Separation of atropisomers by chiral liquid chromatography and thermodynamic analysis of separation mechanism

Abstract

In the pharmaceutical industry, the analysis of atropisomers is of considerable interest from a scientific and regulatory perspective. The compound of interest contains two stereogenic axes due to the hindered rotation around the single bonds connecting the aryl groups, which results in four potential configurational isomers (atropisomers). The separation of the four atropisomers is achieved on a derivatized β-cyclodextrin bonded stationary phase. Further investigation shows that low temperature conditions, including sample preparation (−70 °C), sample storage (−70 °C), and chromatographic separation (6 °C), were critical to preventing interconversion. LC-UV-Laser Polarimetric analysis identified peak 1/2 as a pair of enantiomers and peak 3/4 as another. Thermodynamic analysis of the retention data indicated that the separation of the pairs of enantiomers is primarily enthalpy controlled as indicated by the positive slope of the van’t Huff plot. The difference in absolute Δ (Δ H), ranged from 2.20 kJ/mol to 2.42 kJ/mol.

Термодинамічна Характеристика Обернено-Фазового Хроматографічного Утримання Морфоліній 2-((4-(2-Метоксифеніл)-5-(Піридиніл)-4h-1,2,4-Тріазол-3-Іл)тіо) Ацетату Та Його Технологічних Домішок

“…У роботах [8][9][10] повідомляється про дослідження термодинамічних характеристик утримування різних сполук.…”

Molecular Recognition of the HPLC Whelk-O1 Selector towards the Conformational Enantiomers of Nevirapine and Oxcarbazepine

“…Consequently, the demand for methodologies to thoroughly characterize atropoisomers and provide conformationally pure chiral compounds has increased in recent decades, pushing towards a progressive boosting of separation sciences and in particular of chromatographic techniques such as HPLC with chiral stationary phases (CSP-HPLC). In recent years, the development of novel chiral stationary phases (CSPs) for high performance liquid chromatography and technological innovations have made HPLC a potential choice for the separation of conformational enantiomers [ 13 , 14 ]. Moreover, in particular when coupled to other techniques such as NMR or circular dichroism spectroscopy, CSP-HPLC is a valid support in the comprehension of the stereomutation process of atropoisomers and in the assignment of the absolute configuration [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

Enantiomeric separation of prothioconazole and prothioconazole‐desthio on chiral stationary phases

“…Chiral molecules include a pair of enantiomers. 4,5 The use of inefficient pesticide isomers is a waste of resources. 1 The development and application of pesticides have played an important role in agriculture, however, showing risks on environment and human health, of which more than 30% commercial pesticides are chiral compounds with one or more chiral centers.…”

“…2,3 The identification of enantiomers has attracted much attention due to the fact that one enantiomer probably shows high efficiency with low toxicity and the unwanted enantiomer is toxic to environment with little effect. 4,5 The use of inefficient pesticide isomers is a waste of resources. Moreover, irrigation and rainfall runoff transport pesticide residues in plants and soils to rivers, lakes and sea, which poses a great risk to human health.…”