Enantioselective Suzuki–Miyaura Chemistry: Route Evolution for the Synthesis of PKMYT1 Inhibitor XL495

An asymmetric synthetic route to XL495, an atropisomeric PKMYT1 inhibitor, is reported. While a kilogram-scale and practical process was established by classic salt resolution, concerns related to the commercial process led to the study of an enantioselective alternative. The new route leverages an enantioselective Suzuki-Miyaura reaction as a key step in the atroposelective synthesis of biaryl compounds. A crystallization method for selectively purifying the target atropisomer was developed through high-throughput experimentation (HTE), enabling an enantiomeric excess (ee) of >95%. This new chemistry has been demonstrated and shows promise for utility at large scale, typical of a late-stage clinical and commercial route, due to significant improvements in overall yield, process mass intensity (PMI), and production efficiency.