WO2015018507A2 - Nouveau procédé de préparation de febuxostat - Google Patents

Nouveau procédé de préparation de febuxostat Download PDF

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Publication number
WO2015018507A2
WO2015018507A2 PCT/EP2014/002079 EP2014002079W WO2015018507A2 WO 2015018507 A2 WO2015018507 A2 WO 2015018507A2 EP 2014002079 W EP2014002079 W EP 2014002079W WO 2015018507 A2 WO2015018507 A2 WO 2015018507A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
febuxostat
formula
ammonia
Prior art date
Application number
PCT/EP2014/002079
Other languages
English (en)
Other versions
WO2015018507A3 (fr
Inventor
Theocharis V. KOFTIS
Efstratios Neokosmidis
Sakellarios TRAKOSSAS
Theodoros Panagiotidis
Thanos Andreou
Anastasia-Aikaterini VARVOGLI
Original Assignee
Pharmathen S.A.
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 Pharmathen S.A. filed Critical Pharmathen S.A.
Priority to ES14750307T priority Critical patent/ES2772131T3/es
Priority to JP2016532260A priority patent/JP6585044B2/ja
Priority to EP14750307.2A priority patent/EP3030551B1/fr
Priority to CN201480044498.XA priority patent/CN105452228B/zh
Publication of WO2015018507A2 publication Critical patent/WO2015018507A2/fr
Publication of WO2015018507A3 publication Critical patent/WO2015018507A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a novel preparation method for 2-(3-cyano-4-isobutoxyphenyl)- 4-methyl-l,3-thiazole-5-carboxylic acid (Febuxostat) via novel and high yielded conversion of a formyl group in to a cyano group.
  • Febuxostat is an inhibitor of xanthine oxidase, which was discovered by the Japanese company Teijin Pharma Ltd and it is indicated for use in the treatment of hyperuricemia and chronic gout. Its chemical name is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl- l,3-thiazole-5-carboxylic acid. It is marketed under the brand names Adenuric in Europe, Feburic in Japan and Uloric in USA and Canada.
  • Febuxostat ethyl ester is prepared from 4-cyanophenol, through a five-step process.
  • Febuxostat can be prepared from its respective ethyl ester via alkaline hydrolysis, as in the previous case.
  • the process employs, in the final step, the use of palladium catalyst and, moreover, the reaction is performed at elevated temperatures (145 °C) for 48 hours, conditions that raise the energy cost and are, in general, difficult to transfer in industrial scale.
  • the invention provides a process for the convertion of a formyl group of compound of formula II into a cyano group of compound of formula III, wherein R ⁇ is a hydrogen atom, an alkyl, alkenyl, or alkynyl group and R 2 is an alkyl, alkenyl, or alkynyl group, in the presence of ammonia and either oxygen and metal catalyst or iodine.
  • Another object of this invention is to provide a novel process for the preparation of Febuxostat, exhibiting improved yield, safe reagents and industrially applicable techniques.
  • a further object of the invention is a process for the production of Febuxostat, comprising the following steps: a) alkylation of compound of formula Ila where Ri is a hydrogen atom and R 2 is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group to form a compound of formula lib where Ri is wo-butyl and R 2 is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group; conversion of the formyl group of compound of formula lib to cyano group, to produce compound of formula Illb, in the presence of: i) ammonia, oxygen, and a metal catalyst, or, ii) ammonia and iodine;
  • the transformation of the formyl group to cyano group in a compound of formula II, in either of the processes described above, is performed in the presence of i) ammonia, oxygen, and a metal catalyst or ii) ammonia and iodine.
  • Another object of the present invention is a process, for the preparation of Febuxostat, comprising the conversion of the formyl group of compound of general formula II, to cyano group of compound of formula III, in the presence of: i) ammonia, oxygen and a metal catalyst, or, ii) ammonia and iodine, and subsequent conversion of the compound of general formula III to Febuxostat.
  • Conversion of the compound of general formula III to Febuxostat is readily achieved when R 2 is other than hydrogen by removing the alkyl, alkenyl, or alkynyl group and, where Ri is other than z ' so-butyl, converting R t to so-butyl.
  • Rj is a hydrogen atom, an alkyl, alkenyl, or alkynyl group and R 2 is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group in the presence of ammonia and either oxygen and metal catalyst or iodine.
  • the present invention also encompasses the preparation of Febuxostat or salts thereof, through this novel transformation, included in the process in the below scheme.
  • the process is advantageous over prior art methods, due to the fact that it features high reaction yields, leads to compounds with chemical purities suitable for pharmaceutical purposes, uses more safe reagents and possesses characteristics suitable for industrialization.
  • a particular object of the invention is to provide a process for the preparation of Febuxostat, comprising the following steps: a) alkylation of compound of formula Ila where Ri is a hydrogen atom and R 2 is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group to compound of formula lib where Ri is an / ' so-butyl group and R 2 is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group; conversion of the formyl group of compound of formula lib to cyano group, to produce compound of formula Illb, in the presence of : i) ammonia, oxygen and a metal catalyst, or, ii) ammonia and iodine;
  • Suitable ester groups for preparation of Febuxostat are methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert-butyl preferably an ethyl ester group.
  • the etherification reaction is performed with an isobutyl halide, preferably isobutyl bromide, in the presence of a base.
  • the base can be an inorganic base.
  • Preferable inorganic bases are metal hydroxides and carbonates. More preferable inorganic bases are potassium carbonate, sodium carbonate, lithium carbonate.
  • the base may also be an organic base.
  • Preferable organic bases are amines. More preferable organic bases are trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, NN-dimethylaminopyridine.
  • the reaction is performed at temperatures that range between 25-100 °C. Preferable temperatures are 50-80 °C.
  • Solvents suitable for the reaction are polar aprotic solvents.
  • Preferable polar aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, acetone, t-butyl methyl ether.
  • the conversion of the formyl group to cyano group is performed with ammonia, an oxygen source and a metal catalyst.
  • a metal catalyst various compounds of metals may be used.
  • Non-limiting examples of metals are copper, iron, zinc, tin, ruthenium, palladium, rhodium, iridium, silver, cobalt, nickel, manganese, molybenium, vanadium and rhenium.
  • Preferred metals are copper, iron, ruthenium, palladium, iridium and silver. More preferred metals are copper, iron and ruthenium.
  • Non-limiting examples of metal catalysts are oxides, hydroxides, salts of metals with the conjugated base of either strong acids, such as hydrohalides, sulfuric acid, nitric acid, or organic acids, such as triflic acid and acetic acid.
  • the amount of ammonia used at the reaction may well vary, depending on the scale of the reaction and the conditions employed to it. Normally, at reactions involving such volatile reagents, the latter are used in great excess. Moreover, the amount of ammonia used in the reaction depends on the form in which the reagent is available. Non-limiting examples are aqueous solutions of ammonia and gaseous ammonia.
  • the solvent can be a typical organic solvent.
  • Preferable organic solvents are polar aprotic solvents.
  • Preferable polar aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, acetone, /-butylmethylether.
  • the temperature, at which the reaction is performed may range from room temperature to the boiling point of the respective solvent.
  • step b is performed with ammonia and molecular iodine.
  • typical organic solvents can be used, preferably polar aprotic solvents, as defined above.
  • the amount of ammonia is according to the nature of the reagent, as defined above.
  • the temperature at which the reaction is performed may range from 0 °C to the boiling point of the respective solvent.
  • the hydrolysis of the ester may be performed under basic conditions.
  • Such conditions involve a strong inorganic base.
  • Preferable bases are metal oxides, hydroxides and carbonates. More preferable bases are alkali metal and alkaline earth oxides, hydroxides and carbonates. More preferable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, barium oxide, sodium carbonate, potassium carbonate and lithium carbonate.
  • the reaction may be performed in a variety of solvents, depending mainly on the nature of the base used at it. Typical organic solvents suitable for this reaction are polar protic and aprotic solvents, as well as mixtures of them with water.
  • Preferred polar aprotic solvents are tetrahydrofuran, acetone, t-butyl methyl ether, ethyl acetate.
  • Preferred polar protic solvents are lower alcohols. More preferable solvents are methanol, ethanol, n-propanol and z ' sO-propanol.
  • the reaction can be performed at room temperature to the boiling point of used solvent. Preferable temperature range is from 20 to 80 °C.
  • Another object of the invention is to provide an alternate process for the preparation of Febuxostat, comprising the following steps:
  • the metal catalyst used in step b is a copper catalyst, an iron catalyst, or a ruthenium catalyst.
  • the metal catalyst is a copper catalyst.
  • the copper catalyst may be selected from inorganic compounds and salts of copper, of oxidative state (I) or (II).
  • Preferable compounds and salts are copper halides, copper nitrate, copper acetate, copper sulfate, copper triflate, copper oxide and their hydrates.
  • the conversion of the formyl group of formula II to cyano group of formula III is carried out in the presence of ammonia, an oxygen source and a metal catalyst.
  • the above described conversion is carried out in a polar aprotic solvent.
  • Preferred aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone and tetrahydrofuran.
  • the above described conversion of the formyl group of formula II to cyano group of formula III is carried out in temperatures ranging from 20 °C to the boiling point of the solvent, wherein the reaction is performed.
  • Preferable temperature range is 50-140 °C. More preferable temperature range is 60-120 °C. Even more preferable temperature range is 70-1 10 °C.
  • said conversion of the formyl group of formula II to cyano group of formula III is performed under oxygen atmosphere.
  • the percentage of the oxygen which is present in the reaction atmosphere may range from 1% to 100%. Preferable range is 5% to 100%. More preferable range is 20% to 100%.
  • reaction time may vary depending on the percentage of oxygen present in the air supply, used in the reaction.
  • the reaction time may also vary, depending on the pressure developed or applied to the reaction.
  • the conversion of the formyl group of formula II to cyano group of formula III may also be achieved with ammonia and iodine.
  • said conversion is carried out in a polar aprotic solvent.
  • Preferred aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, acetonitrile and tetrahydrofuran.
  • the above mentioned conversion of the formyl group of formula II to cyano group of formula III is carried out in temperatures ranging from 0 °C to the boiling point of the solvent, wherein the reaction is performed.
  • Preferable temperature range is 0-100 °C. More preferable temperature range is 10-60 °C. Even more preferable temperature range is 10-40 °C.
  • Another object of the present invention is a process for the preparation of Febuxostat, as described above, comprising the conversion of the formyl group of compound of formula II, to nitrile group of compound of formula III, comprising: i) ammonia, oxygen, and a metal catalyst, or, ii) ammonia and iodine, and subsequently converting the compound of formula III to Febuxostat.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation d'acide 2-(3-cyano-4-isobutoxyphényl)-4-méthyl-1,3-thiazole-5-carboxylique (febuxostat) par un processus de conversion inédit et à haut rendement d'un groupe formyle en un groupe cyano.
PCT/EP2014/002079 2013-08-07 2014-07-30 Nouveau procédé de préparation de febuxostat WO2015018507A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
ES14750307T ES2772131T3 (es) 2013-08-07 2014-07-30 Un nuevo proceso para la preparación de Febuxostat
JP2016532260A JP6585044B2 (ja) 2013-08-07 2014-07-30 フェブキソスタットの調製のための新規方法
EP14750307.2A EP3030551B1 (fr) 2013-08-07 2014-07-30 Nouveau procédé de préparation de febuxostat
CN201480044498.XA CN105452228B (zh) 2013-08-07 2014-07-30 制备非布索坦的新颖方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP2013002361 2013-08-07
EPPCT/EP2013/002361 2013-08-07

Publications (2)

Publication Number Publication Date
WO2015018507A2 true WO2015018507A2 (fr) 2015-02-12
WO2015018507A3 WO2015018507A3 (fr) 2015-10-22

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ID=51302690

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Application Number Title Priority Date Filing Date
PCT/EP2014/002079 WO2015018507A2 (fr) 2013-08-07 2014-07-30 Nouveau procédé de préparation de febuxostat

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JP (2) JP6585044B2 (fr)
CN (1) CN105452228B (fr)
ES (1) ES2772131T3 (fr)
WO (1) WO2015018507A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113072519A (zh) * 2021-04-01 2021-07-06 福建海西新药创制有限公司 一种利用微反应装置连续生产非布司他的方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108440443A (zh) * 2018-05-16 2018-08-24 无棣锐新医药化工有限公司 非布索坦中间体的制备方法
CN109503512B (zh) * 2018-12-28 2021-05-07 大连理工大学 一种非布司他及其中间体的合成方法
CN109503513B (zh) * 2018-12-29 2020-09-25 嘉实（湖南）医药科技有限公司 一种非布司他中间体的“一锅法”合成方法

Citations (5)

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Publication number Priority date Publication date Assignee Title
EP0513379B1 (fr) 1990-11-30 1996-09-11 Teijin Limited Derive de 2-arylthiazole et composition pharmaceutique contenant ce derive
JP2706037B2 (ja) 1993-04-13 1998-01-28 帝人株式会社 シアノ化合物およびその製造方法
JP3202607B2 (ja) 1996-08-01 2001-08-27 帝人株式会社 ２−（４−アルコキシ−３−シアノフェニル）チアゾール誘導体の製造法
WO2010142653A1 (fr) 2009-06-11 2010-12-16 Chemo Ibérica, S.A. Procédé de préparation de fébuxostat
CN101412700B (zh) 2007-10-19 2011-06-08 上海医药工业研究院 非布司他的晶型及其制备方法

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JP2834971B2 (ja) * 1993-05-25 1998-12-14 帝人株式会社 ２−（４−アルコキシ−３−シアノフェニル）チアゾール誘導体の製造法およびその新規製造中間体
ATE508129T1 (de) * 2004-03-30 2011-05-15 Vertex Pharma Als inhibitoren von jak und anderen proteinkinasen geeignete azaindole
CN102079731A (zh) * 2009-11-26 2011-06-01 上海和臣医药工程有限公司 一种2-(3-氰基-4-(2-甲基丙氧基)苯基)-4-甲基-5-噻唑甲酸的合成方法
CN101723915B (zh) * 2009-12-25 2012-01-25 北京赛科药业有限责任公司 一种制备非布索坦中间体的方法
WO2011141933A2 (fr) * 2010-05-12 2011-11-17 Msn Laboratories Limited Procédé pour la préparation d'acide 2-[3-cyano-4-(2-méthylpropoxy)phényl]-4-méthylthiazole-5-carboxylique et ses sels acceptables sur le plan pharmaceutique
US20130303780A1 (en) * 2010-11-08 2013-11-14 Siva Rama Prasad Vellanki Process for the preparation of 2-arylthiazole derivatives

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
EP0513379B1 (fr) 1990-11-30 1996-09-11 Teijin Limited Derive de 2-arylthiazole et composition pharmaceutique contenant ce derive
JP2706037B2 (ja) 1993-04-13 1998-01-28 帝人株式会社 シアノ化合物およびその製造方法
JP3202607B2 (ja) 1996-08-01 2001-08-27 帝人株式会社 ２−（４−アルコキシ−３−シアノフェニル）チアゾール誘導体の製造法
CN101412700B (zh) 2007-10-19 2011-06-08 上海医药工业研究院 非布司他的晶型及其制备方法
WO2010142653A1 (fr) 2009-06-11 2010-12-16 Chemo Ibérica, S.A. Procédé de préparation de fébuxostat

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Title
M. B. SMITH; J. MARCH: "March's Advanced Organic Chemistry", pages: 1287

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113072519A (zh) * 2021-04-01 2021-07-06 福建海西新药创制有限公司 一种利用微反应装置连续生产非布司他的方法

Also Published As

Publication number Publication date
JP6585044B2 (ja) 2019-10-02
JP2017509581A (ja) 2017-04-06
CN105452228A (zh) 2016-03-30
CN105452228B (zh) 2018-10-09
ES2772131T3 (es) 2020-07-07
JP2019194203A (ja) 2019-11-07
WO2015018507A3 (fr) 2015-10-22

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