Process Development for the Preparation of a Monopril Intermediate by a Trimethylsilyl-Modified Arbuzov Reaction

Abstract

A safe, rugged process for the manufacture of a Monopril intermediate using a trimethylsilyl-mediated Arbuzov reaction was developed. The problems encountered and overcome in iterations from pilot plant to manufacturing are described. The final process gives high-quality product (99.9% purity) in 82% yield. One key was developing an addition sequence to allow for the safe control of the reaction exotherm, complicated by the reflux temperature which decreased with conversion of reagents. Quantitative assessment of the reaction boiling point and exotherm led to the selection of the best addition and heating protocol. The output quality was assured by development of a thermally controlled process that crystallized the product without passing through an intermediate oil dispersion. Alternative conditions for safe control of the exotherm are suggested. Routine safety testing is demonstrated to be critical for rapid development of a safe, optimized process.