In this study,the synthetic route of Fadraciclib(1,CYC065),a small molecule inhibitor of cyclin kinase,was optimized.Using 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(2)as raw material,2-chloro-3-cyano-4,6-dimethylpyridine(3)was obtained by reflux reaction with phosphorus oxychloride.Compound 3 was reduced by zinc powder to obtain 3-cyano-4,6-dimethylpyridine(4),which was then reduced by Raney Ni/H2,and the amino group was protected by di-tert-butyl dicarbonate.The key intermediate(4,6-dimethylpyridin-3-yl)methylamine(6,in the form of trifluoroacetate)was obtained after deprotection.Compound N-[(4,6-dimethylpyridin-3-yl)methyl]-2-fluoro-9-isopropyl-9H-purine-6-amine(9)was obtained by nucleophilic substitution of 6 with 6-chloro-2-fluoro-9H-purine(7)and isopropanol bromide.The target compound 1 was obtained by microwave reaction of 9 with(2R,3S)-3-aminopent-2-ol(10).The total yield of this route was 9.0％(based on 2)with cheap and easily available raw materials 2,and the cost was also reduced by microwave reactor,which provided a reference for the industrial synthesis of 1 and its structural analogues.
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