GB855170A - 6-demethyl-6-deoxytetracycline and the 4-epimers thereof - Google Patents

Abstract

The invention relates to 6-demethyl-6-deoxytetracycline having the formula: <FORM:0855170/IV(b)/1> the 4-epimer thereof, and salts of these compounds with an acid or a base and complexes with metal salts, e.g. aluminium, magnesium and calcium, e.g. aluminium gluconate. The base is obtained by catalytically reducing by means of hydrogen a 6-demethyltetracycline of formula: <FORM:0855170/IV(b)/2> wherein Z is hydrogen, chlorine or bromine, or the 4-epimer thereof, in a solvent solution in the presence of a substance which forms a chelate ring with a peri-dioxygenated hydro-naphthalene, e.g. boric acid, boron trihalides such as boron trifluoride, aluminium salts such as aluminium chloride and magnesium salts such as magnesium acetate. Where Z is hydrogen one mole of hydrogen is used and where Z is chlorine or bromine 2 moles of hydrogen are used. The reduction is carried out at temperatures of 0 DEG C. to 100 DEG C. and preferably at room temperature to 50 DEG C. and at hydrogen pressures of 1/2 to 100 atmospheres. The catalyst may be a metal of the platinum family especially 5% palladium hydroxide on charcoal. Specified solvents are water, dioxane, glacial acetic acid, 2-ethoxyethanol and ethyl acetate; a mixture of water and dimethylformamide (1 : 1) containing perchloric acid is preferred. The 4-epimer of 6-demethyl-6-deoxytetracycline is produced by allowing a concentrated solution of 6-demethyl-6-deoxytetracycline to stand at pH 3 to 5 and preferably 3,5 to 4,5 for 1 to 7 days. A suitable solvent is methanol, ethanol, butanol, acetone, 2-ethoxyethanol, 2-methoxypropanol, glacial acetic acid, tetrahydrofuran dimethylformamide and mixtures thereof. A suitable buffer is sodium dihydrogen phosphate. Acid salts are prepared by treating the 6-demethyl-6-deoxytetracycline with an acid, e.g. hydrochloric, sulphuric, phosphoric and trichloroacetic at pH below 4. Alkali metal and alkaline earth metal salts are obtained by treating the 6-demethyl-6-deoxytetracycline with a base such as sodium hydroxide, potassium hydroxide, calcium hydroxide or barium hydroxide at a pH above 6,0. The free 6-demethyl-6-deoxytetracycline may be obtained by adjusting a solution of the salt to pH 4 to 6. 6-demethyl-6-deoxytetracycline aluminium gluconate complex is produced by mixing 6-demethyl-6-deoxytetracycline with aluminium gluconate in aqueous solution. 6-demethyl-6-deoxytetracycline is a broad spectrum antibiotic more active against staphyloccus aureus than tetracycline and possessing some stability in acid and alkaline aqueous media. Specification 855,169 is referred to.