Enantiomeric Separation of Moxifloxacin and Its (R,R)-Isomer by Ligand-Exchange Chiral Chromatography

A new stereospecific LC method for the separation and quantification of moxifloxacin and its (R,R)-enantiomer in bulk drug was developed and validated by ligand-exchange liquid chromatography on a reversed phase column using aqueous mobile phase containing the chiral reagent l-isoleucine-Cu(II). The UV detector was operated at 293 nm. The flow rate of mobile phase was set at 0.9 mL min^?1. The achiral ODS column offers good separation of the two enantiomers in less than 20 min. The test concentration was 1,000 μg mL^?1 in the mobile phase. This method was capable of detecting the (R,R)-enantiomer of moxifloxacin up to 0.1 μg mL^?1 for a 20 μL injection volume. The drug was subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. There was no interference of degradants with the (R,R)-enantiomer in the developed method. The developed chiral RP-LC method was validated with respect to linearity, accuracy, precision and robustness. The percentage recovery for the (R,R)-enantiomer in bulk drug samples ranged from 98.1 to 104.4%. The test solution was found to be stable in the mobile phase for 48 h after preparation.     

A Validated LC Method for Determination of the Enantiomeric Purity of Montelukast Sodium in Bulk Drug Samples and Pharmaceutical Dosage Forms

A new and accurate chiral liquid chromatographic method has been developed for determination of the enantiomeric purity of montelukast sodium (R enantiomer) in bulk drugs and dosage forms. Normal phase chromatographic separation was performed on an immobilized amylose-based chiral stationary phase with n-hexane–ethanol–1,4-dioxane–trifluoroacetic acid–diethylamine 65:25:10:0.3:0.05 (v/v) as mobile phase at a flow rate of 1.0 mL min^?1. The elution time was approximately 15 min. The resolution (R _S) between the enantiomers was >3. The mobile phase additives trifluoroacetic acid and diethylamine played a key role in achieving chromatographic resolution between the enantiomers and also in enhancing chromatographic efficiency. Limits of detection and quantification for the S enantiomer were 0.07 and 0.2 μg, respectively, for a test concentration of montelukast sodium of 1,000 μg mL^?1 and 10 μL injection volume. The linearity of the method for the S enantiomer was excellent (R ² > 0.999) over the range from the LOQ to 0.3%. Recovery of the S enantiomer from bulk drug samples and dosage forms ranged from 97.0 to 103.0%, indicative of the high accuracy of the method. Robustness studies were also conducted. The sample solution stability of montelukast sodium was determined and the compound was found to be stable for a study period of 48 h.     

Efficient access to N-protected derivatives of (R,R,R)- and (S,S,S)-octahydroindole-2-carboxylic acid by HPLC resolution

The preparation of the proline analogue (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (Oic) and its enantiomer, (2R,3aR,7aR)-Oic, is described. A racemic precursor has been synthesized in good yield and subjected to HPLC resolution on a chiral column. The high efficiency of both the synthetic and chromatographic procedures has allowed the isolation of multigram quantities of each amino acid in enantiomerically pure form and suitably protected for use in peptide synthesis.     

LC-MS-MS Determination of (S,R)-Penehyclidine in Rat Plasma

A sensitive and selective method for determination of (S,R)-penehyclidine in rat plasma by liquid chromatography-tandem mass spectrometry is described. The procedure employed the use of an internal standard (I.S.) and a simple protein precipitation step. The method developed was linear from 0.1 to 100 ng mL^?1, with a sensitivity of 0.1 ng mL^?1 as the lower limit of quantification. The intra- and inter-day assay accuracy (relative error) was within 8.27% and precision (RSD) was below 6.7%. It was successfully applied to pharmacokinetic studies of (S,R)-penehyclidine in rat plasma.     

Chiral Separation of (R,R)-Tadalafil and Its Enantiomer in Bulk Drug Samples and Pharmaceutical Dosage Forms by Chiral RP-LC

A new simple isocratic chiral RP-LC method has been developed for the separation and quantification of the enantiomer of (R,R)-tadalafil in bulk drugs and dosage forms with an elution time of about 20 min. Chromatographic separation of (R,R)-tadalafil and its enantiomer was achieved on a bonded macro cyclic glycopeptide stationary phase. The method resolves the (R,R)-tadalafil and its enantiomer with a resolution (R _s) greater than 2.4 in the developed chiral RP-LC. The mobile phase used for the separation and quantification of (R,R)-tadalafil and its enantiomer involves a simple mixture of reverse phase solvents and the cost of analysis was drastically decreased. The test concentration is 0.4 mg mL⁻¹ in the mobile phase. This method is capable of detecting the enantiomer of (R,R)-tadalafil up to 0.0048 μg wrt test concentration 400 μg mL⁻¹ for a 20 μL injection volume. The drug was subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. There was no interference of degradants with (R,R)-tadalafil and its enantiomer in the developed method. The developed chiral RP-LC method was validated with respect to linearity, accuracy, precision and robustness. The percentage recovery for the enantiomer of (R,R)-tadalafil in bulk drug samples and in dosage forms ranged from 97.0 to 102.5%. The test solution was found to be stable in the mobile phase for 48 h after preparation.     

A Validated LC Method for the Determination of Chiral Purity of (1S)-6,11-Dioxo-1,2,3,4,6,11-Hexahydropyridazino[1,2-b]Phthalazine-1-Carboxylic Acid: A Key Intermediate of Cilazapril

A simple and accurate normal phase liquid chromatographic method was developed for the determination of chiral purity of (1S)-6,11-dioxo-1,2,3,4,6,11-hexahydropyridazino[1,2-b]phthalazine-1-carboxylic acid, S-enantiomer used as key intermediate in the manufacturing of cilazapril bulk drug. Chromatographic separation between (1S)-6,11-dioxo-1,2,3,4,6,11-hexahydropyridazino[1,2-b]phthalazine-1-carboxylic acid, and its opposite enantiomer (1R)-6,11-dioxo-1,2,3,4,6,11-hexahydropyridazino[1,2-b]phthalazine-1-carboxylic acid, R-enantiomer was achieved using a Chiralpak AD-H column using a mobile phase containing hexane, isopropyl alcohol and tri-fluoro acetic acid (80:20:0.1 v/v/v). The resolution between the two enantiomers was found to be more than 3.2. The limit of detection (LOD) and limit of quantitation (LOQ) of the R-enantiomer was 0.15 and 0.5 μg mL^?1, respectively, for 10 μL injection volume. The percentage recoveries of the R-enantiomer ranged from 96.5 to 105.3 in the bulk samples of (1S)-6,11-dioxo-1,2,3,4,6,11-hexahydropyridazino[1,2-b]phthalazine-1-carboxylic acid. The test solution and mobile phase was observed to be stable up to 24 h after the preparation. The developed method was validated as per International Conference on Harmonization guidelines in terms of LOD, LOQ, precision, linearity, accuracy, robustness and ruggedness.     

LC-MS-MS Determination of (S,R)-Penehyclidine in Rat Plasma

A sensitive and selective method for determination of (S,R)-penehyclidine in rat plasma by liquid chromatography-tandem mass spectrometry is described. The procedure employed the use of an internal standard (I.S.) and a simple protein precipitation step. The method developed was linear from 0.1 to 100 ng mL⁻¹, with a sensitivity of 0.1 ng mL⁻¹ as the lower limit of quantification. The intra- and inter-day assay accuracy (relative error) was within 8.27% and precision (RSD) was below 6.7%. It was successfully applied to pharmacokinetic studies of (S,R)-penehyclidine in rat plasma.

     

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F 3 was achieved from the chiral bithiazole-type primary alcohols [(S)- and (R)-4-ethoxycarbonyl-2′-(1-hydroxymethylethyl)-2,4′-bithiazoles 8], which were obtained based on the enzymatic resolution of racemic alcohol 8 and its acetate 9. From a direct comparison by means of chiral HPLC between natural cystothiazole F 3 and synthetic compounds [(4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles 3], natural cystothiazole F 3 was found to be a 33:67 diastereomeric mixture [(4R,5S,6E,14S)-3:(4R,5S,6E,14R)-3 = 33:67].     

Synthesis,Enantiomeric Resolution and Biological Evaluation of HIV Capsid Inhibition Activity for Racemic, (S)- and (R)-PF74

PF74 is a capsid-targeting inhibitor of HIV replication that effectively perturbs the highly sensitive viral uncoating process. A lack of information regarding the optical purity (enantiomeric excess) of the single stereogenic centre of PF74 has resulted in ambiguity as to the potency of different samples of this compound. Herein is described the synthesis of enantiomerically enriched (S)- and (R)-PF74 and further enrichment of the samples (≥98%) using chiral HPLC resolution. The biological activities of each enantiomer were then evaluated, which determined (S)-PF74 (IC₅₀ 1.5 µM) to be significantly more active than (R)-PF74 (IC₅₀ 19 µM). Computational docking studies were then conducted to rationalise this large discrepancy in activity, which indicated different binding conformations for each enantiomer. The binding energy of the conformation adopted by the more active (S)-PF74 (ΔG = −73.8 kcal/mol) was calculated to be more favourable than the conformation adopted by the less active (R)-enantiomer (ΔG = −55.8 kcal/mol) in agreement with experimental observations.     

Solid-state structure determination and solution-state NMR characterization of the (2R,4R)/(2S,4S)- and (2R,4S)/(2S,4R)-diastereomers of the agricultural fungicide propiconazole,the (2R,4S)/(2S,4R)-symmetrical triazole constitutional isomer,and a ditriazole analogue

Single-crystal X-ray diffraction analysis was used to determine the structure of a racemic diastereomer of the agricultural fungicide propiconazole [1-(2-(2,4-dichlorophenyl)-4-n-propyl-1,3-dioxolane-2-yl-methyl)-1-H-1,2,4-triazole] and of two by-products (a symmetrical 1,3,4-triazole racemic-constitutional isomer and a propiconazole ditriazole analogue). All three crystalline racemic-diastereomers had (2R,4S)/(2S,4R)-stereochemistry in which then-propyl group was observed in atrans-to-phenyl disposition. Propiconazole (2R,4S)/(2S,4R)-diastereomer gives crystals belonging to the monoclinic space group P2₁,/a, and, at 293 K,a=8.1192(3),b=18.9769(6),c=10.7137(4) å,Β=99.765(3)?,V=1626.8(1) å³, Z=4,R(F)=0.060, andR _w(F)=0.058. The constitutional isomer by-product (2R,4S)/(2S,4R)-1-(2-(2,4-dichlorophenyl)-4-n-pro-pyl-1,3-dioxolane-2-yl-methyl)-1-H-1,3,4-triazole gives crystals belonging to the monoclinic space group P2₁/n, and, at 293 K,a=11.1763(6),b=10.7716(4),c=14.5804(8) å,Β=107.445(4)?,V=1674.6(1) å³, Z=4,R(F)=0.043, andR _w(F)=0.043. The ditriazole byproduct (2R,4S)/(2S,4R)-1-(2-(2-chloro-4-(1,2,4-triazole-1-yl)phenyl)-4-n-propyl-1,3-dioxolane-2-yl-methyl)-1-H-1,2,4-triazole gives crystals belonging to the triclinic space groupP¯ 1, and, at 193 K,a=5.3329(8),b=8.3738(7),c=20.240(2) å, α=84.213(6)?,Β=87.20(1)?,γ=86.23(1)?,V=896.5(2) å³, Z=2,R(F)=0.046, andR _w(F)=0.051. The presence of both propiconazole (2R.4S)- and (2S,4R)-enantiomers enables the formation of a crystalline racemic modification, while the diastereomeric propiconazole (2R,4R)- and (2S,4S)-enantiomers are viscous oils. In the absence of its enantiomorphic partner, the propiconazole (2R,4S)- or (2S,4R)-enantiomers remain as viscous oils rather than form chiral crystals.     

Crystal structure of (S,S)-diphenylethanediammonium (R,R)-tartrate

Summary The crystal structure of (–)-diphenylethanediammonium-(R,R)-tartrate was determined. From this structure determination, the (S,S) configuration was assigned to the (–)-diphenylethanediamine. The asymmetric unit of the crystal structure contains two units of the title compound plus one molecule of ethanol and one water molecule, which form an intricate network of 19 hydrogen bonds.

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Die Kristallstruktur von (S,S)-Diphenylethandiammonium-(R,R)-tartrat

Zusammenfassung Es wurde die Kristallstruktur von (–)-Diphenylethandiammonium-(R,R)-tartrat bestimmt. Aus dieser Strukturbestimmung ergab sich die Zuordnung der (S,S)-Konfiguration zum (–)-Diphenylethandiamin. Die asymmetrische Einheit der Kristallstruktur besteht aus zwei Formeleinheiten der Titelverbindung sowie einem Molekül Ethanol und einem Wassermolekül, welche ein komplexes Netzwerk von insgesamt 19 Wasserstoffbrücken bilden.

     

A synthesis of levetiracetam based on (S)-N-phenylpantolactam as a chiral auxiliary

The synthesis of levetiracetam and its enantiomer by deracemization of (±)-2-bromobutyric acid using either (S)- or (R)-N-phenylpantolactam as chiral auxiliaries, followed by S_N2 substitution of the bromine atom by a 2-oxopyrrolidin-1-yl group and amidation of the carboxylic acid, is described.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Convenient access to sterically hindered C2 chiral 2,2,5,5-tetraphenyltetrahydrofuran-3,4-diols: intramolecular selective 1,4-cyclocondensation of (2R,3R)- and (2S,3S)-1,1,4,4-tetraphenylbutanetetraols

Sterically hindered C₂ chiral (3R,4R)- and (3S,4S)-2,2,5,5-tetraphenyltetrahydrofuran-3,4-diols have been conveniently prepared in a very high yield via heterogeneous intramolecular selective 1,4-cyclocondensation of (2R,3R)- and (2S,3S)-1,1,4,4-tetraphenylbutanetetraol in concentrated hydrohalic acids, respectively. Preliminary examination of additives for the Barbas–List reaction showed that in certain cases, the hindered C₂ chiral tetrahydrofuran-3,4-diols were better chiral auxiliaries than enantiopure (R)- and (S)-1,1′-bi-2-naphthols.     

Application of amide-stabilized sulfur ylide reactivity to the stereodivergent synthesis of (R,S)- and (S,R)-reboxetine

A simple access to (R,S)- and (S,R)-reboxetine from a single chiral sulfonium salt 4 is reported. This approach, based on a stabilized sulfur ylide-mediated epoxidation, followed by a regioselective opening reaction, enables the preparation of these two potentially biologically active compounds in 35.6% and 13.7% overall yield.     

Synthesis of anti-Alzheimer (R)-arundic acid

The asymmetric synthesis of the anti-Alzheimer agent (R)-arundic acid has been performed via a diastereoselective photodeconjugation reaction as the key-step. The synthetic approach involves a readily available chiral auxiliary, diacetone-d-glucose, and allows access to either enantiomer as illustrated by the synthesis of (S)-arundic acid. Both enantiomers were obtained in 88% ee using the same chiral auxiliary.     

Solvent-induced chirality switching in the enantioseparation of regioisomeric hydroxyphenylpropionic acids via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol

The enantioseparation of three hydroxyphenylpropionic acid isomers via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol has been demonstrated. The racemates of all three acid isomers were successfully separated with high efficiency (0.56–0.84) after single crystallization. For 2-hydroxy-3-phenylpropionic acid 4, the configuration of the less-soluble salt was controlled by the crystallization solvent: the (R)-4 salt was crystallized from water, while 2-propanol afforded the (S)-4 salt. The chiral recognition mechanism of the three acids was discussed based on the crystal structures of the diastereomeric salts.     

New cyclic aminals derived from rac-trans-1,2-diaminocyclohexane: synthesis and crystal structure of racemic 1,8,10,12-tetraazatetracyclo[8.3.1.1.8,1202,7] pentadecane and a route to its enantiomerically pure (R,R) and (S,S) isomers

New enantiomerically pure macrocyclic aminals (2R,7R)- and (2S,7S)-1,8,10,12-tetraazatetracyclo[8.3.1.1.^8,120^2,7]pentadecane (4a and 4b) were obtained by a three component reaction between their respective pure enantiomer of trans-1,2-diaminocyclohexane, ammonia, and formaldehyde. Additionally, the X-ray structure of the racemic compound 4 and the specific rotations of the racemic and optically pure compounds were determined. To further understand the synthetic utilities of enantiomers 4a and 4b, Mannich-type reactions with 1H-benzotriazole were performed, affording (3aR,7aR)- and (3aS,7aS)-1,1′-{[2,3,3a,4,5,6,7,7a-octahydro-1H-1,3-benzimidazole-1,3-diyl]bis(methylene)}bis-1H-benzotriazole (9 and 10) and allowing for new possibilities related to the preparation of chiral ligands for asymmetric catalysis.     

An efficient synthesis of (R)- and (S)-8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene

Racemic 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as a potent inhibitor of phosphoinositide 3-kinase (PI3K). In order to investigate the effects of its two enantiomers on tumor cell lines, we designed a novel synthesis for (R)-S14161 and (S)-S14161 using a chemical resolution and derivation strategy. The readily available 3-(tert-butyldimethylsilyloxy)-salicylaldehyde underwent a tandem oxa-Michael–Henry reaction with trans-4-fluoro-β-nitrostyrene in the presence of a catalytic amount of l-proline and triethylamine to give the 3-nitro-2H-chromene. Upon removal of the TBS protecting group, the resolution of the resulting racemic 2-(4-fluorophenyl)-8-hydroxy-3-nitro-2H-chromene was achieved via diastereomeric ester formation using (S)-(+)-α-methoxyphenylacetic acid as the derivatizing agent, followed by aminolysis. Finally, the ethyl ether formation of each enantiomer furnished (R)-S14161 and (S)-S14161 in enantiomerically pure forms. The absolute configurations of these chiral molecules were determined by a circular dichroism method. The two enantiomers showed no marked differences in inhibition of growth of human myeloma LP1 and OPM-2 cells.     

Asymmetric synthesis of (S,R)- and (R,R)-methiin stereoisomers

Abstract

An asymmetric synthesis of (+)- and (–)-methiine (S-methyl-(R)-cysteine sulfoxide) diastereomers has been developed. These natural sulfur compounds were isolated from a variety of Brassica vegetables. As the starting compound, (R)-cysteine was used, which was methylated to form (R)-S-methylcysteine. Then the oxidation of S-methylcysteine with tert-butyl hydroperoxide catalyzed by the chiral tetra(isopropylate)titanium/(S)- or (R)-Binol complex led to the formation of (1?R,2S)-(+)- or (1?R,2R)-(–)-methiin stereomers.