WO2013008242A1 - Procédé de préparation d'un dichlorhydrate d'acide 4-(4-méthylpipérazino- méthyl)benzoïque très pur - Google Patents

Procédé de préparation d'un dichlorhydrate d'acide 4-(4-méthylpipérazino- méthyl)benzoïque très pur Download PDF

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Publication number
WO2013008242A1
WO2013008242A1 PCT/IN2011/000463 IN2011000463W WO2013008242A1 WO 2013008242 A1 WO2013008242 A1 WO 2013008242A1 IN 2011000463 W IN2011000463 W IN 2011000463W WO 2013008242 A1 WO2013008242 A1 WO 2013008242A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzoic acid
methylpiperazino
acid dihydrochloride
impurity
methyl
Prior art date
Application number
PCT/IN2011/000463
Other languages
English (en)
Inventor
Amala Kishan Kompella
Kali Satya Bhujanga Rao Adibhatla
Veera Swamy Balina
Venkaiah Chowdary Nannapaneni
Original Assignee
Natco Pharma Limited
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 Natco Pharma Limited filed Critical Natco Pharma Limited
Priority to PCT/IN2011/000463 priority Critical patent/WO2013008242A1/fr
Publication of WO2013008242A1 publication Critical patent/WO2013008242A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride(I) is the key intermediate for Imatinib mesylate(IA) and is approved under the trademark "Gleevec ®" by the US Food and Drug Administration for the treatment of Chronic Myelogenous Leukemia before and after the failure of interferon alpha.
  • JP20031 19184 disclosed preparation of 4-(4-methylpiperazino)methylbenzoic acid dihydrochloride of purity 98% by the reaction of p-(chloromethyl)benzoic acid and excess of 1 -methylpiperazine(greater than 5moles).
  • JP20031 19185 essentially discloses a similar process employing excess moles of N- methyl piperazine rendering the process uneconomical.
  • JP2002338558 discloses three step process for the preparation of 4-(4-methylpiperazino) methylbenzoic acid dihydrochloride by the reaction of 1-methylpiperazine with 4- chloromethyl benzonitrile in xylene in the presence of potassium carbonate. Hydrolysis of the intermediate product with concentrated HC1 affords 4-[(4-methyl-l - piperazinyl)methyl]benzoic acid dihydrochloride.
  • 4-(4-methylpiperazino)methylbenzoic acid dihydrochloride is the key intermediate for imatinib mesylate. As such, there is a need for a process to generate 4-(4- methylpiperazino)methylbenzoic acid dihydrochloride of high purity economically and safely on commercial scale. This may then be conveniently used as an intermediate in the preparation of highly pure Imatinib mesylate directly suitable for therapeutic applications.
  • Impurity (III) The main objective of the present invention is to provide an improved process for the preparation of highly pure (>99.0%) 4-(4-methyl piperazinomethyl) benzoic acid dihydrochloride in which impurity-Ill content is less than 0.3%. Another objective of the invention is to provide a process for preparation of highly pure (>99%) 4-(4-methylpiperazino)methylbenzoic acid dihydrochloride through the condensation of 4-bromomethyl benzoic acid(II) and N-methyl piperazine in potassium carbonate and in n-butanol medium.
  • the present invention can be illustrated by the following scheme:
  • step-9 can be optionally purified further by the following process
  • Step-I Preparation of 4-bromo methyl benzoic acid (II): p-Toluic acid (200g, 1 .46moles) was charged in chloroform(2L). N-Bromo succinimide(261 .4, 1 .46moles) and dibenzoyl peroxide(2.8g, 0.01 17moles)were added successively. The temperature of the reaction mass was raised to reflux and maintained at that temperature for 20hours. It was brought to room temperature, filtered and washed with chloroform (I L) and water (2L) successively. The crude 4-brommethyl benzoic acid was dried in oven at 50-60°C for two hours.
  • the dried product(320g) was suspended in ethyl acetate (960ml) and stirred at room temperature for 3hours. The product was filtered, washed with ethyl acetate(320ml) and dried to yield 4-bromomethyl benzoic acid (200g, 63%) of 97.5% purity by HPLC.
  • Step-2 Preparation of highly pure (>99%) 4-(4-Methylpiperazino)methyl benzoic acid dihydrochloride (I) ;
  • the organic layer was pH adjusted with isopropanolic hydrochloride solution (120ml) and maintained under stirring for one hour.
  • the product was filtered and washed with n-butanol( 100ml) to get 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride .

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

Abstract

Cette invention concerne la préparation d'un dichlorhydrate d'acide 4-(4-méthylpipérazinométhyl)benzoïque (I) très pur (> 99 %) à partir de matériaux de départ disponibles dans le commerce et bon marché à des rendements élevés. Par conséquent, le composé du titre (I) est préparé par réaction d'acide 4-bromométhylbenzoïque (II) avec une 1-méthylpipérazine en présence de carbonate de potassium dans un milieu de n-butanol à température ambiante. Cette invention concerne également un procédé de préparation d'acide 4-bromométhylbenzoïque (II).
PCT/IN2011/000463 2011-07-12 2011-07-12 Procédé de préparation d'un dichlorhydrate d'acide 4-(4-méthylpipérazino- méthyl)benzoïque très pur WO2013008242A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2011/000463 WO2013008242A1 (fr) 2011-07-12 2011-07-12 Procédé de préparation d'un dichlorhydrate d'acide 4-(4-méthylpipérazino- méthyl)benzoïque très pur

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2011/000463 WO2013008242A1 (fr) 2011-07-12 2011-07-12 Procédé de préparation d'un dichlorhydrate d'acide 4-(4-méthylpipérazino- méthyl)benzoïque très pur

Publications (1)

Publication Number Publication Date
WO2013008242A1 true WO2013008242A1 (fr) 2013-01-17

Family

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PCT/IN2011/000463 WO2013008242A1 (fr) 2011-07-12 2011-07-12 Procédé de préparation d'un dichlorhydrate d'acide 4-(4-méthylpipérazino- méthyl)benzoïque très pur

Country Status (1)

Country Link
WO (1) WO2013008242A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105001205A (zh) * 2015-07-03 2015-10-28 齐鲁天和惠世制药有限公司 一种伊马替尼杂质d的制备方法
CN106905263A (zh) * 2017-03-09 2017-06-30 常州沃腾化工科技有限公司 一种4‑(4‑甲基‑1‑哌嗪基甲基)苯甲酸二盐酸盐的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4623486A (en) 1985-05-29 1986-11-18 Pfizer Inc. [4-substituted benzoyloxy]-N-substituted-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides having anti-arthritic activity
JP2002338558A (ja) 2001-05-14 2002-11-27 Ihara Chem Ind Co Ltd （４−アルキル−１−ピペラジニルメチル）安息香酸誘導体の製造方法
JP2003119184A (ja) 2001-10-11 2003-04-23 Toray Ind Inc 置換ピペラジニルメチル芳香族酸誘導体の製造方法
JP2003119185A (ja) 2001-10-11 2003-04-23 Toray Ind Inc Ｎ−メチルピペラジントルイル酸誘導体の製造方法
WO2008051597A1 (fr) * 2006-10-26 2008-05-02 Sicor Inc. Procédé pour la préparation d'imatinib

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4623486A (en) 1985-05-29 1986-11-18 Pfizer Inc. [4-substituted benzoyloxy]-N-substituted-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides having anti-arthritic activity
JP2002338558A (ja) 2001-05-14 2002-11-27 Ihara Chem Ind Co Ltd （４−アルキル−１−ピペラジニルメチル）安息香酸誘導体の製造方法
JP2003119184A (ja) 2001-10-11 2003-04-23 Toray Ind Inc 置換ピペラジニルメチル芳香族酸誘導体の製造方法
JP2003119185A (ja) 2001-10-11 2003-04-23 Toray Ind Inc Ｎ−メチルピペラジントルイル酸誘導体の製造方法
WO2008051597A1 (fr) * 2006-10-26 2008-05-02 Sicor Inc. Procédé pour la préparation d'imatinib

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2010, YAO, R. ET AL: "Synthesis of 4-[(4-methylpiperazin-1-yl) methyl] benzoic acid dihydrochloride", XP002665552, Database accession no. 2011:275657 *
DATABASE WPI Week 200364, Derwent World Patents Index; AN 2003-674143, XP002665553 *
YAO RISHENG ET AL: "Synthesis of 4-[(4-methylpiperazin-1-yl) methyl] benzoic acid dihydrochloride", JINGXI HUAGONG - FINE CHEMICALS, ZHONGGUO HUAGONG XUEHUI, DALIAN, CN, vol. 27, no. 11, 1 January 2010 (2010-01-01), pages 1100 - 1102,1120, XP009154690, ISSN: 1003-5214 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105001205A (zh) * 2015-07-03 2015-10-28 齐鲁天和惠世制药有限公司 一种伊马替尼杂质d的制备方法
CN106905263A (zh) * 2017-03-09 2017-06-30 常州沃腾化工科技有限公司 一种4‑(4‑甲基‑1‑哌嗪基甲基)苯甲酸二盐酸盐的制备方法
CN106905263B (zh) * 2017-03-09 2019-06-14 常州沃腾化工科技有限公司 一种4-(4-甲基-1-哌嗪基甲基)苯甲酸二盐酸盐的制备方法

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