WO2014072884A1 - Procédé de synthèse d'apixaban - Google Patents

Procédé de synthèse d'apixaban Download PDF

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Publication number
WO2014072884A1
WO2014072884A1 PCT/IB2013/059776 IB2013059776W WO2014072884A1 WO 2014072884 A1 WO2014072884 A1 WO 2014072884A1 IB 2013059776 W IB2013059776 W IB 2013059776W WO 2014072884 A1 WO2014072884 A1 WO 2014072884A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
preferably selected
phenyl
formula
compound
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PCT/IB2013/059776
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English (en)
Inventor
Venkat Raman JAYARAMAN
Nilav PATEL
Manoj Borsaniya
Kamlesh Kanzariya
Piyush Rana
Sudhir Shah
Dinesh Panchasara
Sanjiv Tomer
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Alembic Pharmaceuticals 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.)
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Application filed by Alembic Pharmaceuticals Limited filed Critical Alembic Pharmaceuticals Limited
Publication of WO2014072884A1 publication Critical patent/WO2014072884A1/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
    • C07D401/10—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 linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the Process for the preparation of Apixaban and novel intermediates useful in the synthesis of Apixaban (I)
  • Apixaban (BMS-562247-01, tradename Eliquis) is an anticoagulant for the prevention of venous thromboembolism and venous thromboembolic events. It is a direct factor Xa inhibitor.
  • US6967208B2 discloses a series of coagulation factor Xa inhibitors l-(4-methoxyphenyl)-7-oxo-6-[4- (2-oxopiperidin-l-yl)phenyl]-4,5-dihydropyrazolo[5,4-c]pyridine-3-carboxamide (also known as Apixaban).
  • US7396932 discloses process for the preparation of Apixaban by condensing compound of formula II and compound of formula III in the presence of base.
  • the present invention addresses these issues and provides novel process for making Apixaban.
  • the present invention also provides novel intermediates for the synthesis of Apixaban.
  • R 1 is selected from OR a , NR b R c , CI, Br, I, SR a ;
  • R a is H, Ci-C 6 alkyl, aryl, aryl substituted with alkyl group;
  • R b and R c are selected from Ci-C 6 , alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl;
  • N R b R c is a 3-8 membered ring consisting of: carbon atoms, N and 0-1 O atoms
  • Y is selected from phenyl, pyridyl or pyrimidyl
  • Z is selected from CI, Br, I, CN, N02, NH2 or 5-10 membered heterocycle ring containing from 1-4 heteroatoms selected from the group consisting of N,0 and S substituted with 0-2 R d ;
  • R 3 is selected from ester, amide, nitrile, carboxylic acid
  • R 2 is selected from halogen, mesylate, tosylate, 0-S0 2 -Ph, OR a , where in R a is H, Ci-C 6 alkyl, aryl, aryl substituted with alkyl group.
  • Another object of the present invention to provide process for the preparation of compound of formula
  • R 1 is preferably selected from NR b R ;
  • NR b R° is preferably selected from morpholino, pyrolidino, pipieridino;
  • Y is preferably selected from phenyl
  • Z is preferably selected from pyridine 2-one
  • R 2 is preferably selected from halogen, tosylate and mesylate;
  • R is preferably selected from ester, carboxylic acid.
  • Base that used for the preparation of compound of formula V is selected from the group comprising of organic base such as pyridine, dimethyl amine and trimethyl amine and Inorganic base such as KOH, NaOH, K 2 C0 3 , Na 2 C0 3 , CaC0 3 , NH 4 and the like.
  • Aprotic solvent may be selected from the group consisting of chlorinated and ether solvent.
  • Chlorinated solvent is selected from methyl chloride, dichloride methane, and chloroform;
  • ether solvent is selected from tetrahydrofuran, dimethyl ether, polyethylene glycol, dioxin, diethyl ether.
  • Further object of the present invention is to provide a novel process for the preparation of Apixaban comprising a step of reacting compound of formula V with compound of formula VI or salt thereof in the presence of aq. alcoholic solvent to obtain compound of formula VII.
  • R 1 is selected from OR a , NR b R c , CI, Br, I, SR a ;
  • R a is H, C C 6 alkyl, aryl, aryl substituted with alkyl group;
  • R b and R c are selected from Ci-C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl;
  • N R b R c is a 3-8 membered ring consisting of: C atoms, N and 0-1 O atoms;
  • Y is selected from phenyl, pyridyl or pyrimidyl
  • Z is selected from CI, Br , I, CN, N02, NH2 or 5-10 membered heterocycle ring containing 1-4 heteroatoms selected from the group consisting of N,0 and S substituted with 0-2 R d ;
  • R is selected from halogen, OR a , mesylate, tosylate, 0-S0 2 -Ph;
  • R 3 is selected from from ester, amide, nitrile, carboxylic acid
  • R is selected from OR a where in H, Ci-C 6 alkyl, aryl, aryl substituted with alkyl group;
  • R 1 is preferably selected from NR b R ;
  • NR b R is preferably selected from morpholino, pyrolidino, pipieridino;
  • Y is preferably selected from phenyl
  • Z is preferably selected from pyridine 2-one
  • R 2 is preferably selected from halogen, tosylate and mesylate;
  • R is preferably selected from ester, carboxylic acid.
  • Aq. alcoholic solvent that used in the preparation of compound of formula VII is mixture of alcohol and water.
  • Alcoholic solvent is selected from the group consisting of Ci to C 8 carbon. The preferred one is ethanol, methanol and isopropyl alcohol.
  • Yet another object of the present invention is to provide a process for the synthesis of Apixaban (I) from the compound of formula VII wherein R 3 is ester or carboxylic acid is reacted with ammonia.
  • Another object of present invention is to provide a novel compound of formula V and its use in the synthesis of Apixaban
  • R 1 is selected from OR a , NR b R c , SR a ;
  • R a is H, Ci-C 6 alkyl, aryl, aryl substituted with alkyl group;
  • R b and R c are selected from CI -6, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl;
  • N R b R c is a 3-8 membered ring consisting of: carbon atoms, N and 0-1 O atoms;
  • Y is selected from phenyl, pyridyl or pyrimidyl
  • Z is selected from CI, Br , I, CN, N02, NH2 or 5-10 membered heterocyclic ring containing from 1-4 heteroatoms selected from the group consisting of N,0 and S substituted with 0-2 R d ;
  • R 3 is selected from ester, amide, nitrile, carboxylic acid.
  • R 1 is preferably selected from NR b R ;
  • NR b R° is preferably selected from morpholino, pyrolidino, pipieridino;
  • Y is preferably selected from phenyl
  • Z is preferably selected from pyridine 2-one
  • R 3 is preferably selected from ester, carboxylic acid.
  • R 1 is selected from OR a , NR b R c , CI, Br, I, SR a ;
  • R a is H, Ci-C 6 alkyl, aryl, aryl substituted with alkyl group;
  • R b and R c are selected from CI -6, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl;
  • N R b R c is a 3-8 membered ring consisting of: carbon atoms, N and 0-1 O atoms
  • Y is selected from phenyl, pyridyl or pyrimidyl
  • Z is selected from CI, Br , I, CN, N02, NH2 or 5-10 membered heterocycle ring containing from 1-4 heteroatoms selected from the group consisting of N,0 and S substituted with 0-2 R d ;
  • R 3 is selected from ester, amide, nitrile, carboxylic acid ;
  • R 2 is selected from halogen, mesylate, tosylate, 0-S0 2 -Ph, OR a .
  • R 1 is preferably selected from NR b R ;
  • NR b R° is preferably selected from morpholino, pyrolidino, pipieridino;
  • Y is preferably selected from phenyl
  • Z is preferably selected from pyridine 2-one
  • R 2 is preferably selected from halogen, tosylate and mesylate;
  • R is preferably selected from ester, carboxylic acid.
  • Base that used for the preparation of compound of formula V is selected from the group comprising of organic base such as pyridine, diethyl amine and trimethyl amine and Inorganic base such as KOH, NaOH, K 2 C0 3 , Na 2 C0 3 , CaC0 3 , NH 4 and the like. More Preferable inorganic base is K 2 C0 3 and organic base is pyridine The quantity of base used in this step may range from about 1 to about 3 molar equivalents, per mole of compound (IV).
  • Aprotic solvent may be selected from the group consisting of chlorinated and ether solvent.
  • Chlorinated solvent is selected from methyl chloride, dichloride methane, and chloroform;
  • ether solvent is selected from tetrahydrofuran, dimethyl ether, polyethylene glycol, dioxin, diethyl ether.
  • the amount of solvent that preferably used in this step may range from about 5 to 30 volumes to compound of formula (IV).
  • Further embodiment of present invention is to provide Process for the preparation of Apixaban comprising a step of reacting compound of formula V with a compound of formula VI or salt thereof in the presence of aq. alcoholic solvent.
  • R 1 is selected from OR a , NR b R c , CI, Br, I, SR a ;
  • R a is H, C C 6 alkyl, aryl, aryl substituted with alkyl group;
  • R b and R c are selected from CI -6, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl;
  • N R b R c is a 3-8 membered ring consisting of: carboan atoms, N and 0-1 O atoms
  • Y is selected from phenyl, pyridyl or pyrimidyl;
  • Z is selected from CI, Br , I, CN, N02, NH2 or 5-10 membered heterocyclic ring containing from 1-4 heteroatoms selected from the group consisting of N,0 and S substituted with 0-2 R d ;
  • R is halogen, OR a , mesylate, tosylate, 0-S0 2 -Ph;
  • R 3 is selected from ester, amide, nitrile, carboxylic acid.
  • Aq alcoholic solvent that used in the preparation of compound of formula VII is mixture of alcohol and water.
  • Alcoholic solvent is selected from the group consisting of CI to C8 carbon. The preferred one is ethanol, methanol and isopropyl alcohol.
  • the amount of solvent that preferably used in this step may range from about 5 to 30 volumes to compound of formula (V).
  • the salt of compound of formula VI is hydrochloride, hydrobromide or hydroiodide salt.
  • Yet another object of the present invention is to provide a process for the synthesis of Apixaban (I) from the compound of formula VII wherein R 3 is ester or carboxylic acid is reacted with ammonia.
  • Further embodiment of present invention is to provide a process for the synthesis of Apixaban (I) from the compound of formula VII wherein the compound of formula VII is treated with ammonia when R is ester or carboxylic acid.
  • One of the embodiments of present invention provides novel compound of formula V.
  • R 1 is selected from OR a , NR b R c , CI, Br, I, SR a ;
  • R a is H, C C 6 alkyl, aryl, aryl substituted with alkyl group;
  • R b and R c are selected from CI -6, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl;
  • N R b R c is a 3-8 member ring consisting of: carbon atoms, N and 0-1 O atoms
  • Y is selected from phenyl, pyridyl or pyrimidyl
  • Z is selected from CI, Br , I, CN, N02, NH2 or 5-10 membered heterocyclic ring containing from 1-4 heteroatoms selected from the group consisting of N,0 and S substituted with 0-2 R d ;
  • R 3 is selected from ester, amide, nitrile, carboxylic acid
  • R 1 is preferably selected from NR b R°;
  • NR b R is preferably selected from morpholino, pyrolidino, pipieridino;
  • Y is preferably selected from phenyl
  • Z is preferably selected from pyridine 2-one
  • R is preferably selected from ester, carboxylic acid.
  • Ethyl l-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7tetrahydro-lH- pyrazolo[3,4-c]pyridine-3-carboxylate 100 gm is heated with Ethylene glycol-NH 3 (5-6 % w/w) (1000 ml) in pressure reactor at 115-120°C for 1.5 hrs. After the completion of reaction it is cooled to 35-40°Cand the product is precipitated by addition of water (600 ml). The solid is filtered and dried. Yield 75%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne un procédé pour la préparation d'apixaban et des nouveaux intermédiaires à utiliser dans la synthèse d'apixaban (I).
PCT/IB2013/059776 2012-11-12 2013-10-30 Procédé de synthèse d'apixaban WO2014072884A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3289/MUM/2012 2012-11-12
IN3289MU2012 2012-11-12

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WO2014072884A1 true WO2014072884A1 (fr) 2014-05-15

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106117200A (zh) * 2016-06-27 2016-11-16 青岛云天生物技术有限公司 预防或治疗关节置换静脉血栓药物阿哌沙班的制备方法
EP3228619A1 (fr) 2016-04-04 2017-10-11 Zaklady Farmaceutyczne Polpharma SA Procédé de preparation d' apixabam
CN110204541A (zh) * 2018-02-28 2019-09-06 新发药业有限公司 一种阿哌沙班的制备方法
WO2022180531A1 (fr) 2021-02-23 2022-09-01 Teva Pharmaceutical Industries Ltd Compositions pharmaceutiques à dose fixe

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WO2003049681A2 (fr) * 2001-12-10 2003-06-19 Bristol-Myers Squibb Company Synthese de 4,5-dihydropyrazolo[3,4-c]pyrid-2-ones
US20030191115A1 (en) * 2001-09-21 2003-10-09 Pinto Donald J.P. Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US7396932B2 (en) 2004-09-28 2008-07-08 Bristol-Myers Squibb Company Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones
CN101967145B (zh) * 2010-09-09 2012-07-04 华东理工大学 一种抗血栓药物阿匹沙班的制备方法
CN102675314A (zh) * 2012-06-14 2012-09-19 南京正科制药有限公司 一种阿哌沙班的合成方法

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CN101967145B (zh) * 2010-09-09 2012-07-04 华东理工大学 一种抗血栓药物阿匹沙班的制备方法
CN102675314A (zh) * 2012-06-14 2012-09-19 南京正科制药有限公司 一种阿哌沙班的合成方法

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DUPLANTLER A J ET AL: "7-OXO-4,5,6,7-TETRAHYDRO-1H-PYRAZOLOÄ3,4-CÜPYRIDINES AS NOVEL INHIBITORS OF HUMAN EOSINOPHIL PHOSPHODIESTERASE", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 41, no. 13, 1 January 1998 (1998-01-01), pages 2268 - 2277, XP002938447, ISSN: 0022-2623, DOI: 10.1021/JM9800090 *
PINTO D ET AL: "Discovery of 1-[4-(Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 50, 1 January 2007 (2007-01-01), pages 5339 - 5356, XP007915445, ISSN: 0022-2623, [retrieved on 20070310], DOI: 10.1021/JM070245N *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3228619A1 (fr) 2016-04-04 2017-10-11 Zaklady Farmaceutyczne Polpharma SA Procédé de preparation d' apixabam
CN106117200A (zh) * 2016-06-27 2016-11-16 青岛云天生物技术有限公司 预防或治疗关节置换静脉血栓药物阿哌沙班的制备方法
CN106117200B (zh) * 2016-06-27 2018-02-02 张士伟 预防或治疗关节置换静脉血栓药物阿哌沙班的制备方法
CN110204541A (zh) * 2018-02-28 2019-09-06 新发药业有限公司 一种阿哌沙班的制备方法
WO2022180531A1 (fr) 2021-02-23 2022-09-01 Teva Pharmaceutical Industries Ltd Compositions pharmaceutiques à dose fixe

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