Pilot Scale Synthesis of a Novel Nonpeptide Angiotensin II Receptor Antagonist

Abstract

FR143187 is a novel nonpeptide angiotensin II receptor antagonist under development at Fujisawa Pharmaceutical Co. for the treatment of hypertension. Development of a process for preparation on a large scale is described. The optimized process is 10 steps in length and uses only commercially available materials for each step. Efficient methylation of the 2-position of a pyrrole derivative was achieved by reduction of a Mannich base via the quaternary ammonium salt. Selective cyanation directed by a solvent effect was also investigated. Process improvement efforts focused on optimized reaction conditions for each step, leading to a high-quality product according to a new and concise synthetic route.