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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

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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 refining, and the yield of qualified azilsartan through repeated refining is extremely low like this, the process It is cumbersome, increases the cost, and is not conducive to industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: Preparation of Azilsartan

[0038] The first step: preparation of compound 2

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

[0040] The second step: the preparation of compound 3

[0041] Add 10g of compound 2 to a 500mL four-neck flask, add it into 100mL tetrahydrofuran solution under stirring, cool down to 0-5°C, add 6.3mL triethylamine, add dropwise tetrahydrofuran dissolved in 3mL ethyl chloroformate (1.2eq) Solution, after dripping, keep warm for about 1h. After the reaction was completed, 100...

Embodiment 2

[0044] Embodiment 2: the preparation of Azilsartan

[0045] The preparation of compound 3 was as described in Example 1; 10 g of compound 3 was added to a 250 mL three-neck flask, and added to a mixed solution of 50 mL of tetrahydrofuran and 50 mL of water under stirring conditions, and 2.4 g of lithium hydroxide monohydrate was added, and kept for 50- 60°C, react for about 15h. After the reaction was completed, the temperature was lowered to 20-25°C, the pH was adjusted to 1-2 with 2N hydrochloric acid, and a solid was precipitated, kept stirring for 1-2 hours, filtered with suction, and dried to obtain 8.4 g of off-white solid, namely azilsartan, with an HPLC purity of 99.70 %, the yield is 95.0%.

Embodiment 3

[0046] Embodiment 3: the preparation of azilsartan

[0047] The preparation of Compound 3 was the same as described in Example 1; a mixed solution of 50 mL of tetrahydrofuran and 50 mL of water was added to a 250 mL three-neck flask, 10 g of Compound 3 was weighed and added to the reaction flask under stirring, 3.3 g of potassium hydroxide was added, and the temperature was kept for 40 React at -50°C for about 9-10h. After the reaction, cool down to 20-25°C, adjust the pH to 1-2 with 2N hydrochloric acid, and precipitate a solid, keep stirring for 1-2h, filter with suction, and dry to obtain 8.1g of off-white solid, namely Azilsartan, the HPLC purity is 99.55%, and the yield is 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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