Simultaneous diastereo- and enantioseparation of farnesoid X receptor (FXR) agonists with a quinine carbamate-based chir
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ORIGINAL PAPER
Simultaneous diastereo- and enantioseparation of farnesoid X receptor (FXR) agonists with a quinine carbamate-based chiral stationary phase Roccaldo Sardella & Maura Marinozzi & Federica Ianni & Antonella Lisanti & Benedetto Natalini
Received: 1 June 2012 / Revised: 24 July 2012 / Accepted: 9 August 2012 / Published online: 30 August 2012 # Springer-Verlag 2012
Abstract In the frame of a project aimed at finding nonsteroidal farnesoid X receptor (FXR) agonists, we identified 4-(2,4-dimethoxyphenyl)-3,6-dimethyl-1-(2-tolyl)-4,8-dihydro-1H-pyrazole[3,4-e][1,4]thiazepin-7-one (1) as a hit endowed with FXR activity. Most of the compounds synthesised during the hit-to-lead optimisation work were characterised by the presence of two chiral centres and were therefore obtained as mixtures of anti(±)- and syn(±)-diastereoisomers. A restricted sub-set of species harboured with a carboxylic acid group on the distal phenyl ring of the biphenyl (a(±)5 (A1) and s(±)5 (S1)) or the phenoxyphenyl (a(±)6 (A2) and s(±)6 (S2)) moiety at C-4 position of the pyrazole[3,4-e][1,4]thiazepin-7-one core, resulted in suitable diastereo- and enantioresolution with a quinine (QN) carbamate-derived chiral stationary phase (CSP). Differently from the compounds usually analysed with QN-based CSPs, the couples A1/S1 and A2/S2 were atypical selectands, in which the two chiral carbon atoms reside at a remote position with respect to the carboxylic function, the main “point of attack” to the CSP. We produced evidence that the scarcely employed normal-phase (NP) eluent systems represent the elective choice for achieving the simultaneous diastereo- and enantioseparation of this class of compounds over the usually preferred reversed-phase (RP) and polar-organic (PO) modes of elution. Indeed, after the optimisation of the eluent composition, NP conditions allowed to obtain profitable enantioselectivity profiles, along
Published in the special issue Analytical Science in Italy with guest editor Aldo Roda. R. Sardella : M. Marinozzi : F. Ianni : A. Lisanti : B. Natalini (*) Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy e-mail: [email protected]
with excellent diastereoselectivity levels (α(A1) 01.07, RS(A1) 01.15; α(S1) 01.09, RS(S1) 01.47; α(A2) 01.08, RS(A2)01.31; and α(S2)01.06, RS(S2)01.18). The optimised NP methods are suitable for simultaneously providing information on the diastereo- and enantiopurity of the investigated compounds. Keywords Farnesoid X receptor agonists . Quinine carbamate-based chiral stationary phase . Enantioseparation . Diastereoseparation . Ion-exchange liquid chromatography . Normal-phase conditions Abbreviations AA Ammonium acetate ACN Acetonitrile AcOH Acetic acid BA Bile acid BzA Benzoic acid CDCA Chenodeoxycholic acid CEA Cyclohexylamine CECA Cyclohexanecarboxylic acid DEA Diethylamine DEAA Diethylammonium acetate DIPEA N,N-diisopropylethylamine ETN Ethanolamine EtOH Ethanol FA Formic acid FXR Farnesoid X receptor IPA 2-p
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