WO2012156983A1 - Procédés pour la préparation de 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]-1,3-oxazolidin-5-yl}méthyl)-2-thiophènecarboxamide - Google Patents

Procédés pour la préparation de 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]-1,3-oxazolidin-5-yl}méthyl)-2-thiophènecarboxamide Download PDF

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WO2012156983A1
WO2012156983A1 PCT/IN2012/000064 IN2012000064W WO2012156983A1 WO 2012156983 A1 WO2012156983 A1 WO 2012156983A1 IN 2012000064 W IN2012000064 W IN 2012000064W WO 2012156983 A1 WO2012156983 A1 WO 2012156983A1
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formula
phenyl
compound
oxo
chloro
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Dodda Mohan Rao
Pingili Krishna Reddy
Buthukuri Venkat Reddy
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Symed Labs Ltd
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Symed Labs Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to processes 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.
  • Rivaroxaban is a novel anticoagulant used for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is under review in US and approved in several countries of Europe. 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.
  • Rivaroxaban is chemically described as 5-chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl] -1,3 -oxazolidin-5 -yl ⁇ methyl)-2-thiophene-carboxamide (herein after referred as rivaroxaban) and is r hown below:
  • U.S. Patent No. US 7,585,860 describes morpholinyl oxazolidinone thiophene carboxamides including rivaroxaban or pharmaceutically acceptable acid addition salts thereof, a pharmaceutical composition and a method of treatment.
  • the US '860 patent also discloses a process for the preparation of rivaroxaban which
  • the processes of the present invention are simple, eco-friendly, economic, reproducible, robust and are well amenable on industrial scale.
  • the present invention relates to processes 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.
  • the present invention provides 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 of formula (I),
  • Rl is C i -8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
  • the present invention provides an alternate 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
  • R is C i -8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;
  • the present invention provides rivaroxaban (I) having the compound of structural formula III
  • Rl is C i -8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
  • the present invention provides rivaroxaban (I) having the compound of structural formula Ilia
  • Rl is C i.g alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
  • the present invention provides rivaroxaban (I) having the compound of structural formula II
  • the present invention provides rivaroxaban (I) having the compound of structural formula V
  • R is C i -8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;
  • Fig. 1 is a schematic representation of the processes of present invention.
  • the present invention is directed to processes 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.
  • Rl is C i -8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl; b) reacting the compound of formula (III) with a compound 4- ⁇ 4-[(5S)-5-
  • reaction step (a) comprising the reaction of compound of formula IV with suitable reagent selected from alkyl chloro formates like ethyl chloro formate, isobutyl chloro formate; sub. or unsub. phenyl chloroformates like phenyl chloroformate, 4-nitrophenyl chloroformate; aryl alkyl chloroformate like benzyl chloroformate and the like.
  • suitable reagent selected from alkyl chloro formates like ethyl chloro formate, isobutyl chloro formate; sub. or unsub. phenyl chloroformates like phenyl chloroformate, 4-nitrophenyl chloroformate; aryl alkyl chloroformate like benzyl chloroformate and the like.
  • suitable reagent selected from alkyl chloro formates like ethyl chloro formate, isobutyl chloro formate; sub. or unsub. phenyl chloroformates like
  • the bases that can be used in the reaction steps (a) and (b) are organic bases such as triethylamine, tripropylamine, pyridine, diisopropylamine, diisopropylethylamine, tributylamine;
  • Inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and the like; or a mixture thereof, preferably organic base. Most preferably tri ethyl amine is being used.
  • the solvents that can be used in step (a) and (b) include but are not limited to halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as ethyl acetate, propyl acetate, isopropyl acetate, tertiary butyl acetate and the like; ethers such as tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP) and the like; or a mixture thereof.
  • halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like
  • reaction steps (a) and b) are performed separately or can be carried out by single pot.
  • reaction temperature in reaction steps (a) and b) can range from about -10°C to about 30°C, preferably from about -5°C to about 10°C.
  • the time period required for the completion of the reaction step (a) can range from about 30 minutes to about 5 hours, preferably about 30 minutes.
  • the time period required for the completion of the reaction step (b) can range from about 30 minutes to about 20 hours, preferably 10 hours.
  • R is C i -8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;
  • the solvent(s) that can be used is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; alkyl ethers such as tetrahydrofuran, dioxane and the like; esters such as ethyl acetate, isopropyl acetate and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile and the like; N,N-dialkylamides such as ⁇ , ⁇ -dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide, sulfoxides and sulfones (e.g. dimethyl sulfoxide and sulfolane); halogenated hydrocarbons such as dichloromethane, chloroform and the like;
  • reaction is performed in the absence of solvents.
  • the reaction temperature can be in the range of about 25°C to about 150°C or the boiling point of the solvent(s) used, preferably about 65°C.
  • the preferred reaction temperature can range from about 100°C to about 150°C, preferably about 120°C.
  • the time required for the reaction to complete may vary depending on the reaction temperature and the nature of the reagents and solvents employed.
  • the time period required can range from about 30 minutes to about 48 hours, preferably about 10 hours.
  • the bases that can be used optionally include are organic bases or inorganic bases.
  • the organic bases that can be used include, but are not limited to triethylamine, pyridine and the like;
  • Inorganic bases include one or more of alkali metal carbonates, such as sodium carbonate or potassium carbonate, sodium hydrogen carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide and the like or mixtures thereof, preferably organic base.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain, or cyclic hydrocarbon radical
  • saturated hydrocarbon radicals include, but are not limited to groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylme hyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • aryl by itself or as part of another substituent, means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (often from 1 to 3 rings) which are fused together or linked covalently.
  • Aryl includes, but is not limited to, “heteroaryl” groups.
  • the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
  • the working-up of 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, centriiugation and the like.
  • process steps of present invention can be carried out by one pot synthesis.
  • intermediates or their salts used here in the processes of the present invention may exist in either crystalline or amorphous or mixtures thereof.
  • intermediate compound aminomethyloxazolidinone (II) can be used in any salt form and morph.
  • aminomethyloxazolidinone (II) isolated salt form like hydrochloride in pure form or purified form of its free base makes improved reaction management possible in the following reaction with chlorothiophenecarbonyl compound with unwanted side reactions being avoided and a purer product being obtained, so that the elaborate chromatographic purification can be avoided.
  • the compound of formula I obtained by the processes of present invention is optionally purified by making slurry in polar solvents at ambient or mild temperatures or recrystallization using solvents or by acid base or carbon treatment.
  • Rl is C i -8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
  • Rl is C i -8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
  • R is C i.g alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and aryl alkyl, substituted or unsubstituted phenyl;
  • the processes of present invention does not involve purification steps thus provides the final product rivaroxaban with higher yields and purities.
  • the yield of the intermediates and the final product is about 80%, or more, more preferably, the yield is about 80% to about 90%, most preferably, the yield is about 90% to about 95%, or more, by weight.
  • the product obtained by the processes described above can have high enantiomeric excess.
  • the amount of R-enantiomer is less than about 1% as measured by area percentage by chiral HPLC, more preferably less than about 0.5%, and most preferably less than about 0.15% by chiral HPLC.
  • the processes according to the present invention preferably yields (+)-rivaroxaban or a pharmaceutically acceptable salt thereof in substantially pure enantiomeric form.
  • the ratio of (+) : (-) as obtained by the process of present invention may be at least about 99: 1 , such as at least about 99.8:0.2, or more preferably at least about 99.9 : 0.1.
  • (+)-rivaroxaban or salt thereof prepared by a processes according to the present invention has an enantiomeric purity of at least about 99.7%, or more preferably at least about 99.9%.
  • (+) rivaroxaban is commonly called as rivaroxaban thus can be referred here in either way.
  • compound of formula (I) can be present in tautomeric forms. This is known to the person skilled in the art, and such compounds are likewise within the scope of the invention.
  • the rivaroxaban (I) obtained by the processes of the present invention preferably has an average particle size greater than 300 ⁇ .
  • the term "average particle size” or “particle size” as used herein refers to the volume mean diameter of particles.
  • Rivaroxaban (I) can be further micronized to obtain particles with dc>o >60 ⁇ , more preferably dc>o > 40 ⁇ , and most preferably d%> 30 ⁇ ⁇ .
  • dg 0 > x means that at least 90 % by volume of the particles have a particle size above x.
  • the particle size can be determined by laser light scattering for instance using a Malvern Mastersizer Apparatus MS 2000 equipped with a Hydro S dispersion unit using purified water as the dilution medium.
  • Micronized rivaroxaban can be obtained for instance by single or multistage micronization in the dry state using dry mills, such as cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills.
  • rivaroxaban or its pharmaceutically acceptable salts obtained by the processes described above has residual organic solvents or organic volatile impurities comprises less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; less than about 500ppm of N- methylpyrolidine (NMP), less than about 700ppm of tetrahydrofuran, less than about 600ppm of dichloromethane, less than about 400ppm of acetonitrile, ethylene glycol, less than lOOOppm of methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, acetic acid, n-hexane, n-heptane, less than 800ppm of ⁇ , ⁇ -dimethyl formamide (DMF), less tha lOOOppm of dimethyl acetamide (DMA).
  • NMP N- methylpyrolidine
  • DMF dimethyl formamide
  • DMA dimethyl
  • the present invention provides simple, ecofriendly, inexpensive, reproducible, robust processes for preparation of rivaroxaban (I) which are well adaptable on a commercial scale.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Selon la présente invention, R est un alkyle en C1-8 à chaîne linéaire ou ramifié tel que méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, arylalkyle, phényle substitué ou non substitué; en une quantité inférieure ou égale à 0,1 % en aire telle que déterminée par CLHP. La présente invention concerne des procédés pour la préparation de 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]-l,3-oxazolidin-5-yl méthyl)-2-thiophène-carboxamide. Dans un mode de réalisation de la présente invention, il est décrit un procédé pour la préparation de 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]-1,3-oxazolidin-5-yl}méthyl)-2-thiophènecarboxamide de formule (I).
PCT/IN2012/000064 2011-05-16 2012-01-30 Procédés pour la préparation de 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]-1,3-oxazolidin-5-yl}méthyl)-2-thiophènecarboxamide Ceased WO2012156983A1 (fr)

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IN1667/CHE/2011 2011-05-16

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2753619A2 (fr) 2011-09-08 2014-07-16 Cadila Healthcare Limited Procédés et intermédiaires destinés à la préparation de rivaroxaban
EP2844654A1 (fr) 2012-05-02 2015-03-11 Symed Labs Limited Procédé perfectionné pour la préparation de rivaroxaban utilisant de nouveaux intermédiaires
CN104422743A (zh) * 2013-09-04 2015-03-18 广东东阳光药业有限公司 一种抗凝血药物的分离检测方法
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
WO2015104605A1 (fr) 2014-01-08 2015-07-16 Wockhardt Limited Procédé de préparation de rivaroxaban ou d'un sel pharmaceutiquement acceptable de ce dernier
CN104792891A (zh) * 2015-04-07 2015-07-22 成都百裕科技制药有限公司 一种r构型利伐沙班中间体的检测方法
US9469628B2 (en) 2014-01-23 2016-10-18 Symed Labs Limited Processes for the preparation of highly pure Rivaroxaban crystal modification I
CN108152412A (zh) * 2017-12-20 2018-06-12 乐普药业股份有限公司 一种用液相色谱法分离测定利伐沙班及其有关物质的方法

Citations (5)

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US20030153610A1 (en) * 1999-12-24 2003-08-14 Alexander Straub Substituted oxazolidinones and their in the field of blood coagulation
US20070066611A1 (en) * 2003-09-15 2007-03-22 Bayer Healthcare Ag Method for the production of 4-(4-aminophenyl)-3-morpholinone
US7351823B2 (en) * 2004-01-15 2008-04-01 Bayer Healthcare Ag Preparation process
US20100298293A1 (en) * 2007-06-20 2010-11-25 Bayer Schering Pharma Atiengesellschaft Substituted oxazolidinones and their use
US20110034465A1 (en) * 2009-04-28 2011-02-10 Apotex Pharmachem Inc. Processes for the preparation of rivaroxaban and intermediates thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030153610A1 (en) * 1999-12-24 2003-08-14 Alexander Straub Substituted oxazolidinones and their in the field of blood coagulation
US20070066611A1 (en) * 2003-09-15 2007-03-22 Bayer Healthcare Ag Method for the production of 4-(4-aminophenyl)-3-morpholinone
US7351823B2 (en) * 2004-01-15 2008-04-01 Bayer Healthcare Ag Preparation process
US20100298293A1 (en) * 2007-06-20 2010-11-25 Bayer Schering Pharma Atiengesellschaft Substituted oxazolidinones and their use
US20110034465A1 (en) * 2009-04-28 2011-02-10 Apotex Pharmachem Inc. Processes for the preparation of rivaroxaban and intermediates thereof

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2753619A2 (fr) 2011-09-08 2014-07-16 Cadila Healthcare Limited Procédés et intermédiaires destinés à la préparation de rivaroxaban
EP2844654A1 (fr) 2012-05-02 2015-03-11 Symed Labs Limited Procédé perfectionné pour la préparation de rivaroxaban utilisant de nouveaux intermédiaires
AU2012378913B2 (en) * 2012-05-02 2017-04-13 Symed Labs Limited Improved process for preparing rivaroxaban using novel intermediates
CN104422743A (zh) * 2013-09-04 2015-03-18 广东东阳光药业有限公司 一种抗凝血药物的分离检测方法
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
WO2015104605A1 (fr) 2014-01-08 2015-07-16 Wockhardt Limited Procédé de préparation de rivaroxaban ou d'un sel pharmaceutiquement acceptable de ce dernier
US9469628B2 (en) 2014-01-23 2016-10-18 Symed Labs Limited Processes for the preparation of highly pure Rivaroxaban crystal modification I
CN104792891A (zh) * 2015-04-07 2015-07-22 成都百裕科技制药有限公司 一种r构型利伐沙班中间体的检测方法
CN108152412A (zh) * 2017-12-20 2018-06-12 乐普药业股份有限公司 一种用液相色谱法分离测定利伐沙班及其有关物质的方法

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