Asymmetric Synthesis of LFA-1 Inhibitor BIRT2584 on Metric Ton Scale

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• 作者：Xiao-Jun Wang ; Rogelio P. Frutos ; Li Zhang ; Xiufeng Sun ; Yibo Xu ; Thomas Wirth ; Thomas Nicola ; Lawrence J. Nummy ; Dhileep Krishnamurthy ; Carl A. Busacca ; Nathan Yee ; Chris H. Senanayake
• 刊名：Organic Process Research & Development
• 出版年：2011
• 出版时间：September 16, 2011
• 年：2011
• 卷：15
• 期：5
• 页码：1185-1191
• 全文大小：864K
• 年卷期：v.15,no.5(September 16, 2011)
• ISSN：1520-586X

文摘

The synthesis of LFA-1 inhibitor BIRT2584 on metric-ton scale was accomplished by means of a safe and robust process. Highlights of the process include the asymmetric synthesis of the key advanced intermediate by implementation of Seebach鈥檚 self-regeneration of stereocenters principle, and a Ph₃PCl₂-induced dehydration of a critical urea followed by a regioselective bromination to give the elaborated 1H-imidazo[1,2-a]imidazol-2-one. A sulfonyl chloride intermediate was produced through Br/Mg exchange of iodoimidazole followed by addition to SO₂ in THF and subsequent oxidation. In a one-pot operation, the sulfonyl chloride was directly reacted with l-alaninamide using NaOH as base in aqueous DMF/THF to give BIRT2584.