Enantiomers of C₅‐chiral 1‐acetyl‐3,5‐diphenyl‐4,5‐dihydro‐(1H)‐pyrazole derivatives: Analytical and semipreparative HPLC separation, chiroptical properties, absolute configuration, and inhibitory activity against monoamine oxidase

Abstract

The HPLC enantiomer separation of a novel series of C(5)-chiral 1-acetyl-3-(4-hydroxy- and 2,4-dihydroxyphenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole derivatives, with inhibitory activity against monoamine oxidases (MAO) type A and B, was accomplished using polysaccharide-based chiral stationary phases (CSPs: Chiralpak AD, Chiralcel OD, and Chiralcel OJ). Pure alcohols, such as ethanol and 2-propanol, and typical normal-phase binary mixtures, such as n-hexane and alcohol modifier, were used as mobile phases. Single enantiomers of several analytes examined were isolated on a semipreparative scale, and their chiroptical properties were measured. The assignment of the absolute configuration was established for one compound by single-crystal X-ray diffraction method and for the other three by CD spectroscopy. The inhibitory activity against MAO of racemic samples and single enantiomers were evaluated in vitro.

Interactions between pyrazole derived enantiomers and Chiralcel OJ: Prediction of enantiomer absolute configurations and elution order by molecular dynamics simulations

“…That is, the interaction between the (S)-isomer and the CSP is stronger than the (R)-isomer such that the (R)-isomer elutes first followed by the (S)-isomer when the enantiomers are separated by HPLC. This is coincident with the experimental results reported in previous literature [37]. In contrast, the interaction between the (R)-isomer and the CSP is stronger than the (S)-isomer in vacuum or non-polar solvent n-hexane, indicating that the (S)-isomer elutes first followed by the (R)-isomer.…”

“…It was reported that the (R)-enantiomer of the compound 1 was eluted first followed by the (S)-isomer when they were separated using four types of mobile phases, n-hexane/ethanol (70/30), n-hexane/2-propanol (60/40), ethanol and 2-propanol [37]. Fig.…”

“…Compound 1 (Fig. 1) was separated on Chiralpak AD and the (R)-isomer eluted first in n-hexane/2-propanal (60/40) mobile phase, while the (S)-isomer eluted first in n-hexane/ethanol (70/30) mobile phase [37]. The (+)-isomer of an analogue (compound 9 in Fig.…”

“…1) was separated using four types of mobile phases on chiralcel OJ ( Fig. 1) [37]. In contrast to imidazole derivatives, there is a polar OH group in compound 1 and the (R)-enantiomer was eluted first followed by the (S)-enantiomer in all mobile phases [37].…”

“…1) [37]. In contrast to imidazole derivatives, there is a polar OH group in compound 1 and the (R)-enantiomer was eluted first followed by the (S)-enantiomer in all mobile phases [37]. In this paper, systematic study was performed to investigate the influence of solvents and temperature on the separation of the two enantiomers of the pyrazole derived compound.…”