Novel rearrangements of an N-oxide degradate formed from oxidation of a morpholine acetal substance P antagonist

✍ Scribed by Zhao, Zhongxi Zack (author);Qin, Xue Zhi (author);Wu, Allen (author);Yuan, Yang (author)

• Book ID: 102400066
• Publisher: John Wiley and Sons Inc.
• Year: 2004
• Tongue: English
• Weight: 88 KB
• Volume: 93
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.20115

✦ Synopsis

Compound 1 [5-[2(R)-[1(R)-(3,5-bistrifluoromethylphenyl) ethoxy]-3(s)-(4-fluorophenyl)morpholin-4-ylmethyl]-3h-[1,2,3] triazol-4-ylmethyl]dimethylamine represents a new class of potent, orally active substance P antagonists, which possess a characteristic structural feature-a cis-2-alkoxy-3-arylmorpholine core. The oxidative degradation of 1 in drug substance and formulations was found to occur through the two trialkylamine oxides, which undergo secondary degradations to give rise to observed degradation products. In this study, the five primary degradation products of the N-oxide 2 formed from the oxidation of the morpholine core of 1 were identified by LC/MS and MS/MS. The N-oxide 2 undergoes novel thermal rearrangements, which were proposed to follow elimination/addition mechanisms. An unusual, facile [1,3]-sigmatropic rearrangement was also demonstrated.