Preparation method of imiquimod

Abstract

The invention relates to a preparation method of an antiviral drug imiquimod, wherein the preparation method comprises the steps: (1) with 4-hydroxyquinoline as a starting material, nitrifying to obtain 3-nitro-4-hydroxyquinoline; (2) carrying out chlorination and amination on 3-nitro-4-hydroxyquinoline to obtain 3-nitro-4-isobutyl amine quinoline; (3) carrying out hydrogenation on 3-nitro-4-isobutyl amine quinoline to obtain 3-amino-4-isobutyl amine quinoline, and separating in a formate mode; (4) carrying out cyclization, oxidation and ammoniation on 3-amino-4-isobutyl amine quinoline, carrying out a reaction in a same reactor, and thus obtaining an imiquimod crude product; and (5) preparing a hydrochloride of imiquimod from the imiquimod crude product, purifying, and carrying out alkaline hydrolysis to obtain the high-purity imiquimod. In the method, the imiquimod is prepared from 4-hydroxyquinoline as the starting material, and the total yield can reach 55%; the method has the advantages of high yield, less reaction steps, less discharge of three wastes, mild and more complete reaction conditions, and simple and convenient operation, is suitable for industrialized production, and has relatively high practical value. The obtained product is more stable in quality, and the purity can reach more than 99.7%.

Description

technical field [0001] The invention relates to a preparation method of imiquimod, in particular to a preparation method of high-purity imiquimod. Background technique [0002] Imiquimod (Imiquimod), chemical name 4-amino-1-isobutyl-1H-imidazo[4,5-c]-quinoline, is an antiviral drug with immunomodulatory effect developed by 3M Pharmaceutical Company of the United States. For the treatment of genital warts in adults. Imiquimod is disclosed in U.S. Patents 4,689,338 and 5,238,944 and has structure (VII) [0003] [0004] In the prior art, it is known that there are many synthetic routes of imiquimod, which can be summarized as follows: (1) synthetic with 3-nitro-4-hydroxyquinoline as raw material; (2) synthetic with 3-nitro-4-hydroxyquinoline; base-2,4-dihydroxyquinoline as raw material; (3) 3-nitro-4-hydroxyquinolin-2-one as raw material; (4) 2,4,5-tribromoimidazole as Synthesis of raw materials; (5) Synthesis of raw materials with 2-bromobenzoic acid. [0005] Among th...

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Problems solved by technology

[0010] 1) When preparing the starting material 3-nitro-4-hydroxyquinoline, fuming nitric acid is often used as a nitrating agent in the nitration reaction, but fuming nitric acid has a large safety hazard in production and is more expensive, so it is not suitable for industrial production ;

[0011] 2) When preparing the intermediate 3-nitro-4-isobutylaminoquinoline, the chlorination reaction of the first step is to chlorinate the 3-nitro-4-hydroxyquinoline with phosphorus oxychloride earlier, after A series of treatments to obtain the intermediate 3-nitro-4-chloro-quinoline, the second step of amination reaction and then amine substitution reaction with isobutylamine to obtain 3-nitro-4-isobutylamino Quinoline, the above two-step operation also increases the production cost;

[0012] 3) When preparing the intermediate 3-amino-4-isobutylaminoquinoline, because the amino group of the intermediate is exposed to the air and is easily oxidized, operations such as conventional distillation and concentration will cause 3-amino-4-isobutyl The quality of aminoquinoline decreases, thereby reducing the yield and quality of the product

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