In this paper,the synthesis method of epidermal growth factor receptor tyrosine kinase inhibitor Mobocertinib(TAK788)was improved.Using 2,4-dihydroxy-5-pyrimidinecarboxylic acid(1)as raw material,intermediate 2,4-Dichloropyrimidine-5-formyl chloride(2)was obtained by reflux reaction with thionyl chloride,and then esterified with isopropanol to obtain 2,4-dichloropyrimidine-5-carboxylic acid isopropyl ester(3).Subsequently,the key intermediate 2-Chloro-4-(1-methyl-1H-indole-3-yl)pyrimidine-5-carboxylic acid isopropyl ester(4)was obtained by Friedel-Crafts reaction of 3 with N-methylindole catalyzed by ferric chloride.2-((4-Fluoro-2-methoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indole-3-yl)pyrimidine-5-carboxylic acid isopropyl ester(5)was obtained by C-N coupling reaction of 4 with 4-fluoro-2-methoxy-5-nitroaniline catalyzed by p-toluenesulfonic acid monohydrate.2-((4-(2-(dimethylamino))ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indole-3-yl)pyrimidine-5-carboxylic acid isopropyl ester(6)was obtained by nucleophilic substitution of 5 with N,N,N'-trimethylethylenediamine.6 was reduced by iron powder under the condition of ethanol and ammonium chloride aqueous solution to obtain 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indole-3-yl)pyrimidine-5-carboxylic acid isopropyl ester(7).2-((5-(3-chloropropanamido)-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indole-3-yl)pyrimidine-5-carboxylic acid isopropyl ester(8)was obtained by condensation reaction of 7 with 3-chloropropionyl chloride,and finally the target compound Mobocertinib was obtained by refluxing under alkaline conditions with an overall yield of 53.9％.
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