DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF PIRFENIDONE”

Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

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 a process for the preparation of pirfenidone.

BACKGROUND OF THE INVENTION
Pirfenidone, also known as 5-methyl-1-phenyl-2-(1H)-pyridone, is represented by the structure of formula I.

Pirfenidone is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
The object of the present invention is to provide a process for the preparation of pirfenidone with improved yield and purity.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of pirfenidone, a compound of formula I,

the process comprising reacting a compound of formula II,

with a compound of formula III,

wherein, X is selected from the group consisting of Cl, Br, I, in the presence of a base, a copper catalyst and a phase transfer catalyst.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic XRPD of crystalline pirfenidone as obtained in Example 7.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of pirfenidone, a compound of formula I,

the process comprising reacting a compound of formula II,

with a compound of formula III,

wherein, X is selected from the group consisting of Cl, Br, I, in the presence of a base, a copper catalyst and a phase transfer catalyst.
In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C.
A suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkali metal such as sodium metal; alkyl lithium such as n-butyl lithium; tertiary amines such as triethylamine, N,N-diisopropylethylamine; ammonia, pyridine, piperidine, 4-dimethylaminopyridine. Preferably the base selected is potassium carbonate.
A suitable copper catalyst includes, but is not limited to copper powder, cuprous oxide, cupric oxide, cuprous iodide, cupric iodide, cuprous bromide, cupric bromide, cuprous chloride, cupric chloride, zinc precipitated copper powder, cupric acetate, copper sulphate or the like. Preferably, the copper catalyst selected is copper powder.
A suitable phase transfer catalyst includes, but is not limited to crown ethers such as dibenzo-18-crown-6-ether and the like, pillararenes, calixarenes, thiacalixarenes, cycloparaphenylenes, cyclophanes, cyclodextrins, quaternary ammonium salts such as tetra-n-butyl ammonium bromide, tetra-n-butyl ammonium fluoride, phosphonium salts, pyridinium salts, 1,8-diazabicycloundec-7-ene, triethylenediamine. Preferably, the phase transfer catalyst selected is dibenzo-18-crown-6-ether.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, heptane, hexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; or mixtures thereof. Preferably, the solvent selected is dimethyl formamide.
In one embodiment, the present invention provides a process for the preparation of pirfenidone comprising reacting the compound of formula II with iodobenzene, the compound of formula III in the presence of a base, a copper catalyst and a phase transfer catalyst.
In one embodiment, the reaction may be carried out in the absence of a solvent.
The reaction may be carried out at a temperature in the range of about 25ºC to about 130ºC. The reaction is carried out for a period of about 2 hours to about 20 hours. Preferably the reaction is carried out at a temperature of about 120ºC to about 125ºC for a period of about 10 hours to about 15 hours.
In one embodiment, the present invention provides a process for the preparation of pirfenidone comprising reacting the compound of formula II with iodobenzene in the presence of a base, a copper catalyst and a phase transfer catalyst, wherein the iodobenzene comprises less than 0.15% of diiodobenzene, preferably less than 0.05% of diiodobenzene.
In one embodiment, the present invention provides a process for the preparation of pirfenidone comprising reacting the compound of formula II with iodobenzene in the presence of a base, a copper catalyst and a phase transfer catalyst, wherein the iodobenzene is substantially free of diiodobenzene.
In one embodiment, the present invention provides a process for the preparation of pirfenidone comprising reacting the compound of formula II with iodobenzene in the presence of a base, a copper catalyst and a phase transfer catalyst, wherein the iodobenzene comprises less than 0.15% of bromobenzene, preferably less than 0.05% of bromobenzene.
In one embodiment, the present invention provides a process for the preparation of pirfenidone comprising reacting the compound of formula II with iodobenzene in the presence of a base, a copper catalyst and a phase transfer catalyst, wherein the iodobenzene is substantially free of bromobenzene.
In one embodiment, the present invention provides a process for the preparation of pirfenidone comprising reacting the compound of formula II with iodobenzene in the presence of a base, a copper catalyst and a phase transfer catalyst, wherein the pirfenidone obtained is free of bromobenzene, iodobenzene and diiodobenzene.
The pirfenidone can be further purified by a process comprising:
(a) reacting pirfenidone with an acid to give a pirfenidone salt;
(b) treating the pirfenidone salt with a base to give pirfenidone.
In (a) of the above process, pirfenidone is reacted with an acid to give a pirfenidone salt.
A suitable acid includes but is not limited to ¬¬¬¬¬hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid, acetic acid. Preferably, the acid selected is hydrochloric acid.
The reaction may be carried out at a temperature in the range of about 25ºC to about 45ºC. The reaction is carried out for a period of about 1 hour to about 5 hours. Preferably the reaction is carried out at a temperature of about 40ºC to about 45ºC for a period of about 1 hour to about 2 hours.
In (b) of the above process, the pirfenidone salt is treated with a base to give pirfenidone.
A suitable base includes but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. Preferably, the base selected is sodium hydroxide.
The reaction may be carried out at a temperature in the range of about 25ºC to about 45ºC. The reaction is carried out for a period of about 1 hour to about 5 hours. Preferably the reaction is carried out at a temperature of about 40ºC to about 45ºC for a period of about 1 hour to about 2 hours.
In one embodiment, the present invention provides pirfenidone with purity of at least 99.99% w/w, as determined by HPLC.
In one embodiment, the present invention provides pirfenidone wherein the content of di(5-methyl-2-pyridone)benzene impurity is less than 0.05% w/w, as determined by HPLC.
In one embodiment, the present invention provides pirfenidone which is substantially free of 5-methylpyridin-2-amine (compound of formula IV) and 5-methyl-2-(lH)-pyridone (compound of formula II) and iodobenzene (compound of formula III) or halobenzene.
In one embodiment, the present invention provides pirfenidone free of any of the below listed impurities-

.
wherein R is selected from CH3, -COOH; X is selected from OH, Cl, Br or I; m may be 0 or 1, n may be 0 or 1 and in compound of formula VI and VIII, R = CH3 is not in the 5-position.
In one embodiment, the present invention provides pirfenidone free of any of the below listed impurities-

X XI XII
In one embodiment, the present invention provides a process for the preparation of pirfenidone with a purity of at least 99.99% w/w, the process comprising:
(a) reacting the compound of formula II with the compound of formula III, wherein, X is selected from the group consisting of Cl, Br, I, in the presence of a base, a copper catalyst, a phase transfer catalyst and optionally in the presence of a solvent;
(b) optionally, concentrating the reaction mixture;
(c) optionally, extracting the reaction mixture with haloalkanes;
(d) optionally, treating the reaction mixture with esters;
(e) optionally, subjecting the pirfenidone to acid-base treatment.
In (a) of the above process, the reaction conditions are as discussed supra.
In (b) of the above process, the reaction mixture is concentrated by complete evaporation of the solvent.
In (c) of the above process, the reaction mixture is extracted with haloalkanes from the group consisting of dichloromethane, chloroform, ethylene dichloride, and the like.
In (d) of the above process, the reaction mixture is treated with esters selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like.
In (e) of the above process, the pirfenidone is subjected to acid-base treatment as discussed supra.
In one embodiment, the present invention provides a process comprising recrystallizing pirfenidone from ethyl acetate.
In one embodiment, the present invention further provides a process for recrystallizing pirfenidone from ethyl acetate comprising
(a) forming reaction mixture of crude pirfenidone in ethyl acetate;
(b) heating the reaction mixture of step (a);
(c) cooling the reaction mixture of step (b) to obtain suspension;
(d) isolating pirfenidone from the suspension of step (c);
(e) forming solution of pirfenidone obtained in step (d) with hydrochloric acid;
(f) neutralizing the solution of step (e) with sodium hydroxide solution to obtain suspension; and
(g) filtering the suspension to obtain pure pirfenidone.

In one embodiment, the present invention provides a process for the preparation of pirfenidone comprising reacting the compound of formula II with iodobenzene in the presence of a base, a copper catalyst, wherein the iodobenzene comprises less than 0.15% of bromobenzene, preferably less than 0.05% of bromobenzene.
In one embodiment, the present invention provides a process for the preparation of pirfenidone comprising reacting the compound of formula II with iodobenzene in the presence of a base, a copper catalyst, wherein the iodobenzene is substantially free of bromobenzene.
In one embodiment, the present invention provides a process for the preparation of pirfenidone comprising reacting the compound of formula II with iodobenzene in the presence of a base, a copper catalyst, wherein the pirfenidone obtained is free of bromobenzene, iodobenzene and diiodobenzene.
In one embodiment, the present invention provides pharmaceutical compositions comprising pirfenidone or salt thereof obtained by the processes herein described, having a D50 and D90 particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns. The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state pirfenidone into any of the foregoing desired particle size range.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

EXAMPLE 1 Preparation of pirfenidone
A mixture of 5-methyl-2-(lH)-pyridone (10g), potassium carbonate (19g), Cu (2g), dibenzo-18-crown-6-ether (0.1g), iodobenzene (12.27mL) in dimethyl formamide (100mL) was stirred at about 120°C to about 125°C for about 12h. The reaction mixture was cooled to about 70°C to about 80°C and dimethyl formamide was evaporated. Dichloromethane was added to the obtained residue. The reaction mixture was stirred for about 20min at about room temperature and was filtered over hyflo bed. Water was added to the filtrate and the pH was adjusted to about 12 to about 14 using sodium hydroxide solution. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with brine solution, was treated with charcoal and was distilled completely. Ethyl acetate was added to the residue and the reaction mixture was heated to about 55°C to about 60°C. The reaction mixture was cooled to about 0°C to about 5°C and stirred for about 1h. The solid obtained was filtered and washed with cool ethyl acetate. Yield: 12g (70.58%)
Purity (by HPLC): 99.32%
Single Maximum Impurity: 0.26%
Bromobenzene: Not detected
Iodobenzene: Not detected
Diiodobenzene: Not detected

EXAMPLE 2 Preparation of pirfenidone
A mixture of 5-methyl-2-(lH)-pyridone (10g), potassium carbonate (19g), Cu (0.36g), dibenzo-18-crown-6-ether (0.1g), iodobenzene (11.31mL) in dimethyl formamide (50mL) was stirred at about 130°C to about 135°C for about 15h. The reaction mixture was cooled to about 80°C to about 85°C and dimethyl formamide was evaporated. Dichloromethane was added to the obtained residue. The reaction mixture was stirred for about 20min at about room temperature and was filtered over hyflo bed. Water was added to the filtrate and the pH was adjusted to about 12 to about 14 using sodium hydroxide solution. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with brine solution, was treated with charcoal and was distilled completely. Ethyl acetate was added to the residue and the reaction mixture was heated to about 55°C to about 60°C. The reaction mixture was cooled to about 0°C to about 5°C and stirred for about 1h. The solid obtained was filtered, washed with cool ethyl acetate and recrystallized from ethyl acetate to get a white solid. Yield: 10g
Purity (by HPLC): 99.97%
Total impurity: 0.03%
Single Maximum Impurity: 0.01%
Bromobenzene: Not detected
Iodobenzene: Not detected
Diiodobenzene: Not detected
Di(5-methyl-2-pyridone)benzene impurity: Not detected

EXAMPLE 3 Preparation of pirfenidone
A mixture of 5-methyl-2-(lH)-pyridone (10g), potassium carbonate (18.99g), Cu (4g), dibenzo-18-crown-6-ether (0.1g), iodobenzene (12.27mL) in dimethyl formamide (100mL) was stirred at about 120°C to about 125°C for about 12h . The reaction mixture was cooled to about 70°C to about 80°C and dimethyl formamide was evaporated completely under vacuum. Ethyl acetate was added to the obtained residue. The reaction mixture was stirred for about 20min at about room temperature and was filtered over hyflo bed. Water was added to the filtrate and the pH was adjusted to about 12 to about 14 using 30% sodium hydroxide solution followed by addition of activated charcoal. The reaction mixture was stirred, filtered over hyflo bed and the two layers were separated. The organic layer was washed with brine solution and was distilled completely. Ethyl acetate was added to the obtained residue and the reaction mixture was heated to about 55°C to about 60°C. Methyl tert-butyl ether was added to the reaction mixture at about 45°C to about 50°C. The reaction mixture was cooled to about 0°C to about 5°C and stirred for about 2h. The solid obtained was filtered, washed with methyl tert-butyl ether and isolated from a mixture of ethyl acetate and methyl tert-butyl ether to get a white solid.
Yield: 13g (76.47%)
Purity (by HPLC): 99.75%
Total impurity: 0.25%
Single Maximum Impurity: 0.07%
Bromobenzene: Not detected
Iodobenzene: Not detected
Diiodobenzene: Not detected

EXAMPLE 4 Purification of pirfenidone
To a mixture of pirfenidone (10g) and water (40mL) at about 20°C to about 30°C was added hydrochloride acid solution till the pH of the mixture is about 2 to about 3. The reaction mixture was heated to about 40°C to about 45°C. The reaction mixture was filtered and the pH of the filtrate was adjusted to about 11 to about 14 by using sodium hydroxide solution at about 40°C to about 45°C. The reaction mixture was cooled to about 0°C to about 5°C and was stirred for about 2h. The solid obtained was filtered, washed with chilled water and dried under vacuum at about 40°C to about 45°C. Yield: 9g
Purity (by HPLC): 99.98%
Single Maximum Impurity: 0.01%
Bromobenzene: Not detected
Iodobenzene: Not detected
Diiodobenzene: Not detected

EXAMPLE 5 Purification of pirfenidone
To a mixture of Pirfenidone (10g) and water (40mL) at about 20°C to about 30°C was added aqueous hydrochloride acid solution and the reaction mixture was heated to about 40°C to about 45°C. The reaction mixture was filtered and ethyl acetate was added to the filtrate. The reaction mixture was stirred for about 15min and the two layers were separated. The pH of the aqueous layer was adjusted to about 11 to about 14 by using sodium hydroxide solution at about 40°C to about 45°C. The reaction mixture was cooled to about 0°C to about 5°C and was stirred for about 2h. The solid obtained was filtered, washed with chilled water and dried under vacuum at about 40°C to about 45°C. Yield: 9g
Purity (by HPLC): 99.99%
Total impurity: 0.01%
Bromobenzene: Not detected
Iodobenzene: Not detected
Diiodobenzene: Not detected

EXAMPLE 6 Purification of Pirfenidone
Pirfenidone (10g) was dissolved in ethyl acetate (30mL) at about 60°C to about 65°C. Activated charcoal was added to the reaction mixture. The reaction mixture was gradually cooled to about to about 0°C to about 5°C, stirred for 2h, filtered and washed with ethyl acetate to get pirfenidone.
Yield: 9g
Purity (by HPLC): 99.98%
Single Maximum Impurity: 0.01%
Bromobenzene: Not detected
Iodobenzene: Not detected
Diiodobenzene: Not detected

EXAMPLE 7 Purification of pirfenidone
Pirfenidone (10g) was dissolved in ethyl acetate at about 60°C to about 65°C. Activated charcoal was added to the reaction mixture. The reaction mixture was gradually cooled to about to about 0°C to about 5°C, stirred for 2h, filtered and washed with ethyl acetate to get white solid which was further purified in hot water.
Yield: 8g
Purity (by HPLC): 99.99%
Total impurity: 0.01%
Bromobenzene: Not detected
Iodobenzene: Not detected
Diiodobenzene: Not detected
XRPD peaks of crystalline pirfenidne:

Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
8.86 9.97 26.81 30.38 2.94 4.69
14.38 6.15 45.75 30.78 2.90 1.74
15.05 5.88 26.67 31.65 2.82 14.88
16.66 5.32 0.41 32.50 2.75 9.09
18.51 4.79 100.00 33.00 2.71 1.05
18.86 4.70 52.63 33.89 2.64 0.77
19.97 4.44 3.46 35.64 2.51 1.41
21.12 4.20 14.47 37.16 2.41 3.91
22.12 4.01 10.16 37.80 2.38 1.64
22.74 3.90 34.28 38.49 2.33 0.85
23.00 3.86 31.93 39.55 2.27 2.89
24.45 3.64 56.47 40.37 2.23 0.41
27.13 3.28 37.19 41.74 2.16 0.42
27.36 3.25 40.87 43.49 2.08 1.70
28.30 3.15 4.41 45.41 1.99 8.87
29.03 3.07 3.94 46.51 1.95 3.53
29.77 3.00 5.28 47.80 1.90 2.73

EXAMPLE 8 Preparation of pirfenidone
A mixture of 5-methyl-2-(lH)-pyridone (20g), potassium carbonate (38g) and Cu (0.36g), iodobenzene (30.67mL) in dimethyl formamide (100mL) was stirred at about 145°C to about 150°C for about 20h. The reaction mixture was cooled to about 80°C to about 85°C and dimethyl formamide was evaporated completely under vacuum. Dichloromethane was added to the obtained residue. The reaction mixture was stirred for about 20min at about room temperature and was filtered over hyflo bed. Water was added to the filtrate and the pH was adjusted to about 12 to about 14 using 30% sodium hydroxide solution. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with 10% brine solution, was treated with charcoal and was distilled completely. Ethyl acetate was added to the obtained residue and the reaction mixture was heated to about 55°C to about 60°C. The reaction mixture was gradually cooled to about 0°C to about 5°C and stirred for about 1h. The solid obtained was filtered, washed with cool ethyl acetate and dried.
Yield: 17g (50%)
Purity (by HPLC): 97.53%
Total impurity: 2.47%
Single Maximum Impurity: 0.97%

EXAMPLE 9 Preparation of pirfenidone
A mixture of 5-methyl-2-(lH)-pyridone (21.8g), anhydrous potassium carbonate (30.4g), zinc precipitated copper powder (0.25g) and iodobenzene (40mL) was stirred and refluxed for 18h at about 180°C to about 185°C. The reaction mixture was cooled and benzene (150mL) was added to it. The reaction mixture was filtered and the filtrate was decolorized with charcoal. The filtrate was then evaporated to give an oil which on precipitation with petroleum ether and cooling gave 16g (42%) of the product as a brown solid.
Purity (by HPLC): 89.36%
Total impurity: 10.55%
Single Maximum Impurity: 1.74%

EXAMPLE 10 Preparation of pirfenidone
A mixture of 5-methyl-2-(lH)-pyridone (10g), potassium carbonate (19g) and Cu powder (4g), iodobenzene (20.58g) in dimethyl formamide was stirred at about 115°C to about 125°C for about 15hours. The reaction mixture was cooled to about 80°C to about 90°C and dimethyl formamide was distilled out completely under vacuum. The reaction mixture was cooled to about 25°C to about 30°C and dichloromethane was added to the reaction mixture. Further activated charcoal was added to reaction mixture and stirred and was filtered over hyflo bed. Aqueous sodium hydroxide solution was added to the filtrate and the two layers were separated. The organic layer was washed with 10% brine solution, treated with activated charcoal and was distilled completely. Ethyl acetate was added to the obtained residue and the reaction mass was heated to about 65°C to about 75°C. The reaction mixture was gradually cooled to about 0°C to about 5°C and stirred for about 1 hour. The solid obtained was filtered, and washed with cool ethyl acetate. To the above wet material aqueous hydrochloric acid was added and reaction mass was heated to about 40°C to about 45°C and filtered. The pH of filtrate was adjusted to about 9 to about 11 using 25% sodium hydroxide solution. The reaction mass was filtered and washed with water to obtain solid residue.
,CLAIMS:WE CLAIM

1. A process for the preparation of pirfenidone, a compound of formula I,

the process comprising reacting a compound of formula II,

with a compound of formula III,

wherein, X is selected from the group consisting of Cl, Br, I, in the presence of a base, a copper catalyst and a phase transfer catalyst.

2. The process as defined in claim 1, wherein the base is selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, tertiary amines.

3. The process as defined in claim 1, wherein the copper catalyst is selected from the group consisting of copper powder, cuprous oxide, cupric oxide, cuprous iodide, cupric iodide, cuprous bromide, cupric bromide, cuprous chloride, cupric chloride, cupric acetate, copper sulphate.
4. The process as defined in claim 1, wherein the phase transfer catalyst is selected from the group consisting of crown ethers, pillararenes, calixarenes, thiacalixarenes, cycloparaphenylenes, cyclophanes, cyclodextrins, quaternary ammonium salts, phosphonium salts, pyridinium salts.

5. The process as defined in claim 1, further comprising purifying the compound of formula I by a process comprising:
(a) reacting pirfenidone with an acid to give a pirfenidone salt;
(b) treating the pirfenidone salt with a base to give pirfenidone.

6. The process as defined in claim 5, wherein the acid is selected from the group consisting of ¬¬¬¬¬hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid, acetic acid.

7. The process as defined in claim 5, wherein the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.

Dated this 6th day of December, 2016

(Signed)____________________
DR. MADHAVI KARNIK
GENERAL MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED