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Apixaban related substance and preparation method and application thereof

A related substance, a technology for apixaban, applied in the field of apixaban related substances and their preparation, can solve problems such as difficult removal of impurities, and achieve the effects of mild reaction conditions, high purity and good controllability

Active Publication Date: 2019-02-22
湖北扬信医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] When the inventor used the literature route, such as the methods disclosed in WO2017187245, US20150353543 and WO2014075648, to carry out the final synthesis of apixaban, he found that the final product contained an impurity with a peak area greater than 0.1%, and the impurity was present in the finished product of apixaban Difficult to remove

Method used

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  • Apixaban related substance and preparation method and application thereof
  • Apixaban related substance and preparation method and application thereof
  • Apixaban related substance and preparation method and application thereof

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preparation example Construction

[0023] This embodiment provides a preparation method of related substance A of apixaban, comprising the following steps:

[0024] (1) In the first organic solvent, under basic conditions, compound II (chemical name: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiper Pyridin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester) and 5-chloropentanoic acid ethyl ester A nucleophilic substitution reaction occurs at 0-100°C until the compound II disappears. After adding an appropriate amount of water to the reaction liquid to precipitate a solid, it is suction filtered, the filter cake is washed with water and isopropanol, and purified by column chromatography to obtain Intermediate III;

[0025] (2) Dissolve intermediate III in the second organic solvent, add strong alkali solution to the reaction solution under ice bath, adjust the pH of the reaction solution to 10-11, after the addition, adjust the temperature of the reaction solution to 0-40°C, hyd...

Embodiment 1

[0044] Embodiment 1 of the present invention provides a kind of preparation method of intermediate III, and its synthetic route is as follows:

[0045]

[0046] Specifically adopt the following method to prepare:

[0047] Compound II (2.0g, 4.9mmol), N,N-diisopropylethylamine (1.2mL, 7.4mmol), ethyl 5-chlorovalerate (0.97g, 5.9mmol) and N,N-dimethyl Add methyl formamide (12mL) into the reaction bottle and mix evenly, react the reaction solution at 80°C for 7 hours, detect the reaction by TLC until compound II disappears, add water (12mL) to the reaction solution, after the solid precipitates, continue to stir for 0.5 hours , suction filtration, and the filter cake was washed with water and isopropanol to obtain a crude product, which was purified by column chromatography to obtain a light yellow solid, namely compound III.

[0048] The light yellow solid obtained by this method was 1.8 g, and the yield was 68%.

[0049] The intermediate III prepared in the present embodim...

Embodiment 2

[0053] Embodiment 2 of the present invention provides a method for preparing intermediate III, which is specifically prepared by the following method:

[0054] Compound II (1.3 g, 3.2 mmol), triethylamine (0.7 mL, 4.8 mmol), ethyl 5-chlorovalerate (0.63 g, 3.8 mmol) and N,N-dimethylformamide (8 mL) were added Mix well in the reaction flask, react the reaction solution at 80°C for 7 hours, detect the reaction by TLC until compound II disappears, add water (8mL) to the reaction solution, after the solid precipitates, continue to stir for 0.5 hours, filter with suction, and filter the cake with water Wash with isopropanol to obtain a crude product, which is purified by column chromatography to obtain a light yellow solid, namely compound III.

[0055] The light yellow solid obtained by this method was 1.1 g, and the yield was 64%.

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Abstract

The invention discloses an apixaban related substance A, so that quality control of an apixaban synthesis process is facilitated. The invention also discloses a preparation method of the substance. The preparation method comprises the following steps: (1) in an alkaline condition, carrying out a nucleophilic substitution on 1-(4-methoxyl phenyl)-7-oxo-6-[4-(2-oxo piperidine-1-yl)-4,5,6,7-tetrahydro-1H-indazol[3,4-C]-pyridine-3-ethyl carboxylate and 5-chloro-ethyl valerate to obtain an intermediate III; and (2) carrying out a hydrolysis reaction on the intermediate III under the action of strong base to obtain a compound A. The preparation method disclosed by the invention is mild in reaction condition, good in controllability, relatively high in yield and high in purity, and the substancecan be used as a standard substance, so that the quality of apixaban in the preparation process is controlled and researched.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical manufacturing, in particular to a substance related to apixaban and its preparation method and application. Background technique [0002] Apixaban (Apixaban), the molecular formula is C 25 h 25 N 5 o 4 , whose chemical name is 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl) Phenyl]-1H-oxazolo[3,4-C]pyridine-3-carbonylamine. Apixaban is a novel factor Xa inhibitor jointly developed by Pfizer and Bristol-Myers Squibb for the prevention of venous thromboembolism in adults after total hip or total knee replacement and the prevention of stroke in patients with non-valvular atrial fibrillation and systemic embolism, treatment and prevention of deep vein thromboembolism and pulmonary embolism. [0003] Patent documents such as WO2017187245, US20150353543, WO2014075648 and CN105254630 have reported the synthesis of apixaban, and the synthesis method of the last step is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04G01N30/06
CPCC07D471/04G01N30/06
Inventor 宋学攀
Owner 湖北扬信医药科技有限公司
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