抗肿瘤化合物的合成抗肿瘤药物妥卡替尼的合成  

Synthesis of Tucatinib as Anticancer Drug

作　　者：包斐芸 赵圣印[1] BAO Feiyun;ZHAO Shengyin(College of Chemistry and Chemical Enginerring,Donghua University,Shanghai 201620,China)

机构地区：[1]东华大学化学与化工学院,上海201620

出　　处：《合成化学》2024年第12期1061-1066,共6页Chinese Journal of Synthetic Chemistry

基　　金：湖南氩氡医药科技有限公司资助项目(HX105210655)。

摘　　要：妥卡替尼为新型酪氨酸激酶抑制剂,为满足临床需求,以2-氨基-5-硝基苯腈和N,N-二甲基甲酰胺二甲基缩醛(DMF-DMA)为原料,经缩合反应生成甲脒类化合物7。7经锌粉还原、与二硫化碳在三乙胺存在下反应生成二硫代氨基甲酸三乙胺盐,该化合物与2-氨基-2-甲基-1-丙醇在溴化铜作用下进行脱硫环合,构建含有噁唑环的中间体17。最后将7-(2-甲基-4-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶(6)与中间体17在醋酸作用下环合得到妥卡替尼,收率58.5%。通过单晶X-射线衍射对妥卡替尼一水合物的单晶结构进行分析,并结合^(1)H NMR和^(13)C NMR确证了妥卡替尼的结构。该合成路线较短、操作简便,具有潜在的工业化生产前景。Tucatinib is a new generation of tyrosine kinase inhibitor.In order to meet clinical requirement,the compound 7 was prepared from 2-amino-5-nitrobenzonitrile and N,N-dimethylformamide dimethyl acetal(DMF-DMA)via condensation.Next,it was reduced with zinc powder and reacted with carbon disulfide in the presence of triethylamine to provide triethylamine dithiocarbamate.It was subjected to cyclize with 2-amino-2-methyl-1-propanol using copper bromide to give oxazole intermediate 17.Finally,Tucatinib was synthesized from 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline(6)and 17 with 58.5%yield.The single crystal structure of Tucatinib monohydrate was collected through single crystal X-ray diffraction.Along with ^(1)H NMR and ^(13)C NMR spectrum analysis the structure of the product was confirmed.This methodology has advantages of short synthetic steps and simple post-treatment.It has a good industrial aspect.

关 键 词：妥卡替尼 乳腺癌 脱硫环合 合成改进 单晶结构 

分 类 号：O621.3[理学—有机化学]