Early Process Development and Scale-up of a Tetrazole-Containing Soluble Guanylate Cyclase Stimulator

This paper describes the research and development of a practical and efficient process for manufacturing a soluble guanylate cyclase stimulator, 1. The newly developed process includes an efficient telescoped process consisting of four consecutive reactions: tetrazole formation, difluoromethylation of a tetrazole moiety, deprotection, and tert-butyldiphenylsilyl (TBDPS) protection. Although regioselectivity in difluoromethylation of the tetrazole moiety was moderate, the selective TBDPS protection gave the desired regioisomer exclusively. We addressed safety issues related to thermally unstable tetrazole compounds and developed a safe process based on the thermal analysis results in which operating temperatures were controlled and the dangerous compounds were not isolated. Notably, the need for chromatographic purifications was avoided for all synthetic steps. This highly efficient and safe process was successfully demonstrated on a pilot scale to yield 24.6 kg of 1 with high quality. Overall yield was improved from 35% by the medicinal chemistry route to 45%.