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Synthetic methods of related substances F and G of rivaroxaban

A related substance, rivaroxaban technology, applied in the direction of organic chemistry, etc., can solve the problems of lack of impurities and cumbersome synthesis methods of impurities

Active Publication Date: 2015-09-09
汕头经济特区鮀滨制药厂
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, on the basis of the experimental research on the patented process route, combined with the quality standards of rivaroxaban, the patent of the present invention found that Cai Zhengyan and the patent WO2012035057 lacked some known impurities, and the impurity synthesis method was cumbersome

Method used

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  • Synthetic methods of related substances F and G of rivaroxaban
  • Synthetic methods of related substances F and G of rivaroxaban
  • Synthetic methods of related substances F and G of rivaroxaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Add (S)-5-chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 , 3-oxazolidin-5-yl}methyl)-2-carboxamide. In 100 mL aqueous solution of 16 g of hydrochloride, react at room temperature for 2 hours. Concentrate to remove water in the reaction solution, wash with 30 mL of methanol, filter, concentrate the filtrate, and dry to obtain (S)-5-chloro-N-( {2-oxo-3-[ 4-( 3-oxo- 4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-carboxamide, under the protection of argon at room temperature, add 4.5 mL of anhydrous triethylamine to (S ) -5-chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl )-2-carboxamide in 600 mL of anhydrous tetrahydrofuran suspension, and then 5 mL of acetyl chloride was added dropwise, and reacted at room temperature for 2 hours. TCL (EA / MeOH=10:1) tracking shows that some raw materials still exist. Anhydrous 2.2 mL of triethylamine and 2.2 mL of acetyl chloride were added successively to continue the reaction for 2 hours. TCL ...

Embodiment 2

[0062] Add (S)-5-chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 , 3-oxazolidin-5-yl}methyl)-2-carboxamide. In 1.3mL aqueous solution of 180 g of hydrochloride, react at room temperature for 2.5 hours. Concentrate to remove water in the reaction solution, wash with 500 mL methanol, filter, concentrate the filtrate, and dry to obtain (S)-5-chloro-N-( {2-oxo-3-[ 4-( 3-oxo- 4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-carboxamide, under the protection of argon at room temperature, add 500 mL of anhydrous triethylamine to (S ) -5-chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl )-2-carboxamide in 8.0L of anhydrous tetrahydrofuran suspension, and then 70 mL of acetyl chloride was added dropwise, and reacted at room temperature for 2 hours. TCL (EA / MeOH=10:1) tracking shows that some raw materials still exist. Then add anhydrous 25mL triethylamine and 25mL acetyl chloride to continue the reaction for 2 hours, TCL (EA / MeOH=10 / 1) monitoring,...

Embodiment 3

[0064] Add (S)-5-chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 , 3-oxazolidin-5-yl}methyl)-2-carboxamide. In 1.2 mL aqueous solution of 160 g of hydrochloride, react at room temperature for 2 hours. Concentrate to remove water in the reaction solution, then wash with 400 mL of methanol, filter, concentrate the filtrate, and dry to obtain (S)-5-chloro-N-( {2-oxo-3-[ 4-( 3-oxo- 4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-carboxamide, under the protection of argon at room temperature, add 46 mL of anhydrous triethylamine to (S ) -5-chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl )-2-carboxamide in 7 L of anhydrous tetrahydrofuran suspension, and then 6 mL of acetyl chloride was added dropwise, and reacted at room temperature for 2 hours. TCL (EA / MeOH=10:1) tracking shows that some raw materials still exist. Then add 25 mL of anhydrous triethylamine and 25 mL of acetyl chloride to continue the reaction for 2 hours. TCL (EA / MeOH=10 / 1)...

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Abstract

The invention provides synthetic methods of related substances F and G of rivaroxaban. With the adoption of the synthetic methods of the related substances F and G of the rivaroxaban, the yield is high, and industrial production and technology transformation are realized easily.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis and relates to a new synthesis method of related substances F and G of rivaroxaban. Background technique [0002] Thrombotic disease is a kind of disease that seriously endangers human health. It can affect multiple organs and systems throughout the body, and its morbidity, disability and mortality are high. Anticoagulant therapy has always been the core of the rescue and prevention of thrombotic diseases. Xa is a serine protease located at the intersection of the intrinsic coagulation pathway and the extrinsic coagulation pathway, and plays an important role in the coagulation cascade reaction. It finally regulates the generation of thrombin by cleaving prothrombin, so inhibiting Xa can Produces a highly effective anticoagulant effect. [0003] Rivaroxaban (rivaroxaban, 1, formula 1), the chemical name is 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) -Phenyl]-1,3-oxazolidin-5-y...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 冯汝洁施涯邻吴毅武贝荣丙陈海龙
Owner 汕头经济特区鮀滨制药厂
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