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Preparation method of azilsartan intermediate

A compound and reaction temperature technology, applied in the field of preparation of azilsartan intermediates, can solve the problems of increased synthesis cost, low yield, and difficulty in obtaining

Active Publication Date: 2012-10-17
BEIJING COLLAB PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The main disadvantage of this method is the low yield (only 23%), and the product needs to be purified by column chromatography
[0005] Subsequently, Journal of Medicinal Chemistry 39 (26) 5228-5235 (1996) has reported a similar preparation method, uses chloroformic acid-2-ethylhexyl to replace above-mentioned ethyl chloroformate, although yield improves to some extent (52% ), but because the 2-ethylhexyl chloroformate is expensive and difficult to obtain, the synthesis cost is increased

Method used

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  • Preparation method of azilsartan intermediate

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Experimental program
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Effect test

Embodiment 1

[0034] 1.0 g (2.25 mmol) of 2-ethoxy-1-[(2'-(hydroxyamidino)biphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylic acid methyl ester (ie The compound represented by formula II) was added to a 50ml three-neck flask, dissolved in 20ml tetrahydrofuran, then added 0.37g (2.25mmol) N,N'-carbonyldiimidazole, heated to reflux (at a temperature of about 66°C) for 16 hours, cooled, The solvent was distilled off under reduced pressure, 30ml of water was added to the residue, extracted with dichloromethane (30ml×3), and the obtained dichloromethane solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.74 g of the compound represented by formula I, with a yield of 70%.

[0035] 1 HNMR (CDCl3): δ1.447(3H, s), δ3.687(3H, s), δ4.484(2H, s), δ5.638(2H, s), δ6.950-7.882(11H, m ),δ9.38(1H,brs)

Embodiment 2

[0037] 10.0 g (22.5 mmol) of 2-ethoxy-1-[(2'-(hydroxyamidino)biphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylic acid methyl ester (ie The compound represented by formula II) was added to a 250ml three-neck flask, dissolved in 100ml tetrahydrofuran, and then 3.7g (22.5mmol) N,N'-carbonyldiimidazole and 3.4g (22.5mmol) 1,8-diazabicyclo [5.4.0] Undec-7-ene (DBU), heated to reflux (about 66°C) for 6 hours, evaporated the solvent under reduced pressure, added 100ml of water to the residue, and dichloromethane (100ml×3 ) extraction, the obtained dichloromethane solution was dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 8.6 g of the compound shown in formula I, yield: 81%.

Embodiment 3

[0039] 10.0g (22.5mmol) 2-ethoxy-1-[[2'-(hydroxyamidino)[1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole- Add methyl 7-carboxylate (the compound represented by formula II) into a 250ml three-neck flask, dissolve it with 100ml acetonitrile, add 3.7g (22.5mmol) carbonyldiimidazole and 3.4g (22.5mmol) DBU, and stir the reaction at room temperature overnight , evaporated the solvent under reduced pressure, added 100ml of water to the residue, extracted with dichloromethane (100ml×3), and dried the obtained dichloromethane solution with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 7.9 g of the compound represented by formula I, yield: 75%.

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Abstract

The invention discloses a preparation method of an azilsartan intermediate shown as in the formula I. According to the invention, the intermediate shown as in the formula I is obtained through a condensation cyclization reaction between a compound shown in the formula II and N, N'-carbonyl diimidazole or bis (trichloromethyl) carbonate in an aprotic solvent. Organic alkali can be added in the above reaction system to improve the reaction rate. The preparation method of the azilsartan intermediate shown as in the formula I has the advantages of high yield and low cost.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of an azilsartan intermediate. Background technique [0002] Azilsartan is an angiotensin II receptor antagonist with antihypertensive effects. US Patent US5583141 reported azilsartan intermediate 1-[(2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4- Base) methyl]-2-ethoxy-1H-benzimidazole-7-carboxylate preparation method, the method will 2-ethoxy-1-[(2'-(hydroxyamidino) Benzene-4-yl)methyl]-1H-benzimidazole-7-carboxylic acid methyl ester and ethyl chloroformate carry out ring closure reaction, obtain above-mentioned azilsartan intermediate; Its reaction formula is as follows: [0003] [0004] The main disadvantage of this method is the low yield (only 23%), and the product needs to be purified by column chromatography. [0005] Subsequently, Journal of Medicinal Chemistry 39 (26) 5228-5235 (1996) has reported a similar preparation method, uses chlor...

Claims

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Application Information

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IPC IPC(8): C07D413/10
Inventor 孙志国王宏志谈敦潮邹德超赵大龙王珂
Owner BEIJING COLLAB PHARMA
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