Chiral separation on various modified amino alcohol‐derived HPLC chiral stationary phases

3,5‐Dinitrobenzoyl chloride was previously used for the preparation of (R)‐phenylglycinol‐ and (S)‐leucinol‐derived chiral stationary phases. In this study, 3,5‐bis(trifluoromethyl)benzoyl chloride, 2‐furoyl chloride, 2‐theonyl chloride, 10,11‐dihydro‐5H‐dibenzo[b,f]azepine‐5‐carbonyl chloride, diphenylcarbamoyl chloride, and 1‐adamantanecarbonyl chloride were used to prepare six new phenylglycinol‐derived chiral stationary phases (CSPs) and five new leucinol‐derived CSPs. Using these 11 CSPs, chiral separation of nine π‐acidic amino acid derivatives and five π‐basic compounds was performed, and the separation results were compared. An adamantyl‐derived CSP showed good separation. Chirality 28:276–281, 2016. © 2016 Wiley Periodicals, Inc.     

Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin.

The effects of 100 mg indomethacin daily for three weeks on blood pressure and urinary excretion of prostaglandin F2 alpha were studied in a double-blind, placebo-controlled comparison of two groups of patients with essential hypertension, eight receiving propranolol and seven thiazide diuretics. Compared with placebo, adding indomethacin to the patients'' established antihypertensive treatment increased blood pressure by 14/5 Hg supine and 16/9 mm Hg erect in the patients receiving propranolol, and by 13/9 mm Hg supine and 16/9 mm Hg erect in the patients receiving thiazide diuretics (all p less than or equal to 0.05). The excretion of the major urinary metabolite of prostaglandin F2 alpha was reduced by 67% in the propranolol-treated patients and by 57% in those receiving a thiazide diuretic. Body weight increased by 0 . 8 kg (propranolol) and 1 . 1 kg (thiazide diuretic) when indomethacin was given, but there were no significant changes in creatinine clearance, urinary sodium excretion, or packed cell volume in either treatment group. These results suggest that products formed by the arachidonic acid cyclo-oxygenase contribute to the regulation of blood pressure during treatment with both propranolol and thiazide diuretics. Inhibition of the cyclo-oxygenase with indomethacin partially antagonises the hypotensive effect of these drugs.     

Chiral HPLC analysis of milnacipran and its FMOC-derivative on cellulose-based stationary phases

The HPLC enantioseparation of the last generation antidepressive drug milnacipran (+/-)-1 was investigated on different cellulose-based chiral stationary phases (CSPs). On carbamate-type columns, Chiralcel OD and OD-H (+/-)-1 could be separated with alpha value about 1.20 but the resolution was quite low because of the tailing of the peaks. Direct determination of (+/-)-1 with high selectivity and resolution was obtained on Chiralcel OJ in normal phase mode elution. Precolumn derivatization of milnacipran with Fmoc-Cl gave compound (+/-)-2 which was enantioseparated on all the investigated CSPs and allowed enhanced UV or fluorimetric detection. The Chiralpak IB, that could be considered the immobilized version of Chiralcel OD-H, was found completely ineffective in the chiral recognition of (+/-)-1 and moderately efficient in the separation of (+/-)-2.     

Chiral separation of pheniramine-like 3-phenyl-3-heteroarylpropylamines by CE and HPLC methods

Analytical CE and HPLC methods were developed for the chiral separation of halogen-substituted 3-phenyl-3-(2-pyridyl)propylamines 1-4 (1: 3-(4-fluorophenyl) approximately, 2: 3-(3,4-difluorophenyl) approximately, 3: 3-(4-chlorophenyl) approximately, 4: 3-(3,4-dichlorophenyl) approximately ), 3-(4-fluorophenyl)-3-(2-thiazolyl)propylamine (5), and 3-(4-fluorophenyl)-3-(1-benzylimidazol-2-yl)propylamine (6), which are building blocks for the preparation of very potent arpromidine-type histamine H(2) receptor agonists. All amines were enantioseparated by CE with resolutions of at least 1.8 using alpha-, beta-, or gamma-cyclodextrin (CD) as chiral selectors. With heparin as buffer additive for CE the optical antipodes of 1-4 and 6 were separated with resolutions > or = 1.8. On RP-18 columns the separation of the (+)-(S)-acetylmandelic acid amides of racemic 2 (R = 0.9, alpha = 1.07) and the thioureas prepared by addition of 6 to 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (R = 2.0, alpha = 1.20) was successful, whereas the diastereomeric ureas prepared from 3 and (+)-(S)-1-(1-naphthyl)ethyl isocyanate could not be resolved. Separation of the diastereomeric isoindoles prepared from 1-5, o-phthaldialdehyde and 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranoside was achieved on a RP-18 phase (R > or = 0.4, a > or = 1.02). Direct separation of the enantiomers of 3 and 4 was achieved on a Cyclobond I column (R > or = 0.9, alpha > or = 1.07). alpha- and beta-CD were also useful as mobile phase additives for HPLC (3 and 4: RP-18 column, beta-CD, R > or = 0.4, alpha > or = 1.03; 3: RP-18 column, alpha-CD: R = 0.5, alpha = 1.04).     

Chiral separation of Frovatriptan isomers by HPLC using amylose based chiral stationary phase

A stereospecific HPLC method for separation of Frovatriptan enantiomers in bulk drug and pharmaceutical formulations was developed and validated on a normal-phase amylose derivertized chiral column. The effects of the organic modifiers namely 2-propanol, ethanol and diethyl amine (DEA) in the mobile phase were optimized to obtain the best enantiomeric separation. Calibration curves were linear over the range of 200-6150 ng/mL, with a regression coefficient (R(2)) of 0.9998. The limit of detection (LOD) and limit of quantification (LOQ) were 65 ng/mL and 200 ng/mL, respectively. The method was accurate and precise and suitable for the intended purpose. Analysis results were compared with the results obtained by using a validated chiral CE method and found to be in very good agreement. This method can be successfully applied to the enantiomeric purity analysis of Frovatriptan in pharmaceutical bulk drug samples and formulations.     

Chiral stationary phases in HPLC for the stereoselective determination of methadone

An extensive study of the behavior of three chiral stationary phases (CSP) used in liquid chromatography (LC) is presented for the stereoselective determination of methadone. The following chromatographic columns were selected: a cellulose, Chiralcel OJ; a modified cyclodextrin, Cyclobond I 2000 RSP, and a protein, Chiral‐AGP. Retention factors, enantioselectivity, efficiency, and resolution were tested by modifying the composition of the mobile phase as well as the temperature. The mechanism for the chiral recognition of methadone on each support was discussed. Optimal chromatographic parameters were obtained for the three supports tested, and methadone enantiomers were separated in less than 20 minutes. The cellulose‐based column gave the best resolution, but this CSP was not adapted to clinical analyses of methadone. Under optimized conditions, the cyclodextrin‐ and protein‐based columns allowed an excellent separation of methadone enantiomers, but no interference with the primary metabolite was found only with Chiral‐AGP. Chirality 11:319–325, 1999. © 1999 Wiley‐Liss, Inc.     

Direct enantioselective separation of some propranolol analogs by HPLC on normal and reversed cellulose chiral stationary phases

The enantiomeric separation of several racemic aryloxyaminopropan-2-ol derivatives related to propranolol on normal and reversed phase of cellulose tris (3,5-dimethylphenylcarbamate) chiral stationary phases known as Chiralcel OD and Chiralcel OD-R were studied. It was observed that the chiral separation depends on the substitution pattern of the aryl group, i.e., 1-naphthyl, 2-naphthyl, and phenyl group and polarity on the basic nitrogen in the side chain. In both normal and reversed phase modes the (+)-R-enantiomer eluted first in all of the analogs resolved. It can be concluded that: (1) substituents on the side chain did affect the interaction of the enantiomers with the polar carbamate moiety in the CSP; and (2) the dipole-dipole stacking between the π-donor 3,5-dimethylphenyl carbamate group pending from the glucose rings of the CSP and π-acceptor aryl group of the analyte is crucial for the efficient chiral discrimination. The chiral recognition mechanism(s) between these analogs and the chiral stationary phases are proposed. © 1996 Wiley-Liss, Inc.     

Enantiomeric separation of some piperidine-2,6-dione drugs using chiralcel OJ-R column

A newly developed reversed phase cellulose tris(4-methyl benzoate) known as Chiralcel OJ-R was used to investigate the chiral recognition and enantiomeric separation of eight racemic piperidine-2,6-dione compounds—namely, aminoglutethimide and its major metabolite acetylaminoglutethimide, glutethimide, cyclohexylamino-glutethimide, pyridoglutethimide, thalidomide, phenglutarimide, and 3-phenylacetyl-amino-2,6-piperidinedione (antineoplaston A-10). Chiral separation of these compounds was achieved under varying ratios of the mobile phase, except for phenglutarimide and 3-phenylacetylamino-2,6-piperidinedione, for which separation was unsuccessful. Possible chiral recognition mechanisms are also presented. Chirality 9:10–12, 1997. © 1997 Wiley-Liss, Inc.     

Enantiomer separation of fungicidal triazolyl alcohols by normal phase HPLC on polysaccharide‐based chiral stationary phases

Three fungicidal triazolyl alcohols (triadimenol, hexaconazole, and cis/trans‐1‐4‐chlorophenyl‐2‐1H‐1,2,4‐triazol‐1‐yl‐cycloheptanol) were completely separated into enantiomers by chiral HPLC using polysaccharide‐based chiral stationary phases. A better separation was achieved on cellulose and amylose carbamate phases compared with a cellulose ester phase. Peak shapes were almost symmetrical except for two cases, where tailing of the first eluted enantiomer and unusual symmetric peak broadening were observed. The effect of eluents on enantioseparation was also investigated. Chirality 11:195–200, 1999. © 1999 Wiley‐Liss, Inc.     

Carbamates of cellulose bonded on silica gel: Chiral discrimination ability as HPLC chiral stationary phases

Four cellulose mixed 10-undecenoate/carbamate derivatives, simultaneously bearing 10-undecenoyl and variously substituted phenylaminocarbonyl groups, were chemically bonded on allylsilica gel. The study of the effect of these substitutions on the performance of the resulting chiral supports, and a comparison with the recently described 10-undecenoate/3,5-dimethylphenylcarbamate derivative, are presented. In this study heptane/2-propanol or heptane/chloroform mixtures were used as mobile phases. Chirality 10:283–288, 1998. © 1998 Wiley-Liss, Inc.     

Chiral separation of bioactive cyclic Mannich ketones by HPLC and CE using cellulose derivatives and cyclodextrins as chiral selectors

The chiral separation of cyclic Mannich ketones of potential pharmaceutical interest is investigated using HPLC and CE. These Mannich ketones show a marked antibacterial and antifungal activity. In HPLC, stationary phases containing cellulose derivatives or beta-cyclodextrin were used and in CE different cyclodextrins, such as beta-CD, gamma-CD, carboxymethyl-beta-CD and succinyl-beta-CD were added to the background electrolyte as chiral selectors.     

Chiral separations on polysaccharide stationary phases using polar organic mobile phases

About 30% of a chemically diverse set of compounds were found to separate on four polysaccharide chiral stationary phases using polar organic mobile phases. No structural features appeared to correlate to successful separations. Titrations between normal and polar organic mobile phases suggested that separation mechanisms do not differ between these mobile phases. Attempts made to control retention met with varying degrees of success. Addition of hexane to alcohols had minor effects on retention although this was occasionally beneficial. Addition of water to alcohols increased retention. Addition of water to acetonitrile decreased retention. Addition of alcohol to acetonitrile also proved beneficial to the separation of some compounds. Loading studies performed to mimic preparative separations indicated that the benefits of polar organic mobile phases are largely due to increased solubility.     

Enantiomeric separation of mineralocorticoid receptor (hMR) antagonists using the Chiralcel OJ-H HPLC column with novel polar cosolvent eluent systems

This study demonstrates the increased versatility of the Chiralcel OJ-H stationary phase when using various alcohol/acetonitrile mobile phases. This chiral stationary phase has traditionally been employed in the normal phase mode and more recently with neat alcohols as eluents. Selected isomeric human mineralocorticoid receptor (hMR) antagonist pharmaceutical candidates and synthetic intermediates were separated using the Chiralcel OJ-H HPLC column with novel polar cosolvent eluent systems. The capacity factors, resolution, and selectivity of the chiral separations were assessed while varying the alcohol/acetonitrile composition and alcohol identity. The mixed polar eluents provide separations that are nearly always superior to both the traditional hexane-rich and single-alcohol "polar organic" eluents for the compounds tested in this article.     

Enantioselective separation of cyclic chiral ketones and their corresponding diastereomeric alcohols by HPLC on chiral and chiral/chiral coupled stationary phases

Enantioselective HPLC methods have been developed for the resolution of (RS)-2-phenylcyclohexanone (compound 1) and (RS)-2-phenyltetrahydropyran-4-one (compound 4) and the diastereoselective and enantioselective separations of their respective cis- and trans-alcohols; reduction of compound 1 yields trans- and cis-2-phenyl-1-cyclohexanol (compounds 2 and 3, respectively) and reduction of compound 4 yields trans- and cis-2-phenyl-tetrahydropyran-4-ol (compounds 5 and 6, respectively). Compounds 1, 2, and 3 were stereochemically resolved using a chiral stationary phase (CSP) based upon amylose tris(3,5-dimethylphenyl carbamate) coated on 10 μm silica-gel (Chiralpak AD-CSP). Compounds 4, 5, and 6 were stereochemically resolved on a coupled column system where a column containing a CSP based upon cellulose tris(3,5-dimethylphenyl carbamate) coated on 5 μm silica (Chiralcel OD-H-CSP) was coupled in series to the AD-CSP. The strategy employed in the identification of the peaks in the respective chromatograms is also discussed in this presentation. Chirality 8:551–555, 1996. © 1997 Wiley-Liss, Inc.     

Enantiomeric resolution of chiral sulfoxides on polysaccharide phases by HPLC

The enantiomeric resolution of chiral sulfoxides was investigated on amylose (S)-α-methylbenzyl carbamate phase coated on aminopropylated 7 μm silica with 500Å diameter pores. This was shown to be very successful in the separation of alkyl/aryl, aryl/aryl, and non-aromatic sulfoxides. The effect of pore size using naked silica was also investigated, demonstrating that the pore size does not affect the resolution. © 1996 Wiley-Liss, Inc.     

Chiral HPLC separation and CD spectra of the enantiomers of the alkaloid tacamonine and related compounds.

The HPLC enantiomeric separation of racemic indole alkaloids tacamonine, 17 alpha-hydroxytacamonine, deethyleburnamonine, and vindeburnol was accomplished using Chiralpak AD and Chiralcel OD as chiral stationary phases. Small structural differences affect the enantioselectivity ability of these phases. Single enantiomers of tacamonine and vindeburnol were isolated by semipreparative HPLC and their CD spectra and optical rotations were measured.