Kinetic and mechanistic insight into the thermodynamic degradation of saxagliptin

The dipeptidyl peptidase-IV inhibitor saxagliptin (Onglyza) can undergo a thermodynamically favored cyclization to form the corresponding cyclic amidine. The kinetics and mechanism of this conversion were examined to develop a commercial synthesis that afforded saxagliptin with only trace levels of this key byproduct. Important findings of this work are the identification of a profound solvent effect and the determination of an autocatalytic pathway. Both of these phenomena result from transition structures involving proton transfer.     

On-line high-performance liquid chromatography-solvent evaporation - high-performance liquid chromatography - capillary gas chromatography - flame ionisation detection for the analysis of mineral oil polyaromatic hydrocarbons in fatty foods

An automated on-line method is described that involves a first LC separation on a large column, evaporation of a 6-ml fraction in an on-line solvent evaporator, a second LC separation using a different mobile phase, fractionating the components of interest and transfer to GC through the in-line vaporiser/overflow interface. The method is designed for the injection of a large amount of food extract (e.g. up to 200 mg of fat) and is applied to the analysis of mineral oil material in a linseed oil.     

Pd complexes of iminophosphine ligands: A homogeneous molecular catalyst for Suzuki–Miyaura cross-coupling reactions under mild conditions

The complexes formed by combining Pd(OAc)₂ and iminophosphine ligands (P^N) are active catalysts in Suzuki–Miyaura cross-coupling reactions under mild conditions. Aryl bromides and iodides, as well as benzyl chlorides give the corresponding coupled products in high yields at low temperatures (25–50 °C) using these catalysts. Iminophosphines containing the most sterically demanding groups attached to the N-imino moiety were the most effective ligands. New divalent Pd complexes of known iminophosphines were synthesised and their activity was compared with the in situ generated catalyst system. The complex resulting from the oxidative addition of 4-bromo anisole [Pd(4-CH₃OC₆H₄)Br(P^N)] was more active than the in situ generated system. However, palladacycles containing the iminophosphine ligand (e.g., {[C₆H₄CH(Me)₂St-Bu]Pd(P^N)}⁺PF₆⁻) were less active than the in situ generated catalyst due to the greater stability of the complexes that involve two bidentate ligands. Poisoning tests demonstrated that homogeneous mononuclear palladium species containing the iminophsophine ligand were responsible for the catalytic activity.     

Mixed Semicontinuous Perturbation of Nonconvex State-Dependent Sweeping Process

In this paper we prove a result on the existence of solutions of a first-order differential inclusion governed by a class of nonconvex sweeping process. The moving set involved in the process is prox-regular and depends both on the time and on the state.     

Diagnostic potential of autofluorescence for an assisted intraoperative delineation of glioblastoma resection margins

The intrinsic autofluorescence properties of biological tissues can be affected by the occurrence of histological and biochemical alterations induced by pathological processes. In this study the potential of autofluorescence to distinguish tumor from normal tissues was investigated with the view of a real-time diagnostic application in neurosurgery to delineate glioblastoma resection margins. The autofluorescence properties of nonneoplastic and neoplastic tissues were analyzed on tissue sections and homogenates by means of a microspectrofluorometer, and directly on patients affected by glioblastoma multiforme, during surgery, with a fiber-optic probe. Scan-microspectrofluorometric analysis on tissue sections evidenced a reduction of emission intensity and a broadening of the main emission band, along with a redshift of the peak position, from peritumoral nonneoplastic to neoplastic tissues. Differences in both spectral shape and signal amplitude were found in patients when the glioblastoma lesion autofluorescence was compared with those of cortex and white matter taken as healthy tissues. Both biochemical composition and histological organization contribute to modify the autofluorescence emission of neoplastic, with respect to nonneoplastic, brain tissues. The differences found in the in vivo analysis confirm the prospects for improving the efficacy of tumor resection margin delineation in neurosurgery.     

Sequential amination/annulation/aromatization reaction of carbonyl compounds and propargylamine: a new one-pot approach to functionalized pyridines

A general one-pot synthesis of pyridines 4a-t from the reaction of dialkyl acyclic/cyclic ketones 1a-i, methyl, aryl/heteroaryl ketones 1m-r, and aldehydes bearing alpha-hydrogens 1s,t with propargylamine 2 is described. Gold and copper salts are efficient catalysts for the reaction of ketones with 2. The formation of the pyridines 4 is suggested to proceed through the sequential amination of carbonyl compounds followed by regioselective 6-endo-dig cyclization of the N-propargylenamine (N-propargyldienamine) intermediate 3(5) and aromatization reaction. Whereas the preparation of linear polycyclic pyridine 4i can be carried out by reacting cholestan-3-one 1i with 2, the angular polycyclic pyridine 4j has been obtained starting from cholest-5-en-3-one 1j. Selectivity of the reaction of polycyclic dicarbonyls 1k,l with 2 has also been investigated.     

Clear and pigmented water epoxy systems: a study on the hardening kinetics on the basis of the variations of the viscoelastic moduli

The hardening reaction of a two-can water epoxy polyamide system was investigated on the basis of the variation of the viscoelastic moduli G′ and G′′. Unpigmented (clear varnish) and TiO₂ pigmented formulations, at two different TiO₂ concentrations, were taken into account. Time and frequency sweep procedures were carried out using the stress-controlled rheometer Haake RS 150. The behavior of G′ and G′′ vs time was fitted to a four-parameter asymptotic model through the whole course of the hardening process. Frequency sweep data, obtained at increasing times during the whole hardening process, were plotted to the generalized Cole and Cole behavior model and the corresponding mechanical spectra were drawn. An interpretation for some aspects of the cross-linking progress is discussed and possible future developments are briefly outlined. Received: 15 January 2000 Accepted: 13 November 2000     

Radiofrequency ablation planning: An application of semi-infinite modelling techniques

In radiofrequency (RF) ablation a needle-shaped probe is inserted into the patient’s body in order to heat and subsequently destroy the malignant tissue around the needle tip. The determination of the optimal probe position poses an intricate problem, as it requires the modelling of the tumour destruction depending on the attained temperature as well as the incorporation of constraints that prohibit puncturing bones or other risk structures.In this work we present a new optimization procedure that reflects both aspects adequately. We assess tumour destruction by solving the underlying system of partial differential equations using a finite element method. Next we show how the probe’s position and orientation can be optimized by gradient-based methods. Ensuring that risk structures are not harmed by the probe is easily modelled using semi-infinite constraints in the optimization problem.Techniques to reduce the semi-infinite problem to a standard nonlinear constrained optimization problem are introduced and demonstrated as a proof-of-concept on real clinical data. The results indicate the high potential of this combination of PDE-based simulation and numerical optimization for RF ablation planning.