Structure elucidation and total synthesis of a unique group of trace impurities in Tipranavir® drug product

✍ Scribed by Carl A. Busacca; Scot Campbell; Anjan Saha; Jon C. Lorenz; Karl Grozinger; Paul-James Jones; Nelu Grinberg; Sherry Shen; Heewon Lee; Fenghe Qiu; Alice Granger; Zhanna Yuabova; Dan Norwood; Chris H. Senanayake

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 185 KB
• Volume: 43
• Category: Article
• ISSN: 0749-1581
• DOI: 10.1002/mrc.1672

✦ Synopsis

Four unknown trace impurities (7-10) were observed in the capsule formulation of the HIV drug Tipranavir  after prolonged storage at 30 • C/70% RH. Extensive NMR and LC/MS analyses revealed the compounds to be covalent adducts between TRIS, an excipient of the formulation, and diastereomeric Tipranavir alcohols formed via slow air oxidation of the drug substance. The structures were ultimately confirmed by total synthesis with final purification by chiral, preparative supercritical fluid chromatography. A novel Favorskii rearrangement to furnish butyrolactones was also uncovered during the synthesis.