摘要
以2-氨基-4-氯吡啶为起始原料,经过缩合、取代、环合、乌尔曼反应和水合肼还原硝基5步反应得到中间体4-([1,2,4]三唑并[1,5-a]吡啶-7-氧基)-3-甲基苯胺(Ⅷ)。2-氨基-5-硝基苯腈先与N,N-二甲基甲酰胺二甲基缩醛(DMF-DMA)缩合,再与4-([1,2,4]三唑并[1,5-a]吡啶-7-氧基)-3-甲基苯胺环合得到N-[3-甲基-4-([1,2,4]三唑并[1,5-a]吡啶-7-氧基)苯基]-6-硝基-4-喹唑啉胺(ⅩⅦ),再经硝基还原得到N^(4)-[3-甲基-4-([1,2,4]三唑并[1,5-a]吡啶-7-氧基)苯基]-4,6-喹唑啉二胺(ⅩⅧ)。同时,采用二硫化碳和2-氨基-2-甲基-1-丙醇为原料,经两步反应制备4,5-二氢-4,4-二甲基-2-(甲硫基)唑三氟甲磺酸盐,收率68.6%。最后,N^(4)-[3-甲基-4-([1,2,4]三唑并[1,5-a]吡啶-7-氧基)苯基]-4,6-喹唑啉二胺和4,5-二氢-4,4-二甲基-2-(甲硫基)唑三氟甲磺酸盐以三乙胺为碱进行缩合反应得到妥卡替尼,收率62.8%,HPLC纯度99.08%。采用~1HNMR、CNMR和HRMS对产物结构进行了表征。
Tucatinib,with a yield of 62.8%and HPLC purity of 99.08%,was synthesized via condensation reaction of N^(4)-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]-4,6-quinazolinediamine and4,5-dihydro-4,4-dimethyl-2-(methylthio)oxazole trifluoromethanesulfonate using triethylamine as base,and further characterized by ^(1)HNMR,CNMR and HRMS.Of the reactants,intermediate N^(4)-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]-4,6-quinazolinediamine was prepared by a series of condensation,cyclization and reduction reaction of 2-amino-5-nitrobenzonitrile with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline,which was obtained from 2-amino-4-chloropyridine through five steps of condensation,substitution,cyclization,Ullmann reaction and reduction of nitro group,while intermediate4,5-dihydro-4,4-dimethyl-2-(methylthio)oxazole trifluoromethanesulfonate with a yield of 68.6%was prepared through a two-step reaction of carbon disulfide and 2-amino-2-methyl-1-propanol under mild conditions.
作者
黄加香
刘洋
王巳天
赵圣印
HUANG Jiaxiang;LIU Yang;WANG Sitian;ZHAO Shengyin(College of Chemistry,Chemical Engineering and Biotechnology,Donghua University,Shanghai 201620,China)
出处
《精细化工》
EI
CAS
CSCD
北大核心
2022年第9期1894-1900,共7页
Fine Chemicals
关键词
妥卡替尼
酪氨酸激酶抑制剂
乳腺癌
改进工艺
医药原料
tucatinib
tyrosine kinase inhibitor
breast cancer
improved synthesis
drug materials
