FIELD OF THE INVENTION
The present invention relates to an industrially feasible and cost effective process for the preparation of Pirfenidone having Formula I.

Pirfenidone (Formula I)
BACKGROUND OF THE INVENTION
Pirfenidone is a small molecule whose chemical name is 5-methyl-l-phenyl-2-(lH)-pyridone. Its use for the manufacture of a medicament for the preparation and/or prevention of fibrotic lesions is first described in EP0383591.
US3974281 and US3839346 describe the preparation of Pirfenidone (Formula I) starting from 5- methyl-2-pyridone (Formula II) in the presence of anhydrous sodium carbonate, copper powder / zinc precipitated copper powder, iodobenzene (Formula III), under reflux for 18 hours, furnishing crude Pirfenidone, which is then crystallized in benzene and petroleum ether.

This process has major drawback of difficulty in removal of iodobenzene from crude product. When the iodobenzene or bromobenzene is used as solvent or in excess quantities, their removal from the initially obtained crude product requires the use of large amounts of nonpolar solvents like heptane, hexane, pentane or petroleum ether. These nonpolar solvents have the proper solubilizing power for iodobenzene or bromobenzene residues, whereas they also dissolve the product Pirfenidone, though poorly, which in turn affects the yield of the final product i.e. Pirfenidone. Besides, the use of excess reagents, large volumes of nonpolar solvents lead to higher manufacturing costs and environmental problems. Due to use of zinc during the precipitation of copper powder, the load of effluent is higher. Further, the use of benzene as a crystallization solvent is of utmost concern, because of its carcinogenic properties. Thus, it would be highly advantageous to minimize the quantities of these reagents and solvents, both from economic, health and environmental point of view.
US8519140B2 discloses the synthesis of Pirfenidone of Formula I from 5-methyl-2-pyridone of Formula II and bromobenzene of Formula IV with CU2O catalyst to obtain crude Pirfenidone:

N ^O
H Formula II

Br
Formula IV

Cu20 DMF, K2C03

HiC

^^

Pirfenidone (Formula I)
The known processes suffer from the drawbacks such as (a) use of carcinogenic solvent viz. benzene as crystallization solvent in the final stage, (b) costlier reagent such as iodobenzene, (c) use of zinc precipitated copper powder makes the process costlier, environmental non-friendly and industrially unviable, (d) use of metal chelate to remove copper metal from the product and (e) long work-up and repeated extraction make the prior-art process less productive and infeasible at industrial scale.

In view of the preparation methods available for Pirfenidone, there is a need for simple, industrially scalable having mild reaction conditions, cost effective and environmental friendly processes for the preparation of Pirfenidone that is free from one or more of the above mentioned drawbacks and achieves good yield and purity.
To overcome the disadvantages of the state of the art, the present invention provides a process for the synthesis of Pirfenidone by reacting 5-methyl-2-pyridone with halobenzene in-solvent in the presence of catalyst and a base and in the presence of ligand.
The problem has been solved by the applicant by providing an improved process, which allows a convenient and efficient synthesis of Pirfenidone.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a representative PXRD pattern of Pirfenidone. FIG. 2 is a representative DSC curve of Pirfenidone. FIG. 3 is a representative TGA curve of Pirfenidone.
OBJECT OF THE INVENTION
It is a principal object of the present invention to improve upon one or more limitations from the prior arts by providing an improved process for the preparation of Pirfenidone.
It is another object of the present invention to provide a simple, commercially viable, economical and environment friendly process for preparing Pirfenidone, in good yield and purity.
It is still another object of the present invention to provide Pirfenidone substantially free of impurity of Formula A i.e. A^-[2-(phenylamino)ethyl]formamide.

SUMMARY OF THE INVENTION
According to one aspect of the present invention, there is provided an improved and industrially feasible process for the manufacture of Pirfenidone of Formula I, as shown in Scheme 1.
Scheme 1:


X
HUC

Formula II

Solvent, Catalyst
Kt?
Formula V Base> L'9and X = CI, Br and I

HQC

Pirfenidone (Formula I)

It has been unexpectedly found that Pirfenidone is efficiently prepared from process as shown in Scheme 1.
DESCRIPTION OF THE INVENTION
The present invention (Scheme 1) relates to an improved process for the preparation of Pirfenidone comprising the steps of, reacting 5-methyl-2-pyridone of Formula II with halobenzene of Formula V in a solvent in the presence of catalyst, a base and in the presence of ligand.

According to the present invention the solvent is selected from the group comprising of dimethylformamide (DMF), dimethylsulfoxide (DMSO); hexamethylphosphoramide (HMPA), n-butanol, dimethyl acetamide (DMAC), dioxane, dimethoxy ethane, toluene, sulfolane, water, N-methyl pyrrolidone (NMP) and mixtures thereof. In a preferred embodiment dimethylformamide (DMF) is used as solvent.
According to the present invention the catalyst is selected from the group comprising of copper powder, copper(I)halide and copper(I)oxide. In a preferred embodiment copper powder is used as catalyst.
According to the present invention, the reaction is carried out in the presence of a base selected from the group comprising of alkali or alkaline earth metal carbonates, bicarbonates, phosphates and hydroxides preferably K2CO3, Na2C03, NaHCCh, NasPCU, K3PO4, KOH and NaOH. In a preferred embodiment the reaction is carried out in the presence of K2CO3.
According to the present invention, the reaction is carried out in the presence of ligand selected from the group comprising of ethylene diamine, 1,2-cyclohexyl diamine and PEG-400 and the like. In a preferred embodiment ethylene diamine is used as ligand.
According to the present invention, the reaction is carried out in presence of ligand, wherein ligand is used in 0.1 - 0.3 mole equivalent with respect to 5-methyl-2-pyridone. In a preferred embodiment, ligand is used in 0.18 - 0.22 mole equivalent with respect to 5-methyl-2-pyridone. In a more preferred embodiment, ligand is used in 0.2 mole equivalent with respect to 5-methyl-2-pyridone.
According to the present invention, the reaction is carried out at temperatures sufficient to form Pirfenidone, preferably at 100°C«150°C.
In an embodiment, if the ligand such as ethylene diamine is not used, then the reaction is carried out at temperatures 135°C-150°C, preferably at 140°C-145°C.

In another embodiment, if the ligand such as ethylene diamine is used, then the reaction is carried out at temperatures 100°C-130°C and preferably at 110°C-125°C.
According to present invention, coupling of 5-methyl-2-pyridone with bromobenzene is carried out at reduced temperature and in lesser time by using catalyst in presence of ligand.
The reaction is carried out under an inert gas atmosphere wherein the inert gas is selected from the group comprising of nitrogen, argon, etc.
According to present invention, coupling of 5-methyl-2-pyridone with bromobenzene is carried out at reduced temperature and in lesser time by addition of catalyst optionally in lots. However, if the addition of catalyst is done in lot-wise manner, then the reaction is carried out at temperatures 100°C-130°C.
According to present invention, Pirfenidone is substantially free of impurity of Formula A, wherein impurity of Formula A is preferably less than about 0.15% and more preferably less than about 0.10%.
According to present invention, the crystalline Pirfenidone can be characterized by X-ray powder diffraction peaks at about 8.8, 14.3, 15.0, 18.4, 21.0 and 24.4 deg±0.2° 20.
According to present invention, the crystalline Pirfenidone can be characterized by X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1.
According to present invention, the crystalline Pirfenidone can be characterized by DSC thermogram substantially as shown in FIG. 2.
According to present invention, the crystalline Pirfenidone can be characterized by TGA substantially as shown in FIG. 3.

According to the present invention Pirfenidone is isolated from the reaction mixture by conventional methods as reported in the literature.
The process for the preparation of Pirfenidone as described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples
Example 1: Preparation of Pirfenidone
To a stirred solution of DMF (400 mL), 5-Methyl hydroxyl pyridine (100.0 g), potassium carbonate (126.5 g) and Copper powder (1.2 g) was added. Then Bromobenzene (288.0 g) was also added. Heated the reaction mixture to 140-150°C for 60-70h. After cooling, DM water (400 mL) was added into the reaction mixture and then Toluene (300 mL) was also added and stirred. Filtered the reaction mixture through hyflo bed and washed with Toluene (200 mL). Filtrate was stirred for 20-30 min, and after settling, separate the layers. To the upper organic layer, EDTA solution (100 mL) was added and stirred. Separated the layers, and to the collected upper organic layer, sodium chloride solution (23 g in DM water (100 mL)) was added. Separated the layers, to the upper organic layer, activated charcoal (5.0 g) was added at RT. Heated the reaction mixture to 50-60°C for 30-60 min. Filtered the reaction mixture through hyflo bed (20.0 g) at 50-60°C and further washed with hot Toluene (100 mL) at 50-60°C. Filtered the hot filtrate mL through 0.45 Micron paper at 50-60°C which was further distilled out (8.5-9.0 V) under vacuum at 45-55°C. Then charged Cyclohexane (200 mL) into the reaction mixture and distilled out solvent (2.0 V). After cooling the reaction mixture, Cyclohexane (400 mL) was further added into the reaction mixture which was stirred at 20-30°C for 1-2 h. After cooling to 0-10°C, stirred it for 2-3 h at 0-10°C. Then filtered it and washed with Cyclohexane (2 x 100 mL) at 20-30°C and finally dried under vacuum at 45-50°C for 10-15 h to get 118 g of Pirfenidone. Purity: 99.9%, Yield: 69.5%

Example 2: Purification of Pirfenidone
To a stirred solution of crude Pirfenidone (100.0 g) (obtained as in the example 1) and DM water (300 mL), Cone. HC1 (100 mL) was added and stirred it. Then Cyclohexane (100 mL) was also added into reaction mixture at RT and heat it at 35-40°C for 20-30 min. Separated the layers and collected lower aqueous layer. To the aqueous layer, Cyclohexane (100 mL) was added at RT and heat it at 35-40°C for 20-30 min. Separated the layers and collected lower aqueous layer. To the aqueous layer, activated charcoal (5.0 g) was added and reaction mixture was heated to 40-50°C for 30-60 min. Filtered it through hyflo bed (20.0 g) and washed with hot DM water (100 mL). Filtered the hot filtrate through 0.45 Micron paper at 40-50°C which was further heated to 35-45°C. Adjusted pH by addition of-30% sodium hydroxide (-100 mL). The reaction mixture was cooled, stirred and then filtered under vacuum. To the wet Pirfenidone, DM water (200 mL) was added and stirred for 1-2 h. Filtered the reaction mixture under vacuum and washed with DM water (100 mL) at 20-30°C and finally dried under vacuum at 45-50°C for 10-15 h to get pure 81.0 g of Pirfenidone. Purity: 99.99%, Yield: 81%
Example 3: Preparation of Pirfenidone
A mixture of 5-methyl-2-pyridone (lOO.Og, 0.9163 moles), bromobenzene (273.36g, 1.74 moles), Ethylenediamine(11.01, 0.1832 moles) and K2C03 (126.65g, 0.9163 moles) in DMF (100 mL) was stirred under N2 at 80-90°C for 15-20 min, then copper powder (2.91 g) was added and heated to 120-125°C. Stirring continued for 6 h and another lot of copper powder (2.91 g) was added after cooling to 80-90°C. The reaction mixture was reheated to 120-125°C and continued for 14 h. After completion of reaction (monitored by HPLC), the reaction mixture was cooled to 45-50°C and added DM water (300 mL). pH of reaction mass was adjusted to 10.5 to 11 with aq. ammonia solution at 40-45°C, and toluene (300 mL) was added and stirred The layers were separated and the aqueous layer was extracted with toluene (2x200 mL). The combined organic layer was filtered through hyflo and washed with toluene (100 mL) at 40-45°C.The filtrate was washed with a mixture ofaq. ammonia solution (30%) and aq. NaCl solution (2x200 mL). The final organic layer treated with activated charcoal (5g). The reaction mass was filtered

through hyflo and washed with toluene (2x100 mL). The filtrate was concentrated under vacuum at 45-50°C leaving -500 mL of mass in which cyclohexane (300 mL) was added and stirred at 60-65°C for 30 min to get a clear solution. The mixture was cooled gradually to room temperature, stirred for 2 h, then further cooled to 5°C and stirred for 2 h at this temperature. The solid was filtered, washed with a mixture of toluene and cyclohexane (1:2; 2x150 mL), sucked to dryness at Buchner and finally dried under vacuum at 45-50°C for 13 h to provide 126.0 g of Pirfenidone. Purity 99.96%, Yield: 74.2%
Example 4: Purification of Pirfenidone
To a stirred solution of Pirfenidone (lOOg, 0.5399 moles) (obtained as in the example 3) in DM water (300 mL) was added cone. HC1 (100 mL) and stirred at room temperature for 10-15 min. The reaction mixture was stirred with cyclohexane (100 mL) at 45-50°C for 30 min. After stirring the layers were separated and the aqueous layer was washed with cyclohexane (100 mL) at the same temperature. The aqueous layer was stirred with activated charcoal (5g) at 45-50°C for 1 h, filtered through hyflo followed by 0.45 micron filter and washed with DM water (100 mL). To the combined filtrate was added aqueous NaOH solution (prepared by dissolving 26g NaOH in 120 mL DM water) at 45-50°C and final pH was adjusted to about 10 using 15% aqueous NaOH solution. Stirring was continued at 45-50°C for next 30 min, cooled to room temperature, stirred for 3 h and filtered. The wet material was stirred with DM water (200 mL) at 45-50°C for 2 h, cooled to room temperature, then to 5-10°C and stirred for 2 h. After stirring, the precipitated solid was filtered, washed with DM water (100 mL), suck dried and finally dried at 45-50°C for 12 h to provide 85.2 g of Pirfenidone as white crystalline solid. Purity: 100%, Yield: 85.2%,
Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

Claims:
1. A process for the preparation of Pirfenidone of Formula I,
H-
N^O

Pirfenidone (Formula I)
comprising the steps of:
reacting 5-methyl-2-pyridone of Formula II
hUC
H Formula II
with halobenzene of Formula V

Formula V X = CI, Br and I
in solvent in the presence of copper powder, a base and in the presence of ligand.
2. The process according to claim 1, wherein solvent is selected from the group comprising of dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoramide (HMPA), n-butanol, dimethyl acetamide (DMAC), dioxane, dimethoxy ethane, toluene, sulfolane, water, N-methyl pyrrolidone (NMP) and mixtures thereof.

3. The process according to claim 1, wherein copper powder is added optionally in lots.
4. The process according to claim 1, wherein base is selected from the group comprising of alkali or alkaline earth metal carbonates, bicarbonates, phosphates and hydroxides preferably K2C03, Na2C03, NaHC03) Na3P04, K3P04, KOH and NaOH.
5. The process according to claim 1, wherein ligand is selected from the group comprising of ethylene diamine, 1,2-cyclohexyl diamine and PEG-400.
6. The process according to claim 5, wherein ligand is preferably ethylene diamine.
7. Pirfenidone prepared according to the process of claim 1, which is substantially free of impurity of Formula A

Formula A
8. Pirfenidone prepared according to the process of claim 1, wherein impurity of Formula A is less than 0.15%.
9. Pirfenidone prepared according to the process of claim 1, wherein impurity of Formula A is less than 0.10%.