Synthesizing method of 2-methyl-7-(substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and intermediate thereof

Abstract

The invention relates to an synthesizing method of 2-methyl-7-( substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and an intermediate thereof, mainly solving the technical problems of overlength single-line synthetic route, difficult separation and purification, low productivity, high synthesizing cost, narrow applicability, and the like of the traditional synthesizing method. The process method comprises the following steps of: carrying out substitution reaction on 2,4,5-trichloropyrimidine as a raw material and sodium methyl mercaptideto generate the intermediate, i.e. 2,5-dichloro-4-methylthiopyrimidine; then carrying out the substitution reaction with aromatic amine to generate the intermediate, i.e. 2-aromatic amino-4-methylthio-5-chloropyrimidine; then hydrolyzing the methylthio to generate the intermediate, i.e. 2-aromatic amino-4-hydroxy-5-chloropyrimidine; enabling a hydroxyl compound to generate dichloride under the action of phosphorus oxychloride; and finally carrying out the substitution reaction with amine to obtain the 2-methyl-7-(5-chlorine-2-aromatic amido-pyrimidine-4-amino)-4-(4-(4-methyl piperazine-1-base) piperidine-1-base) isoindoline-1-ketone under the action of hydrogen chloride ethyl acetate.

Description

Technical field: [0001] The invention relates to a synthetic method of a class of important drug molecule 2-methyl-7-(substituted pyrimidine-4-amino)-4-(substituted piperidin-1-yl)isoindoline-1-one and intermediates, That is, 2-methyl-7-(5-chloro-2-arylaminopyrimidine-4-amino)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)iso Synthesis method of indolin-1-one and intermediate 2-arylamino-4,5-dichloropyrimidine. Background technique: [0002] 2-Methyl-7-(5-chloro-2-arylaminopyrimidine-4-amino)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)isoind Indolin-1-ones are an important class of drug molecules, as inhibitors of focal adhesion kinase (FAK), they can be used as drugs to treat the dysfunction of signal cascades related to focal adhesion kinase. ) and thus have antitumor biological activity. Currently there is only one PCT patent application (WO 2006 / 021457) reporting the synthetic route of related compounds. However, we found in the course of the experiment that compound...

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Problems solved by technology

[0008] The object of the present invention is to provide an important drug molecule 2-methyl-7-(5-chloro-2-arylaminopyrimidine-4-amino)- A novel synthetic method for 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)isoindoline-1-one, which mainly solves the problem that the single-line synthetic route of the existing synthetic method is too long and exists Technical problems such as difficult separation and purification, low yield, high synthesis cost, and limited applicability

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