Patent GB-859394-A (GB)
Title: Process for preparing substituted tetracyclines
Filed: 1958-08-07
Abstract: Substituted-N1- (primary or secondary aminomethyl) tetracyclines are prepared by reacting a compound of formula:  <FORM:0859394/IV(b)/1> where TC represents all except the carboxamido group of tetracycline, oxytetracycline, chlortetracycline or bromtetracycline, and B is a primary or secondary amino group with at least one equivalent of a hydrogen replacing agent whereby an active hydrogen located on a carbon atom in a phenolic ring or on an oxygen atom is replaced.  The hydrogen replacing agent is an acid halide, acid anhydride, alkyl haloformate, aralkyl haloformate, phosgene, an epoxide, beta propiolactone, dihydropyran, an olefine, a halogen, a phosphorous halide, halosulphuric acid, iodoacetic acid, a diazonium salt, an isocyanate, nitrous acid, nitric acid, sulphuryl chloride, a diazoalkane, a tertiary alcohol boron trifluoride complex, a sulphur tri-oxide dialkylamine complex, an alkyl orthoformate, phenyllithium and carbon dioxide in sequence, and mercuric acetate and sulphur dichloride.  Radical B may be a secondary amino group consisting of di (lower) alkylamino, pyrrolidino, piperidino, morpholino, 2, 6-dimethyl-morpholino, N1-(lower) alkyl piperazino, pipecolino or dibenzylamino.  Reactions take place at -40 to 50 DEG C. in anhydrous solvents such as pyridine, glacial acetic acid, ethyl carbamate, N, N-dimethyl acetamide, N-methyl-2- pyrrolidone, 1, 2-dimethoxyethane, N, N-di methyl formamide, diethylene glycol dimethyl ether, formamide and dimethyl sulphoxide.  The substituted -N1- (primary or secondary aminomethyl) tetracycline is reduced to the corresponding substituted tetracycline by (a) catalytic reduction by hydrogen in a solvent such as methanol or (b) reduction by means of aqueous solution of a bisulphite especially sodium bisulphite.  Examples describe the preparation of (a) 3-nitrophthalyl -N1- (morpholino-methyl) tetracycline from N1-morpholinomethyl) tetracycline and 3-nitrophthalic anhydride (b) monobenzoyl-N1-(dibenzylamino methyl) tetracycline from N1-(dibenzylaminomethyl) tetracycline and benzoyl chloride (c) p-nitrobenzoyl-N1-(morpholinomethyl) tetracycline using p-nitrobenzoyl chloride and N1-(morpholinomethyl) tetracycline (d) p-toluenesulphonyl-N- (morpholinomethyl) tetracycline using p-toluenesulphonyl-chloride and N1-(morpholinomethyl) tetracycline; (e) p-toluenesulphonyltetracycline by reducing (d) with hydrogen in presence of Raney Nickel catalyst; (f) monobenzoyl-N-1 (morpholinomethyl) tetracycline using benzoyl chloride and N1-(morpholinomethyl) tetracycline; (g) monobenzoyl tetracycline by reducing (b) with catalytic hydrogen or aqueous sodium bisulphite (h) o-carbethoxy-N1 (morpholinomethyl) tetracycline using N1 (morpholinomethyl) tetracycline and ethyl chloro formate; (i) o-carbethoxy-N1-(morpholinomethyl) tetracycline by reducing (j) with catalytic hydrogen or aqueous sodium bisulphite; (k) p-nitrobenzoyl tetracycline by reducing (c) with catalytic hydrogen (d) monobenzoyl -N1- (dibenzylaminomethyl) tetracycline using benzoyl chloride and N1-(dibenzylaminomethyl) tetracycline (m) p-nitrophenylazo-N1-morphilinomethyl tetracycline hydroacetate <FORM:0859394/IV(b)/2> from diazotised p-nitroaniline and N1-morpholinomethyl tetracycline followed by treatment with acetic acid (n) p-nitrophenylazo-N1-pyrrolidino methyl tetracycline dihydroacetate as in (m) using N1-(pyrrolidino methyl) tetracycline. Salts may be formed with hydrochloric, sulphuric, sulphonic, tartaric, hydrobromic, hydriodic, glycollic, citric, acetic and other fatty acids.  The compounds may be used as a general disinfectant and veterinary medicine (see Group VI) or a preservative of fish. Specification 809,585 is referred to.ALSO:A veterinary preparation in the form of a capsule or suspension in a vegetable oil contains a substituted -N 1- (primary-or secondary-aminomethyl) tetracycline prepared by reacting a compound of formula:  <FORM:0859394/VI/1> where TC represents all except the carboxamido group of tetracycline, oxytetracycline, chlortetracycline or bromtetracycline and B represents a primary or secondary amino group, with at least one equivalent of a hydrogen replacing reagent wherein an active hydrogen located on a carbon atom in a phenolic ring or on an oxygen atom is replaced (see Group IV (b)). The tetracycline may be in the form of the hydrochloride, sulphate, sulphamate, tartrate, hydrobromate, hydriodate, glycollate, citrate, maleate, phosphate, succinate or acetate. Aqueous solutions or suspensions may be used as general disinfectants.  The compounds may be used for the preservation of fish at the rate of 0,1 to 1,000 mgm/kg of weight of the fish.  They are used in solution or suspension in a liquid e.g. water or as a powder with a diluent such as talc.  Specification 809,585 is referred to.