New method for synthesizing 4-(1-hydroxyl-1-methyl ethyl)-2-propyl imidazole-5-carboxylic acid ethyl ester

Abstract

The invention discloses a new method for synthesizing 4-(1-hydroxyl-1-methyl ethyl)-2-propyl imidazole-5-carboxylic acid ethyl ester. The 4-(1-hydroxyl-1-methyl ethyl)-2-propyl imidazole-5-carboxylic acid ethyl ester is prepared by the following steps of: cyclizing butyraldehyde and glyoxal serving as initiative raw materials; and hydroxymethylating, oxidizing, esterifying and performing addition. The method provided by the invention has the advantages of mild reaction condition, convenience in purification, recyclability of single solvent, low production cost and environmental friendliness, is easy to operate and is suitable for industrial production.

Description

technical field [0001] The invention relates to a new method for synthesizing olmesartan medoxomil intermediate 4-[1-hydroxyl-1-methyl)ethyl]-2-propylimidazole-5-carboxylic acid ethyl ester. Background technique [0002] The intermediate of the antihypertensive drug olmesartan medoxomil, the chemical name is ethyl 4-[1-hydroxy-1-methyl]-2-propylimidazole-5-carboxylate (CAS RN: 144689-93 -0, referred to as imidazole carboxylate) is an intermediate in the synthesis of olmesartan medoxomil, and its structural formula is as follows: [0003] [0004] Olmesartan (Olmesartan) chemical name: 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4 -Base] methyl] imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester is an imidazole developed by Japan Sankyo (Sankyo) It is an antihypertensive drug, which was launched in the United States under the trade name SenicarTm in May 2002. It is the seventh angiotensin II type 1 receptor antagonist app...

AI Technical Summary

Problems solved by technology

[0007] The disadvantages of this synthetic route are: (1) The raw materials diaminomaleonitrile and trimethyl orthobutyrate are relatively expensive and costly, and are not suitable for commercial use (2) There are many impurities in the product; (3) Ether / dichloromethane mixed solvent needs to be used, and the mixed solvent cannot be recycled, and the amount of waste liquid is large, which is not good for the environment; (4) Ether has a low boiling point (34.6 oC) is volatile, flammable and explosive, and has poor safety in production

[0010] During the preparation of 2-propylbenzimidazole, when o-phenylenediamine is used as a raw material to cyclize with butyric acid, the reaction temperature is difficult to control, and the temperature rises violently when heated , more dangerous, not suitable for industrial scale-up production

[0013]The raw materials of this route are relatively cheap, but the first step uses concentrated sulfuric acid and fuming nitric acid. very big

Also there is above-mentioned disadvantage simultaneously because of adopting methylmagnesium bromide Grignard reagent to need to use ether / dichloromethane mixed solvent

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