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Preparation method of apixaban impurity 1

A technology for apixaban and impurities is applied in the field of drug impurity synthesis to achieve the effects of high reaction yield, good yield and high impurity purity

Active Publication Date: 2020-12-29
HUAIHUA UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The structure of this apixaban impurity 1 is very similar to the structure of apixaban. At present, there is no literature report on the synthesis of this impurity in China. In order to facilitate the detection, analysis and control of the apixaban impurity, it is necessary to provide a simple, Rapid preparation method; with the advancement of the country's drug consistency evaluation work, the preparation method of apixaban impurity 1 is determined, and qualified impurity reference substances are provided, which can play a positive role in the quality control of apixaban

Method used

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  • Preparation method of apixaban impurity 1
  • Preparation method of apixaban impurity 1
  • Preparation method of apixaban impurity 1

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Effect test

Embodiment 1

[0024] Compound 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-6-methyl-1-piperidinyl)phenyl]-2(1H)-pyridinone The preparation of: Add compound 1-(4-aminophenyl)-5,6-dihydro-3-(4-morpholinyl)-2(1H)-pyridone (0.1mol, 27.84g ), compound 5-oxohexanoic acid (0.1mol), aluminum trichloride (0.05mol) and phenylsilane (0.3mol), heated to 40°C for 12h, after the reaction was completed, cooled to room temperature, and the reaction solution Quench to 150mL of water, extract twice with 100mL*2 dichloromethane, combine the organic phase, concentrate the organic phase to leave a volume of about 50mL, add 160mL of n-hexane, cool down to about 10°C and stir for 3h, filter to obtain yellow to off-white The solid is the compound 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-6-methyl-1-piperidinyl)phenyl]-2(1H) - Pyridone (product: 35.32 g, yield: 91.8%).

Embodiment 2

[0026] Compound 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-6-methylpiperidin-1-yl)phenyl]-4,5,6, Preparation of ethyl 7-tetrahydro-1H-pyrazol[3,4-c]pyridine-3-carboxylate: add the compound [(4-methoxyphenyl)hydrazino] ethyl chloroacetate sequentially to the reaction flask Ester (0.08mol, 20.54g) and compound 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-6-methyl-1-piperidinyl)phenyl ]-2(1H)-pyridone (0.08mol, 30.68g), heat up to 90-95°C, add triethylamine (0.16mol, 16.2g) dropwise, after the dropwise addition, continue to react for 3 hours, cool down to room temperature , add dilute hydrochloric acid dropwise, after the dropwise addition, cool down to about 10°C and stir for 2 hours, filter, wash the filter cake with water several times to obtain a yellow solid which is the compound 1-(4-methoxyphenyl)-7-oxo Substituent-6-[4-(2-oxo-6-methylpiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazol[3,4-c] Ethyl pyridine-3-carboxylate (product: 29.74 g, yield: 74.0%).

Embodiment 3

[0028] Preparation of Apixaban impurity 1: add compound 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-6-methylpiperidine-1) to the reaction flask -yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazol[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.02mol, 10.05g) was dissolved in 50mL tetrahydrofuran, added 30% ammonia solution (0.4mol, 23mL), seal the reaction vessel, raise the temperature to 80°C and react for 6h. Stir at about 10°C for 2 hours, filter to obtain an off-white solid that is apixaban impurity 1 (product: 8.33g, yield: 88.0%; purity: 99.2%), ESI: m / z[M+H] + 474.1.

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Abstract

The invention provides a preparation method of an apixaban impurity 1, and relates to the technical field of drug impurity synthesis. The method comprises the following steps: by taking a compound 1-(4-aminophenyl)-5, 6-dihydro-3-(4-morpholinyl)-2-(1H)-pyridone as an initial raw material, carrying out amination reduction acid amine condensation, cyclization-elimination and amine ester exchange three-step reaction to obtain the apixaban impurity 1; according to the method, the reaction raw materials are simple and easy to obtain, the reaction conditions and experimental operation are simple, harsh conditions, expensive reagents, equipment and the like are not needed, meanwhile, the reaction conditions are mild, the process is simple, the reaction time is short, the yield is good, and the apixaban impurity 1 with higher reaction yield and very high impurity purity can be obtained. The invention provides a reliable impurity reference substance for quality control research of apixaban, andhas great significance.

Description

Technical field: [0001] The invention relates to the technical field of drug impurity synthesis, in particular to a preparation method and application of apixaban impurity 1. Background technique: [0002] Apixaban (Apixaban) is a new oral factor Xa inhibitor jointly developed by Pfizer and Bristol-Myers Squibb. It is used for the prevention and treatment of thrombosis, and is effective in preventing venous thromboembolism after hip or knee replacement surgery. Well, there is no increased risk of bleeding. [0003] Apixaban impurity 1(1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-6-methylpiperidin-1-yl)phenyl]- 4,5,6,7-tetrahydro-1H-pyrazol[3,4-c]pyridine-3-carboxamide), its structural formula is as follows: [0004] [0005] The structure of this apixaban impurity 1 is very similar to the structure of apixaban. At present, there is no literature report on the synthesis of this impurity in China. In order to facilitate the detection, analysis and control of the apixaban impurit...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 罗琼林曾瞬钦舒友苏胜培向德轩欧阳跃军林红卫李勇周微
Owner HUAIHUA UNIV
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