Stereoselective Synthesis of ABBV-992 Enabled by a Flow Diazotization and a Partial Reduction of a Pyridone

Bruton’s tyrosine kinase (BTK) is involved in
B-cell receptor
signaling and has been clinically validated as a target by small molecule
inhibition for the treatment of a variety of cancers. ABBV-992 (1) was identified as a novel, potent, selective BTK inhibitor
and advanced to Phase I clinical trials. An enantioselective synthesis
of 1 was developed and scaled to provide 63 g for preclinical
characterization. The route features a diazotization enabled by flow
chemistry, a novel, selective partial reduction of a pyridone, a stereoselective
Ellman imine reduction, and an improved acrylamide formation using
3-chloropropionyl chloride in a masked acrylate strategy.