A modified synthetic
route to BMS-978587 was developed featuring
a chemoselective nitro reduction and a stereospecific Suzuki coupling
as the key bond formation steps. A systematic evaluation of the reaction
conditions led to the identification of a robust catalyst/ligand/base
combination to reproducibly effect the Suzuki reaction on large scale.
The modified route avoided several challenges with the original synthesis
and furnished the API in high overall yield and purity without recourse
to chromatography.
A scalable route to the small molecule TGFβR1 inhibitor BMS-986260 (1) was developed. This alternative approach circumvented the purification of intermediates by column chromatography and provided access to multikilogram quantities of the key intermediate, 6. The safety aspects of the synthetic approach to the other fragment of the API (TosMIC 10) were critically evaluated, and a robust process for its large-scale synthesis was successfully demonstrated.
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