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Method for preparing rivaroxaban

A technology for rivaroxaban and intermediates, applied in the field of preparation of rivaroxaban, can solve the problems of long reaction steps, low route yield, unfavorable large-scale industrial production, etc., achieve low cost, cheap raw materials, and simple operation easy to control effect

Inactive Publication Date: 2014-09-10
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis route has relatively long reaction steps, the intermediates need to be separated and purified by column chromatography, and the route yield is low, which is not conducive to large-scale industrial production.

Method used

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  • Method for preparing rivaroxaban
  • Method for preparing rivaroxaban

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Synthesis of intermediate Ⅰ: 19g 4-(4-aminophenyl)-3-morpholinone and 20g 2-[(2S)-2-oxiranyl-methyl]-1H-isoindole- 1,3(2H)-dione was placed in 180ml of isopropanol and 100ml of water, stirred, heated to 50°C, 19.4g of CDI was dissolved in 50mL of tetrahydrofuran, slowly added dropwise to the above reaction solution, and then heated to reflux for reaction, The reaction was monitored by TLC; after the reaction was completed, when cooled to room temperature, tetrahydrofuran and isopropanol were evaporated under reduced pressure, then heated to 60°C, slowly added 100mL of ethanol dropwise, stirred, cooled to 20°C, suction filtered, and dried to obtain 41g of crude solid , put the solid crude product in 240mL of isopropanol, heat to dissolve, cool down to 15°C to crystallize, filter with suction, and dry to obtain 35.4g of white solid product, yield: 85%;

[0024] Synthesis of Intermediate II: Put 35g of Intermediate I in 280ml of acetonitrile, stir, heat up to 50°C, add 20g...

Embodiment 2

[0027] Synthesis of intermediate Ⅰ: 23g 4-(4-aminophenyl)-3-morpholinone and 29g 2-[(2S)-2-oxiranyl-methyl]-1H-isoindole- 1,3(2H)-diketone was placed in 240ml of isopropanol and 120ml of water, stirred, heated to 50°C, 24.7g of DCC was dissolved in 80mL of tetrahydrofuran, slowly added dropwise to the above reaction solution, and then heated to reflux for reaction, The reaction was monitored by TLC; after the reaction was completed, when cooled to room temperature, tetrahydrofuran and isopropanol were evaporated under reduced pressure, then heated to 60°C, slowly added 150mL of ethanol dropwise, stirred, cooled to 20°C, suction filtered, and dried to obtain 48g solid crude product , put the solid crude product in 280mL of isopropanol, heat to dissolve, cool down to 15°C to crystallize, filter with suction, and dry to obtain 43.5g of white solid product, yield: 87%;

[0028] Synthesis of Intermediate II: Put 40g of Intermediate I in 350ml of tetrahydrofuran, stir, heat up to 45...

Embodiment 3

[0031] Synthesis of intermediate Ⅰ: 28g 4-(4-aminophenyl)-3-morpholinone and 37g 2-[(2S)-2-oxiranyl-methyl]-1H-isoindole- 1,3(2H)-dione was placed in 300ml of isopropyl ether and 150ml of water, stirred, heated to 50°C, 39.1g of CDI was dissolved in 100mL of tetrahydrofuran, slowly added dropwise to the above reaction solution, and then heated to reflux for reaction , TLC monitors the reaction, the reaction is completed, cooled to room temperature, evaporated under reduced pressure to remove tetrahydrofuran and isopropyl ether, then heated to 60 degrees Celsius, slowly added 200mL of ethanol dropwise, stirred, cooled to 20 degrees Celsius, suction filtered, and dried to obtain 56g of solid Crude product, put the solid crude product in 350mL of isopropanol, heat to dissolve, cool down to 15°C to crystallize, filter with suction, and dry to obtain 51g of white solid product, yield: 85%;

[0032] Synthesis of Intermediate II: Put 48g of Intermediate I in 400ml of ethanol, stir, h...

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Abstract

The invention discloses a method for preparing rivaroxaban, and is characterized in that the method comprises the following steps of synthesis of an intermediate I, synthesis of an intermediate II and synthesis of rivaroxaban, wherein the synthesis of the intermediate I comprises the synthetic steps of taking 4-(4-aminophenyl)-3-morpholinone and 2-[(2S)-2-oxiranyl-methyl)-1H-isoindole-1,3(2H)-diketone as raw materials, and in an alcohol solvent, carrying out a reaction with a condensating agent to obtain the intermediate I; the synthesis of the intermediate II comprises the synthetic steps of placing the intermediate I in a solvent, under the action of an amine reagent, carrying out a reaction to generate a primary amine compound, and forming an ammonium salt with an acid reagent to obtain the intermediate II; and the synthesis of rivaroxaban comprises the synthetic steps of placing 5-chlorothiophene carboxylic acid in a solvent, under the action of an acylation reagent, forming an acylated substance, then carrying out a reaction with the intermediate II under the action of an alkali reagent, and thus obtaining rivaroxaban. The method has the beneficial effects of cheap and easily obtained raw materials, simple and easily controlled operation, high reaction yield, high product purity, and low cost.

Description

technical field [0001] The invention relates to a preparation method of rivaroxaban. Background technique [0002] Rivaroxaban is a small-molecule oral anticoagulant jointly developed by Bayer and Johnson & Johnson, and its trade name is Xarelto. It was approved for marketing in Canada and the European Union on September 15 and October 1, 2008, respectively. On July 1, 2011, the FDA approved the drug for the prevention of deep vein thrombosis in patients undergoing knee or hip replacement surgery. Its chemical name is: 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3-oxazoline -5-yl)methyl)thiophene-2-carboxamide. The structure is as formula 1: [0003] [0004] Formula 1 [0005] The formation of thrombus is an important pathogenic factor of cardiovascular diseases such as myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. Antithrombotic therapy has always been the core of rescue measures and prevention strategies for such dis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 林燕峰李泽标刘明元赵永星
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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