Preparation method of pitavastatin calcium intermediate

Abstract

The invention relates to a preparation method of a pitavastatin calcium intermediate, which comprises the following steps: (1) under the protection of nitrogen, carrying out chemical reaction on compounds N7 and NBS and a solvent at 30-80 DEG C to prepare an intermediate product compound N8.1, and (2) adding triphenylphosphine into the reaction solution obtained in the step (1), heating to 60-120DEG C for reaction, cooling to 0-20 DEG C for stirring crystallization after the reaction is finished, and filtering to obtain a compound N8.2, wherein the specific synthetic route is as follows. Thepreparation method has the advantages of mild reaction conditions, no generation of a large amount of bromine-containing and phosphorus-containing wastewater in the reaction process, no influences ofacids and bases on the intermediate product compound N8.1, and difficult decomposition, so the yield of the target product is high and reaches 90% or above, the purity is high and reaches 99% or above, and the product has the advantages of simple post-treatment, greenness and environmental protection, and suitableness for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to a pitavastatin calcium intermediate [[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]methyl]triphenyl bromide Phosphorus preparation method. Background technique [0002] Pitavastation calcium (Pitavastation, NK-104), the first fully synthetic HMG-CoA reductase inhibitor jointly developed by Nissan Chemical and Kowa Co., Ltd. Inhibition of a liver enzyme called HMGCo-A reductase to reduce the ability of the liver to produce cholesterol, thereby improving elevated blood cholesterol levels, is mainly used to treat patients with hypercholesterolemia and familial hypercholesterolemia, because it reduces Lipids work so well that they have been dubbed "super statins." [0003] Among them, the compound [[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]methyl]triphenylphosphonium bromide is one of the important intermediates for preparing pitavastatin calcium. Chinese patent...

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Problems solved by technology

[0006] Although this route is better in terms of yield and cost, due to the use of phosphorus tribromide as the bromination agent in the reaction process, it is necessary to use alkaline water to quench phosphorus tribromide after the reaction, which will consume a large amount of Alkaline water, and produce a large amount of waste water containing bromine and phosphorus; at the same time, brominated intermediates will be affected by acid-base conditions during the quenching process, resulting in unstable products and affecting the total yield of the final product. Therefore, under the increasing pressure of environmental protection Grim now, the route's advantage is being lost

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