Synthesis of [14C] ‐ and [13C6]‐labeled tipranavir and its potential hydroxyl metabolite and the glucuronide conjugate

Tipranavir or Aptivus^® is a non‐peptidic protease inhibitor approved for the combination treatment with ritonavir of HIV infection. Tipranavir labeled with radioactive and stable isotopes of carbon was required for drug metabolism (excretion, distribution, and absorption) studies and to develop bioanalytical methods needed for the support of clinical studies. [7‐¹⁴C]‐Benzoic acid and uniformly labeled benzoic acid (ring‐¹³C₆ 99 at% ¹³C) were used to prepare [¹⁴C]‐ and [¹³C₆]‐labeled tipranavir, respectively. Radioactively labeled tipranavir was prepared with a specific activity of 54 mCi/mmol (2GBq/mmol); it was necessary to dilute its specific activity with unlabeled tipranavir to 28 mCi/mmol (46.45 µCi/mg) because of its instability. The N‐hydroxyl metabolite (12) and the glucuronide conjugate (13), the most abundant metabolites of tipranavir (when administered in conjunction with ritonavir) were also synthesized. Copyright © 2008 John Wiley & Sons, Ltd.