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Preparation method of azilsartan polymorphism

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: 2013-05-22
ZHAOKE PHARMA GUANGZHOU +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Literature (Synthesis of azilsartan[J]. Shu, Beiyan; Wu, esong; en, Junda, ZhongguoYiyao Gongye Zazhi (2010), 41 (12), 881-883.) describes the preparation of the compound, which mentions the The melting point of the compound crystal is 190°C to 191°C, but the detailed crystal preparation method is not disclosed

Method used

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  • Preparation method of azilsartan polymorphism

Examples

Experimental program
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Effect test

Embodiment 1

[0067]Add 10g of azilsartan to 35ml of DMF, heat to 70°C to dissolve the solid, then suction filter while hot, transfer the filtrate to a round bottom flask at 70°C for 10min, then slowly add 40ml of purified water dropwise at this temperature. As the dropwise addition proceeded, a white solid gradually precipitated out. After the dropwise addition was completed, the oil bath was lowered to 50° C. and stirred overnight. Suction filtration while it was hot, the obtained solid was washed with hot water (20mlX3) and ethanol (15mlX2), and vacuum-dried at 50°C for 15 hours 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 into 20ml of ethanol and 30ml of acetone, heat to 60°C, stir and beat for 1 hour, then naturally cool to 20°C, continue to stir for 1 hour, then filter with suction, and vacuum dry the obtained solid at 50°C for 5 hours to obtain azilsartan II Type crystal 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 to dissolve the solid, then suction filter while hot, transfer the filtrate to a round bottom flask, heat to 60°C and keep it for 10min, then slowly add 50ml of purified water. As the dropwise addition proceeded, a white solid gradually precipitated out. 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 (20mlX3) and ethanol (15mlX2), and vacuum dried at 50°C for 15h to obtain 6.8g of azilsartan type I crystalline white powder, 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) polymorph preparation method. Background technique [0002] The chemical name of 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 number 147403-03-0, has the following structure: [0003] [0004] Azilsartan is an angiotensin II receptor antagonist developed by Takeda Corporation of Japan. In February 2011, the U.S. Food and Drug Administration (FDA) approved azilsartan for the treatment of hypertension. This drug is an angiotensin II receptor antagonist that 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 tetrazole in the candesartan structure, making it possib...

Claims

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Application Information

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Patent Type & Authority Applications(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
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