Improvements in the Synthesis of the Third-Generation EGFR Inhibitor Osimertinib

Osimertinib, a third generation potent and specific EGFR inhibitor is an important drug against many forms of cancer. It was synthesized by an improved and highly efficient protocol, revisiting the classical synthetic process and modifying parameters, such as solvents, temperature, reagents, and reaction time. A cost-effective, environmentally friendly methodology for the synthesis of osimertinib was established, which gave shorter reaction times, saved labor by eliminating purification steps through column chromatography, and enhanced yields. Four of the seven steps in total, were proceeded quantitatively or almost quantitatively (ca. 98 %). This synthetic protocol provides a very high overall yield, up to 68 %. In addition, the entire approach enables the preparation of osimertinib analogues and could be extended in the synthesis of other structurally similar bioactive compounds.     

Integer points on the curve

We completely solve diophantine equations of the form where is a positive integer, using a reduction to some quartic elliptic equations, which can be solved with well known methods.

     

Determination of carbendazim,thiabendazole, and<Emphasis Type="Italic"> o-</Emphasis>phenylphenol residues in lemons by HPLC following sample clean-up by ion-pairing

An efficient analytical method is presented involving effective sample clean-up with solid-phase extraction and HPLC-UV analysis for the simultaneous determination of carbendazim, thiabendazole, and o-phenylphenol residues in lemons. Sample preparation involves extraction with acetonitrile acidified with trifluoroacetic acid and an ethyl acetate/petroleum ether mixture. Purification of the crude extract was carried out with liquid–liquid partitioning after addition of an aqueous ammonia solution. Final clean-up was performed on polymeric reversed-phase cartridges pretreated with sodium dodecyl sulfate. Chromatographic analysis was performed on a reversed-phase HPLC column isocratically eluted with an acetonitrile/water/ammonia mixture and UV detection at 254 nm. The chromatographic method is repeatable, reproducible, and sensitive. Fungicide recoveries from lemon samples fortified at levels of 5 and 1 mg kg^–1 were 81–85% for carbendazim, 96–98% for thiabendazole, and 81–106% for o-phenylphenol with coefficients of variation of 2.5–7.4%. Detection limits for carbendazim, thiabendazole, and o-phenylphenol in lemons were 0.21, 0.27, and 0.51 mg kg^–1, respectively.     

Effect of the aspect ratio of silicate platelets on the mechanical and barrier properties of hydrogenated acrylonitrile butadiene rubber (HNBR)/layered silicate nanocomposites

The role of the aspect ratio of the layered silicate platelets on the mechanical and oxygen permeation properties of hydrogenated nitrile rubber (HNBR)/organophilic layered silicate nanocomposites was investigated. Montmorillonite (MMT) and fluorohectorite (FHT) bearing the same type of intercalant (i.e., octadecylamine; ODA), however, showing different aspect ratio was involved in this study. The dispersion of the layered silicates was assessed by X-ray diffraction (XRD) and transmission electron microscopy (TEM), respectively. Increasing aspect ratio (MMT < FHT) resulted in higher stiffness under uniaxial tensile loading. The dispersion state (“secondary structure”) of the organophilic layered silicates reduced dramatically the oxygen permeability of the rubber matrix based on the labyrinth principle. The lowest oxygen permeability was measured for the HNBR/FHT-ODA films in which the layered silicates had the highest aspect ratio. By varying the FHT-ODA volume fraction in the latter compound the mechanical and permeation properties were measured and modelled. It was found that the modified Guth’s and Nielsen’s equations predicted accurately the mechanical and permeation responses, respectively.     

In-plane stability of uniform steel beam-columns on a Pasternak foundation with zero end-shortening

The linearized buckling response of uniform steel beam-columns resting on a Pasternak foundation type is dealt with in this work. The corresponding two-point boundary value problem depends on the two parameters associated with the foundation model, that is, shear layer constant and Winkler spring coefficient, as well as on the axial loading. The fourth-order differential equation of buckling and the consequent characteristic one yield exact values of the buckling loads, which may lead to shape functions, being either one sinusoidal waveform or the sum of two different waveforms. The former case is associated with a single-mode response, while the latter with mode coupling. The conditions for which each of these cases characterizes the beam-column behavior are fully assessed and the dependence on the combination of the aforementioned parameters on the response is discussed in detail. It is found that regardless of the order of coupling, the corresponding mode is not related to rational values of buckling loads and hence this unfavorable phenomenon is excluded in structural design.     

Vibrational energy transfer in O2(X 3sigma(g)-, upsilon=2,3) + O2 collisions at 330 K

Vibrational relaxation of O2(X 3sigma(g)-, upsilon=2,3) by O2 molecules is studied via a two-laser approach. Laser radiation at 266 nm photodissociates ozone in a mixture of molecular oxygen and ozone. The photolysis step produces vibrationally excited O2(a 1delta(g)) that is rapidly converted to O2(X 3sigma(g)-, upsilon=2,3) in a near-resonant adiabatic electronic energy-transfer process involving collisions with ground-state O2. The output of a tunable 193-nm ArF laser monitors the temporal evolution of the O2(X 3sigma(g)-, upsilon=2,3) population via laser-induced fluorescence detected near 360 nm. The rate coefficients for the vibrational relaxation of O2(X 3sigma(g)-, upsilon=2,3) in collision with O2 are 2.0(-0.4)(+0.6) x 10(-13) cm3 s(-1) and (2.6+/-0.4) x 10(-13) cm3 s(-1), respectively. These rate coefficients agree well with other experimental work but are significantly larger than those produced by various semiclassical theoretical calculations.     

Development of an egg-white bioassay for monitoring biotin levels in urine and serum.

This article reports on the development of a simple and cost-effective bioassay for the detection of biotin in urine and serum, based on the very selective binding of avidin and biotin. Avidin was allowed to react without isolating it from egg white. Egg white was treated with the dye HABA, which binds to avidin. Upon subsequent treatment with biotin, HABA is released due to the high affinity of biotin to avidin. The amount of HABA released is proportional to the amount of biotin used.     

A finite difference scheme for computing inertial manifolds

A fully discrete method is presented for computing inertial manifolds of dissipative partial differential equations. In particular, only an approximate spectral decomposition of the dominant differential operator needs to be known. The first few of the smallest eigenvalues and eigenvectors of the discretized operator are approximated using the Lanczos algorithm. Numerical experiments are performed for an equation in one space dimension by discretizing the space variable on a sufficiently fine grid. The basic ideas and techniques are exemplified for selected bifurcation diagrams of an integrated form of the Kuramoto-Sivashinsky equation.This research was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) grant OGP0036901, NSERC and Schweizerischer Nationalfonds zur Förderung der Wissenschaften BEF 0150297, and Forschungsinstitut für Mathematik, ETH Zürich.