Enhanced chromatographic resolution of amine enantiomers as carbobenzyloxy derivatives in high-performance liquid chromatography and supercritical fluid chromatography

The carbobenzyloxy (cbz) protecting group is evaluated for it's potential to enhance the resolution of chiral amine enantiomers using high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC). A series of cbz derivatives of commercially available racemates was prepared and analyzed by enantioselective chromatography using a variety of mobile phases and polysaccharide and Pirkle-type chiral stationary phases (CSPs). The cbz-derivatized product consistently demonstrated enhanced chiral resolution under HPLC and SFC conditions. Improved selectivity and resolution combined with an automated preparative HPLC or SFC system can lead to the rapid generation of highly purified enantiomers of desirable starting materials, intermediates or final products.     

Developing counter current chromatography to meet the needs of pharmaceutical discovery

Experiments have been carried out to evaluate Counter Current Chromatography (CCC) as an alternative purification technique to preparative Reverse Phase High Performance Liquid Chromatography (RP-HPLC) for small molecule pharmaceuticals. The major drawback of CCC is the extensive time required in selecting the solvents to perform the separation. This is equivalent to choosing both the stationary phase and the mobile phase at the same time. In RP-HPLC it is a simple matter of deciding on the gradient, most samples can be purified on a C18 column with a water:acetonitrile gradient. The majority of the initial work was based on a standard test set of commercially available compounds, developed within our group to evaluate the performance of the HPLC apparatus and the column prior to the start of work each day. The work carried out on CCC has shown that the technique offers similar capabilities and can be carried out using similar protocols to RP-HPLC. CCC also has some advantages over RP-HPLC and can be regarded as a valuable addition to the chromatography toolbox.     

1H, 13C and 19F NMR Studies of the Diels-Alder Adduct of p-Fluoranil with Phencyclone. II. Hindered Phenyl Rotations and Anisotropic Effects in a Model Compound for Drugs

Abstract

The Diels-Alder adduct of phencyclone, compound 1, with p-fluoranil, compound 3, has been prepared in refluxing toluene. The adduct, compound 2, has been examined by ¹H, ¹³C and ¹⁹F NMR spectroscopy at 300, 75 and 282 MHz, respectively. At ambient temperature, the unsubstituted bridgehead phenyl groups in adduct 2 are found to exhibit hindered rotation, resulting in slow exchange limit (SEL) ¹H NMR spectra. Full aryl proton assignments are made based on 1D and 2D (COSY45) NMR. The ¹⁹F NMR (proton coupled) reveals one of the two ¹⁹F signals to be a triplet. This resonance collapses to a singlet in the proton decoupled ¹⁹F spectrum, implying an unexpected long range ¹H-¹⁹F coupling. For the ¹³C NMR spectrum, tentative assignments are presented. Data for compound 2 as a model compound for drugs are discussed in terms of the hindered aryl rotation and evidence of magnetic anisotrppic effects.     

Access to pyridines via cascade nucleophilic addition reaction of 1,2,3-triazines with activated ketones or acetonitriles

We studied the cascade nucleophilic addition reactions of 1,2,3-triazines with activated acetonitriles or ketones,which were used to construct highly substituted pyridines that are not easily accessed by conventional methods.The strategy addressed some structural diversity issues currently facing medicinal chemistry,and the resulting pyridines could be used as convenient precursors for the synthesis of related pharmaceuticals.In particular,our method was applied to the syntheses of the marketed drug etoricoxib and several biologically important molecules in a few steps.     

Multi-residue analytical methods using LC-tandem MS for the determination of pharmaceuticals in environmental and wastewater samples: a review

Multi-residue analytical methodologies are becoming the preferred and required tools against single group analysis, as they provide wider knowledge about the occurrence of pharmaceuticals in the environment necessary for further study of their removal, partition and ultimate fate. However, simultaneous analysis of compounds from different groups with quite different physico-chemical characteristics requires a compromise in the selection of experimental conditions, which in some cases are not the best conditions for all the analytes studied. In this article, an overview of analytical methodologies focusing on the simultaneous determination of acidic, neutral and basic compounds belonging to different therapeutical classes is presented. The state-of-the-art of LC-MS/MS for multi-class analysis is reviewed, highlighting the specific requirements for such analysis.     

Simultaneous Determination of Naproxen and Diflunisal using Synchronous Luminescence Spectrometry

Binary mixtures of naproxen and diflunisal can be resolved by using zero-crossing first derivative emission spectrofluorimetry, first derivative constant wavelength synchronous luminescence spectrometry and first derivative constant energy synchronous luminescence spectrometry. These methods do not require any previous separation steps. The lowest quantitation limits for both drugs were obtained with first derivative constant wavelength synchronous luminescence spectrometry (0.002 and 0.015 μg ml⁻¹ for naproxen and diflunisal, respectively). The measurements were performed in 40% methanolic aqueous medium at pH 8.0 provided by adding 0.02 M phosphate buffer solution. The proposed methods were successfully applied to the simultaneous determination of naproxen and diflunisal in pharmaceuticals and human serum samples with high precision and accuracy. Linearity, accuracy, precision, limits of detection, limits of quantitation, and other aspects of analytical validation are included in the text.     

Efficient activation of peroxymonosulfate by hollow cobalt hydroxide for degradation of ibuprofen and theoretical study

Hollow microsphere structure cobalt hydroxide (h-Co(OH)₂) was synthesized via an optimized solvothermal-hydrothermal process and applied to activate peroxymonosulfate (PMS) for degradation of a typical pharmaceutically active compound, ibuprofen (IBP). The material characterizations confirmed the presence of the microscale hollow spheres with thin nanosheets shell in h-Co(OH)₂, and the crystalline phase was assigned to α-Co(OH)₂. h-Co(OH)₂ could efficiently activate PMS for radicals production, and 98.6% of IBP was degraded at 10 min. The activation of PMS by h-Co(OH)₂ was a pH-independent process, and pH 7 was the optimum condition for the activation-degradation system. Scavenger quenching test indicated that the sulfate radical (SO₄^{? ?}) was the primary reactive oxygen species for IBP degradation, which contributed to 75.7%. Fukui index (f ^?) based on density functional theory (DFT) calculation predicted the active sites of IBP molecule for SO₄^{? ?} attack, and then IBP degradation pathway was proposed by means of intermediates identification and theoretical calculation. The developed hollow Co(OH)₂ used to efficiently activate PMS is promising and innovative alternative for organic contaminants removal from water and wastewater.     

Ferric nitrate-promoted oxidative esterification of toluene with N-hydroxyphthalimide: Synthesis of N-hydroxyimide esters

A ferric nitrate-promoted cross-dehydrogenative coupling reaction of N-hydroxyphthalimide (NHPI) with toluene derivatives is reported. The reaction proceeded smoothly using molecular oxygen as an oxidant, providing an efficient method for the synthesis of N-hydroxyimide esters. Furthermore, a plausible mechanism was proposed.