Web Release Date: December 9,
The Synthesis of a Novel Inhibitor of B-Raf Kinase
and
Chemical and Analytical Development, Novartis Pharma, 4002 Basel, Switzerland, and Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, U.S.A.
Received for review September 1, 2005.
Abstract:
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.
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