Method for synthesizing pirfenidone

Abstract

A process for synthesizing pirfenidone from bromobenzene having less than about 0.15% by weight dibromobenzene is disclosed. Also disclosed are processes of synthesizing pirfenidone without using ethyl acetate or n-butanol, and pirfenidone having controlled levels of ethyl acetate, n-butanol, di(5-methyl-2-pyridinone)benzenes, and other impurities having specified retention times. Also disclosed are formulated dosage forms including the disclosed pirfenidone.

1 . A method of synthesizing pirfenidone comprising
 admixing bromobenzene, 5-methyl-2-pyridone, cuprous oxide, and an organic solvent under conditions sufficient to form pirfenidone,   
       wherein the bromobenzene comprises less than about 0.15% by weight or molar ratio dibromobenzene. 
     
     
         2 . The method of  claim 1 , further comprising washing the pirfenidone with a saline solution. 
     
     
         3 . The method of  claim 2 , wherein the saline solution comprises sodium chloride in a range of about 10 wt % to about 15 wt % based on the total weight of the solution. 
     
     
         4 . The method of  claim 1 , further comprising extracting the pirfenidone with an extracting organic solvent. 
     
     
         5 . The method of  claim 4 , wherein the extracting organic solvent comprises toluene. 
     
     
         6 . The method of  claim 1 , wherein the admixing is performed under elevated temperatures. 
     
     
         7 . The method of  claim 6 , wherein the temperature is at least about 100° C. 
     
     
         8 . The method of  claim 1 , further comprising admixing a base with the bromobenzene, 5-methyl-2-pyridone, cuprous oxide, and organic solvent. 
     
     
         9 . The method of  claim 8 , wherein the base is an inorganic base. 
     
     
         10 . The method of  claim 9 , wherein the inorganic base comprises a carbonate. 
     
     
         11 . The method of  claim 10 , wherein the carbonate comprises potassium carbonate. 
     
     
         12 . The method of  claim 1 , wherein the organic solvent comprises dimethyl formamide. 
     
     
         13 . The method of  claim 1 , further comprising crystallizing the pirfenidone from a solvent mixture comprising heptanes and toluene to form purified pirfenidone. 
     
     
         14 . The method of  claim 13 , further comprising recrystallizing the purified pirfenidone by
 dissolving at least a portion of the purified pirfenidone in an acidic aqueous solution at an elevated temperature to form a pirfenidone solution;   adding a basic solution to the pirfenidone solution until the pH is at least about 11; and   cooling the basic pirfenidone solution to a temperature below about 20° C. to form recrystallized pirfenidone.   
     
     
         15 . The method of  claim 14 , wherein the elevated temperature is at least about 40° C. 
     
     
         16 . The method of  claim 14 , wherein the acidic aqueous solution comprises hydrochloric acid. 
     
     
         17 . The method of  claim 14 , wherein the basic solution comprises sodium hydroxide. 
     
     
         18 . The method of  claim 14 , comprising cooling the basic pirfenidone solution to a temperature below about 10° C. 
     
     
         19 . The method of  claim 13 , comprising performing the purifying in the absence of ethyl acetate and butanol. 
     
     
         20 . Pirfenidone prepared by the method of  claim 19 , having a purity of at least 98% by weight or molar ratio and essentially free of ethyl acetate and butanol. 
     
     
         21 . The pirfenidone of  claim 20 , having a purity of at least 99% by weight or molar ratio. 
     
     
         22 . The pirfenidone of  claim 21 , having a purity of at least 99.9% by weight or molar ratio. 
     
     
         23 . Pirfenidone having less than about 0.1% by weight or molar ratio of a di(5-methyl-2-pyridinone)benzene impurity. 
     
     
         24 . The pirfenidone of  claim 23  having less than about 0.05% by weight or molar ratio of a di(5-methyl-2-pyridone)benzene impurity. 
     
     
         25 . Pirfenidone having less than about 0.1% by weight or molar ratio of an impurity which elutes at a relative retention time of about 1.95 compared to the retention time of pirfenidone, when analyzed by liquid chromatography. 
     
     
         26 . The pirfenidone of  claim 25  having less than about 0.05% by weight or molar ratio of the impurity which elutes at a relative retention time of about 1.95. 
     
     
         27 . Pirfenidone having less than about 0.1% by weight or molar ratio of an impurity which elutes at a relative retention time of about 1.24 compared to the retention time of pirfenidone, when analyzed by liquid chromatography. 
     
     
         28 . The pirfenidone of  claim 27  having less than about 0.05% by weight or molar ratio of the impurity which elutes at a relative retention time of about 1.24. 
     
     
         29 . A pharmaceutical composition comprising the pirfenidone of  claim 20  and a pharmaceutically acceptable excipient.