Method of Purifying and using 4-chloro-n-methy1-2-pyridinecarboxamide

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.

We claim: 
     
         1 .- 15 . (canceled) 
     
     
         16 . A method of purifying a compound of Formula II 
       
         
           
           
               
               
           
         
       
       comprising
 a) solving 4-chloro-N-methyl-2-pyridinecarboxamide in an organic solvent, 
 b) adding an alcohol to the solution of step a 
 c) treating the solution of step b with an acid precursor within 5-60 minutes of the addition of alcohol in step b to generate an acid in situ 
 d) isolating the salt of 4-chloro-N-methyl-2-pyridinecarboxamide by precipitation 
 wherein said compound is >98% pure. 
 
     
     
         17 . The method of  claim 16 , wherein the precipitated purified salt of 4-chloro-N-methyl-2-pyridinecarboxamide is further solved in a suitable organic solvent, and is neutralized by adding an aqueous solution of sodium hydroxide. 
     
     
         18 . The method of  claim 16 , wherein the alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, n-pentanol, glycerol or a mixture thereof. 
     
     
         19 . The method of  claim 17 , wherein the organic solvent is tetrahydrofuran, toluene, ethyl acetate, dioxane, methyl tert-butyl ether, dimethoxyethane, dimethylsulfoxid, dimethylformamid, 1-methyl-2-pyrrolidinone or mixtures. 
     
     
         20 . The method of  claim 19 , wherein the organic solvent is tetrahydofuran, toluene or mixtures thereof. 
     
     
         21 . The method of  claim 18 , wherein the alcohol is methanol, ethanol or isopropanol. 
     
     
         22 . The method of  claim 16 , wherein in step c the acid precursor is acylchloride, acylbromide, acetylchloride, acteylbromide, propionylchloride or propionylbromide. 
     
     
         23 . The method of  claim 16 , wherein in the situ preparation of the acid occurs without water. 
     
     
         24 . The method of  claim 16 , comprising adding the acid precursor within 10-30 minutes of the addition of alcohol in step b. 
     
     
         25 . A process for the preparation of a compound of formula IV 
       
         
           
           
               
               
           
         
       
       comprising reacting a purified compound of formula II prepared according to the process of  claim 16  with a compound of 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 
       
       wherein the compound II and compound III are reacted in a solution of an organic solvent in the presence of a base. 
     
     
         26 . A process according to  claim 25 , wherein said organic solvent is 1-methyl-2-pyrrolidinone, dimethylformamide, N,N-dimethylacetamid, dimethyl sulfoxide, sulfolane or mixtures thereof. 
     
     
         27 . A process according to  claim 26 , wherein said organic solvent is 1-methyl-2-pyrrolidinone and/or dimethylformamide. 
     
     
         28 . A process according to  claim 25 , wherein said base is an alkali metal hydroxide or an alkali metal alkoxide. 
     
     
         29 . A process according to  claim 29 , wherein said base is potassium tert-butoxide. 
     
     
         30 . A process according to  claim 28 , wherein said base is potassium tert-butoxide in a tetrahydrofuran solution. 
     
     
         31 . A process according to  claim 25 , wherein the reaction mixture of the compound of formula II and a compound of formula III is heated to a temperature of from 50° C. to 150° C. and acetic acid in water is added. 
     
     
         32 . A process according to  claim 32 , wherein the reaction mixture is heated to a temperature of from 80° C. to 120° C. and after 2-4 hours the temperature is adjusted to between 50° C. to 90° C. 
     
     
         33 . A process according to  claim 25 , 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. 
     
     
         34 . A process according to  claim 25 , wherein 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