Development of an Early Enabling Synthesis for PF-03052334-02: A Novel Hepatoselective HMG-CoA Reductase Inhibitor

详细信息    查看全文

• 作者：Daniel M. Bowles ; David C. Boyles ; Chulho Choi ; Jeffrey A. Pfefferkorn ; Stephanie Schuyler ; Edward J. Hessler
• 刊名：Organic Process Research & Development
• 出版年：2011
• 出版时间：January 21, 2011
• 年：2011
• 卷：15
• 期：1
• 页码：148-157
• 全文大小：358K
• 年卷期：v.15,no.1(January 21, 2011)
• ISSN：1520-586X

文摘

Early process development work toward a promising pyrazole-based HMG-CoA reductase inhibitor is described. PF-03052334-02 (1) was prepared in 14 synthetic steps with a 21% overall yield, highlighted by a modified three-step hydroxypyrazole formation in which the yield was improved from 37% to 73%, a Suzuki/ozonolysis pathway that streamlined the downstream chemistry, and a reversed Wittig olefination strategy that improved the key coupling step from 50% to 95% yield. Multiple process hazards and most chromatography steps were removed, and a highly effective active pharmaceutical ingredient (API) salt formation, purification, and isolation protocol was also developed.