is an open access repository that collects the work of Arts et Métiers ParisTech researchers and makes it freely available over the web where possible. b s t r a c tThis paper assesses and quantifies the detrimental effects of complex tri-dimensional notches subjected to uniaxial and multiaxial fatigue loading. A number of experimental results taken from the technical literature and generated by testing specimens containing complex geometrical features were reanalysed using a critical distance/plane method. The investigated notched samples were tested under uniaxial and multiaxial constant amplitude load histories, considering also the effects of non-zero mean stresses as well as non-proportional loading. The common feature of the considered notched geometries was that the position of the critical location changed as the degree of multiaxiality of the applied loading varied. The relevant linear-elastic stress fields in the vicinity of the crack initiation points were calculated by the Finite Element method and subsequently post-processed using the Modified Wöhler Curve Method in conjunction with the Theory of Critical Distances (the latter theory being applied in the form of the Point Method). This validation exercise confirms the accuracy and reliability of our multiaxial fatigue life assessment technique, which can be efficiently used in situations of practical interest by directly postprocessing the relevant linear-elastic stress fields calculated with commercial Finite Element software packages.

A case history is outlined for the development of a scaleable route to the drug candidate UK-357,903. Despite the partial structural similarities to those of sildenafil (Viagra), the introduction of the central pyridine moiety within UK-357,903 had a significant impact on the commercial process. In particular, the triply activated 2-alkoxypyridyl moiety of UK-357,903 is much more susceptible to nucleophilic attack than the 2-ethoxyphenyl moiety of sildenafil, necessitating the development of new chemistry. Particular items of note are (i) the new six-step route to the advanced 2-ethoxy-5-(4-ethylpiperazinylsulfonyl)nicotinic acid intermediate and the subsequent telescoping to a two-pot process, (ii) the telescoping of the two steps from N-[3-carbamoyl-5-ethyl-1-(2-pyridylmethyl)-1Hpyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamide to UK-357,903 to a single step, with the additional use of a hydroxide trapping agent to give an ambient pressure process yielding clinical quality product, and (iii) the introduction of process modifications to allow for the use of teratogenic 2-methoxyethanol, as both reagent and solvent, in the penultimate process step.

This is the first in a series of three papers describing commercial manufacturing process development for palbociclib (1). This manuscript focuses on the SNAr coupling between aminopyridine 3 and chloropyrimidine 7. The regioselectivity of the SNAr coupling was studied from a synthetic and mechanistic perspective. Grignard bases were identified as the preferred class of bases for this reaction, allowing for a simplified process and reduced usage factor for aminopyridine 3. The development of this SNAr reaction into a scalable commercial manufacturing process is also described.

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or Mg or produce hydrated double sulfates. Methods of trivalent cations of Fe, Cr or A1 were combined preparation and properties are described. with either neutral or acid nicotine sulfate to Philadelphia 18, Pa.