SYNTHESIS OF OXY-9,10-DIOXO-9,10-DIHYDROANTHRACENE-2-CARBOXYLIC ACID,AN ANALOG OF RHEIN WITH IMPROVED SYSTEMIC EXPOSURE IN THE GUINEA-PIG

N,N-Diethyl(2-methoxy-4-methyl)benzamide 4 has been lithiated and trea ted with 2,5-dimethoxybenzaldehyde to give yphenyl)-7-methoxy-5-methyl isobenzofuran-1(3H)-one 5. Reduction and cyclisation gives 4,5,8-trime thoxy-2-methylanthracen-10-ol 7 which is oxidised to give 4,5,8-trimet hoxy-2-methylanthraquinone 8. Demethylation gives the natural product helminthosporin 9, oxidation gives oxy-9,10-dioxo-9,10-dihydroanthrace ne-2-carboxylic acid an analogue of the osteoarthritis drug rhein, Alt ernatively, dimethylrhein methyl ester 12 may be iodinated and the iod ine displaced with methoxide to provide a large-scale synthesis of 3. Plasma concentration data in the guinea pig were obtained for 3, diace tylrhein, dimethylrhein and 4,5-dimethyl-8-fluororhein after oral dosi ng.