Method for preparing fluralana intermediate, prepared intermediate and application of fluralana intermediate

Abstract

A method for preparing a fluralana intermediate, provided by the invention, comprises the following steps: carrying out nucleophilic addition reaction on 1-(3, 5-dichlorophenyl)-2, 2, 2-trifluoroethanone, carrying out acidolysis, reacting with a Grignard reagent, carrying out oxidation, carrying out oxidation cyclization reaction, reacting with hydroxyl(toluenesulfonyloxy)benzene iodide, and reacting with a trimethoxyphosphorus solution to finally generate the fluralan. In the preparation process, a catalyst and dimethoxy zinc are not needed, ultralow-temperature reaction conditions of -78 DEG C are not needed, operation is easy and convenient, meanwhile, reagents such as ozone and dimethyl sulfide which are harmful to the environment are replaced, and the method is more environmentally friendly. The invention also provides the intermediate for preparing the fluralan.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for preparing an intermediate of Frellaner, an intermediate prepared by the same and an application thereof. Background technique [0002] In 2004, Japan's Nissan Chemical Industry Co., Ltd. developed a new type of isoxaline veterinary insecticide Fluralaner (Fluralaner, Merck Co.), and obtained an international patent authorization in 2005, and the compound patent expired The time is 2025. Bravecto (chewable tablet), a new veterinary drug with Frellana as the main active substance, was approved for marketing by the European Union in February 2014, and approved by the FDA for marketing in May. It is mainly used for the treatment of skin parasitic diseases in pets; Approved for the treatment of red mites in chickens; in April 2019, Frellana chewable tablets were approved to be marketed in China (trade name Beveto), this chewable tablet is the earliest and the only one th...

AI Technical Summary

Problems solved by technology

The yield of the key step 1,3-dipolar addition and cyclization reaction of this route is extremely low, and it is almost difficult to obtain the product

Methyl 2-methyl-4-formaldoximobenzoate and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene need to be synthesized separately and cannot be purchased

[0014] 1. However, in this synthetic route, there are the following problems: in the nucleophilic addition of the first step starting material and propenylboronic acid pinacol ester, a catalyst (its structure is shown below) is used to ensure its configuration, The catalyst was independently developed by the laboratory that published the document, and it is difficult to purchase and synthesize. However, the marketed Frellana is a mixture of R and S configurations, and configuration resolution is not required;

[0016] 2. Zinc dimethoxide used in this route is difficult to purchase and expensive;

[0017] 3. Ozone and dimethyl sulfide, etc. are used in this route, which are harmful and unsuitable for industrial production;

[0018] 4. In this route, the ultra-low temperature of -78°C is used, which is difficult to operate, high in cost, and unsuitable for industrial production.

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