GB1077598A — Preparation of n-demethyl tetracyclines

USPTO Abstract

N-Demethyltetracyclines are prepared by oxidizing the manganese or cerium metal chelate of a 12a-deoxytetracycline having at least a 4-dimethylamino group and the 1-, 11-, and 12-keto groups, i.e. <FORM:1077598/C2/1> (or tautomeric forms thereof), and optionally further substituents, by treating it with an oxidizing agent at a pH of 8 to 10 in an aqueous reaction-inert solvent, and recovering the corresponding N-demethyl product from the reaction mixture. Suitable oxidizing agents are air, oxygen, ozone, hydrogen peroxide, alkali metal peroxides, organic peroxides such as benzoyl-, acetyl-, acetyl-benzoyl-, lauroyl-and stearoyl-peroxide, and organic peracids such as peracetic and perbenzoic acids, the peracids optionally being formed in situ by reaction of acetic or benzoic acid with hydrogen peroxide. When organic peroxides are used, free radical initiators such as a , a 1-azodiisobutyronitrile; a ,a 1 - azobis - (a ,a 1 - dimethyl-valeronitrile); dimethyl- and diethyl-a ,a 1-azodiisobutyrate; or 1,11-azodiisobutyrocarbonamide, are preferably present. The chelates are either formed in situ prior to the oxidation, by simple admixture in the reaction solvent of an appropriate soluble managanese or cerium salt and the tetracycline, or may be preformed and added as the chelate. Suitable solvents are water, and aqueous mixtures containing one or more lower alkanols, dimethyl formamide, dioxane, acetonitrile, tetrahydrofuran, and alkyl ethers of glycols. Any tetracycline having the aforesaid essential groups may be used, many being listed. The reaction products may be isolated by removal of the metal ion by precipitation, e.g. with H2S, precipitation of the products by adjusting the pH to their isoelectric point, concentration of the reaction mixture followed by solvent extraction of the products, or absorption of the chelating metal on weakly acidic carboxylic acid resin to leave the products in the eluate. The reaction product mixtures so obtained contain unchanged starting material and other by-products, from which the desired N-demethyltetracycline is isolated by column chromatography. Examples are given for the preparation of the following 6 - deoxytetracyclines: (1) N - demethyl - 6-demethyl-(in the epi form); (2) N-demethyl-6-demethyl- (in the normal form); and also (3) epi-N-demethyltetracycline and many of its analogues with various listed substituent groups.