Structure–Retention Relationship in a Series of Chiral 1,4-Disubstituted Piperazine Derivatives on Carbohydrate Chiral Stationary Phases Zdzislaw Chilmonczyk a,b , Lukasz Sienicki a , Boz ˙ena Lozowicka a , Malgorzata Lisowska-Kuz ´micz b , Anna Jon ´czyk b , HassanY. Aboul-Enein c, * a Institute of Chemistry, University of Bialystok, Pilsudskiego 11/4, 15-443 Bialystok, Poland b National Institute of Public Health, Chelmska 30/34, 00-725 Warsaw, Poland c Pharmaceutical Analysis and Drug Development Laboratory, Biological and Medical Research Department (MBC 03-65), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, SaudiArabia Received 10 November 2004; received in revised form 15 January 2005; accepted 20 January 2005 Available online 14 April 2005 Abstract New racemic 1,4-disubstituted piperazines chemically named ethyl 2-[(4-pyrimidin-2yl-piperazine-1yl)carbonyl]C3-C5-alkanoates 1-7 were synthesized. The compounds were resolved into enantiomers on cellulose tris(4-methylbenzoate) and amylose tris(3,5- dimethylphenylcarbamate) stationary phases using hexane/propan-2-ol mobile phases. The optimum separation conditions for the compounds were obtained on cellulose tris(4-methylbenzoate) with 5% of 2-propanol in hexane. The relationship between structural and chromatographic parameters is discussed. © 2005 Elsevier SAS. All rights reserved. Keywords: 1,4-Disubstituted piperazine; Synthesis; Chiral stationary phases 1. Introduction Homochiral compounds may be obtained by isolation from natural materials, the resolution of racemate, or asymmetric synthesis [1,2]. Chromatographic methods allow not only to resolve mixtures of enantiomers or diastereoisomers, but also to obtain information concerning their enantiomeric or dias- tereomeric purity. The employment of chiral stationary phases is particularly useful since it allows to resolve and analyse chiral compounds without a necessity of derivatisation [2–6]. Among different chiral stationary phases, polysaccharides have been widely used for chiral resolution of many different racemic compounds such as drugs, agrochemicals and ferroelectric liquid crystals [7,8]. In our former papers, we described chromatographic behaviour of someTJT*0.0144 Tc[(disubstituted)-389.6(piperazines)-389.6(with)-389.5(hypnotic [9,10] malathione (a known insecticide) derivatives [11] and 3-amino-2-oxazolidinone derivatives with potential psycho- tropic activity [12] on cellulose and amylose chiral station- ary phases. It has been found that in a series of congeneric compounds enantioselectivity may substantially depend [9,10] or may be independent [11] on the lengths of hydrocarbon chain in homologous compounds or may depend on elec- tronic factors in other structurally related compounds [12]. In the present paper, we describe the synthesis and chromato- graphic behaviour of some new 1,4-disubstituted piperazines 1-7. Their chemical structures are shown in Scheme 1C. This series differ from the ones described before [9,10] in that they are monoamides of alkylmalonic, and alkylacetylacetic acids and in order to evaluate the structure–hypnotic activity rela- tionship of the pure enantiomers. [13–15] 2. Experimental 2.1. Materials Piperazine, diethyl malonate, 1-bromopropane, 1-bromo- butane, 1-bromopentane, 1-bromohexane and 1-bromo- * Corresponding author. Professor HassanY. Aboul-Enein, Pharmaceuti- cal Analysis Laboratory, Department of Biological and Medical Research (MBC 03-65), King Faisal Specialist Hospital & Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. E-mail address: enein@kfshrc.edu.sa (H.Y. Aboul-Enein). Il Farmaco 60 (2005) 439–443 http://france.elsevier.com/direct/FARMAC/ 0014-827X/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.farmac.2005.01.006