DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF HIGHLY PURE ANTI-FIBROTIC DRUG

We, GRANULES INDIA LIMITED,
a company incorporated under the companies act, 1956 having address at
My Home Hub; 2nd Floor; 3rd Block; Madhapur; Hyderabad; Telangana State- 500081, India

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to solvent free Pirfenidone and impurity free Pirfenidone.

The present invention relates to an improved process for the preparation of an anti-fibrotic drug or its pharmaceutically acceptable salts.

The present invention particularly relates to an improved process for the preparation of Pirfenidone or its pharmaceutically acceptable salts.

The present invention more particularly relates to an improved process for the preparation of highly pure Pirfenidone which is commercially feasible.

BACKGROUND OF THE INVENTION
Idiopathic pulmonary fibrosis (IPF) is an irreversible and ultimately fatal disease characterized by progressive loss of the ability of the lungs to absorb oxygen due to scarring. Approximately 100,000 people in the United States and 80,000 to 110,000 in Europe have IPF. IPF inevitably causes shortness of breath and destruction of healthy lung tissue, although some people may experience periods of stability with the disease.

Pirfenidone is an oral dosage form for the treatment of idiopathic pulmonary fibrosis, approved by the US FDA on October 15, 2014, which is sold under the brand name ESBRIET® and the molecular formula is C12H11NO with a molecular weight of 185.23. The structural formula of Pirfenidone is:

Formula I
Pirfenidone was first disclosed in US 2,947,755, however there is no process disclosed in this patent for the preparation of pirfenidone.

S.Gadekar et.al. in the US patent No 3,839,346 disclosed a process for the preparation of Pirfenidone, which involves the condensation of 5-methylpyridin-2(1H)-one with 1-iodo benzene using zinc precipitated copper powder, followed by crystallizing the crude Pirfenidone using hot water. The process is shown in the scheme given below:

Scheme I

Ramachandran et.al. in the US patent No 8,519,140 B2 disclosed a process for the preparation of Pirfenidone by condensing bromobenzene with 5-methyl-2-pyridone using cuprous oxide, in an organic solvent at temperature 125°C for 18 hrs. However, the inventors of the present invention surprisingly have found that only about 80% of the reaction was completed leaving behind unreacted starting materials. The process delineates herein below:

Scheme II

US ‘140 further discloses a process for the purification of Pirfenidone, which involves crystallization of crude Pirfenidone using a solvent mixture comprising heptanes and toluene followed by recrystallization using acid, base treatment. US ‘140 also discloses di(5-methyl-2-pyridone)benzene as an important impurity of Pirfenidone. However, inventors of the present application, after tireless efforts observed that a commercially feasible process with a highly pure pirfenidone may be feasible at a higher temperature of about 135°C and the reaction was found to be completed in 12-13 hrs (saving of about 1/3 time of the disclosed time in US ‘140 patent). Use of Copper powder as a catalyst was one of the significant impactor on the course of the reaction besides rise of temperature of about 10-20°C with respect to the reported temperature of 125°C in US ‘140.

The pharmaceutical compounds are required in highly pure form because of the fear of unknown and potentially harmful effects of impurities. For purposes of patient’s safety, it is highly desirable to limit the amount of impurities present in any medicament administered to a patient. Hence, it is required to prepare Pirfenidone in highly pure form which is suitable for the formulations.

The major disadvantage of the process disclosed in prior-art was the formation of molar amount of Sodium chloride during the reaction and this caries forward in subsequent steps of the process. This has significant effect on the final yield. Also, this is one of the major concerns to meet the ICH guidelines interms of test parameters as Ash content. Inventors of the present invention have found that acid-base treatment during the purification provides highly pure Pirfenidone.

The inventors of the present application were able to develop an improved process for the synthesis of Pirfenidone or its pharmaceutically acceptable salts, which is highly pure, efficient, economical and containing less impurities.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a solvent free Pirfenidone.

Another objective of the present invention is to provide an impurity free Pirfenidone.

Another objective of the preferred embodiment of the present invention is to provide an improved process for the preparation of an anti-fibrotic drug or its pharmaceutically acceptable salts.

Yet another objective of the preferred embodiment of the present invention is to provide an improved process for the preparation of solvent free and impurity free Pirfenidone or its pharmaceutically acceptable salts.

Yet another objective of the preferred embodiment of the present invention is to provide an improved process for the preparation of highly pure Pirfenidone which is commercially feasible.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides solvent free Pirfenidone.

In a preferred aspect, the present invention provides Pirfenidone containing residual solvent less than 200 ppm, wherein the residual solvent is selected from C1-C4 chlorinated alkane or alcohol.

In another aspect, the present invention provides an impurity free Pirfenidone.

In still another aspect, the present invention provides Pirfenidone with less than 0.2% of residue on ignition, specifically less than 0.1%.

In a preferred aspect, the present invention provides an improved process for the preparation of solvent free and impurity free Pirfenidone, which comprises :
a) subjecting the reaction mass to different purification techniques such as solvent crystallization, acid base treatment, solvent extraction, wherein any of the operations are carried out singly or combination of operations is carried out,
b) isolating crude Pirfenidone,
c) dissolving the crude Pirfenidone in a first organic solvent, wherein the first organic solvent is selected from C1-C4 chlorinated alkane, and
d) dissolving the Pirfenidone obtained in step c) in a second organic solvent followed by isolating highly pure Pirfenidone, wherein the second organic solvent is selected from water, alcohol or mixture, the Pirfenidone has no impurity greater than 0.05% by weight or molar ratio.

In a more preferred aspect, the present invention provides an improved process for the preparation of solvent free and impurity free Pirfenidone, which comprises:
a) dissolving crude Pirfenidone in a first organic solvent wherein the first organic solvent is selected from C1-C4 chlorinated alkane,
b) removing the first organic solvent to obtain pure Pirfenidone, and
c) redissolving the Pirfenidone obtained in step b) in a second organic solvent, wherein the second organic solvent is selected from water, alcohol or mixture, followed by treating the solution with a solid adsorbent material, and
d) cooling the solution obtained in step c) to give highly pure Pirfenidone, which has no impurity greater than 0.05%.

In a particular preferred aspect, the present invention provides a separating the pure Pifenidone (I) from the reaction mixture comprises the following steps:
a) providing solution of Pirfenidone in an organic solvent,
b) treating the Pirfenidone solution with hydrose solution,
c) treating solution of step (b) with activated carbon and filtered,
d) evaporating the organic solvent,
e) dissolving the residue in water and followed by treatment with an aqueous acid,
f) treating the solution with activated carbon & filtered,
g) treating the solution of step (f) with a base at temperature ranging between 05-30 oC,
h) treating the mass with a non-polar solvent at temperature 05-30 oC followed by filteration,
i) drying under reduced pressure conditions to recover the crude Pirfenidone (I), and
j) optionally purifying the material of step (i).

In another particular preferred aspect, the present invention provides a purification of Pifenidone (I) obtained in step j comprises the following steps:
a) providing a solution of Pirfenidone in non-polar organic solvent,
b) distilling off the non-polar organic solvent from step (a),
c) treating the residue with aqueous alcoholic solvent mixture at temperature ranging between 30-80°C,
d) cooling the step (c) solution to temperature 0-10°C, and
e) filtering the highly pure material and dried.

In another aspect, the present invention provides an improved process for the preparation of solvent free and impurity free Pirfenidone, which comprises:
a) providing compound of formula (II)

wherein R1 is H or N-protecting group,
b) optional deprotection of compound of formula (II), if R1 represents N-protecting group, followed by reacting with compound of formula (III)

wherein X represents a suitable leaving group, using catalyst, base in a polar solvent to give crude Pirfenidone compound of formula (I),

c) optionally isolating crude Pirfenidone compound of formula (I),
d) dissolving crude Pirfenidone obtained in step c) in a first organic solvent, which is selected from C1-C4 chlorinated alkane,
e) dissolving the Pirfenidone obtained in step (d) in a second organic solvent which is selected from water, alcohol or mixture, and
f) isolating highly pure Pirfenidone, which has total impurities less than 0.05%.

In another preferred aspect, the present invention provides an improved process for the preparation of solvent free and impurity free Pirfenidone, which comprises:
a) providing compound of formula (II)

wherein R1 is H or N-protecting group,
b) optional deprotection of compound of formula (II), if R1 represents N-protecting group, followed by reacting with compound of formula (III)

wherein X represents a suitable leaving group, using copper metal or copper powder, base in a polar solvent to give Pirfenidone compound of formula (I).


In yet another preferred aspect, the present invention provides process for the preparation of Pirfenidone of Formula (I)

Formula I

comprising the steps of:
a. preparing of reaction mixture comprising compound of formula (IIa), base and copper powder as catalyst having particle size range between 5-100 microns in a polar aprotic solvent at a temperature ranging between 30 - 100 oC,

Formula (IIa)
b. adding compound of formula (III) to Step (a) at temperature ranging between 30 - 100 oC and maintained the reaction for 10-30 hrs under reflux;

Formula III
wherein X represents Cl, Br, I, and
c. isolating pure Pirfenidone (I).

In yet another preferred aspect, the present invention provides Pirfenidone having Copper limit less than 100 ppm.

In yet another preferred aspect, the present invention provides Pirfenidone, which is free of its regioisomer impurity, wherein the regioisomer impurity is as given below:

Formula IV
In yet another preferred aspect, the present invention provides substantially pure Pirfenidone (I) having HPLC purity of atleast 99.8 % and regioisomer impurity (IV)

Formula IV

less than 0.05%.

In another embodiment of the present invention provides Crystalline highly pure Pirfenidone (I) Form RS characterized by

a) X-ray powder diffraction pattern comprising of atleast five diffraction angle peaks selected form 8.7, 14.3, 14.9, 18.4, 18.7, 19.8, 21.0, 22.1, 22.9, 24.3, 26.8, 27.2, 30.3 and 32.4 ± 0.5 2?°;

b) DSC isothermal peaks ranging between 104-110°C.

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of crystalline
Pirfenidone (I) designated as Crystalline Form RS.

Fig. 2 is an example of Differential Scanning Calorimetry (“DSC”) curve of Pirfenidone (I).

DETAILED DESCRIPTION OF THE INVENTION
The group R1 as defined herein is selected from hydrogen, suitable nitrogen protecting group selected from Carbobenzyloxy (Cbz), tert-Butyloxycarbonyl (BOC), p-Methoxybenzyl carbonyl (Moz or MeOZ), 9-Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), benzyl Carbamate, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), Tosyl (Ts), sulfonamides. R1 is preferably selected from Benzyl (Bn), tert-Butyloxycarbonyl (BOC).

X represents a suitable leaving group selected from Cl, Br, F, I, alkyl sulfonates such as mesylate, tosylates, and triflate; X is preferably selected from chloro, bromo, more preferably Br.

The term “Highly pure Pirfenidone” within the meaning of the present invention refers to a purified Pirfenidone in amorphous or crystalline form having purity 99.90 wt.%, more preferably at least 99.95 wt.%, and most preferably at least 99.99 wt.% containing less than 0.05% of each impurities. The purity expression whenever referred in the specification means greater than 99.8 % as determined by HPLC.
“C1-C4 chlorinated alkane solvent” as defined in the presence invention is selected from methylene chloride, chloroform, carbon tetrachloride, ethylenedichloride, ethylene chloride, 2,2,2-trichloroethane, or a mixture thereof. Preferably methylene chloride or chloroform. Most preferably methylene chloride.

“Alcohol solvent” as defined in the presence invention is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol. Preferably methanol or n-propanol. Most preferably methanol.

“Catalyst” as defined in the presence invention is selected from copper metal, copper powder, cuprous iodide, cuprous chloride, copper oxide, Rhodium, Nickel, Palladium, Platinum, Ruthenium, Zinc and Iridium and preferably copper powder.

“Base” as defined in the presence invention is selected from C1-6 alkyl amines, NH3, K2CO3, Na2CO3, NaHCO3, NH4OH, Mg(OH)2, CaCO3, Ca(OH)2, KOH, NaOH, NaH, KH, KOtBu, CH3COONa, CH3COOK, (CH3)3CONa, LiOH, N-Methylmorpholine and/or mixtures thereof.

“Acid” as defined in the presence invention is selected from HF, HCl, HBr, HI, HNO3, HNO2, H2SO4, H2SO3, H3PO4, H3PO3.

“Solid adsorbent material” as defined in the present invention is selected from alumina, silica, fuller's earth and activated charcoal. Preferably solid adsorbent material is activated charcoal.

The compound of formula II is reacted with compound of formula III using catalyst, base in a solvent to give crude Pirfenidone which is dissolved in first organic solvent followed by redissolving in a second organic solvent and isolating highly pure Pirfenidone.

Deprotection of compound of formula (II) is carried out in the presence of metal catalyst, hydrogen source, wherein the metal catalyst is selected from Pd, Ni, Pt, Rh (or) the deprotection may be carried out in the presence of an acid which is selected from strong acids such as HCl or CF3COOH (or) the deprotection may carried out in the presence of a base, which is selected from primary or secondary amines.

Suitable acid is selected from organic or inorganic acids. Preferably, the acid is selected from inorganic acids. More preferably, the acid is selected from sulfuric acid, hydrochloric acid and nitric acid.

“Solvent or Anti-solvent” as defined in the presence invention is selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone and/or mixtures thereof.

In a preferred embodiment, the present invention provides Pirfenidone containing residual solvent less than 200 ppm, wherein the residual solvent is selected from C1-C4 chlorinated alkane or alcohol.

In a preferred embodiment, the present invention provides the various methods for the purification of crude Pirfenidone, such as Filtration, Evaporation, Liquid–liquid extraction, solvent-anti solvent method, Crystallization, Recrystallization, Adsorption, Distillation, Fractionation, Sublimation, and Chromatography.

In another preferred embodiment the crude Pirfenidone obtained as reaction mass after completion of the reaction is optionally purified by acid, base treatment followed by treating with a polar or non-polar solvent or mixture thereof.

In yet another preferred embodiment the crude Pirfenidone obtained as reaction mass after completion of the reaction is optionally purified by treating with non-polar solvents followed by acid, base treatment.

In still another preferred embodiment the Pirfenidone obtained as reaction mass after completion of the reaction is optionally purified by acid base treatment in presence of non polar solvent.

The polar solvent as defined above is selected from THF, EA, acetone, dimethylsulfoxide, nitromethane, Propylene carbonate, dimethylformamide, N-methylpyrrolidone, N-methylmorpholine, ?-butyrolactone, acetonitrile, Formic acid, n-Butanol, Isopropanol (IPA), n-Propanol, Ethanol, Methanol, Acetic acid, Water, Dichloromethane (DCM), Diethyl ether, Chloroform, 1,4-Dioxane, and Benzene,

The non polar solvent as defined above is selected from MTBE, DIPE Toluene, Cyclohexane, pentane, hexane, heptane, and Cyclopentane.

In a preferred embodiment, the present invention provides an improved process for the preparation of solvent free and impurity free Pirfenidone, which comprises:
a) dissolving the crude Pirfenidone in dichloromethane solvent,
b) removing the dichloromethane solvent,
c) dissolving the product obtained in step b) in methanolic water, and
d) isolating highly pure Pirfenidone, which has no impurity greater than 0.05% by weight or molar ratio.

In a more preferred embodiment, the present invention provides an improved process for the preparation of solvent free and impurity free Pirfenidone, which comprises:
a) dissolving the crude Pirfenidone in dichloromethane solvent,
b) removing the dichloromethane solvent,
c) dissolving the product obtained in step b) in methanolic water, followed by treating the reaction mixture with charcoal at 60-65°C, and
d) the reaction mixture of step c) was cooled to 10-15°C to give highly pure Pirfenidone, which has no impurity greater than 0.05% by weight or molar ratio.

In a particularly preferred embodiment of the present invention, wherein ptionally purifying comprising steps of:
a. providing a solution of Pirfenidone in non-polar organic solvent,
b. distill off the non-polar organic solvent from step (a),
c. treating the residue with aqueous alcoholic solvent mixture at temperature ranging between 30-80°C,
d. cooling the step iii solution to temperature 0-10°C and
e. filtering the highly pure material and dried.

The non-polar solvent is selected from the group consisting of chloroform, 1,4-dioxane, dichloromethane, carbon tetrachloride, toluene, ethyl acetate, isopropyl acetate and alcoholic solvent in aqueous alcoholic mixture is selected from n-butanol, isopropanol, ethanol, methanol and mixture thereof .

In one of the particular embodiment of the present invention, non-polar solvent is dichloromethane.

In another preferred embodiment, the present invention provides a process for the preparation of solvent free and impurity free Pirfenidone, which comprises :
a) reacting compound of formula (IIa)

with compound of formula (IIIa)

using catalyst, base in a solvent, to give crude Pirfenidone compound of formula (I)

b) optionally isolating crude Pirfenidone compound of formula (I),
c) dissolving Pirfenidone in a first organic solvent selected from C1-C4 chlorinated alkane, and
d) dissolving the Pirfenidone obtained in step c) in a second organic solvent which is selected from water, alcohol or mixture, and
e) isolating highly pure Pirfenidone, which has no impurity greater than 0.05%.

In a more preferred embodiment, the present invention provides a process for the preparation of solvent free and impurity free Pirfenidone, which comprises :
a) reacting compound of formula (IIa)

with compound of formula (IIIa)

using copper metal or copper powder, potassium carbonate in N,N-dimethylformamide, to give crude Pirfenidone compound of formula (I)

b) isolating crude Pirfenidone compound of formula (I),
c) dissolving the crude Pirfenidone in dichloromethane solvent,
d) removing the dichloromethane solvent,
e) dissolving the product obtained in step d) in methanolic water, and
f) isolating highly pure Pirfenidone, which has no impurity greater than 0.05% by weight or molar ratio.

In a more preferred embodiment, the present invention provides an improved process for the preparation of solvent free and impurity free Pirfenidone, which comprises :
a) reacting compound of formula (IIa)

with compound of formula (IIIa)

using copper metal or copper powder, potassium carbonate in N,N-dimethylformamide, to give crude Pirfenidone compound of formula (I)

b) isolating crude Pirfenidone compound of formula (I).

In a preferred embodiment, process for the preparation of Pirfenidone of formula (I) compriring the steps of:
a) preparing of reaction mixture comprising compound of formula (IIa), base and copper powder as catalyst having particle size range between 5-100 microns in a polar aprotic solvent at a temperature ranging between 30 - 100 oC,

Formula (IIa)

b) adding compound of formula (III) to Step a at temperature ranging between 30- 100 oC and maintained the reaction for 10-30 hrs under reflux;

Formula III

wherein X represents Cl, Br, I,
c) isolating pure Pirfenidone (I).

In the step of activating the reaction mixture according to the present invention, compound of formula (IIa) and base were dissolved in polar aprotic solvent and heated the reaction mass for 30 minutes to 2 hours at the temperature ranges between 30-100°C. To this reaction mixture copper powder as catalyst having particle size range between 10-100 microns was added at the same temperature and maintained for 30 minutes to 2 hours.

In a particular embodiment according to present application, this step was an essential step and it was observed by the inventors that if such maintenance was not carried for atleast 30 minutes to 2 hours, the duration of reaction nearly double the actual time required for the reaction.

In a particular embodiment according to present application, making solution active was in the temperature range of 50-80°C for 1 hour.

In a particular embodiment according to present application, copper powder comprises the particle size = 75 microns.
In the step b of adding the compound of formula (III) to the reaction mixture formed in step a at temperature ranging between 30-100oC and maintained the reaction for 10-30 hours under reflux.

In one of the particular embodiment of the present invention is the maintenance of step b for 10-12 hours under reflux. However, if the reaction is not activated for 1 hour as in the step a, the duration of the reaction step b may exceed 22 hours.

In process step (a) of preparation of reaction mixture by dissolving the Pirfenidone in polar aprotic solvent is selected from Dimethyl formamide (DMF), Hexamethylphosphoramide (HMPA), Dimethylsulfoxide (DMSO), Dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP).

In one of the particular embodiment of the present invention, polar aprotic solvent used in step a is -Dimethyl formamide (DMF).

In process step a of preparation reaction mixture by treating the reaction mixture formed in step (a) is treated with base selected from sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide and cesium carbonate.

In one of the particular embodiment of the present invention, base used in step (a) was potassium carbonate.

In the step c of isolating pure Pirfenidone (I) of the present invention comprising steps of:
a) providing solution of Pirfenidone in an organic solvent,
b) treating the Pirfenidone solution with hydrose solution,
c) treating solution of step (b) with activated carbon and filtered,
d) evaporating the organic solvent,
e) dissolving the residue in water and with an acid,
f) treating the solution of step e with activated carbon & filtered,
g) treating the solution of step f with a base at temperature ranging between 05-30 oC,
h) treating the mass with a non-polar solvent at temperature 05-30 oC followed by filteration,
i) drying under reduced pressure conditions to recover the Pirfenidone (I) and
j) optionally purifying the material of step (a).

In a particular embodiment of the present invention, isolating the pirfenidone in dichloromethane and washing with water.

In another particular embodiment of the present invention, the solution was treated with 10-30%w/v of sodium hydro sulfite solution (hydrose solution) and again with water.

In the step e. acids were selected from hydrochloric acid, sulphuric acid, phosphoric acid and base utilized in step g. is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.

In another particular embodiment of the present invention, the solution was acidifying with aq.HCl.

In another particular embodiment of the present invention, the solution was treated with carbon and followed by basifying with 20% w/v NaOH to adjust the pH 10.5 – 11.5 at temperature 10-15°C.

In another particular embodiment of the present invention, the solution was treated with cyclohexane and maintained for 2-3 hours at 10-15°C and followed by drying the Pifenidone.

The temperature to dry the wet compound ranges from 40-45°C. Further, drying conditions may be employed by a person skilled in the art.
In the step a of providing solution of Pirfenidone in an organic solvent selected from halogenated solvents as methylene chloride, ethylene dichloride, chloroform or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or ether solvents as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxan, dimethylsulfoxide (DMSO), N,N-dimethyl formamide (DMF), non-polar solvents as hexane, cyclohexane, heptane, toluene and the mixture thereof.

In one of the particular embodiment of the present invention, providing solution of Pirfenidone in an organic solvent selected from methylene chloride, ethyl acetate and hexane.

In step h of purification of Pirfenidone (I) of the present invention, comprising steps of:
a) providing a solution of Pirfenidone in non-polar organic solvent,
b) distill off the non-polar organic solvent from step (a),
c) treating the residue with aqueous alcoholic solvent mixture at temperature ranging between 30-80°C,
d) cool the step (c) solution to temperature 0-10°C and
e) filter the highly pure material and dried.

In step (a) of providing solution of the Pirfenidone in an organic solvent was selected from non-polar organic solvent selected from chloroform, 1,4-dioxane, dichloromethane, carbon tetrachloride, toluene, ethyl acetate, isopropyl acetate. The solution obtained was treated with aqueous alcoholic solvent at temperature ranging between 30-80°C and drying the obtained solid.

In a particular embodiment of the present invention, non-polar organic solvent was dichloromethane and alcoholic solvent was methanol.
The highly pure pirfenidone having purity exceeding 99.8% or preferably 99.9% in the crystalline form found to be highly stabilized has been designated as Form RS.

In another embodiment of the present invention provides Crystalline highly pure Pirfenidone (I) Form RS characterized by

a. X-ray powder diffraction pattern comprising of atleast five diffraction angle peaks selected form 8.7, 14.3, 14.9, 18.4, 18.7, 19.8, 21.0, 22.1, 22.9, 24.3, 26.8, 27.2, 30.3 and 32.4 ± 0.5 2?°;

b. DSC isothermal peaks ranging between 104-110°C.

In a preferred embodiment, the present invention provides Pirfenidone with less than 0.2% of residue on ignition, specifically less than 0.1%.
In yet another embodiment, the present invention provides Pirfenidone having less than about 0.05 % of total impurities as measured by HPLC.

In yet another preferred embodiment, the Pirfenidone obtained by the process of present invention has the Copper limit less than 100 ppm. Preferably less than 50 ppm. More, preferably less than 20 ppm.

In yet another preferred embodiment, the Pirfenidone obtained by the process of present invention is free of its regioisomer impurity compound of formula (IV), which is given below:
(IV)

In yet another preferred embodiment, the Pirfenidone obtained by the process of present invention has high solubility and does not form hazy solution.

In a yet another preferred embodiment of the present invention, substantially pure Pirfenidone (I) having HPLC purity of atleast 99.8 % and regioisomer impurity (IV)
(IV)

less than 0.05%.
There were no solvent traces and residues besides any other impurities were found to traceable in a two consecutive laboratory processes conducted in the laboratory.

In one of the particular embodiment, inventors of the present application obtained a highly pure crystalline material possessing HPLC purity 100%. The robust of the process is testimony to the fact that even commercial batches were also found to be having purity exceeding 99 %.

In one of the particular embodiment Perfinidone (I), displays purity of more than 99.5%. The purity of the Perfinidone (I) samples was measured using Chromatography. Chromatography was performed with Waters Alliance HPLC system (MILD, USA) that consists of quaternary pump equipped with a 2695 seperation module with inbuilt auto injector and 2996 photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.

EXAMPLES
Example 1a: Preparation of 5-methyl-1-phenylpyridin-2(1H)-one:
5-Methylpyridin-2(1H)-one (100 Kg), potassium carbonate (127kg) and N,N-Dimethyl formamide (200 L) was charged in clean and dry RBF. Heat the reaction mass to 70-80°C and maintain for 1 hour. Add Copper powder (4.7 Kg with particle size 75 microns) at 70-80°C and maintain for another 1 hour. Add Bromobenzene (173 Kg, HPLC Purity: 99.0%) at 70-80°C and heat the reaction mass to reflux (130-145°C) and maintain for 12 hours for reaction completion. After completion of reaction, mass was cooled to room temperature (25-35°C) and charge Dichloromethane (800 L). The mixture was filtered and washed with dichloromethane (400 L). The filtrate was washed with water (1000 L) and the washed aq.layer was extracted with dichloromethane (250 L). The combined organic layer was washed with 20% sodium hydro sulfite solution (200 L) followed by water (200 L). The organic layer was treated with activated carbon (10 Kg) and wash with dichloromethane (100 L). The combined organic layer was distilled to get residual product to which water (500 L) was charged and acidified with aq. HCl (100 L) to get clear solution. The mass was treated with activated carbon (10 kg) and passed through hyflo. The obtained filtrate was basified with 20% NaOH solution to basic pH (10.5-11.5) at 10-15 °C to crystallize the product. Cyclohexane was charged to the mass and stirred for 2-3 hours at 10-15°C. Finally, the product was separated by filtration and dried to get Pirfenidone (5-methyl-1-phenylpyridin-2(1H)-one).
Yield: 78%
HPLC Purity: >99.8%

Example 1b : Preparation of Highly Pure pirfenidone:
Pirfenidone (130 Kg) was dissolved in dichloromethane (520 L) and passed through leaf, candy and micron filter and washed with dichloromethane (260 L) to get clear solution. Dichloromethane was distilled off from the filtrate to get residual product. The obtained product was dissolved in 15% methanolic water (520 L) and treated with activated carbon (10 Kg) at 55-65°C and wash the carbon with 15% methanolic water (260 L). The clear filtrate from hyflo was slowly cooled to 0-5°C to generate desired product. Maintain the mass for 1-2 hours at 0-5°C. The product was filtered and dried to get highly pure Pirfenidone.
Yield: 82 %;
HPLC: = 99.9%
Residual Solvents: Not Detected
Regioisomer (IV): Not Detected
DSC: Ranges between: 104-110 °C

Example 2a : Preparation of 5-methyl-1-phenylpyridin-2(1H)-one:
5-Methylpyridin-2(1H)-one (100 g), potassium carbonate 127g and N,N-Dimethyl formamide (200 mL) was charged in clean and dry RBF. Heat the reaction mass to 70-80°C and maintain for 1 hour. Add Copper powder (4.7 g with particle size 75 microns) at 70-80°C and maintain for another 1 hour. Add Bromobenzene (173 g, HPLC Purity: 99.0%) at 70-80°C and heat the reaction mass to reflux (130-145°C) and maintain for 12 hours for reaction completion. After completion of reaction, mass was cooled to room temperature (25-35°C) and charge Dichloromethane (800 mL). The mixture was filtered and washed with dichloromethane (200 mL). The filtrate was washed with water (1000 mL) and the washed aq.layer was extracted with dichloromethane (200 mL). The combined organic layer was washed with 20% sodium hydro sulfite solution (200 mL) followed by water (200 mL). The organic layer was treated with activated carbon (10 g) and wash with dichloromethane (100 mL). The combined organic layer was distilled to get residual product to which water (500 mL) was charged and acidified with aq. HCl (100 mL) to get clear solution. The mass was treated with activated carbon (10 g) and passed through hyflo. The obtained filtrate was basified with 20% Sodium hydroxide solution to basic pH (10.5-11.5) at 10-15 °C to crystallize the product. Cyclohexane was charged to the mass and stirred for 2-3 hours at 10-15 °C. Finally, the product was separated by filtration and dried to get Pirfenidone (5-methyl-1-phenylpyridin-2(1H)-one).
Yield: 78%
HPLC Purity: >99.8%

Example 2b: Preparation of Highly Pure pirfenidone:
Pirfenidone (100 g) was dissolved dichloromethane (400 mL) and filtered through hyflo bed and wash with dichloromethane (100 mL) to get clear solution. Dichloromethane was distilled off from the filtrate to get residual product. The obtained product was dissolved in 15% methanolic water (400 mL) and treated with activated carbon (7.5 g) at 55-65°C and wash the carbon with 15% methanolic water (200 mL). The clear filtrate from hyflo was slowly cooled to 0-5°C to crystallize desired product. Maintain the mass for 1-2 hours at 0-5°C. The product was filtered and dried to get highly pure Pirfenidone.
Yield: 81.5 %;
HPLC: = 99.9%
Residual Solvents: Not Detected
Regioisomer (IV): Not Detected
DSC Ranges between: 104-110 °C
,CLAIMS:We Claim:
1) A process for the preparation of Pirfenidone of Formula (I)

comprising the steps of:
a) Preparation of reaction mixture comprising compound of formula (IIa), base and copper powder as catalyst having particle size range between 5-100 microns in a polar aprotic solvents at a temperature ranging between 30 - 100 oC,

Formula (IIa)
b) adding compound of formula (III) to Step a at temperature ranging between 30 – 100 oC and maintained the reaction for 10-30 hrs under reflux,

Formula III

wherein X represents Cl, Br, I, and

c) isolating pure Pirfenidone (I).

2) A process for the preparation of highly pure Pirfenidone (I) according to claim 1, wherein polar aprotic solvent selected from Dimethyl formamide (DMF), Hexamethylphosphoramide (HMPA), Dimethylsulfoxide (DMSO), Dimethyl acetamide (DMAc), N-methylpyrrolidone (NMP).

3) A process for the preparation of highly pure Pirfenidone (I) according to claim 1, wherein base is selected from inorganic base as sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide and cesium carbonate.

4) A process for the preparation of highly pure Pirfenidone (I) according to claim 1, wherein step c) of isolating pure pirfenidone comprising steps of:
a) providing solution of Pirfenidone in an organic solvent,
b) treating the Pirfenidone solution with hydrose solution,
c) treating solution of step b with activated carbon and filtered,
d) evaporating solvent,
e) dissolving the residue in water and with an acid,
f) treating the solution of step e with activated carbon & filtered
g) treating the solution of step f with a base at temperature ranging between 05-30 oC,
h) treating the mass with a non-polar solvent at temperature 05-30 oC followed by filteration,
i) drying under reduced pressure conditions to recover the Pirfenidone (I) and
j) optionally purifying the material of step i.

5) A process for the preparation of highly pure Pirfenidone (I) according to claim 4 ,wherein organic solvent selected from halogenated solvents as methylene chloride, ethylene dichloride, chloroform or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or ether solvents as diethyl ether, diisopropyl ether, non-polar solvents as hexane, cyclohexane, heptane, toluene and the mixture thereof .

6) A process for the preparation of highly pure Pirfenidone (I) according to claim 4, wherein acid used in step e. is selected from hydrochloric acid, sulphuric acid, phosphoric acid and base utilized in step g. is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.

7) A process for the preparation of highly pure Pirfenidone (I) according to claim 4, wherein step j) of optionally purifying comprising steps of:
a) providing a solution of Pirfenidone in non-polar organic solvent,
b) distill off the non-polar organic solvent from step (a),
c) treating the residue with aqueous alcoholic solvent mixture at temperature ranging between 30-80°C,
d) cool the step iii solution to temperature 0-10°C and
e) filter the highly pure material and dried.

8) A process for the preparation of highly pure Pirfenidone (I) according to claim 7, wherein non-polar organic solvent selected from chloroform, 1,4-dioxane, dichloromethane, carbon tetrachloride, toluene, ethyl acetate, isopropyl acetate and alcoholic solvent in aqueous alcoholic mixture is selected from n-butanol, isopropanol, ethanol, methanol and mixture thereof .

9) Highly pure Pirfenidone (I) characterized by
a) HPLC purity of atleast 99.8 % and regioisomer impurity (IV)

Formula IV
less than 0.05% or devoid of regioisomer impurity,
a) characterized by X-ray powder diffraction pattern comprising of atleast five diffraction angle peaks selected form 8.7, 14.3, 14.9, 18.4, 18.7, 19.8, 21.0, 22.1, 22.9, 24.3, 26.8, 27.2, 30.3 and 32.4 ± 0.5 2?° and
c) DSC isothermal peak ranging between 104-110°C.

Dated this Twenty Seventh (27th) of January 2017

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883