New ligands for nickel catalysis from diverse pharmaceutical heterocycle libraries.

Ligands are essential for controlling the reactivity and selectivity of reactions catalysed by transition metals. Access to large phosphine ligand libraries has become an essential tool for the application of metal-catalysed reactions industrially, but these existing libraries are not well suited to new catalytic methods based on non-precious metals (for example, Ni, Cu and Fe). The development of the requisite nitrogen- and oxygen-based ligand libraries lags far behind that of the phosphines and the development of new libraries is anticipated to be time consuming.

Pharmaceutical process chemistry: evolution of a contemporary data-rich laboratory environment.

Over the past 20 years, the industrial laboratory environment has gone through a major transformation in the industrial process chemistry setting. In order to discover and develop robust and efficient syntheses and processes for a pharmaceutical portfolio with growing synthetic complexity and increased regulatory expectations, the round-bottom flask and other conventional equipment familiar to a traditional organic chemistry laboratory are being replaced. The new process chemistry laboratory fosters multidisciplinary collaborations by providing a suite of tools capable of delivering deeper process understanding through mechanistic insights and detailed kinetics translating to greater predictability at scale.

Reduced pain inhibition is associated with reduced cognitive inhibition in healthy aging.

The analgesic effect of heterotopic noxious counter-stimulation (HNCS; "pain inhibits pain") has been shown to decrease in older persons, while some neuropsychological studies have suggested a reduction in cognitive inhibition with normal aging. Taken together, these findings may reflect a generalized reduction in inhibitory processes. The present study assessed whether the decline in the efficacy of pain inhibition processes is associated with decreased cognitive inhibition in older persons.

Preparation and utility of trihaloethyl imidates: useful reagents for the synthesis of amidines.

2,2,2-Trifluoro- and trichloroethyl imidates, which are easily prepared by reaction of a nitrile and a trihaloethanol in the presence of HCl, have proven to be excellent reagents for the preparation of amidines under mild reaction conditions. Depending on the nature of the amine nucleophile, the imidates can react either as the free-base or the hydrochloride salt in a telescoped process. In several cases, the p-bromobenzoate salt of the desired product was directly isolated from the reaction mixture.

The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development.

Starting materials and intermediates used to synthesize pharmaceuticals are reactive in nature and may be present as impurities in the active pharmaceutical ingredient (API) used for preclinical safety studies and clinical trials. Furthermore, starting materials and intermediates may be known or suspected mutagens and/or carcinogens. Therefore, during drug development due diligence need be applied from two perspectives (1) to understand potential mutagenic and carcinogenic risks associated with compounds used for synthesis and (2) to understand the capability of synthetic processes to control genotoxic impurities in the API.

Cu-catalyzed N-arylation of oxazolidinones: an efficient synthesis of the kappa-opioid receptor Agonist CJ-15161.

An efficient method for intermolecular N-arylation of oxazolidinones using catalytic copper in the presence of a bidentate ligand is reported. The conditions allow the use of copper and can be used to prepare enantiopure N-aryl beta-amino alcohols. A short, scalable synthesis of CJ-15,161 is also reported.

Efficient synthesis of [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]-acetic acid, a novel COX-2 inhibitor.

The synthesis of 6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid (1), a selective cyclooxygenase 2 (COX-2) inhibitor, is described. The synthesis relied on a novel indole formation that involved an alkylation/1,4-addition/elimination/isomerization cascade. It was demonstrated that the entire sequence from sulfonamide 13 and bromoketone 14 to the desired indole (1) could be executed in a single pot.

Synthesis of the kappa-agonist CJ-15,161 via a palladium-catalyzed cross-coupling reaction.

Syntheses of CJ-15,161 (1) involving intermolecular N-arylation of an appropriately functionalized diamine, obtained from the precursor alpha-amino acids or, more conveniently, from the corresponding 1,2-amino alcohols via 1,2,3-oxathiazolidine-2,2-dioxide 22, are reported.