Laboratory-Scale Semipreparative Enantioresolution of Phenylethanolic-Azole Heme Oxygenase-1 Inhibitors
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ORIGINAL
Laboratory‑Scale Semipreparative Enantioresolution of Phenylethanolic‑Azole Heme Oxygenase‑1 Inhibitors Federica Ianni1 · Andrea Carotti1 · Sebastiano Intagliata2 · Antonio Macchiarulo1 · Bezhan Chankvetadze3 · Valeria Pittalà2 · Roccaldo Sardella1,4 Received: 10 July 2020 / Revised: 21 September 2020 / Accepted: 25 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract In the present work, the development and application of two HPLC methods enabling the semipreparative enantioresolution of 1-(biphenyl-3-yl)-2-(1H-imidazol-1-yl)ethanol (1) and 1-[4-[(4-bromobenzyl)oxy]phenyl]-2-(1H-imidazol-1-yl)ethanol (2), two among the most potent and selective heme oxygenase-1 (HO-1) inhibitors known, are described. During the optimization step, different chiral stationary phase (CSP) features were evaluated, especially focusing the attention on (1) the type (electron-donating and electron-withdrawing) and position of the substituents in the phenyl moiety; (2) the physical coating or covalent immobilization of the modified polymer chain. Additionally, the effect of different types and amount of alcohol in the normal-phase eluent as well as of the column temperature, were investigated. For compound 1, Lux Cellulose-1 CSP containing cellulose tris(3,5-dimethylphenylcarbamate) was identified as the optimal choice in combination with a mobile phase consisting of n-hexane/ethanol—85/15 (v/v). Conversely, for compound 2, Lux Cellulose-2 CSP containing the cellulose tris(3-chloro-4-methyl phenylcarbamate)-based chiral selector was identified as the optimal choice, running the analysis with a n-hexane/ethanol/2-propanol—80/15/5 (v/v/v) mobile phase. Keywords Heme oxygenase-1 inhibitors · Imidazole · Polysaccharide-based stationary phases · Racemic approach · Semipreparative-scale enantioresolution
Introduction
Federica Ianni and Andrea Carotti contributed equally to this work. * Valeria Pittalà [email protected] * Roccaldo Sardella [email protected] 1
Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, Italy
2
Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
3
Institute of Physical and Analytical Chemistry, School of Exact and Natural Sciences, Tbilisi State University, Chavchavadze Ave 3, 0179 Tbilisi, Georgia
4
Center for Perinatal and Reproductive Medicine, University of Perugia, Santa Maria della Misericordia University Hospital, Sant’Andrea Delle Fratte, 06132 Perugia, Italy
The preparative-scale enantioselective separation of enantiomers by chromatography on chiral stationary phases (CSPs) has gained large acceptance over the last 20 years, and the so-called “racemic approach” is now considered as a valuable alternative to enantioselective synthesis for the efficient preparation of enantiomerically pure compounds [1–4]. Apart from the pharmaceutical industry, the enantioselective liquid-chromatography methods are increasingly applied also in academia, where cost reduct
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