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WO2012041263A2 - 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 with a high optical purity - Google Patents

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 with a high optical purity 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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oxo
compound
phenyl
isoindol
dione
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PCT/CZ2011/000095
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French (fr)
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WO2012041263A3 (en
Inventor
Miroslav Urbasek
Pavel Hradil
Martin Grepl
Petra Fialova
Vladimir Oremus
Petr Slezar
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Farmak, A.S.
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Publication of WO2012041263A3 publication Critical patent/WO2012041263A3/en

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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

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 (I) is obtained by reaction of 2-((2R)-2-hydroxy-3-[4-(3- oxo-4-moφholinyl)phenyl]amino-propyl)- lH-isoindol- l,3(2H)-dione (III), containing the (2S)- isomer (Illb), with N,N-carbonyldiimidazole in tetrahydrofuran, preferably without the presence of the catalyst 4-dimethylaminopyridine, said reaction being carried out in such a manner that it is terminated at a moment when the reaction mixture still contains the unreacted compound of formula III in an amount which is in the range of a 3 to 5 fold the initial amount of the (2S)- isomer in the starting substance of formula III.

Description

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 with a high optical purity Technical Field
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.
Figure imgf000003_0001
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.
Figure imgf000003_0002
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. Background Art
Manufacture 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,
Figure imgf000004_0001
is described in the patent document no. WO 01/47919 as preparation of an intermediate of synthesis of 5 -chloro-N-( { (5 S)-2-oxo-3 - [4-(3 -oxo-4-morpholin)-phenyl]- 1 ,3 -oxazolidin-5-yl} - methyl)-2-thiophene-carboxamide, the compound of formula II, known under the generic name rivaroxaban.
Figure imgf000004_0002
(Π) The manufacturing process of rivaroxaban described in the German patent no. DE
19 962 924 and subsequently in WO 01/47919 describes a reaction of N-(4- aminophenyl)morpholinone, the compound of formula VII, with (S)-2- (phthalimidomethyl)oxirane, the compound of formula IV, which has been obtained by a reaction of (S)-epichlorohydrin, the compound of formula V, with phthalimide, the compound of formula VI, giving (2R)-2-hydro y-3-[4-(3-oxo-4-mo holinyl)phenyl]aminopropyl-lH-isoindol-l ,3(2H)- dione, the compound of formula III, which further reacts with NN-carbonyldi imidazole (CDI) and the catalyst 4-dimethylaminopyridine, producing 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. A subsequent reaction of the compound of formula I with aqueous methylamine releases (5S)-2-oxo-3-[4-(3-oxo-4-mo holinyl)phenyl]-5-ami omethyl- l ,3-oxazolidme, the compound of formula VIII, which is acylated with 5-chlorothiophene-2-carboxylic acid chloride to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-mo holin)-phenyl]- l ,3-o azolidin-5-yl} -methyl)- 2-thiophene-carboxamide, the compound of formula II, in accordance with the reaction scheme below. The isomeric purity of the produced rivaroxaban, the compound of formula II, refined by column chromatography, is 99%.
Figure imgf000005_0001
Figure imgf000005_0002
A similar procedure is described in an article in J. Med. Chem. 2005, 48, 5900-5908. Preparation of a variously deuterated intermediate I is described in WO 2009/023233 and uses the same synthetic path as described above. Optically active carbon is introduced into the molecule of rivaroxaban and its intermediates by reaction of phthalimide with (S)-epichlorohydrin. From the commercially commonly available (S)-epichlorohydrin it is possible to obtain rivaroxaban in the isomeric purity of 98.5 to 99.0% by the above mentioned synthetic path, which is, however, insufficient for the production of a pharmaceutically acceptable product. Moreover, in this stage partial racemization occurs, which means that even from a 100% (S)-epichlorohydrin the isomeric purity of rivaroxaban of 99.9% would not be achieved. The 2-((2R)-2-hydroxy-3-[4-(3-oxo-4- moi"pholinyl)phenyl]amino-propyl)-l H-isoindol- l ,3(2H)-dione used, the compound of formula III, thus represents a mixture of the optical isomers 2-((2R)-2-hydroxy-3-[4-(3-oxo-4- moi"phoIinyI)phenyl]amino-propyl)- lH-isoindol- l ,3(2H)-dione, the compound of formula III,
Figure imgf000006_0001
(HI) and 2-((2S)-2-hydro y-3-[4-(3-oxo-4-moφholinyl)phenyl]amino-propyl)- l H-isoindol- l ,3(2H)- dione, the compound of formula Illb,
Figure imgf000006_0002
(Illb) wherein the amount of the isomer of formula Illb may achieve up to 2%. It is possible to obtain, from such mixture of optical isomers by the above described synthetic route, 2-( {(5S)-2-oxo-3-[4- (3-oxo-4-morpholinyl)phenyl]-l ,3-oxazolidin-5-yl}methyl)-l H-isoindol- l ,3(2H)-dione, the compound of formula I, in the isomeric purity of 98 to 99.5% and, by subsequent reactions, rivaroxaban, the compound of formula II, with the isomeric purity of 98 to 99.5%. For the preparation of a pharmaceutically usable product this isomeric purity is insufficient; therefore, purifying operations to increase the isomeric purity have to be introduced.
Disclosure of Invention
The method according to the present invention eliminates the above cited disadvantages. 2-( {(5S)-2-oxo-3-[4-(3-oxo-4-moφholiny])phenyl]- 1 ,3-oxazolidin-5-y] } methyl)- 1 H-isoindol- l ,3(2H)-dione, the compound of formula I, is formed directly from the reaction mixture with the isomeric purity of at least 99.9%,
Figure imgf000007_0001
which compound provides, by subsequent reactions, rivaroxaban, the compound of formula II, with the isomeric purity of at least 99.9%.
Figure imgf000007_0002
(ID
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,
Figure imgf000008_0001
containing the (2S)-isomer, the compound of formula Illb,
Figure imgf000008_0002
with N,N-carbonyldiimidazole in a solvent, the 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.
In a preferable embodiment 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.
In another preferred embodiment the reaction is performed in boiling tetrahydrofuran or 2- methyltetrahydrofuran.
In still another preferable embodiment 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. Detailed Description of Invention
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,
Figure imgf000009_0001
which is based on the fact that the isomer 2-((2R)-2-hydroxy-3-[4-(3-oxo-4- mo holinyl)phenyl]amino-propyl)-lH-isoindol-l,3(2H)-dione, the compound of formula III, reacts considerably faster with NN-carbonyldiimidazole than the isomer 2-(2S)-2-hydroxy-3-[4- (3-o o-4-mo holinyl)phenyl]amino-propyl)-lH-isoindol-l,3(2H)-dione, the compound of formula Illb.
Figure imgf000009_0002
Figure imgf000009_0003
(Illb)
This different reactivity can preferably be used in the manufacture of optically pure 2- ( {(5S)-2-oxo-3-[4-(3-oxo-4-moφholinyl)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- carbonyldiimidazole preferably being in a molar 1 to 1 .2 fold the amount of that of the compound of formula III, and carrying the reaction out in such a manner that, after the termination of the reaction, the reaction mixture still contains the unreacted compound of formula III in an amount which is a 3 to 5 fold the initial content of the (2S) isomer in the starting compound III. After the reaction 2-({(5S)-2-oxo-3-[4-(3-o o-4-mo holinyl) henyl]-l ,3-oxazolidin-5-yl}methyl)- lH- isoindol-l ,3(2H)-dione, the compound of formula I, is isolated with the isomeric purity of at least 99.9%;
Figure imgf000010_0001
A reaction of 2-( {(5S)-2-o o-3-[4-(3-oxo-4-moφholinyl)phenyl]- l ,3-oxazolidin-5- yl}methyl)- lH-isoindol- l ,3(2H)-dione, the compound of formula (I), with an aqueous solution of methylamine in ethanol produces (5S)-2-oxo-3-[4-(3-oxo-4-moφholinyl)phenyl]-5-aminomethyl- 1 ,3-oxazolidine, the compound of formula VIII, which, after isolation, reacts with 5- chlorothiophene-2-carboxylic acid chloride, thus giving 5-chloro-N-( {(5S)-2-oxo-3-[4-(3-oxo-4- moφholin)-phenyl]- l ,3-oxazolidin-5-yl} -methyl)-2-thiophene-carboxamide, the compound of formula II, with the isomeric purity of at least 99.9%.
Figure imgf000010_0002
(ID Brief Description of Drawings
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).
Working Examples
Example 1 : Preparation 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
(2R)-2-Hydro y-3-[4-(3-oxo-4-moφholinyl)phenyl]amino-propyl-lH-isoindol-l ,3(2H)- dione (10.0 g; 25 mmol), the compound of formula III, containing 1.0 % of the (2S)-isomer was charged into a flask and tetrahydrofuran (200 ml) was added. NN-carbonyldiimidazole (4.1 g; 25 mmol) was added to the stirred mixture. The mixture was heated up to boil and refluxed for 5 hours.
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. 9 g (85 % of theory) of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l ,3-oxazolidin-5-yl} methyl)- lH-isoindol- l ,3(2H)-dione with the isomeric purity of 99.98% were obtained, HPLC purity 99.7%, m. p. = 221 - 223 °C. The polymorphous structure of the compound (I) was also characterized with the X-ray powder diffraction (Fig. 1) with the characteristic 2 theta angles 4.63; 12.00; 13.9; 15.3; 15.87 and 24.55.
Example 2: Preparation of (S)-2-phthalimidomethyi)oxirane, compound of formula IV
Phthalimide (10 g; 0,059 mol), benzyl triethyl ammonium chloride (1.3 g), sodium carbonate
(6.5 g) were charged into a flask and isopropanol (60 ml) was added. (S)-epichlorohydrin (1 1.4 g; 0.053 mol) was added dropwise to the stirred content of the flask during 30 minutes, maintaining the temperature at 20 to 40°C. The mixture was stirred at the laboratory temperature for 20 hours, cooled to the temperature of 10°C and a solution of potassium /eri-butanolate (9.2 g) in isopropanol (50 ml) was added dropwise. The reaction mixture was further stirred at a temperature of 5 to 10°C for 2 hours.
The resulting suspension was aspirated and washed with cooled isopropanol (15 ml), the white substance was stirred up in 50 ml of water and stirred for 0.5 hour. The white product was aspirated and washed with water (30 ml). The thoroughly aspirated product was dried freely at a temperature up to 60°C. 8.4 g of (S)-2-phthalimidomethyl)oxirane were obtained, which was employed in the subsequent stage without refining.
Example 3: (2R)-2-Hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyI]aminopropyl-lH-isoindol- l,3(2H)-dione, the compound of formula III
(S)-2-(Phthalimidomethyl)oxirane (12.0 g; 0.06 mol) and N-(4-aminophenyl)- morpholinone (10.0 g; 0.05 mol) were charged into a flask and methanol (200 ml) and water (20 ml) were added. The mixture was heated up to boil and refluxed for 20 hours. The white suspension was cooled to the temperature of 15°C, stirred for 1 hour, aspirated and washed with methanol (20 ml) at the temperature of 15°C.
The thoroughly aspirated product was dried in a vacuum drier at a temperature up to 60°C. 15.5g (75 % of theory) of (2R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]aminopropyl- l H-isoindol- l ,3(2H)-dione with the isomeric purity of 99.0% were obtained.
Example 4: Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin- 5-yl}methyl)-lH-isoindol-l,3(2H)-dione, compound of formula I
(2R)-2-Hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]amino-propyl- lH-isoindol- l ,3(2H)- dione (7.9 g; 20 mmol), the compound of formula III, containing 1.5% of the (2S)-isomer, was charged into a flask and 2-methyltetrahydrofuran (180 ml) was added. N,N-carbonyldiimidazole (3.9 g; 24 mmol) was added to the stirred mixture. The mixture was heated up to boil and refluxed for 3 hours.
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). The thoroughly aspirated product was dried in a vacuum drier at a temperature up to 60°C. 6.5 g (77 % of theory) of 2-({(5S)-2-oxo-3-[4-(3- oxo-4-morpholinyl)phenyl]-l ,3-oxazolidin-5-yl}methyl)-lH-isoindol-l,3(2H)-dione with the isomeric purity of 99.98% were obtained. Example 5: Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin- 5-yl}methyl)-lH-isoindol-l,3(2H)-dione, compound of formula I
(2R)-2-Hydroxy-3-[4-(3-oxo-4-mo holinyl)phenyl]amino-propyl-lH-isoindol-l,3(2H)- dione (10.0 g; 25 mmol), the compound of formula III, containing 0.3% of the (2S)-isomer, was charged into a flask and tetrahydrofuran (200 ml) was added. N,N-carbonyldiimidazole (4.26 g; 26 mmol) was added to the stirred mixture. The mixture was heated up to boil and refluxed for 4 hours.
The white suspension was cooled to the temperature of 15°C, stirred for 1.5 hours, aspirated and washed with cooled tetrahydrofuran (50 ml). The product was dried in a vacuum drier at a temperature up to 60°C. 9.5 g (90 % of theory) of 2-({(5S)-2-oxo-3-[4-(3-oxo-4- moi holinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindol-l ,3(2H)-dione with the isomeric purity of 99.98% were obtained, HPLC purity 97.5%.
Example 6: Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyI)phenyl]-l,3-oxazolidin- 5-yl}methyl)-lH-isoindol-l,3(2H)-dione, compound of formula I
(2R)-2-Hydroxy-3-[4-(3-oxo-4-mo holinyl)phenyl]amino-propyl-lH-isoindol-l,3(2H)- dione (10.0 g; 25 mmol), the compound of formula III, containing 0.5% of the (2S)-isomer, was charged into a flask and tetrahydrofuran (200 ml) was added. NN-carbonyldiimidazole (4.26 g; 26 mmol) was added to the stirred mixture. The reaction mixture was continuously analyzed by HPLC. After reacting for 3.5 hours a content of the starting compound III at the level of 1.5% was found in the reaction mixture. The reaction was stopped. The white suspension was cooled to 22 °C, stirred for 2 hours, aspirated and washed with cold tetrahydrofuran (50 ml). The product was dried in a vacuum drier at 60 °C. 9.0 g (85% of theory) of 2-({(5S)-2-oxo-3-[4-(3-o o-4-mo holiny])phenyl]-l ,3-oxazolidin-5-yl} methyl)- 1H- isoindol-l ,3(2H)-dione having the isomeric purity 99.98% was obtained; HPLC purity 97.0%.
Example 7: Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyI)phenyI]-l,3-oxazolidin- 5-yl}methyl)-lH-isoindol-l,3(2H)-dione, compound of formula I
(2R)-2-Hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]amino-propyl-lH-isoindol-l,3(2H)- dione (10.0 g; 25 mmol), the compound of formula III, containing 1.0% of the (2S)-isomer, was charged into a flask and 2-methyltetrahydrofuran (180 ml) was added. N.N-carbonyldiimidazole (4.8 g; 30 mmol) was added to the stirred mixture. The reaction mixture was heated up to boil. After reacting for 3 hours a content of the starting compound III at the level of 3% was found in the reaction mixture. The reaction was stopped.

Claims

C L A I M S
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,
Figure imgf000015_0001
by reaction of 2-((2R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]amino-propyl)-lH- isoindol-l ,3(2H)-dione, the compound of formula III, containing the (2S)-isomer, the compound of formula Illb, with N,N-carbonyldiimidazole
Figure imgf000015_0002
characterized in that the reaction is carried out in such a manner that it is terminated at a moment when the reaction mixture still contains the unreacted compound of formula III in an amount which is in the range of a 3 to 5 fold the initial content of the (2S)-isomer in the starting substance of formula III.
The method according to claim 1 , characterized in that the amount of N,N- carbonyldiimidazole used in the reaction is a 1.0 to 1.2 fold the molar amount of the compound of formula III.
The method according to claims 1 and 2, characterized in that the reaction is carried out in tetrahydrofuran or 2-methyltetrahydrofuran.
The method according to claims 1 to 3, characterized in that the reaction is carried out under boiling of the solvent.
The method according to claims 1 to 4, characterized in that the reaction is carried out without the presence of the catalyst 4-dimethylaminopyridine.
The method according to claims 1 to 5, characterized in that the compound of formula I is crystallized from a suitable solvent, said 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.
Crystalline, highly optically pure 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l ,3- oxazolidin-5-yl} methyl)- lH-isoindol-1 , 3 (2H)-dione, the compound of formula (I), characterized by X-ray powder diffraction with characteristic 2 theta angles - 4.63; 12.00; 13.9; 15.3 ; 15.87; and 24.55.
PCT/CZ2011/000095 2010-09-30 2011-09-27 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 with a high optical purity WO2012041263A2 (en)

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EP3309158A1 (en) 2012-12-21 2018-04-18 Farma GRS, d.o.o. Crystalline form k of rivaroxaban and process for its preparation
WO2016030669A1 (en) * 2014-08-25 2016-03-03 Cipla Limited Process for the preparation of rivaroxaban
CN110054623A (en) * 2019-05-29 2019-07-26 浙江燎原药业股份有限公司 A kind of preparation method of Rivaroxaban intermediate
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