Synthesis development of a naphthyridinone p38 kinase inhibitor

In this review the development of a viable large-scale synthesis of a p38 kinase inhibitor is discussed. Multiple strategies have been explored in devising syntheses to the intermediates containing the p38 kinase inhibitor's naphthyridinone core to allow the appendage of difluorophenyl and 4-N-tert-butylpiperidine fragments. A novel Heck lactamization reaction was discovered upon reacting 2,6-dichloroacrylanilide with a trihalo-substituted pyridine leading to the rapid synthesis of the naphthyridinone core. Investigations led to the development of two syntheses of 4-N-tert-butyl-chloropiperidine, including a novel methyl Grignard addition to an acetone iminium intermediate to build the tert-butyl group. The chemoselective addition of a 4-N-tertbutyl-chloropiperidine Grignard reagent to a pyridine oxide intermediate followed by re-aromatization using isobutylchloroformate and pyridine as solvent completed the synthesis of this potentially important p38 kinase inhibitor.