Structure–Retention Relationship in a Series of Chiral 1,4-Disubstituted Piperazine Derivatives on Carbohydrate Chiral Stationary Phases

Il Farmaco 60 (2005) 439–443 http://france.elsevier.com/direct/FARMAC/

Structure–Retention Relationship in a Series of Chiral 1,4-Disubstituted Piperazine Derivatives on Carbohydrate Chiral Stationary Phases Zdzisław Chilmonczyk a,b, Łukasz Sienicki a, Boz˙ena Łozowicka a, Małgorzata Lisowska-Kuz´micz b, Anna Jon´czyk b, Hassan Y. Aboul-Enein c,* a

Institute of Chemistry, University of Białystok, Piłsudskiego 11/4, 15-443 Białystok, Poland b National Institute of Public Health, Chełmska 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, Saudi Arabia 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(3,5dimethylphenylcarbamate) 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 diastereomeric 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 some 1,4disubstituted piperazines with hypnotic-sedative activity,

[9,10] malathione (a known insecticide) derivatives [11] and 3-amino-2-oxazolidinone derivatives with potential psychotropic activity [12] on cellulose and amylose chiral stationary 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 electronic factors in other structurally related compounds [12]. In the present paper, we describe the synthesis and chromatographic 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 relationship of the pure enantiomers. [13–15] 2. Experimental

* Corresponding author. Professor Hassan Y. Aboul-Enein, Pharmaceutical 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: [email protected] (H.Y. Aboul-Enein). 0014-827X/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.farmac.2005.01.006

2.1. Materials Piperazine, diethyl malonate, 1-bromopropane, 1-bromobutane, 1-bromopentane, 1-bromohexane and 1-bromo-

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Scheme 1. Synthesis of compounds 1-7.

heptane were purchased from Aldrich (Milwaukee, WI). 2-Chloropyrimidine was supplied by Fluka (Switzerland), anhydrous ethanol obtained from by POCH (Gliwice, Poland) and silica gel 60H from Merck (Darmstadt, Germany). Solvents of HPLC grade and chiral column were purchased from S. Witko. 2.2. Preparation of compounds 1-7 1-(2-Pyrimidyl)-piperazine (A) was obtained as described in [16]. 2-Alkylpropanedioic acid diethyl ester (B). To a solution of sodium ethanolate (1 eq.) and diethyl malonate (1 eq.) in anhydrous ethanol (65 ml), 1.11 eq. of 1-bromoalkane was added dropwise and the mixture was stirred at 50–60 °C for 12 h. The mixture was decanted and ethanol was removed under reduced pressure. The remaining oil was distilled under reduced pressure. 2-Propanepropanedioic acid diethyl ester. Bp 112– 115 °C (16 mmHg). Rf: 0.31 (hexane-AcOEt 90:10). 1H NMR (CDCl3, 200 MHz) d (ppm): 0.93 (t, J = 7,2 Hz, 3H); 1.25 (t, J = 3.7 Hz, 6H); 1.29–1.4 (m, 2H); 1.81–1.92 (m, 2H); 3.31 (t, J = 7.5 Hz, 1H); 4.19 (k, J = 7.1 Hz, 4H). 2-Butanepropanedioic acid diethyl ester. Bp 119– 123 °C (16 mmHg). Rf: 0.43 (hexane-AcOEt 90:10). 1H NMR

(CDCl3, 200 MHz) d (ppm): 0.89 (t, J = 6.6 Hz, 3H); 1.25 (t, J = 2.5 Hz, 6H); 1.28–1.33 (m, 4H); 1.83–1.94 (m, 2H); 3.21 (t, J = 7.5 Hz, 1H); 4.19 (k, J = 7,1 Hz, 4H). 2-Pentanepropanedioic acid diethyl ester. Bp 138– 144 °C (16 mmHg). Rf: 0.55 (hexane-AcOEt 90:10). 1H NMR (CDCl3, 200 MHz) d (ppm): 0.88 (t, J = 6.5 Hz, 3H); 1.26 (t, J = 7.2 Hz, 6H); 1.31–1.36 (m, 6H); 1.86–1.9 (m, 2H); 3.31 (t, J = 7.5 Hz, 1H); 4.19 (k, J = 7.1 Hz, 4H). 2-Hexanepropanedioic acid diethyl ester. Bp 156– 160 °C (16 mmHg). Rf: 0.58 (hexane-AcOEt 90:10). 1H NMR (CDCl3, 200 MHz) d (ppm): 0.87 (t, J = 6.4 Hz, 3H); 1.23– 1.29 (m, 14H, CH2); 1.82–1.93 (m, 2H); 3.3 (t, J = 7.5 Hz, 1H); 4.19 (k, J = 7.1 Hz, 4H). 2-Heptanepropanedioic acid diethyl ester. Bp168– 173 °C (16 mmHg). Rf: 0,.3 (hexane-AcOEt 90:10). 1H NMR (CDCl3, 200 MHz) d (ppm): 0.7 (t, J = 6. Hz, 3H); 1.25–1.3 (m, 16H, CH2); 1.86–1.89 (m, 2H); 3.3 (t, J = 7.5 Hz, 1H); 4.19 (k, J = 7.1 Hz, 4H). 1,4-Disubstituted piperazine (C). 1-(2-Pyrimidyl)piperazine A (1 eq.) was added to 2-alkylpropanedioic acid diethyl ester B (2 eq.). The mixture was stirred at boil temperature for 6–7 h. The product was purified by silica gel dry-column flash chromatography (hexane-AcOEt 75:25) to give oil. Ethyl 2-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]pentanoate (1). (0.661 g) 38% yield. Rf: 0.64 (hexaneAcOEt 50:50). 1H NMR (CDCl3, 200 MHz) d (ppm): 0.96 (t, J = 7.2 Hz, 3H); 1.26 (t, J = 7.1 Hz, 3H); 1.34–1.42 (m, 2H); 1.89–2.01 (m, 2H); 3.57–3.93 (m, 9H, CH); 4.20 (k, J = 7.1 Hz, 2H); 6,55 (t, J = 4.7 Hz, 1H); 8.35 (d, J = 4.8 Hz, 2H). 13C NMR (CDCl3, 50 MHz) d (ppm): 169.77 (C); 167.21 (C); 161.24 (C); 157.54 (CH); 110.30 (CH); 61.07 (CH2); 48.66 (CH); 45.49 (CH2); 43.49 (CH2); 43.27 (CH2); 41.84 (CH2); 30.91 (CH2); 20.53 (CH2); 13.96 (CH3); 13.67 (CH3). IR (CHCl3) m (cm–1): 2965; 2935; 2874; 1735; 1644; 1586; 1552; 1497; 1441; 1393; 1358; 1308; 1263; 1241; 1028; 983. GC (min) tR: 11.22. MS (EI, 70 eV) m/z (%): 320 (23, M+); 305 (6); 291 (10); 200 (3); 191 (15); 163 (26); 134 (79); 122 (86); 108 (100); 56 (41); 43 (14). HPLC (min): OJ t1 = 24.69; t2 = 26.18; AD t1 = 19.44; t2 = 21.06. Ethyl 2-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]hexanoate (2). (0.801 g) 48% yield. Rf: 0,40 (hexaneAcOEt 50:50). 1H NMR (CDCl3, 200 MHz) d (ppm): 0.90 (t, J = 6.9 Hz, 3H); 1.22–1.35 (m, 7H, CH2); 1.94 (m, 2H); 3.55– 3.91 (m, 9H, CH); 4.14 (k, J = 7.2 Hz, 2H); 6.55 (t, J = 4.8 Hz, 1H); 8.33 (d, J = 4.7 Hz, 2H). 13C NMR (CDCl3, 50 MHz) d (ppm): 169.74 (C); 167.18 (C); 161.18 (C); 157.50 (CH); 110.26 (CH); 61.01 (CH2); 48.83 (CH); 45.45 (CH2); 43.44 (CH2); 43.22 (CH2); 41.80 (CH2); 29.41 (CH2); 28.54 (CH2); 22.26 (CH2); 13.92 (CH3); 13.61 (CH3). IR (CHCl3) m (cm–1): 2962; 2931; 2862; 1735; 1644; 1586; 1552; 1497; 1442; 1393; 1358; 1308; 1251; 1235; 1022; 983. GC (min) tR: 11.57. MS (EI, 70 eV) m/z (%): 334 (20, M+); 291 (9); 214 (3); 163 (28); 134 (79); 122 (94); 108 (100); 56 (40); 43 (14). HPLC (min): OJ t1 = 17.98; t2 = 19.98; AD t1 = 19.45; t2 = 20.80.

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Ethyl 2-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]heptanoate (3). (1.278 g) 77% yield. Rf: 0.64 (hexaneAcOEt 50:50). 1H NMR (CDCl3, 200 MHz) d (ppm): 0.88 (t, J = 6.5 Hz, 3H); 1.23–1.32 (m, 9H, CH2); 1.93–1.96 (m, 2H); 3.55–3.92 (m, 9H, CH); 4.19 (k, J = 7.2 Hz, 2H); 6.55 (t, J = 4.8 Hz, 1H); 8.33 (d, J = 4.8 Hz, 2H). 13C NMR (CDCl3, 50 MHz) d (ppm): 169.77 (C); 167.21 (C); 161.23 (C); 157.53 (CH); 110.29 (CH); 61.04 (CH2); 48.91 (CH); 45.48 (CH2); 43.48 (CH2); 43.26 (CH2); 41.84 (CH2); 31.34 (CH2); 28.82 (CH2); 26.95 (CH2); 22.15 (CH2); 13.95 (CH3); 13.74 (CH3). IR (CHCl3) m (cm–1): 2960; 2930; 2860; 1731; 1644; 1586; 1552; 1497; 1441; 1393; 1358; 1308; 1263; 1243; 1181; 1115; 1017; 983. GC (min) tR: 12.05. MS (EI, 70 eV) m/z (%): 348 (18, M+); 291 (9); 231 (3); 228 (3); 163 (28); 134 (74); 122 (100); 108 (97); 56 (40); 43 (16). HPLC (min): OJ t1 = 15.88; t2 = 17.58; AD t1 = 18.98; t2 = 20.20. Ethyl 2-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]octanoate (4). (1.31 g) 80% yield. Rf: 0.61(hexane-AcOEt 50:50). 1 H NMR (CDCl 3 , 200 MHz) d (ppm): 0.87(t, J = 6.2 Hz, 3H); 1.23–1.30 (m, 11H, CH2); 1.94–1.96 (m, 2H); 3.55–3.92 (m, 9H, CH); 4.19 (k, J = 7.1 Hz, 2H); 6.54 (t, J = 4.7 Hz, 1H); 8.33 (d, J = 4.7 Hz, 2H). 13C NMR (CDCl3, 50 MHz) d (ppm): 169.87 (C); 167.31 (C); 161.29 (C); 157.62 (CH); 110.37 (CH); 61.15 (CH2); 49.02 (CH); 45.56 (CH2); 43.55 (CH2); 43.34 (CH2); 41.92 (CH2); 31.39 (CH2); 28.95 (CH2); 28.92 (CH2); 27.34 (CH2); 22.37 (CH2); 14.04 (CH3); 13.88 (CH3). IR (CHCl3) m (cm–1): 2959; 2929; 2859; 1731; 1644; 1586; 1552; 1497; 1441; 1393; 1358; 1308; 1263; 1237; 1020; 983. GC (min) tR: 12.31. MS (EI, 70 eV) m/z (%): 362 (11, M+); 291 (8); 242 (2); 163 (26); 134 (69); 122 (100); 108 (90); 56 (40); 43 (17). HPLC (min): OJ t1 = 14.84; t2 = 16.45; AD t1 = 19.24; t2 = 19.24. Ethyl 2-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]nonanoate (5). (1.2 g) 75% yield. Rf: 0.60 (hexane-AcOEt 50:50). 1H NMR (CDCl3, 200 MHz) d (ppm): 0.87 (t, J = 6.22 Hz, 3H); 1.22–1.30 (m, 13H, CH2); 1.94 (m, 2H); 3.55–3.92 (m, 9H, CH); 4.19 (k, J = 7.1 Hz, 2H); 6.55 (t, J = 4.8 Hz, 1H); 8.33 (d, J = 4.8 Hz, 2H). 13C NMR (CDCl3, 50 MHz) d (ppm): 169.74 (C); 167.18 (C); 161.20 (C); 157.50 (CH); 110.26 (CH); 61.01 (CH2); 48.88 (CH); 45.46 (CH2); 43.45 (CH2); 43.24 (CH2); 41.81 (CH2); 31.47 (CH2); 29.11 (CH2); 28.84 (CH2); 28.76 (CH2); 27.27 (CH2); 22.31 (CH2); 13.93 (CH3); 13.80 (CH3). IR (CHCl3,) m (cm–1): 2959; 2928; 2857; 1732; 1644; 1586; 1552; 1497; 1441; 1393; 1358; 1308; 1236; 983. GC (min) tR: 12.69. MS (EI, 70 eV) m/z (%): 377 (12); 291 (9); 256 (3); 163 (26); 134 (66); 122 (100); 108 (84); 56 (34); 43 (19). HPLC (min): OJ t1=13.20; t2 = 15.17; AD t1 = 18.63; t2 = 18.63. Ethyl (2RS)-2-{[(2S)-2-methyl-4-pyrimidin-2-ylpiperazin-1-yl] carbonyl} heptanoate (6). (0.239 g). 36% yield. Rf: 0.64 (hexane-AcOEt 50:50). 1H NMR (CDCl3, 200 MHz) d (ppm): 0.88 (t, J = 6.7 Hz, 3H, CH3); 1.19–1.31 (m, 12H, CH2, CH3); 1.99–2.05 (m, 2H, CH2); 2.97–3.81 (m, 5H, CH, CH2); 4.14–4.18 (m, 2H, CH2); 4.52–4.65 (m, 2H, CH2); 4.71–4.91 (m, 1H, CH); 6.53 (t, J = 4.7 Hz, 1H, CH); 8.31 (d, J = 4.7 Hz, 2H, CH). 13C NMR (CDCl3, 50 MHz) d (ppm):

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170.06 (C); 170.04 (C); 167.48 (C); 167.23 (C); 161.94 (C); 157.76 (CH); 110.20 (CH); 61.28 (CH2); 61.22 (CH2); 49.44 (CH); 49.35 (CH); 47.57 (CH2); 47.22 (CH2); 45.77 (CH); 45.55 (CH); 43.43 (CH2); 43.28 (CH2); 40.76 (CH2); 31.58 (CH2); 31.54 (CH2); 29.48 (CH2); 29.24 (CH2); 27.28 (CH2); 27.15 (CH2); 22.38 (CH2); 16.72 (CH3); 15.46 (CH3); 14.83 (CH3); 14.80 (CH3); 13.92 (CH3). IR (CHCl3) m (cm–1): 2960; 2930; 2859; 1732; 1639; 1587; 1552; 1504; 1452; 1433; 1366; 1268; 1179; 1014. GC (min) tR: 11.90. MS (EI, 70 eV) m/z (%): 362 (19, M+); 228 (7); 177 (36); 163 (9); 134 (53); 122 (100); 108 (34); 56 (11); 43 (15). HPLC (min): OJ t1 = 11.11; t2 = 11.11; AD t1 = 15.66; t2 = 18.84. Ethyl (2RS)-2-{[(2R)-2-methyl-4-pyrimidin-2-ylpiperazin-1-yl] carbonyl} heptanoate (7). (0.593 g). 48% yield. Rf: 0.70 (hexane-AcOEt 50:50). 1H NMR (CDCl3, 200 MHz) d (ppm): 0.88 (t, J = 6.7 Hz, 3H, CH3); 1.15–1.31 (m, 12H, CH2, CH3); 1.95–2.05 (m, 2H, CH2); 2.96–3.78 (m, 5H, CH, CH2); 4.13–4.18 (m, 2H, CH2); 4.52–4.65 (m, 2H, CH2); 4.71–4.91 (m, 1H, CH); 6.54 (t, J = 4.7 Hz, 1H, CH); 8.31 (d, J = 4.7 Hz, 2H, CH). 13C NMR (CDCl3, 50 MHz) d (ppm): 170.08 (C); 170.04 (C); 167.52 (C); 167.20 (C); 161.99 (C); 157.72 (CH); 110.24 (CH); 61.26 (CH2); 61.18 (CH2); 49.43 (CH); 49.31 (CH); 47.50 (CH2); 47.26 (CH2); 45.72 (CH); 45.51 (CH); 43.49 (CH2); 43.26 (CH2); 40.79 (CH2); 31.57 (CH2); 31.54 (CH2); 29.45 (CH2); 29.04 (CH2); 27.24 (CH2); 27.10 (CH2); 22.37 (CH2); 16.78 (CH3); 15.44 (CH3); 14.87 (CH3); 14.87 (CH3); 13.94 (CH3). IR (CHCl3) m (cm–1): 2961; 2931; 2859; 1731; 1639; 1587; 1552; 1504; 1452; 1378; 1366; 1325; 1268; 1049; 1014. GC (min) tR: 11.97. MS (EI, 70 eV) m/z (%): 362 (11, M+); 228 (9); 177 (42); 163 (10); 134 (57); 122 (100); 108 (37); 56 (11); 43 (13). HPLC (min): OJ t1 = 10.91; t2 = 10.91; AD t1 = 15.20; t2 = 17.52. 2.3. Chromatography The HPLC analyses were performed using a Shimadzu liquid chromatograph consisting of a LC-10AS pump, variable wavelength UV SPD-10A detector and Valco (Cincinatti, Ohio) valve injector equipped with 20 µl loop. Daicel Chiralcel OJ (10 µ, 4,6 mm × 250 mm) column packed with silica coated with cellulose tris(4-methylbenzoate) and Daicel Chiralpak AD (10 µ, 4,6 mm × 250 mm) column packed with on silica coated with amylose tris(3,5-dimethylphenylcarbamate) were used and were obtained from Daccol Industries (Tokyo, Japan). The mobile phases were the mixtures of hexane/propan-2-ol [80:20; 90:10; 95:5; 99:1 (v/v)]. All chromatograms were recorded at room temperature with a flow rate of 1 ml min–1 [100:0 (v/v); 0,22 ml min–1 ], using a UV detector set at 242 nm. The system hold-up time (tm) was determined as the first baseline disturbance due to the elution of 1,3,5 tert-butyl benzene. The reported retention factors are the means of three replicate determinations.

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3. Results and discussion Compounds 1-7 were synthesized according to Scheme 1. Ethyl (2RS)-2-{[(2S)-2-methyl-4-pyrimidin-2-ylpiperazin-1yl]carbonyl}heptanoate (6) and ethyl (2RS)-2-{[(2R)-2methyl-4-pyrimidin-2-ylpiperazin-1-yl]carbonyl}heptanoate (7) were prepared from homochiral (S)- and (R)-4pyrimidin-2-yl-2-methylpiperazine fragments, respectively, and 2-pentylmalonate. Compounds 6 and 7 existed as diastereomeric pairs of compounds (2R,2’S&2S,2’S and 2S,2’R&2R,2’R, respectively), each pair being enantiomeric to the other. The chromatographic behaviour of compounds 1-7 was examined on two polysaccharide stationary phases namely cellulose tris(4-methylbenzoate) and amylose tris(3,5dimethylcarbamate) under different conditions (Table 1). Enantiomeric resolution of homologous compounds 1-5 was achieved on cellulose tris(4-methylbenzoate) with hexanepropan-2-ol (5%, v/v) with enantioselectivities ranging from 1.06 to 1.15 (Table 1). The resolution of compounds 6 and 7 into diastereomeric (2R,2’S&2S,2’S and 2S,2’R&2R,2’R for compounds 6 and 7, respectively) as well as enantiomeric (2R,2’S(6)&2S,2’R(7) and 2S,2’S(6)&2R,2’R(7)) pairs was obtained on amylose tris(3,5-dimethylcarbamate) with hexane-2-propanol 95:5 (v/v) as mobile phase with diastereoselectivities of ranging from 1.20 and 1.15, respectively. Because enantiomeric pairs were not identified, it was not possible to decide about enantioselectivities but in principle they could be either 1.11 and 1.24 or 1.08 and 1.03. For compounds 1-5, the retention factors of their enantiomers diminished together with the growing number of carbon atoms in R aliphatic substituent (Fig. 1) reflecting growing steric and/or hydrophobic interactions of the substituents and the enantioselectivity was almost constant for the whole series of compounds. The result was different from that obtained on the very same stationary phase for acetylacetic acid derivatives of A where the retention factor for the strongly retained enantiomers grew initially with the growing number of carbon atoms giving thus maximum of enantioselectivity for 3–6 carbon atoms in the R aliphatic chain [9,10]. On amylose tris(3,5-dimethylphenylcarbamate) only compounds 1-3 were resolved into their respective enantiomers. The retention factors for compounds 1-5 exhibited lesser dependence on the carbon chain length in R substituent (changing from

Fig. 1. The relationship between alkyl chain length and retention factors for compounds 1-7 on cellulose tris(4-methylbenzoate) (solid lines) and amylose tris(3,5-dimethylcarbamate) (dashed lines) with hexane-2-propanol 95:5 (v/v) mobile phase; flow rate 1 ml/ min–1; room temperature; k = 242 nm.

6.15 to 6.93 for more retained enantiomers) than it was observed on cellulose stationary phase (where the corresponding factors changed from 4.76 to 8.22 for). Thus the destabilising effect of aliphatic R chain appeared to be much stronger on cellulose than on amylose chiral stationary phase. It has been suggested for compounds of the general structure C that probably it is not the difference between cellulose and amylose configuration (linear versus helical, respectively) that influences the enantioselectivity [10]. The difference in the compounds behaviour on both stationary phases could be explained by considering that carbamates may form hydrogen bonds with appropriate acceptors via the amide hydrogen atom. Accordingly, hydrogen bond formation between the NH-carbamate group of the stationary phase and a carbonyl group of the solute may thus be considered (Fig. 2). The bond does not seem to be much influenced by the steric and hydrophobic factors. On the other hand, on cellulose tris(4methylbenzoate) where a hydrogen bond between the solutes and the stationary is not formed, steric and hydrophobic factors seem to influence to a greater extent solute-stationary phase complex stabilisation. Data obtained for compounds 6 and 7 (possessing a pentyl (C5H11) substituent similar to compound 3) suggest that introducing a methyl substituent into the piperazine ring brings about much bigger solute-stationary phase complex destabilisation (on both examined stationary

Table 1 Retention factors and selectivities for compounds 1-7 on cellulose tris(4-methylbenzoate) (entries 1–15) and amylose tris(3,5-dimethylcarbamate) (entries 16-18) with hexane-2-propanol mobile phases; flow rate 1 ml/min–1; room temperature; k = 242 nm Mobile phase Entry Compound 1 2 3 4 5 6 7

1 k1 0.50 0.40 0.39 0.39 0.33 0.20 0.22

0:100 2 k2 0.50 0.40 0.39 0.39 0.39 0.26 0.22

3 a 1.00 1.00 1.00 1.00 1.18 1.28 1.00

4 k1 1.40 1.13 0.82 0.80 0.84 0.67 0.64

80:20 5 k2 1.40 1.13 0.82 0.80 0.84 0.67 0.64

6 a 1.00 1.00 1.00 1.00 1.00 1.00 1.00

7 k1 3.82 2.66 2.35 2.15 1.93 1.68 1.63

90:10 8 k2 3.82 2.85 2.35 2.15 2.13 1.68 1.63

9 a 1.00 1.07 1.00 1.00 1.10 1.00 1.00

10 k1 7.75 5.64 4.99 4.65 4.15 3.49 3.40

95:5 11 k2 8.20 6.26 5.53 5.20 4.76 3.49 3.40

12 a 1.06 1.11 1.11 1.11 1.15 1.00 1.00

13 k1 23.9 20.5 23.12 21.66 13.86 10.26 12.49

99:1 14 k2 25.17 20.50 23.12 26.35 17.94 10.26 12.41

15 a 1.05 1.00 1.00 1.22 1.29 1.00 1.14

16 k1 6.39 6.39 6.22 6.32 6.15 5.15 4.98

95:5 17 k2 6.93 6.83 6.62 6.32 6.15 6.20 5.74

18 a 1.08 1.07 1.06 1.00 1.00 1.20 1.15

Z. Chilmonczyk et al. / Il Farmaco 60 (2005) 439–443 [6] [7]

[8]

[9]

[10]

Fig. 2. The schematic structure of hydrogen bonds between amylose tris(3,5dimethylcarbamate) and 1,4-disubstituted piperazines.

phases, at least for the less retained enantiomers) than addition of one carbon atom to R substituent (compound 3 versus 4).

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