GB1100884A - Oxytetracycline esters and preparation thereof - Google Patents

Abstract

The invention relates to tetracycline compounds having the formulae <FORM:1100884/C2/1> <FORM:1100884/C2/2> <FORM:1100884/C2/3> wherein A is -CH3 or YSCH2, Y being primary or secondary C1-C12 alkyl; R11CO(R11 bein C1-C3 alkyl); phenyl; mono- or di-substituted phenyl; benzoyl; -CF3; or R1CH2 (R1 being mono- or di-substituted C1-C6 alkyl, C1-C6 carbalkoxy, halo, phenyl, mono- or di-substituted phenyl, or furyl); each substituent of mono- or di-substituted alkyl being C1-C6 alkoxy, C1-C6 carbalkoxy or halo and when two substituents are on the same carbon, at least one is C1-C6 carbalkoxy; and each substituent of mono- or di-substituted phenyl being C1-C6 alkyl, alkoxy or carbalkoxy, or nitro; and wherein B is hydrogen; or wherein A with B is methylene; and wherein R1 is alkanoyloxy, phenoxyalkanoyloxy or C1-C6 alkoxy-alkanoyloxy, in which the alkanoyloxy groups are C2-C6; and acid addition or metal salts, and metal salt complexes of these compounds. The compounds, which are O5-monoacyl oxytetracyclines, and also the corresponding O12a-acyl derivatives of the compounds (i.e. O5,O12a-diacyl oxytetracyclines), are prepared by treating the corresponding O12a-monoacyl oxytetracycline or the corresponding O10,O12adiacyltetracycline, or a metal salt thereof, in aqueous solution with at least one equimolar proportion of alkali metal hydroxide, or in alcoholic solution with alkali metal alcoholate, to effect a re-arrangement of the acyl groups. The product may be treated, inert solvent, with one equivalent of acid, metallic base, or metal salt to give the corresponding salt or complex. The reaction temperature is preferably between 0 DEG and 50 DEG C. Dedradation of the esters may be minimized by conducting the reaction in the presence of 1 to 2 equivalents of a solvent-soluble polyvalent metal salt, e.g. salts of Ca, Mg, Zn, Cd, Cu, Ni or Co, and preferably magnesium chloride hexahydrate, many other suitable Mg salts being listed. The products are isolated by adjusting the reaction mixture pH to 2-7 and extracting with an immiscible solvent, e.g. ethyl acetate. When a polyvalent metal is present, the product may be recovered as the metal-ester complex, which is precipitated by adjusting the pH to 6-8. Additional processes mentioned are catalytic hydrogenation of the inventive products, under acid conditions with a palladium catalyst, to give the corresponding epimeric 6-deoxy-oxytetracyclines; also Raney nickel desulphurization of the benzylmercaptan adducts to give a -6-deoxy-oxytetracycline esters; mild acid treatment, e.g. with saturated methanolic HC1 to effect dehydration to 5a,6-anhydro-O5acyl oxytetracyclines; and formation of mixed esters by further esterification of the inventive compounds. Preparations of starting materials, i.e. O12a - monoacyl - and O10,O12a - di - acyl oxytetracyclines, are described, involving esterification of the mono-esters with this anhydride in pyridine, and hydrolysis of appropriate di-esters to the corresponding mono-esters with ammonium hydroxide.