Development of a Second-Generation, Highly Efficient Manufacturing Route for the HIV Integrase Inhibitor Raltegravir Potassium

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• 作者：Guy R. Humphrey ; Philip J. Pye ; Yong-Li Zhong ; Remy Angelaud ; David Askin ; Kevin M. Belyk ; Peter E. Maligres ; Danny E. Mancheno ; Ross A. Miller ; Robert A. Reamer ; Steven A. Weissman
• 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：73-83
• 全文大小：433K
• 年卷期：v.15,no.1(January 21, 2011)
• ISSN：1520-586X

文摘

A manufacturing route for the synthesis of raltegravir potassium 1 was developed via a thermal rearrangement of amidoxime DMAD adducts 6 to construct the key, highly functionalized hydroxypyrimidinone core 7. Utilizing this route 1 was prepared in nine linear chemical steps with 22% overall yield. A second-generation synthesis was subsequently developed that solved the key chemical, productivity, and environmental impact issues of the initial synthesis. Highlights of the new synthesis include a highly selective methylation, 3鈭?-fold higher productivity, and a 65% reduction of combined organic and aqueous waste produced. The efficient second-generation manufacturing route provides raltegravir potassium 1 in 35% overall yield.