The Synthesis of a Novel Inhibitor of B-Raf Kinase

A scaleable synthetic route to [4,7‘]bis-isoquinolinyl-1-yl-(2-tert-butyl-pyrimidine-5-yl)amine (1), an inhibitor of B-Raf kinase is described. The key step in the synthesis is the Pd-catalyzed Negishi coupling of 4-bromo-1-chloroisoquinoline with trifluoromethanesulfonic acid isoquinoline-7-yl este...

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Published inOrganic process research & development Vol. 10; no. 1; pp. 70 - 77
Main Authors Denni-Dischert, Donatienne, Marterer, Wolfgang, Bänziger, Markus, Yusuff, Naeem, Batt, David, Ramsey, Tim, Geng, Peng, Michael, Walter, Wang, Run-Ming B, Taplin, Francis, Versace, Richard, Cesarz, David, Perez, Lawrence B
Format Journal Article
LanguageEnglish
Published American Chemical Society 01.01.2006
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Summary:A scaleable synthetic route to [4,7‘]bis-isoquinolinyl-1-yl-(2-tert-butyl-pyrimidine-5-yl)amine (1), an inhibitor of B-Raf kinase is described. The key step in the synthesis is the Pd-catalyzed Negishi coupling of 4-bromo-1-chloroisoquinoline with trifluoromethanesulfonic acid isoquinoline-7-yl ester to yield 1-chloro[4,7‘]bis-isoquinolinyl. This intermediate is transformed to the desired drug substance in one additional step, by reaction with 2-tert-butyl-5-aminopyrimidine in the presence of NaH. A special focus was put on the finally successful removal of traces of Zn and Pd in the drug substance, which came from the Negishi coupling.
ISSN:1083-6160
1520-586X
DOI:10.1021/op0501601