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WO2018083709A1 - Procédé amélioré pour la préparation de 5-méthyl-1-phényl-2-1 (h)-pyridone pure - Google Patents

Procédé amélioré pour la préparation de 5-méthyl-1-phényl-2-1 (h)-pyridone pure Download PDF

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Publication number
WO2018083709A1
WO2018083709A1 PCT/IN2017/000127 IN2017000127W WO2018083709A1 WO 2018083709 A1 WO2018083709 A1 WO 2018083709A1 IN 2017000127 W IN2017000127 W IN 2017000127W WO 2018083709 A1 WO2018083709 A1 WO 2018083709A1
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WO
WIPO (PCT)
Prior art keywords
reaction mixture
methyl
pyridone
phenyl
pure
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IN2017/000127
Other languages
English (en)
Inventor
Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Ghojala Venkat Reddy
Koppera RAVINDER REDDY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MSN Laboratories Pvt Ltd
Original Assignee
MSN Laboratories Pvt Ltd
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 MSN Laboratories Pvt Ltd filed Critical MSN Laboratories Pvt Ltd
Publication of WO2018083709A1 publication Critical patent/WO2018083709A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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 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)
  • 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.
  • 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 present inventors developed improved process for the preparation of pure 5- methyl-1 -phenyl-2- 1 (H) _ pyidone by greater yield with high purity.
  • 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).
  • 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.
  • PXRD Powdered X-Ray Diffraction
  • 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
  • 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.
  • 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).
  • 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:
  • step-a) or step-c) 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.
  • 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.
  • 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.
  • 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).
  • 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:
  • the another embodiment of the present invention provides a process for the preparation of 5-methyl- 1 -phenyl-2- 1 (H)-pyridone, comprising:
  • step j) adding water to the compound obtained in step h) or step i),
  • the preferred embodiment of the present invention provides a process for the preparation of 5-methyl- 1 -phenyl-2- 1 (H)-pyridone, comprising:
  • 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.
  • 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.
  • particle size of a drug may also affect the release, dissolution, absorption and therapeutic action of pharmaceutical product.
  • 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.
  • 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.
  • 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.
  • 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.
  • diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, microcrystalline cellulose, magnesium stearate and mixtures thereof.
  • 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.
  • a liquid chromatographic system is to be equipped with variable wavelength U V- detector; Column: Kromasil C I 8, 250*4.6mm, 5 ⁇ (or) equivalent; Flow Rate: 1 .0 mL/min; Wavelength: 220 nm; Column temperature: 25°C; Injection volume: 5 ⁇ ; 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 0.22 ⁇ 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.

Landscapes

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

Abstract

La présente invention concerne un procédé amélioré pour la préparation de 5-méthyl-1-phényl -2( I H)-pyridone pure de formule I.
PCT/IN2017/000127 2016-11-07 2017-11-06 Procédé amélioré pour la préparation de 5-méthyl-1-phényl-2-1 (h)-pyridone pure Ceased WO2018083709A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201641037930 2016-11-07
IN201641037930 2016-11-07

Publications (1)

Publication Number Publication Date
WO2018083709A1 true WO2018083709A1 (fr) 2018-05-11

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Family Applications (1)

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PCT/IN2017/000127 Ceased WO2018083709A1 (fr) 2016-11-07 2017-11-06 Procédé amélioré pour la préparation de 5-méthyl-1-phényl-2-1 (h)-pyridone pure

Country Status (1)

Country Link
WO (1) WO2018083709A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112409246A (zh) * 2019-08-21 2021-02-26 北京凯因科技股份有限公司 一种新型吡非尼酮的晶型及其制备方法
CN119661429A (zh) * 2024-12-16 2025-03-21 南京工业大学 一种草酰二肼聚合物铜催化剂催化制备吡非尼酮的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110003863A1 (en) * 2009-06-03 2011-01-06 Intermune, Inc. Method for synthesizing pirfenidone
US20120071518A1 (en) * 2008-03-07 2012-03-22 Solanan, Inc. Treatment of Sepsis with 5-Ethyl-1-Phenyl-2(1H)-Pyridone
WO2016122420A1 (fr) * 2015-01-26 2016-08-04 Ulkar Kimya Sanayii Ve Ticaret A. S. Procédé amélioré de synthèse et de purification de pirfénidone
CN105906558A (zh) * 2016-05-04 2016-08-31 河南师范大学 抗纤维化药物吡非尼酮晶型及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120071518A1 (en) * 2008-03-07 2012-03-22 Solanan, Inc. Treatment of Sepsis with 5-Ethyl-1-Phenyl-2(1H)-Pyridone
US20110003863A1 (en) * 2009-06-03 2011-01-06 Intermune, Inc. Method for synthesizing pirfenidone
WO2016122420A1 (fr) * 2015-01-26 2016-08-04 Ulkar Kimya Sanayii Ve Ticaret A. S. Procédé amélioré de synthèse et de purification de pirfénidone
CN105906558A (zh) * 2016-05-04 2016-08-31 河南师范大学 抗纤维化药物吡非尼酮晶型及其制备方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112409246A (zh) * 2019-08-21 2021-02-26 北京凯因科技股份有限公司 一种新型吡非尼酮的晶型及其制备方法
CN112409246B (zh) * 2019-08-21 2023-04-07 北京凯因科技股份有限公司 一种吡非尼酮的晶型及其制备方法
CN119661429A (zh) * 2024-12-16 2025-03-21 南京工业大学 一种草酰二肼聚合物铜催化剂催化制备吡非尼酮的方法

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