Investigation of Heck coupling on 6-bromo[2,3-d]thienopyrimidines for construction of new EGFR inhibitor lead structures

With the aim of identifying new lead structures for EGFR inhibition, a study of palladium catalysed Heck coupling between (R)-6-bromo-N-(1-phenylethyl)thieno[2,3-d]pyrimidin-4-amine and various acrylates was performed. The Heck coupling was highly dependent on type of catalyst, solvent, base type and the use of tetrabutylammonium chloride as additive. The products were stable in the dark, but underwent trans–cis isomerization upon exposure to light. Kinase profiling indicate that acrylates grafted on the [2,3-d]thienopyrimidines is an attractive scaffold for identification of potent and highly selective EGFR inhibitors.