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Synthesis and enantioseparation of derivatives of propranolol

Synthesis and enantioseparation of derivatives of propranolol DOI: 10.2478/v10219-012-0012-x ACTA FACULTATIS PHARMACEUTICAE UNIVERSITATIS COMENIANAE Tomus LIX 2012 SYNTHESIS AND ENANTIOSEPARATION OF DERIVATIVES OF PROPRANOLOL Cizmáriková, R. ­ Chudáciková, S. ­ Valentová, J. ­ Némethy, A. Comenius University in Bratislava, Faculty of Pharmacy, Department of Chemical Theory of Drugs, Propranolol is one of the first prepared and in therapeutic praxis used beta- adrenolytics. In this paper novel derivatives of propranolol with cyclohexylamino and pyrrolidin-1-yl groups in hydrophilic part were prepared. HPLC-enantioseparation propranolol (as reference compound) and of the prepared derivatives has been achieved using a Chiralpak AD CSP based on the amylose tris (3,5-dimethylphenylcarbamate).(R)-enantiomer of the propranolol was prepared by stereoselective synthesis using Jacobsen catalyst. Keywords: propranolol ­ -blockers ­ enantioseparation ­ HPLC ­ Chiralpak AD CSP INTRODUCTION Propranolol is the nonselective adrenergic antagonist (1, 2 - blocker) and can be used in the treatment of angina pectoris and hypertension. This drug can be also used in the treatment or prevention hyperthyroidism, migraine, pheochromocytoma, menopause, and anxiety (Crowter&Smith, 1968, Florenz et al., 1969, Cizmáriková, 2002). Several of derivatives of propranolol with different substitution in hydrophilic part of molecule (piperazine, piperidine, 2-methylpiperidine and morpholine moieties) were studied on the anticonvulsive activity (Fischer, 2002, Lohman, 1990). Propranolol and its derivatives present an aryloxyaminopropanol structure and have been prepared in two steps from -naphthol. Reaction of -naphthol with chloromethyloxirane was obtained 1-naphthoxymethyloxirane, which in the next step with amines gives racemic bases (Bruchatá et al., 2006, Eshghi&Porkar, 2003). Propranolol is chiral molecule and their (S)-(-)-enantiomer is 100 more active than (R)(+)-enantiomer [9]. Moreover (R)-(-)-propranolol is known to act as a contraceptive (Bevinakatti&Banerji, 1991). 5 The most widely used technique for separation and quantification of enantiomers is enantioselective HPLC. Chiral separation by liquid chromatography can be performed either indirectly using achiral derivatization agent forming diastereoisomeric pairs, which can be resolved under a chiral conditions or directly using chiral stationary phases (Bojarski, 2012). There are many of chiral selectors used for separation of -blockers. Chiral separation of propranolol and analogues can be performed using different chiral stationary phases with proteins (Bojarski, 2012), cyclodextrins (Mathett et al., 1996), and/or cellulose tris(substituted phenylcarbamate) (Aboul-Enein&Bakr, 1998), macrocyclic antibiotics as vancomycin, teicoplanin (Cizmáriková et al., 2005). (R)-propranolol was prepared by stereoselective synthesis using the Jacobsen catalyst. Racemic 1-naphthoxymethyloxirane reacted with catalyst [(R, R)-N, N'-bis (3,5-di-tertbutylsalicylidene)-1,2 diaminato-cyclohexane-(2 -)] cobalt and by kinetic resolution gives the (S)-1-naphthoxymethyloxirane and the (R)-1-naphthoxypropane-1,2-diol. In the following reaction enantioselective 1-naphtoxymethyloxirane with isopropylamine gives (R)-(+)-propranolol. EXPERIMENTAL The melting points were determined using a Kofler Micro Hot Stage and were quated uncorrected. The purity of the newly prepared compounds was assessed using silicagel plates UV 254 (Merck) and the solvent system of ethylacetate:diethylamine (9:1 v/v) was used. UV spectra were run on spectrophotometer Hewlett-Packard 8452 in methanol. IR spectra were recorded using FTIP IMPACT 400 D (Nicolett) spectrometer in KBr tablets. 1H NMR were recorded on the Varian Gemini 2000 Spectrometer operating at 300 MHz for protons. Synthesis Isopropylamino-3-(1-naphthoxy)propan-2-ol, 1-cyclohexylamino-3-(1naphthoxy)propan-2-ol, 1-pyrrolidin-1-yl-3-(1-naphthoxy)propan-2-ol, were prepared reaction obtained 1-naphthoxyoxirane intermediate with amines (isopropylamine, cyclohexylamine and pyrrolidine) according to [7,8]. Stereoselective (R)-enantiomer of propranolol was prepared using Jacobsen catalyst according to [15]. Yield 55 %. M.p.86-88 °C, []D20 = -12.5° (1% CH3OH). HPLC-chromatography Instruments HPLC system AGILENT 1200, consisting of a quaternary pump and diode detector. High-performance liquid chromatography (HPLC) was carried out using the chiral stationary phases (Chiralpac AD) based on the amylose tris (3,5-dimethylphenylcarbamate) (0.46x25). The mobile phase consisted of hexane/ethanol/methanol/diethylamine 78/ 11/11/0.1, 80/3.75/11.25/0.1, 80/10/10/0.1, 85/2.5/7.5/0.1, 85/3.75/11.25/0.1, 90/2.5/7.5/0.1 v/v/v/v. Samples for analysis were prepared as approximately 1mg .ml-1 solution in mobile phase. Separation were carried out at flow rate of 0.8 ml /min and the column temperature was maintained at 25 ºC. Chromatograms were scanned at wavelength 267nm ±8nm. Chromatographic characteristics The separation factor was expressed as = k2/k1, where k1,k2 are retention factors for the first and second eluting enantiomer. The retention factor k´ was calculated as follows. k1= (t1-t0)/ t0 and k2= (t2-t0)/ t0, where t0 , t1 and t2 are the dead elution time and elution time of enantiomers 1 and 2. The stereochemical resolution factor (Rs) of the first and second eluting enantiomer was calculated by the ratio of the difference between the retention times t1 and t2 to the arithmetic mean of the two peaks widths w1 and w2: RS=2 (t2-t1) / (w1+ w2). Chemicals All HPLC grade solvents were obtained from Merck (Germany). RESULTS AND DISCUSSION The aim of this study was to prepare new derivatives of propranolol (1isopropylamine-3-(1-naphthoxy)propan-2-ol) with cyclohexylamino and pyrrolidin-1-yl in basic part of molecule. New compounds were prepared by a two-step synthesis from -naphthol. 1-Naphthoxymethyloxirane intermediate prepared by the reaction naphthol with chloromethyloxirane with amine (cyclohexylamine, pyrrolidine) gives final products. These were isolated in the form of free bases or salts with fumaric acid (Table 1). Table 1. Physico-chemical parameters of prepared compounds OH O CH2 CH CH2 R Compound R Form of compound NHCH(CH3)2 base NHCH(CH3)2 fumarate HN I Ia II Summary formula vzorec C16H21O2N C36H46O8N2 C15H23O2N C42H56O8N2 Mr [g/mol] 259.35 634.77 249.35 M.p. [°C] 93-95C A 182-184 B 84-86 A 175-177 B Yield [%] 77 0.37 base IIa HN fumarate 7 III C17H21O2N C38H46O8N2 71-72 A 134-136 B base IIIa fumarate a- hexane, b-ethylacetate c- m.p.= 95 (Schaus et al., 2002) The purity of the final products was checked by TLC in mobile phase ethylacetate:diethylamine (9:1 v/v). Structures of prepared compounds were confirmed by IR, UV and 1H-NMR spectra (Tables 2, 3, 4). The stretching vibration of the characteristic group in the IR spectra were (OH), (NH) (base), (C=C), (CAl=CAr) (Table 2). Table 2. Values of max and log in UV spectra, = m2mol-1 log 1 max 2 log 2 Compounds max 1 [nm] [nm] I 290 2.74 230 3.48 II 292 2.82 230 3.53 III 288 2.83 230 3.47 max 3 [nm] 214 214 214 log 3 3.62 3.66 3.61 The UV spectra of bases display bands corresponding to transition at max =214290 nm, log = 2.74-3.66 (Table 3). Table 3. Values of streching vibration in IR spectra of prepared bases Compounds (OH) (NH) (CH) (C=C) [cm-1] [cm-1] [cm-1] [cm-1] I 3427 3269 2924-2963 1582, 1596, 1630 II 3417 3278 2927 1582, 1596, 1630 III 3421 2952, 1578 2875, 2818 (ArOalk) [cm-1] 1242 1241 1239 H-NMR spectra of free bases showed proton signals of the aminopropanol chain (Table 4). Table 4. 1H NMR spectral data of bases (ppm) Compound [ppm] I Number of protons multiplicity Ar-H2 Ar-H5 Ar-H8 ArOCH2CH(OH)CH2 ArOCH2CH(OH)CH2 ArOCH2CH(OH)CH2 (CH3)CH-NH NHCHCH2CH2-kruh NHCHCH2-kruh NCH2 NCH2CH2 6.81 7.80 8.22 4.21 3.96 2.82 1.11 1H, d 1H, d 1H, d 2H, d 1H, m 2H, d 3H, d 6.74 7.80 8.25 4.21 3.96 3.52 1.25 1.71 [ppm] II Number of protons multiplicity 1H, d 1H, d 1H, d 2H, d 1H, m 2H, d 2H, m 2H, m 8.26 4.19 3.81 2.66 2.55 1.26 6.79 1H, d 1H, d 1H, d 2H, d 1H, m 2H, d 2H, t 2H, m [ppm] III Number of protons multiplicity The prepared compounds (II, III) possess as reference compound propranolol a stereogenic centre and exist in form of two stereoisomers. It thus seems advisable to resolve the racemic mixture and show the express some chromatographic characteristic of each enantiomer. The HPLC method used in this study employed a derivative amylose as chiral stationary phase and a mixture of hexane:ethanol:methanol:diethylamine at different ratio as mobile phase. The results of an enantioseparation are summarised in Table 5. It is evident that is no significant difference in the separation of the enantiomers on the used chiral stationary phase. Stereoselective (R)-enantiomer of propranolol was prepared using the Jacobsen catalyst. Racemic 1-naphthoxymethyloxirane reacted with catalyst [(R, R)-N, N'-bis (3,5-di-tertbutylsalicylidene) -1,2 diaminato-cyclohexane-(2 -)] cobalt and was kinetic resolved in its (S)-1-naphthoxymethyloxirane and (R)-3-naphthoxypropane-1,2-diol. (S)-1naphthoxymethyloxirane by reaction with isopropylamine gives (R)-(+)-propranolol. Chromatograms of the prepared derivatives II, III show two peaks as reference com pound propranolol I (Table 5, Figures 1, 2, 3). Table 5. Chromatographic data for enantioseparation of the prepared compounds on bonded chiral stationary phases Compounds t1 t2 k1 k2 RS Mobile phase [min] [min] I A 6.13 10.15 0.59 1.64 2.70 5.36 I B 6.77 11.85 0,76 2,97 3,90 8,46 II C 6.36 10,42 1,22 2,63 1,41 4,39 II D 5.30 8.10 0.81 1.77 2.18 4.34 III ED 8.78 11.41 1.28 1.96 1.53 2.97 III F 7.27 10.79 0.93 1.86 2.00 6.40 A - Mobile phase: hexane:ethanol:methanol:diethylamine 80/3,75/11.25/0.1 at compound I B - Mobile phase: hexane:ethanol:methanol:diethylamine 85/3,75/11.25/0.1 at compound I C - Mobile phase: hexane:ethanol:methanol:diethylamine 90/2.5/7.5/0.1 at compound II D - Mobile phase: hexane:ethanol:methanol:diethylamine 85/2,5/7.5/0.1 at compound II E - Mobile phase: hexane:ethanol:methanol:diethylamine 80/ 10/10/01 at compound III F - Mobile phase: hexane:ethanol:methanol:diethylamine 78/11/11/01 at compound III In the used mobile phases was separation of compounds II and III on base line with the separation factors in the range 3.90-1.41 and with resolution factor RS in the range 6.40-2.97. In the paper (Valentová et al., 2003) racemic propranolol was semipreparative resolved on the CHIRALPAC AD using hexane:ethanol:methanol:dietylamine 85/3.75/11/0.1 v/v/v/v as mobile phase in 99% enantiomeric purity and subsequent using chiroptical characterization was determined absolute configuration the separated enantiomers. The enantiomeric elution order was determined to be (R)- before (S)-enantiomer induced CD complexes formed in situ with molybdenum tetraacetate. DAD1 A, Sig=247,4 Ref=400,100 (14_06_2011\FLU000002.D) 11.902 6.725 mAU min Figure 1. Separation of enantiomers of compound I (propranolol) DAD1 B, Sig=265,8 Ref=400,100 (CHIR_BBLOK\10_06_2009\BBLOC000000.D) 5 .3 0 1 mAU 14 0 6 8 10 12 14 16 min Figure 2 Separation of enantiomers of compound II DAD1 A, Sig=247,4 Ref=400,100 (29_10_2010A\013-1301.D) 7 .2 7 4 mAU min Figure 3 Separation of enantiomers of compound III http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Facultatis Pharmaceuticae Universitatis Comenianae de Gruyter

Synthesis and enantioseparation of derivatives of propranolol

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Abstract

DOI: 10.2478/v10219-012-0012-x ACTA FACULTATIS PHARMACEUTICAE UNIVERSITATIS COMENIANAE Tomus LIX 2012 SYNTHESIS AND ENANTIOSEPARATION OF DERIVATIVES OF PROPRANOLOL Cizmáriková, R. ­ Chudáciková, S. ­ Valentová, J. ­ Némethy, A. Comenius University in Bratislava, Faculty of Pharmacy, Department of Chemical Theory of Drugs, Propranolol is one of the first prepared and in therapeutic praxis used beta- adrenolytics. In this paper novel derivatives of propranolol with cyclohexylamino and pyrrolidin-1-yl groups in hydrophilic part were prepared. HPLC-enantioseparation propranolol (as reference compound) and of the prepared derivatives has been achieved using a Chiralpak AD CSP based on the amylose tris (3,5-dimethylphenylcarbamate).(R)-enantiomer of the propranolol was prepared by stereoselective synthesis using Jacobsen catalyst. Keywords: propranolol ­ -blockers ­ enantioseparation ­ HPLC ­ Chiralpak AD CSP INTRODUCTION Propranolol is the nonselective adrenergic antagonist (1, 2 - blocker) and can be used in the treatment of angina pectoris and hypertension. This drug can be also used in the treatment or prevention hyperthyroidism, migraine, pheochromocytoma, menopause, and anxiety (Crowter&Smith, 1968, Florenz et al., 1969, Cizmáriková, 2002). Several of derivatives of propranolol with different substitution in hydrophilic part of molecule (piperazine, piperidine, 2-methylpiperidine and morpholine moieties) were studied on the anticonvulsive activity (Fischer, 2002, Lohman, 1990). Propranolol and its derivatives present an aryloxyaminopropanol structure and have been prepared in two steps from -naphthol. Reaction of -naphthol with chloromethyloxirane was obtained 1-naphthoxymethyloxirane, which in the next step with amines gives racemic bases (Bruchatá et al., 2006, Eshghi&Porkar, 2003). Propranolol is chiral molecule and their (S)-(-)-enantiomer is 100 more active than (R)(+)-enantiomer [9]. Moreover (R)-(-)-propranolol is known to act as a contraceptive (Bevinakatti&Banerji, 1991). 5 The most widely used technique for separation and quantification of enantiomers is enantioselective HPLC. Chiral separation by liquid chromatography can be performed either indirectly using achiral derivatization agent forming diastereoisomeric pairs, which can be resolved under a chiral conditions or directly using chiral stationary phases (Bojarski, 2012). There are many of chiral selectors used for separation of -blockers. Chiral separation of propranolol and analogues can be performed using different chiral stationary phases with proteins (Bojarski, 2012), cyclodextrins (Mathett et al., 1996), and/or cellulose tris(substituted phenylcarbamate) (Aboul-Enein&Bakr, 1998), macrocyclic antibiotics as vancomycin, teicoplanin (Cizmáriková et al., 2005). (R)-propranolol was prepared by stereoselective synthesis using the Jacobsen catalyst. Racemic 1-naphthoxymethyloxirane reacted with catalyst [(R, R)-N, N'-bis (3,5-di-tertbutylsalicylidene)-1,2 diaminato-cyclohexane-(2 -)] cobalt and by kinetic resolution gives the (S)-1-naphthoxymethyloxirane and the (R)-1-naphthoxypropane-1,2-diol. In the following reaction enantioselective 1-naphtoxymethyloxirane with isopropylamine gives (R)-(+)-propranolol. EXPERIMENTAL The melting points were determined using a Kofler Micro Hot Stage and were quated uncorrected. The purity of the newly prepared compounds was assessed using silicagel plates UV 254 (Merck) and the solvent system of ethylacetate:diethylamine (9:1 v/v) was used. UV spectra were run on spectrophotometer Hewlett-Packard 8452 in methanol. IR spectra were recorded using FTIP IMPACT 400 D (Nicolett) spectrometer in KBr tablets. 1H NMR were recorded on the Varian Gemini 2000 Spectrometer operating at 300 MHz for protons. Synthesis Isopropylamino-3-(1-naphthoxy)propan-2-ol, 1-cyclohexylamino-3-(1naphthoxy)propan-2-ol, 1-pyrrolidin-1-yl-3-(1-naphthoxy)propan-2-ol, were prepared reaction obtained 1-naphthoxyoxirane intermediate with amines (isopropylamine, cyclohexylamine and pyrrolidine) according to [7,8]. Stereoselective (R)-enantiomer of propranolol was prepared using Jacobsen catalyst according to [15]. Yield 55 %. M.p.86-88 °C, []D20 = -12.5° (1% CH3OH). HPLC-chromatography Instruments HPLC system AGILENT 1200, consisting of a quaternary pump and diode detector. High-performance liquid chromatography (HPLC) was carried out using the chiral stationary phases (Chiralpac AD) based on the amylose tris (3,5-dimethylphenylcarbamate) (0.46x25). The mobile phase consisted of hexane/ethanol/methanol/diethylamine 78/ 11/11/0.1, 80/3.75/11.25/0.1, 80/10/10/0.1, 85/2.5/7.5/0.1, 85/3.75/11.25/0.1, 90/2.5/7.5/0.1 v/v/v/v. Samples for analysis were prepared as approximately 1mg .ml-1 solution in mobile phase. Separation were carried out at flow rate of 0.8 ml /min and the column temperature was maintained at 25 ºC. Chromatograms were scanned at wavelength 267nm ±8nm. Chromatographic characteristics The separation factor was expressed as = k2/k1, where k1,k2 are retention factors for the first and second eluting enantiomer. The retention factor k´ was calculated as follows. k1= (t1-t0)/ t0 and k2= (t2-t0)/ t0, where t0 , t1 and t2 are the dead elution time and elution time of enantiomers 1 and 2. The stereochemical resolution factor (Rs) of the first and second eluting enantiomer was calculated by the ratio of the difference between the retention times t1 and t2 to the arithmetic mean of the two peaks widths w1 and w2: RS=2 (t2-t1) / (w1+ w2). Chemicals All HPLC grade solvents were obtained from Merck (Germany). RESULTS AND DISCUSSION The aim of this study was to prepare new derivatives of propranolol (1isopropylamine-3-(1-naphthoxy)propan-2-ol) with cyclohexylamino and pyrrolidin-1-yl in basic part of molecule. New compounds were prepared by a two-step synthesis from -naphthol. 1-Naphthoxymethyloxirane intermediate prepared by the reaction naphthol with chloromethyloxirane with amine (cyclohexylamine, pyrrolidine) gives final products. These were isolated in the form of free bases or salts with fumaric acid (Table 1). Table 1. Physico-chemical parameters of prepared compounds OH O CH2 CH CH2 R Compound R Form of compound NHCH(CH3)2 base NHCH(CH3)2 fumarate HN I Ia II Summary formula vzorec C16H21O2N C36H46O8N2 C15H23O2N C42H56O8N2 Mr [g/mol] 259.35 634.77 249.35 M.p. [°C] 93-95C A 182-184 B 84-86 A 175-177 B Yield [%] 77 0.37 base IIa HN fumarate 7 III C17H21O2N C38H46O8N2 71-72 A 134-136 B base IIIa fumarate a- hexane, b-ethylacetate c- m.p.= 95 (Schaus et al., 2002) The purity of the final products was checked by TLC in mobile phase ethylacetate:diethylamine (9:1 v/v). Structures of prepared compounds were confirmed by IR, UV and 1H-NMR spectra (Tables 2, 3, 4). The stretching vibration of the characteristic group in the IR spectra were (OH), (NH) (base), (C=C), (CAl=CAr) (Table 2). Table 2. Values of max and log in UV spectra, = m2mol-1 log 1 max 2 log 2 Compounds max 1 [nm] [nm] I 290 2.74 230 3.48 II 292 2.82 230 3.53 III 288 2.83 230 3.47 max 3 [nm] 214 214 214 log 3 3.62 3.66 3.61 The UV spectra of bases display bands corresponding to transition at max =214290 nm, log = 2.74-3.66 (Table 3). Table 3. Values of streching vibration in IR spectra of prepared bases Compounds (OH) (NH) (CH) (C=C) [cm-1] [cm-1] [cm-1] [cm-1] I 3427 3269 2924-2963 1582, 1596, 1630 II 3417 3278 2927 1582, 1596, 1630 III 3421 2952, 1578 2875, 2818 (ArOalk) [cm-1] 1242 1241 1239 H-NMR spectra of free bases showed proton signals of the aminopropanol chain (Table 4). Table 4. 1H NMR spectral data of bases (ppm) Compound [ppm] I Number of protons multiplicity Ar-H2 Ar-H5 Ar-H8 ArOCH2CH(OH)CH2 ArOCH2CH(OH)CH2 ArOCH2CH(OH)CH2 (CH3)CH-NH NHCHCH2CH2-kruh NHCHCH2-kruh NCH2 NCH2CH2 6.81 7.80 8.22 4.21 3.96 2.82 1.11 1H, d 1H, d 1H, d 2H, d 1H, m 2H, d 3H, d 6.74 7.80 8.25 4.21 3.96 3.52 1.25 1.71 [ppm] II Number of protons multiplicity 1H, d 1H, d 1H, d 2H, d 1H, m 2H, d 2H, m 2H, m 8.26 4.19 3.81 2.66 2.55 1.26 6.79 1H, d 1H, d 1H, d 2H, d 1H, m 2H, d 2H, t 2H, m [ppm] III Number of protons multiplicity The prepared compounds (II, III) possess as reference compound propranolol a stereogenic centre and exist in form of two stereoisomers. It thus seems advisable to resolve the racemic mixture and show the express some chromatographic characteristic of each enantiomer. The HPLC method used in this study employed a derivative amylose as chiral stationary phase and a mixture of hexane:ethanol:methanol:diethylamine at different ratio as mobile phase. The results of an enantioseparation are summarised in Table 5. It is evident that is no significant difference in the separation of the enantiomers on the used chiral stationary phase. Stereoselective (R)-enantiomer of propranolol was prepared using the Jacobsen catalyst. Racemic 1-naphthoxymethyloxirane reacted with catalyst [(R, R)-N, N'-bis (3,5-di-tertbutylsalicylidene) -1,2 diaminato-cyclohexane-(2 -)] cobalt and was kinetic resolved in its (S)-1-naphthoxymethyloxirane and (R)-3-naphthoxypropane-1,2-diol. (S)-1naphthoxymethyloxirane by reaction with isopropylamine gives (R)-(+)-propranolol. Chromatograms of the prepared derivatives II, III show two peaks as reference com pound propranolol I (Table 5, Figures 1, 2, 3). Table 5. Chromatographic data for enantioseparation of the prepared compounds on bonded chiral stationary phases Compounds t1 t2 k1 k2 RS Mobile phase [min] [min] I A 6.13 10.15 0.59 1.64 2.70 5.36 I B 6.77 11.85 0,76 2,97 3,90 8,46 II C 6.36 10,42 1,22 2,63 1,41 4,39 II D 5.30 8.10 0.81 1.77 2.18 4.34 III ED 8.78 11.41 1.28 1.96 1.53 2.97 III F 7.27 10.79 0.93 1.86 2.00 6.40 A - Mobile phase: hexane:ethanol:methanol:diethylamine 80/3,75/11.25/0.1 at compound I B - Mobile phase: hexane:ethanol:methanol:diethylamine 85/3,75/11.25/0.1 at compound I C - Mobile phase: hexane:ethanol:methanol:diethylamine 90/2.5/7.5/0.1 at compound II D - Mobile phase: hexane:ethanol:methanol:diethylamine 85/2,5/7.5/0.1 at compound II E - Mobile phase: hexane:ethanol:methanol:diethylamine 80/ 10/10/01 at compound III F - Mobile phase: hexane:ethanol:methanol:diethylamine 78/11/11/01 at compound III In the used mobile phases was separation of compounds II and III on base line with the separation factors in the range 3.90-1.41 and with resolution factor RS in the range 6.40-2.97. In the paper (Valentová et al., 2003) racemic propranolol was semipreparative resolved on the CHIRALPAC AD using hexane:ethanol:methanol:dietylamine 85/3.75/11/0.1 v/v/v/v as mobile phase in 99% enantiomeric purity and subsequent using chiroptical characterization was determined absolute configuration the separated enantiomers. The enantiomeric elution order was determined to be (R)- before (S)-enantiomer induced CD complexes formed in situ with molybdenum tetraacetate. DAD1 A, Sig=247,4 Ref=400,100 (14_06_2011\FLU000002.D) 11.902 6.725 mAU min Figure 1. Separation of enantiomers of compound I (propranolol) DAD1 B, Sig=265,8 Ref=400,100 (CHIR_BBLOK\10_06_2009\BBLOC000000.D) 5 .3 0 1 mAU 14 0 6 8 10 12 14 16 min Figure 2 Separation of enantiomers of compound II DAD1 A, Sig=247,4 Ref=400,100 (29_10_2010A\013-1301.D) 7 .2 7 4 mAU min Figure 3 Separation of enantiomers of compound III

Journal

Acta Facultatis Pharmaceuticae Universitatis Comenianaede Gruyter

Published: Jan 1, 2012

References