a hydrate, solvate or salt thereof under reaction conditions sufficient to form a compound of formula (B) or a salt thereof: 
       
       
         
           
           
               
               
           
         
          and 
         (e) contacting a compound of formula (B) or a salt thereof with a compound of formula (C) or a salt thereof: 
       
       
         
           
           
               
               
           
         
         under reaction conditions sufficient to yield a compound of formula (A). 
       
     
     
         2 . The method of  claim 1 , wherein the reaction conditions of step (a) comprise a reagent selected from the group consisting of acetic anhydride and formic acid, acetic acid monoanhydride and carbonic acid, and trifluoroacetic acid anhydride and formic acid. 
     
     
         3 . The method of  claim 1 , wherein the reaction conditions of step (a) comprise a solvent selected from the group consisting of dichloromethane, chloroform, isopropyl acetate, acetonitrile, and tetrahydrofuran. 
     
     
         4 . The method of  claim 1 , wherein the reaction conditions of step (a) comprise a temperature of about −10° C. to about 40° C. 
     
     
         5 . The method of  claim 1 , wherein the reaction conditions of step (b) comprise an ammonium reagent. 
     
     
         6 . The method of  claim 1 , wherein the reaction conditions of step (b) comprise a solvent selected from the group consisting of acetic acid, toluene, benzene, and isopropanol. 
     
     
         7 . The method of  claim 1 , wherein the reaction conditions of step (b) comprise a temperature of about 80° C. to about 120° C. 
     
     
         8 . The method of  claim 1 , wherein the reaction conditions of step (c) comprise a base. 
     
     
         9 . The method of  claim 1 , wherein the reaction conditions of step (c) comprise a solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, methyl-tert-butyl ether, and diethyl ether. 
     
     
         10 . The method of  claim 1 , wherein the reaction conditions of step (c) comprise a first temperature of about −20° C. to about 40° C. and a second temperature of about −10° C. to about 50° C. 
     
     
         11 . The method of  claim 1 , wherein the reaction conditions of step (d) comprise a chlorinating reagent. 
     
     
         12 . The method of  claim 1 , wherein the reaction conditions of step (d) comprise a solvent selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, methyl-tert-butyl ether, and chloroform. 
     
     
         13 . The method of  claim 1 , wherein the reaction conditions of step (d) comprise a temperature of about −20° C. to about 40° C. 
     
     
         14 . The method of  claim 1 , wherein the reaction conditions of step (e) comprise an organic base. 
     
     
         15 . The method of  claim 1 , wherein the reaction conditions of step (e) comprise a solvent selected from the group consisting of dichloromethane, dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran toluene, methyl-tert-butyl ether, and chloroform. 
     
     
         16 . The method of  claim 1 , wherein the reaction conditions of step (e) comprise a temperature of about 0° C. to about 40° C.