WO2014020458A1 - Procédé amélioré de préparation du rivaroxaban - Google Patents

Procédé amélioré de préparation du rivaroxaban Download PDF

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Publication number
WO2014020458A1
WO2014020458A1 PCT/IB2013/055062 IB2013055062W WO2014020458A1 WO 2014020458 A1 WO2014020458 A1 WO 2014020458A1 IB 2013055062 W IB2013055062 W IB 2013055062W WO 2014020458 A1 WO2014020458 A1 WO 2014020458A1
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WO
WIPO (PCT)
Prior art keywords
mixture
rivaroxaban
water
process according
sulfolane
Prior art date
Application number
PCT/IB2013/055062
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English (en)
Inventor
Venkat Raman JAYARAMAN
Sanjiv Tomer
Kamlesh Kanzariya
Nilav PATEL
Mitul Dolia
Original Assignee
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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Publication date
Application filed by Alembic Pharmaceuticals Limited filed Critical Alembic Pharmaceuticals Limited
Publication of WO2014020458A1 publication Critical patent/WO2014020458A1/fr

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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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

Definitions

  • the present invention relates to a process for the preparation of 5-chloro-N-( ⁇ (5S)-2-oxo-3- [4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl ⁇ methyl)-2-thiophen-carboxamide (I) by reacting 5-chlorothiphene-2-carbonyl chloride and 4-[4-((S)-4-aminomethyl-2- oxoimidazolidin-l-yl)phenyl]morpholine-3-one hydrochloride in the presence of buffer reagent.
  • the compound of the formula (I) acts as inhibitor of clotting factor Xa and can be employed as agent for the prophylaxis and/or treatment of thromboembolic disorders, in particular myocardial infarction, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transient ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses.
  • the compound of formula (I) also known as rivaroxaban and marketed in a number of countries under the trade designation Xarelto.
  • WO-A 01/47919 disclosed the compound of formula (I).
  • WO-A 01/47919 also describes a method for preparing the compound of the formula (I) in the gram range starting from the same starting compounds 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l ,3(2H)-dione (II), 4-(4- aminophenyl)-3-morpholinone (III) and 5-chlorothiophene-2-carbonyl chloride (IV):
  • (V) is converted with a phosgene equivalent into 2-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-l,3-oxazolidin-5-yl ⁇ -methyl)- lH-isoindole-l,3(2H)dione (VI).
  • DE 1030011 1.5 discloses an alternative process for synthesizing the compound of the formula (I) starting from 5-chlorothiophene-2-carbonyl chloride (IV), (2S)-3-aminopropane- 1,2-diol hydro-chloride (VIII) and 4-(4-aminophenyl)-3-morpholinone (III):
  • (IX) is converted into 5- chlorothiophene-2-carboxylic acid ((S)-3-bromo-2-hydroxypropyl)amide (X), which is then reacted with 4-(4-aminophenyl)-3-morpholinone (III) to give 5-chlorothiophene-2-carboxylic acid ⁇ (R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]-propyl ⁇ amide (XI).
  • (XI) is reacted with phosgene or a phosgene equivalent to give 5-chloro-N-( ⁇ (5S)-2-oxo-3-[4- (3-oxo-4-morpholinyl)phenyl]-l ,3-oxazolidin-5-yl ⁇ methyl)-2-thiophenecarboxamide(I).
  • US7351823B2 discloses an alternative process for synthesizing the compound of the formula (I) by reacting by reacting 4- ⁇ 4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl ⁇ morpholin-3-one (VII) hydrochloride with 5-chlorothiophene-2-carbonyl chloride (IV), characterized in that the reaction is carried out in a solvent selected from the group of ether, alcohol, ketone and water or in a mixture thereof with use of an inorganic base.
  • the ' 823 patent does not disclose the chemical purity of the rivaroxaban obtained by the modified process.
  • the experimental example (d, 3 step) describes a melting point of 230 °C for rivaroxaban after recrystallization from acetic acid, filtration, washing with acetic acid and water and drying. The reported melting point is lower than the melting point of rivaroxaban with 100% chemical purity described in the WO-A 01/47919, i.e. 232-233 °C, and which corresponds to crystalline form I.
  • the authors of the present invention have found that the rivaroxaban obtained by the modified process disclosed in the ' 823 patent contains high amounts of specific impurities, and therefore the process is not suitable for the preparation of compound (I) on an industrial scale.
  • One significant undesired by-product found in the rivaroxaban obtained by the modified process disclosed in the example (d, 2 nd step) of the '823 patent is the N,N'-bis[ ⁇ (5,S)-2-oxo- 3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5- yl ⁇ methyl]urea, which has not been previously described in the literature.
  • the object of the present invention derives therefrom, of providing a simplified process for preparing the compound (I) on the industrial scale, avoiding toxic solvents or reagents, especially in the last steps of the process.
  • It is an object of the present invention is to provide a process for the preparation of Rivaroxaban (I) comprising a step of reacting 4-[4-((S)-5-aminomethyl-2-0xo-l,3- oxazolidine-3-yl]-phenyl-morpholin-3-onehydrochloride(VII) with 5-chlorothiphene-2- carbonyl chloride (IV), in the presence of buffer reagent and a solvent selected form the group of ketone, aromatic hydrocarbon, polar aprotic solvent, water or mixture thereof or mixture of two or more solvents.
  • preferred polar aprotic solvents are sulfolane, N-methyl pyrollidine, 1,3-Dimethyl -3,4,5,6-tetrahydro-2(lH)-pyrimidinone(DMPU), Hexamethylphosphoramide (HMPA), Dimethylformamide, water or mixture thereof or mixture of two or more solvents.
  • DMPU 1,3-Dimethyl -3,4,5,6-tetrahydro-2(lH)-pyrimidinone
  • HMPA Hexamethylphosphoramide
  • Dimethylformamide water or mixture thereof or mixture of two or more solvents.
  • mixture of sulfolane and water Preferably, mixture of sulfolane and water.
  • solvents are: ketone such as methyl ethyl ketone, methyl isobutyl ketone or acetone or mixture thereof; aromatic hydrocarbon such as toluene, xylene or water or mixture of two or more solvents.
  • ketone such as methyl ethyl ketone, methyl isobutyl ketone or acetone or mixture thereof
  • aromatic hydrocarbon such as toluene, xylene or water or mixture of two or more solvents.
  • More Preferred buffer reagents are sodium acetate, sodium citrate, sodium phosphate, calcium acetate, calcium citrate, calcium phosphate, specifically sodium acetate.
  • Further object of the present invention is to provide process for the purification of Rivaroxaban comprising the steps of
  • the crystallization according to IV) is achieved by decreasing the temperature of Rivaroxaban crystallization mixture.
  • antisolvents are hexane, heptane, cyclohexane or water. More preferred antisolvent is water.
  • present invention provides a process for the preparation of Rivaroxaban (I) comprising a step of reacting 4-[4-((S)-5-aminomethyl-2-0xo-l,3-oxazolidine-3-yl]-phenyl- morpholin-3-onehydrochloride(VII) with 5-chlorothiphene-2-carbonylchloride (IV) in the presence of buffer reagent and a solvent selected form the group of ketone, aromatic hydrocarbon, polar aprotic solvent, water or mixture thereof or mixture of two or more solvents.
  • dipolar aprotic solvents examples include sulfolane, N-methyl pyrollidine ( MP), l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU),
  • Hexamethylphosphoramide HMPA
  • Dimethylformamide water or mixture thereof or mixture of two or more solvents.
  • solvents are: ketone such as methyl ethyl ketone, methyl isobutyl ketone or acetone or mixture thereof; aromatic hydrocarbon such as toluene, xylene; water or mixture of two or more solvents.
  • ketone such as methyl ethyl ketone, methyl isobutyl ketone or acetone or mixture thereof
  • aromatic hydrocarbon such as toluene, xylene
  • water or mixture of two or more solvents Preferably, mixture of toluene, acetone and water
  • Examples of preferred buffer reagent used herein above includes but not limited to: citrate buffer, acetate buffer, phosphate buffer or mixture thereof.
  • More preferred buffer reagents are sodium acetate, sodium citrate, sodium phosphate, calcium acetate, calcium citrate or calcium phosphate, especially sodium acetate.
  • the present invention also provides process for the purification of Rivaroxaban comprising the steps of
  • preferred antisolvents are hexane, heptanes, cyclohexane or water. More preferred antisolvent is water.
  • Rivaroxaban is heated up to 100-130 °C in sulfolane to obtained clear solution.
  • water is added to the said solution at 100-130 °C.
  • Reaction mixture is cooled to obtain crystals of Rivaroxaban.
  • Rivaroxaban obtained by the present invention having purity at least 99.0 area % determined by HPLC.
  • Example 2 The above solid from Example 1 is suspended in 20 ml Sulfolane, heated the reaction mixture at 120°C, and added drop wise 30 ml water at 105-110 ° C. After cooling to 25-30°C, the precipitated reaction product is filtered off and washed with water. Dried the solid.
  • Example 2 The above solid from Example 1 is suspended in 20 ml Sulfolane, heated the reaction mixture at 120°C. After cooling to 25-30°C, the precipitated reaction product is filtered off. Dried the solid. Melting point 232-233 °C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Cette invention concerne un procédé de préparation de 5-chloro- N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]-1,3-oxazolidin-5-yl}- méthyl)-2-thiophène-carboxamide (I) par réaction d'un chlorure de 5-chlorothiophène-2-carbonyle et d'un chlorhydrate de 4-[4-((S)- 4-aminométhyl-2-oxoimidazolidin-1-yl)phényl]morpholine-3-one en présence d'un réactif de tamponnage. (I)
PCT/IB2013/055062 2012-08-01 2013-06-20 Procédé amélioré de préparation du rivaroxaban WO2014020458A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2219MU2012 2012-08-01
IN2219/MUM/2012 2012-08-01

Publications (1)

Publication Number Publication Date
WO2014020458A1 true WO2014020458A1 (fr) 2014-02-06

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104211694A (zh) * 2014-08-14 2014-12-17 广东东阳光药业有限公司 一种改进的制备Xa因子抑制剂的方法
EP2459555B1 (fr) 2009-07-31 2021-11-03 KRKA, D.D., Novo Mesto Méthodes de cristallisation de rivaroxaban

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1906191B (zh) * 2004-01-15 2010-05-26 拜耳先灵制药股份公司 制备方法
WO2011012321A1 (fr) * 2009-07-31 2011-02-03 Krka, D.D., Novo Mesto Méthodes de cristallisation de rivaroxaban
CN103145698A (zh) * 2013-03-01 2013-06-12 江西同和药业有限责任公司 一种利伐沙班中间体的制备方法及利伐沙班的新合成方法
WO2013121436A2 (fr) * 2012-02-06 2013-08-22 Megafine Pharma (P) Ltd Procédé de préparation de rivaroxaban et de ses intermédiaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1906191B (zh) * 2004-01-15 2010-05-26 拜耳先灵制药股份公司 制备方法
WO2011012321A1 (fr) * 2009-07-31 2011-02-03 Krka, D.D., Novo Mesto Méthodes de cristallisation de rivaroxaban
WO2013121436A2 (fr) * 2012-02-06 2013-08-22 Megafine Pharma (P) Ltd Procédé de préparation de rivaroxaban et de ses intermédiaires
CN103145698A (zh) * 2013-03-01 2013-06-12 江西同和药业有限责任公司 一种利伐沙班中间体的制备方法及利伐沙班的新合成方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2459555B1 (fr) 2009-07-31 2021-11-03 KRKA, D.D., Novo Mesto Méthodes de cristallisation de rivaroxaban
CN104211694A (zh) * 2014-08-14 2014-12-17 广东东阳光药业有限公司 一种改进的制备Xa因子抑制剂的方法

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