Novel rearrangements of an N-oxide degradate formed from oxidation of a morpholine acetal substance P antagonist.
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.
Zhao
Zhongxi Zack
ZZ
Pharmaceutical Research and Development, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. zuezhi_qin@merck.com
Qin
Xue-Zhi
XZ
Wu
Allen
A
Yuan
Yang
Y
D013058:Mass Spectrometry; D009025:Morpholines / Q000737:chemistry*; D010084:Oxidation-Reduction; D013373:Substance P / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000737:chemistry*
C496987:(5-(2(R)-(1(R)-(3,5-bistrifluoromethylphenyl) ethoxy)-3(s)-(4-fluorophenyl)morpholin-4-ylmethyl)-3h-(1,2,3) triazol-4-ylmethyl)dimethylamine; D009025:Morpholines; D014230:Triazoles; D013373:Substance P