氘代AZD9291的合成

Synthesis of Deuterated AZD9291

吲哚和2,4-二氯嘧啶经偶联反应制得3-(2-氯嘧啶-4-基)-1H-吲哚(1);1与CD3I经取代反应制得3-(2-氯嘧啶-4-基)-1-(甲基-d3)-吲哚(2);2经两步亲核取代反应制得N'-(2-二甲基氨基乙基)-2-甲氧基-N'-甲基-N-{4-[1-(甲基-d3)吲哚-3-基]嘧啶-2-基}-5-硝基苯-1,4-二胺(4);4经还原后,与氯丙酰氯发生缩合反应合成了氘代AZD9291,总收率8.5%,其结构经1H NMR,13C NMR和ESI-MS表征。

The synthesis of deuterated AZD9291 was reported. 3-（ 2-Chloropyrimidin-4-yl）-1H- indole（ 1） was prepared by coupling reaction of indole with 2,4-dichloropyrimidine. 3-（ 2-Chloropyrimidin-4-yl）-1-（ methyl-d3）-lindole（ 2） was obtained by substitution reaction of 1 with iodomethane-d3. N＇-（ 2-dimethylaminoethyl）-2-methoxy-N＇-methyl-N-{ [4-（ 1- methyl-d3） indol-3-yl]pyrimidin-2-yl} benzene-1,2,4-triamine（ 4） was obtained by two substitution reactions from 2. Then deuterated AZD9291 in total yield of 8. 5% was synthesized by condensation reaction following the reduction 4. The structure was confirmed by1 H NMR,13 C NMR and ESI-MS.