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

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.