Synthesis of carbon-14 labeled CI-1012 and CI-1013, potential anti-HIV agents

Abstract

14C-Labeled CI-1012 and CI-1013 of the 2,2′-dithiobis[benzamide] and benzisothiazolone series, inhibitors of viral replication and potential anti-HIV agents, were prepared. The radiolabeling of CI-1013, a six-step synthetic sequence, started with the treatment of N-t-BOC-aniline (2) with 2·0 equivalents of t-BuLi, followed by carboxylation of the ortho-lithiated center in the resulting lithiated dianion 2b with [14C]carbon dioxide, to give N-t-BOC-2-Amino-[7-14C]benzoic acid (3). Product 3 was then deprotected with trifluoroacetic acid to give 2-Amino-[7-14C]benzoic acid as its TFA salt (4). The latter was diazotized and treated with Na2S2, generated in situ, to give 2,2′-dithiobis[7-14C]benzoic acid (5). The acid chloride from 5, obtained by treatment with thionyl chloride, was subsequently coupled with L-isoleucine tert-butyl ester and deprotected with TFA to produce [S-(R*,R*)]-2-{2-[2-(1-Carboxy-2-methylbuty)[14C]carb-amoyl)phenyldisulfanyl]-[7-14C]benzoylamino}-3-methylpentanoic acid ([14C2]CI-1013) (8). Treatment of 8 with bromine yielded the benzisothiazolene, [S(R*,R*)]-3-Methyl-2-(3-oxo-3H-[3-14C]benz[d]isothiazol-2-yl)pentanoic acid ([14C]CI-1012) (9). Copyright © 1999 John Wiley & Sons, Ltd.