Process for the preparation of 4-carbonyl)amino]-3-fluorophenoxy}-n-ethylpyridine-2-carboxamide, its salts and monohydrate

Abstract

The present invention relates to a process for preparing 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, its salts and monohydrate.

What is claimed is: 
     
         1 . A process for preparing of the compound of the formula (I) 
       
         
           
           
               
               
           
         
         its salt or monohydrate by treating the compound of the formula (IV) 
       
       
         
           
           
               
               
           
         
         with the compound of formula (V) 
       
       
         
           
           
               
               
           
         
         in a reaction mixture and thereafter the solved compound of the formula (I) is treated with an acid to form a salt of the compound of the formula (I) which precipitates from the solution containing the solved compound of the formula (I). 
       
     
     
         2 . The process of  claim 1  for preparing the monohydrate of the compound of the formula (I) wherein the salt of the compound of the formula (I) is then treated with an aqueous basic solution to precipitate the monohydrate of the compound of the formula (I). 
     
     
         3 . The process of  claim 2  wherein the monohydrate of the compound of the formula (I) precipitates at a temperature of from 35° C. to 45° C. 
     
     
         4 . The process of  claim 2  for preparing of the compound of the formula (I) wherein the monohydrate is dried under reduced pressure until the compound of the formula (I) is formed. 
     
     
         5 . The process of  claim 1  wherein the solution comprising the solved compound of the formula (I) and what from the salt of the compound of the formula (I) precipitates is the reaction mixture or is a separate solution of the compound of the formula (I) prepared after isolation of the compound of the formula (I) from the reaction mixture. 
     
     
         6 . The process of  claim 1  wherein the acid is generated in situ in the reaction mixture after the compound of the formula (I) is formed by adding to the reaction mixture a protic substance and an acid precursor. 
     
     
         7 . The process of  claim 6  wherein the acid is generated in situ in the reaction mixture after the compound of the formula (I) is formed by adding to the reaction mixture an alcohol and an acylchloride. 
     
     
         8 . The process of  claim 7  wherein the alcohol is ethanol and the acylchloride is acetylchloride. 
     
     
         9 . The process of  8   claim 1  wherein the compound of the formula (IV) is prepared by reacting the compound of the formula (III) 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl, 
         or 
         R 1  and R 2  are joined and, taken together with the carbon atom to which they are attached, form a 4- to 7-membered cycloalkyl ring, 
       
       with the compound of the formula (II) 
       
         
           
           
               
               
           
         
       
       in the presence of a base, followed by adding an acid to deliver the compound of the formula (IV). 
     
     
         10 . The process of  claim 9  wherein the compound of the formula (III) is used in a solution of a suitable organic solvent and is formed by reacting 4-amino-3fluorophenol with the compound of the formula (VI) 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl, 
         or 
         R 1  and R 2  are joined and, taken together with the carbon atom to which they are attached, form a 4- to 7-membered cycloalkyl ring. 
       
     
     
         11 . The process of  claim 9  wherein the compound of the formula (II) is used in a solution of a suitable organic solvent which solution is prepared by neutralization the hydrochloric acid salt of the compound of the formula (II) with a base. 
     
     
         12 . The process of  claim 9  wherein the compound of the formula (II) it is solved in a suitable organic solvent, treated with an acid which is generated in situ by adding a protic substance and an acid precursor, precipitated as a salt of the compound of the formula (II), and neutralized by adding an aqueous solution of a base. 
     
     
         13 . The process of  claim 12  wherein the protic substance is an alcohol and the acid precursor is an acylchloride. 
     
     
         14 . The compound of the formula (I) 
       
         
           
           
               
               
           
         
         its monohydrate or salt in a high purity form wherein the compound of the formula (I), its monohydrate or salt is contaminated with one or more anilinic substances each in an amount of from 0.0001% to a maximum of 0.05% by weight based on the amount of the compound of the formula (I). 
       
     
     
         15 . The compound of  claim 14  wherein the compound of the formula (I), its monohydrate or salt is contaminated with 4-amino-3-fluorophenol and/or 4-(4-amino-3-fluorophenoxy)pyridine2-carboxylic acid methylamide each in an amount of from 0.0001% to a maximum of 0.05% by weight based on the amount of the compound of the formula (I).