Azilsartan polymorph and preparation method thereof
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A technology of polymorph and crystal form, applied in the direction of organic chemistry, can solve the problems of difficult removal of impurities, unsatisfactory removal effect, poor solubility, etc., and achieve the effect of easy separation, simple operation and high yield
Inactive Publication Date: 2013-04-17
BEIJING PHARMA GRP CO LTD
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In the process of preparing azilsartan, it was found that several impurities were difficult to remove and the solubility of azilsartan in various solvents was poor. The impurity removal effect of recrystallization in solvents such as ethyl acetate, methanol, ethanol and not ideal
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example 1
[0019] Example 1: Recrystallization of azilsartan in ethanol-tetrahydrofuran system.
[0020] Add 0.3g of Azilsartan to the reaction flask, add 1.5mL of ethanol, raise the temperature to reflux, drop 1mL of tetrahydrofuran into the reaction flask, all the solids are dissolved, at the same temperature, after 2min, a white solid precipitates out, keep at the same temperature for 30min, and then cool down to room temperature (20°C), filtered, and the obtained solid was air-dried at 60°C to constant weight to obtain the crystal form B of azilsartan. Purity>99%, simple impurity<0.1%.
[0021]
example 2
[0022] Example 2: Recrystallization of azilsartan in water-tetrahydrofuran system.
[0023] Add 42.6g of Azilsartan into the reaction flask, add 213mL of water, stir and raise the temperature to 70°C, slowly add 213mL of tetrahydrofuran into the reaction flask, the solid is completely dissolved, at the same temperature, after 30min, a white solid gradually precipitates out, continue to be at the same temperature for 30min , lowered to room temperature (20°C), stirred for 1 h, filtered, and the obtained white solid was air-dried at 60°C to constant weight to obtain the crystal form B of azilsartan. The yield is 95.1%, the purity is >99%, and the single heterogeneity is <0.1%.
example 3
[0024] Example 3: Recrystallization of azilsartan in water-tetrahydrofuran system.
[0025] Add 7g of azilsartan to the reaction flask, add 35mL of water, add 35mL of tetrahydrofuran, heat up to reflux, 10min later, a white solid precipitates, after 30min, naturally cool to room temperature (20°C), filter, and the obtained solid is air-dried at 60°C to Constant weight, to obtain azilsartan crystal form B. Yield 97%, purity>99%.
[0026]
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Abstract
The invention discloses an azilsartan polymorph and a preparation method thereof. An azilsartan polymorph X-ray powder diffraction diagram has peaks at 2theta positions of 18.8 plus / minus 0.2, 21.158 plus / minus 0.2, 21.992 plus / minus 0.2, 22.652 plus / minus 0.2, 23.132 plus / minus 0.2 and 24.9 plus / minus 0.2 degrees. The preparation method of the azilsartan polymorph comprises the following steps of: firstly, adding azilsartan into a solvent which has a relatively poor dissolution to the azilsartan and can separate out the azilsartan from tetrahydrofuran; secondly, adding the tetrahydrofuran; and finally, separating out a solid again to obtain a target product, wherein the solvent is water or ethanol, preferably water, and the volume ratio of water to the tetrahydrofuran is less than 10:1, preferably 1:1. The azilsartan polymorph and the preparation method thereof have the benefits as follows: the azilsartan polymorph is easy to separate and high in stability; the preparation method is simple and convenient; the high-purity azilsartan can be easily prepared; and the preparation method is applicable to industrial application.
Description
technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) Polymorphs of biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (azilsartan) and methods for their preparation. Background technique [0002] Azilsartan (2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4- base] methyl] benzimidazole-7-carboxylic acid), its structural formula is as figure 1 Shown is an angiotensin Ⅱ receptor antagonist developed by Japan's Takeda Corporation (Takeda). Takeda's 20 mg and 40 mg azilsartan (trade name Azilva) (Azilsartan) is marketed in Japan for the treatment of hypertension. Aazilsartan is a once-daily angiotensin II type 1 (AT1) receptor antagonist. [0003] [0004] Formula 1 [0005] According to Example 1 of Chinese Patent CN1067890, the preparation method of the compound shown in formula 1 is disclosed, 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2 , 4-oxadiazol-3-...
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