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Synthetic method of apixaban transition-state impurities

A synthetic method, the technology of apixaban, which is applied in the field of synthesis of transitional impurities of apixaban, and achieves the effects of high purity, simple process and easy operation

Inactive Publication Date: 2019-10-25
新乡双鹭药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] With the advancement of the country's drug consistency research work, determining the preparation method of impurity compounds and providing qualified reference substances can play a positive role in the quality control of apixaban, but there is currently no 1-(4 -Methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-3 -Related literature reports on the preparation method of morpholino-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

Method used

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  • Synthetic method of apixaban transition-state impurities
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  • Synthetic method of apixaban transition-state impurities

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Embodiment 1

[0031] 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro The synthesis of -1H-3-morpholino-pyrazolo [3,4-c] pyridine-3-carboxylic acid ethyl ester is characterized in that the synthetic method specifically comprises the following steps:

[0032] (1) Add 30g of AB (5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl) successively to a 500ml four-neck flask -2(1H)-pyridone CAS: 545445-44-1 molecular weight 355.43), 28.2g AS (chloro[(4-methoxyphenyl) hydrazono] ethyl acetate CAS: 27143-07-3 molecular weight 256.69 ), 150ml dichloromethane, stirring and dissolving;

[0033] (2) Add 30.6 ml of triethylamine to the product obtained in step (1), heat in a water bath at 60° C., reflux for 6 hours, remove the water bath and naturally drop to room temperature;

[0034] (3) The product obtained in the step (2) is subjected to suction filtration, the filter cake is added in a 1L flask, and 500ml of n-hexane is added to the filter cake obtained a...

Embodiment 2

[0041] 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro -1H-3-morpholino-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester, is characterized in that, synthetic method specifically comprises the following steps:

[0042] (1) Add 100gAB (5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl)-2( 1H)-pyridone CAS: 54544544-1 molecular weight 355.43), 94g AS (chloro[(4-methoxyphenyl) hydrazono] ethyl acetate CAS: 27143-07-3 molecular weight 256.69), 400ml dichloromethane , stir to dissolve;

[0043] (2) Add 102ml triethylamine to the product obtained in step (1), add 400ml saturated sodium chloride solution after heating to reflux for 6 hours, stir and separate phases;

[0044] (3) Add 100g of anhydrous sodium sulfate and 6g of 100-120 mesh silica gel to the organic phase after phase separation in step (2), and suction filter after stirring for 30 minutes;

[0045] (4) The filter residue obtained by suction filtration in step (3) is r...

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Abstract

The invention discloses a synthetic method of apixaban transition-state impurities. The synthetic method specifically comprises the following steps that (1) AB (5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone, CAS: 545445-44-1, and the molecular weight is 355.43), AS (chloro[(4-methoxyphenyl)hydrazono]ethyl acetate, CAS: 27143-07-3, and the molecular weight is 256.69), and dichloromethane are sequentially added into a flask, and stirring and dissolving are conducted; (2) alkaline matter is added into a product obtained in the step (1), heating reflux is conducted, and then the temperature is decreased to the room temperature; and (3) a product obtained in the step (2) is subjected to suction filtration, normal hexane is added into a filter cake obtained after suction filtration, stirring and pulping are conducted, then suction filtration is conducted, and a target product is obtained.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing transitional impurities of apixaban. Background technique [0002] Apixaban (Apixaban) is an oral anticoagulant drug with selectivity and affinity for coagulation factor Xa, jointly developed by Bristol-Myers Squibb and Pfizer, and its trade name is Eliquis, which was launched in March 2011 The European Union approved the marketing; in December 2012, the FDA approved the drug to be launched in the United States, and then the drug was successively launched in other regions and countries. Clinically, it is used for the prevention of venous thromboembolic events (VTE) in adult patients undergoing elective hip or knee replacement. It is also used abroad to prevent stroke in patients with atrial fibrillation. At present, the indications of this drug are still in the clinical stage in China. [0003] 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 李璞葛永彪郭本泉
Owner 新乡双鹭药业有限公司