Preparation of a HMG-CoA Reductase Inhibitor via an Optimized Imidazole-Forming Condensation Reaction

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• 作者：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
• 刊名：Organic Process Research & Development
• 出版年：2008
• 出版时间：November 21, 2008
• 年：2008
• 卷：12
• 期：6
• 页码：1183-1187
• 全文大小：147K
• 年卷期：v.12,no.6(November 21, 2008)
• ISSN：1520-586X

文摘

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.