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Azilsartan intermediate and preparation method thereof

An intermediate and ethoxy technology, applied in the field of medicine, can solve the problems of difficult purification, complicated operation, poor solubility, etc., and achieve the effects of improving purity and yield, improving production efficiency, and simple reaction process.

Inactive Publication Date: 2012-10-17
JIANGSU SIMCERE PHARMACEUTICAL R & D CO LTD +1
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Problems solved by technology

[0009] The synthetic method disclosed in the Chinese patent CN92105152 is 2-ethoxy-1-[(2'-cyano biphenyl-4-yl) methyl]-1H-benzimidazole-7-carboxylic acid methyl ester (formula II compound) is the starting material, after hydroxylamine hydrochloride and 28% sodium methoxide react in dimethyl sulfoxide, then add the formula II compound to react, and finally the formula I compound can be obtained, and the yield can reach 90%; but the actual research found that, Also produce a large amount of compounds such as formula III and formula IV when the compound of formula I is generated, wherein the amount of formula III is almost equal to that of formula I, and the compound of formula I, formula II, formula III and formula IV is in a general solvent Poor solubility, difficult to purify by conventional methods
According to the literature description, first neutralize with triethylamine and hydroxylamine hydrochloride in dimethyl sulfoxide, remove triethylamine hydrochloride by filtration, wash the filter cake with tetrahydrofuran, concentrate the mother liquor to remove tetrahydrofuran, and obtain dimethyl sulfoxide of free hydroxylamine After the solution, the compound of formula II is added. After the reaction, steps such as dilution, extraction, pickling, extraction, alkalization, extraction, drying, concentration and recrystallization are required. The operation is cumbersome and the yield is only 55%.
[0011] In the Chinese patent CN102344415A, formula II is used as the starting material. In ethanol solution, under the action of triethylamine and 50% hydroxylamine aqueous solution, it is refluxed for 24 hours, and the target product is obtained by cooling and crystallization. The highest molar yield is only 71.7%, and it is not described. The purity of the product obtained
Subsequent studies have shown that a large amount of compounds of formula III and IV are produced while the compound of formula I is generated, and the compound of formula III (i.e. amide impurity) and the compound of formula I have no significant difference in solubility in absolute ethanol at room temperature, and the reaction A large amount of compounds of formula III generated cannot be effectively removed

Method used

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  • Azilsartan intermediate and preparation method thereof
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  • Azilsartan intermediate and preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0031] 2-Ethoxy-1-[(2'-cyanobiphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylic acid ethyl ester (0.50g, 1.18mmol), 50% hydroxylamine Aqueous solution (0.39g, 5.88mmol) in dimethyl sulfoxide (5mL), reacted at 90°C for 8 hours, cooled down, added 12.5mL of water, filtered to obtain 0.47g of the target product, yield 87.23%, HPLC self-normalized purity 93.26 %.

[0032] The above target product 2-ethoxy-1-[[2'-(N'-hydroxyaminomethylimino)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid ethyl ester NMR H spectrum and C spectrum are as follows:

[0033] 1 H-NMR (400MHz, DMSO-d 6 )δ1.18(3H,t),1.42(3H,t),4.22(2H,q),4.62(2H,q),5.54(2H,s),5.56(2H,s),6.94(2H,d ), 7.19(1H,t), 7.28(1H,d), 7.34-7.48(6H,m), 7.70(1H,d), 9.21(1H,s).

[0034] 13 C-NMR (400MHz, DMSO-d 6 )δ13.94,14.41,46.22,61.07,66.63,115.91,120.78,121.49,122.86,125.93,126.92,128.56,128.86,129.83,130.04,130.80,133.21,135.56,139.79,139.85,141.61,151.95,158.28,165.76 .

[0035] MS (ESI + )m / z459.2[M+H] +

Embodiment 2

[0037] 2-Ethoxy-1-[(2'-cyanobiphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylic acid ethyl ester (1.00g, 2.35mmol), 50% aqueous solution of hydroxylamine (0.78g, 11.82mmol) in ethanol (10mL), reflux for 24 hours, lower the temperature, add 25mL of water, filter to obtain the target product 0.90g, yield 83.52%, HPLC self-normalized purity 83.32%.

Embodiment 3

[0039] 2-Ethoxy-1-[(2'-cyanobiphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylic acid ethyl ester (1.01g, 2.37mmol), 50% aqueous solution of hydroxylamine (0.94g, 14.24mmol) in ethanol (10mL), reflux for 24 hours, cool down, add 25mL of water, filter to obtain the target product 0.89g, yield 81.77%, HPLC self-normalized purity 80.72%.

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Abstract

The invention relates to the technical field of an azilsartan intermediate and preparation technology thereof. In the invention, the azilsartan intermediate is 2-ethoxy-1-[[2'-(N'-hydroxylaminomethylimino)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (compound of formula VI); and a preparation method thereof comprises the step of reacting between 2-ethoxy-1-[(2'-cyanbiphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylate and hydroxylamine aqueous solution. The invention provides a new azilsartan intermediate; the preparation method solves the problem of the prior art that a great quantity of impurities such as amide and the like are generated in the preparation of other azilsartan intermediates, and improves the purity and yield of the product; the reaction time is reduced from 24 hours to 8 hours to finish the reaction, thus the production efficiency is improved; and moreover, the after-treatment does not need the complicated production steps of acid extraction, alkali dissociation and the like, and the target product can be directly separated out by cooling and adding water after the reaction.

Description

technical field [0001] The present invention relates to a new azilsartan intermediate and a preparation method thereof, in particular to 2-ethoxy-1-[[2'-(N'-hydroxyaminomethylimino)biphenyl-4- Base] methyl]-1H-benzimidazole-7-ethyl carboxylate (compound of formula VI) and a preparation method thereof belong to the field of medicine. [0002] [0003] Formula VI. Background technique [0004] Azilsartan is a selective angiotensin II receptor antagonist (ARB for short), has antihypertensive and central nervous effects, and can be used alone or in combination with other antihypertensive drugs. [0005] The preparation and therapeutic use of azilsartan have been described in Chinese patent CN92105152, and the important intermediate 2-ethoxyl-1-[[2'-(N'-hydroxyaminomethyrine The synthesis of amino)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid methyl ester (Formula I) is described. [0006] [0007] Formula I [0008] The preparation method of the compound of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/26
Inventor 张连第朱玉成陈琪王玲玲
Owner JIANGSU SIMCERE PHARMACEUTICAL R & D CO LTD