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Synthesis method of novel anticoagulation drug

A synthetic method and technology of rivaroxaban, applied in the field of preparation of pharmaceutical compounds, can solve the problems of difficult production operation, low yield, corrosion equipment, etc., and achieve the effect of simple production operation, low price and reduced cost

Active Publication Date: 2014-04-16
YOUCARE PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] But the last step of this route is the same as the method of WO0147919, which still does not solve the problems of corrosion of equipment during industrial production, difficulty in production operation, and generation of acidic waste gas and waste water. rate is not high

Method used

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  • Synthesis method of novel anticoagulation drug
  • Synthesis method of novel anticoagulation drug
  • Synthesis method of novel anticoagulation drug

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0059]

[0060] Add 5.4g 4-(4-aminophenyl)-3-morpholinone, 8.5g (S)-2-(2-oxiranylmethyl)-1H-isoindole-1 in 250mL reaction flask, 3-diketone, 140mL of a mixture of ethanol and water (V:V=9:1), heated and refluxed for 12h. Filter and wash the filter cake with ethanol. Dry to obtain 10.2 g of white solid, which is intermediate A, and the molar yield is 92% (based on 4-(4-aminophenyl)-3-morpholinone).

example 2

[0062]

[0063] Add 3.6g of intermediate a, 90mL of tetrahydrofuran, 2.9g of N,N-carbonyldiimidazole (CDI), and a catalytic amount of 4-dimethylaminopyridine (DMAP) into a 250ml reaction flask, raise the temperature to 60°C and stir for 24h, then evaporate under reduced pressure Solvent, to obtain a yellow solid, add 100ml of dichloromethane and 100ml of water, stir to dissolve and separate the liquids, the water layer is extracted once with 100ml of dichloromethane, the organic layer is combined, dried with anhydrous sodium sulfate and concentrated to dryness to obtain a white solid 3.3 g, is intermediate b, and the molar yield is 87% (based on intermediate A).

example 3

[0065]

[0066] Add 4.2g of intermediate b and 100mL of ethanol to a 250ml reaction flask, add dropwise 10.2mL of 40% methylamine aqueous solution, raise the temperature and reflux and stir for 1 hour, then evaporate the solvent to dryness under reduced pressure to obtain a white solid. Add 100ml of 50% hydrochloric acid ethanol solution, stir at room temperature for 4 hours, and filter to obtain 2.8g of white solid, which is morpholinone hydrochloride. The molar yield is 86% (based on intermediate B).

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Abstract

The invention relates to a synthesis method of a novel anticoagulation drug, which comprises the step that 4-[4-[(5S)-5-(aminomethyl)-2-oxo-3-oxazolidinyl]phenyl]-2-molindone or salt thereof reacts with 5-penphene-2-carboxylic acid in the presence of a condensing agent N', N-carbonyldiiazole (CDI) or N, N'-dicyclohexyl carbodiimide (DCC).

Description

Technical field: [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a preparation method of an anticoagulant drug rivaroxaban. Background technique: [0002] The structural formula of Rivaroxaban is as follows: [0003] [0004] It was jointly developed by Bayer Pharmaceuticals of Germany and Johnson & Johnson of the United States. It was approved for marketing in Canada and the European Union in 2008 under the product name Xarelto. Rivaroxaban is the world's first oral direct factor Xa inhibitor, which can highly selectively and competitively inhibit free and bound factor Xa and prothrombin activity, and prolong the activated partial thromboplastin time plate in a dose-dependent manner (PT) and prothrombin time (aPTT), thereby prolonging the coagulation time and reducing thrombin formation. It has the characteristics of high bioavailability, broad disease spectrum for treatment, stable dose-effect relationship, convenie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 葛志敏许雪蓉武艳朋张红陈林杨磊
Owner YOUCARE PHARMA GROUP
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