DESC:TITLE: NOVEL PROCESS FOR PREPARATION OF CRYSTALLINE FORM OF PIRFENIDONE

FIELD OF THE INVENTION
The present invention relates to Novel process for preparation of crystalline form of Pirfenidone compound of formula I, which is industrially advantageous and economically significant.

BACKGROUND OF THE INVENTION
Pirfenidone is an anti-fibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). It works by reducing lung fibrosis through down regulation of the production of growth factors and procollagens I and II. Pirfenidone was approved by USFDA for the treatment of idiopathic pulmonary fibrosis on October 15, 2014 and marketed under trade name ESBRIETR®. Pirfenidone was first approved in Japan for the treatment of IPF after clinical trials, under the trade name of PIRESPA® by Shionogi & Co. In 2011, Pirfenidone was approved in Europe for use in the treatment of idiopathic pulmonary fibrosis under the trade name ESBRIET®. Pirfenidone was approved in Canada in 2012 under the trade name ESBRIET®. Pirfenidone is chemically known as 5-methyl-1-phenyl-2-l(H)-pyridone and represented by the following structural formula (I)

There exist many prior art methods in the Literature disclosing the process for preparation of Pirfenidone.

The process for the preparation of pirfenidone was first disclosed in US 3839346 (hereafter US ‘346). The disclosed process involves reaction of 5-methyl-2-(1H)-pyridone with iodobenzene in presence of anhydrous potassium carbonate and zinc precipitated copper powder and benzene. The obtained Pirfenidone was further crystallized from hot water to get pirfenidone. The reaction scheme as disclosed in US ‘346 is given below.

The process for the preparation of Pirfenidone disclosed in US 3839346 makes the use of toxic iodobenzene and hence may not be safe and economical. Further, the reaction between 5-methyl-2(1H) pyridone and iodobenzene is carried out at higher temperature. The reaction of iodobenzene at evaluated temperature may not be safe and economical.

Indian patent publication IN 1414/MUM/2015 (Hereafter IN ‘1414) discloses the process for preparation of Pirfenidone comprising reacting 2-hydroxy-5-methyl pyridine with bromobenzene in presence of a Copper (I) iodide, a base and a solvent followed by isolation to obtain Pirfenidone. The reaction scheme disclosed in IN ‘1414 is given below.

United state patent publication US 20180/009753A1 (hereafter US ‘753) discloses the process for preparation of Pirfenidone comprising reacting 5-Methyl-2-pyridone with bromobenzene in presence of a copper iodide, a base and a polar protic solvent to obtain Pirfenidone. The reaction scheme as disclosed in US ‘753 is given below.

PCT publication W0 2002/085858 discloses the purification process for pirfenidone, which involves dissolution of pirfenidone in 5% aqueous acetic acid at 90°C and adding 25% aqueous sodium hydroxide followed by isolating pure pirfenidone.

PCT publication WO 2008/147170 (hereafter WO ‘170) discloses the process for preparation of Pirfenidone which comprising reacting 2-amino-5-methylpyridine by a diazo reaction in acid medium to give 5-methyl-2-pyridone. The obtained 5-methyl-2-pyridone is reduced in presence of copper with iodobenzene to obtain Crude Pirfenidone, which is further purified by acetone and activated carbon to obtain pure Pirfenidone. The reaction scheme as disclosed in WO ‘170 is given below.

Chinese patent publication CN 105315198A discloses the process for preparation of crystal form of Pirfenidone comprising dissolving pirfenidone in an ester solvent, cooling and crystallization under stirring followed by filtering to separate the solid and the separated solid was dried to obtain crystalline form I of Pirfenidone.

Chinese patent publication CN 105906558A (hereafter CN ‘558) discloses the process for preparation of crystal of form Pirfenidone comprising dissolving the Pirfenidone in a solvent, heating the reaction mixture and isolating crystal of Pirfenidone followed by drying. The reaction scheme disclosed in CN ‘558 is given below.

PCT publication WO 2018/083709 discloses the process for preparation of pure Pirfenidone comprising dissolving the crude Pirfenidone in a suitable organic solvent at a suitable temperature, optionally treating the reaction mixture with charcoal, filtering the reaction mixture, combining with suitable anti-solvent and isolating pure Pirfenidone.

PCT publication WO 2017/122139 (hereafter WO ‘139) discloses the process for the purification of Pirfenidone comprising treating pirfenidone with alkaline base followed by isolation to obtain pure pirfenidone.

Further the above PCT publication WO ‘139 discloses the process for preparing pirfenidone having a particle size with D90 from 50 microns to 500 microns, comprising dissolving pirfenidone in an organic solvent, and further addition of an anti-solvent to the above reaction mass followed by isolation to obtain Pirfenidone.

Indian patent publication IN 20174109848 discloses the preparation of Pirfenidone having particle size (d0.9) < 200 µm by providing a solution of Pirfenidone having particle size ? 250 µm in organic solvent followed by addition of water and isolation to obtain Pirfenidone having particle size (d0.9) < 200 µm.

All the prior arts discussed above suffer from many disadvantages like tedious and cumbersome workup procedures such as multiple crystallizations or isolation steps, and thus resulting in low overall yields of the product. Pirfenidone obtained by the processes described in the prior art does not have satisfactory purity and unacceptable amounts of impurities are formed along with Pirfenidone at various stages of the processes that are difficult to purify and affecting the purity of final compound.

Therefore, there is a need of Novel process for process for preparation of crystalline form of Pirfenidone with high purity and with a particle size D90 < 500 µm which overcomes the drawbacks of prior publications. The present inventors have found an efficient process for the preparation crystalline form of Pirfenidone or which offers advantages over the prior art processes in terms of High purity, less effluents and simple scalable procedure suitable for large scale production.

OBJECT OF THE INVENTION

The primary object of the present invention is to provide a simple, economic safe industrially viable process for preparation of substantially Pirfenidone compound of formula I.

Another object of the present invention is to provide a novel process for preparation of crystalline form of Pirfenidone of compound of formula I with high purity.

One more object of the present invention is to provide a process for preparation of Pirfenidone having particle size < 500 µm.

SUMMARY OF THE INVENTION
One embodiment of the present invention provides a process for the preparation of Pirfenidone of compound of formula I

the process comprising reacting 2-amino-5-methylpyridine compound of formula III

with bromobenzene of compound of formula IV

in presence of suitable copper catalyst and a base under sufficient conditions to provide Pirfenidone, wherein the reaction is carried without any additional solvent.

Another embodiment of the present invention provides a process for purification of Pirfenidone comprising the steps of:
a) Treating Pirfenidone with a quaternary ammonium salt in a suitable solvent; and
b) isolating Pirfenidone.

Another embodiment of the present invention provides a process for the preparation of crystalline form of Pirfenidone having particle size D90 < 500 µm comprising:
c) Treating Pirfenidone with a quaternary ammonium salt in a suitable solvent; and
d) isolating Pirfenidone having particle size D90 < 500 µm

Another embodiment of the present invention provides crystalline form of Pirfenidone characterized by an X-ray diffraction (XRPD) pattern substantially in accordance with Figure 01.

BRIEF DESCRIPTION OF DRAWING
The accompanying drawing, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 01: X-ray powder diffraction spectrum (XRPD) of crystalline form of Pirfenidone.

DEFINITION
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25ºC and normal pressure unless otherwise designated.

All temperatures used herein are in degrees Celsius unless specified otherwise.

All ranges recited herein include the endpoints, including those that recite a range "between" two values.

As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.

The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.

DETAILED DESCRIPTION

In an attempt to develop a Novel process for preparation of crystalline form of Pirfenidone in pure form with lower particle size and to overcome the disadvantages of prior art, the present inventors have developed a process which results in high purity and good yield of Pirfenidone.

The novel process of preparation of crystalline form of Pirfenidone as per the present invention is summarized in the following schematic representation.

As per the present invention, the use of a quaternary ammonium salt during the purification of Pirfenidone helps in achieving the clear solution rather than a hazy solution at lower temperatures as compared to the prior art processes.

One embodiment of the present invention provides a process for the preparation of Pirfenidone of compound of formula I

the process comprising reacting 2-amino-5-methylpyridine compound of formula III

with bromobenzene of compound of formula IV

in presence of a suitable copper catalyst and a base under sufficient conditions to provide Pirfenidone, wherein the reaction is carried without adding any additional solvent.

The starting material of formula III of the present invention is commercially available or can be prepared by the prior art process such as the process as described in, but not limited to, US 5981576.

The starting material bromobenzene of formula (IV) is commercially available or can be prepared by the prior art processes.

The suitable copper catalyst used herein for the reaction of formula (III) with formula
(IV) is selected from, but not limited to, copper (I) chloride, copper (I) bromide, copper (I) iodide, copper powder and the like; preferably selected from copper (I) Iodide.

The suitable base used herein for the reaction of formula (III) with formula (IV) is selected from alkali metal carbonates such as but not limited to potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and the like; alkali metal hydroxide such as but not limited to potassium hydroxide, sodium hydroxide, lithium hydroxide and the like, or mixtures thereof; organic base such as but not limited to triethylamine, diisopropylethylamine and the like. Preferably the suitable base is potassium carbonate.

The reaction of formula (III) with formula (IV) can be suitably carried out at a temperature of about 20°C to about 150°C, preferably at about 100°C to about 150°C for sufficient period of time to complete the reaction, preferably for 1 to 24 hrs, more preferably for 8-12 hrs.

The product formed in the reaction mixture can be isolated by the techniques known in the art.

The product isolated has the particle size of D90 > 1000 µm.

Another embodiment of the present invention provides a novel process for purification of crystalline form of Pirfenidone comprising the steps of:
a) Treating Pirfenidone with a suitable quaternary ammonium salt in a suitable solvent; and
b) isolating Pirfenidone.

The suitable quaternary ammonium salt used in the step a) may be selected from, but not limited to, such as tetra-n-butyl ammonium bromide (TBAB), tetra-n-butyl ammonium fluoride (TBAF), tetra-n-butyl ammonium chloride (TBAC), tetra-n-butyl ammonium iodide (TBAI), tetra-n-butyl ammonium hydrogen bromide (TBAHB) and), tetra-n-butyl ammonium nitrite. Preferably, the quaternary ammonium salt selected is tetra-n-butyl ammonium bromide (TBAB)

The suitable solvent used in the step a) may be selected from but not limited to water, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, methanol, ethanol, butanol, tert-butanol, propanol, isopropanol, acetone, chloroform or mixture of solvents. Preferably, the suitable solvent is water.

In the process of step a), treatment of Pirfenidone with quaternary ammonium salt can be suitably carried out at a temperature of about 10°C to about 90°C, preferably at about 65°C to about 75°C for sufficient period of time to complete the reaction, preferably for 0.5 to 2.5 hrs, more preferably for 2 to 2.5 hrs.

The product formed can be isolated by the techniques known in the art such as cooling the reaction mass followed by filtration etc.

The wet product obtained above may be dried under vacuum at any temperature between 50° to 80°C.

The dried material of Pirfenidone can optionally be milled and/or sieved and/or micronized.

In some embodiments, the Pirfenidone obtained according to the present invention is having the particle size of D90 < 500 µm.

In some embodiments the Pirfenidone obtained according to present invention is of Crystalline in nature.

EXAMPLES
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

Example 01:
Preparation of 5-methylpyridin-2(1H)-one [Formula III]
Charged 1200 ml process water, stirred and cooled it at 0°C to 30°C and slowly charged 545 gm conc. sulphuric acid; chilled the reaction mixture at -5°C to + 5°C and charged the 300 gm 2-Amino-5-methylpyridine at -5°C to + 5°C and stirred the reaction mass. Added the 230 gm sodium nitrite solution to the reaction mixture at same temperature and stirred it for 60 minutes, raised the temperature up to 25-35°C and maintained for 2 hrs cooled the reaction mass it at 10-20°C. Added NaOH solution (335 gm NaOH in 600 ml water) to the reaction mass and adjusted pH (6.0 to 8.0) and stirred at 10-20°C. Heated the reaction mixture to 15-20°C and charged 1200 ml Dichloromethane; slowly stirred the reaction mass slowly at 28-38°C. product is isolated by the addition of ethyl acetate to the residual mass followed by stirring, cooling and filtration to obtain 250 gm of 5-methylpyridine-2(1H)-one.
Yield: 82.5%
HPLC purity: 99.59%

Example 2:
Preparation of Pirfenidone.
Taken 200 gm of 5-methylpyridine-2(1H)-one in round bottom flask. Added 720 gm bromobenzene followed by addition of 303 gm potassium carbonate and 20 gm copper(I) iodide at temperature 135°C to 145°C for 10-12 hrs. After completion of the reaction, 1400 ml toluene was added and filtered the mass. The mother liquor is washed with sodium hydroxide, EDTA disodium hydrate and brine solutions. Activated carbon is added to the organic layer and filtered the product through Hyflo powder followed by distillation of organic layer under vacuum. Product was isolated from the mixture of cyclohexane, toluene and isopropyl alcohol to obtain 226 gm Pirfenidone.
Yield: 66%
HPLC purity: 99.6%

Example 3:
Preparation of Pure Pirfenidone [Formula I]
700 ml purified water was taken in round bottom flask followed by charging of 175 gm pirfenidone and 8.8 gm Tetrabutylammonium bromide (TBAB). Heated the reaction mass to 65-75°C, maintained the reaction mass for 30 minutes. Gradually cooled the reaction mass up to 10-20°C. Maintained the reaction mass at 10-20°C for 30 minutes and filtered the product under vacuum. Dried the product under vacuum at 55-65°C to obtain 155 gms crystalline pure Pirfenidone.
HPLC Purity: ? 99.90%
Yield: 88.5%

Example 4:
Preparation of Pure Pirfenidone [Formula I]
100 ml purified water is taken in round bottom flask followed by charging of 20 gm pirfenidone and 1.0 gm Tetrabutylammonium nitrite (TBAN). Heated the reaction mass up to 65-75°C, maintained the reaction mass for 30 minutes then gradually cooled the reaction up to 10-20°C. Again maintained at 10-20°C for 30 minutes and filtered the product under vacuum. Dried the product under vacuum at 55-65°C to obtain 17.5 gm crystalline pure Pirfenidone.
HPLC Purity: ? 99.77%
Yield: 87.5%

Example 5:
Preparation of Pure Pirfenidone [Formula I]
100 ml purified water is taken in round bottom flask followed by charging of 20 gm pirfenidone and 1.0 gm Tetrabutylammonium hydrogenbromide (TBAHB). Heated the reaction mass up to 65-75°C, maintained the reaction mass for 30 minutes then gradually cooled the reaction up to 10-20°C. Again maintained at 10-20°C for 30 minutes and filtered the product under vacuum. Dried the product under vacuum at 55-65°C to get 17.0 gm crystalline pure Pirfenidone.
HPLC Purity: ? 99.69%
Yield: 85.0%

Example 6:
Preparation of Pure Pirfenidone [Formula I]
75 ml purified water is taken in round bottom flask followed by charging of 15 gm pirfenidone and 0.75 gm Tetrabutylammonium iodide (TBAI). Heated the reaction mass up to 65-75°C, maintained the reaction mass for 30 minutes then gradually cool the reaction up to 10-20°C. Again maintained at 10-20°C for 30 minutes and filtered the product under vacuum. Dried the product under vacuum at 55-65°C to get 13.2 gm crystalline pure Pirfenidone.
HPLC Purity: ? 99.71%
Yield: 88.0%

Dated this 28th day of January, 2021

T. Srinivasa Reddy,
(IN/PA/2444)
Senior Manager, IPM
ZCL Chemicals Ltd. ,CLAIMS:We Claim:

1. A process for the purification of Pirfenidone compound of formula I:

comprising the steps of:
a) Treating Pirfenidone with a quaternary ammonium salt in a suitable solvent; and
b) isolating Pirfenidone.

2. The process according to claim 1, wherein the quaternary ammonium salt is selected from tetra-n-butyl ammonium bromide (TBAB), tetra-n-butyl ammonium fluoride (TBAF), tetra-n-butyl ammonium chloride (TBAC), tetra-n-butyl ammonium iodide (TBAI), tetra-n-butyl ammonium hydrogen bromide (TBAHB) and tetra-n-butyl ammonium nitrite.

3. The process according to claim 1, wherein the solvent in step a) is selected from water, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, methanol, ethanol, butanol, tert-butanol, propanol, isopropanol, acetone, chloroform or mixtures thereof.

4. The process according to claim 1, wherein step a) comprises treating Pirfenidone with quaternary ammonium salt at a temperature ranging from 10°C to 90°C.

5. The process according to claim 1, wherein isolation of Pirfenidone in the step b) comprises isolation by filtration.

6. The process according to claim 5, wherein the process comprises cooling the reaction mixture before filtration.

7. A process for the preparation of Pirfenidone comprising:

a) reacting 2-amino-5-methylpyridine compound of formula III

b) with bromobenzene of compound of formula IV

in presence of a suitable copper catalyst and a base under sufficient conditions to provide Pirfenidone, wherein the reaction is carried without adding any additional solvent.

8. The process according to claim 7, wherein the copper catalyst is selected from copper (I) chloride, copper (I) bromide, copper (I) iodide and copper powder.

9. The process according to claim 7, wherein the base is selected from alkali metal carbonates, alkali metal hydroxide and an organic base or mixtures thereof.

10. The process according to claim 1 or claim 7, wherein Pirfenidone is in crystalline form.

Dated this 28th day of January, 2021

T. Srinivasa Reddy,
(IN/PA/2444)
Senior Manager, IPM
ZCL Chemicals Ltd.