Method for synthesizing pirfenidone

Abstract

A process for synthesizing pirfenidone from bromobenzene having less than about 0.15% by weight dibromobenze 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.

What is claimed: 
     
         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 1 , further comprising extracting the pirfenidone from the organic solvent mixture with an extracting organic solvent. 
     
     
         4 . The method of  claim 3 , wherein the extracting organic solvent comprises toluene. 
     
     
         5 . The method of  claim 1 , further comprising admixing a base with the bromobenzene, 5-methyl-2-pyridone, cuprous oxide, and organic solvent. 
     
     
         6 . The method of  claim 5 , wherein the base comprises a carbonate. 
     
     
         7 . The method of  claim 6 , wherein the carbonate comprises potassium carbonate. 
     
     
         8 . The method of  claim 1 , wherein the organic solvent comprises dimethyl formamide. 
     
     
         9 . The method of  claim 1 , further comprising crystallizing the pirfenidone from a solvent mixture comprising heptanes and toluene to form purified pirfenidone. 
     
     
         10 . The method of  claim 9 , 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 base to the pirfenidone solution until the pH is at least about 11 to form a basic pirfenidone solution; and   cooling the basic pirfenidone solution to a temperature below about 20° C. to form recrystallized pirfenidone.   
     
     
         11 . The method of  claim 9 , comprising performing the crystallizing in the absence of ethyl acetate and in the absence of butanol. 
     
     
         12 . Pirfenidone prepared by a method 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. 
     
     
         13 . The pirfenidone of  claim 12 , wherein the method further comprises
 crystallizing the pirfenidone from a solvent mixture comprising heptanes and toluene to form purified pirfenidone.   
     
     
         14 . The pirfenidone of  claim 13 , wherein the method further comprises
 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 base to the pirfenidone solution until the pH is at least about 11 for form a basic pirfenidone solution; and 
 cooling the basic pirfenidone solution to a temperature below about 20° C. to form recrystallized pirfenidone, 
   
       wherein the recrystallizing is done in the absence of ethyl acetate and in the absence of butanol. 
     
     
         15 . The recrystallized pirfenidone of  claim 12 , having a purity of at least 98% by weight or molar ratio and being essentially free of ethyl acetate and essentially free of butanol. 
     
     
         16 . Pirfenidone having less than about 0.1% by weight or molar ratio of a di(5-methyl-2-pyridinone)benzene impurity. 
     
     
         17 . The pirfenidone of  claim 16 , having less than about 0.05% by weight or molar ratio of a di(5-methyl-2-pyridone)benzene impurity. 
     
     
         18 . The pirfenidone of  claim 16 , having a purity of at least 98% by weight or molar ratio and being essentially free of ethyl acetate and essentially free of butanol.