Structure elucidation and total synthesis of a unique group of trace impurities in Tipranavir drug product.
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.
Busacca
Carl A
CA
Department of Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA. cbusacca@rdg.boehringer-ingelheim.com
Campbell
Scot
S
Saha
Anjan
A
Lorenz
Jon C
JC
Grozinger
Karl
K
Jones
Paul-James
PJ
Grinberg
Nelu
N
Shen
Sherry
S
Lee
Heewon
H
Qiu
Fenghe
F
Granger
Alice
A
Yuabova
Zhanna
Z
Norwood
Dan
D
Senanayake
Chris H
CH
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
D000438:Alcohols; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; C107201:tipranavir