Structural analysis of an impurity of the drug landiolol

Abstract

In a course of development and preparation of landiolol (1a), a known ultra-short-acting β-blocker, process quality control by HPLC and LC-MS analysis consistently showed an impurity peak ranging from 0.05% to 0.15 % and exhibiting a molecular mass m/z 887. To identify the hitherto unknown impurity, we prepared one of the possible landiolol derivatives with the same molecular mass for proper spectral characterization (NMR and MS). Its equivalence with the unknown impurity was then confirmed by LC-MS analysis. Ultimately, using fragmentation patterns in LC-MS and selective two-dimensional NMR experiments, the structure of the impurity was assigned as [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-{4-[(2S)-2-hydroxy-3-(3-{4-[(2S)-2-hydroxy-3-[(2-{[(morpholin-4-yl)carbonyl]amino}ethyl)amino]propoxy]phenyl}-N-(2-{[(morpholin-4-yl)carbonyl]amino}ethyl)propanamido)propoxy]phenyl}propanoate (2). It was found that the impurity was present in two rotameric forms at room temperature. The synthesis and NMR characterization of (2) are discussed.