Efficient Synthesis of a Small Molecule, Nonpeptide Inhibitor of LFA-1

A three-stage process for the synthesis of LFA-1 inhibitor 1 from amine 4 with an overall yield of 65% is described. The key stage involves a Ph3PCl2-induced dehydration/cyclization of urea 6 followed by a regioselective bromination to give 1H-imidazo[1,2-a]imidazol-2-one 9. Br/Mg exchange of 9 followed by addition to SO2 in THF and subsequent oxidation produces a sulfonyl chloride which is directly reacted with l-alaninamide using K2CO3 as base in aqueous DMF/THF to give 1 in a one-pot operation. The process was implemented for the production of 1 on a metric ton scale.