NMR Studies of Drugs. Applications of Achiral and Chiral Lanthanide Shift Reagents to a 5-Substituted-4-thiazolidinone

The 60 MHz ¹H NMR spectra of racemic 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone, 1, have been studied in CDCl₃ solution at 28° with the achiral lanthanide shift reagent (LSR), tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium (III), 2, and the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene)- (+)-camphoratojeuropium(III), 3, and tris[3-(trifluoromethylhydroxymethylene-(+) -camphorato]europium (III), 4, Significant enantiomeric shift differences were observed in the presence of added 3, for the aryl protons of 1 that should permit direct determination of enantiomeric excess. Relative magnitudes of lanthanide-induced shift for the different nuclei of 1 with the three LSRs are compared and discussed in terms of preferred LSR binding sites. A favored conformation of 1 with respect to rotation about the C(5)-CH₂ bond is suggested.     

Magnetic solid‐phase extraction based on carbon nanosphere@Fe3O4 for enantioselective determination of eight triazole fungicides in water samples

In this work, a carbon nanosphere decorated by Fe₃O₄ nanoparticles was prepared, characterized and used as the magnetic adsorbent. Eight commonly used chiral triazole fungicides, including penconazole, uniconazole, paclobutrazol, triazolone, tebuconazole, hexaconazole, triticonazole and epoxiconazole were extracted from two environmental water samples (river water and lake water) by magnetic solid‐phase extraction, followed by the enantiomeric analysis on a Chiralpark IC column coupled with a triple quadrupole mass spectrometry to evaluate their possible stereoselective degradation occurring in the water samples. The possible factors affecting the extraction performance, such as amount of used adsorbents, pH and ionic strength of water solution, types and volumes of desorption solvents were systematically investigated. Under the optimum conditions, extraction yields of eight triazole fungicides were above 80% and the concentration factors were as high as 1000. Method detection and quantification limits for the enantiomers of eight triazole fungicides were in the range of 0.56–6.95 ng/L. Satisfactory accuracy (relative recovery 77.8–93.5%), good intraday precision (RSD 4.3–9.8%) and interday precision (RSD 3.1–7.9%) were also obtained. The developed method provided the simplicity of operation, rapidity and high enrichment factor, which can be used to monitor and evaluate the behavior of the individual enantiomer of chiral triazole fungicides.     

酶促水解法拆分布洛芬乙酯的工艺研究

以布洛芬乙酯为反应底物,探索了酶促水解法拆分布洛芬的工艺。以曲拉通X-100为表面活性剂,利用南极假丝酵母脂肪酶B（CAL-B）催化拆分外消旋布洛芬乙酯,并对表面活性剂含量、有机溶剂种类和添加量、酶量、缓冲溶液pH、温度及时间等反应条件进行了优化;得到的最佳反应条件为：在pH为9.0的缓冲溶液中,添加80 mg曲拉通X-100、50 μL二氯甲烷和15 mg CAL-B,于30℃下反应48 h;在该条件下,S-布洛芬乙酯的剩余率（C）为65%,布洛芬乙酯的对映体过量值（ees）为94%。     

Comparison of chiral NMR solvating agents for the enantiodifferentiation of amines

Chiral, enantiomerically pure organic-soluble acids are often used as NMR chiral solvating agents (CSAs) for analyzing the enantiopurity of amines. However, the reports that describe CSAs for amines provide limited comparisons to other previously reported reagents. As such, it is difficult to know which among the many CSAs to pick when studying a new amine. We report a comparison of thirteen commercially available CSAs for the analysis of primary, secondary and tertiary amines in chloroform-d. (R)-α-methoxyphenylacetic acid, (R)-(-)-O-acetylmandelic acid, (R)-2-methoxy-2-(1-naphthyl)propionic acid and (R)-(-)-1,1′-binaphthyl-2,2′-diylhydrogenphosphate are identified as the best four to use as a starting point for the analysis of a new amine.     

Development of a capillary electrophoresis method for the determination of the chiral purity of dextromethorphan by a dual selector system using quality by design methodology

Dextromethorphan is a centrally acting antitussive drug, while its enantiomer levomethorphan is an illicit drug with opioid analgesic effects. As capillary electrophoresis has been proven as an ideal technique for enantiomer analysis, the present study was conducted in order to develop a capillary electrophoresis‐based limit test for levomethorphan. The analytical target profile was defined as a method that should be able to determine levomethorphan with acceptable precision and accuracy at the 0.1 % level. From initial scouting experiments, a dual selector system consisting of sulfated β‐cyclodextrin and methyl‐α‐cyclodextrin was identified. The critical process parameters were evaluated in a fractional factorial resolution IV design followed by a central composite face‐centered design and Monte Carlo simulations for defining the design space of the method. The selected working conditions consisted of a 30/40.2 cm, 50 μm id fused‐silica capillary, 30 mM sodium phosphate buffer, pH 6.5, 16 mg/mL sulfated β‐cyclodextrin, and 14 mg/mL methyl‐α‐cyclodextrin at 20°C and 20 kV. The method was validated according to ICH guideline Q2(R1) and applied to the analysis of a capsule formulation. Furthermore, the apparent binding constants between the enantiomers and the cyclodextrins as well as complex mobilities were determined to understand the migration behavior of the analytes.     

Direct asymmetric aldol reactions catalyzed by nanocrystalline copper(II) oxide

The direct asymmetric aldol reactions of aromatic and heteroaromatic aldehydes with acetone to afford chiral β-hydroxy carbonyl compounds in good yields and good to moderate enantioselectivities are realized using nanocrystalline copper(II) oxide in the presence of (1S,2S)-(−)-1,2-diphenylethylenediamine at −30 °C. The catalyst can be reused for four cycles with consistent activity and enantioselectivity.     

Density functional theory calculations of novel Rh(I) diphosphinite catalysts

Novel Rh(I) diphosphinite catalysts [Rh((R,R)-3,4-(bis(O-diphenylphosphino)-1,2,5,6-tetra-O-methyl-chiro-inositol)]+ ([Rh-CANDYPHOS]+) and [Rh((R,R)-3,4-(bis(O-diphenylphosphino)-1,2,5,6-tetra-O-ethyl-chiro-inositol)]+ ([Rh-EtCP]+) have been prepared utilizing naturally-occurring resources. Potential energy surfaces for the catalyzed asymmetric hydrogenation of the prochiral enamides methyl-(Z)-α-acetamido cinnamate, methyl-(Z)-α-acetamido cinnamic acid and dimethyl itaconate have been surveyed using density function theory (DFT) methods. Key transition states were identified from previous [Rh((R,R)-DUPHOS)]+ studies for the two diastereoisomeric manifolds 1 and 2. Transition state energies were found starting from models based on (1) the X-ray structure of the active complex (CANDYPHOS)(η⁴-(Z,Z)-cyclo-octa-1,5-diene)-rhodium(I) tetrafluoroborate CHCl₃ solvate [3] and (2) models in which the complex (without substrate) started with C2 molecular symmetry. The difficulties encountered in calculations of the transition state energies of large cations are outlined and limitations noted. Transition state enthalpy values are compared with the observed experimental free energy differences results and previous studies 1 and 2. The predictive aspects of the calculations appear to be limited with the starting models playing an important part in the absolute value of the final energies.     

Enantioselective analysis of mirtazapine and its two major metabolites in human plasma by liquid chromatography-mass spectrometry after three-phase liquid-phase microextraction

A three-phase liquid-phase microextraction (LPME) method using porous polypropylene hollow fibre membrane with a sealed end was developed for the extraction of mirtazapine (MRT) and its two major metabolites, 8-hydroxymirtazapine (8-OHM) and demethylmirtazapine (DMR), from human plasma. The analytes were extracted from 1.0 mL of plasma, previously diluted and alkalinized with 3.0 mL 0.5 mol L⁻¹ pH 8 phosphate buffer solution and supplemented with 15% sodium chloride (NaCl), using n-hexyl ether as organic solvent and 0.01 moL L⁻¹ acetic acid solution as the acceptor phase. Haloperidol was used as internal standard. The chromatographic analyses were carried out on a chiral column, using acetonitrile-methanol-ethanol (98:1:1, v/v/v) plus 0.2% diethylamine as mobile phase, at a flow rate of 1.0 mL min⁻¹. Multi-reaction monitoring (MRM) detection was performed by mass spectrometry (MS-MS) using a triple-stage quadrupole and electrospray ionization interface operating in the positive ion mode. The mean recoveries were in 18.3-45.5% range with linear responses over the 1.25-125 ng mL⁻¹ concentration range for all enantiomers evaluated. The quantification limit (LOQ) was 1.25 ng mL⁻¹. Within-day and between-day assay precision and accuracy (2.5, 50 and 100 ng mL⁻¹) showed relative standard deviation and the relative error lower than 11.9% for all enantiomers evaluated. Finally, the method was successfully used for the determination of mirtazapine and its metabolite enantiomers in plasma samples obtained after single drug administration of mirtazapine to a healthy volunteer.     

Enantioselective comprehensive two‐dimensional gas chromatography of lavender essential oil

The enantiomeric composition of several chiral markers in lavender essential oil was studied by flow modulated comprehensive two‐dimensional gas chromatography operated in the reverse flow mode and hyphenated to flame ionization and quadrupole mass spectrometric detection. Two capillary column series were used in this study, 2,3‐di‐O‐ethyl‐6‐O‐tert‐butyldimethylsilyl‐β‐cyclodextrin or 2,3,6‐tri‐O‐methyl‐β‐cyclodextrin, as the chiral column in the first dimension and α polyethylene glycol column in the second dimension. Combining the chromatographic data obtained on these column series, the enantiomeric and excess ratios for α‐pinene, β‐pinene, camphor, lavandulol, borneol, and terpinen‐4‐ol were determined. This maybe a possible route to assess the authenticity of lavender essential oil.