WO2014075648A1 - A method of preparing apixaban - Google Patents

A method of preparing apixaban Download PDF

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Publication number
WO2014075648A1
WO2014075648A1 PCT/CZ2013/000149 CZ2013000149W WO2014075648A1 WO 2014075648 A1 WO2014075648 A1 WO 2014075648A1 CZ 2013000149 W CZ2013000149 W CZ 2013000149W WO 2014075648 A1 WO2014075648 A1 WO 2014075648A1
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WO
WIPO (PCT)
Prior art keywords
oxo
apixaban
formula
reaction
ethyl
Prior art date
Application number
PCT/CZ2013/000149
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English (en)
French (fr)
Inventor
Ludmila Hejtmankova
Josef Jirman
Original Assignee
Zentiva, K.S.
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 Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2014075648A1 publication Critical patent/WO2014075648A1/en

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention relates to a new procedure for preparing apixaban of formula I, chemically l-(4- methoxyphenyl)-7-oxo-6- [4-(2-oxopiperidin- 1 -yl)phenyl] -4,5 ,6,7-tetrahydro- 1 H-pyrazolo [3 ,4- c]pyridine-3-carboxamide, especially to an intermediate of its preparation (II), chemically ethyl ester of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl] -4,5 ,6,7- tetrahydro- 1 H-pyrazolo [3, 4-c]pyridine-3-carboxy lie acid, by a modified Ullmann reaction.
  • Apixaban a compound acting as an anticoagulant, which is used for the treatment of both venous and arterial thromboembolism, was first described in the document EP 1 427 415, which describes the basic synthetic approaches to the preparation of apixaban and similar molecules and briefly also describes pharmaceutical formulations. It this patent the sequence of reactions illustrated in Scheme 1 is used for its preparation.
  • apixaban is also described in the later WO03049681, according to which, inter alia, apixaban of formula I is prepared as indicated in Scheme 2.
  • the object of this invention provides a method for the preparation of apixaban of formula I
  • apixaban of formula I is prepared, which is converted, by reaction with ammonia in a suitable solvent, to apixaban of formula I, which is isolated and optionally crystallized.
  • 1,2-Diamines as ligands are added in amounts in the range of 20-60 molar %, more specifically in amounts in the range of 30-40 molar %.
  • potassium phosphate K 3 P0 4 is used as the phosphoric acid salt and N ⁇ '-dimemylethylenediamine is used as the ligand.
  • Suitable solvents for this reaction are, e.g., solvents from the group of ethers, expressed by the general formula R ⁇ -O-R 2 , wherein R 1 and R 2 are identical or different and are selected from the group including a Ci to C 5 alkyl or cycloalkyl, cyclopentyl methyl ether being especially suitable.
  • the resulting compound of formula II is transformed to apixaban of formula I using well- know procedures, e.g. by reaction of the compound II with ammonia in a suitable solvent.
  • the reaction of the compound II to apixaban is carried out in ethylene glycol, preferably with heating, e.g. to 120 °C, and at an elevated pressure.
  • the resulting apixaban is conveniently isolated by adding the ethylene glycol solution after the reaction and cooling to a Q to C 4 alcohol and isolating the resulting precipitated solid apixaban.
  • the ethylene glycol solution after the reaction and cooling is added, i.e. slowly added dropwise or poured, into ethanol.
  • apixaban This procedure of isolation of apixaban provides a simple method that is suitable for application in the industrial scale and avoids further chromatographic purification, as described, e.g., in J Med. Chem. 2007, 50, page 5354.
  • Apixaban prepared this way can be further crystallized by methods known from the state of the art, e.g., from an ethylene glycol/ethanol mixture.
  • the preparation method in accordance with this invention provides a process that allows preparing apixaban in two reaction steps in a high yield.
  • reaction is carried out with inorganic bases of the type of alkali metal hydroxides, alkali metal carbonates, preferably Cs 2 C0 3 , alkali metal phosphates.
  • inorganic bases of the type of alkali metal hydroxides, alkali metal carbonates, preferably Cs 2 C0 3 , alkali metal phosphates.
  • the best results have been achieved with potassium phosphate as the base in a two- to five-fold molar amount; ground or micronized potassium phosphate can be conveniently used.
  • Another important parameter of the reaction is the solvent used.
  • DMSO dimethyl sulfoxide
  • DMF dimethyl formamide
  • CPME cyclopentyl methyl ether
  • the solvent is characterized by strongly hydrophobic properties, solubility of water in CPME is only 0.3% and it can be dried both with a molecular sieve and by azeotropic distillation.
  • Copper powder, copper(I) or copper(II) salts can be used as the source of copper(II) ions.
  • the use of the price convenient and air stable cuprous iodide in an amount of 5-10 mole % has been evaluated as optimum.
  • apixaban The isolation of apixaban from the reaction mixture described in the basic patent requires purification of the product on a silica gel column. This approach is not suitable for technological applications. We have unexpectedly found out that if the reaction mixture is slowly dosed to ethanol, apixaban will precipitate out from the solution in the form of well filterable crystals in a sufficient yield.
  • a stirrer was inserted in the container and it was closed under an inert atmosphere. Being stirred by a magnetic stirrer the mixture was heated up in an oil bath to 110°C for 6 h. After cooling the reaction mixture was diluted with a solvent, the solid salts were isolated by filtration and thoroughly washed on the filter. The filtrate was concentrated and the crude product was obtained in the yield of 84%.
  • Ethyl 6-(4-iodophenyl)-l-(4- methoxyphenyl)-7-oxo-4,5,6,7-tetrahycho-lH-pyrazolo[3,4-c]pyridine-3-carboxylate (0.538 g; 1.04 mmol) was dissolved in 1 ml of DMF in a sealable pressure container fitted with a magnetic stirrer; piperidin-2-one (0.15 g; 1.5 mmol), Cul (18.4 mg; 0.096 mmol), K3PO 4 (0.457 g; 2.15 mmol) and N,N'-dimemylethylenediamine (15 ⁇ ; 0.136 mmol) were added.
  • the mixture was heated in an oil bath to 90°C for 20 hours.
  • the conversion was monitored with HPLC.
  • the reaction mixture contained 36% of the product 30.3% of the acid V and 2.5% of the starting compound.
  • the reaction mixture was diluted with water and the product was extracted with ethyl acetate. After concentration the product was obtained in the yield of 0.237 g, i.e. 48.6%, with the HPLC content of the desired substance of 68%.
  • Ethyl l-(4-memoxyphenyl)-7-oxo-6-[4-(2-oxol-piperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH- pyrazol-[3,4-c]pyridine-3-carboxylate (4.5 g; 9.2 mmol) was sealed in an ampoule with 40 ml of ethylene glycol containing 15% by weight of ammonia. The ampoule was placed in an oil bath and heated up to 120°C for 1 h. After cooling the reaction mixture was poured to 50 ml of ethanol. The crystalline product was separated in the yield of 90%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
PCT/CZ2013/000149 2012-11-13 2013-11-12 A method of preparing apixaban WO2014075648A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2012-784A CZ304846B6 (cs) 2012-11-13 2012-11-13 Způsob přípravy APIXABANU
CZPV2012-784 2012-11-13

Publications (1)

Publication Number Publication Date
WO2014075648A1 true WO2014075648A1 (en) 2014-05-22

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PCT/CZ2013/000149 WO2014075648A1 (en) 2012-11-13 2013-11-12 A method of preparing apixaban

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CZ (1) CZ304846B6 (cs)
WO (1) WO2014075648A1 (cs)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015111073A3 (en) * 2014-01-21 2015-11-12 Wanbury Ltd. A process for the preparation of apixaban and its intermediates
CN109369642A (zh) * 2018-09-18 2019-02-22 湖北扬信医药科技有限公司 一种阿哌沙班有关物质及其制备方法和用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003049681A2 (en) 2001-12-10 2003-06-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
EP1427415A1 (en) 2001-09-21 2004-06-16 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor xa inhibitors
US20060069258A1 (en) 2004-09-28 2006-03-30 Rafael Shapiro Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones
WO2012168364A1 (en) * 2011-06-10 2012-12-13 Dipharma Francis S.R.L. Apixaban preparation process

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100130543A1 (en) * 2008-09-15 2010-05-27 Auspex Pharmaceuticals, Inc. Pyrazole carboxamide inhibitors of factor xa
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1427415A1 (en) 2001-09-21 2004-06-16 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor xa inhibitors
WO2003049681A2 (en) 2001-12-10 2003-06-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
US20060069258A1 (en) 2004-09-28 2006-03-30 Rafael Shapiro Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones
WO2012168364A1 (en) * 2011-06-10 2012-12-13 Dipharma Francis S.R.L. Apixaban preparation process

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"J Med. Chem.", vol. 50, 2007, WORKERS OF THE BRISTOL-MYERS SQUIBB COMPANY, pages: 5339 - 5356
J. MED. CHEM., vol. 50, 2007, pages 5354
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 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015111073A3 (en) * 2014-01-21 2015-11-12 Wanbury Ltd. A process for the preparation of apixaban and its intermediates
CN109369642A (zh) * 2018-09-18 2019-02-22 湖北扬信医药科技有限公司 一种阿哌沙班有关物质及其制备方法和用途

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CZ304846B6 (cs) 2014-12-03
CZ2012784A3 (cs) 2014-05-21

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