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WO2015198259A1 - Procédé de synthèse de rivaroxaban et intermédiaire pour la production de celui-ci - Google Patents

Procédé de synthèse de rivaroxaban et intermédiaire pour la production de celui-ci Download PDF

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Publication number
WO2015198259A1
WO2015198259A1 PCT/IB2015/054777 IB2015054777W WO2015198259A1 WO 2015198259 A1 WO2015198259 A1 WO 2015198259A1 IB 2015054777 W IB2015054777 W IB 2015054777W WO 2015198259 A1 WO2015198259 A1 WO 2015198259A1
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WO
WIPO (PCT)
Prior art keywords
compound
reaction
oxo
rivaroxaban
methylamine
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/IB2015/054777
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English (en)
Inventor
Massimo Ferrari
Emanuele Ghezzi
Marcello Ghezzi
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Erregierre SpA
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Erregierre SpA
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Filing date
Publication date
Application filed by Erregierre SpA filed Critical Erregierre SpA
Publication of WO2015198259A1 publication Critical patent/WO2015198259A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a process for the synthesis of Rivaroxaban, and to a salt that forms as an intermediate in said synthesis.
  • Rivaroxaban is an active substance developed by Bayer Pharma AG is marketed under the name Xarelto ® in the form of tablets for oral administration.
  • the substance acts as a direct and highly selective inhibitor of factor Xa, interrupting the sequence of blood coagulation steps and consequently inhibiting the formation of thrombin and the development of thrombi; is used as an anticoagulant, for example for the prevention of strokes in patients with atrial fibrillation or blood clots in the veins (deep vein thrombosis) that may form following surgical procedures.
  • Rivaroxaban is the INN name of the compound with lUPAC name (S)-5- chloro-A/- ⁇ [2-oxo-3-[4-(3-oxomorpholine4-yl)phenyl]-oxazolidine-5-yl]- methyl ⁇ thiophene-2-carboxamide, havin the following structural formula:
  • the aim of the invention is to provide an alternative process for the preparation of Rivaroxaban. Summary of the invention
  • the invention relates to the compound (5S)-4- ⁇ 4- [5-(aminomethyl)-2-oxo-1 ,3-oxazolidine-3-yl]-phenyl ⁇ morpholine-3-one nitrate, compound (V), intermediate of the process described above.
  • the present invention originates from having identified that it is possible to obtain high purity Rivaroxaban from a specific intermediate compound consisting of the nitrate salt of (5S)-4- ⁇ 4-[5-(aminomethyl)-2-oxo-1 ,3-oxazolidine-3-yl]- phenyl ⁇ morpholine-3-one (Compound V).
  • the first aspect of the invention relates to a novel process for the synthesis of Rivaroxaban comprising the steps a) to d) reported above.
  • step a compound 4-(4-aminophenyl)morpholine-3-one (I) is reacted with compound (S)-(+)-N(2,3-epoxypropyl)phthalimide (II); compounds (I) and (II) are both commercially available.
  • the reaction is carried out using as solvent an alcohol having a low number of carbon atoms, preferably methanol, and preferably with a slight stoichiometric excess of the compound (II), for example with a molar ratio of the compound (II) and the compound (I) of between 1 .2 and 1 .3; the reaction temperature is preferably between 50 °C and the boiling temperature of the solvent (65 °C in the case of methanol).
  • the reaction time is between about 15- 25 hours.
  • the compound (III) produced in the reaction is insoluble in the reaction solvent from which it precipitates as a solid and is recovered by means known to those skilled in the art, by filtration for example, preferably washing it with a solvent like the one used for the reaction and subsequent drying.
  • step b) the compound (III) obtained in the previous step is reacted with ⁇ , ⁇ -carbonyldiimidazole (CDI), a product that is commonly available commercially.
  • CDI ⁇ , ⁇ -carbonyldiimidazole
  • the CDI causes the formation of the cyclic carbamate between the alcohol and the secondary amine of the compound (III), leading to the formation of the compound (IV).
  • the CDI is used in slight stoichiometric excess, in a molar ratio with respect to the compound (III) of between 1 .2 and 1 .3, for example.
  • the compounds (III) and CDI are suspended in a suitable solvent, an halogenated aliphatic or aromatic hydrocarbon for example (chlorobenzene is preferred), the solution is brought to a temperature of between about 80 °C and maintained at this temperature for a period of several hours.
  • the mass is brought to room temperature and the product obtained is filtered and lastly dried.
  • Step c) is carried out in two phases, wherein in the first phase, the phthalimide group is removed from the compound (IV) with formation of the corresponding amine, and in the second phase, the salt of the amine forms with nitric acid.
  • the compound (IV) is reacted with methylamine.
  • Methylamine CH3-NH2
  • Methylamine is a gas, and is preferably used in aqueous solution. Methylamine is used in high stoichiometric excess with respect to the compound (IV). After having loaded the reactants, its inside temperature is brought to a value of about 60 °C, for a period of several hours.
  • the mass is distilled until a dense residue containing the compound (5S)-4- ⁇ 4-[5- (aminomethyl)-2-oxo-1 ,3-oxazolidine-3-yl]-phenyl ⁇ morpholine-3-one is obtained, wherein the phthalimido radical of the compound (IV) is replaced by a primary amine.
  • the residue is typically dissolved with water and alcohol.
  • step c) to the mixture thus obtained nitric acid in aqueous solution is added, typically at a temperature of about 25 °C, causing salification of the amine produced in the previous phase.
  • the intermediate thus precipitated is filtered and washed with a lower alcohol (C1-C5) and dried thus recovering the compound (V).
  • the 5-chlorothiophene-2-carbonyl chloride is not a commercial product and must be prepared shortly before use.
  • a chlorinating reagent such as phosphorus trichloride (PC ), phosphorus pentachloride (PCI5) or, preferably, thionyl chloride (SOCI2) are used to produce this reagent, working in a suitable solvent, such as a halogenated hydrocarbon for example; the reaction occurs in the presence of N,N- dimethylformamide with reaction catalyst function.
  • reaction between the compound (V) and 5-chlorothiophene-2-carbonyl chloride is carried out in a suitable reactor, in the presence of triethylamine with the function of neutralising the hydrochloric acid that is freed.
  • the reaction is carried out at a temperature of between -5 and 35 °C, while slowly adding a solution of 5-chlorothiophene-2-carbonylchloride to the compound (V) suspended in a solvent, preferably an halogenated hydrocarbon.
  • a solvent preferably an halogenated hydrocarbon.
  • the reaction is relatively fast, and requires a timeframe of about one hour for its completion.
  • water is added to the reaction mass, obtaining a heterogeneous biphasic system, wherein the product is the insoluble part, while in the aqueous phase the salts present in the reaction remain dissolved.
  • the desired product can be recovered by known methods, for example by means of centrifugation, washing the solid mass obtained with solvent and then with water and final drying.
  • Rivaroxaban On a diffractometric analysis of the powders (XRPD), the Rivaroxaban thus obtained has the same polymorphic form, form I, as the product obtained in example 44 of patent application WO 01 /47919 A1 , in which the compound was described for the first time.
  • step d) The crude Rivaroxaban obtained in step d) can then be subjected to purification operations, as is well known in the field, in view of its use in the pharmaceutical sector.
  • This example relates to the preparation of 2- ⁇ (fl)-2-hydroxy-3-[4-(3-oxo- morpholine-4-yl)-phenylamino]-propyl ⁇ isoindol-1 ,3-dione, step a) of the process.
  • the mass is heated to around 60 °C and maintained at this temperature for 20 hours, then cooled to 0-10 °C. There is precipitation of the desired product, which is filtered and washed with 30.0 kg of methanol. The product obtained is oven-dried, obtaining 17.0 kg of the desired compound (III), with a reaction yield equal to 82.7%.
  • This example relates to the preparation of 2- ⁇ (S)-2-oxo-3-[4-(3-oxo- morpholine-4-yl)phenyl]-oxazolidine-5-yl-methyl ⁇ -isoindol-1 ,3-dione, step b) of the process.
  • This example relates to preparation of the compound (5S)-4- ⁇ 4-[5- (aminomethyl)-2-oxo-1 ,3-oxazolidine-3-yl]phenyl ⁇ morpholine-3-one nitrate, step c) of the process. 17.0 kg of the compound (IV) obtained in example 2, 170 kg of ethanol and
  • the mass obtained is distilled under vacuum until a dense residue is obtained; 170 kg of ethanol and 34.0 kg of water are added to the residue.
  • This example relates to the preparation of 5-chlorothiophene-2-carbonyl chloride, to be used in step d) of the process.
  • This example relates to the preparation of Rivaroxaban.
  • This example refers to the purification of Rivaroxaban.
  • the mass is heated to solution at about 90 °C to be filtered and thus allow elimination of any mechanical impurities present, then the solvent used to dissolve the crude product (the acetic acid) is almost completely eliminated by vacuum distillation, without going below 90 °C, thus reobtaining the solid product in the form of almost dry residue.
  • the product thus obtained is dried at 80-90 °C.

Landscapes

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

Abstract

L'invention concerne un procédé de production de Rivaroxaban, un composé représenté par la formule structurale suivante : (I) par obtention d'un nouvel intermédiaire dudit procédé.
PCT/IB2015/054777 2014-06-26 2015-06-25 Procédé de synthèse de rivaroxaban et intermédiaire pour la production de celui-ci Ceased WO2015198259A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI20141160 2014-06-26
ITMI2014A001160 2014-06-26

Publications (1)

Publication Number Publication Date
WO2015198259A1 true WO2015198259A1 (fr) 2015-12-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2015/054777 Ceased WO2015198259A1 (fr) 2014-06-26 2015-06-25 Procédé de synthèse de rivaroxaban et intermédiaire pour la production de celui-ci

Country Status (1)

Country Link
WO (1) WO2015198259A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018127762A1 (fr) * 2017-01-04 2018-07-12 Unichem Laboratories Ltd Procédé amélioré pour la préparation de rivaroxaban impliquant un nouvel intermédiaire
WO2022180531A1 (fr) 2021-02-23 2022-09-01 Teva Pharmaceutical Industries Ltd Compositions pharmaceutiques à dose fixe

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047919A1 (fr) 1999-12-24 2001-07-05 Bayer Aktiengesellschaft Oxazolidinones substituees et leur utilisation dans le domaine de la coagulation sanguine
WO2011012321A1 (fr) 2009-07-31 2011-02-03 Krka, D.D., Novo Mesto Méthodes de cristallisation de rivaroxaban
WO2012035057A2 (fr) * 2010-09-14 2012-03-22 Medichem S.A. Procédé de détermination du caractère approprié à la distribution d'un lot de dérivé de thiophène-2-carboxamide
WO2013053739A1 (fr) * 2011-10-10 2013-04-18 Laboratorios Lesvi, S. L. Procédé de préparation d'inhibiteurs du facteur xa
WO2013120465A1 (fr) * 2012-02-16 2013-08-22 Zentiva, K.S. Procédé de préparation de rivaroxaban fondé sur l'utilisation de (s)-épichlorohydrine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047919A1 (fr) 1999-12-24 2001-07-05 Bayer Aktiengesellschaft Oxazolidinones substituees et leur utilisation dans le domaine de la coagulation sanguine
WO2011012321A1 (fr) 2009-07-31 2011-02-03 Krka, D.D., Novo Mesto Méthodes de cristallisation de rivaroxaban
WO2012035057A2 (fr) * 2010-09-14 2012-03-22 Medichem S.A. Procédé de détermination du caractère approprié à la distribution d'un lot de dérivé de thiophène-2-carboxamide
WO2013053739A1 (fr) * 2011-10-10 2013-04-18 Laboratorios Lesvi, S. L. Procédé de préparation d'inhibiteurs du facteur xa
WO2013120465A1 (fr) * 2012-02-16 2013-08-22 Zentiva, K.S. Procédé de préparation de rivaroxaban fondé sur l'utilisation de (s)-épichlorohydrine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018127762A1 (fr) * 2017-01-04 2018-07-12 Unichem Laboratories Ltd Procédé amélioré pour la préparation de rivaroxaban impliquant un nouvel intermédiaire
US11034683B2 (en) 2017-01-04 2021-06-15 Unichem Laboratories Ltd Process for the preparation of rivaroxaban involving novel intermediate
US11891384B2 (en) 2017-01-04 2024-02-06 Unichem Laboratories Ltd Process for the preparation of Rivaroxaban involving novel intermediate
WO2022180531A1 (fr) 2021-02-23 2022-09-01 Teva Pharmaceutical Industries Ltd Compositions pharmaceutiques à dose fixe

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