WO2013118130A1 - 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 - Google Patents

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 Download PDF

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Publication number
WO2013118130A1
WO2013118130A1 PCT/IN2012/000086 IN2012000086W WO2013118130A1 WO 2013118130 A1 WO2013118130 A1 WO 2013118130A1 IN 2012000086 W IN2012000086 W IN 2012000086W WO 2013118130 A1 WO2013118130 A1 WO 2013118130A1
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WIPO (PCT)
Prior art keywords
oxo
phenyl
chloro
formula
oxazolidin
Prior art date
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PCT/IN2012/000086
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English (en)
Inventor
Dodda Mohan Rao
Buthukuri Venkat Reddy
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Symed Labs 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 Symed Labs Limited filed Critical Symed Labs Limited
Priority to PCT/IN2012/000086 priority Critical patent/WO2013118130A1/fr
Publication of WO2013118130A1 publication Critical patent/WO2013118130A1/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

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-thiophene-carboxamide.
  • Rivaroxaban is a novel anticoagulant approved in US and Europe for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and for non-valvular atrial fibrillation to reduce stroke risk in cardiac patients.
  • Rivaroxaban is structurally related to the antibacterial compound Linezolid (Zyvox) is enantiomerically pure. Rivaroxaban is available in the market under the brand name Xarelto® as 10 mg tablets in Europe and US.
  • Rivaroxaban is chemically described as 5-chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-l,3-oxazolidin-5-yl ⁇ methyl)-2-thiophene-carboxamide (herein after referred by generic name rivaroxaban) and is represented by the structural formula I shown below:
  • carboxamides including rivaroxaban or pharmaceutically acceptable acid addition salts thereof, a pharmaceutical composition and a method of treatment.
  • Th xaban which is illustrated
  • the process of the present invention is simple, eco-friendly, economic, reproducible, robust and is well suited on commercial scale.
  • the present invention relates to a process for the preparation of 5-chloro-N-( ⁇ (5S)-2- oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1, 3-oxazolidin-5-yl ⁇ methyl)-2-thiophene- carboxamide (I).
  • the present invention relates to a process for the preparation of 5-chloro-N- ( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1, 3-oxazolidin-5-yl ⁇ methyl)-2-thiophene- carboxamide of formula (I)
  • Fig. 1 is a schematic representation of the process of present invention.
  • the present invention is directed to a process for the preparation of 5-chloro-N-( ⁇ (5S)-2- oxo-3 - [4-(3 -oxo-4-morpholinyl) phenyl] - 1 ,3 -oxazolidin-5 -yl ⁇ methyl)-2-thiophene-carboxamide (I) ⁇
  • substituted phenyl boronic acids that can be used include but are not limited to 3,4,5- triflourophenyl boronic acid, 3,5-bis(trifluoromethyl) phenyl boronic acid, 4-nitrophenyl boronic acid, 2-iodophenyl boronic acid, 2-bromo phenyl boronic acid and the like; preferably 2- iodophenyl boronic acid.
  • reagent boric acid and / or sub. or unsub. phenyl boronic acid employed herein can be typically in the range from about 0.05 mole to about 5 moles on 1 mole of compound of formula III taken. Preferably, from about 0.01 mole to about 0.25 mole on 1 mole of the compound of formula III taken.
  • the solvents that can be used in the reaction between compound of formula II and III include but are not limited to halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; hydrocarbons such as toluene, xylene, n-heptane and the like; or a mixture thereof.
  • halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like
  • hydrocarbons such as toluene, xylene, n-heptane and the like
  • a mixture thereof Preferably dichloromethane or toluene is being used.
  • reaction can be performed in the absence of solvent(s) i.e., neat.
  • the reaction can be performed at temperature typically from about 25°C to about boiling point of the solvent(s) used.
  • the reaction time required for the completion may range from about 24 hours to about 96 hours, preferably from about 24 hours to about 48 hours.
  • reaction mixtures especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
  • the process of present invention avoids the use of hazardous reagents like thionyl chloride and intermediate 5-chloro-thiophene-2-carbonyl chloride and carcinogenic reagent pyridine which were used in the process described in patent US ' 860.
  • reagents used herein like boric acid or sub. or unsubstituted phenyl boronic acids are cheaper and commercially available and also does not give rise to the formation of impurities or side products unlike in prior art processes.
  • the process of present invention also avoids base and process step like decomposition, extractions, washings unlike processes described in prior art.
  • the process of present invention does not involve purification steps thus provides the final product rivaroxaban with higher yields and purities.
  • optically pure compound is being obtained by using the optically pure intermediate compound of formula II and no sign of racemisation is being observed and the pure racemic compound is being obtained by using the racemic intermediate compound of formula II.
  • the product obtained by the process of present invention can be analyzed by the analytical methods described in Journal of medicinal chemistry 2005, vol. 48, No. 19, pg. 5900- 08.
  • the intermediate compounds of (II), (III) are known per se to the person skilled in the art or can be prepared by customary methods.
  • US 7,585,860 which is herein incorporated for reference.
  • the present invention provides simple, ecofriendly, inexpensive, reproducible, robust process for the preparation of rivaroxaban (I) which is well suited on a commercial scale.
  • Example 1 1.625 gms of 5-chlorothiophene-2-carboxylic acid and 155mg (2.5 mmol) of boric acid and 82 ml of toluene were charged into a clean and dry R.B. flask. To the resultant clear colour less reaction mixture 3.2 g. (11 mmol) of 4- ⁇ 4-[(5S)-5-(aminomethyl)-2-oxo-l,3- o azolidin-3-yl]phenyl ⁇ -mo holin-3-one (chiral purity : 99.7% ) was added. The resultant reaction mixture was heated to reflu for about 48 hours and the water formed was removed azeotropically by dean-Stark apparatus.
  • Example 2 16.25g (O.lmol) of 5-chloro-thiophene-2-carboxylic acid, 3.25g (0.026 mol) of phenylboronic acid and 820 ml of toluene were charged into a clean and dry R.B. flask. To the clear colorless reaction solution 29.
  • Example 4 1.625g (10 mmol) of 5-chloro-thiophene-2-carboxylic acid, (0.248 g, (1 mmol) of 2-iodophenyl boronic acid and 50 ml of dichloromethane were charged into a clean and dry R.B flask. To the resultant clear colourless reaction solution 2.91g (lOmmol) of 4- ⁇ 4-[(5S)-5- (aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]-phenyl ⁇ -morpholin-3-one (chiral purity: 99.9%) was added and stirred at about 30°C for about 48 hrs.
  • Example 5 1.625g (10 mmol) of 5-chloro-thiophene-2-carboxylic acid, 0.62g (2.5 mmol) of 2- iodophenyl boronic acid and 80 ml of toluene were charged into a clean and dry R.B Flask. To the resultant clear colourless reaction solution 2.91g (lOmmol) of 4- ⁇ 4-[5-(aminomethyl)-2-oxo- l,3-oxazolidin-3-yl]-phenyl ⁇ -morpholin-3-one was added and heated to reflux for 36 hrs. The water formed was removed azeotropically by dean-Stark apparatus.
  • reaction mixture was cooled to about 30°C, 20 ml of water was added and stirred for 15 min at about 30°C.
  • the solid separated was filtered and washed with water and toluene.
  • the wet solid obtained was recrystallized in acetic acid to afford racemic rivaroxaban as white crystalline solid.

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

Abstract

La présente 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). Selon un aspect, la présente 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 de formule (I). Par conséquent, il est nécessaire de mettre en oeuvre un procédé amélioré pour la préparation de rivaroxaban, ce qui évite l'utilisation de produits chimiques dangereux et également la formation d'isomères et autres impuretés liées à ce procédé tout en pouvant obtenir le rendement et la pureté désirés pour ce composé.
PCT/IN2012/000086 2012-02-06 2012-02-06 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 WO2013118130A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2012/000086 WO2013118130A1 (fr) 2012-02-06 2012-02-06 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

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2012/000086 WO2013118130A1 (fr) 2012-02-06 2012-02-06 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

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WO2013118130A1 true WO2013118130A1 (fr) 2013-08-15

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104650057A (zh) * 2013-11-22 2015-05-27 重庆医药工业研究院有限责任公司 一种制备利伐沙班的方法
CN104833740A (zh) * 2015-05-13 2015-08-12 成都百裕科技制药有限公司 利伐沙班中间体的高效液相色谱检测方法
US9469628B2 (en) 2014-01-23 2016-10-18 Symed Labs Limited Processes for the preparation of highly pure Rivaroxaban crystal modification I
KR101811123B1 (ko) 2016-02-19 2017-12-20 일동제약(주) 신규의 모르폴린 이인산염 및 이를 이용한 고순도 리바록사반의 제조방법

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009138375A1 (fr) * 2008-05-14 2009-11-19 Syngenta Limited Procédé pour la fabrication d'amides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009138375A1 (fr) * 2008-05-14 2009-11-19 Syngenta Limited Procédé pour la fabrication d'amides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PLEISS ET AL.: "Syntheses of [14C]BAY 59-7939 and its radiolabeled metabolite M-4.", J LABEL COMPD. RADIOPHARM, vol. 49, 2006, pages 929 - 934, XP003032404 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104650057A (zh) * 2013-11-22 2015-05-27 重庆医药工业研究院有限责任公司 一种制备利伐沙班的方法
CN104650057B (zh) * 2013-11-22 2019-04-23 重庆医药工业研究院有限责任公司 一种制备利伐沙班的方法
US9469628B2 (en) 2014-01-23 2016-10-18 Symed Labs Limited Processes for the preparation of highly pure Rivaroxaban crystal modification I
CN104833740A (zh) * 2015-05-13 2015-08-12 成都百裕科技制药有限公司 利伐沙班中间体的高效液相色谱检测方法
KR101811123B1 (ko) 2016-02-19 2017-12-20 일동제약(주) 신규의 모르폴린 이인산염 및 이를 이용한 고순도 리바록사반의 제조방법

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