WO2011070588A1 - Procédé de préparation d'imatinib et de ses sels - Google Patents

Procédé de préparation d'imatinib et de ses sels Download PDF

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Publication number
WO2011070588A1
WO2011070588A1 PCT/IN2010/000752 IN2010000752W WO2011070588A1 WO 2011070588 A1 WO2011070588 A1 WO 2011070588A1 IN 2010000752 W IN2010000752 W IN 2010000752W WO 2011070588 A1 WO2011070588 A1 WO 2011070588A1
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WO
WIPO (PCT)
Prior art keywords
methyl
imatinib
potassium
sodium
hydroxide
Prior art date
Application number
PCT/IN2010/000752
Other languages
English (en)
Inventor
Ajit Annu Kamath
Ganesh Gurpur Pai
Ashish Mohan Ujagare
Xiao He
Shaohong Wu
Xin Shen
Jidong Yang
Huaxing Zhan
Original Assignee
Arch Pharmalabs Limited
Shanghai Parling Pharmatech Co., 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 Arch Pharmalabs Limited, Shanghai Parling Pharmatech Co., Ltd. filed Critical Arch Pharmalabs Limited
Priority to US13/203,141 priority Critical patent/US20110306763A1/en
Priority to EP10812949.5A priority patent/EP2509973A1/fr
Publication of WO2011070588A1 publication Critical patent/WO2011070588A1/fr

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    • 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

Definitions

  • the present invention relates to an improved process for the preparation of imatinib of the formula I comprising reaction between 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)- benzene- 1,3-diamine of the formula II with 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid derivatives of the formula III in the presence of a base.
  • R is C1-C4 alkyl group
  • Imatinib is known as an inhibitor of protein-tyrosine kinase and is indicated for the treatment of chronic myeloid leukemia (CML). Imatinib also has potential for the treatment of various other cancers that express these kinase including acute lymphocyte leukemia and certain solid tumors. It can also be used for the treatment of atherosclerosis, thrombosis, restenosis, or fibrosis. Thus, imatinib can also be used for the treatment of non-malignant diseases. Imatinib is usually administered orally in the form of a suitable salt, e.g., in the form of imatinib mesylate.
  • CML chronic myeloid leukemia
  • Imatinib 4-(4-methyl piperazine -1- methyl) -N-4-methyl-3-[4- (3- pyridyl) pyrimidine-2-amino] - benzamide and is represented by the following structural formula:
  • Imatinib Mesylate is an inhibitor of signal transduction (STI571) invented by Novartis AG after 7 years of hard work; it is the first inhibitor of cancer signal transduction ratified in the whole world. It is sold by Novartis as Gleevec capsules containing imatinib mesylate in amounts equivalent to 100 mg or 400 mg of imatinib free base.
  • Imatinib Mesylate is the rare drug in America, European Union and Japan. In May 10, 2001, it was ratified by American Food and Drug Administration (FDA) to treat the chronic myelogenous leukemia patients.
  • FDA American Food and Drug Administration
  • EP0564409 (US5521 184) describes the process for the preparation of imatinib and the use thereof, especially as an anti tumour agent.
  • One synthetic process as described in scheme-I comprises using 2-methyl-5-nitroaniline as the raw material which is reacted with cyanamide to obtain guanidine; cyclization reaction with 3-dimethylamino-l-(3-pyridyl)-2-propylene-l- ketone; reduction step of nitro to amine and condensation reaction with 4- (Chloromethyl)benzoyl chloride and N-methylpiperazidine to obtain Imatinib (WO 2004/108669).
  • Scheme-2 describes the successful process for the synthesis of Imatinib using 4-methyl-3- nitroanilines as the raw material, comprising reacting 4-methyl-3-nitroanilines with 4- (Chloromethyl)benzoyl chloride and N-methyl piperazidine in turns; followed by reduction of nitro group to amino group; then reaction with cyanamide to obtain guanidine; finally cyclization reaction with 3- dimethyl amino- 1 -(3- pyridyl)-2- propylene-1 -ketone to obtain Imatinib (WO 03/066613).
  • the said PCT application discloses the use of 4-4-(methyl piperazin-l-ylmethyl)-benzoic acid methyl ester as one of the raw material but rest of the reactants are different from that of N-(5-amino -2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine in presence of trimethyl aluminium.
  • CN1630648A describes a process comprising reaction of 3- bromine-4- methyl aniline with 4-(4-methyl-piperazin- methyl) methyl benzoate in presence of trimethyl-Aluminum to obtain N-(4-methyl-3-bromobenzene)-4-(4-methyl-piperazin- 1 -methyl)-benzamide, which further reacts with 2-amino-4-(3-pyridyl)- pyrimidine in presence of palladium as catalyst to obtain Imatinib.
  • CN101016293A describes another process using N-(4-methyl-3-3- aminophenyl)-4-(4- methyl-piperazin-1 -methyl)- benzamide as the raw material.
  • the said raw material is reacted with 2-halogen-4-(3-pyridyl)- pyrimidine to obtain Imatinib.
  • halogenated agent such as phosphorus oxychloride
  • 2-halogeno-4- methyl- (3-pyridyl) - pyridine is lachrymator and corrosive and has great influence to the surroundings.
  • EP0564409 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4-(3- pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in the presence of high quantity of pyridine to starting reactant amine N-(5-amino -2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine.
  • the ratio of the pyridine to the said reactant is 138 which is equivalent to about 40 parts v/w.
  • Use of such a large quantity of pyridine is unsafe as it is a toxic solvent according to ICH guidelines.
  • the workup of the reaction comprises evaporation of the remaining pyridine and further processing, which finally involves chromatography for purification, which is highly undesirable on industrial scale because it is expensive and time consuming.
  • US2006/0149061 and US20060223817 also discloses a similar synthetic approach comprising the use of similar pyridine /starting amine ratio (140 equivalents which is equals about 41 parts v/w).
  • the product obtained is purified by slurring in ethyl acetate.
  • WO2004/074502 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride wherein solvent like dimethyl pharmamide , dimethyl acetamide, N-methyl pyrilidinone are used as solvents instead of pyridine.
  • solvent like dimethyl pharmamide , dimethyl acetamide, N-methyl pyrilidinone are used as solvents instead of pyridine.
  • the method described in this patent application lacks an advantage in that the coupling reaction produces the hydrohalide salt of imatinib, e.g. imatinib trihydrochloride monohydrate, which has to be treated with a base in order to afford the imatinib base, thus an extra step is required.
  • WO2008/1 17298 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in presence of a base selected from potassium carbonate, sodium carbonate, potassium or sodium hydroxide.
  • a base selected from potassium carbonate, sodium carbonate, potassium or sodium hydroxide.
  • WO2008/136010 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in presence of base potassium hydroxide resulting into 78.6% yield of crude imatinib base.
  • Preparation of crude requires imatinib hydrochloride preparation during the workup which is then basified to get base in crude form.
  • This also describes maleate salt preparation as mode of purification which is again basified to give pure Imatinib base.
  • US patent application 2008/0103305 discloses a process comprising reacting N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine or its alkyl derivative and an acid salt of 4-[(4-methyl-l-piperazinyl)-methyl] benzoyl derivative as given below in the scheme-3 using pyridine in an amount of about 2 to 10 volumes per gram of the said amine.
  • the drawback associated with this process is use of pyridine especially when reaction is performed on large scale. -3
  • 1 is leaving group like halogen, mesyl or tosyl group
  • HA is an acid
  • esters of 4-(4-Methyl-piperazin-l-ylmethyl)- benzoic acid as a starting material instead of hazardous acid chloride.
  • Byproducts are simple alcohols in place of corrosive hydrogen chloride
  • the object of the present invention is to develop a simple, safe and efficient process for the preparation of substantially pure imatinib base and salt thereof.
  • the object of the present invention is to provide a process for the coupling reaction between the ester of 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid replacing corresponding hazardous acid chloride and N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2- pyrimidine amine.
  • Another aspect of the present invention is to provide the simple bases those can be used for the coupling of 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester and N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2 -pyrimidine amine.
  • the present invention discloses a new and efficient process for the preparation of imatinib comprising reacting 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3- diamine with 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester replacing hazardous4- (4-Methyl-piperazin-l-ylmethyl)-benzoic acid chloride in a suitable solvent and simple base to yield substantially pure imatinib base in about 90% yield.
  • a process for the preparation of imatinib which comprises the reaction of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)- benzene-l,3-diamine (II) also referred as N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2- pyrimidine amine with 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester (III) in the presence of a base in a suitable solvent to yield substantially pure imatinib base in about 90% yield.
  • II 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)- benzene-l,3-diamine
  • III 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester
  • R is C1-C4 alkyl group
  • the preparation of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (II) and 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester (III) may be carried out according to prior art methods.
  • R is C1-C4 alkyl group
  • the coupling reaction is carried out using base selected from organic bases such as sodium alkoxide (sodium methoxide, sodium ethoxde, sodium propoxide, sodium butoxide, sodium tert-butoxide), potassium alkoxide (potassium methylate, potassium ethylate, potassium propoxide, potassium butoxide, potassium tert-butoxide), butyllithium, .s-butyllithium and tert-butyllithium; and, inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like.
  • organic bases such as sodium alkoxide (sodium methoxide, sodium ethoxde, sodium propoxide, sodium butoxide, sodium tert-butoxide), potassium alkoxide (potassium methylate, potassium ethylate, potassium propoxide, potassium butoxide, potassium tert-butoxide), butyllithium, .s-butyllithium
  • the concentration of base used in reaction solution is in the range from about 0.1M to about 10M.
  • the coupling reaction is carried at a reaction temperature ranging from about 20 to about 100°C preferably ranging between about 25 to about 30°C.
  • the solvent is selected from straight chain or branched Q-C4 alcohols selected from methanol, ethanol, isopropyl alcohol and the like, ethers selected from tetrahydrofuran, diethyl ether, isopropyl ether and the like, chlorinated hydrocarbons selected from methylene chloride, 1,2-dichloroethane and the like, nitriles selected from acetonitrile and the like, hydrocarbons selected from toluene, dimethylbenzene and the like, esters selected from ethyl acetate and the like, polar aprotic solvents selected from dimethyl sulfoxide, dimethylfomamide and the like or mixture thereof.
  • Q-C4 alcohols selected from methanol, ethanol, isopropyl alcohol and the like
  • ethers selected from tetrahydrofuran, diethyl ether, isopropyl ether and the like
  • chlorinated hydrocarbons selected from methylene chloride,
  • the ester group of 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester (II) is selected from C 1 -C4 straight chain or branched carbon alkyl ester such as methyl ester, ethyl ester, propyl ester, butyl ester, tert-butyl ester, pentyl ester; or substitutive benzyl ester , substituted phenyl ester and the like.
  • the present invention discloses a process comprising reacting 4-Methyl-N-(4-pyridin-3- yl-pyrimidin-2-yl)-benzene-l,3-diamine (II), with 4-(4-Methyl-piperazin-l-ylmethyl)- benzoic acid ester (III) in the presence of a base in a suitable solvent to obtain Imatinib.
  • the process of the present invention overcomes all the limitations cited hereinabove of the processes disclosed in prior art.
  • the reaction is carried out under moderate conditions and is easy to operate.
  • the aminolysis reaction of ester is easy and clean.
  • the byproduct is alcohol which is nontoxic thereby, making the process eco-friendly.
  • the product obtained is substantially pure which does not require salt formation to remove impurities and yield is high and is suitable for industrial production.
  • the spectral data is as follows:
  • DMSO DMSO ) ⁇ : 164.9, 161.3, 161.1, 159.4, 150.8, 147.7, 137.7, 137.1, 134.9, 134.3, 132.3, 129.9, 129.1, 127.7, 127.6, 123.9, 117.2, 1 16.8, 107.5, 59.9, 52.1, 48.9, 42.2, 17.5.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'une base libre d'imatinib, qui consiste à condenser de la 4-méthyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzène-1,3-diamine avec un ester d'acide 4-(4-méthyl-pipérazin-1-ylméthyl)-benzoïque en présence d'une base comportant des bases organiques et des bases inorganiques dans un solvant organique pour former de l'imatinib.
PCT/IN2010/000752 2009-12-10 2010-11-18 Procédé de préparation d'imatinib et de ses sels WO2011070588A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US13/203,141 US20110306763A1 (en) 2009-12-10 2010-11-18 Process for the preparation of imatinib and salts thereof
EP10812949.5A EP2509973A1 (fr) 2009-12-10 2010-11-18 Procédé de préparation d'imatinib et de ses sels

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2853/MUM/2009 2009-12-10
IN2853MU2009 2009-12-10

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WO2011070588A1 true WO2011070588A1 (fr) 2011-06-16

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US (1) US20110306763A1 (fr)
EP (1) EP2509973A1 (fr)
WO (1) WO2011070588A1 (fr)

Cited By (1)

* 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

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015017728A1 (fr) 2013-07-31 2015-02-05 Windward Pharma, Inc. Composés inhibiteurs de tyrosine kinase en aérosol et leurs utilisations
US9630944B2 (en) * 2014-04-04 2017-04-25 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Process for preparing Imatinib and salts thereof, free of genotoxic impurity F
US11464776B2 (en) 2019-05-16 2022-10-11 Aerovate Therapeutics, Inc. Inhalable imatinib formulations, manufacture, and uses thereof
WO2020232236A1 (fr) 2019-05-16 2020-11-19 Aerovate Therapeutics, Inc. Formulations d'imatinib, leur fabrication et leurs utilisations

Citations (12)

* 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
US5521184A (en) 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
WO2003066613A1 (fr) 2002-02-07 2003-08-14 Novartis Ag Derives de n-phenyl-2-pyrimidine-amine
WO2004074502A2 (fr) 2003-02-18 2004-09-02 Cipla Ltd Procede de preparation d’imatinibe et produit ainsi prepare
US20040248918A1 (en) 2003-05-06 2004-12-09 Il Yang Pharm. Co., Ltd. N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof
WO2004108669A1 (fr) 2003-06-02 2004-12-16 Allergan, Inc. Analogues de carbonate et de thiocarbonate de 8-azaprostaglandine utilises en tant qu'agents therapeutiques
US20060149061A1 (en) 2004-12-30 2006-07-06 Huang Anli Novel process for preparing Imatinib
US20060223817A1 (en) 2006-05-15 2006-10-05 Chemagis Ltd. Crystalline imatinib base and production process therefor
CN101016293A (zh) 2007-02-14 2007-08-15 杭州盛美医药科技开发有限公司 一种伊马替尼的制备方法
US20080103305A1 (en) 2006-10-26 2008-05-01 Macdonald Peter Process for the preparation of imatinib
WO2008117298A1 (fr) 2007-03-26 2008-10-02 Natco Pharma Limited Nouveau procédé de préparation d'imatinib
WO2008136010A1 (fr) 2007-05-07 2008-11-13 Natco Pharma Limited Procédé de préparation de l'imatinib base hautement pure

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521184A (en) 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
EP0564409A1 (fr) 1992-04-03 1993-10-06 Ciba-Geigy Ag Dérivés de pyrimidine et procédé pour leur préparation
CN1630648A (zh) 2002-02-07 2005-06-22 诺瓦提斯公司 N－苯基－2－嘧啶胺衍生物
WO2003066613A1 (fr) 2002-02-07 2003-08-14 Novartis Ag Derives de n-phenyl-2-pyrimidine-amine
WO2004074502A2 (fr) 2003-02-18 2004-09-02 Cipla Ltd Procede de preparation d’imatinibe et produit ainsi prepare
US20040248918A1 (en) 2003-05-06 2004-12-09 Il Yang Pharm. Co., Ltd. N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof
WO2004108669A1 (fr) 2003-06-02 2004-12-16 Allergan, Inc. Analogues de carbonate et de thiocarbonate de 8-azaprostaglandine utilises en tant qu'agents therapeutiques
US20060149061A1 (en) 2004-12-30 2006-07-06 Huang Anli Novel process for preparing Imatinib
US20060223817A1 (en) 2006-05-15 2006-10-05 Chemagis Ltd. Crystalline imatinib base and production process therefor
US20080103305A1 (en) 2006-10-26 2008-05-01 Macdonald Peter Process for the preparation of imatinib
CN101016293A (zh) 2007-02-14 2007-08-15 杭州盛美医药科技开发有限公司 一种伊马替尼的制备方法
WO2008117298A1 (fr) 2007-03-26 2008-10-02 Natco Pharma Limited Nouveau procédé de préparation d'imatinib
WO2008136010A1 (fr) 2007-05-07 2008-11-13 Natco Pharma Limited Procédé de préparation de l'imatinib base hautement pure

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SYNTHTIC COMMUNICATIONS, vol. 3597, 2003

Cited By (1)

* 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

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US20110306763A1 (en) 2011-12-15
EP2509973A1 (fr) 2012-10-17

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