Preparation and separation method of olmesartan medoxomil dimer impurity

Abstract

The invention provides a preparation and separation method of an olmesartan medoxomil dimer impurity. The method comprises the following steps: S1, carrying out self-polymerization reactions of olmesartan medoxomil in a vacuum environment with a temperature of 40-60 DEG C to obtain a crude product containing an olmesartan medoxomil dimer impurity; and S2, carrying out elution separation on the olmesartan medoxomil USP impurity C and other components in the crude product obtained in the step S1 by adopting supercritical fluid chromatography, collecting an olmesartan medoxomil dimer impurity peak fraction, and evaporating the collected olmesartan medoxomil dimer impurity fraction to dryness to obtain the olmesartan medoxomil dimer impurity. According to the technical scheme, the olmesartan medoxomil dimer impurity is generated through one-step reaction, the reaction efficiency is high, the steps are simple, convenient, and efficient, the after-treatment is simple, the cost is low, and the pollution is small.

Description

technical field [0001] The invention belongs to the technical field of chemistry, in particular to a method for preparing and separating olmesartan medoxomil dimer impurities. Background technique [0002] Olmesartan Medoxomil was developed by Sankyo of Japan and Forest Laboratories of the United States. It was launched in the United States under the trade name Benicar in May 2002. It was approved in Germany in August of the same year and launched in early October. [0003] Olmesartan medoxomil is a prodrug, which is absorbed through the gastrointestinal tract after oral administration, and is hydrolyzed into a biologically active product called olmesartan to play a role. The drug is well tolerated and can be taken for a long time. From domestic and foreign perspectives, the prospect of sartans is generally optimistic, and the antihypertensive drug market in the 21st century will be dominated by selective angiotensin II receptor inhibitors (ARBs). It will be of great signif...

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Problems solved by technology

[0007] However, the existing literature discloses that Jilin Xiuxiu Pharmaceutical New Drug Development Co., Ltd. adopts a 4-step method to directly synthesize the impurity. This method has many synthesis steps, troublesome post-processing, and high cost. In the synthesis process, various toxic organic solvents ( Such as acyl chloride, toluene, ethyl acetate), which have great pollution to human and environment

[0008] Because the olmesartan medoxomil dimer impurity is a tertiary alcohol ester, the steric hindrance is relatively large, and the self-polymerization of two molecules of olmesartan medoxomil through esterification reaction is difficult to carry out, and the degradation rate by itself is slow under normal conditions, and the yield is low

It has been reported in the literature that the DCC (N,N'-dicyclohexylcarbodiimide) method can be used for the reaction of tertiary alcohol esters, but the yield of the dehydrated dimer is still very low when trying to use DCC directly, because DCC is very easy to cause tertiary alcohols to directly Dehydration instead of esterification gives the product

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