Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof

A technology of benzimidazole and hydroxyamidine, applied in the field of pharmaceuticals, can solve problems affecting product quality, lower yield, increase reaction steps, etc., and achieve the effects of improving drug quality standards, improving quality, and simplifying the process flow

Inactive Publication Date: 2015-03-18
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If it is not purified, it will seriously affect the subsequent reaction and the quality of the final product
Purification will increase the reaction steps, resulting in lower yield and higher cost

Method used

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  • Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof
  • Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof
  • Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The present invention's product 2-ethoxy-1-[[2'-(hydroxyamidino)-biphenyl]-4-yl] methyl-1H-benzimidazole-7-carboxylic acid ethyl ester (compound II ) HPLC analysis method is:

[0031] Octadecylsilane bonded silica gel was used as filler, water-glacial acetic acid (1000:1) was used as mobile phase A, acetonitrile was used as mobile phase B, and the gradient elution was carried out in the following table; the detection wavelength was 254nm; 1ml per minute; column temperature 25°C; sample chamber temperature 20°C.

[0032]

[0033] Accurately weigh about 10 mg of the sample, put it in a 25 ml measuring bottle, add acetonitrile to the mark, shake well, and use it as the test solution. Take 20 μl of mobile phase A and acetonitrile and inject them into the liquid chromatograph respectively, record the chromatogram as the background spectrum, and subtract it when calculating the sample according to the determined background front position. Take 20 μL of the test solution,...

Embodiment 2

[0035]Add 8.42 grams of hydroxylamine hydrochloride to a 250 ml three-neck glass flask, add 50 ml of dimethyl sulfoxide (DMSO) to the reaction flask, stir and dissolve, then add 23.3 grams of 28% sodium methoxide solution (concentration by weight), and the mixture should be at room temperature at 25°C Stir for 20 minutes. Add 2-ethoxy-1-[[2`-cyano-biphenyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid ethyl ester (code C-5) to the reaction solution 10 g in 40 ml DMSO solution. Stir and heat to 100°C, and react for 1.5 hours. Cool down to room temperature, add water and ethyl acetate under stirring, wash and dry the organic layer, and evaporate the solvent under reduced pressure to obtain 5.8 g of the product as a white solid, with a yield of 53.8%. The purity of the product detected by HPLC was 59.3%, and the impurity content of the by-product was 35.6%.

Embodiment 3

[0037] Add 8.48 g of hydroxylamine hydrochloride to a 100 ml single-necked flask, add 40 ml of DMSO, and stir evenly. At 20° C., 12.36 g of triethylamine was added to the reaction flask to produce a large amount of white solid. After stirring for 15 minutes at 20°C, it was filtered. The solid was washed with 100 ml of tetrahydrofuran, the filtrates were combined, and the tetrahydrofuran was evaporated under reduced pressure. A colorless transparent solution was obtained. Add ethyl 2-ethoxy-1-[[2`-cyano-biphenyl]-4-yl]methyl-1H-benzimidazole-7-carboxylate (code C-5) to the solution 10 g, heated to 75°C, and stirred for 15 hours.

[0038] The reaction solution was cooled to room temperature, and a large amount of water was added to precipitate a solid, which was filtered to obtain 6 g of a white solid. Yield 55.7%. HPLC detection, product purity 55.7%, by-product impurity content 39.9%.

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Abstract

The invention relates to a synthesis method of an azilsartan intermediate compound 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof. According to the method, 2-ethoxyl-1-[[2'-cyano-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and esters thereof used as the raw materials react with hydroxylamine hydrochloride aqueous solution under the weak base condition with ethanol as the solvent. The method disclosed by the invention has the advantages of less side reaction, unnecessary purification of the product obtained according to the method and suitability for industrial production; and the method can be used for preparing high-purity azilsartan and azilsartan medoxomil.

Description

technical field [0001] The invention belongs to the field of pharmaceutical technology, in particular to azilsartan intermediate 2-ethoxyl-1-[[2`-(hydroxyamidino)-biphenyl]-4-yl]methyl-1H-benzo Process for the preparation of imidazole-7-carboxylic acid and its ester (compound II). Background technique [0002] The present invention relates to a kind of 2-ethoxy-1-[[2'-(hydroxyamidino)-biphenyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and its ester ( Compound II) preparation method. [0003] [0004] where R is H, or C 1 -C 4 Alkyl, or benzyl, benzhydryl, trityl. [0005] Compound II is an important intermediate for the preparation of antihypertensive drug azilsartan and its esters. Azilsartan is a novel angiotensin II receptor antagonist (ARB). Compared with other antihypertensive drugs, ARB drugs have a unique mechanism of action. By lowering blood pressure, reducing cardiovascular events, and protecting the heart, brain, and kidney target organs, they can r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/26
CPCC07D235/26C07D413/10
Inventor 韩学文张晓军范巧云高立国
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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