Gram-scale stereoselective synthesis of next generation of Trk Inhibitor LOXO-195

A gram-scale stereoselective synthesis of next generation of Trk Inhibitor LOXO-195 is reported. Starting from two commercially available and cheap building blocks, LOXO-195 is prepared via 9 steps in 26% overall yield with excellent enantioselectivity (ee > 99%). The new synthesis reported herein features a development of an efficient Csp 2 -Csp 3 suzuki coupling from key intermediates 19 and 16 , which allows to make LOXO-195 in a more convergent fashion compared to the reported synthetic route.