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

2011; American Chemical Society; Volume: 15; Issue: 5 Linguagem: Inglês

10.1021/op200175t

1520-586X

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 K. Yee, Chris H. Senanayake,

Cell Adhesion Molecules Research

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’s 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.