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WO2016122420A1 - Procédé amélioré de synthèse et de purification de pirfénidone - Google Patents

Procédé amélioré de synthèse et de purification de pirfénidone Download PDF

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Publication number
WO2016122420A1
WO2016122420A1 PCT/TR2015/000030 TR2015000030W WO2016122420A1 WO 2016122420 A1 WO2016122420 A1 WO 2016122420A1 TR 2015000030 W TR2015000030 W TR 2015000030W WO 2016122420 A1 WO2016122420 A1 WO 2016122420A1
Authority
WO
WIPO (PCT)
Prior art keywords
pirfenidone
process according
pyridone
methyl
acid
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/TR2015/000030
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English (en)
Inventor
Hasan KOYUNCU
Emre AKGOL
Omer Reis
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.)
Ulkar Kimya Sanayii Ve Ticaret A S
Original Assignee
Ulkar Kimya Sanayii Ve Ticaret A S
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 Ulkar Kimya Sanayii Ve Ticaret A S filed Critical Ulkar Kimya Sanayii Ve Ticaret A S
Priority to EP15712704.4A priority Critical patent/EP3307714A1/fr
Priority to PCT/TR2015/000030 priority patent/WO2016122420A1/fr
Publication of WO2016122420A1 publication Critical patent/WO2016122420A1/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

  • This invention relates to an improved process for the preparation and purification of pirfenidone.
  • Pirfenidone (1) is a small molecule whose chemical name is 5-methyl-1-phenyl-2-(1 H)- pyridone. Its use for the manufacture of a medicament for the preparation and/or prevention of fibrotic lesions is first described in EP0383591.
  • Pirfenidone is typically synthesized by copper catalyzed N-arylation of 5-methyl-2-pyridone with bromobenzene or iodobenzene, generally at elevated temperatures. There are generally two approaches to the copper catalyzed synthesis of pirfenidone starting from 5-methyl-2- pyridone: i. The use of iodobenzene or bromobenzene as solvent.
  • EP2440543 explains the synthesis of pirfenidone (1) from 5-methyl-2-pyridone (2) and excess bromobenzene (1.8 mol eq) (4) with Cu 2 0 catalysis to obtain crude pirfenidone in 85% yield:
  • Pirfenidone is a small neutral molecule. The absence of acidic or basic sites prevents the isolation and purification of pirfenidone through the formation of salts. As mentioned above, means for isolation or purification of pirfenidone is limited to solvent precipitations/crystallizations. Thus it would be highly advantageous to have additional means of purification for pirfenidone free from reagents, colored impurities and residual solvents etc.
  • the present invention provides a process for the synthesis of pirferidone by reacting 5-methyl-2-pyridone with a low quantity of bromobenzene in a low quantity of polar aprotic solvent in the presence of a copper catalyst and a base.
  • the present invention also provides a method for purification of pirfenidone by initially synthesizing an acid adduct of pirfenidone from crude pirfenidone and then recovering pirfenidone with increased purity.
  • the present invention is a process for the synthesis of pirfenidone (1)
  • said process comprising the steps of; reacting 5-methyl-2-pyridone (2),
  • 5-methyl-2-pyridone (2) is reacted with preferably 1 ,2 - 1 ,4 mole equivalent of bromobenzene.
  • the polar aprotic solvent can be selected from dimethylsulfoxide (DMSO), hexamethylphosphoramide (HMPA) and their mixtures thereof.
  • DMSO dimethylsulfoxide
  • HMPA hexamethylphosphoramide
  • the reaction is carried out in DMSO wherein DMSO is used as 0, 1-1 volume equivalent with respect to weight of 5-methyl-2-pyridone (2).
  • the reaction is carried out in 0,5 volume equivalent DMSO with respect to weight of 5-methyl- 2-pyridone (2).
  • the reaction is carried out in the presence of Cu(l) or Cu(ll) salts, such as CuCI, CuBr, Cul, Cu 2 0, Cu(OAc), Cu(OAc) 2 .
  • the reaction is carried out in the presence of Cu 2 0 or CuBr, wherein the appropriate Cu salt is used in catalytical amount which means that less than stoichiometric amount.
  • the reaction can be carried out in the presence of a base selected from K 2 C0 3 Na 2 C0 3 , Na 3 P0 4 , K 3 P0 4 .
  • the reaction is carried out in the presence 2 C0 3 .
  • reaction is optionally carried out in the presence of an additional base wherein the additional base is 0,05-0,30 mole equivalent of sodium acetate (NaOAc), preferably 0,2 mole equivalent of NaOAc with respect to 5-methyi-2-pyridone (2).
  • additional base is 0,05-0,30 mole equivalent of sodium acetate (NaOAc), preferably 0,2 mole equivalent of NaOAc with respect to 5-methyi-2-pyridone (2).
  • the reaction is carried out at temperatures sufficient to form pirfenidone, preferably >100°C, more preferably >120°C or most preferably at 135-140°C.
  • pirfenidone can be isolated from the reaction mixture by traditional methods.
  • pirfenidone Being a neutral molecule, pirfenidone can only form adducts with strong acids. Acids with pKa>0 was unable to induce adduct formation. Acids with pKa ⁇ 0 are useful acids for adduct formation and isolation. For example, pirfenidone cannot form adducts with acetic acid and phosphoric acid.
  • suitable acids that may form stable adducts with pirfenidone (1) in step a are acids with pKa ⁇ 0.
  • suitable acids used in adduct formation are selected from the group of sulfuric acid (H 2 S0 4 ), hydrochloric acid (HCI), hydrobromic acid (HBr), hydroiodic acid (HI), and methanesulfonic acid (MsOH).
  • strong acid that may form stable adducts with pirfenidone (1) in step a is preferably H 2 S0 4 .
  • the acid adduct formation reaction in step a can be carried out in a solvent selected from acetone, tetrahydrofuran (THF), acetic acid, ethyl acetate, dichloromethane and their mixtures or their mixtures with nonpolar solvents, such as toluene.
  • a solvent selected from acetone, tetrahydrofuran (THF), acetic acid, ethyl acetate, dichloromethane and their mixtures or their mixtures with nonpolar solvents, such as toluene.
  • THF tetrahydrofuran
  • acetic acid acetic acid
  • ethyl acetate dichloromethane
  • dichloromethane dichloromethane
  • nonpolar solvents such as toluene
  • recovery of pirfenidone (1) from pirfenidone adduct (5) in step b can be carried out in a solvent in the presence of a base which is basic enough to neutralize the adduct of formula (5).
  • the base is NaOH.
  • the solvent of step b can be water in which pirfenidone will precipitate after neutralization of the acid adduct form with a suitable base.
  • the solvent can also be an organic solvent such as methanol in which pirfenidone acid adduct can be neutralized.
  • the present invention provides a process for the synthesis and purification of pirfenidone free of major drawbacks of the processes presented in the prior art: a.
  • the use low quantity of bromobenzene (4) is more cost effective and environmentally friendly.
  • the lower quantities of residual bromobenzene (4) in the crude pirfenidone (1) product simplify the isolation and purification process and affect the yields in a positive manner.
  • Pirfenidone acid adduct compounds are highly soluble in water and soluble in alcohols. Thus, pirfenidone can be recovered easily by dissolving it in a proper media, final filtration followed by neutralization with a base. This process also serves as a final purification of pirfenidone to get the product in a pharmaceutically acceptable purity and form.
  • the following examples will illustrate the synthesis, isolation, formation of acid adducts of pirfenidone and recovery of pure pirfenidone from the adduct. These examples should not, however, be construed as limiting the invention:
  • 5-methyl-2-pyridone (2) (20 g, 0,18 mol), K 2 C0 3 (30,4 g, 0,22 mol), NaOAc (3 g, 0,036 mol, 0,2 mol eq), CuBr (2,62 g, 0,018 mol, 0.1 mol eq) [or Cu 2 0 (1 ,29 g, 0,05 mol eq)], Bromobenzene (4) (40,28 g, 0,26 mol, 1 ,4 mol eq) and DMSO (10 mL, 0,5 V eq) was placed in a round bottom flask under a nitrogen atmosphere. Flask was heated to 135-140°C and stirred at this temperature for 6-8 h.
  • reaction medium was cooled down to about 60 °C. Then, 100 mL water was added to the reaction mixture followed by 4 mL NH 4 OH and 100 mL toluene. The resulting mixture was stirred for 15 min and the phases were separated. Aqueous phase was extracted with 2x50 mL toluene then organic phases were combined (all extractions were carried out at about 60°C). Combined organic phases were filtered over a bed of celite after treatment with charcoal. After evaporation of toluene to the dryness, 36,3 g crude pirfenidone was obtained. Crude pirfenidone purity is >99,5% (HPLC analysis, UV detector 310 nm).
  • Precipitated product was filtered, washed with 1 volume equivalent cold acetone and dried in an oven at 50-60°C to furnish pirfenidone adduct in 97-99% yield based on a 1 :1 Pirfenidone:H 2 S0 4 .
  • Precipitated product was filtered, washed with 1 volume equivalent cold acetone and dried in an oven at 50-60°C to furnish 48 g pirfenidone adduct in 94% overall yield and 99.8% purity starting from 5-methyl-2-pyridone.
  • the obtained product is a white solid completely free from Bromobenzene.
  • Pirfenidone H 2 S0 4 adduct obtained in example D was treated as described in example C to obtain 29,3 g pure Pirfenidone in 86% overall yield starting from 5-methyl-2-pyridone and >99,9% purity.

Landscapes

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

Abstract

La présente invention concerne un procédé de synthèse de pirfénidone en faisant réagir de la 5-méthyl-2-pyridone avec une faible quantité de bromobenzène dans une faible quantité de solvant aprotique polaire, en présence d'un catalyseur à base de cuivre et d'une base. La présente invention concerne également un procédé de purification de pirfénidone par synthèse initiale d'un produit d'adduction d'acide de pirfénidone à partir de pirfénidone brute, puis par récupération de la pirfénidone dont la pureté a été augmentée.
PCT/TR2015/000030 2015-01-26 2015-01-26 Procédé amélioré de synthèse et de purification de pirfénidone Ceased WO2016122420A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP15712704.4A EP3307714A1 (fr) 2015-01-26 2015-01-26 Procédé amélioré de synthèse et de purification de pirfénidone
PCT/TR2015/000030 WO2016122420A1 (fr) 2015-01-26 2015-01-26 Procédé amélioré de synthèse et de purification de pirfénidone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2015/000030 WO2016122420A1 (fr) 2015-01-26 2015-01-26 Procédé amélioré de synthèse et de purification de pirfénidone

Publications (1)

Publication Number Publication Date
WO2016122420A1 true WO2016122420A1 (fr) 2016-08-04

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PCT/TR2015/000030 Ceased WO2016122420A1 (fr) 2015-01-26 2015-01-26 Procédé amélioré de synthèse et de purification de pirfénidone

Country Status (2)

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EP (1) EP3307714A1 (fr)
WO (1) WO2016122420A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3266767A2 (fr) 2016-07-08 2018-01-10 Dipharma Francis S.r.l. Procédé de préparation d'un agent antifibrotique
IT201600108927A1 (it) * 2016-10-27 2018-04-27 Dipharma Francis Srl Metodo per sintetizzare un farmaco antifibrotico
WO2018083709A1 (fr) * 2016-11-07 2018-05-11 Msn Laboratories Private Limited, R&D Center Procédé amélioré pour la préparation de 5-méthyl-1-phényl-2-1 (h)-pyridone pure
WO2018178996A1 (fr) * 2017-03-28 2018-10-04 Natco Pharma Limited Procédé amélioré pour la préparation de pirfénidone
US11066368B2 (en) 2016-01-14 2021-07-20 Laurus Labs Limited Process for the preparation and particle size reduction of pirfenidone

Citations (6)

* 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
US3974281A (en) 1972-12-18 1976-08-10 Affiliated Medical Research, Inc. 5-Methyl-1-phenyl-2-(1H)-pyridone compositions and methods of use
EP0244053A2 (fr) 1986-04-30 1987-11-04 Tektronix, Inc. Reflectomètre dans le domaine du temps à deux canaux
EP0383591A2 (fr) 1989-02-15 1990-08-22 Yamauchi, Shitotomo Utilisation de la 5-méthyl-1-phényl-2-(1H)-pyridone pour la prévention et le traitement des lésions fibrotiques
WO2003014087A1 (fr) * 2001-08-06 2003-02-20 Asahi Glass Company, Limited Procede de preparation de 5-methyl-1-phenyl-2(1h)-pyridinone
WO2010141600A2 (fr) * 2009-06-03 2010-12-09 Intermune, Inc. Procédé de synthèse amélioré de la pirfénidone

Patent Citations (7)

* 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
US3974281A (en) 1972-12-18 1976-08-10 Affiliated Medical Research, Inc. 5-Methyl-1-phenyl-2-(1H)-pyridone compositions and methods of use
EP0244053A2 (fr) 1986-04-30 1987-11-04 Tektronix, Inc. Reflectomètre dans le domaine du temps à deux canaux
EP0383591A2 (fr) 1989-02-15 1990-08-22 Yamauchi, Shitotomo Utilisation de la 5-méthyl-1-phényl-2-(1H)-pyridone pour la prévention et le traitement des lésions fibrotiques
WO2003014087A1 (fr) * 2001-08-06 2003-02-20 Asahi Glass Company, Limited Procede de preparation de 5-methyl-1-phenyl-2(1h)-pyridinone
WO2010141600A2 (fr) * 2009-06-03 2010-12-09 Intermune, Inc. Procédé de synthèse amélioré de la pirfénidone
EP2440543A2 (fr) 2009-06-03 2012-04-18 Intermune, Inc. Procédé de synthèse amélioré de la pirfénidone

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11066368B2 (en) 2016-01-14 2021-07-20 Laurus Labs Limited Process for the preparation and particle size reduction of pirfenidone
EP3266767A2 (fr) 2016-07-08 2018-01-10 Dipharma Francis S.r.l. Procédé de préparation d'un agent antifibrotique
EP3266767A3 (fr) * 2016-07-08 2018-02-21 Dipharma Francis S.r.l. Procédé de préparation d'un agent antifibrotique
IT201600108927A1 (it) * 2016-10-27 2018-04-27 Dipharma Francis Srl Metodo per sintetizzare un farmaco antifibrotico
WO2018083709A1 (fr) * 2016-11-07 2018-05-11 Msn Laboratories Private Limited, R&D Center Procédé amélioré pour la préparation de 5-méthyl-1-phényl-2-1 (h)-pyridone pure
WO2018178996A1 (fr) * 2017-03-28 2018-10-04 Natco Pharma Limited Procédé amélioré pour la préparation de pirfénidone

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Publication number Publication date
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