Method for synthesizing pitavastatin calcium intermediate by microchannel reactor

Abstract

The invention relates to a method for synthesizing a pitavastatin calcium intermediate in a microchannel reactor. Fluorobenzene and phthalic anhydride are used as raw materials, a target product 2-(4-fluoro-benzoyl)-benzoic acid is synthesized through the microchannel reactor, and in the reaction process, and a carbonate compound is used for replacing aluminum trichloride in the prior art to serve as a catalyst, so the catalyst treatment before industrial production is avoided, meanwhile, a large amount of aluminum-containing wastewater is not generated in the reaction process, the method is green and environment-friendly, the reaction condition is mild, the reaction time is short, the product yield is high and reaches 92% or above, the purity is high and reaches 99% or above, the product post-treatment is simple, the cost is reduced, and the method is suitable for industrial production.

Description

Technical field [0001] The present invention belongs to the art of the drug synthesis, and more particularly to a method of microchannel reactor synthesizing pattycittrine intermediate 2- (4-fluorine-benzoyl)-benzoic acid. Background technique [0002] Pitavastation, NK-104, the first full-synthetic HMG-COA reductase inhibitor jointly developed by two companies in Nissan Chemistry and Xing and Corporate Co., Ltd., which belongs to statins, mainly through hmgco- The inhibition of the hepatic enzyme of the reductase to reduce the ability of the liver to produce cholesterol, and thus improve the elevated serum cholesterol level, mainly used to treat high cholesterol hypermia and family-sex high cholesterolemia, because of its lipid-lowering effect Ok, it is called "super statins". [0003] Among them, Compound 2- (4-fluorine-benzoyl)-benzoic acid is one of the important intermediates of the preparation of guttytin. At present, in the preparation of the intermediate, fluorobenzene an...

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Problems solved by technology

[0006] In the traditional kettle reaction, the reaction volume is large, and the probability of collision between the catalyst and the alkylbenzene is small, resulting in the need for a strong Lewis acid to catalyze the above reaction. In the Chinese patent CN101948382A, although the organic amine trifluoromethanesulfonate is used in the reaction process Salt as a catalyst, but such catalysts are expensive, and will produce triflate and other fluorine-containing solid wastes, which are difficult to handle in the post-treatment process and cause pollution to the environment; The disadvantages of the reaction, such as severe heat release, more impurities, etc.; at the same time, the raw material phthalic anhydride is excessive during the reaction, which is not easy to remove, the whole reaction time is long, and the yield and purity still need to be improved

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