Synthesis of 14C‐labeled and 13C‐,15N‐labeled dasatinib and its piperazine N‐dealkyl metabolite

Abstract

AbstractDasatinib (SPRYCEL®) is a multiple kinase inhibitor approved for the treatment of chronic myelogenous leukemia and Philadelphia chromosome‐positive acute lymphoblastic leukemia in patients with resistance to prior therapy, including imatinib mesylate (Gleevec®). Radiolabeled dasatinib and its piperazine N‐dealkyl metabolite were synthesized to investigate absorption, distribution, metabolism, and elimination of the compounds in humans and animals. These compounds were prepared following a three‐step sequence, which included thiazole carboxamide formation via cyclization of labeled thiourea with a brominated oxyacrylamide precursor. In the final step a common intermediate was converted to either [14C]dasatinib or the radiolabeled piperazine N‐dealkyl metabolite with labeling in the aminothiazole ring. Syntheses of both compounds were achieved with radiochemical purities in excess of 98%. Stable‐labeled dasatinib and the piperazine N‐dealkyl metabolite were also needed for use as mass spectral internal standards in support of bioanalytical assays. By following the same route used for the carbon‐14 synthesis, [13C4, 15N2]dasatinib and the [13C4, 15N2]metabolite were prepared with labeling in both the dichloropyrimidine and thiazole ring systems. This convergent process introduced stable isotope labeling through (1, 2, 3‐13C3) diethyl malonate and [13C,15N2]thiourea. Copyright © 2008 John Wiley & Sons, Ltd.