Process Development and Large-Scale Synthesis of a c-Met Kinase Inhibitor

A highly convergent synthesis of c-Met kinase inhibitor 1 has been demonstrated on a multikilogram scale using three key fragments: dihalotricyclic core 2, chiral sulfamide side chain 3, and pyrazole boronic ester 4. The chirality in sulfamide side chain 3 was installed using the cheap and readily available starting material (S)epichlorohydrin. A total of 2.71 kg of 1 were isolated in seven steps (the longest linear sequence).