Synthesis method of rivaroxaban

A synthesis method and technology of rivaroxaban, applied in the production of bulk chemicals, organic chemistry and other directions, can solve the problems of unfavorable industrial production, difficult to obtain, high price, etc., to avoid the use of expensive raw materials, improve yield, improve The effect of production efficiency

Inactive Publication Date: 2020-06-09
JIANGSU ZHONGBANG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The yield of this route is low, and the raw material (S)-3-amino-1,2-propanediol hydrochloride is rarely sold in

Method used

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  • Synthesis method of rivaroxaban
  • Synthesis method of rivaroxaban
  • Synthesis method of rivaroxaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Drop into 4.0g 40% methylamine aqueous solution, 36g ethanol and 7.2g 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) in 100ml four-necked reaction flask Phenyl]-5-oxazolidinyl]methyl]-1H-isoindole-1,3(2H)-dione, stir and heat up to 70°C, keep the temperature for 3 hours, image 3 The main raw material came out at 4.346 minutes, the reaction of the raw material was complete, the system was evaporated to dryness under reduced pressure, 40g of purified water and 2.2g of sodium carbonate were added, stirred to dissolve, and 13.4g of 30% 5-chlorothiophene-2-formyl chloride was added dropwise at 10°C Solution, insulation reaction 1 hour monitoring reaction completes, Figure 4 The main raw material peaked at 2.633 minutes, and the reaction of the raw material was complete. Add 50g of acetone and continue to stir for 0.5 hours, filter to obtain a white solid, rinse with 30g of purified water and 30g of acetone, and dry in vacuum to obtain 6.9g of dry product of rivaroxaban (yield ...

Embodiment 2

[0037] Drop into 4.0g 40% aqueous methylamine solution, 36g methanol and 7.2g 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) in 100ml four-necked reaction flask Phenyl]-5-oxazolidinyl]methyl]-1H-isoindole-1,3(2H)-dione, stir and heat up to 70°C, keep warm for 3 hours, evaporate the system to dryness under reduced pressure, add 40g Purified water and 2.2g of sodium carbonate were stirred and dissolved, and 13.4g of 30% 5-chlorothiophene-2-formyl chloride toluene solution was added dropwise at 10°C, and kept for 1 hour to monitor the completion of the reaction, and 50g of acetone was added to continue stirring for 0.5 hours, and filtered to obtain white The solid was rinsed with 30 g of purified water and 30 g of acetone, respectively, and dried under vacuum to obtain 6.7 g of dry product of rivaroxaban (90.0% yield, 99.88% purity);

Embodiment 3

[0039]Drop into 4.0g 40% methylamine aqueous solution, 36g ethanol and 7.2g 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) in 100ml four-necked reaction flask Phenyl]-5-oxazolidinyl]methyl]-1H-isoindole-1,3(2H)-dione, stir and heat up to 60°C, keep warm for 3 hours, evaporate the system to dryness under reduced pressure, add 40g Purified water and 2.2g of sodium carbonate were stirred and dissolved, and 13.4g of 30% 5-chlorothiophene-2-formyl chloride toluene solution was added dropwise at 10°C, and kept for 1 hour to monitor the completion of the reaction, and 50g of acetone was added to continue stirring for 0.5 hours, and filtered to obtain white The solid was rinsed with 30 g of purified water and 30 g of acetone, respectively, and dried under vacuum to obtain 6.8 g of dry product of rivaroxaban (91.3% yield, 99.83% purity);

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Abstract

The invention discloses a synthetic method of rivaroxaban. According to the method, rivaroxaban is prepared by adopting a one-pot method; 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-5-oxazolidinyl]methyl]-1H-isoindol-1,3(2H)-one in an alcohol solvent is subjected to an ammonolysis reaction in the presence of an alkali to remove a protective group, then to evaporation to remove the alcohol solvent, and finally to condensation with 5-chlorothiophene-2-formyl chloride under the action of an acid-binding agent, wherein the reaction alcohol solvent is alcohol with a carbon number of 4 or below, the alkali is an organic alkali or inorganic alkali, a condensation reaction solvent is water, and the acid-binding agent is potassium carbonate or sodium carbonate. The method has the advantages ofmild reaction conditions, simple post-treatment, conservation of a large amount of manpower and material resources, and applicability to large-scale industrial production.

Description

Technical field: [0001] The invention relates to a synthesis method of rivaroxaban, in particular to a method for preparing rivaroxaban by a one-pot method, and belongs to the technical field of chemical drug synthesis. Background technique: [0002] Rivaroxaban, English name Rivaroxaban, domestic product name is Xarelto, CAS number: 366789-02-8, molecular formula: C 19 h 18 ClN 3 o 5 S, its structural formula is as follows (formula 1): [0003] [0004] Rivaroxaban is a new oral anticoagulant drug jointly developed by Bayer and Johnson & Johnson. It was approved for marketing in Canada and the European Union on September 15 and October 1, 2008, respectively. Now approved for marketing in 29 countries including China, it is used to prevent the formation of venous thromboembolism and pulmonary embolism after hip and knee replacement surgery in adult patients. On June 19, 2009, Rivaroxaban was approved by the State Food and Drug Administration and launched in China...

Claims

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Application Information

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IPC IPC(8): C07D413/14
CPCC07D413/14Y02P20/55
Inventor 薛谊吴小刚刘力萍唐景玉高倩秦春梅
Owner JIANGSU ZHONGBANG PHARMA
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