GB1100885A - Oxytetracycline esters and preparation thereof - Google Patents

Abstract

The invention relates to esters of 6-deoxyoxytetracycline having the formulae <FORM:1100885/C2/1> <FORM:1100885/C2/2> wherein A is -CH3 or YSCH2, Y being primary or secondary C1-C12 alkyl; R11CO (R11 being C1-C3 alkyl); phenyl; mono- or di-substituted phenyl; benzoyl; -CF3; or R1CH2 (R11 bein mono- or di-substituted C1-C6 alkyl, C1-C6 carbalkoxy, halo, phenyl, mono- or di-substituted phenyl, or furyl); each substitunte 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; wherein R3 is alkanoyloxy, phenoxyalkanoyloxy or alkoxyalkanoyloxy, in which the alkanoyloxy groups are C2-C6; and wherein R2 and R4 are each hydroxyl, alkanoyloxy, phenoxyalkanoyloxy or alkoxyalkanoyloxy, in which the alkanoyloxy groups are C2-C6; and also to the O12a-phenoxyalkanoyloxy - and alkoxyalkanoyloxyderivatives of oxytetracycline, wherein the alkoxy group is C1-C6, and to the acid addition and metal salts of the said compounds. The lower esters, i.e. the O12a-monoacyl and O5,O12a-diacyl compounds, may be prepared by esterifying the corresponding non-esterified tetracycline compound or the O5-acyl ester, whichever is appropriate, with at least one molar proportion of carboxylic anhydride or preferably carboxylic acid chloride, in an inert solvent such as acetone, tetrahydrofuran, methyl esters of ethylene glycol, diethylene glycol or preferably dioxane, at about 0 DEG to 50 DEG C. The ester is obtained by precipitating unesterified reactant as the hydrochloride, and adding the mother liquor to a large volume of non-solvent for the ester, e.g. hexane, when the required ester is precipitated. The higher esters of the invention, i.e. the O10,O12a-di-acyl and O5,O10,O12a-tri-acyl esters, are prepared by esterifying the corresponding non-esterified or less-esterified tetracycline with 2-8 molar proportions of carboxylic anhydride in the presence of 2-8 molar proportions of pyridine, at 15 DEG -40 DEG C., if required in an inert solvent such as dimethylformamide. The aforesaid lower esters may alternatively be prepared by mild hydrolysis of the corresponding O10,O12aand O5,O10,O12a-esters, respectively, for example by treatment with aqueous ammonium hydroxide. The products may be treated, in an inert solvent, with one equivalent of acid or metallic base to provide the corresponding salt, which may be recovered by evaporation of the solvent or by addition of a non-solvent.