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WO2012004801A1 - Procédé de préparation de mésylate d'imatinib - Google Patents

Procédé de préparation de mésylate d'imatinib Download PDF

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Publication number
WO2012004801A1
WO2012004801A1 PCT/IN2010/000453 IN2010000453W WO2012004801A1 WO 2012004801 A1 WO2012004801 A1 WO 2012004801A1 IN 2010000453 W IN2010000453 W IN 2010000453W WO 2012004801 A1 WO2012004801 A1 WO 2012004801A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
imatinib mesylate
imatinib
solution
contents
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/IN2010/000453
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Rapolu Raji Reddy
Bandi Vamsi Krishna
Bhimireddy Srinivasa 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.)
Hetero Research Foundation
Original Assignee
Hetero Research Foundation
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 Hetero Research Foundation filed Critical Hetero Research Foundation
Priority to PCT/IN2010/000453 priority Critical patent/WO2012004801A1/fr
Priority to BRPI1003375-0A priority patent/BRPI1003375A2/pt
Publication of WO2012004801A1 publication Critical patent/WO2012004801A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings

Definitions

  • the present invention provides a process for the preparation of imatinib mesylate in high purity.
  • Imatinib mesylate chemically 4-[(4-methyl-l-piperazinyl)methyl]-N-[4-methyl- 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide mesylate and has the structural formula:
  • Imatinib mesylate is known as an inhibitor of tyrosine kinases and is indicated for the treatment of chronic myeloid leukemia (CML), Philadelphia chromosome positive leukemia, for patients in chronic phase and in blast crisis, accelerated phase and also for malignant gastrointestinal stromal tumors. It selectively inhibits activation of target proteins involved in cellular proliferation. Imatinib mesylate also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. Imatinib mesylate is approved under the trademark "Gleevec ® " under marketed by Novartis.
  • PCT publication no. WO 99/03854 disclosed alpha crystal form and beta crystal form of imatinib mesylate.
  • imatinib mesylate alpha crystal form can be prepared by suspending imatinib in ethanol and adding methanesulfonic acid, heating under reflux and isolating.
  • PCT publication no. WO 2005/077933 described a process for preparing alpha 2 crystalline form of imatinib mesylate, which comprises suspending imatinib in isopropanol and adding methanesulfonic acid, heating under reflux and isolating.
  • U.S. patent publication no. 2007/0265288 described a method of preparing crystalline imatinib mesylate alpha form, which comprises suspending imatinib in isopropyl alcohol and adding methanesulfonic acid.
  • PCT publication no. WO 2009/151899 described a process for the preparation of crystalline imatinib mesylate alpha form, which comprises providing a solution or suspension of imatinib in tetrahydrofuran and adding methanesulfonic acid in tetrahydrofuran.
  • the present invention is intended to enhance the purity of imatinib mesylate.
  • the present invention is directed to reduce or remove genotoxic impurities from imatinib mesylate.
  • an object of the present invention is to provide a process for the preparation of imatinib mesylate in high purity.
  • a process for the preparation of imatinib mesylate in high purity which comprises:
  • step (b) heating the reaction mass obtained in step (a) at reflux;
  • step (c) reacting 4-(4-methylpiperazinomethyl)benzoyl chloride obtained in step (c) with N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidine amine in the presence of dimethyl amino pyridine and pyridine;
  • step (d) maintaining the reaction mass obtained in step (d) at below 35°C;
  • step (g) heating the contents obtained in step (g) at above 65°C;
  • step (h) i) adding a solution of methanesulfonic acid in isopropanol to the solution obtained in step (h) at above 65°C;
  • step (i) maintaining the solution obtained in step (i) at reflux;
  • highly pure imatinib mesylate refers to imatinib mesylate having the content of 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride or N-(2-methyl-5- aminophenyl)-4-(3-pyridyl)-2-pyrimidine-amine less than 10 parts per million (ppm).
  • the organic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide and acetonitrile, and more preferable organic solvent is dimethylformamide.
  • the reaction mass may preferably be maintained in step (e) at about 0 to 30°C and more preferably at about 20 to 30°C.
  • step (h) The contents are heated in step (h) may preferably at about 65 to 95°C and more preferably at about 70 to 80°C.
  • step (i) may preferably be carried out at about 65 to 95°C and more preferably at about 70 to 80°C.
  • Highly pure imatinib mesylate may be isolated in step (k) by methods known such as filtration or centrifugation.
  • step (a) heating the contents obtained in step (a) at above 65°C;
  • step (b) adding a solution of methanesulfonic acid in isopropanol to the solution obtained in step (b) at above 65°C;
  • step (c) maintaining the solution obtained in step (c) at reflux;
  • highly pure imatinib mesylate refers to imatinib mesylate having the content of 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride or N-(2-methyl-5- aminophenyl)-4-(3-pyridyl)-2-pyrimidine-amine less than 10 ppm.
  • Step (b) may preferably be carried out at about 65 to 95°C and more preferably at about 70 to 80°C.
  • step (c) The addition of methanesulfonic acid solution in step (c) may preferably be carried out at about 65 to 95°C and more preferably at about 70 to 80°C.
  • Isolation of highly pure imatinib mesylate in step (e) may preferably be carried out by methods known such as filtration or centrifugation.
  • the solid was added to the mixture of N-(2-Methyl-5-aminophenyl)-4-(3-pyridinyl)-l-pyrimidine-amine (50 gm), pyridine (300 ml) and dimethylamino pyridine (2 gm) at 0 to 15°C slowly for 1 hour.
  • the temperature of the reaction mass was raised to 25 to 30°C and stirred for 1 1 hours at 25 to 30°C.
  • Water (750 ml) and dichloromethane (800 ml) were added to the reaction mass and the pH was adjusted to 9.0 to 9.8 with liquid ammonia (500 ml). The layers were separated and aqueous layer was extracted.
  • the total organic layer was dried and the solvent was distilled off completely under vacuum at below 60°C.
  • acetone 500 ml
  • the reaction mass was stirred for 1 hour at 25 to 30°C and then cooled to 10 to 15°C.
  • the reaction mass was stirred for 1 hour at 10 to 15°C and filtered.
  • the wet solid obtained was suspended in methanol (750 ml). The contents were heated to reflux and stirred for 1 hour at reflux. The reaction mass was cooled to 25°C and stirred for 1 hour. The separated solid was filtered and dried at 60°C to obtain 135 gm of imatinib.
  • Imatinib (100 gm) as obtained in example 1 was suspended in isopropanol (1500 ml) at 25 to 30°C and then heated to 70 to 75°C. To the solution thus obtained was added methanesulfonic acid (20 gm) in isopropanol (40 ml) slowly for 45 minutes at 70 to
  • reaction mass was cooled to 25 to 30°C and stirred for 30 minutes at 25 to 30°C.
  • the solid obtained was collected by filtration and dried at 60°C to obtain 108 gm of highly pure imatinib mesylate.
  • Imatinib mesylate 99.83%
  • Imatinib (5 gm) was suspended in isopropanol (70 ml) at 25 to 30 C and then heated to 70 to 75°C. To the solution thus obtained was added methanesulfonic acid (1 gm) in isopropanol (2 ml) slowly for 45 minutes at 70 to 75°C. The contents were heated to reflux and stirred for 2 hours at reflux. The reaction mass was cooled to 25 to 30°C and stirred for 30 minutes at 25 to 30°C, filtered. The solid obtained was dried at 60°C to obtain 5 gm of highly pure imatinib mesylate.
  • Imatinib mesylate 99.82%

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de mésylate d'imatinib de grande pureté. Selon ce procédé, une solution d'acide méthanesulfonique dans de l'isopropanol est ajoutée à la suspension de base libre d'imatinib dans de l'isopropanol, entre 70 et 750°C, la masse de réaction est maintenue au reflux pendant 2 heures et 30 minutes et du mésylate d'imatinib de grande pureté est isolé.
PCT/IN2010/000453 2010-07-07 2010-07-07 Procédé de préparation de mésylate d'imatinib Ceased WO2012004801A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IN2010/000453 WO2012004801A1 (fr) 2010-07-07 2010-07-07 Procédé de préparation de mésylate d'imatinib
BRPI1003375-0A BRPI1003375A2 (pt) 2010-07-07 2010-09-13 processo para a preparaÇço do mesilato de imatinib em alta pureza

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2010/000453 WO2012004801A1 (fr) 2010-07-07 2010-07-07 Procédé de préparation de mésylate d'imatinib

Publications (1)

Publication Number Publication Date
WO2012004801A1 true WO2012004801A1 (fr) 2012-01-12

Family

ID=45440825

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2010/000453 Ceased WO2012004801A1 (fr) 2010-07-07 2010-07-07 Procédé de préparation de mésylate d'imatinib

Country Status (2)

Country Link
BR (1) BRPI1003375A2 (fr)
WO (1) WO2012004801A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012131711A1 (fr) * 2011-03-31 2012-10-04 Ind-Swift Laboratories Limited Procédé amélioré pour la préparation d'imatinib et de son sel de mésylate
CN103058991A (zh) * 2012-12-28 2013-04-24 南京艾德凯腾生物医药有限责任公司 一种α晶型甲磺酸伊马替尼的制备方法
WO2014003411A1 (fr) * 2012-06-25 2014-01-03 제일약품주식회사 Procédé de préparation de la forme cristalline α du mésylate d'imatinib
CN104974134A (zh) * 2015-05-19 2015-10-14 连云港宏创药业有限公司 甲磺酸伊马替尼的精制方法
CN111961031A (zh) * 2019-05-20 2020-11-20 浙江尖峰药业有限公司 一种甲磺酸伊马替尼的制备方法

Citations (3)

* 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
US20080306100A1 (en) * 2004-09-09 2008-12-11 Natco Pharma Limited Phenylaminopyrimidine derivatives as inhibitors of bcr-abl kinase
US20100087444A1 (en) * 2007-03-12 2010-04-08 Dr. Reddy's Laboratories Ltd. Imatinib mesylate

Patent Citations (3)

* 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
US20080306100A1 (en) * 2004-09-09 2008-12-11 Natco Pharma Limited Phenylaminopyrimidine derivatives as inhibitors of bcr-abl kinase
US20100087444A1 (en) * 2007-03-12 2010-04-08 Dr. Reddy's Laboratories Ltd. Imatinib mesylate

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012131711A1 (fr) * 2011-03-31 2012-10-04 Ind-Swift Laboratories Limited Procédé amélioré pour la préparation d'imatinib et de son sel de mésylate
US8912325B2 (en) 2011-03-31 2014-12-16 Ind-Swift Laboratories Limited Process for preparation of imatinib and its mesylate salt
WO2014003411A1 (fr) * 2012-06-25 2014-01-03 제일약품주식회사 Procédé de préparation de la forme cristalline α du mésylate d'imatinib
JP2015521656A (ja) * 2012-06-25 2015-07-30 ジェ イル ファーマシューティカル カンパニー リミテッド メシル酸イマチニブ結晶型αの製造方法
CN103058991A (zh) * 2012-12-28 2013-04-24 南京艾德凯腾生物医药有限责任公司 一种α晶型甲磺酸伊马替尼的制备方法
CN104974134A (zh) * 2015-05-19 2015-10-14 连云港宏创药业有限公司 甲磺酸伊马替尼的精制方法
CN111961031A (zh) * 2019-05-20 2020-11-20 浙江尖峰药业有限公司 一种甲磺酸伊马替尼的制备方法

Also Published As

Publication number Publication date
BRPI1003375A2 (pt) 2013-01-08

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