Large-Scale Asymmetric Synthesis of the 3,6,7,8-Tetrahydrochromeno[7,8-d]imidazole BYK 405879: A Promising Candidate for the Treatment of Acid-Related Diseases

Abstract

A process for the synthesis of the potassium-competitive acid blocker BYK 405879 (8) was established based on the approach used in medicinal chemistry (asymmetric hydrogenation of prochiral ketone 15 and Mitsunobu cyclization of the resulting alcohol 34). Several critical reaction steps were optimized. The synthesis of prochiral ketones was accomplished using ethyl 3-(2-methylphenyl)-3-oxopropanoate instead of 1-[1-(2-methylphenyl)vinyl]pyrrolidine, a reagent that was difficult to prepare and possesses limited shelf life. The catalyst loading of the asymmetric hydrogenation step was reduced significantly from a S/C ratio of 100:1 to a S/C ratio of 2500:1 by benzyl protection of ketone 15. After the Mitsunobu cyclization, the removal of byproduct was easily accomplished through acid−base extraction, and pure BYK 405879 (8) was then obtained by means of crystallization in the presence of succinic acid.