Process for preparation of grapiprant

Abstract

The invention relates to process for the preparation of grapiprant and its intermediates thereof. The invention also relates to grapiprant having a purity 98% or more and compounds of Formula (A), (B), (C) and (D) in an amount of 0.5 or less, relative to grapiprant, by area percentage of HPLC. The invention also relates to an amorphous form of grapiprant and process for preparation thereof.

1 - 3 . (canceled) 
     
     
         4 . A process for preparation of Grapiprant, the process comprising reacting a compound of Formula (II), 
       
         
           
           
               
               
           
         
         with ethyl (p-tolylsulfonyl) carbamate. 
       
     
     
         5 . The process according to  claim 4 , wherein the compound of Formula (II) is reacted with ethyl (p-tolylsulfonyl)carbamate in the presence of a base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium tert-butoxide, triethyl amine, diisopropyl amine, diisopropylethylamine, pyridine, morpholine, piperidine, DBU, or DABCO. 
     
     
         6 . The process according to  claim 4 , wherein the compound of Formula (II) is prepared by a process comprising:
 (a) reacting a compound of Formula (VII) with a compound of Formula (VIII),   
       
         
           
           
               
               
           
         
       
       to obtain a compound of Formula (VI); 
       
         
           
           
               
               
           
         
         (b) converting the compound of Formula (VI) into a compound of Formula (V); 
       
       
         
           
           
               
               
           
         
         (c) converting the compound of Formula (V) into a compound of Formula (IV); 
       
       
         
           
           
               
               
           
         
         (d) converting the compound of Formula (IV) into a compound of Formula (III); and 
       
       
         
           
           
               
               
           
         
         (e) converting the compound of Formula (III) into a compound of Formula (II). 
       
     
     
         7 . The process according to  claim 6 , wherein the reaction at step (a) is performed in the presence of one or more polar aprotic solvents. 
     
     
         8 . The process according to  claim 6 , wherein the compound of Formula (VI) at step (b) is reacted with a reducing reagent selected from Pd/C—H 2 , Raney Ni, ruthenium, rhodium, platinum, hydrazine hydrate, zinc metal in aqueous ammonium chloride, zinc metal with sodium hydroxide, or lithium aluminum hydride. 
     
     
         9 . The process according to  claim 6 , wherein the compound of Formula (V) at (c) is reacted with propionic acid and propionic anhydride and with a base to obtain the compound of Formula (IV). 
     
     
         10 . The process according to  claim 9 , wherein the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, sodium hydride, or potassium hydride. 
     
     
         11 . The process according to  claim 6 , wherein the compound of Formula (V) at step (d) is reacted with thionyl chloride and a metal azide to obtain the compound of Formula (III). 
     
     
         12 . The process according to  claim 11 , wherein the metal azide is selected from sodium azide or potassium azide. 
     
     
         13 . The process according to  claim 6 , wherein the compound of Formula (III) at step (e) is converted into the compound of Formula (II) by using a reducing reagent selected from palladium/ammonium acetate, zinc/formic acid, zinc/acetic acid, or by hydrogenation. 
     
     
         14 . The process according to  claim 4 , wherein the grapiprant obtained is in amorphous form. 
     
     
         15 . The process according to  claim 14 , wherein the amorphous form of grapiprant is prepared by the process comprising:
 (a) providing a solution of grapiprant in one or more solvents; and   (b) obtaining the amorphous form of grapiprant by the removal of the one or more solvents.   
     
     
         16 . The process according to  claim 15 , wherein the solvent at step (a) comprises one or more of methanol, ethanol, isopropanol, 1-butanol, tert-butanol, acetonitrile, propionitrile, chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane, acetone, cyclohexane, hexane, toluene and xylene, dimethyl formamide, dimethyl sulphoxide, THF and dioxane. 
     
     
         17 . The process according to  claim 15 , wherein the removal of the solvent at step (b) comprises one or more of distillation, distillation under vacuum, spray drying, agitated thin film drying (“ATFD”), and freeze drying (lyophilization).