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Synthesis method of triphenyl candesartan

A technology for the synthesis of triphenylcandesartan, which is applied in the field of synthesis of triphenylcandesartan, and can solve the problems of long synthetic process flow, loss of raw materials or intermediates, and low yield of triphenylcandesartan , to achieve the effects of improving production efficiency, reducing losses, increasing yield and production efficiency

Inactive Publication Date: 2020-11-17
ZHEJIANG KINGLYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The above existing technical solutions have the following defects: the synthesis process of triphenylcandesartan involves many reactions, the required synthesis process is relatively long, and there will inevitably be raw materials or Loss of intermediates, resulting in low yield of triphenylcandesartan

Method used

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  • Synthesis method of triphenyl candesartan
  • Synthesis method of triphenyl candesartan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The synthetic method of triphenylcandesartan comprises the following processing steps:

[0054] S1: preparing tributyltin azide, specifically comprising the following steps:

[0055]Step a: Add 200kg of sodium azide into 600kg of water, stir and dissolve to obtain mixed solution a;

[0056] Step b: Control the reaction temperature to 20°C, add 670 kg of tributyltin chloride to the mixed solution a obtained in step a, stir and react for 3.5 hours, and obtain the mixed solution b;

[0057] Step c: add 1200 kg of toluene to the mixed liquid b for stirring and extraction, leave to stand and separate layers, and wash the organic layer with 600 kg of saturated sodium chloride water to obtain a toluene solution of tributyltin azide.

[0058] S2: preparing candesartan intermediate C7, specifically comprising the following steps:

[0059] Add 310kg of ethyl 2-ethoxy-1-[[(2'-cyanobiphenyl-4-substituted)methyl]benzimidazole]-7-carboxylate to the tributyl carboxylate prepared in ...

Embodiment 2

[0073] The synthetic method of triphenylcandesartan comprises the following processing steps:

[0074] S1: preparing tributyltin azide, specifically comprising the following steps:

[0075] Step a: Add 200kg of sodium azide into 600kg of water, stir and dissolve to obtain mixed solution a;

[0076] Step b: Control the reaction temperature to 10°C, add 670kg of tributyltin chloride to the mixed solution a obtained in step a, stir and react for 4 hours, and obtain the mixed solution b;

[0077] Step c: add 1200 kg of toluene to the mixed liquid b for stirring and extraction, leave to stand and separate layers, and wash the organic layer with 600 kg of saturated sodium chloride water to obtain a toluene solution of tributyltin azide.

[0078] S2: preparing candesartan intermediate C7, specifically comprising the following steps:

[0079] Add 310kg of ethyl 2-ethoxy-1-[[(2'-cyanobiphenyl-4-substituted)methyl]benzimidazole]-7-carboxylate to the tributyl carboxylate prepared in st...

Embodiment 3

[0093] The synthetic method of triphenylcandesartan comprises the following processing steps:

[0094] S1: preparing tributyltin azide, specifically comprising the following steps:

[0095] Step a: Add 200kg of sodium azide into 600kg of water, stir and dissolve to obtain mixed solution a;

[0096] Step b: Control the reaction temperature to 25°C, add 670 kg of tributyltin chloride to the mixed solution a obtained in step a, stir and react for 3 hours, and obtain the mixed solution b;

[0097] Step c: add 1200 kg of toluene to the mixed liquid b for stirring and extraction, leave to stand and separate layers, and wash the organic layer with 600 kg of saturated sodium chloride water to obtain a toluene solution of tributyltin azide.

[0098] S2: preparing candesartan intermediate C7, specifically comprising the following steps:

[0099] Add 310kg of ethyl 2-ethoxy-1-[[(2'-cyanobiphenyl-4-substituted)methyl]benzimidazole]-7-carboxylate to the tributyl carboxylate prepared in s...

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Abstract

The invention relates to the field of candesartan preparation, and particularly discloses a synthesis method of triphenyl candesartan. The synthesis method of triphenyl candesartan comprises the following steps: S1, preparation of tributyl tin azide: carrying out azide reaction on tributyl tin chloride and sodium azide to obtain tributyl tin azide; S2, preparation of a candesartan intermediate C7:carrying out a tetrazole reaction on 2-ethoxy-1-[[(2'-nitrile biphenyl-4-substituted)methyl]benzimidazole]-7-carboxylic acid ethyl ester and tributyltin azide to obtain a candesartan intermediate C7;S3, preparation of a candesartan intermediate C8: carrying out hydrolysis reaction on the candesartan intermediate C7 in an alkaline agent, then reacting with hydrochloric acid, and acidifying to obtain a candesartan intermediate C8; and S4, preparation of a triphenyl candesartan intermediate: reacting the candesartan intermediate C8 with a triphenyl compound to obtain the triphenyl candesartan intermediate. The preparation method disclosed by the invention has the advantages of shortening the process flow and improving the yield.

Description

technical field [0001] The invention relates to the technical field of candesartan, in particular to a synthesis method of triphenylcandesartan. Background technique [0002] Candesartan is a good active ingredient of antihypertensive drugs. As a prodrug form, candesartan cilexetil is absorbed through the intestinal tract in vivo, and is completely hydrolyzed into the active metabolite of candesartan, which binds to the angiotensin II subtype I receptor (AT1) with high selectivity , produce antihypertensive effect. [0003] Triphenylcandesartan, chemical name: 2-ethoxy-3-[[4-[2-(1-trityl-1H-tetrazol-5-yl)phenyl]phenyl] Methyl]-3H-benzimidazole-4-carboxylic acid, its structural formula is as shown in (I) formula, is the key intermediate of synthetic candesartan cilexetil. [0004] [0005] Existing common triphenylcandesartan synthetic technique such as the synthetic route in candesartan cilexetil literature (Kubo K, Kohara Y, etc., J.Med.Chem, 1993,36:2182-2196; Kubo K...

Claims

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Application Information

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IPC IPC(8): C07D403/10
CPCC07D403/10
Inventor 赵斌锋盛凯蔓张晓伟姜成唐雄峰
Owner ZHEJIANG KINGLYUAN PHARMA
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