title: Structure elucidation and total synthesis of a unique group of trace impurities in Tipranavir drug product.
abstract: Four unknown trace impurities (7-10) were observed in the capsule formulation of the HIV drug Tipranavir after prolonged storage at 30 degrees 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.
authors.affiliation: Department of Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA. cbusacca@rdg.boehringer-ingelheim.com
authors.forename: Carl A
authors.initials: CA
authors.lastname: Busacca
authors.forename: Scot
authors.initials: S
authors.lastname: Campbell
authors.forename: Anjan
authors.initials: A
authors.lastname: Saha
authors.forename: Jon C
authors.initials: JC
authors.lastname: Lorenz
authors.forename: Karl
authors.initials: K
authors.lastname: Grozinger
authors.forename: Paul-James
authors.initials: PJ
authors.lastname: Jones
authors.forename: Nelu
authors.initials: N
authors.lastname: Grinberg
authors.forename: Sherry
authors.initials: S
authors.lastname: Shen
authors.forename: Heewon
authors.initials: H
authors.lastname: Lee
authors.forename: Fenghe
authors.initials: F
authors.lastname: Qiu
authors.forename: Alice
authors.initials: A
authors.lastname: Granger
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Yuabova
authors.forename: Dan
authors.initials: D
authors.lastname: Norwood
authors.forename: Chris H
authors.initials: CH
authors.lastname: Senanayake
mesh_terms: D000438:Alcohols / Q000737:chemistry; D004340:Drug Contamination; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry*; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry*; D013449:Sulfonamides
chemical_list: D000438:Alcohols; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; C107201:tipranavir