Scalable Synthesis of ABBV-105 Enabled by Suzuki Coupling with Low Pd Loading, Ru-Catalyzed Asymmetric Hydrogenation, and Acylation Using Impinging Jet

Abstract

Evolution of a synthetic process to prepare ABBV-105, a Bruton’s tyrosine kinase (BTK)-inhibitor, on multikilogram scale is described. The first-generation route utilized chiral resolution of the penultimate intermediate (7). Either Bartoli or Leimgruber–Batcho indole synthesis was used to prepare the key intermediate, indole boronate ester (23). As the demand for the API increased, the first-generation route was found to be low-yielding and expensive. It required column chromatography, had multiple alerting structures from the mutagenic impurity assessment, and suffered from lack of robustness. In the second-generation route a novel Ru-catalyzed asymmetric hydrogenation of 1,2,5,6-tetrahydropyridine (21) was developed to establish the stereocenter. Compound 21 was accessed via Suzuki coupling of 23, prepared by Friedel–Crafts acylation, with vinyl bromide (24) in the presence of very low loading of a Pd catalyst (0.15 mol % Pd). Finally, the penultimate intermediate (7) was coupled with acryloyl chloride using an impinging jet to prepare the API. Detailed kinetic and mechanistic work was conducted to control the persistent impurities formed in the API step. The second-generation route was robust, chromatography-free and high-yielding with low mutagenic liability.