Preparation method of azilsartan intermediate

A technology for intermediates and solid bases, applied in the field of preparation of pharmaceutical compounds, can solve problems such as unfavorable reactions, miscellaneous products, high prices, etc., and achieve the effects of improving yield, low cost, and simple recovery

Active Publication Date: 2014-06-25
SICHUAN OPEN MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The catalyst tetrabutylammonium fluoride is expensive, and the one-pot cooking method leads to a very mixed product, which is not conducive to the next reaction

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Take 42.4g (0.61mol) of hydroxylamine hydrochloride, add it to 85ml 95% ethanol, stir, 0-20°C, add 10g of anhydrous sodium sulfate, slowly add 19.45g (0.49mol) of sodium hydroxide, and filter when the reaction system stops exothermic , 25g of compound of formula (II) (0.061mol), 61.5g of triethylamine (0.61mol), 125ml of ethanol were added to the filtrate, refluxed at 75-80°C for 16 hours, cooled to room temperature, and filtered to obtain intermediate compound of formula (I). Body 15.4g. Detected by HPLC: 83.363% of the intermediate of formula (I), 8.784% of the amide.

Embodiment 2

[0046] Take 196.8g (1.2mol) of hydroxylamine sulfate, add it to 420ml 90% ethanol, stir, 0-20°C, add 50g of anhydrous sodium sulfate, slowly add 60.5g (1.08mol) of potassium hydroxide, and filter when the reaction system stops exothermic 125g of the compound of formula (II) (0.3mol), 87.6g of diethylamine (1.2mol), 600ml of ethanol were added to the filtrate, refluxed at 75-80°C for 16 hours, cooled to room temperature, and filtered to obtain the intermediate compound of formula (I). Body 79.0g. Detected by HPLC: 85.741% of the intermediate of formula (I), 7.518% of the amide.

Embodiment 3

[0048] Take 210g (3mol) of hydroxylamine hydrochloride, add it to 420ml 95% ethanol, stir, 0-20°C, add 50g of anhydrous sodium sulfate, slowly add 84g (2.1mol) of sodium hydroxide, filter when the reaction system stops exothermic, the filtrate Add 125g of compound of formula (II) (0.3mol), 310g of triethylamine (3mol), 600ml of ethanol, reflux at 75-80°C for 16 hours, cool to room temperature, and filter to obtain 79.0g of intermediate of formula (I). Detected by HPLC: 86.906% of the intermediate of formula (I), 3.076% of the amide.

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PUM

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Abstract

The invention discloses a preparation method of an azilsartan intermediate. The preparation method of the azilsartan intermediate comprises the following steps: dissociating hydroxylamine hydrochloride through alkali in ethanol which is 90-95% in mass percentage, filtering, adding a compound as shown in formula (II) in the specification, triethylamine and ethanol to filtrate, implementing a reflux reaction, cooling and crystallizing after the reaction, and filtering to obtain the target intermediate as shown in formula (I). The target intermediate prepared by the preparation method disclosed by the invention is high in content, and low in content of amide impurities, which is generally less than 10%.

Description

technical field [0001] The invention belongs to the preparation of pharmaceutical compounds, in particular to a preparation method of an angiotensin II receptor antagonist azilsartan intermediate. Background technique [0002] Azilsartan is an angiotensin Ⅱ receptor antagonist researched and developed by Takeda Pharmaceutical Co., Ltd., Japan. It can be taken orally as a powerful antihypertensive drug. Its preparation and therapeutic use have been described in the specification of Chinese invention patent CN92105152.2. Among them, the compound of the following formula (I), namely, 2-ethoxy-1-{[((2'-hydroxyaminomethylimino)biphenyl)-4-yl]methyl}-1H-benzimidazole -7-Carboxylic acid is an important intermediate in the synthesis of azilsartan. [0003] (I) [0004] The method for preparing formula (I) compound has been described in detail in document J.Med.chem.1996.Vo39 (26) 5528-5235 and Chinese patent CN92105152.2: take formula (II) compound, i.e. 1-[((2' -Nitrylbipheny...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/26
CPCC07D235/26
Inventor 刘波骆俊清魏岚但汉兴刘琳宛燕飞丁昭莉
Owner SICHUAN OPEN MEDICINE CO LTD
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