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WO2015011617A1 - Procédé pour la préparation de rivaroxaban - Google Patents

Procédé pour la préparation de rivaroxaban Download PDF

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Publication number
WO2015011617A1
WO2015011617A1 PCT/IB2014/063191 IB2014063191W WO2015011617A1 WO 2015011617 A1 WO2015011617 A1 WO 2015011617A1 IB 2014063191 W IB2014063191 W IB 2014063191W WO 2015011617 A1 WO2015011617 A1 WO 2015011617A1
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WO
WIPO (PCT)
Prior art keywords
formula
reaction mixture
compound
rivaroxaban
preparation
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/IB2014/063191
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English (en)
Inventor
Ketan HIRPARA
Pankaj Kumar Singh
Kdv JESUNADH
Mukesh Kumar Sharma
Chandra Has Khanduri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2015011617A1 publication Critical patent/WO2015011617A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07D413/12—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 chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention provides processes for the preparation of rivaroxaban.
  • the present invention also provides processes for the preparation of a rivaroxaban intermediate.
  • Rivaroxaban is chemically 5-chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl] - 1 ,3 -oxazolidin-5-yl ⁇ methyl)-2-thiophenecarboxamide of Formula I .
  • Rivaroxaban is used as an anti-thrombotic agent.
  • U.S. Publication No. 2007/0066615 provides a process for the preparation of 5- chloro-N-((2R)-2-hydroxy-3 - ⁇ [4-(3 -oxo-4-morpholinyl)-phenyl] amino ⁇ propyl)-2- thiophenecarboxamide of Formula II
  • U.S. Patent No. 8,106, 192 provides a process for the preparation of 5-chloro-N- ((2R)-2-hydroxy-3 - ⁇ [4-(3 -oxo-4-morpholinyl)-phenyl] amino ⁇ propyl)-2- thiophenecarboxamide of Formula II (named as N- ⁇ (R)-2-Hydroxy-3-[4-(3- oxomo holin-4-yl)phenylamino]propyl ⁇ -5 -chloro-thiophene-2-carboxamide), wherein a mixture of N-((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide and 4-(4- aminophenyl)-3-mo ⁇ holinone in toluene is admixed with collidine and ethanol and the reaction mixture is heated at 103°C to 105°C for 6 hours. The reaction mixture is admixed with
  • the present invention provides industrially feasible processes for the preparation of rivaroxaban.
  • the present invention also provides processes for the preparation of a rivaroxaban intermediate in good yield and purity.
  • the present inventors have found that the formation of the azetidinol impurity of Formula III appearing at a relative retention time (RRT) of 0.83, and the impurity appearing at a relative retention time (RRT) of 1.45 is controlled to be at a minimum level when the reaction between 4-(4-aminophenyl)morpholin-3-one and 5-chloro-N-[(2S)-2- oxiranylmethyl]-2-thiophenecarboxamide is carried out in the presence of inexpensive and readily available acid catalysts containing an alkali metal, an alkaline earth metal, or zinc metal. As a result, the overall yield is increased. This reaction also avoids the use of chromatography and the generation of corrosive by-products.
  • a first aspect of the present invention provides a process for the preparation of 5- chloro-N-((2R)-2-hydroxy-3 - ⁇ [4-(3 -oxo-4-morpholinyl)-phenyl] amino ⁇ propyl)-2- thiophenecarboxamide intermediate of Formula II
  • a second aspect of the present invention provides a process for the preparation of rivaroxaban of Formula I
  • a third aspect of the present invention provides a process for the preparation of 5- chloro-N-((2R)-2-hydroxy-3 - ⁇ [4-(3 -oxo-4-morpholinyl)-phenyl] amino ⁇ propyl)-2- thiophenecarboxamide intermediate of Formula II
  • an acid catalyst selected from lithium perchlorate, magnesium perchlorate, magnesium trifluoromethanesulfonate, zinc perchlorate, or zinc
  • a fourth aspect of the present invention provides a process for the preparation of rivaroxaban of Formula I
  • an acid catalyst selected from lithium perchlorate, magnesium perchlorate, magnesium trifluoromethanesulfonate, zinc perchlorate, or zinc trifluoromethanesulfonate to obtain an intermediate of Formula II;
  • the compounds of Formula IV and Formula V may be prepared by the processes known in the literature, such as those described in U.S. Patent No. 7,157,456 or U.S. Publication No. 2007/0066615, or by the processes described herein.
  • the compound of Formula IV is reacted with the compound of Formula V in the presence of an acid catalyst containing an alkali metal, an alkaline earth metal, or zinc metal in a solvent.
  • acid catalysts containing an alkali metal, an alkaline earth metal, or zinc metal include lithium perchlorate, magnesium perchlorate, magnesium trifluoromethanesulfonate, zinc perchlorate, or zinc trifluoromethanesulfonate.
  • solvents to be used for the reaction of the compound of Formula IV with the compound of Formula V include alcohols such as methanol, ethanol, and iso-propanol; ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, cyclopentylmethyl ether, and tertiary butyl ether; alkyl acetates such as ethyl acetate; ketones such as acetone; chlorinated hydrocarbons such as dichloromethane; acetonitrile; dimethylformamide; dimethylsulf oxide; sulfolane; or mixtures thereof.
  • alcohols such as methanol, ethanol, and iso-propanol
  • ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, cyclopentylmethyl ether, and tertiary butyl ether
  • alkyl acetates such as ethyl acetate
  • ketones such as
  • the compound of Formula IV is reacted with the compound of Formula V at about 10°C to about 35°C.
  • the intermediate of Formula II may be isolated from the reaction mixture by methods such as cooling, decantation, filtration, concentration, distillation, evaporation, centrifugation, or a combination thereof, followed by drying.
  • the intermediate of Formula II may be purified using an alcohol solvent such as methanol, ethanol, isopropanol, or denatured spirit; water; or mixtures thereof, followed by further drying.
  • the intermediate of Formula II prepared by the processes of the present invention may be converted into rivaroxaban of Formula I by following the processes known in the literature, such as by the process described in U.S. Patent No. 8, 106,192, or by the process described herein.
  • the X-ray Powder Diffraction (XRPD) pattern of rivaroxaban of Formula I was recorded using a PANalytical ® X'Pert Pro X-Ray Powder Diffractometer in the range 3 to 40 degree 2 theta under a tube voltage of 45 kV and a current of 40 mA.
  • the copper radiation of wavelength 1.54 angstrom and an X'celetor ® detector were used.
  • HPLC High Performance Liquid Chromatography
  • Dilute hydrochloric acid 800 mL of concentrated hydrochloric acid diluted in 1370 mL of water was added to the reaction mixture over 15 minutes to 20 minutes at 25 °C to 40°C, and the reaction mixture was stirred for 3 hours at the same temperature.
  • the reaction mixture was cooled to 25 °C to 30°C.
  • the aqueous layer was separated and washed with toluene (1000 mL).
  • the aqueous layer was recovered completely at 60°C to 70°C.
  • Methanol 300 mL was added to the resulting mass, and the solvent was recovered completely.
  • Methanol 2000 mL was added to the resulting mass, and it was heated to 70°C to 80°C.
  • reaction mixture was cooled to 25°C to 30°C over 30 minutes, followed by further cooling to -20°C to -25°C and stirring for 6 hours at this temperature.
  • the solid was filtered under nitrogen and suck dried.
  • the solid was washed with cold methanol (500 mL) and dried at 50°C to 55°C overnight under vacuum and unloaded under nitrogen atmosphere to obtain (2S)-l-amino-3-chloropropan-2-ol hydrochloride.
  • 5-Chlorothiophene-2-carboxylic acid 500 g was added to toluene (2500 mL) and the reaction mixture was heated to 70°C to 80°C.
  • Thionyl chloride 275 mL was added to the reaction mixture over 90 minutes, and the reaction mixture was stirred for 1 hour at 70°C to 80°C.
  • the reaction mixture was heated at 100°C to 105°C for 4 hours to 5 hours.
  • the reaction mixture was cooled to 60°C to 65 °C, and the solvent was completely recovered at 60°C to 65°C under vacuum to obtain 5-chlorothiophene-2-carbonylchloride.
  • N-((S)-3-Chloro-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (from Example 3; 100 g) was dissolved in dichloromethane (300 mL) and dimethylformamide (200 mL). Pulverized potassium carbonate (98 g) was added to the reaction mixture at 25°C to 30°C, and the reaction mixture was stirred for 15 hours at this temperature.
  • the solid obtained was suck dried, and then further dried at 55°C to 60°C for 12 hours to obtain 5-chloro-N-((2R)-2-hydroxy-3- ⁇ [4-(3- oxo-4-mo ⁇ holinyl)-phenyl]amino ⁇ propyl)-2-thiophenecarboxamide.
  • Example 9 Preparation of seed of crystalline modification I of rivaroxaban (Formula I) A mixture of rivaroxaban (30 g) in dichloromethane (810 mL) and methanol (300 mL) was stirred at 35°C to 40°C to obtain a solution. Activated carbon (1.5 g) was added to the reaction mixture, and the reaction mixture was stirred for 30 minutes at 35°C to 40°C. The reaction mixture was filtered through a Hyflo ® bed and the filtrate was concentrated to obtain a white solid compound. The white solid was suspended in methanol (300 mL) and dichloromethane (240 mL). The reaction mixture was heated to 50°C and then cooled to 25°C to 30°C. The slurry obtained was stirred for 1 hour at 25°C to 30°C. The precipitate was filtered and dried at 60°C to 65°C under vacuum to obtain the seed of crystalline modification I of rivaroxaban.
  • Rivaroxaban 100 g was added to acetic acid (1800 mL) at 25°C to 30°C and the reaction mixture was heated to 75°C to 80°C to obtain a clear solution.
  • Activated carbon (2.55 g) was added to the reaction mixture, and the reaction mixture was stirred for 30 minutes at 75°C to 80°C.
  • the reaction mixture was filtered through a Hyflo ® bed and the bed was washed with acetic acid (200 mL). Acetic acid was recovered up to 1500 mL under vacuum at 50°C to 55°C to obtain a white slurry.
  • the mixture was cooled to 25°C to 30°C and it was stirred for 1 hour at 25°C to 30°C.
  • the solid was filtered and suck dried.
  • the solid was washed with de-ionized water (200 mL) and suck dried.
  • De-ionized water 500 mL was added to the wet solid.
  • the pH of the reaction mixture was adjusted to 6.5 to 7.5 with aqueous sodium bicarbonate, and the reaction mixture was stirred for 1 hour at 25°C to 30°C.
  • the solid was filtered and suck dried.
  • the solid was washed with de-ionized water (200 mL) and dried at 55°C to 60°C under vacuum for 12 hours to obtain pure rivaroxaban.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des procédés pour la préparation de rivaroxaban. La présente invention concerne également des procédés de préparation d'un intermédiaire de rivaroxaban.
PCT/IB2014/063191 2013-07-23 2014-07-17 Procédé pour la préparation de rivaroxaban Ceased WO2015011617A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2195/DEL/2013 2013-07-23
IN2195DE2013 2013-07-23

Publications (1)

Publication Number Publication Date
WO2015011617A1 true WO2015011617A1 (fr) 2015-01-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2014/063191 Ceased WO2015011617A1 (fr) 2013-07-23 2014-07-17 Procédé pour la préparation de rivaroxaban

Country Status (1)

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WO (1) WO2015011617A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104788444A (zh) * 2015-05-12 2015-07-22 浙江天顺生物科技有限公司 利伐沙班的制备方法
CN104817550A (zh) * 2015-05-26 2015-08-05 山东铂源药业有限公司 一种利伐沙班的制备方法
CN104910141A (zh) * 2015-05-12 2015-09-16 浙江天顺生物科技有限公司 一种利伐沙班中间体5-氯-n-(2-环氧乙烷基甲基)-2-噻吩甲酰胺的制备方法
US10076908B2 (en) 2014-01-31 2018-09-18 Hewlett-Packard Development Company, L.P. Ink supplies and methods to prepare ink supplies
CN110849994A (zh) * 2019-11-25 2020-02-28 湖南九典制药股份有限公司 一种利伐沙班中有关物质的分离方法
CN112110910A (zh) * 2019-06-19 2020-12-22 上海特化医药科技有限公司 制备利伐沙班中间体的方法及由其制备利伐沙班的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004101557A1 (fr) * 2003-05-19 2004-11-25 Bayer Healthcare Ag Composes heterocycliques
US7157456B2 (en) 1999-12-24 2007-01-02 Bayer Healthcare Ag Substituted oxazolidinones and their use in the field of blood coagulation
DE102007032347A1 (de) * 2007-07-11 2009-01-15 Bayer Healthcare Ag Aminoacyl-Prodrugs
US8106192B2 (en) 2003-01-07 2012-01-31 Bayer Pharma Aktiengesellschaft Method for producing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7157456B2 (en) 1999-12-24 2007-01-02 Bayer Healthcare Ag Substituted oxazolidinones and their use in the field of blood coagulation
US8106192B2 (en) 2003-01-07 2012-01-31 Bayer Pharma Aktiengesellschaft Method for producing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
WO2004101557A1 (fr) * 2003-05-19 2004-11-25 Bayer Healthcare Ag Composes heterocycliques
US20070066615A1 (en) 2003-05-19 2007-03-22 Bayer Heathcare Ag Heterocyclic compounds
DE102007032347A1 (de) * 2007-07-11 2009-01-15 Bayer Healthcare Ag Aminoacyl-Prodrugs

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10076908B2 (en) 2014-01-31 2018-09-18 Hewlett-Packard Development Company, L.P. Ink supplies and methods to prepare ink supplies
CN104788444A (zh) * 2015-05-12 2015-07-22 浙江天顺生物科技有限公司 利伐沙班的制备方法
CN104910141A (zh) * 2015-05-12 2015-09-16 浙江天顺生物科技有限公司 一种利伐沙班中间体5-氯-n-(2-环氧乙烷基甲基)-2-噻吩甲酰胺的制备方法
CN104788444B (zh) * 2015-05-12 2018-11-06 浙江天顺生物科技有限公司 利伐沙班的制备方法
CN104817550A (zh) * 2015-05-26 2015-08-05 山东铂源药业有限公司 一种利伐沙班的制备方法
CN104817550B (zh) * 2015-05-26 2017-06-16 山东铂源药业有限公司 一种利伐沙班的制备方法
CN112110910A (zh) * 2019-06-19 2020-12-22 上海特化医药科技有限公司 制备利伐沙班中间体的方法及由其制备利伐沙班的方法
CN112110910B (zh) * 2019-06-19 2024-03-19 上海特化医药科技有限公司 制备利伐沙班中间体的方法及由其制备利伐沙班的方法
CN110849994A (zh) * 2019-11-25 2020-02-28 湖南九典制药股份有限公司 一种利伐沙班中有关物质的分离方法
CN110849994B (zh) * 2019-11-25 2022-07-01 湖南九典制药股份有限公司 一种利伐沙班中有关物质的分离方法

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