Sulfonyl pyridines have utility both as constituents of bioactive molecules and as synthetic intermediates. Typical methods for their preparation have suffered from the use of odiferous thiols, capricious oxidation steps, poor atom economy, and production of significant amounts of hazardous waste. Scientists in process research at Merck recently published a nice, straightforward, and one-pot approach which addresses all of these issues.Their method involves direct displacement of chloropyridines (they do also demonstrate that the methodology applies equally to other halides and triflates) with sulfinic acid salts in the presence of tetrabutylammonium chloride (TBACl). [The TBACl is postulated to enhance the solubility of the sulfinic acid salt in the solvent used (Dimethylacetamide, DMAc)]. The method works equally well for electron-deficient, electron-neutral, and electron-rich chloropyridines and is operationally straightforward (See examples above – an equivalent of HCl is required to protonate, and hence activate, the pyridine in the case of the latter two classes of substrate). The products are isolated in high yield simply by quenching with water and filtration of the resulting slurry.
Tagsallosteric amine basicity animal PK anti-viral AstraZeneca beta-secretase bioactivation Boehringer Ingelheim cancer cardiotoxicity CGRP CNS penetration computational method CYP450 fluorine free drug gpcr hepatotoxicity hERG isostere kinase LipE Merck metabolism mTOR Novartis P-gp Pain Pfizer Phase I Phase II Phase III POC PPB protein binding PSA reactive metabolite review Roche solubility Structural alert Structure Based Design synthesis toxicity X-ray data