Process Development of a Potent Bradykinin 1 Antagonist

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• 作者：Karsten Menzel ; Fouzia Machrouhi ; Matthew Bodenstein ; Anthony Alorati ; Cameron Cowden ; Andrew W. Gibson ; Brian Bishop ; Norihiro Ikemoto ; Todd D. Nelson ; Michael H. Kress ; Doug E. Frantz
• 刊名：Organic Process Research & Development
• 出版年：2009
• 出版时间：May 15, 2009
• 年：2009
• 卷：13
• 期：3
• 页码：519-524
• 全文大小：142K
• 年卷期：v.13,no.3(May 15, 2009)
• ISSN：1520-586X

文摘

As part of Merck’s continued research effort on inflammation and pain, a safe synthesis of an orally bioavailable and CNS penetrant bradykinin 1 antagonist was developed and demonstrated on kilogram scale. The key step included a novel regioselective metal−halogen exchange reaction on 1,2-dibromo-5-chloro-3-fluorobenzene using isopropyl magnesium chloride to install the 1,2,4-oxadiazole ring structure. Suzuki cross-coupling reaction between a highly functionalized and sterically hindered electrophile and boronic ester generated the biaryl ring system, which was converted to the target molecule (1) using standard chemistry. The safe installation of a 1,2,4-oxadiazole ring proved to be challenging since the original synthetic route relied on the preparation of a highly functionalized benzonitrile using potassium cyanide and resulted in low yields and large amounts of potentially hazardous waste. Overall, a safe and robust synthesis was developed, which occurred in eight linear steps with an overall yield of 28%.