Arylsulfonamides are attractive pharmacophores for drug candidates. Fragmentation behaviors of selected aromatic sulfonamides were investigated using electrospray ionization mass spectrometry in the positive ion mode. Some of the sulfonamides afforded unique loss of 64 (loss of SO(2)) ions upon collision-induced dissociation followed by intramolecular rearrangements in the gas phase. This SO(2) elimination-rearrangement pathway leading to the generation of [M + H - SO(2)](+) ions appeared to be susceptible to substitutions on the aromatic (Ar) ring that would affect the Ar--sulfur bond strength and the stability of the partially positive charge developed at the ipso position upon bond dissociation. Electron withdrawing groups such as chlorine attached to the aromatic ring at ortho position seem to promote the SO(2) extrusion. Although this fragmentation pathway in atmospheric pressure ionization MS is less predictable than in electron impact MS, it is a frequently encountered reaction. The absence of this fragmentation pathway in some of the arylsulfonamides indicates that other factors such as nucleophilicity of the nitrogen may also play a role in the process. With respect to the site of attachment of the migrating NR'R'', ipso-substitution on the aromatic ring is evident since this fragmentation mechanism is operative in the fully ortho-substituted arylsulfonamides.

The development of a novel, cost-effective synthesis of the vitronectin receptor antagonist SB-273005 became necessary as the compound proceeded to Phase 1. A practical synthesis of the compound presented challenges to the process chemist. Chief among the challenges was developing an enantioselective route to the compound. Second was either developing a scalable Mitsunobu coupling of the side chain to the main body or finding alternate chemistry. In this paper we will describe the chemistry we developed which allowed us to make over a hundred kilograms of SB-273005 by a process that we believe is suitable for even larger scale manufacturing.

An unusual pharmaceutical solid containing a pleuromutilin derivative, succinic acid and water is studied with a combination of physiochemical methods. The parent pleuromutilin derivative creates a host structure that contains large channels, which are occupied by variable amounts of both succinic acid and water. The inherent disorder of the system does not lend itself to detailed single-crystal X-ray diffraction studies; hence a combination of powder X-ray diffraction (PXRD) and solid-state NMR (SSNMR) techniques were used to characterize this system and understand its behavior. A variety of one and two-dimensional SSNMR experiments were used to understand the proton transfer and the hydrogen bonding network, including 1 H-13 C heteronuclear correlation experiments and measurements of the principal components of 13 C chemical shift tensors. This crystal system can exist as two distinct phases; a hemisuccinate phase containing a doubly ionized succinate molecule with two cations of the pleuromutilin derivative, and a succinic acid rich phase which contains a singly ionized succinate molecule hydrogen bonded to another fully protonated succinic acid for every mole of the pleuromutilin derivative. Individual particles can contain mixtures of these two phases, leading to a range of apparent stoichiometries between the succinic acid and pleuromutilin derivative. Both phases are variable hydrates and were characterized by gravimetric vapor sorption and variable humidity 13 C SSNMR techniques.

Both 6.6""-dimethyl-(dmqpy) and 6,6""-dimethyl-4',4'"-diphenyl-2,2' : 6',2" : 6",2"' : 6"',2""-quinquepyridine (dmpqpy) have been found to form dinuclear double helical silver(1) complexes [Ag,(dmqpy),][ClO,], 1 and [Ag2(dmpqpy)2][C10,]2~2H20 2. The introduced terminal methyl groups play a crucial role in the assembly processes. According to their crystal structures, the ligand adopts the usual [2 + 31 co-ordination mode in 1 and the silver(1) is five-co-ordinated with a flattened and distorted trigonal-bipyramidal geometry. In 2 the ligand dmpqpy adopts a [2 + 1 + 21 mode and is unexpectedly tetradentate with the central pyridyl nitrogen atom having no direct co-ordination and acting as a rigid spacer. The silver(1) atoms are four-co-ordinated. It is supposed that the increased conjugation and rigidity caused by the phenyl groups at the 4',4"' positions makes it difficult for the central pyridine nitrogen to co-ordinate to Ag'. Strong intramolecular n-n stacking interactions exist in complex 1, but the stacking effects in 2 are much weaker. The NMR results indicate that both complexes adopt more symmetric configurations in solution than in the solid state.