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Imidazole-5-carboxylic acid derivant and method of preparing the same

A compound and azide technology, applied in the field of drug synthesis, can solve the problem of high polarity of the molecular structure of EXP3174, and achieve the effects of rich and diverse raw material sources, low production cost and high conversion rate

Active Publication Date: 2012-05-02
HUIZHOU XINLITAI PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Studies have shown that the active metabolite EXP3174 of losartan potassium in the body has a stronger antihypertensive effect than losartan potassium, but the molecular structure of EXP3174 is relatively polar, and it is difficult to pass through the cell membrane through passive absorption such as diffusion

Method used

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  • Imidazole-5-carboxylic acid derivant and method of preparing the same
  • Imidazole-5-carboxylic acid derivant and method of preparing the same
  • Imidazole-5-carboxylic acid derivant and method of preparing the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] 2-Butyl-4-chloro-1-[2'-(1-trityl-1H-tetrazol-5-yl)-1,1'-biphenyl-methyl]-5-hydroxymethyl Base-1H-imidazole

[0041] 37.7 g of 2-butyl-4-chloro-5-hydroxymethyl-1H-imidazole, 4-bromomethyl-2'-(1-trityl-1H-tetrazol-5-yl)-linked Benzene 111.5g, K 2 CO 3 56g and 800mL of anhydrous DMF were mixed, and the reaction was stirred at 90°C for 6h. Cool, add 1000g of ice water, and continue stirring for 1h. Extracted with ethyl acetate, washed the organic phase with water, washed with saturated NaCl solution, anhydrous NaCl 2 SO 4 dry. Concentrate under reduced pressure to a small volume, cool, place, and precipitate a solid, filter with suction, wash with a small amount of ethyl acetate, and dry to obtain the title 2-butyl-4-chloro-1-[2'-(1-trityl -1H-tetrazol-5-yl)-1,1'-biphenyl-methyl]-5-hydroxymethyl-1H-imidazole 113.0 g, yield 89.5%.

[0042] 1 H-NMR (CDCl 3 , 400MHz): δ0.80(t, 3H), δ1.25(m, 2H), δ1.49(m, 2H), δ2.56(t, 2H), δ4.73(s, 2H), δ5 .58(s, 2H), δ6.94-7.54(m, ...

Embodiment 2

[0044] 2-Butyl-4-chloro-1-[2'-(1-trityl-1H-tetrazol-5-yl)-1,1'-biphenyl-methyl]-imidazole-5- carboxylic acid

[0045] 2-Butyl-4-chloro-1-[2'-(1-trityl-1H-tetrazol-5-yl)-1,1'-biphenyl-methyl]-5-hydroxy Dissolve 6.60g of methylimidazole in 20mL of water, cool to below 0°C, add dropwise 150mL of 1% KMnO 4 Aqueous solution, after dripping, was stirred and reacted at 50°C for 16h. Suction filtration, add 50mlL1mol / L NaS to the filtrate 2 o 3 aqueous solution, and then adjust the pH to 3 with 1mol / L hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated NaCl solution, anhydrous NaCl 2 SO 4 Drying, concentration to dryness under reduced pressure, flash column chromatography, to obtain the title 2-butyl-4-chloro-1-[2'-(1-trityl-1H-tetrazol-5-yl)- 6.00 g of 1,1'-biphenyl-methyl]-imidazole-5-carboxylic acid, yield 88.2%.

[0046] 1 H-NMR (CDCl 3 , 400MHz): δ0.80(t, 3H), δ1.25(m, 2H), δ1.49(m, 2H), δ2.56(t, 2H), δ5.58(s, 2H), δ6 .94-7.54(m, 23H)

Embodiment 3

[0048] 2-Butyl-4-chloro-1-[2'-(1-trityl-1H-tetrazol-5-yl)-1,1'-biphenyl-methyl]-5-aldehyde -1H-imidazole

[0049] 37.3 g of 2-butyl-4-chloro-5-formyl-1H-imidazole, 4-bromomethyl-2'-(1-trityl-1H-tetrazol-5-yl)-biphenyl 111.5g, K 2 CO 3 56g and 800mL of anhydrous DMF were mixed, and the reaction was stirred at 90°C for 6h. Cool, add 1000g of ice water, and continue stirring for 1h. Extracted with ethyl acetate, washed the organic phase with water, washed with saturated NaCl solution, anhydrous NaCl 2 SO 4 Dry, concentrate under reduced pressure to a small volume, cool, place, precipitate solid, filter, wash with a small amount of ethyl acetate, and dry to obtain the title 2-butyl-4-chloro-1-[2'-(1-trityl 119.4 g of methyl-1H-tetrazol-5-yl)-1,1'-biphenyl-methyl]-5-hydroxymethyl-1H-imidazole, yield 90.0%.

[0050] 1 H-NMR (CDCl 3 , 400MHz): δ0.80(t, 3H), δ1.25(m, 2H), δ1.49(m, 2H), δ2.56(t, 2H), δ5.58(s, 2H), δ6 .94-7.54(m, 23H), δ9.61(s, 1H)

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Abstract

The present invention relates to an imidazole-5-carboxylic acid derivatives (I, with a chemical name as 2-butyl-4-chlorine-1-[2'-(1H-tetrazolo-5-group)-1, 1'-xenyl-methyl]-imidazole-5-carboxylic acid, 1-[(isopropoxy)- carbonyloxy]-methyl ester), and a preparation method thereof. The compound in Formula II is produced through the condensation reaction between a compound in Formula III and a compound in Formula IV under the condition with organic base or inorganic base, and the compound in Formula I can be produced after the R1 group in the compound in Formula II is transformed into tetrazole. The present invention also relates to an application of the compound in Formula I or a salt thereof acceptable in pharmacy in preparation of the antihypertensive.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a kind of imidazole-5-carboxylic acid derivative (I, chemical name: 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl )-1,1'-biphenyl-methyl]-imidazole-5-carboxylic acid, 1-[(isopropoxy)-carbonyloxy]-methyl ester) and its preparation method, and its anti-high Use of blood pressure medications. Background technique [0002] Hypertension is a major disease that threatens human health. Finding high-efficiency and low-toxic antihypertensive drugs can help relieve social pressure and family burden, and has good social and economic benefits. [0003] Angiotensin II (AngII), the major vasoconstrictor hormone of the renin-angiotensin-aldosterone system (RAAS), plays an important role in the pathophysiology of a variety of chronic diseases, particularly its role in blood pressure regulation Especially prominent, so AngII receptor is considered to be a good target for the development of antihyperten...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/10A61K31/4178A61P9/12
Inventor 安东郭建辉
Owner HUIZHOU XINLITAI PHARMA
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