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A kind of preparation method of Azilsartan

A technology of methyl ester and hydroxylamine hydrochloride, which is applied in the field of medicine, can solve the problems of prolonging the production cycle, cumbersome post-processing operations, and increasing costs, and achieve the effects of reducing the use of organic solvents, shortening the production cycle, and reducing the cost of raw materials

Active Publication Date: 2018-01-09
中国人民解放军第二三〇医院 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The problem with this method is that the yield of the second step cyclization reaction is low, only 23%, and requires column chromatography purification, which is difficult to meet market demand
The problem that this method exists is that the reaction time of the first step is long, the operation is cumbersome and the yield is low. At first, it is necessary to dissociate hydroxylamine hydrochloride in dimethyl sulfoxide in advance, filter, wash with tetrahydrofuran, add cyano compound to react after merging the filtrate, and react After 15 hours, add water to extract with ethyl acetate, extract with dilute hydrochloric acid, adjust the pH and then extract with ethyl acetate, which prolongs the production cycle, increases the difficulty of operation, and leads to an increase in cost
The problem that this method exists is that in the first two steps, the consumption of dimethyl sulfoxide and tetrahydrofuran is large, and the solubility of azilsartan methyl ester in ethyl acetate is very poor, so it needs to use a large amount of solvent extraction, and then obtain the product through repeated purification. The price is expensive, the recycling is difficult, and the post-processing operation is cumbersome, which greatly increases the production cost

Method used

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  • A kind of preparation method of Azilsartan
  • A kind of preparation method of Azilsartan

Examples

Experimental program
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Effect test

Embodiment 1

[0028] 1) Synthesis of Azilsartan Methyl Ester

[0029] Add hydroxylamine hydrochloride (34.7g, 0.5mol) and triethylamine (65.8g, 0.65mol) to 240ml of dioxane and stir at room temperature for 30min, then add 2-ethoxy-1-(2'-cyanobiphenyl -4-yl)methylbenzimidazole-7-carboxylic acid methyl ester (41.2g, 0.1mol), stirred at 85-90°C until TLC showed that the reaction was complete (about 9h), cooled to room temperature and added N'N-carbonyl Diimidazole (19.5g, 0.12mol), stirred for 1.5h, evaporated to dryness under reduced pressure, added 200ml of water, adjusted pH to 4 with 8% dilute hydrochloric acid under stirring, filtered with suction, washed with water, washed with ethanol, dried to obtain 42.5g of white powder, collected The rate is 90.3%.

[0030] 2) Synthesis of Azilsartan

[0031] Add azilsartan methyl ester (23.5g, 0.05mol) to 120ml of 5% sodium hydroxide solution, stir the reaction at 60-65°C until TLC shows that the reaction is complete (about 1h), then cool down to...

Embodiment 2

[0037] 1) Synthesis of Azilsartan Methyl Ester

[0038] Add hydroxylamine hydrochloride (34.7g, 0.5mol), DBU (98.9g, 0.65mol) to 240ml of dioxane and stir at room temperature for 30min, add 2-ethoxy-1-(2'-cyanobiphenyl-4 -yl) Methylbenzimidazole-7-carboxylate (41.2g, 0.1mol), stir the reaction at 85-90°C until TLC shows that the reaction is complete (about 8h), cool to room temperature and add N'N-carbonyldiimidazole (19.5g, 0.12mol), stirred for 1.5h, evaporated the solvent under reduced pressure, added 200ml of water, adjusted the pH to 4 with 8% dilute hydrochloric acid under stirring, filtered with suction, washed with water, washed with ethanol, and dried to obtain 44.3g of white powder, yield 94.2 %.

[0039] 2) Synthesis of Azilsartan

[0040] Add azilsartan methyl ester (32.9g, 0.07mol) to 210ml of 4% sodium hydroxide solution, stir the reaction at 55-60°C until TLC shows that the reaction is complete (about 2h), then cool down to 10-15°C , 5% dilute hydrochloric acid...

Embodiment 3

[0042] 1) Synthesis of Azilsartan Methyl Ester

[0043] Add hydroxylamine hydrochloride (20.8g, 0.3mol) and triethylamine (45.5g, 0.45mol) to 120ml of dioxane and stir at room temperature for 30min, then add 2-ethoxy-1-(2'-cyanobiphenyl -4-yl)methylbenzimidazole-7-methyl carboxylate (20.6g, 0.05mol), stir the reaction at 85-90°C until TLC shows that the reaction is complete (about 7h), cool to room temperature and add N'N-carbonyl Diimidazole (9.7g, 0.06mol), stirred for 2h, evaporated to dryness under reduced pressure, added 120ml of water, adjusted pH to 4 with 5% dilute hydrochloric acid under stirring, filtered with suction, washed with water, washed with acetone, dried to obtain 21.5g of white powder, yield 91.4%.

[0044] 2) Synthesis of Azilsartan

[0045] Add azilsartan methyl ester (18.3g, 0.04mol) to 60ml of 8% sodium hydroxide solution, stir the reaction at 50-55°C until TLC shows that the reaction is complete (about 1.5h), cool down to 15-20 ℃, 5% dilute hydroch...

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Abstract

The invention provides a preparation method of azilsartan. The method comprises the following steps: enabling 2-ethyoxyl-1-(2'-cyanobiphenyl-4-yl) methylbenzimidazole-7-methyl formate used as a starting raw material to carry out addition with hydroxylamine hydrochloride and carry out cyclization with N',N-carbonyl diimidazole in sequence to obtain azilsartan methyl ester, and then, carrying out hydrolysis to prepare azilsartan. The azilsartan is prepared by two-step reaction. The preparation method has the advantages that the raw materials are easily available, the reaction conditions are gentle, the operation is simple and easy to implement, the synthesis route is short, the yield is high, the purity of the azilsartan is good, the industrial production is adapted, and the like.

Description

technical field [0001] The invention relates to the field of medicine, in particular, the invention relates to a preparation method of azilsartan. Background technique [0002] 2-Ethoxy-1-{[2′-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} Benzimidazole-7-carboxylic acid (azilsartan), molecular formula C 25 h 20 N 4 o 5 , the English name is Azilsartan, and the structural formula (I) is as follows [0003] [0004] Azilsartan is an angiotensin II receptor antagonist developed by Japan's Takeda Pharmaceutical Company. It is mostly used to treat hypertension. It was launched in 2012. This drug is the next generation product of candesartan cilexetil, which can be used alone or Used together with other antihypertensive drugs, the clinical effect is better than similar products losartan and olmesartan medoxomil. Has broad market prospects. [0005] Patent EP520423 (reference 1) in 1992 disclosed a synthetic method of azilsartan. The method comprises the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/10
CPCC07D413/10
Inventor 苑振亭王绍杰赵勇曲华平韩江升
Owner 中国人民解放军第二三〇医院