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Preparation method of rivaroxaban

A technology of rivaroxaban and organic solvents, applied in the field of medicine, can solve problems such as inability to carry out industrial production, incomplete substrate reaction, toxicity yield, etc., and achieve the effect of low cost, simple operation and high yield

Inactive Publication Date: 2014-10-08
TIANJIN WEIJIE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] In this method, the substrate 4-(4-aminophenyl)-3-morpholinone (II) reacts with 2-(chloromethyl)oxirane under reflux conditions under the action of isophthalic acid to generate the compound (XII), but because isophthalic acid is easy to form a salt with the substrate 4-(4-aminophenyl)-3-morpholinone (II), resulting in incomplete reaction of the substrate
In addition, when compound (XIV) is prepared from compound (XII), since N,N-dimethylformamide is used to heat to 150°C, the reaction temperature is too high, so this method will also encounter many problems in the industrialization process. question
[0015] From the above analysis, it can be seen that in the current methods for preparing rivaroxaban, some methods cannot be industrialized, and some methods can be industrialized, but in the last step of production, toxic reagents are used and there are low yields and high costs. shortcoming

Method used

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  • Preparation method of rivaroxaban
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Examples

Experimental program
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Embodiment 1

[0032] a) Preparation of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3 (2H)-Diketone (IV)

[0033] Add absolute ethanol (1.48kg) and process water (467g) in the reaction bottle of 3L, start stirrer and stir, then add 4-(4-aminophenyl)-3-morpholinone (II) (62.3 g) and 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-2-ketone (III) (65.9g), start heating to 70°C, React for 4 hours, stop heating, cool down to 35°C, filter with suction, rinse the solid with 90% ethanol (150g), pump the mother liquor back into the reaction flask, evaporate 1kg of solvent, and add 2-[(2S)- 2-Oxiranylmethyl]-1H-isoindole-1,3(2H)-2-ketone (III) (32.9g), heated to 70°C, reacted for 4 hours, stopped heating, cooled to 30°C , suction filtration, the solid was rinsed with 90% ethanol (100 g), and the filtrate was treated as waste liquid, and the solids obtained by suction filtration twice were combined and dried. 121.8 g of product were obtained, purity: 96%, melting ...

Embodiment 2

[0042] a) Preparation of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3 (2H)-Diketone (IV)

[0043] Add absolute ethanol (1.48kg) and process water (467g) in the reaction bottle of 3L, start stirrer and stir, then add 4-(4-aminophenyl)-3-morpholinone (II) (62.3 g) and 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-2-ketone (III) (65.9g), start heating to 70°C, React for 4 hours, stop heating, cool down to 25°C, filter with suction, rinse the solid with 90% ethanol (150g), pump the mother liquor back into the reaction flask, distill 1kg of solvent, add 2-[(2S)- 2-Oxiranylmethyl]-1H-isoindole-1,3(2H)-2-ketone (III) (32.9g), heated to 70°C, reacted for 4 hours, stopped heating, cooled to 35°C , suction filtration, the solid was rinsed with 90% ethanol (100 g), and the filtrate was treated as waste liquid, and the solids obtained by suction filtration twice were combined and dried. 117.8 g of product were obtained, purity: 90%, melting point:...

Embodiment 3

[0052] a) Preparation of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3 (2H)-Diketone (IV)

[0053] Add absolute ethanol (1.48kg) and process water (467g) in the reaction flask of 3L, start to stir, then add 4-(4-aminophenyl)-3-morpholinone (II) (62.3g) and 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-2-ketone (III) (65.9g), start heating to 70°C, react for 4 hours , stop heating, cool down to 35°C, filter with suction, rinse the solid with 90% ethanol (150g), pump the mother liquor back into the reaction flask, evaporate 1kg of solvent, and add 2-[(2S)-2-cyclo Oxyethylmethyl]-1H-isoindole-1,3(2H)-2-ketone (III) (39.54g), heated to 70°C, reacted for 4 hours, stopped heating, cooled to 30°C, and suction filtered , The solid was rinsed with 90% ethanol (100 g), the filtrate was treated as waste liquid, and the solid obtained by suction filtration twice was combined and dried. 122.9 g of product were obtained, purity: 96%, melting point: 2...

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Abstract

The invention discloses a preparation method of rivaroxaban. According to the preparation method, by taking 4-(4-aminophenyl)-3-morpholone (II) and 2-[(2S)-2-oxiranylmethyl]-1H-isoindazole-1,3(2H)-2 ketone (III) as starting materials, rivaroxaban is prepared through the ring-opening reaction between amine and epoxy, the ring-closing reaction of carbonyldiimidazole, the deprotection of ethanol amine and the butting reaction between amine and acyl chloride. The preparation method of the rivaroxaban, which is disclosed by the invention, is easy to operate, can prevent a toxic solvent or reagent from being used in the last-step production and therefore can obtain a high-purity product; in addition, the preparation method is high in yield, low in cost and suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a preparation method of rivaroxaban. Background technique [0002] Rivaroxaban, the English name is Rivaroxaban, the chemical name is 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl] -1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide, its structural formula is: [0003] [0004] Rivaroxaban is a highly selective oral drug that directly inhibits factor Xa developed by Bayer AG. Factor Xa is the intersection of extrinsic and intrinsic coagulation pathways, and is a key point in the coagulation process. Rivaroxaban is the first oral direct inhibitor of factor Xa, which can directly inhibit factor Xa in a free or bound state with high selectivity, produce anticoagulant effect, interrupt the endogenous and exogenous pathways of coagulation cascade, and inhibit coagulation Enzyme production and thrombosis. [0005] In view of the good market prospect of rivaroxaban, a...

Claims

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Application Information

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IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 宋洪海王兴锋黄海平林松
Owner TIANJIN WEIJIE PHARMA
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