Synthesis of deuterium, tritium, and carbon-14 labeled BIRB 796, a p38 MAP kinase inhibitor

摘要

l-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-l-yl]urea (BIRB 796), currently in clinical trials for the treatment of inflammatory diseases, is a potent inhibitor of p38 MAP kinase. Labeled BIRB 796 with stable and radioactive isotopes was required for metabolism, distribution, and absorption studies. We first report the synthesis of carbon-14 labeled BIRB 796 with a specific activity of 2GBq/mmol (54.2 mCi/mmol), using [~(14)C]-phosgene under modified Schotten-Baumann conditions; second the preparation of tritium-labeled BIRB 796 with a specific activity of 659 GBq/mmol (17.81 Ci/mmol) by reductive dehalogenation of iodo-BIRB 796 with tritium gas; and finally, the synthesis of ~2H_8-BIRB 796 using morpholine-2,2,3,3,5,5,6,6-~2H_8 with isotopic enrichment of 98.9 at% ~2H.