Development of a Scalable Synthesis of a GPR40 Receptor Agonist

Early process development and salt selection for AMG 837, a novel GPR40 receptor agonist, is described. The synthetic route to AMG 837 involved the convergent synthesis and coupling of two key fragments, (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (1) and 3-(bromomethyl)-4'-(trifluoromethyl)biphenyl (2). The chiral beta-alkynyl add 1 was prepared in 35% overall yield via classical resolution of the corresponding racemic acid (+/-)-1. An efficient and scalable synthesis of (+/-)-1 was achieved via a telescoped sequence of reactions including the conjugate alkynylation of an in situ protected Meldrum's add derived acceptor prepared from 3. The biaryl bromide 2 was prepared in 86% yield via a 2-step Suzuki-Miyaura coupling-bromination sequence. Chemoselective phenol alkylation mediated by tetrabutylphosphonium hydroxide allowed direct coupling of and 2 to afford AMG 837. Due to the poor physiochemical stability of the free acid form of the drug substance, a sodium salt form was selected for early development, and a more stable, crystalline hemicalcium salt dihydrate form was subsequently developed. Overall, the original 12-step synthesis of AMG 837 was replaced by a robust 9-step route affording the target in 25% yield.