[go: up one dir, main page]

WO2010014022A1 - Procédé de préparation d'imatinib - Google Patents

Procédé de préparation d'imatinib Download PDF

Info

Publication number
WO2010014022A1
WO2010014022A1 PCT/PL2009/000077 PL2009000077W WO2010014022A1 WO 2010014022 A1 WO2010014022 A1 WO 2010014022A1 PL 2009000077 W PL2009000077 W PL 2009000077W WO 2010014022 A1 WO2010014022 A1 WO 2010014022A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
methyl
formula
pyridin
solvent
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/PL2009/000077
Other languages
English (en)
Inventor
Henryk Gruza
Slawomir Mirek
Artur Jezewski
Artur Wrzosek
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.)
Temapharm Sp Z Oo
Original Assignee
Temapharm Sp Z Oo
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 Temapharm Sp Z Oo filed Critical Temapharm Sp Z Oo
Publication of WO2010014022A1 publication Critical patent/WO2010014022A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines

Definitions

  • the invention concerns the process for the preparation of 4-(4-methylpiperazin-l- ylmethyl)-N- ⁇ 4-methyl-3-[4-(pyridin-3 -yl)pyrimidin-2-ylamino]phenyl ⁇ benzamide of the Formula 1, known under the international non-proprietary name (INN) of Imatinib.
  • Imatinib is a selective tyrosine kinase inhibitor, used first of all in the treatment of tumours, mainly chronic myeloid leukaemia.
  • Imatinib has been first disclosed in the patent document EP 0 564 409. Two methods for the preparation of Imatinib have been indicated in this document.
  • the first synthetic route named the Method (a), consists in reacting the compound defined by the Formula III in this document with the compound defined by the Formula IV in this document, whereas at least one carbon atom in the benzene ring has to be substituted with nitro group or lower alkoxy group that is. in turn, substituted with fluorine atom or a bulky group defined by the Formula (II) in the discussed document.
  • the other carbon atoms of the ring may be substituted with halogen atoms.
  • the functional groups of both substrates react to form a 6-membered heterocyclic ring containing two nitrogen atoms.
  • one of the substrates already contains the heterocyclic ring including two nitrogen atoms, and the substituents of the benzene ring are defined otherwise - necessarily one of the substituents bears an amino group. Also in this case, at least one of the remaining carbon atoms of the benzene ring may be substituted with a halogen atom.
  • the European Patent No. EP 0 564 409 presents the synthesis of Imatinib following the Method (b).
  • 2-methyl-5-nitroaniline is converted into 2-methyl-5-nitrophenylguanidine nitrate which, in the second step, is condensed with 3-dimethylamino-l-(pyridin-3-yl)prop-2-en-l-one to yield N-(2-methyl-5- nitrophenyl)-4-(pyridin-3-yl)-pyrimidin-2-ylamine.
  • N-(5-amino-2-methylphenyl)-4-(pyridin-3-yl)-pyrimidin-2- ylamine is obtained which, in turn, is acylated with 4-(4-methylpiperazin-l-ylmethyl)-benzoyl chloride.
  • the process for the preparation of Imatinib according to the invention is characterised in that the 2-methyl-5-halogenoaniline of the Formula 2 is converted into the salt of the 2- methyl-5-halogenophenylguanidine of the Formula 3, which is then condensed with the 3- dialkylamino-l-(pyridin-3-yl)prop-2-en-l-one of the Formula 4 to yield the N-(2-methyl-5- halogenophenyl)-4-(pyridin-3-yl)-pyrimidin-2-ylamine of the Formula 5.
  • the compound of the Formula 5 is reacted with 4-(4-methylpiperazin-l-ylmethyl)benzamide of the Formula 6 to yield the resulting Imatinib.
  • Imatinib can be converted into the addition salt, preferably the mesylate, in the reaction with methanesulphonic acid.
  • the salt of the 2-methyl-5-halogenophenylguanidine used is the nitrate.
  • the alkyl substituent in the 3-dialkylamino-l-(pyridin-3-yl)prop-2-en-l -one of the Formula 4 is a straight-chained or branched C1-C4 aliphatic group, an aliphatic- aromatic group or an aromatic group.
  • the 3-dialkylamino-l-(pyridin-3-yl)prop-2-en-l-one used is 3-dimethyl- amino-l-(pyridin-3-yl)prop-2-en-l-one of the Formula 4.
  • the 2-methyl-5-halogenoaniline is reacted with cyanamide in an organic solvent.
  • the 2-methyl-5-halogenoaniline used is 2-methyl-5-bromoaniline or 2- methyl-5-iodoaniline.
  • the 2-methyl-5-halogenoaniline is used in an inorganic salt form, most preferably in a hydrochloride form.
  • the solvent used is an alcohol, preferably a C 1 -C4 alcohol, most preferably tert-butanol.
  • the 2-methyl-5-halogenophenylguanidine of the Formula 3, obtained in the first step, is isolated by extraction with an organic solvent, preferably selected from esters, ethers, halogenated solvents, aromatic hydrocarbons, most preferably with ter/-butyl-ethyl ether or toluene.
  • organic solvent preferably selected from esters, ethers, halogenated solvents, aromatic hydrocarbons, most preferably with ter/-butyl-ethyl ether or toluene.
  • condensation of the 2-methyl-5-halogenophenylguanidine nitrate of the Formula 3 with the 3-dialkylamino-l-(pyridin-3-yl)prop-2-en-l-one of the Formula 4 is carried out under alkaline conditions, in an organic solvent.
  • the condensation is carried out in the presence of a base, most preferably selected from the group comprising metal hydrogen carbonates, metal alkoxylates, metal hydroxides, metal carbonates, most preferably sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, caesium carbonate.
  • a base most preferably selected from the group comprising metal hydrogen carbonates, metal alkoxylates, metal hydroxides, metal carbonates, most preferably sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, caesium carbonate.
  • C1-C4 alcohols ketones, DMSO, DMF, or aromatic hydrocarbons, most preferably w-butanol, are used as a solvent.
  • reaction of the N-(2-methyl-5-halogenophenyl)-4-(pyridin-3-y])- pyrimidin-2-ylamine of the Formula 5 with 4-(4-methylpiperazin-l-ylmethyl)benzamide of the Formula 6 is carried out in an organic solvent, in the presence of a copper catalyst.
  • reaction of the N-(2-methyl-5-halogenophenyl)-4-(pyridin-3-yl)- pyrimidin-2-ylamine of the Formula 5 with 4-(4-methylpiperazin-l-ylmethyl)benzamide of the Formula 6 is carried out in an organic solvent, in the presence of an amine ligand.
  • reaction of the N-(2-methyl-5-halogenophenyl)-4-(pyridin-3-yl)- pyrimidin-2-ylamine of the Formula 5 with 4-(4-methylpiperazin- 1 -ylmethyl)benzamide of the Formula 6 is carried out in an organic solvent, in the presence of a copper catalyst and an amine ligand.
  • the product of the reaction of the N-(2-methyl-5-halogenophenyl)-4- (pyridin-3-yl)-pyrimidin-2-ylamine of the Formula 5 with 4-(4-methylpiperazin-l- ylmethyl)benzamide of the Formula 6 is isolated by extraction in an organic solvent/water system, optionally with addition of a copper-complexing agent.
  • DMF DMSO
  • ethers aromatic hydrocarbons, acetonitrile, or N- methylimidazole, most preferably dioxane, are used as a solvent.
  • the amine catalyst used is a primary or secondary amine, a diamine, especially a 1 ,2-diamine, or an aliphatic derivative of a 1,2-diamine, most preferably trans- N,N'-cyclohexyl-l,2-diamine as well as N,N'-dimethylethylenediamine.
  • the copper catalyst used is a copper halide, most preferably copper(I) iodide.
  • the extraction is carried out in the methylene chloride/water system.
  • the copper-complexing compounds most preferably edetic acid (EDTA) or ammonia, are used in order to remove copper.
  • EDTA edetic acid
  • ammonia ammonia
  • WO 03/066613 in which 3-bromo-4-methylaniline is the starting compound, that after conversion into N-(3-bromo-4-methylphenyl)-4-(4-methyl-piperazin-l-ylmethyl)benzamide is reacted with 4-(3-pyridyl)-2-pyrimidineamine, the reaction of an amino group and a bromine atom served to join the part comprising heterocyclic rings with the fragment comprising benzene rings and a piperazine ring.
  • the synthesis according to the invention consists in obtaining a secondary amide from a primary amide.
  • a 500-mL reactor was charged with 10.2 g of cyanamide (242.6 mmol, 1.2 eq), 44.6 g of 5-bromo-2-methylaniline hydrochloride (200 mmol, 1.0 eq). and 200 g of tert-butanol.
  • the reaction mixture was heated to reflux (temperature 85°C) and stirred at reflux for 4 h.
  • 200 g of toluene was added to the reactor, and distillation was carried out to remove t ⁇ rt-butanol from the reaction medium. 200 g of the distillate was stripped off what resulted in an increase of temperature to 96°C.
  • a 1 L-reactor is charged with 52.5 g of 5-bromo-2-methylphenylguanidine nitrate (171.7 mmol, 1.0 eq), 30.2 g of 3-dimethylamino-l-(pyridin-3-yl)prop-2-en-l-one (171.3 mmol, 1.0 mmol), 28.0 g of sodium hydrogen carbonate (333.3 mmol, 1.9 mmol) and 300 g of M-butanol.
  • the reaction mixture was heated to reflux (temperature of 120°C) and stirred at reflux under nitrogen for 16 h. After that time, the reaction mixture was cooled down to 80°C and 150 g of TBME ether was added.
  • the reaction mixture was cooled down to 30°C, and then 200 g of methanol were added.
  • the contents of the reactor was filtered off, and the precipitate was washed with 50 g methanol on a filter funnel.
  • the precipitate from the filter was returned to the reactor, and 200 g of water and 300 g of methylene chloride were added subsequently.
  • the solution prepared in that manner was combined with the first crop of the product obtained after evaporating of the solvents.
  • the whole product was stirred in the reactor for 30 minutes, and then the layers were separated.
  • the aqueous layer was extracted with 100 g of methylene chloride.
  • the organic phases were combined, and then washed consecutively with 100 g of water, 100 g of 1.2% aqueous EDTA solution, 100 g of water, and finally dried over MgSO 4 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur un procédé de préparation d'imatinib qui consiste à convertir la 2-méthyl-5-halogénoaniline de la Formule 2 en sel de 2-méthyl-5-halogénophénylguanidine de la Formule 3, qui est ensuite condensé avec la 3-dialkylamino-1-(pyridin-3-yl)prop-2-en-1-one de la Formule 4 pour donner la N-(2-méthyl-5-halogénophényl)-4-(pyridin-3-yl)-pyrimidin-2-ylamine de la Formule 5, qui est ensuite mise à réagir avec le 4-(4-méthylpipérazin-1-ylméthyl)benzamide de la Formule 6, et l'imatinib obtenu est facultativement converti en son sel d'addition.
PCT/PL2009/000077 2008-08-01 2009-07-30 Procédé de préparation d'imatinib Ceased WO2010014022A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP-385805 2008-08-01
PL385805A PL215042B1 (pl) 2008-08-01 2008-08-01 Sposób wytwarzania imatinibu

Publications (1)

Publication Number Publication Date
WO2010014022A1 true WO2010014022A1 (fr) 2010-02-04

Family

ID=41168537

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/PL2009/000077 Ceased WO2010014022A1 (fr) 2008-08-01 2009-07-30 Procédé de préparation d'imatinib

Country Status (2)

Country Link
PL (1) PL215042B1 (fr)
WO (1) WO2010014022A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011157450A1 (fr) 2010-06-18 2011-12-22 Krka, D. D., Novo Mesto Nouvelle forme polymorphique d'imatinib base et préparation de ses sels
WO2013120852A1 (fr) 2012-02-13 2013-08-22 Grindeks, A Joint Stock Company Intermédiaires pour un nouveau procédé de préparation d'imatinib et d'inhibiteurs de tyrosine kinase associés
WO2013136141A1 (fr) * 2012-03-13 2013-09-19 Fresenius Kabi Oncology Ltd. Procédé amélioré pour la préparation de la forme alpha de mésylate d'imatinib
CN103980230A (zh) * 2014-05-27 2014-08-13 西北大学 一种制备4-(4-甲基哌嗪-l-甲基)苯甲酰胺的方法
CN106854198A (zh) * 2015-12-08 2017-06-16 湖南华腾制药有限公司 一种伊马替尼的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0564409A1 (fr) * 1992-04-03 1993-10-06 Ciba-Geigy Ag Dérivés de pyrimidine et procédé pour leur préparation
WO2003066613A1 (fr) * 2002-02-07 2003-08-14 Novartis Ag Derives de n-phenyl-2-pyrimidine-amine
WO2004108699A1 (fr) * 2003-06-06 2004-12-16 Natco Pharma Limited Nouveau procede de preparation du medicament anticancereux imatinibe et de nouveaux analogues de ce medicament
WO2008059551A2 (fr) * 2006-11-16 2008-05-22 F.I.S. Fabbrica Italiana Sintetici S.P.A. Procédé de préparation d'imatinib et d'intermédiaires correspondants

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0564409A1 (fr) * 1992-04-03 1993-10-06 Ciba-Geigy Ag Dérivés de pyrimidine et procédé pour leur préparation
WO2003066613A1 (fr) * 2002-02-07 2003-08-14 Novartis Ag Derives de n-phenyl-2-pyrimidine-amine
WO2004108699A1 (fr) * 2003-06-06 2004-12-16 Natco Pharma Limited Nouveau procede de preparation du medicament anticancereux imatinibe et de nouveaux analogues de ce medicament
WO2008059551A2 (fr) * 2006-11-16 2008-05-22 F.I.S. Fabbrica Italiana Sintetici S.P.A. Procédé de préparation d'imatinib et d'intermédiaires correspondants

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BEN DE LANGE ET AL: "Aromatic Amination of Aryl Bromides Catalysed by Copper/beta-Diketone Catalysts: The Effect", SYNLETT, no. 18, 2006, pages 3105 - 3109, XP002551205 *
JÜRG ZIMMERMANN ET AL: "Phenylamino-Pyrimidine (PAP) Derivatives: A New Class of Potent and Selective Inhibitors of Protein Kinase C (PKC)", ARCHIV DER PHARMAZIE (WEINHEIM, GERMANY), vol. 329, no. 7, 1996, pages 371 - 376, XP002551208 *
SRIVARI CHANDRASEKHAR ET AL: "Copper-Catalyzed N-Arylation of Amines/Amides in Poly(ethylene glycol) as recyclable Solvent Medium", SYNTHESIS, no. 5, 2006, pages 839 - 842, XP002551207 *
SZAKÁCS Z ET AL: "Acid-Base Profiling of Imatinib (Gleevec) and Its Fragments", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 48, no. 1, 1 January 2005 (2005-01-01), pages 249 - 255, XP002389622, ISSN: 0022-2623 *
TAKASHI IKAWA ET AL: "Pd-Catalyzed Amidation of Aryl Chlorides Using Monodentate Biaryl Phosphine Ligans: a Kinetic, Computational, and Synthetic Investigation", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 129, no. 43, 2007, pages 13001 - 13007, XP002551206 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011157450A1 (fr) 2010-06-18 2011-12-22 Krka, D. D., Novo Mesto Nouvelle forme polymorphique d'imatinib base et préparation de ses sels
WO2013120852A1 (fr) 2012-02-13 2013-08-22 Grindeks, A Joint Stock Company Intermédiaires pour un nouveau procédé de préparation d'imatinib et d'inhibiteurs de tyrosine kinase associés
WO2013136141A1 (fr) * 2012-03-13 2013-09-19 Fresenius Kabi Oncology Ltd. Procédé amélioré pour la préparation de la forme alpha de mésylate d'imatinib
CN103980230A (zh) * 2014-05-27 2014-08-13 西北大学 一种制备4-(4-甲基哌嗪-l-甲基)苯甲酰胺的方法
CN103980230B (zh) * 2014-05-27 2016-02-17 西北大学 一种制备4-(4-甲基哌嗪-l-甲基)苯甲酰胺的方法
CN106854198A (zh) * 2015-12-08 2017-06-16 湖南华腾制药有限公司 一种伊马替尼的制备方法
CN106854198B (zh) * 2015-12-08 2019-11-05 湖南华腾医药有限公司 一种伊马替尼的制备方法

Also Published As

Publication number Publication date
PL215042B1 (pl) 2013-10-31
PL385805A1 (pl) 2010-02-15

Similar Documents

Publication Publication Date Title
US8877932B2 (en) Anhydrous lenalidomide form-I
TW591019B (en) Novel processes
CA2980965C (fr) Procede de preparation d'antagonistes des recepteurs androgeniques et de leurs intermediaires
PL209475B1 (pl) Pochodne N-fenylo-2-pirymidynoaminy oraz sposoby ich wytwarzania
JP5265562B2 (ja) イマチニブおよびその中間体の調製方法
WO2010014022A1 (fr) Procédé de préparation d'imatinib
EP1833815B1 (fr) Procede de preparation d'une base d'imatinibe
WO2012015999A2 (fr) Procédé de préparation de mésylate d'imatinib
JP6513105B2 (ja) トリアジン、ピリミジン及びピリジン誘導体の新規製造方法
KR102582197B1 (ko) 2-([1,2,3]트리아졸-2-일)-벤조산 유도체의 제조
PL211464B1 (pl) Sposób wytwarzania granisetronu, lub jego farmaceutycznie dopuszczalnej soli
CN105849106A (zh) 阿哌沙班合成中的关键中间体和杂质：阿哌沙班二醇酯
EP2608791B1 (fr) Procédé pour la préparation d'imatinib base
JP2009143918A (ja) Ｎ−ｂｏｃ化合物の脱保護
EP3004065B1 (fr) Procede de preparation d'un compose pyridazine
FI82456B (fi) Foerfarande foer framstaellning av nya terapeutiskt anvaendbara 1-fenyl-1,2,4-tiadiazin-1-oxidderivat.
WO2013120852A1 (fr) Intermédiaires pour un nouveau procédé de préparation d'imatinib et d'inhibiteurs de tyrosine kinase associés
Mlostoń et al. Optically active imidazoles derived from enantiomerically pure trans-1, 2-diaminocyclohexane
NZ281460A (en) Processes for preparation of clonidine derivatives, intermediate complexes and process for preparation of the intermediates
JP2019131487A (ja) トリアリールトリアジン化合物及び、その製造方法
CZ294344B6 (cs) Způsob výroby arylamidů heteroaromatických karboxylových kyselin
JP6169721B2 (ja) パピローマウイルスの治療で用いることができるヒドラジンの合成方法
US6737530B2 (en) Process
CN105777616A (zh) 色瑞替尼的合成中间体及其制备方法
WO2008101860A1 (fr) Nouveau procédé de préparation de 5-(4-chlorophényl)-1-(2,4-dichlorophényl)-4-méthyl-n-(pipéridin-1-yl)pyrazole-3-carboxamide

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09788412

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09788412

Country of ref document: EP

Kind code of ref document: A1