Rivaroxaban purification method

A technology of rivaroxaban and crude products, applied in the direction of organic chemistry and the like, can solve the problems of easy corrosion reaction equipment, high toxicity of acetonitrile, unsuitable for industrialization, unsuitable for industrialized production, etc., and achieves the effect of facilitating industrialized production

Inactive Publication Date: 2014-10-22
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the strong acidity of acetic acid, it is easy to corrode the reaction equipment, so it is not suitable for industrial production.
Document WO2012035057 also reports a method for refining rivaroxaban with a mixed solvent of DMSO and acetonitrile, but acetonitrile is highly toxic and unsuitable for industrialization

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: Preparation of crude product of rivaroxaban

[0029] Preparation method of reference (J.Med.Chem.48:5900-5908, 2005).

[0030] The first step: 2-((2R)-2-hydroxyl-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl)-1H-isoindole-1, Preparation of 3(2H)-diketone (IV)

[0031] 2-[(2S)-Oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (II) (5.68g, 27.9mmol) and 4-(4 -Aminophenyl)-3-morpholinone (III) (5.37g, 27.9mmol) was suspended in ethanol-water (9:1, 140ml) solution, and refluxed for 14h (the raw materials gradually dissolved and formed after a period of time) precipitate), the precipitate was filtered off, washed with ether and dried under vacuum, the combined mother liquors were concentrated under reduced pressure and a second portion of 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindrate was added Indole-1,3(2H)-diketone (II) (2.84g, 14.0mmol) in ethanol-water (9:1, 70ml) suspension, reflux reaction for 13h, filtered, washed with ether, dried under vacuum, 10.14 g of w...

Embodiment 2

[0038] Embodiment 2: the refinement of rivaroxaban crude product

[0039] Suspend the crude product of 4 g of rivaroxaban in 60 ml of ethylene glycol methyl ether and heat it to 125 ° C, add 0.4 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while it is hot, and cool the mother liquor to room temperature. Suction filtration, the precipitated product was filtered out, washed with ethylene glycol methyl ether, and dried to obtain 3.46 g of white solid, recrystallization yield: 86.5%. HPLC purity 99.74%, ee%: 99.96%. DSC melting temperature: 230°C. 1 HNMR (400MHz, d 6 -DMSO): 9.00-8.93(t, J=5.6Hz, 6Hz, 1H), 7.70(d, J=4Hz, 1H), 7.60-7.53(d, J=8.8Hz, 2H), 7.44-7.37(d , J=8.2Hz, 2H), 7.21-7.17(d, J=4Hz, 1H), 4.80-4.89(m, 1H), 4.24-4.15(m, 3H), 4.00-3.94(m, 2H), 3.89 -3.82(m, 1H), 3.75-3.68(m, 2H), 3.64-3.58(t, J=5.6Hz, 2H); the 2θ angles of powder diffraction are: 8.960°, 16.481°, 25.582°, 26.608°, 19.483°, 19.877°, 21.654°, ...

Embodiment 3

[0040] Embodiment 3: the refinement of rivaroxaban crude product

[0041] Suspend the crude product of 5 g of rivaroxaban in 50 ml of ethylene glycol methyl ether and heat it to 140 ° C, add 1.5 g of activated carbon, stir the resulting solution at this temperature for 10 minutes, then filter while it is hot, and cool the mother liquor to 60°C. Suction filtration, the precipitated product was filtered out, washed with ethylene glycol methyl ether, and dried to obtain 4.3 g of white solid; recrystallization yield: 86.0%. HPLC purity 99.67%.

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Abstract

The invention provides a rivaroxaban purification method. The method comprises the following steps: dissolving a rivaroxaban coarse product in ethylene glycol monomethyl ether or n-butanol under a heating condition, adding active carbon after clarification, carrying out suction filtration when the solution is still hot, crystallizing and cooling the mother liquor, and filtering so as to obtain the crystallization product rivaroxaban. The rivaroxaban purification method has the following advantages: (1) ethylene glycol monomethyl ether or n-butanol is used to carry out recrystallization to avoid the complicated chromatogram purification; (2) compared to the acetate, ethylene glycol monomethyl ether or n-butanol will not corrode the reaction equipment and is convenient for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for purifying rivaroxaban. Background technique [0002] Rivaroxaban (Rivaroxaban, trade name: Xarelto) chemical name: 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl ) phenyl]-1,3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide, which corresponds to general formula (I), molecular formula is: C 19 h 18 N 3 o 5 SCl, molecular weight: 435.88g / mol. [0003] [0004] Rivaroxaban is an oral direct inhibitor of factor Xa jointly developed by Bayer and Johnson & Johnson. It was approved for marketing in Canada and the European Union in September and October 2008, and is mainly used clinically to prevent venous thromboembolism in patients undergoing hip or knee replacement. In 2011, the US FDA approved it for deep vein thrombosis. Compared with other anticoagulant drugs, rivaroxaban has predictable pharmacokinetic and pharmacodynamic properties, combined with rapid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 温颖玲蔡正艳周伟澄张文强黄火明陈小明
Owner SHANGHAI INST OF PHARMA IND
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