Efficient Solution-Phase Synthesis of 4,5,7-Trisubstituted Pyrrolo[3,2-d]pyrimidines
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  • 作者:Weihe Zhang ; Jing Liu ; Michael A. Stashko ; Xiaodong Wang
  • 刊名:ACS Combinatorial Science
  • 出版年:2013
  • 出版时间:January 14, 2013
  • 年:2013
  • 卷:15
  • 期:1
  • 页码:10-19
  • 全文大小:369K
  • 年卷期:v.15,no.1(January 14, 2013)
  • ISSN:2156-8944
文摘
We have developed an efficient and robust route to synthesize 4,5,7-trisubstituted pyrrolo[3,2-d]pyrimidines as potent kinase inhibitors. This solution-phase synthesis features a SNAr substitution reaction, cross-coupling reaction, one-pot reduction/reductive amination and N-alkylation reaction. These reactions occur rapidly with high yields and have broad substrate scopes. A variety of groups can be selectively introduced into the N5 and C7 positions of 4,5,7-trisubstituted pyrrolopyrimidines at a late stage of the synthesis, thereby providing a highly efficient approach to explore the structure鈥揳ctivity relationships of pyrrolopyrimidine derivatives. Four synthetic analogs have been profiled against a panel of 48 kinases and a new and selective FLT3 inhibitor 9 is identified.

Keywords:

pyrrolopyrimidine; SNAr displacement; coupling reaction; reductive amination; N-alkylation

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