Development and Pilot-Scale Demonstration of a Process for Inhibitors of the HIV Nucleocapsid Protein, NCp7

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Abstract

A manufacturing process to prepare two antiretroviral agents that denature the HIV-1 nucleocapsid protein (NCp7) has been developed and demonstrated on a pilot scale. 2,2‘-Dithiobis(benzoyl chloride) (4), prepared from commercially available 2,2‘-dithiobis(benzoic acid) (3), was coupled directly with l-isoleucine to give the potential anti-HIV compound [S-(R*,R*)]-2-{[2-[[2-[(1-carboxy-2-methylbutyl)carbamoyl]phenyl]dithio]benzoyl]amino}-3-methylpentanoic acid (2) thereby eliminating the α-amino acid protection and deprotection steps used in the original synthesis. Compound 2 was oxidized by bromine to a second potential anti-HIV compound [S-(R*,R*)]-3-methyl-2-(3-oxo-3H-benzo[d]isothiazol-2-yl)pentanoic acid (1). The intermediacy of the hydrobromide salt of 1 provided an effective purity control in the production of the pharmaceutical agent. Cost, operational, safety, environmental, and equipment considerations were taken into account during the course of development.

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