The 14C, 13C,and 15N syntheses of a potent VEGFR‐2 kinase inhibitor,Brivanib, and its prodrug,Brivanib Alaninate

The interruption of tyrosine kinase vascular endothelial growth factor receptor‐2 (VEGFR‐2) signaling by the binding of a small molecule inhibitor, for example, Brivanib, to VEGFR‐2 kinase domain has been shown as an effective method of slowing angiogenesis and tumor progression. ¹⁴C]Brivanib, 13 and its prodrug ¹⁴C]Brivanib Alaninate, 15 were prepared to support preclinical and clinical studies. Their respective stable isotope‐labeled versions, ¹³CN₂]Brivanib, 21 and ¹³CN₂]Brivanib Alaninate, 28, were also prepared to support bioanalytical LC‐MS analyses of clinical samples. All of the four title compounds were synthetically derived from the respective isotopically labeled common pyrrolotriazinone intermediate, 6 or 16. This labeled central core pyrrolotriazinone was also conveniently used to synthesize other structurally related drug discovery candidates. Copyright © 2011 John wiley & Sons, Ltd.