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.

• Brady, P
• Harper, K
• Sorensen, B
• Greszler, S
• Lai, C
• Florjancic, A
• Zhao, G
• Shelat, B
• Storer, G
• Henry, R
• Hansen, T

• Centralized Organic Synthesis Group, Small Molecule Therapeutic & Platform Technologies, AbbVie Inc., North Chicago, Illinois 60044, United States

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