A kind of synthetic method of vemodinil

Abstract

The invention discloses a synthesis method of vismodegib. The method comprises the following reactions: firstly, enabling 2-chloro-5-nitrophenyl boronic acid and 2-bromopyridine to make a coupled reaction to generate an intermediate 2-(2-chloro-5-nitro) phenylpyridine; reducing nitro in the 2-(2-chloro-5-nitro) phenylpyridine to amino so as to obtain 2-(2-chloro-5-amino) phenylpyridine; finally, enabling the 2-(2-chloro-5-amino) phenylpyridine and 2-chloro-4-methyl sulfuryl benzaldehyde to make a catalytic reaction to generate the vismodegib. The synthesis method is low in price of raw materials, easy in raw material obtaining, simple and convenient to operate and less in consumption of a catalyst; the reaction product is high in yield, reaction conditions are mild, and aftertreatment is simple in technology and mainly adopts column separation, so that industrial mass production can be realized.

Description

Technical field [0001] The invention relates to a synthesis method of vilmodinil. Background technique [0002] Vismodegib (Vismodegib), trade name Erivedge, chemical name 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzyl Amide, approved by the US Food and Drug Administration (FDA) in 2012, is used as a small molecule targeted inhibitor of the Hedgehog pathway for the treatment of base cell carcinoma. Vermodinil can effectively inhibit the Smoothened oncoprotein of the Hedgehog pathway, and has good solubility, free rate and clinical effects. At present, there are three main synthesis processes reported in the literature for vermodinil: [0003] The synthesis method disclosed in WO2009126863 is shown in synthesis route 1. Although the route of this method is short, the raw material cost is high. In addition, the preparation process of pyridine-2-zinc (II)-chloride requires the use of flammable and explosive n-butyl lithium, which is difficult to achieve indus...

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Problems solved by technology

[0006] The synthetic method disclosed in CN102731373A, as shown in synthetic route 2, has the following disadvantages: the price of p-chlorobenzoic acid as a raw material is high, and active diphenylphosphoryl azide is required for rearrangement, which is dangerous when used Sexuality, and expensive, resulting in high production costs of vemodini

[0009] The synthetic method disclosed in WO2006028958, as shown in synthetic route 3, the raw materials used in this method are difficult to obtain and expensive; benzoyl is used for protection, and high temperature and strong alkaline conditions are required for deprotection; the reaction steps are too long and the reaction conditions Harsh, resulting in extremely high production costs

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