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Intermediate of telmisartan, preparation and use thereof

A technology for telmisartan and intermediates, applied in the field of preparation of telmisartan, can solve the problems of short reaction time, small environmental pollution, serious environmental pollution, etc., and achieve the advantages of industrial production, small environmental pollution and safe operation Effect

Active Publication Date: 2009-02-11
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In order to solve the deficiencies such as low preparation yield, long reaction time and serious environmental pollution of telmisartan in the prior art, the invention provides a new intermediate for preparing telmisartan and its preparation, and A kind of preparation method of telmisartan with high yield, short reaction time and little environmental pollution

Method used

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  • Intermediate of telmisartan, preparation and use thereof
  • Intermediate of telmisartan, preparation and use thereof
  • Intermediate of telmisartan, preparation and use thereof

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0040] Example 1: Preparation of 7-methyl-2-propyl-3H-benzimidazole-5-carbonyl chloride

[0041] In a 250ml there-necked flask, add 11g of 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid, 100ml of thionyl chloride and 1ml of DMF, heat to reflux under stirring for half an hour, and recover excess chlorine under reduced pressure Sulfoxide was dissolved, 100 ml of toluene was added, stirred and filtered to dryness to obtain 7-methyl-2-propyl-3H-benzimidazole-5-carbonyl chloride, which was directly used in the next step.

Embodiment 2

[0042] Example 2: Preparation of 7-methyl-N-(2-(methylamino)phenyl)-2-n-propyl-3H-benzimidazole-5-carboxamide

[0043] In a 500ml three-necked flask, 9.5g of N-methyl-o-phenylenediamine hydrochloride and 300ml of dichloromethane were added, stirred and cooled to between 0 and 5°C, and benzimidazole acid chloride obtained in the previous step was added. Triethylamine was added dropwise at a temperature, and stirring was continued for half an hour after the dropwise addition, the reaction solution was suction filtered, the filtrate was concentrated to dryness, the residue was dissolved in 300 ml of 5% dilute hydrochloric acid, and 5% sodium hydroxide solution was used under stirring. The pH value of the solution was adjusted to 11, a white solid was precipitated, suction filtered, the filter cake was washed with water until neutral, and dried to constant weight under an infrared lamp to obtain 7-methyl-N-(2-(methylamino)phenyl) -2-n-propyl-3H-benzimidazole-5-carboxamide, yield 8...

Embodiment 3

[0044] Example 3: 4'-((4-methyl-6-(2-methylamino)phenylcarbamoyl)-2-n-propyl-1H-benzimidazol-1-yl)methyl)biphenyl - Preparation of methyl 2-carboxylate

[0045] Add 7-methyl-N-(2-(methylamino)phenyl)-2-n-propyl-3H-benzimidazole-5-carboxamide 10g, 300ml acetonitrile in a 500ml there-necked flask with nitrogen protection, Stir and cool to between 0~5 ℃, add 4g of sodium hydride and stir for 10 minutes, add 9g of 4'-bromomethylbiphenyl-2-carboxylic acid benzyl ester in batches under insulation, continue to stir for half an hour after the addition, the reaction The liquid was poured into 500 ml of water, the aqueous phase was extracted with dichloromethane, the dichloromethane layers were combined, and concentrated to dryness to obtain 4'-((4-methyl-6-(2-methylamino)phenylcarbamoyl)-2 - n-propyl-1H-benzimidazol-1-yl)methyl)biphenyl-2-carboxylate methyl ester. Yield 62%.

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Abstract

The invention supplies an intermediate to make intermediate of Telmisartan that has the structure of 4'-((4- methyl-6-(2- methylamino) carbanilino)-2-propyl-1H- benzimidazole-1-radicle) methyl) biphenyl-2-carboxylic acid. It has the advantages of high yield, save operation, low environment pollution, etc.

Description

(1) Technical field [0001] The present invention relates to a new intermediate for preparing telmisartan: 4'-((4-methyl-6-(2-methylamino)phenylcarbamoyl)-2-n-propyl-1H- Benzimidazol-1-yl)methyl)biphenyl-2-carboxylic acid, its preparation method and its application in the preparation of telmisartan. (2) Background technology [0002] Telmisartan is a novel non-peptide angiotensin II (AT II) receptor antagonist, which has the characteristics of high efficiency, small dose, long duration of action and low toxicity for hypertensive diseases. It was first marketed in the United States in 1999 by the German company Boehringer Ingelheim under the trade name Micardis. [0003] The chemical name of Telmisartan is: 4'-(4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-n-propyl-1H-benzimidazole-1 - base) methyl) biphenyl-2-carboxylic acid, the structural formula is as follows: [0004] [0005] The synthetic route (Scheme 1) reported in the literature J.Med.Chem.1993, 36, 4040-4051 is...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/08
Inventor 唐朝军陈为人
Owner ZHEJIANG MENOVO PHARMA