The discovery, development and implementation of two chemical routes to ABT-869 is reported. Optimization of the first-generation heterocycle formation and Suzuki coupling is briefly described. Key features of the second-generation synthesis include the development of a safe hydrazine condensation by utilizing an inorganic base to increase the onset temperature of exothermic decomposition. The second-generation Suzuki reaction is discussed in detail, culminating in the use of an oxygen monitor as a PAT to maximize reproducibility on scale.
A convergent, scalable synthesis of dipeptidyl peptidase-4 inhibitor, ABT-279, has been developed and demonstrated on multikilogram scale. The cis-2,5-disubstituted pyrrolidine is generated by cyclization of a Boc-amine onto an alkynyl ketone followed by stereospecific reduction of the resulting acyliminium intermediate. The amine coupling partner was prepared by a novel Hofmann rearrangement promoted by 1,3-dibromo-5,5-dimethylhydantoin. The final product was isolated as the l-malic acid salt. The scale-up campaign consisted of 15 steps and delivered 42 kg of ABT-279 in 14% overall yield. A second-generation synthesis that addresses some of the issues encountered during scale-up was developed and demonstrated on kilogram scale.
An expedient asymmetric synthesis
of TRPV1 antagonist 1 has been developed and demonstrated
on multikilogram scale. The enabling route to 1 is detailed
herein and characterized by the following key transformations: an
aldol-cyclodehydration sequence to install the chromanone, and an
auxiliary-mediated diastereoselective reductive amination.
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