Synthetic method for preparing olmesartan medoxomil intermediate through continuous flow

Abstract

The invention discloses a synthetic method for preparing an olmesartan medoxomil intermediate through continuous flow, which belongs to the technical field of drug synthesis. The method comprises the following steps: step (1), dissolving a compound 2-propyl-4,5-imidazole dicarboxylic acid ethyl ester I in an organic solvent to form a reaction phase A; step (2), taking a commercially purchased methyl magnesium chloride solution as a reaction phase B; step (3), pumping the reaction phase A and the reaction phase B into a mixer by using a plunger pump at a certain flow rate, then feeding the mixture into a reactor, retaining for a certain time, quenching by using an acid water phase C, feeding the mixture into an oil-water continuous liquid separator, separating liquid to obtain an organic solution of a compound as shown in a formula II, desolventizing, and recrystallizing to obtain the compound as shown in the formula II. The technical problems of low purity and high cost in the existing preparation process are solved, the product is high in purity and few in impurities, the content of the key impurity A, the key impurity B and the key impurity C can be controlled to be 0.1% or below, the raw materials are cheap and easy to obtain, the reaction condition is mild, operation is easy and convenient, the synthesis efficiency is high, and the method is suitable for industrial production. A novel continuous flow path is provided for preparing the olmesartan medoxomil and the intermediate.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to the synthesis of olmesartan medoxomil intermediate 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester prepared by continuous flow method. Background technique [0002] Olmesartan medoxomil (formula III) is a novel angiotensin B receptor (AT1) inhibitor (ARB) jointly developed by Japan's Sankyo (Daiichi Sankyo) and U.S. Forest Laboratories. The English name is: Olmesartan Medoxomil , in May 2002, was approved by the US FDA for marketing, and the trade name was Benicar. In August 2002, it was approved to go on the market in Germany. It was approved for registration in China in 2013, and the product name is Aotan. In 2020, it will enter the second batch of national centralized procurement catalogues. [0003] [0004] Olmesartan medoxomil has unique pharmacokinetic and pharmacodynamic properties compared with other ARBs. Olmesartan m...

AI Technical Summary

Problems solved by technology

[0015] However, the control level of impurity A and impurity B in the examples is still 1.5%, and the synthesized olmesartan medoxomil cannot meet the requirements of raw materials, and there is no control of impurity C

And the amount of solvent used is large, the reaction time is long, generally 30 minutes to 48 hours, the production capacity is limited, and it is difficult to meet the demand for olmesartan medoxomil intermediates

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