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A method of preparing an apixaban impurity B

A technology of apixaban, impurity, applied in the field of chemistry

Inactive Publication Date: 2018-06-15
深圳市祥根生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Apixaban impurity B is an important impurity, and there is no relevant information to report the synthesis of this impurity, and it is also necessary to have a qualified impurity reference substance for quality analysis of apixaban

Method used

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  • A method of preparing an apixaban impurity B
  • A method of preparing an apixaban impurity B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] Example 1: Preparation of Apixaban Impurity B Intermediate

[0013] Add 1 g of SM-1 to a 20 mL round bottom flask, followed by 0.8 mL of DIPEA and 500 mg of SM-2. The temperature of the mixture was raised to 80°C, and the reaction was stirred for 8h. The TLC test showed that there was product formation. After the reaction, the reaction solution was cooled to room temperature, filtered, and purified by column chromatography to obtain 1 g of the target intermediate product TM-1 with a purity of 96% (yield 85%).

Embodiment 2

[0014] Example 2: Preparation of Apixaban Impurity B

[0015] Take 1 g of the product TM-1 obtained in step 1 in a 20 mL round bottom flask, dissolve it in 6 mL THF / NH3, raise the temperature of the mixture to 80 ° C, and react for 8 h. After the reaction was completed, the reaction solution was cooled to room temperature, and the thin layer chromatography test showed that a product was formed. The reaction solution was distilled under reduced pressure and purified by column chromatography to obtain 0.8 g of the target product APXB-Impurity B with a purity of 97% (yield 92%).

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Abstract

A method of preparing an apixaban impurity B is disclosed. The apixaban impurity B (APIX-Impurity B) is prepared through an alkylation reaction and an ester-amide exchange reaction. A reaction solution is subjected to concentration, purification and other types of treatment to increase the yield and purity. The method is technically easy to operate and purity is high. Research of quality control reference substances is already an important part of strict requirements on drug consistency evaluation so that the method has good market application value. The method provides a qualified reference substance for quality control of apixaban that is a cardiovascular system drug.

Description

technical field [0001] The invention belongs to the field of chemistry, and in particular relates to a preparation method of apixaban impurity B. Background technique [0002] Apixaban (ELIQUIS) is an oral selective activated factor X inhibitor jointly developed by Pfizer and Bristol-Myers Squibb. It can prevent and treat thrombosis, and the adverse reaction of bleeding is far less than that of the old medicine. It is the main anticoagulant drug used in clinical practice for more than 50 years. Apixaban impurity B is an important impurity, and there is no relevant data to report the synthesis of this impurity, and it is also necessary to have a qualified impurity reference substance for quality analysis of apixaban. Contents of the invention [0003] [0004] "Ranges" are disclosed herein in terms of lower limits and upper limits. There can be one or more lower bounds, and one or more upper bounds, respectively. A given range is defined by selecting a lower limit an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 张亮唐武黄生宏
Owner 深圳市祥根生物科技有限公司