Diethyl Ether → m-Tetrahydropyranyloxybenzenesulfonyl chloride

Participants

Reaction Steps

The synthesis of HIV protease inhibitor UIC-98-056 with hydroxyethylene and hydroxyethylamine isosteres is outlined in FIG. 3. The known lactone 1 was converted to acid 2 by lithium hydroxide mediated hydrolysis followed by protection of the alcohol functionality as tert-butyldimethylsilyl ether (Ghosh et al., 1998, Synthesis, 937 (Review); Ghosh et al., 1991, J. Org. Chem. 56:6500; Evens et al., 1985). The previously described (Ghosh et al., 1992, J. Chem. Soc., Chem. Co., 273; Ghosh et al., 1998, Synthesis, 937 (Review)) azido epoxide 3 was reacted with isobutylamine in 2-propanol at 80° C. for 4 h and the resulting azidoalcohol was treated with m-tetrahydropyranyloxybenzenesulfonyl chloride 4 (Metanilic acid was diazotized at 0° C. and the resulting salt was boiled with water to obtain 3-hydroxybenzene sulfonic acid which was then treated with thionyl chloride/catalytic DMF/reflux to obtain sulfonyl chloride. The hydroxy group of the resulting 3-hydroxybenzene sulfonyl chloride was protected as THP ether by treating with DHP/catalytic PPTS in methylene chloride to get 4 as an oil.) in the presence of aqueous NaHCO3 to provide the sulfonamide derivative 5. The azide functionality of 5 was hydrogenated over 10% Pd—C in methanol to afford the corresponding amine which was coupled with the acid 2 in the presence of 1-[3-dimethylaminopropyl]-3-ethylcarodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) to afford the amide 6. Removal of the BOC group by treatment with aqueous hydrochloric acid and alkoxycarbonylation of the resulting amine with the known (Ghosh et al., 1993a) mixed active carbonate 7 in methylene chloride in the presence of 3 equivalents of triethylamine (Et3N) 23° C. for 12 h afforded the inhibitor 8 (UIC-98-056).

Provenance & Evidence