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A green and efficient method for synthesizing azilsartan in an aqueous phase

A water-phase, green technology, applied in the field of medicine, can solve the problems of low yield, serious, environmental pollution, etc., and achieve the effects of high purity, convenient separation and purification, and overcoming high toxicity.

Active Publication Date: 2020-04-28
CHANGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] At present, the yields of existing methods for synthesizing Azilsartan are relatively low, and the environmental pollution is more serious. Since Azilsartan plays a pivotal role in antihypertensive drugs, it is urgent to develop a method with a higher yield. A new method for the green synthesis of azilsartan with high and better purity

Method used

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  • A green and efficient method for synthesizing azilsartan in an aqueous phase
  • A green and efficient method for synthesizing azilsartan in an aqueous phase
  • A green and efficient method for synthesizing azilsartan in an aqueous phase

Examples

Experimental program
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Effect test

Embodiment 1

[0023] 1-[(2'-(hydroxyamidino)[1,1-biphenyl]-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester (5mmol ), phenyl chloroformate (12.5mmol) and 30mL water were added to a 100mL two-neck flask, stirred evenly, NaOH (20mmol) was added, refluxed at 100°C for 3h, cooled and left standing, filtered, adjusted to pH 3 with 1mol / L dilute HCl ~4, the solid obtained by suction filtration was recrystallized with ethanol to obtain azilsartan with a purity of 99.3% and a yield of 82%.

[0024] White solid; mp: 201-204°C; 1 H NMR (300MHz, DMSO-d 6 ): δ=13.15 (bs, 1H, NH), 12.5 (bs, 1H, OH), 7.68-7.63 (m, 3H, ArH), 7.56-7.53 (m, 2H, ArH), 7.51-7.45 (m, 1H, ArH), 7.25(d, J=8.3Hz, 2H, ArH), 7.21(t, 1H, ArH), 7.06(d, J=8.3Hz, 2H, ArH), 5.67(s, 2H, N- CH 2 -ArH), 4.59(q, 2H, OCH 2 CH 3 ), 1.38(t, J=7.1Hz, 3H, OCH 2 CH 3 ). 13 C NMR (75MHz, DMSO-d 6 ):δ=168.03,159.97,158.75,142.13,141.20,138.21,137.67,132.35,131.77,131.14,130.69,129.35,128.28,127.12,123.98,122.63,121.94...

Embodiment 2

[0026] With reference to the method of Example 1, methyl chloroformate was used as a raw material in the reaction to participate in the reaction, and the yield of azilsartan was 80%, and the purity was 99.2%.

Embodiment 3

[0028] With reference to the method of Example 1, in the reaction, isopropyl chloroformate was used as a raw material to participate in the reaction, and the yield of azilsartan was 78%, and the purity was 99.1%.

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Abstract

The invention relates to a method for greenly and efficiently synthesizing azilsartan in water phase, belonging to the field of medicines. The method comprises the following steps: by taking water asa solvent and 1-[(2'-hydroxyamidino)[1,1-biphenyl]-4-yl]-2-ethoxyl-1H-benzimidazole-7-methyl formate and carbonylation reagent as starting raw materials, performing one-step reaction under base interaction to synthesize azilsartan. Esterification, cyclization and hydrolysis reactions are simplified into one step, so that the reaction time is extremely shortened, the reaction yield is increased, and the purity of the product is high. By taking water as a reactive solvent, the defects of the prior art that an organic solvent is high in toxicity, production is insafe and the like can be overcome,and a simple and efficient green synthesis method is provided for synthesis of azilsartan.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a green and efficient method for synthesizing azilsartan in water phase. Background technique [0002] Azilsartan, chemical name: 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl ) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid, the structural formula is as follows: [0003] [0004] It is a new generation of angiotensin II receptor antagonist developed by Takeda Corporation of Japan. Compared with other sartan antihypertensive drugs on the market, azilsartan has better therapeutic effect and lower side effects. [0005] In the prior art, there are mainly two methods for synthesizing the bulk drug of azilsartan, namely chloroformate cyclization method and carbonyl cyclization method. Both synthetic pathways are based on 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester as starting material, after Oximation, cyclization, and hyd...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/10
CPCC07D413/10
Inventor 李正义殷乐刘大伟肖唐鑫孙小强
Owner CHANGZHOU UNIV