Fluorinated piperidine acetic acids as gamma-secretase modulators.

We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing.

Impact of an error in the column hold-up time for correct adsorption isotherm determination in chromatography II. Can a wrong column porosity lead to a correct prediction of overloaded elution profiles?

The adsorption isotherm was determined for phenol in methanol/water on a C-8 stationary phase using frontal analysis in staircase mode, assuming different total column porosities, from 1 to 87%. Each set of adsorption isotherm data, with a certain column porosity, was fitted to various adsorption models and the generated parameters were used to calculate overloaded elution band profiles that were compared with experiments. It was found that the bi-Langmuir model had an optimum fit for a porosity that corresponds well with the value found experimentally.

Impact of an error in the column hold-up time for correct adsorption isotherm determination in chromatography I. Even a small error can lead to a misunderstanding of the retention mechanism.

The impact of a realistic error in the column hold-up time on the determination of the adsorption isotherm model was systematically investigated. Frontal analysis and the inverse method were used for the accurate determination of the adsorption isotherm. The true retention times of the breakthrough curves were used with a known hold-up time as reference.

Multiparallel microfluidic high-performance liquid chromatography for high-throughput normal-phase chiral analysis.

The suitability of the Eksigent Express 800 microfluidic eight-channel HPLC instrument for multiparallel normal-phase chiral analysis in support of high-throughput pharmaceutical process research was investigated. Analysis of test mixtures containing the two enantiomers of benzoin and the closely related (R,S)-dihydrobenzoin, was carried out in a 96-well microplate, affording rapid (<2 h) and accurate assessment of enantiopurity. In a second example, use of the instrument to support high-throughput catalyst screening of the asymmetric hydrogenation of a prochiral unsaturated ester is presented, in which method development (gradient screening of four columns and two eluents, followed by optimization to afford a fast analytical method) and analysis of a 96-well microplate was carried out within a single working day.

Investigation of the stability of Chiralpak AD chiral stationary phase under various solvent conditions and development of a method to identify stationary phase-derived polymer contamination.

The stability of Chiralpak AD chiral stationary phase under various solvent conditions was investigated. An analytical method for the detection of the presence of solubilized Chiralpak AD coating was developed using CD spectroscopy (CD signal at 245 nm). In addition, NMR analysis of the solubilized polymer revealed a characteristic signal for the 3,5-dimethylphenyl carbamate methyl protons at around 2.