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

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.