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 S_NAr 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; S_NAr displacement; coupling reaction; reductive amination; N-alkylation