Azilsartan preparation method

A compound and reaction technology, applied in the field of medicine, can solve the problems such as low yield of Azilsartan, unfavorable industrial production, and many deethylated impurities, and achieve the effects of shortening reaction time, reducing content and improving yield

Active Publication Date: 2013-08-14
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The main defect of above-mentioned two kinds of methods all is that the deethylation impurity that generates in the ring-closing reaction is more, is difficult to be reduced to below 0.1% by

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0037] Example 1: Preparation of Azilsartan

[0038] Step 1: Preparation of compound 2

[0039] Add 20g of compound 1 to a 500mL four-neck flask, add 10.14g (3eq) hydroxylamine hydrochloride dissolved in 100mL dimethyl sulfoxide solution under stirring, heat to 90℃, add 30.95g (6eq) in batches under stirring ) Sodium carbonate, add and keep the reaction for 9-10h, after the reaction is completed, reduce to room temperature, add 100mL of water and stir to precipitate a solid, cool to 0-5℃, continue to stir for about 1h, suction filtration and dry to obtain 15.2g compound 2, yield It is 70.4%.

[0040] Step 2: Preparation of compound 3

[0041] Add 10g of compound 2 to a 500mL four-necked flask, add to 100mL of tetrahydrofuran solution with stirring, cool to 0-5°C, add 6.3mL of triethylamine, dropwise add 3mL of ethyl chloroformate (1.2eq) in tetrahydrofuran The solution is dripped and incubated for about 1h. After the reaction, 100 mL of water was added, and the mixture was stirred ...

Example Embodiment

[0044] Example 2: Preparation of Azilsartan

[0045] The preparation of compound 3 is the same as that described in Example 1. Add 10g of compound 3 to a 250mL three-necked flask, add to a mixed solution of 50mL of tetrahydrofuran and 50mL of water with stirring, add 2.4g of lithium hydroxide monohydrate, and keep it warm for 50- 60°C, react for about 15h. After the reaction, the temperature was lowered to 20-25°C, the pH was adjusted to 1-2 with 2N hydrochloric acid, a solid was precipitated, and the mixture was stirred for 1-2h, suction filtered, and dried to obtain 8.4g of off-white solid, namely Azilsartan. The HPLC purity was 99.70. %, the yield was 95.0%.

Example Embodiment

[0046] Example 3: Preparation of Azilsartan

[0047] The preparation of compound 3 is the same as that described in Example 1. Add a mixed solution of 50 mL of tetrahydrofuran and 50 mL of water into a 250 mL three-necked flask, weigh 10 g of compound 3 and add it to the reaction flask with stirring, add 3.3 g of potassium hydroxide, and keep warm for 40 React at -50°C for about 9-10 hours. After the reaction, the temperature is lowered to 20-25°C. The pH is adjusted to 1-2 with 2N hydrochloric acid. A solid is precipitated. The mixture is kept warm and stirred for 1-2 hours, filtered with suction and dried to obtain 8.1g of white solid, that is Azilsartan has a HPLC purity of 99.55% and a yield of 91.6%.

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Abstract

The invention relates to an azilsartan (a hypertension treating medicine) preparation method, and belongs to the field of medicines. The method has the beneficial effects that a compound 1 serves as an initial raw material of the reaction, the azilsartan is prepared through three reaction steps of hydroxylammonium chloride addition, ethyl chloroformate acylation and cyclization hydrolysis under the alkali action, and the cyclization and hydrolysis reaction steps of the prior art are combined into one step, so that conventional 4-5 steps are reduced to three steps, and the reaction time is shortened; and the yield is increased, the content of ethyoxyl-removing impurities is greatly reduced, experimental operations are simplified, the cost is lowered, the azilsartan with high purity is obtained, the high performance liquid chromatography (HPLC) purity is more than 99.5%, and the ethyoxyl and amide-removing impurities are all less than 0.1%.

Description

Technical field: [0001] The invention relates to a preparation method of azilsartan, a drug for treating hypertension, and belongs to the field of medicine. Background of the invention: [0002] The development of angiotensin II receptor antagonist antihypertensive drugs began in the 1970s. The first marketed drug of this type of product was losartan potassium, which was developed by Dupont&Merck in 1994. Since the listing in Sweden, sartan drugs have developed rapidly. So far, there have been valsartan, candesartan cilexetil, irbesartan, eprosartan, tasosartan, telmisartan and olmesartan cilexetil 8 unilateral preparations and 4 compound preparations have been approved for marketing by the US FDA. [0003] Azilsartan is currently the only sartan drug that is an angiotensin II receptor antagonist in the fourth phase of clinical trials. It has a significant clinical effect in the treatment of adult hypertension. It was developed by Japan's Takeda Industry Co., Ltd. and launc...

Claims

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Application Information

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IPC IPC(8): C07D413/10
Inventor 傅凯敏
Owner 迪嘉药业集团股份有限公司
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