Preparation of a HMG-CoA Reductase Inhibitor via an Optimized Imidazole-Forming Condensation Reaction
Daniel M. Bowles, Gary L. Bolton, David C. Boyles, Timothy T. Curran, RICHARD H. HUTCHINGS, Scott D. Larsen, Jonathan M. Miller, William K.C. Park, Kurtis G. Ritsema, David C. Schineman, Markus Tamm · Organic Process Research & Development · 2008
Development work toward an enabling synthesis of preparative scale batches of an imidazole-based HMG-CoA reductase inhibitor is described. The desired target was synthesized in 16% yield over 7 steps, highlighted by an imidazole-forming condensation reaction in which the yield was improved from 20% to >70% via modification of the solvent, acid, and amine equivalents. The step 2 acylation was improved, and a problematic benzyl ester in step 4 was converted into the corresponding benzyl amide to decrease trans-amidation during the step 5 imidazole formation. A highly effective salt formation and crystallization protocol was also developed.