WO2012041263A2 - Procédé de fabrication d'une 2-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]- l,3-oxazolidin-5-yl}méthyl)-lh-isoindol-l,3(2h)-dione à la pureté optique élevée - Google Patents

Procédé de fabrication d'une 2-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]- l,3-oxazolidin-5-yl}méthyl)-lh-isoindol-l,3(2h)-dione à la pureté optique élevée Download PDF

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Publication number
WO2012041263A2
WO2012041263A2 PCT/CZ2011/000095 CZ2011000095W WO2012041263A2 WO 2012041263 A2 WO2012041263 A2 WO 2012041263A2 CZ 2011000095 W CZ2011000095 W CZ 2011000095W WO 2012041263 A2 WO2012041263 A2 WO 2012041263A2
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WO
WIPO (PCT)
Prior art keywords
oxo
compound
phenyl
isoindol
dione
Prior art date
Application number
PCT/CZ2011/000095
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English (en)
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WO2012041263A3 (fr
Inventor
Miroslav Urbasek
Pavel Hradil
Martin Grepl
Petra Fialova
Vladimir Oremus
Petr Slezar
Original Assignee
Farmak, A.S.
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Publication date
Application filed by Farmak, A.S. filed Critical Farmak, A.S.
Publication of WO2012041263A2 publication Critical patent/WO2012041263A2/fr
Publication of WO2012041263A3 publication Critical patent/WO2012041263A3/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
    • 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

Definitions

  • the invention relates to a method of manufacturing 2-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-l ,3-oxazolidin-5-yl ⁇ methyl)-lH-isoindol-l ,3(2H)-dione, the compound of formula I, with a high chemical urity.
  • This compound is the key intermediate for synthesis of 5-chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-l ,3-oxazolidin-5-yl ⁇ -methyl)-2-thiophene-carboxamide, the compound of formula II, which is known as rivaroxaban.
  • Optical purity of rivaroxaban directly depends on the optical purity of the compound of formula I.
  • Rivaroxaban a derivative of oxazolidinone, is a direct reversible inhibitor of the activated factor Xa. It has been proposed for indication in prophylaxis of vein thromboembolism in effective replacement of the hip or knee joint in adults, treatment of phlebothrombosis, prophylaxis of a thromboembolic brain event in patients with atrial fibrillation, treatment of acute coronary events, especially of instable angina pectoris and a number of other indications.
  • the object of the invention comprises a method of manufacturing highly optically pure 2- ( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]- l ,3-oxazolidin-5-yl ⁇ methyl)- lH-isoindol- l ,3(2H)-dione, the compound of formula I, by reaction of 2-((2R)-2-hydroxy-3-[4-(3-oxo-4- moi holinyl)phenyl]amino-propyl)-lH-isoindol- l,3(2H)-dione, the compound of formula III,
  • reaction being preferably carried out in such a way that it is terminated at a moment when the reaction mixture still contains the unreacted compound III in an amount which is in the range of a 3 to 5 fold of the initial amount of the (2S)-isomer in the starting compound III.
  • the molar amount of the NN-carbonyldiimidazole used in the reaction is a 1.0 to 1.2 fold of the amount of the compound of formula III.
  • reaction is performed in boiling tetrahydrofuran or 2- methyltetrahydrofuran.
  • the desired conversion of the reaction is preferably achieved without the use of catalysis by 4-dimethylaminopyridine.
  • Still another preferable embodiment comprises purification of the crude compound I by crystallization from a suitable solvent, the solvent being 2-methoxyethanol, tetrahydrofuran, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or a mixture of solvents which contains at least one of the said solvents.
  • a suitable solvent the solvent being 2-methoxyethanol, tetrahydrofuran, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or a mixture of solvents which contains at least one of the said solvents.
  • the invention relates to a method of manufacturing highly optically pure 2-( ⁇ (5S)-2-oxo- 3-[4-(3-oxo-4-mo holinyl)phenyl]-l ,3-oxazolidin-5-yl ⁇ methyl)- lH-isoindol-l ,3(2H)-dione, the compound of formula I,
  • This different reactivity can preferably be used in the manufacture of optically pure 2- ( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4-mo ⁇ holinyl)phenyl]-l ,3-oxazolidin-5-yl ⁇ methyl)-l H-isoindol- l ,3(2H)-dione, the compound of formula I, by adding N,N-carbonyldiimidazole to a suspension of (2R)-2-hydroxy-3-[4-(3-o o-4-mo holinyl)phenyl]amino- ro yl- lH-isoindol- l ,3(2H)-dione, the compound of formula III, containing the (2S)-isomer, the substance of formula Illb, in tetrahydrofuran, preferably without the use of the catalyst 4-dimethylaminopyridine, said N,N- carbonyldi
  • Fig. 1 X-ray powder diffraction of 2-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3- oxazolidin-5-yl ⁇ methyl)- lH-isoindol-l,3(2H)-dione, the compound of formula (I).
  • the white suspension was cooled to the temperature of 20°C, stirred for 1.5 hours, aspirated and washed with tetrahydrofuran (50 ml).
  • the product was poured into a flask with 2- methoxyethanol (175 ml). The mixture was heated up to boil and stirred until dissolution.
  • Active carbon 0.5 g was added to the solution and filtered off while hot after 10 minutes and washed with 2-methoxyethanol (10 ml).
  • the solution was cooled to the laboratory temperature and stirred for 1 hour.
  • the resulting crystals were aspirated and washed with methanol (100 ml).
  • the aspirated product was dried in a vacuum drier at a temperature up to 60°C.
  • Phthalimide (10 g; 0,059 mol), benzyl triethyl ammonium chloride (1.3 g), sodium carbonate
  • the white suspension was cooled to the temperature of 20°C, stirred for 1.5 hours, aspirated and washed with 2-mefhyltetrahydrofuran (50 ml).
  • the product was added into a flask with N,N-dimethylformamide (100 ml). The mixture was heated up to 100°C and stirred until dissolution.
  • Active carbon 0.5 g was added to the solution and filtered off while hot after 10 minutes and washed with NN-dimethylformamide (5 ml).
  • the solution was cooled to the temperature of 20°C, diluted with water (400 ml) and stirred for 1 hour. The resulting product was aspirated and thoroughly washed with water (100 ml).

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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)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne une 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]-l,3-oxazolidin- 5-yl} méthyl)- lH-isoindol- l,3(2H)-dione (I) très pure optiquement obtenue par réaction d'une 2-((2R)-2-hydroxy-3-[4-(3- oxo-4-morpholinyl)phényl]amino-propyl)- lH-isoindol- l,3(2H)-dione (III), contenant l'isomère (2S) (IIIb), avec N,N-carbonyldiimidazole dans du tétrahydrofuranne, de préférence sans la présence du catalyseur 4-diméthylaminopyridine, ladite réaction étant menée de façon à ce qu'elle soit terminée au moment où le mélange réactionnel contient encore le composé n'ayant pas réagi de formule III en quantité allant de 3 à 5 fois la quantité initiale de l'isomère (2S) dans la substance de départ de formule III.
PCT/CZ2011/000095 2010-09-30 2011-09-27 Procédé de fabrication d'une 2-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]- l,3-oxazolidin-5-yl}méthyl)-lh-isoindol-l,3(2h)-dione à la pureté optique élevée WO2012041263A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2010-714 2010-09-30
CZ20100714A CZ2010714A3 (cs) 2010-09-30 2010-09-30 Zpusob výroby 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morfolinyl)fenyl]-1,3oxazolidin-5-yl}methyl)-1H-isoindol-1,3(2H)-dionu ve vysoké optické cistote

Publications (2)

Publication Number Publication Date
WO2012041263A2 true WO2012041263A2 (fr) 2012-04-05
WO2012041263A3 WO2012041263A3 (fr) 2012-06-21

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Country Status (2)

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CZ (1) CZ2010714A3 (fr)
WO (1) WO2012041263A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016030669A1 (fr) * 2014-08-25 2016-03-03 Cipla Limited Procédé de préparation du rivaroxaban
EP3309158A1 (fr) 2012-12-21 2018-04-18 Farma GRS, d.o.o. Forme crystalline k du rivaroxaban et procédé de préparation
CN110054623A (zh) * 2019-05-29 2019-07-26 浙江燎原药业股份有限公司 一种利伐沙班中间体的制备方法
CN111675705A (zh) * 2020-08-11 2020-09-18 北京鑫开元医药科技有限公司 一种4-(4-氨基苯基)吗啉-3-酮衍生物的制备方法

Citations (2)

* 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
WO2009023233A1 (fr) 2007-08-14 2009-02-19 Concert Pharmaceuticals, Inc. Dérivés d'oxazolidinones substituées

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004002044A1 (de) * 2004-01-15 2005-08-04 Bayer Healthcare Ag Herstellverfahren

Patent Citations (3)

* 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
DE19962924A1 (de) 1999-12-24 2001-07-05 Bayer Ag Substituierte Oxazolidinone und ihre Verwendung
WO2009023233A1 (fr) 2007-08-14 2009-02-19 Concert Pharmaceuticals, Inc. Dérivés d'oxazolidinones substituées

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. MED. CHEM., vol. 48, 2005, pages 5900 - 5908

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3309158A1 (fr) 2012-12-21 2018-04-18 Farma GRS, d.o.o. Forme crystalline k du rivaroxaban et procédé de préparation
WO2016030669A1 (fr) * 2014-08-25 2016-03-03 Cipla Limited Procédé de préparation du rivaroxaban
CN110054623A (zh) * 2019-05-29 2019-07-26 浙江燎原药业股份有限公司 一种利伐沙班中间体的制备方法
CN111675705A (zh) * 2020-08-11 2020-09-18 北京鑫开元医药科技有限公司 一种4-(4-氨基苯基)吗啉-3-酮衍生物的制备方法

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WO2012041263A3 (fr) 2012-06-21
CZ2010714A3 (cs) 2012-04-11

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