Development of a Total Telescoped Synthesis of a Renin Inhibitor Containing 3,4,5-Substituted Piperidine with Sterically Hindered Amide Bonds

Abstract

A telescoped synthesis for the manufacturing of a renin inhibitor containing 3,4,5-substituted piperidine with sterically hindered amide bonds via a five-step synthetic route is described. Highlights of this scalable synthesis include: (1) the byproduct-controlled amidation protocol using Ghosez’s reagent in the presence of a mild acid scavenger for the formation of the first sterically hindered amide bond; (2) the chemoselective hydrolysis of a sterically hindered ester; (3) an efficient amidation reaction employing a soluble carbodiimide leading to the second sterically hindered amide bond; (4) filtration of the fumarate salt of the final drug substance, being the only necessary isolation step throughout the total synthesis. Without the necessity of isolating any intermediates, this telescoped process conserved equipment usage, consumed less solvents, and minimized process waste generation, energy consumption, personnel exposure, and environmental impact. It furnished kilogram quantities of high-quality active pharmaceutical ingredients.