Preparation method of azilsartan medoxomil process impurities

A technology for azilsartan medoxomil and process impurities, which is applied in the field of preparation of azilsartan medoxomil process impurities, and can solve the problems of stable purification and separation to obtain qualified impurity reference substances, etc.

Inactive Publication Date: 2018-11-16
成都诺维尔生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Two kinds of impurities A and C are easy to produce in the synthesis process of azilsartan medoxomil, and are the main impurities in the process, but affected by their stability, it is difficult to purify and separate the qualified impurity reference substance from the process reaction product, and these two This impurity has important reference value for azilsartan medoxomil synthesis process research and quality research, so it needs to be synthesized by other methods

Method used

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  • Preparation method of azilsartan medoxomil process impurities
  • Preparation method of azilsartan medoxomil process impurities
  • Preparation method of azilsartan medoxomil process impurities

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Embodiment 1

[0031] A preparation method of azilsartan medoxomil process impurity, comprising the following steps:

[0032] A, azilsartan methyl ester A4 is dissolved in organic solvent;

[0033] B, add catalyst and alkali, stir at 0 ℃;

[0034] C. Add the DMF solution of 4-halomethyl-5-methyl-1,3-dioxol-2-one into the reaction system. After the addition is complete, the temperature rises to complete the reaction, add acid to adjust the pH value, and filter , to obtain impurity A.

Embodiment 2

[0036] A preparation method of azilsartan medoxomil process impurity, comprising the following steps:

[0037] A, first hydrolyze Azilsartan methyl ester A4 to obtain Azilsartan, then dissolve Azilsartan in an organic solvent;

[0038] B, add catalyst and alkali, stir at 5 ℃;

[0039] C. Add the DMF solution of 4-halomethyl-5-methyl-1,3-dioxol-2-one into the reaction system. After the addition is complete, the temperature rises to complete the reaction, add acid to adjust the pH value, and filter , to obtain impurity C.

Embodiment 3

[0041] This embodiment is on the basis of embodiment 1:

[0042] The organic solvent is selected from acetone.

[0043] The halogen in the 4-halomethyl-5-methyl-1,3-dioxol-2-one refers to chlorine.

[0044] The catalyst is potassium iodide.

[0045] The base is selected from sodium carbonate.

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Abstract

The invention provides a preparation method of azilsartan medoxomil process impurities. The method comprises the following steps: A) azilsartan medoxomil A4 is dissolved in an organic solvent; or azilsartan medoxomil A4 is hydrolyzed to obtain azilsartan, and the azilsartan is dissolved in the organic solvent; B) a catalyst and alkali are added and stirred at the temperature of 0-5 DEG C; C) a DMFsolution of 4-halomethyl-5-methyl-1,3-dioxole-2-ketone is added in a reaction system, after charging is completed, a heating reaction is carried out, acid addition is carried out to adjust a pH value, and filtering is carried out to obtain a product. A synthesis route f the azilsartan medoxomil process impurities is designed, the azilsartan medoxomil process impurities can be successfully obtained with high yield, and a qualified impurities reference substance is obtained.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for preparing azilsartan medoxomil process impurities. Background technique [0002] Azilsartan medoxomil (INN) is an angiotensin II receptor antagonist (sartan) drug for the treatment of hypertension. It was developed by Japan's Takeda Pharmaceutical Company (Takeda) in 2010 and completed Phase III clinical trials Trial, approved by US FDA in 2011 [0003] [0004] allow. Its structure is as follows: [0005] Azilsartan medoxomil is the prodrug of Azilsartan, which is obtained by esterification of Azilsartan with 4,5-dimethyl-1,3-dioxol-2-one (medoxomil). Zilsartan medoxomil is hydrolyzed into azilsartan after entering the body. [0006] [0007] The synthetic technique of azilsartan medoxomil is as follows: [0008] Since the N-H on the oxadiazolone ring has a certain acidity, if the hydrolysis process of the azilsartan methyl ester intermediate A4 is not c...

Claims

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Application Information

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IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 支永刚王彬伍谭春兰
Owner 成都诺维尔生物医药有限公司
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