WO2014075648A1 - Procédé de préparation d'apixaban - Google Patents
Procédé de préparation d'apixaban Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oxo
- apixaban
- formula
- reaction
- ethyl
- Prior art date
Links
- XUWHAWMETYGRKB-UHFFFAOYSA-N O=C1NCCCC1 Chemical compound O=C1NCCCC1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- ATNPZEGMKLGIFA-UVTDQMKNSA-N CCOC(/C(/Cl)=N/Nc(cc1)ccc1OC)=O Chemical compound CCOC(/C(/Cl)=N/Nc(cc1)ccc1OC)=O ATNPZEGMKLGIFA-UVTDQMKNSA-N 0.000 description 1
- 0 CCOC(c(c(CCN1c(cc2)ccc2I)c2C1=O)n[n]2-c(cc1)ccc1O*)=O Chemical compound CCOC(c(c(CCN1c(cc2)ccc2I)c2C1=O)n[n]2-c(cc1)ccc1O*)=O 0.000 description 1
- DOONVRNBSUAOKN-UHFFFAOYSA-N CCOC(c(c(CCN1c(cc2)ccc2I)c2C1=O)n[n]2-c(cc1)ccc1OC)=O Chemical compound CCOC(c(c(CCN1c(cc2)ccc2I)c2C1=O)n[n]2-c(cc1)ccc1OC)=O DOONVRNBSUAOKN-UHFFFAOYSA-N 0.000 description 1
- PULNLYVCJSOXKS-UHFFFAOYSA-N CCOC(c(c(CCN1c(cc2)ccc2N(CCCC2)C2=O)c2C1=O)n[n]2-c(cc1)ccc1OC)=O Chemical compound CCOC(c(c(CCN1c(cc2)ccc2N(CCCC2)C2=O)c2C1=O)n[n]2-c(cc1)ccc1OC)=O PULNLYVCJSOXKS-UHFFFAOYSA-N 0.000 description 1
- MJONJJGFHRDMDX-UHFFFAOYSA-N CCOC(c(c(CCN1c(cc2)ccc2N(CCCC2)C2=O)c2C1=O)n[n]2-c(cc1)ccc1[O]1CC1)=O Chemical compound CCOC(c(c(CCN1c(cc2)ccc2N(CCCC2)C2=O)c2C1=O)n[n]2-c(cc1)ccc1[O]1CC1)=O MJONJJGFHRDMDX-UHFFFAOYSA-N 0.000 description 1
- QNZCBYKSOIHPEH-UHFFFAOYSA-N COc(cc1)ccc1-[n]1nc(C(N)=O)c(CCN2c(cc3)ccc3N(CCCC3)C3=O)c1C2=O Chemical compound COc(cc1)ccc1-[n]1nc(C(N)=O)c(CCN2c(cc3)ccc3N(CCCC3)C3=O)c1C2=O QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 description 1
- UWWMPOYYIGCWEH-UHFFFAOYSA-N O=C(C(N1CCOCC1)=CCC1)N1c(cc1)ccc1I Chemical compound O=C(C(N1CCOCC1)=CCC1)N1c(cc1)ccc1I UWWMPOYYIGCWEH-UHFFFAOYSA-N 0.000 description 1
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%.
Landscapes
- 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)
Abstract
La présente invention porte sur un procédé de préparation d'apixaban de formule (I), dans lequel du 6-(4-iodophényl)-1-(4-méthoxyphényl)-7-oxo-4,5,6,7-tétrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate d'éthyle de formule (III) est amené à réagir avec de la pipéridin-2-one de formule (IV) en présence d'une base et d'un ligand et sous catalyse par du cuivre ou par des ions cuivre(II), un sel de l'acide phosphorique étant utilisé comme base et une amine provenant du groupe des 1,2-diamines étant utilisée comme ligand dans un solvant aprotique, et du 1-(4-méthoxyphényl)-7-oxo-6-[4-(2-oxo-1-pipéridin-1-yl)phényl]-4,5,6,7-tétrahydro-1H-pyrazol-[3,4-c]pyridine-3-carboxylate d'éthyle est préparé, lequel est converti, par réaction avec de l'ammoniac dans un solvant approprié, en apixaban de formule (I), qui est isolé et éventuellement cristallisé.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CZPV2012-784 | 2012-11-13 | ||
CZ2012-784A CZ304846B6 (cs) | 2012-11-13 | 2012-11-13 | Způsob přípravy APIXABANU |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014075648A1 true WO2014075648A1 (fr) | 2014-05-22 |
Family
ID=49724921
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CZ2013/000149 WO2014075648A1 (fr) | 2012-11-13 | 2013-11-12 | Procédé de préparation d'apixaban |
Country Status (2)
Country | Link |
---|---|
CZ (1) | CZ304846B6 (fr) |
WO (1) | WO2014075648A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015111073A3 (fr) * | 2014-01-21 | 2015-11-12 | Wanbury Ltd. | Procédé de préparation d'apixabane et de ses intermédiaires |
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003049681A2 (fr) | 2001-12-10 | 2003-06-19 | Bristol-Myers Squibb Company | Synthese de 4,5-dihydropyrazolo[3,4-c]pyrid-2-ones |
EP1427415A1 (fr) | 2001-09-21 | 2004-06-16 | Bristol-Myers Squibb Company | Composes contenant du lactame et leurs derives en tant qu'inhibiteurs du facteur xa |
US20060069258A1 (en) | 2004-09-28 | 2006-03-30 | Rafael Shapiro | Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones |
WO2012168364A1 (fr) * | 2011-06-10 | 2012-12-13 | Dipharma Francis S.R.L. | Procédé de préparation d'apixaban |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2611657T3 (es) * | 2008-09-15 | 2017-05-09 | Auspex Pharmaceuticals, Inc. | Inhibidores de pirazol-carboxamida del 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 |
-
2012
- 2012-11-13 CZ CZ2012-784A patent/CZ304846B6/cs not_active IP Right Cessation
-
2013
- 2013-11-12 WO PCT/CZ2013/000149 patent/WO2014075648A1/fr active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1427415A1 (fr) | 2001-09-21 | 2004-06-16 | Bristol-Myers Squibb Company | Composes contenant du lactame et leurs derives en tant qu'inhibiteurs du facteur xa |
WO2003049681A2 (fr) | 2001-12-10 | 2003-06-19 | Bristol-Myers Squibb Company | Synthese de 4,5-dihydropyrazolo[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 (fr) * | 2011-06-10 | 2012-12-13 | Dipharma Francis S.R.L. | Procédé de préparation d'apixaban |
Non-Patent Citations (3)
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015111073A3 (fr) * | 2014-01-21 | 2015-11-12 | Wanbury Ltd. | Procédé de préparation d'apixabane et de ses intermédiaires |
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 |
Also Published As
Publication number | Publication date |
---|---|
CZ2012784A3 (cs) | 2014-05-21 |
CZ304846B6 (cs) | 2014-12-03 |
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