Related applications

This patent application claims the benefit of priority of our Indian patent appl ication number IN 201641037930 filed on 07 ^th November 2016 which is incorporated herein by reference.

Field of the invention

The present invention pertains to improved process for the preparation of pure 5- methyl- l -phenyl-2- l (H)-pyridone. The chemical structure of said compound is represented by the following formula (I)

Formula (I)

The chemical name 5-melhyl- l -phenyl-2- l (H)-pyridone of formula (I) is generic-al ly known as Pirfenidone. Pirfenidone is belongs to the chemical class of pyridonc for the trealment of idiopathic pulmonary fibrosis (IPF). Pirfenidone was approved under the brand name of Esbi iet© by USFDA in 2014 to Genentech USA. Esbriet® was available with dosage strength of 267 mg for oral administration.

Background of the invention

US 3839346 (published on October 01 , 1974) first disclosed 5-methyl- 1 -phenyl-2- l (H)-pyridone as a product and its method of preparation comprising: admixing 5-methyl-2- ( 1 H)-pyridone, anhydrous potassium carbonate, zinc precipitated copper ipowdcr and iodo benzene and slirred for 1 8 hours at reflux temperature. The mixture is cooled and treated with 1 50 ml of benzene. The reaction mixture is cooled and filtered. The filtrate is decolorized with charcoal and evaporated to oil which on further, triturated with petroleum ether and

I crystallized from hot water to provide 5-melhyl- 1 -phenyl-2- l(H)-pyridone.

The above reported process involves the use of petroleum ether and iodo benzene which are highly inflammable and expensive respectively. Hence, the above reported process is not suitable for industrial scale preparations.

US 8519040 (Published on August 27, 2013) described different type of methods for the purification of 5-methyl- 1 -phenyl-2- l(H)-pyridone, one method is such as via precipitation from the solvent mixture of toluene and heptane. Another method is further crystallization by dissolving in acidic solution and then basifying followed by cooling to get crystalline 5-methyl- 1 -phenyl-2- 1 (H)-pyndone.

. The major disadvantage of above methods involves the loss of yield during precipitation or crystallization and also requires large amounts of solvents for said methods which in turn decreases the yield of the final product and increases the cost of the product.

None of the above prior art references describes the purification method by avoiding crystallization from acidic and basic solutions or precipitation from toluene and heptane.

In pharmaceutical industry there is always a need to develop an improved process for the preparation of pure 5-methyl- 1 -phenyl-2- 1 (H)-pyridone which is economic, cco-friendly and suitable for industrial scale up.

The present inventors developed improved process for the preparation of pure 5- methyl-1 -phenyl-2- 1 (H) ^_ pyidone by greater yield with high purity.

Brief description of the invention

The mam aspect of the present invention is to provide a process for the preparation of pure 5-melhyl-l -phenyl-2- l(H)-pyridone of formula (I).

Advantages of the present invention:

Preparation of pure 5-methyl- 1 -phenyl-2- l(H)-pyridone having atleast 99.7% purity, by HPLC (using solvent and anti-solvent method) which is economic, eco-friendly and suitable for industrial scale methods.

Brief description of the drawings

Figure- 1: Illustrates the characteristic Powdered X-Ray Diffraction (PXRD) pattern of pure 5-methyl- l-phenyl-2-l(tf)-pyridone of formula (I) obtained according to example-2.

Figurc-2: Illustrates the characteristic Powdered X-Ray Diffraction (PXRD) pattern of pure 5-methyl- 1 -phenyl-2- 1 (H)-pyridone of formula (I) obtained according to example-4.

Detailed description of the invention

Unless otherwise specified, as used herein the term "suitable solvent" refers to the solvent selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol. n-butanol and isobutanol, "chloro solvents" such as to methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone, "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, benzene, n-pentane, cycloheptane, niethylcyclohexane, m-, o-, or p-xylenc and the like; "nitrite solvents" such as acetonitrile, propionitrile; "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate and tert-butyl acetate; "ether solvents" such as tetrahydrofuran, diethyl ether and methyl tert-butyl ether; "polar solvents" such as water, "polar aprotic solvents" such as dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide etc.

As used herein the term "suitable base" refers to the bases selected from alkali metal hydroxides like lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate and alkali metal bicarbonatcs like sodium bicarbonate, potassium bicarbonate, alkali metal alkoxides like sodium tertiary butoxide, potassium tertiary butoxide; organic bases like methylaminc. ethylamine. isopropy!amine, diisopropyl ethylamine, triethylamine / and ammonia or their aqueous solution.

As used herein the term "suitable acid" refers to the acid selected from inorganic acids like hydrochloric acid (HO), hydrobromic acid (HBr), hydroiodic acid (HI), sulphuric acid (H2SO4); organic acids like acetic acid (AcOH), methanesu!phonic acid (MsOH). para- toluenesulphonic acid (/>-TsOH), tri fluoric acetic acid (TFA).

The main aspect of the present invention provides an improved process for the preparation of pure 5-methyl- 1 -phenyl-2- 1 (H)-pyridone of formula (I), comprising:

a) Dissolving 5-methyl-l-phenyl-2-l(H)-pyridone in a suitable organic solvent, b) optionally, treating the reaction mixture with charcoal,

c) filtering the reaction mixture,

d) adding suitable anti-solvent to the reaction mixture obtained in step-a) or step-c), e) isolating pure 5-methyl- 1 -phenyl-2- l(H)-pyridone.

wherein, step-a) of the above process is carried out at temperature about 25°C to about 80°C; the suitable organic solvent is selected from 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 or mixture with water. In step-b), optionally, treating the obtained reaction mixture with charcoal betwecn 25°C to 75°C. Charcoal treatment is for making particle free solution and as well as decolouri/.ation of the reaction mixture.

In step-d), the suitable anti-solvent is adding/combining to the. reaction mixture obtained in step-a) or step-c). The suitable anti-solvent is selected from hydrocarbon solvents such as n- hexane, n-heptane _; benzene, n-pentane, cycloheptane, methy!cyc!ohexane. m-. o-. or p- xylene. The said step d) process is carried out at a temperature ranging from 20°C to rellux temperature of the solvent used in step a).

In step-e), the isolation is carried out by filtration and drying to provide pure 5-methyl- 1- phenyl-2-l(/Y)-pyridone.

The preferred embodiment of the present invention provides a process for the preparation of pure 5-methyl- l-phenyl-2-l(H)-pyridone of formula (I), comprising of:

a) Dissolving 5-methyl- 1 -phenyl-2- 1 (H)-pyridone in ethyl acetate,

b) treating the reaction mixture with charcoal,

c) filtering the reaction mixture obtained in step-b),

d) combining n-heptane with the filtrate obtained in step-c),

e) isolating pure 5-methyl- 1 -phenyl-2- 1 (H)-pyridone.

wherein, the 5-methyl- 1 -phenyl-2- l(H)-pyridone obtained by the present invention having a purity of at least 99.97% by HPLC.

The another embodiment of the present invention provides a process for the preparation of 5-methyl- 1 -phenyl-2- 1 (H)-pyridone, comprising:

a) heating a mixture of dimethylformamide, 2-hydroxy-5-methyl pyridine. potassium carbonate, copper powder and bromobenzene,

b) stirring the reaction mixture.

c) cooling the reaction mixture,

d) adding water and toluene to the reaction mixture,

e) separating the aqueous and organic layers,

f) adding charcoal to the organic layer,

g) filtering the reaction mixture,

h) distilling off the solvent from the filtrate obtained in step-g),

i) optionally co-distilled with water,

j) adding water to the compound obtained in step h) or step i),

k) heating the reaction mixture,

I) cooling the reaction mixture.

m) filtering the solid to provide 5-methyl- 1 -phenyl-2- l(H)-pyridone.

The preferred embodiment of the present invention provides a process for the preparation of 5-methyl- 1 -phenyl-2- 1 (H)-pyridone, comprising:

a) Heating a mixture of dimelhylformamide, 2-hydroxy-5-melhyl pyridine, potassium carbonate, copper powder and bromobenzene to I35-140°C b) stirring the reaction mixture for 15-25 hrs at same temperature,

c) cooling the reaction mixture to 25-30°C,

d) adding water and toluene to the reaction mixture and stirring for 15 min.

e) separating the both aqueous and organic layers,

0 adding charcoal to the organic layer and stirring for 20 min,

g) filtering the reaction mixture and washing with toluene,

h) distilling off the solvent from the filtrate obtained in step-g),

i) co-distilling the reaction mixture with water,

j) adding water to the obtained compound,

k) heating the reaction mixture temperature to 80-85°C and stirring for 20 min, I) cooling the reaction mixture to 0-5°C and stirring for 45 min,

m) filtering the solid, washing the material with water and then dried to provide 5- methyl- 1 -phenyl-2- 1 (H)-pyridone. wherein, the crude 5-methyl-l-pheny!-2-l(H)-pyridone obtained according to the above invention having purity around 98% by HPLC and not morethan 2% of total of 5- methylpyridin-2-ol, 2-amino-5-methyl pyridine, phenol and 5-methyl-2-phenoxypyridine impurities.

The another embodiment of the present invention provides 5-methyl- 1 -phenyl-2- 1 (/J)- pyridone of formula (I) having not morethan 0.15% of total of 5-melhylpyridin-2-ol.2-amino- 5-methyl pyridine, phenol impurities.

In yet the another embodiment of the present invention provides 5-methyl- 1 -phenyl- 2- 1 (H)-pyridone compound of formula (I) free of 5-methylpyridin-2-ol and 2-amino-5-methyl pyridine impurities.

It is noted in the art that the particle size of a drug may also affect the release, dissolution, absorption and therapeutic action of pharmaceutical product.

Based on the available literature and knowledge of skilled person in the art, it is evident that apart from various factors, process parameters like temperature and mode of addition of a solvent/anti solvent during crystallization play a major role in the particle size and shape of the product. Likewise the 5-methyl- 1 -phenyl-2- 1 (H)-pyridonc compound of formula (1) also showing different particle size by varying process parameters like temperature and mode of addition of a solvent/anii solvent during crystallization of 5-methyl- 1 -phenyl-2- 1 (H)-pyridone compound of formula (I).

5-Methyl-l -phenyl-2- 1 (H)-pyridone compound of formula (I) obtained by the present invention can be micronized by using conventional techniques or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, pin mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product.

5-Methyl-l -phenyl-2- 1 (H)-pyridone compound of formula (1) obtained by the present invention having the particle size D(90) about 510 to 800 microns which can further micronized or milled to get the desired finer material. 5-Methyl-l -phenyl-2- 1 (H)-pyridonc compound of formula (1) obtained by the present invention is also showing particle size D90 about 100 to 800 microns and it can be micronized by using conventional techniques or milled to get the desired particle size and well below 100 microns.

The other aspect of the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of pure 5-methyl- 1 -phenyl-2- 1 (H)-pyridone and one or more pharmaceutically acceptable carriers, excipients or diluents.

Pharmaceutical compositions containing pure 5-methyl- 1 -phenyl-2- 1 (H)-pyridone of the present invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agenls. and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

The oral pharmaceutical composition may contain one or more additional excipients such as diluents, binders, disintegrants and lubricants. Exemplary diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, microcrystalline cellulose, magnesium stearate and mixtures thereof. Exemplary binders are selected from L-hydroxy propyl cellulose, povidone, hydroxypropyl methyl cellulose, hydroxylethyl cellulose and pre- gelatinized starch.

Exemplary disintegrants are selected from croscarmellose sodium, cros-povidone, sodium starch glycolateand low substituted hydroxylpropyl cellulose.

Exemplary lubricants are selected from sodium stearyl fumarate, magnesium stearate. zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silicon dioxide. A specific lubricant is selected from magnesium stearate, zinc stearate, calcium stearate and colloidal silicon dioxide.

PXRD analysis of the present invention was carried out using BRUKER-AXS D8 Advance model X-Ray diffractometer using Cu-Ka radiation of wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.

Particle size distribution (PSD) method of analysis of the present invention was performed using Malvern Mastersizer 3000 instrument. I I PLC Method of Analysis:

Apparatus. A liquid chromatographic system is to be equipped with variable wavelength U V- detector; Column: Kromasil C I 8, 250*4.6mm, 5 μιη (or) equivalent; Flow Rate: 1 .0 mL/min; Wavelength: 220 nm; Column temperature: 25°C; Injection volume: 5μί; Auto sampler temperature: 5°C; Buffer: add 3.0 gms of I -octane sulphonic acid sodium salt anhydrous, sonicate in 2.0 ml of orthophosphoric acid (85%) into l OOOmL of Miili-Q- Water and mix well. Filtered this solution through 0.22μΓη nylon membrane and degas it. Mobi le phase-A : Buffer: ( 100%) v/v; Mobile phase-B: Acetonitrile: Buffer (70:30 v/v) ^' ; Diluent : Acetonitri le: water (70:30) v/v; Needle wash: Diluent; Elution: Gradient.

The process described in the present invention was demonstrated in 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:

Exnmplc-1 : Preparation of crude 5-mcthyM -phcnyl-2(l H)-pyridonc (crude Pirfcnidonc)

2-Hydroxy-5-methyl pyridine ( 100 gms) and dimethyl formamide (200 ml) were added into a clean and dry round bottom flask at 25-30°C. To the resulted reaction mixture, potassium carbonate ( 1 52 gm), copper powder (2.91 gms) and bromo benzene (259 gms/ 1 73.8 ml) were added at 25-30°C and heated to 1 25- 1 30°C and stirred for 1 8-20 hrs at same temperature. Cooled the reaction mixture to 25-30°C, filtered and washed with toluene (500 ml). The filtrate was washed with 1 5% aqueous NaCI solution followed by filtered on hyflow bed. Separated the organic and aqueous layers. Add toluene (500 ml) to the resulted aqueous layer and stirred for 5- 10 min and separate the aqueous and organic layer. Combined both the organic layers and washed with 1 5% aqueous NaCI solution Charcoal (5 gms) was added lo the organic layer at 25-30°C and stirred for 1 5-20 min. at same temperature. Fillered the reaction mixture on hyflow bed and washed with toluene. Distilled off the solvent completely from the filtrate under reduced pressure and co-distil led with water ( 100 ml). Water (400 ml) was added to the obtained solid compound and heated the reaction mixture lo 75-S0°C and stirred for 30-45 min at same temperature. Slowly cooled the reaction mixture to 0-5°C and stirred for 30-45 min. Filtered the, obtained compound and washed with cool water. Unload and dried the resulted material lo. get the title compound. (Yield: 1 25 gms. 67.7%) Exnmnle-2: Preparation of pure 5-mcthyl- l -phenyl-2(l H)-pyridonc of formula I

Crude 5-methyl- l -phenyi-2( l /-/)-pyridone (20 gms) and ethyl acetate (80 ml) were charged into a clean and dry round bollom flask at 25-30°C. Heated the reaction mixture lo 70-75°C and stirred for 30-45 min at same temperature. Charcoal ( I gm) was added lo the reaction mixture at 70-75°C and stirred for 45 min at same temperature. Filtered (he reaction mixture through hyflow bed and washed with ethyl acetate. n-Heptane ( 100 ml) was slowl y added to the above filtrate at 70-75°C for 30 min. Cooled the reaction mixture to 0-5°C and stirred for 45 min at same temperature. Filtered the precipitated compound and washed with n-heptane and dried to get the title compound.

(Yield: 19 gms, 87.5%; HPLC purity: 99.9%).

The above obtained pure 5-methyl- l -phenyl-2( l /7)-pyridone is characterized by powdered X- Ray Diffractogram as illustrated in Figure- 1 which is having characteristic peaks at 8.8. 14.3. 14.9, 18.4, 1 8.8, 19.9, 2 1 .0, 22. 1 , 22.7, 22.9. 24.4, 27. 1 , 27.3 ± 0.2° of 2-theia.

Examplc-3: Preparation of 5-mcthyl- l -phcnyl-2(l H)-pyridonc (crude Pirfcnidonc)

Dimethyl formamide (200 mt), 2-hydroxy-5-methyl pyridine ( 100 gms). potassium carbonate ( 1 52 gms), copper powder (2.91 gms) and bromo benzene (257. 1 gms) were added into a clean and dry round bottom flask under nitrogen atmosphere at 25-30"C. l-leaied the reaction mixture to I 35- 140°C and slirred for 20 hrs at same temperature. Cooled the reaction mixture to 25-30°C. Water and toluene were added to the reaction mixture and slirred for 1 5 min. Separated the both organic and aqueous layers. Extracted the aqueous layer with toluene. Combined the total organic layers at 25-30°C and added charcoal (5 gms) and then stirred for 20 min at same temperature. Filtered the reaction mixture through hy- flow bed and then washed with toluene. Distilled off the solvent completely from the filtrate under reduced pressure and co-disti lled with water ( 100 ml). Water (400 ml) was added lo ihc above obtained material and heated to 85-90°C and stirred for 20 min at same temperature. Slowly cooled the reaction mixture lo 0-5°C and slirred for 45 min. Filtered the precipitated sol id, washed with chilled water and then dried to provide the title compound. (Yield: 148 gms. Purity by HPLC: 98%, 5-methyl pyridin-2-ol : not detected; 2-amino-5-methyl pyridine: nol detected, phenol: 0.13%, 5-methyl-2-phenoxypyridine: 1 .77%; water content: 0.2% w/w) Example-4: Preparation of pure 5-mcthyl-l -phcnyl-2(lH)-pyridonc

Crude 5-methyl- l -pheny!-2( l H)-pyridone ( 1 25 gms) was added to ethyl acetate (500 ml) at 25-30°C and stirred for 1 5 min at same temperature. Heated the reaction mixture to 70- 75°C and stirred for 45 min at same temperature. Charcoal (6.3 gms) was added to the reaction mixture at 70-75°C and stirred for 30 min at same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. n-Heptane (625 ml ) was slowly added to the above filtrate at 70-75°C and stirred for 1 0 min. at same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at same temperature. Filtered the precipitated solid, washed with n-heptane and then dried to gel the title compound.

(Yield: 99.2 gms, Purity by HPLC: . 99.7% w/w, Total impurities: not morethan 0.02%. residual solvents: methanol : not detected/melhylene chloride: not detected, ethyl acetate : 53 ppm, n-heptane: 309 ppm, toluene: not detected).

The PXRD pattern of the above obtained pure compound was illustrated in figure-2.

Example-5: Preparation of pure 5-mcthyl- l -phcnyl-2( IH)-pyridone

Crude 5-methyl- l -phenyl-2( I H)-pyridone (50 gms) was added to ethyl acetate (200 ml) at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 60 min at same temperature. Charcoal (2.5 gms) was added to the reaction mixture at 70-75°C and stirred for 20 min at same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Cooled the obtained filtrate to 25-30°C. n-Heptane ( 1 25 ml) was slowly added to the above reaction mixture at 25-30°C and stirred for 20 min. Cooled the reaction mixture to 0-5°C and stirred for 60 min at same temperature. Filtered the precipitated solid, washed with n-heptane and then dried to get title compound. (Yield : 2 1 gms)