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Preparation method for important impurity of apixaban intermediate

A technology of apixaban and intermediates, applied in the field of preparation of important impurities, can solve the problems such as no literature reports in the preparation method

Inactive Publication Date: 2019-06-14
SHANDONG XINHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The important impurity of the apixaban intermediate involved in the present invention is 3-morpholino-1-(4-(2-oxo-5,6-dihydropyridin-1(2H)-yl)phenyl) The structure of -5,6-dihydro-2(1H)-one is shown below, and the preparation method of this important impurity has not been reported in the literature

Method used

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  • Preparation method for important impurity of apixaban intermediate
  • Preparation method for important impurity of apixaban intermediate
  • Preparation method for important impurity of apixaban intermediate

Examples

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Embodiment 1

[0017] Take a 250mL four-necked glass reaction bottle, install mechanical stirring, reflux condenser, add 0.39g of 1-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one and Add 0.1g of 5,6-dihydropyridin-2(1H)-one, add 50mL of dimethyl sulfoxide, then add 0.28g of anhydrous potassium carbonate and 0.2g of cuprous iodide into the reaction flask, replace with nitrogen three times, and keep the reaction The system was heated up to 150°C under a nitrogen atmosphere to react; after the reaction was detected by TLC, the heating was stopped, and the reaction liquid was naturally cooled to room temperature with stirring, added 50 mL of water and 1 mL of ammonia water and stirred for 30 minutes, extracted three times with 200 mL of ethyl acetate, and then saturated with The organic layer was washed with 30 mL of saline, the organic layer was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated, and then the concentrate was subjected to column chromatography ...

Embodiment 2

[0019] Take a 250mL four-necked glass reaction bottle, install mechanical stirring, reflux condenser, add 0.22g of 1-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one and Add 0.085g of 5,6-dihydropyridin-2(1H)-one, add 50mL of toluene, then add 0.37g of anhydrous cesium carbonate and 0.11g of tris(triphenylphosphine)cuprous bromide into the reaction flask, replace with nitrogen three times , keep the reaction system warming up to 120°C under nitrogen atmosphere; after the reaction is detected by TLC, stop heating, and the reaction solution is naturally cooled to room temperature under stirring, add 50mL water and 1mL ammonia water and stir for 30 minutes, extract three times with 200mL ethyl acetate, Then the organic layer was washed with 30 mL of saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and then the concentrate was subjected to column chromatography (dichloromethane:methanol was 50:1~10:1 for gr...

Embodiment 3

[0021] Take a 250mL four-necked glass reaction flask, install mechanical stirring, reflux condenser, add 0.30g of 1-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one and 0.1g of 5,6-dihydropyridin-2(1H)-one, add 50mL of N,N-dimethylformamide, then 0.46g of potassium phosphate, 0.1g of cuprous iodide and N,N-dimethylformamide Diamine was added to the reaction flask, replaced by nitrogen three times, and the reaction system was heated to 80°C under nitrogen atmosphere; after the reaction was detected by TLC, the heating was stopped, and the reaction solution was naturally cooled to room temperature with stirring, and 50 mL of water and 1 mL of ammonia were added and stirred for 30 minutes, extracted three times with 200mL ethyl acetate, then washed the organic layer with 30mL of saturated brine, dried the organic layer with anhydrous sodium sulfate, filtered, concentrated the filtrate, and then carried out column chromatography (dichloromethane:methanol ratio of 50 :1~10:...

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Abstract

The invention provides a preparation method for an important impurity of an apixaban intermediate. The preparation method is characterized by comprising the following steps: taking 1-(4-iodine phenyl)-3-morpholino-5,6-dihydropyridine-2(1H)-ketone and 5,6-dihydropyridine-2(1H)-ketone as initial raw materials and then performing Ullman coupling reaction under a nitrogen atmosphere. The preparation method for preparing the important impurity of the apixaban intermediate with high purity and high yield is firstly provided. The important impurity can be used for researching reference substance of apixaban impurity during the process of researching and developing generic drug apixaban.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of important impurities of an apixaban intermediate. Background technique [0002] Apixaban (Apixaban) is an oral selective activated factor X inhibitor jointly developed by Pfizer and Bristol-Myers Squibb. In January 2013, it obtained the import drug license issued by the State Food and Drug Administration of China. It is used for adult patients undergoing elective hip or knee replacement to prevent venous thromboembolic events. It was officially launched in China in April 2013. [0003] 3-morpholino-1-(4-(2-oxo-5,6-dihydropyridin-1(2H)-yl)phenyl)-5,6-dihydro-2(1H)-one is Important organic impurity in apixaban intermediate. [0004] The important impurity of the apixaban intermediate involved in the present invention is 3-morpholino-1-(4-(2-oxo-5,6-dihydropyridin-1(2H)-yl)phenyl) The structure of -5,6-dihydro-2(1H)-one is shown below, and there is no liter...

Claims

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Application Information

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IPC IPC(8): C07D211/86
Inventor 徐启乐牛笑怡沈红
Owner SHANDONG XINHUA PHARMA
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