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During the process development for multigram-scale synthesis of olmesartan medoxomil (OM), two principal regioisomeric process-related impurities were observed along with the final active pharmaceutical ingredient (API). The impurities were identified as N-1- and N-2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl derivatives of OM. Both compounds, of which N-2 isomer of olmesartan dimedoxomil is a novel impurity of OM, were synthesized and fully characterized by differential scanning calorimetry (DSC), infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their 1H, 13C and 15N nuclear magnetic resonance signals were fully assigned. The molecular structures of N-triphenylmethylolmesartan ethyl (N-tritylolmesartan ethyl) and N-tritylolmesartan medoxomil, the key intermediates in OM synthesis, were solved and refined using single-crystal X-ray diffraction (SCXRD). The SCXRD study revealed that N-tritylated intermediates of OM exist exclusively as one of the two possible regioisomers. In molecular structures of these regioisomers, the trityl substituent is attached to the N-2 nitrogen atom of the tetrazole ring, and not to the N-1 nitrogen, as has been widely reported up to the present. This finding indicates that the reported structural formula of N-tritylolmesartan ethyl and N-tritylolmesartan medoxomil, as well as their systematic chemical names, must be revised. The careful analysis of literature spectroscopic data for other sartan intermediates and their analogs with 5-(biphenyl-2-yl)tetrazole moiety showed that they also exist exclusively as N-2-trityl regioisomers. [ABSTRACT FROM AUTHOR]

Covalently-bonded atoms of Groups IV-VII tend to have anisotropic charge distributions, the electronic densities being less on the extensions of the bonds (σ-holes) than in the intervening regions. These σ-holes often give rise to positive electrostatic potentials through which the atom can interact attractively and highly directionally with negative sites (e.g., lone pairs, π electrons and anions), forming noncovalent complexes. For Group VII this is called "halogen bonding" and has been widely studied both computationally and experimentally. For Groups IV-VI, it is only since 2007 that positive σ-holes have been recognized as explaining many noncovalent interactions that have in some instances long been known experimentally. There is considerable experimental evidence for such interactions involving groups IV and VI, particularly in the form of surveys of crystal structures. However we have found less extensive evidence for Group V. Accordingly we have now conducted a survey of the Cambridge Structural Database for crystalline close contacts of trivalent nitrogen, phosphorus and arsenic with six different types of electronegative atoms in neighboring molecules. We have found numerous close contacts that fit the criteria for σ-hole interactions. Some of these are discussed in detail; in two instances, computed molecular electrostatic potentials are presented. [ABSTRACT FROM AUTHOR]

Several studies show a synergistic effect between intumescent formulations and aluminosilicates, such as zeolites and clays, but little is known about the effect of acidity of these additives on the synergistic action. In this work, H-ZSM-5 zeolite was submitted to desilication treatments for 30 min and for 2 h, and silicalite-1 was synthesized. The objective was to obtain samples of equivalent crystalline structure, but with different amounts of acid sites, in order to evaluate the effect of acid concentration of H-ZSM-5 zeolites on the synergistic action with an intumescent formulation composed by ammonium polyphosphate and pentaerythritol in polypropylene. H-ZSM-5 zeolites and silicalite were characterized by X-ray diffraction, nitrogen adsorption analysis and temperature-programmed desorption of ammonia. The desilication produced H-ZSM-5 zeolites with similar volumes of mesopores in both treatments, but the zeolite resulting from 2 h of desilication presented a higher concentration of acid sites than the zeolite from 30 min. The flame-retardant properties were evaluated by UL-94 classification, limiting oxygen index, glow-wire, thermogravimetric analysis and heating microscopy. The results showed that increasing the concentration and accessibility of the acid sites of H-ZSM-5 zeolites the flame-retardant properties of the studied composites improved. It is suggested that the increase of acid site concentration positively influences the catalysis of the reaction between ammonium polyphosphate and pentaerythritol, favoring the production of the precursors of the intumescent layer. [ABSTRACT FROM AUTHOR]