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.

Boron Reagents in Process Chemistry: Excellent Tools for Selective Reductions

“…229 Contrary to literature reports, sodium cyanoborohydride did not accomplish the reduction. Neither sodium triacetoxyborohydride nor dimethylamine borane were effective for the reductive cleavage.…”

“…In the synthesis of a new anti-hypertension drug, FR-143187, Zanka and co-workers needed to cleave an alkyltrimethylammonium iodide . Contrary to literature reports, sodium cyanoborohydride did not accomplish the reduction.…”

Non-Peptide Angiotensin II Receptor Antagonists: Chemical Feature Based Pharmacophore Identification

“…In the Catalyst AT 1 -antagonist-subset database, 98 of 138 AT 1 antagonists mapped the hypothesis as direct hits. New compounds reported recently in the literature were found in the query. ,,− The 3D database search in WDI resulted in only 73 structures (0.15% of the entire WDI). Thirty-seven of them were registered in the ensemble database 45 as AT 1 antagonists, six as AT 1 /AT 2 antagonists, and one as ACE inhibitor.…”

Large-Scale Carbonyl Reductions in the Pharmaceutical Industry

“…NaBH 4 , either by itself or in combination with other reagents (AcOH with simultaneous lactam reduction), CaCl 2 (in situ synthesis of Ca­(BH 4 ) 2 ), Na­(OAc) 3 BH (catalytic; methyl ester reduction in the presence of tert -butyl ester), and ZnCl 2 (with concomitant aryl nitrile reduction to amine)) have been employed on process scale for ester reduction to the alcohol. Heating is often required since esters are less reactive than aldehydes or ketones.…”