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WO2018178996A1 - Improved process for the preparation of pirfenidone - Google Patents

Improved process for the preparation of pirfenidone Download PDF

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Publication number
WO2018178996A1
WO2018178996A1 PCT/IN2017/050243 IN2017050243W WO2018178996A1 WO 2018178996 A1 WO2018178996 A1 WO 2018178996A1 IN 2017050243 W IN2017050243 W IN 2017050243W WO 2018178996 A1 WO2018178996 A1 WO 2018178996A1
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WO
WIPO (PCT)
Prior art keywords
pirfenidone
formula
compound
methyl
preparation
Prior art date
Application number
PCT/IN2017/050243
Other languages
French (fr)
Inventor
Sashikanth Suthrapu
Naveena TANKASALA
Veman Reddy ANDRU
Maruthinath KARICHETI
Janaki Rama Rao Ravi
Durga Prasad Konakanchi
Pulla Reddy Muddasani
Venkaiah Chowdary Nannapaneni
Original Assignee
Natco Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Natco Pharma Limited filed Critical Natco Pharma Limited
Publication of WO2018178996A1 publication Critical patent/WO2018178996A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

  • the present invention is relates to improved process for the production of Pirfenidone which is commercially viable, industrially advantageous, providing high yield and purity.
  • the invention is also related to purification of Pirfenidone.
  • Pirfenidone chemically is known as 5-methyl-l-phenylpyridin-2(lH)-one of formula I
  • Pirfenidone is an anti-fibrotic drug for the treatment of idiopathic pulmonary fibrosis.
  • the US3839346 is described the process for the preparation of Pirfenidone which comprises reaction of 5- methyl-2(lH) pyridone by treating with iodobenzene in presence of anhydrous potassium carbonate and zinc precipitated copper powder and reflected to obtain the crud Pirfenidone.
  • the crud Pirfenidone decolorized in benzene.
  • the decolorized Pirfenidone is crystalized in petroleum ether and further crystallized from hot water to obtain the desired Pirfenidone.
  • the WO2012107831 is described the process for the preparation of Pirfenidone in one pot by reaction of 5-ethyl-2(lH)-pyridone with butyl aldehyde and a compound of the acrylic.
  • a process for the preparation of 5-ethyl-l- phenyl-2(lH)- pyridone comprising reaction of 5-ethyl-2(lH)-pyridone with phenyl halide in the presence of CmO and a base.
  • the present invention provides a method for purification of Pirfenidone and an improved process for producing Pirfenidone in high purity and high yield.
  • the advantages of the process include simplicity, eco-friendliness and suitability of commercial use.
  • the present invention provides a process for preparing a compound of formula I,
  • the present invention is to provide the process for the preparation of 5-methyl-2(lH)-pyridone of formula (III) comprising the steps: a) treating the 2-amino-5-methylpyridine of formula (II) with 5% sulfuric acid and sodium nitrite in water affords 5-methyl-2(lH)-pyridinone.
  • the presence invention is to provide the purification of Pirfenidone of formula (I) comprising steps: a) dissolved the Pirfenidone in water; b) heat the reaction mixture up to clear solution; c) added the activated carbon; d) filter the reaction mass in hot condition; e) cool the filtrate up to 5-10 0 C; f) filter the compound and wash with water.
  • the present invention aims to provide improved process for preparation of Pirfenidone and purification of Pirfenidone.
  • the present invention provides a process for preparing a compound of formula I, said method comprising the steps of a) reacting compound of 5-methyl-2(lH)-pyridone of formula (III)
  • the invention refers improved process of Pirfenidone of formula (I) by reacting the 1 to 1.5 mole of bromobenzene of formula (IV) with compound of 5-methyl-2(lH)-pyridone of formula (III).
  • the polar solvent used in step a) is selected from dipolar aprotic solvents such as dimethylformamide (DMF), N-methylpyrrolidone, and dimethyl sulfoxide (DMSO); and acetone preferably dimethylformamide.
  • dipolar aprotic solvents such as dimethylformamide (DMF), N-methylpyrrolidone, and dimethyl sulfoxide (DMSO); and acetone preferably dimethylformamide.
  • the base used in step a) is inorganic base, is selected from the group of sodium carbonate, sodium bicarbonate, and potassium carbonate preferably potassium carbonate.
  • step a) maintained within the range of approximately 100 to 150° C, preferably in the range of 125-130°C.
  • the present invention is to provide the process for the preparation of 5-methyl-2(lH)-pyridone of formula (III) comprising the steps: a) treating the 2-amino-5-methylpyridine of formula (II) with 5% sulfuric acid and sodium nitrite in water affords 5-methyl-2(lH)-pyridinone.
  • the presence invention is to provide the purification of Pirfenidone of formula (I) comprising steps: a) dissolved the Pirfenidone in water; b) heat the reaction mixture up to clear solution; c) add the activated carbon; d) filter the reaction mass in hot condition; e) cool the filtrate up to 5-10 0 C; f) filter the compound and wash with water.
  • the 2-Amino-5-methylpyridine (100 gm) was added pre cooled water (5 It) at 0- 5°C.
  • the aq. solution of Sodium nitrite is added to reaction mixture over a period of 45-60 min at 0-5°C and stir for 45-60 min at 0-5°C.
  • Slowly heat the reaction mixture to 60-65°C and stir for 15-30 min at 60-65°C.
  • the reaction mixture cool to 5-10°C and adjust the pH of reaction mixture to 7.0-8.0 with 15% aq. sodium hydroxide solution.
  • the reaction mixture was heated 60-65°C and distil off reaction mass up to 6.0-6.5 volume under vacuum.
  • the reaction mixture cool to 30 ⁇ 2°C and added Dichloromethane (1000.0 mL).
  • the 5-methyl-2(lH)-pyridinone (70.0 g) was added to Dimethylformamide (70.0 mL) at 25-30°C.
  • Potassium carbonate (106.3 g) activated copper powder (2.04 g) and Bromobenzene (151.0 g) at 25-30°C and stir for 5-10 mits.
  • the reaction mixture heated to 125-130°C for 22.0-24.0 hours.
  • the reaction mixture cool to 25-30°C and filter the salts.
  • the salts were leached with toluene at 55-60°C and filtered.
  • the layers are separated and added Toluene (280.0 mL) to aqueous layer.
  • the reaction mixture was heated to 55-60°C and separate the Toluene layer.
  • the toluene layer was dried with 15%) NaCl solution and separate the organic layer.
  • the organic layer was treated with activated carbon at 25-30°C and filtered.
  • the filtrate was distil out completely under vacuum at ⁇ 60°C and added the toluene (35.0 mL) and n-Heptane (245.0 mL) solvent mixture.
  • the reaction mixture was heated to 75-80°C and stir for 1 hour.
  • the reaction mixture was cool to 25-30°C and stir for 45-60 min. Filter the compound and wash with solvent mixture of n- Heptane (63.0 mL) and Toluene (7.0 mL).
  • the 5-methyl-2(lH)-pyridinone (80gm) was added to water (1200 ml) and heat the reaction mixture to 80-85°C. Added the Activated carbon at 80-85°C and stir for 15-30 min at 80-85°C. The reaction mixture filter through hyflow at 80-85°C and wash with hot water. The filtrate was cool to 5-10°C and stir for 45-60 min at 5- 10°C. The compound was filter and was with chilled water.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

The present invention relates to improved process for the production of Pirfenidone which is comprises reacting the compound of 5-methyl-2(1H)-pyridone of formula (III) with bromobenzene (IV) in polar solvent, in presence of base and activated Cu powder to obtain the compound of formula (I). The present invention is also related to purification of Pirfenidone.

Description

IMPROVED PROCESS FOR THE PREPARATION OF PIRFENIDONE
FIELD OF THE INVENTION
The present invention is relates to improved process for the production of Pirfenidone which is commercially viable, industrially advantageous, providing high yield and purity. The invention is also related to purification of Pirfenidone.
BACKGROUND OF THE INVENTION
Pirfenidone chemically is known as 5-methyl-l-phenylpyridin-2(lH)-one of formula I
Figure imgf000002_0001
Pirfenidone is an anti-fibrotic drug for the treatment of idiopathic pulmonary fibrosis.
The US3839346 is described the process for the preparation of Pirfenidone which comprises reaction of 5- methyl-2(lH) pyridone by treating with iodobenzene in presence of anhydrous potassium carbonate and zinc precipitated copper powder and reflected to obtain the crud Pirfenidone. The crud Pirfenidone decolorized in benzene. The decolorized Pirfenidone is crystalized in petroleum ether and further crystallized from hot water to obtain the desired Pirfenidone.
The process for the preparation of Pirfenidone discloses in US3839346 makes the use of toxic iodobenzene and hence may not be safe and economical. In further reaction between 5- methyl-2(lH) pyridone and iodobenzene is carried out evaluated temperature to give the crude Pirfenidone. The reaction of iodobenzene at evaluated temperature is may not be safe and economical. The WO 2008147170 is described the process for the preparation of Pirfenidone which comprises 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 Pirfenidone.
The WO2012107831 is described the process for the preparation of Pirfenidone in one pot by reaction of 5-ethyl-2(lH)-pyridone with butyl aldehyde and a compound of the acrylic. There is also provided a process for the preparation of 5-ethyl-l- phenyl-2(lH)- pyridone comprising reaction of 5-ethyl-2(lH)-pyridone with phenyl halide in the presence of CmO and a base.
Therefore, there is a need to develop an improved, commercially viable and environment friendly process for preparing Pirfenidone with high yield and purity using non-hazardous conditions, environment friendly and easy to handle reagents and solvents.
SUMMARY OF THE INVENTION
The present invention provides a method for purification of Pirfenidone and an improved process for producing Pirfenidone in high purity and high yield. The advantages of the process include simplicity, eco-friendliness and suitability of commercial use.
In one aspect the present invention provides a process for preparing a compound of formula I,
Figure imgf000003_0001
said method comprising the steps of a) reacting the compound of 5-methyl-2(lH)-pyridone of formula (III)
Figure imgf000004_0001
with bromobenzene (IV) in polar solvent, in presence of base and activated Cu powder to obtain the compound of formula (I).
Yet another aspect, the present invention is to provide the process for the preparation of 5-methyl-2(lH)-pyridone of formula (III) comprising the steps: a) treating the 2-amino-5-methylpyridine of formula (II) with 5% sulfuric acid and sodium nitrite in water affords 5-methyl-2(lH)-pyridinone.
Yet another aspect, the presence invention is to provide the purification of Pirfenidone of formula (I) comprising steps: a) dissolved the Pirfenidone in water; b) heat the reaction mixture up to clear solution; c) added the activated carbon; d) filter the reaction mass in hot condition; e) cool the filtrate up to 5-10 0 C; f) filter the compound and wash with water.
DETAIL DESCRIPTION OF THE INVENTION
The present invention aims to provide improved process for preparation of Pirfenidone and purification of Pirfenidone.
In one embodiment, the present invention provides a process for preparing a compound of formula I,
Figure imgf000005_0001
said method comprising the steps of a) reacting compound of 5-methyl-2(lH)-pyridone of formula (III)
Figure imgf000005_0002
with bromobenzene (IV) in polar solvent, in presence of base and activated Cu powder to obtain the compound of formula (I).
More specifically, the invention refers improved process of Pirfenidone of formula (I) by reacting the 1 to 1.5 mole of bromobenzene of formula (IV) with compound of 5-methyl-2(lH)-pyridone of formula (III).
The polar solvent used in step a) is selected from dipolar aprotic solvents such as dimethylformamide (DMF), N-methylpyrrolidone, and dimethyl sulfoxide (DMSO); and acetone preferably dimethylformamide.
The base used in step a) is inorganic base, is selected from the group of sodium carbonate, sodium bicarbonate, and potassium carbonate preferably potassium carbonate.
The temperature of step a) maintained within the range of approximately 100 to 150° C, preferably in the range of 125-130°C.
In second embodiment, the present invention is to provide the process for the preparation of 5-methyl-2(lH)-pyridone of formula (III) comprising the steps: a) treating the 2-amino-5-methylpyridine of formula (II) with 5% sulfuric acid and sodium nitrite in water affords 5-methyl-2(lH)-pyridinone.
In third embodiment, the presence invention is to provide the purification of Pirfenidone of formula (I) comprising steps: a) dissolved the Pirfenidone in water; b) heat the reaction mixture up to clear solution; c) add the activated carbon; d) filter the reaction mass in hot condition; e) cool the filtrate up to 5-10 0 C; f) filter the compound and wash with water.
The following examples are illustrative the invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
EXAMPLES
Example-1: preparation of 5-methyl-2(lH)-pyridinone:
The 2-Amino-5-methylpyridine (100 gm) was added pre cooled water (5 It) at 0- 5°C. The aq. solution of Sodium nitrite is added to reaction mixture over a period of 45-60 min at 0-5°C and stir for 45-60 min at 0-5°C. Slowly heat the reaction mixture to 60-65°C and stir for 15-30 min at 60-65°C. The reaction mixture cool to 5-10°C and adjust the pH of reaction mixture to 7.0-8.0 with 15% aq. sodium hydroxide solution. The reaction mixture was heated 60-65°C and distil off reaction mass up to 6.0-6.5 volume under vacuum. The reaction mixture cool to 30±2°C and added Dichloromethane (1000.0 mL). The Dichloromethane layer separated and Distil off 2.0-2.5 volume under vacuum at < 35°C. The reaction mixture cool to 25- 30°C and stir for 45-60 min at 25-30°C. Filter the solid and wash with Di chl orom ethane . Example-2: preparation of 5-Methyl-l-phenylpyridin-2(lH)-one:
The 5-methyl-2(lH)-pyridinone (70.0 g) was added to Dimethylformamide (70.0 mL) at 25-30°C. To this reaction mixture added the Potassium carbonate (106.3 g), activated copper powder (2.04 g) and Bromobenzene (151.0 g) at 25-30°C and stir for 5-10 mits. The reaction mixture heated to 125-130°C for 22.0-24.0 hours. The reaction mixture cool to 25-30°C and filter the salts. The salts were leached with toluene at 55-60°C and filtered. Added the 15% sodium chloride solution to filtrate and adjust the pH to > 12.0 with 32% aq. Sodium hydroxide. The layers are separated and added Toluene (280.0 mL) to aqueous layer. The reaction mixture was heated to 55-60°C and separate the Toluene layer. The toluene layer was dried with 15%) NaCl solution and separate the organic layer.
The organic layer was treated with activated carbon at 25-30°C and filtered. The filtrate was distil out completely under vacuum at < 60°C and added the toluene (35.0 mL) and n-Heptane (245.0 mL) solvent mixture. The reaction mixture was heated to 75-80°C and stir for 1 hour. The reaction mixture was cool to 25-30°C and stir for 45-60 min. Filter the compound and wash with solvent mixture of n- Heptane (63.0 mL) and Toluene (7.0 mL).
Example-3: purification of 5-Methyl-l-phenylpyridin-2(lH)-one:
The 5-methyl-2(lH)-pyridinone (80gm) was added to water (1200 ml) and heat the reaction mixture to 80-85°C. Added the Activated carbon at 80-85°C and stir for 15-30 min at 80-85°C. The reaction mixture filter through hyflow at 80-85°C and wash with hot water. The filtrate was cool to 5-10°C and stir for 45-60 min at 5- 10°C. The compound was filter and was with chilled water.

Claims

We claim:
1. A process for purification of Pirfenidone of formula (I) comprising steps: a) dissolve the Pirfenidone in water; b) heat the reaction mixture up to clear solution; c) add the activated carbon; d) filter the reaction mass in hot condition; e) cool the filtrate up to 5-10 0 C; f) filter the compound and wash with water.
2. The process for the preparation of Pirfenidone of formula (I) according to claim- 1 is comprising the steps of: a) reacting compound of 5-methyl-2(lH)-pyridone of formula (III)
Figure imgf000008_0001
with bromobenzene (IV) in polar solvent, in presence of base and activated Cu powder to obtain the compound of formula (I).
3. The process according to the claim-1 to 2, wherein bromobenzene used in mole ratio of 1 to 1.5 mole.
4. The process according to claim-1 to 3, wherein polar solvent is selected from dipolar aprotic solvents such as dimethylformamide (DMF), N-methylpyrrolidone, and dimethyl sulfoxide (DMSO) acetone and/or mixture thereof.
5. The process according to claim-1 to 4, wherein base is selected from the group of sodium carbonate, sodium bicarbonate, and potassium carbonate.
6. The process according to claim-1 to 5, where the reaction temperature maintained within the range of 100 to 150° C.
PCT/IN2017/050243 2017-03-28 2017-06-19 Improved process for the preparation of pirfenidone WO2018178996A1 (en)

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IN201741011006 2017-03-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112409246A (en) * 2019-08-21 2021-02-26 北京凯因科技股份有限公司 Novel pirfenidone crystal form and preparation method thereof

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3839346A (en) 1972-12-18 1974-10-01 Affiliated Med Res N-substituted pyridone and general method for preparing pyridones
DE2555411A1 (en) * 1972-12-18 1976-06-10 Affiliated Med Res PHARMACEUTICAL COMPOSITION WITH AN N-SUBSTITUTED PYRIDONE
WO2003014087A1 (en) * 2001-08-06 2003-02-20 Asahi Glass Company, Limited Process for preparation of 5-methyl-1-phenyl-2(1h) -pyridinone
CN1817862A (en) * 2006-03-15 2006-08-16 浙江省医学科学院 Production of pyriphenanthrenone as anti-fibrosis medicine
WO2008147170A1 (en) 2007-05-29 2008-12-04 Cell Therapy Technology, S.A. De C.V. New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same
WO2010141600A2 (en) * 2009-06-03 2010-12-09 Intermune, Inc. Improved method for synthesizing pirfenidone
CN102558040A (en) * 2011-12-28 2012-07-11 辰欣药业股份有限公司 Method for preparing pirfenidone
WO2012107831A1 (en) 2011-02-11 2012-08-16 Signa S.A. De C.V. Method of making a pyridone compound, 5-ethyl-1-phenyl-2-(1h)-pyridone, and intermediates thereof
WO2016122420A1 (en) * 2015-01-26 2016-08-04 Ulkar Kimya Sanayii Ve Ticaret A. S. An improved method for the synthesis and purification of pirfenidone

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3839346A (en) 1972-12-18 1974-10-01 Affiliated Med Res N-substituted pyridone and general method for preparing pyridones
DE2555411A1 (en) * 1972-12-18 1976-06-10 Affiliated Med Res PHARMACEUTICAL COMPOSITION WITH AN N-SUBSTITUTED PYRIDONE
WO2003014087A1 (en) * 2001-08-06 2003-02-20 Asahi Glass Company, Limited Process for preparation of 5-methyl-1-phenyl-2(1h) -pyridinone
CN1817862A (en) * 2006-03-15 2006-08-16 浙江省医学科学院 Production of pyriphenanthrenone as anti-fibrosis medicine
WO2008147170A1 (en) 2007-05-29 2008-12-04 Cell Therapy Technology, S.A. De C.V. New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same
WO2010141600A2 (en) * 2009-06-03 2010-12-09 Intermune, Inc. Improved method for synthesizing pirfenidone
WO2012107831A1 (en) 2011-02-11 2012-08-16 Signa S.A. De C.V. Method of making a pyridone compound, 5-ethyl-1-phenyl-2-(1h)-pyridone, and intermediates thereof
CN102558040A (en) * 2011-12-28 2012-07-11 辰欣药业股份有限公司 Method for preparing pirfenidone
WO2016122420A1 (en) * 2015-01-26 2016-08-04 Ulkar Kimya Sanayii Ve Ticaret A. S. An improved method for the synthesis and purification of pirfenidone

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112409246A (en) * 2019-08-21 2021-02-26 北京凯因科技股份有限公司 Novel pirfenidone crystal form and preparation method thereof
CN112409246B (en) * 2019-08-21 2023-04-07 北京凯因科技股份有限公司 Crystal form of pirfenidone and preparation method thereof

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