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
  • C07D413/14—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)

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• 2010
  • 2010-09-30 CZ CZ20100714A patent/CZ2010714A3/cs unknown
• 2011
  • 2011-09-27 WO PCT/CZ2011/000095 patent/WO2012041263A2/en active Application Filing

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