Susceptibility of morpholine substituents to photo-oxidative decomposition-identification of photo-oxidative degradants of linezolid (PNU-100766)

✍ Scribed by Gary E. Martin; Russell H. Robins; Phil B. Bowman; Wayne K. Duholke; Kathleen A. Farley; Brian D. Kaluzny; Jane E. Guido; Sandra M. Sims; Thomas J. Thamann; Brian E. Thompson; Toshihide Nishimura; Yukimi Noro; Tsutoma Tahara

• Publisher: Journal of Heterocyclic Chemistry
• Year: 1999
• Tongue: English
• Weight: 507 KB
• Volume: 36
• Category: Article
• ISSN: 0022-152X
• DOI: 10.1002/jhet.5570360140

✦ Synopsis

Parenteral formulations of linezolid (PNU-100766), a novel ( (S) )-3-(4'-fluorophenyl)-5- (N)-acetamidomethyloxazolidin-2-one antibiotic, were subjected to photo-stability testing as required by ICH guidelines. Direct, reversed phase chromatographic evaluation of the photo-irradiated solutions revealed two chromatographically broad degradants. Following preparative chromatographic isolation, the structures of both degradants were determined by mass spectrometric, (\mathrm{nmr}), and vibrational spectroscopic methods. The degradant structures formed by decomposition involving photo-oxidation of the morpholine, followed by a carbon-carbon bond scission to a formyloxyethylformamide-containing degradant. Facile hydrolytic cleavage of the formate ester in acidic media gave the second chromatographically broad degradant containing a (\mathrm{N})-2-hydroxyethylformamide group. The formamide substituent underwent further hydrolysis in acidic media to the corresponding secondary amine.