Synthesis of ABT-378, an HIV Protease Inhibitor Candidate:  Avoiding the Use of Carbodiimides in a Difficult Peptide Coupling

An alternative to carbodiimide-mediated peptide coupling protocols has been developed for a carboxylic acid prone to decomposition by polymerization. This method, involving the in situ generation of an acyl imidazolide, has been applied to the preparation of a lead clinical HIV protease inhibitor candidate, ABT-378. The nature of the polymerization and optimization of the new reaction conditions are presented.