Pilot-Plant Preparation of an α_vβ₃ Integrin Antagonist. Part 3. Process Research and Development of a Diisopropylcarbodiimide and Catalytic 1-Hydroxybenzotriazole Peptide Coupling

Abstract

Studies directed toward the process research, development, and scale-up preparation of the potential r v β 3 integrin antagonist 1 are described. A convergent approach is detailed wherein tetrahydropyrimidine hydroxybenzoic acid 2 is linked to the β-amino acid ester 3 via a diisoproylcarbodiimide, catalytic HOBt coupling reaction. Saponification of the resulting ethyl ester, isolation of the corresponding zwitterion, H 3 PO 4 salt formation, crystallization, and acetonitrile-to-acetone exchange give rise to 1 as a crystalline monohydrate in 67% overall yield from 4.