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Azilsartan polymorphic preparation method

A technology of crystal and dihydrogen, applied in the field of preparation of polymorphs of azilsartan, can solve problems such as undisclosed crystal preparation methods

Active Publication Date: 2015-11-18
ZHAOKE PHARMA GUANGZHOU +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The literature (Synthesisofazilsartan[J]. Shu, Beiyan; Wu, esong; en, Junda, ZhongguoYiyaoGongyeZazhi (2010), 41(12), 881-883.) describes the preparation method of the compound, which mentions the melting point of the compound crystal It is 190°C~191°C, but the detailed crystal preparation method is not disclosed

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0067]10g of Azilsartan was added to 35ml of DMF, heated to 70°C, the solid was dissolved, filtered while hot, and the filtrate was transferred to a round-bottomed flask at 70°C for 10min, and then 40ml of purified water was slowly added dropwise at this temperature. As the dropwise addition proceeded, a white solid gradually precipitated. After the dropwise addition was completed, the oil bath was lowered to 50° C. and stirred overnight. Suction filtration while hot, the obtained solid was washed with hot water (20ml×3) and ethanol (15ml×2), and vacuum-dried at 50°C for 15h to obtain 7.9g of Azilsartan type I crystalline white powder with a yield of 79% and a melting point of 200.9°C.

Embodiment 2

[0069] Add 10g of Azilsartan to 20ml of ethanol and 30ml of acetone, heat to 60°C, stir and beat for 1 hour, then cool to 20°C naturally, continue stirring for 1h and then suction filtration, the obtained solid is vacuum-dried at 50°C for 5h to obtain Azilsartan II Type crystalline white powder 8.4g, yield 84%, melting point 162.8 ℃.

Embodiment 3

[0071] Add 10g of Azilsartan to 30ml of DMSO, heat to 60°C for the solid to dissolve, filter while hot, transfer the filtrate to a round-bottomed flask and heat to 60°C for 10min, then slowly add 50ml of purified water dropwise at this temperature . As the dropwise addition proceeded, a white solid gradually precipitated. After the dropwise addition was completed, the oil bath was lowered to 40° C. and stirred overnight. Suction filtration while hot, the obtained solid was washed with hot water (20ml×3) and ethanol (15ml×2), and vacuum-dried at 50°C for 15h to obtain azilsartan type I crystalline white powder 6.8g, yield 68%, melting point 199.8°C.

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Abstract

The invention discloses a preparation method of an azilsartan polymorphism. The preparation method includes the preparation method of two crystals of a compound, namely, 1-[[2'-(4, 5-dihydro-5-oxo-1, 2, 4-oxadiazole-3-group) [1, 1' biphenylyl]-4-group] methyl]-2-ethyoxyl-1H-benzimidazole-7-carboxylic acid, wherein the preparation step of the type I crystal comprises a dissolving process, a devitrification process and a crystal collecting, washing and drying process; and the preparation step of the type II crystal comprises a stirring and washing process, a cooling process and a crystal collecting and drying process. By adopting the preparation method, two polymorphism types can be directly gained; the preparation method is simple in process and high in purity and yield of products, is suitable for industrial production, and has important significance in medicine quality control and clinical effect.

Description

technical field [0001] The present invention relates to 1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'biphenyl]-4-yl ]Methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid (also known as Azilsartan) polymorphic preparation method. Background technique [0002] The chemical name for Azilsartan is 1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'biphenyl ]-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid, trade name Azilsartan, CAS No. 147403-03-0, has the following structure: [0003] [0004] Azilsartan is an angiotensin II receptor antagonist developed by Takeda Corporation of Japan. Azilsartan was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hypertension in February 2011. This drug is an angiotensin II receptor antagonist and can be used alone or with other blood pressure lowering drugs. The 4,5-dihydro-5-oxo-1,2,4-oxadiazole ring in its structure is the bioisostere of the tetrazole in the candesartan structure, making ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/10
Inventor 张孝清包金远蒋玉伟刘宝孙瑞琴
Owner ZHAOKE PHARMA GUANGZHOU