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Structure elucidation and total synthesis of a unique group of trace impurities in Tipranavir ® drug product
Author(s) -
Busacca Carl A.,
Campbell Scot,
Saha Anjan,
Lorenz Jon C.,
Grozinger Karl,
Jones PaulJames,
Grinberg Nelu,
Shen Sherry,
Lee Heewon,
Qiu Fenghe,
Granger Alice,
Yuabova Zhanna,
Norwood Dan,
Senanayake Chris H.
Publication year - 2005
Publication title -
magnetic resonance in chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.483
H-Index - 72
eISSN - 1097-458X
pISSN - 0749-1581
DOI - 10.1002/mrc.1672
Subject(s) - chemistry , diastereomer , total synthesis , natural product , supercritical fluid , drug , organic chemistry , stereochemistry , combinatorial chemistry , pharmacology , medicine
Abstract 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. Copyright © 2005 John Wiley & Sons, Ltd.