Patent GB-765591-A (GB)
Title: Esters of 4-amino-2-hydroxybenzoic acids mono-substituted at the nitrogen atom and aprocess for their production
IPC: C07D295/12
Filed: 1954-08-25
Abstract: The invention comprises esters of a 4-amino-2-hydroxy-benzoic acid mono-substituted at the nitrogen atom having the general formula <FORM:0765591/IV(b)/1> in which X is an organic radical, Y is a straight or branched aliphatic carbon chain containing from 1 to 10 carbon atoms, and Z1 and Z2 are the same or different alkyl groups each of which contains from 1 to 6 carbon atoms, or Z1 is a hydrogen atom and Z2 is an alkyl group containing from 1 to 6 carbon atoms, or the grouping: <FORM:0765591/IV(b)/2> is a nitrogen containing heterocyclic radical.  The radical X may be for example a methyl, ethyl, butyl, secondary amyl, benzyl, 3-(p-nitrophenyl) - propyl, p - tolyl, 3 - hydroxyphenyl -, b  - dimethylaminoethyl, b  - isopropyl-aminoethyl, 1 - methyl - 2 - methyl - 3 - diethyl-aminopropyl, b  - piperidinoethyl or b  - thiazolidinoethyl group; Z1 and Z2 may be groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or hexyl or Z1, may be hydrogen and Z2 an alkyl group containing from 1 to 6 carbon atoms or the grouping: <FORM:0765591/IV(b)/3> may be the radical of a heterocyclic ring system, e.g. a piperidino, morpholino, thiazolidino or pyrrolidino group.  The products of the invention may be obtained by reacting an ester of 4-amino-2-hydroxybenzoic acid in which the alcoholic ester component is one of the radicals defined under X, optionally in an anhydrous organic solvent such as isopropanol or secondary butanol and preferably in a non-polar solvent such as benzene, toluene or xylene, with an amino-substituted alkyl halide of the formula: <FORM:0765591/IV(b)/4> in which Hal is a halogen atom and Y, Z1 and Z2 are as defined above.  Examples of amino-substituted alkyl halides mentioned include chloroethyldimethylamine, bromo- or chloroethyldiethylamine, 2 - chloro - 1 - dibutyl-amino - propane, 1 - bromo - 1 - methyl - 2-methyl - 3 - diethylamino - propane, 3 - isobutyl-amino-propyl chloride, piperidinoethyl iodide and morpholinoethyl iodide.  When free 4-amino-2-hydroxybenzoic acids are reacted with an amino-substituted alkyl halide of the above kind and an organic solvent for both reactants is employed, e.g. isopropanol, the alkylaminoalkyl ester of the 4-amino-2-hydroxybenzoic acid is obtained together with the alkylaminoalkyl ester of 4 - (alkylaminoalkylamino) - 2 - hydroxybenzoic acid in which the ester group X is identical with the group: <FORM:0765591/IV(b)/5> The reactions are carried out by heating the reactants together under reflux or at elevated pressure.  In examples: the methyl ester of 4 - (diethylaminoethylamino) - 2 - hydroxy benzoic acid is obtained by heating under reflux 4 - amino - 2 - hydroxy - benzoic acid methyl ester with diethylamino ethyl chloride in benzene, removing the benzene, extracting the product with dilute hydrochloric acid, adding ammonia to the extract and extracting the desired ester with isopropyl chloride, the hydrochloride and picrate are referred to (1); the n - propyl ester of 4 - (diethylaminoethyl-amino) - 2 - hydroxybenzoic acid is similarly prepared from the n-propyl ester of 4-amino-2-hydroxybenzoic acid and diethylaminoethyl chloride and the product is converted to the hydrochloride with ethanolic hydrochloric acid (2); the n-butyl ester of 4-(diethylaminoethyl-amino)-2-hydroxybenzoic acid is similarly prepared by heating the n-butyl ester of 4-amino-2-hydroxybenzoic acid in butyl acetate with diethylaminoethyl chloride and is converted into the hydrochloride (3); the b -diethylaminoethyl ester of 4-(diethyl aminoethylamino-2-hydroxybenzoic acid is similarly prepared by (a) heating the b -diethylaminoethyl ester of 4-amino-2-hydroxybenzoic acid with diethylamino ethyl chloride in benzene uder reflux, the mixture of esters obtained being converted to the corresponding hydrochlorides, the unchanged 4-amino - 2 - hydroxybenzoic acid b  - diethyl-amino ethyl ester hydrochloride separated by fractional crystallization from water and the dihydrochloride of the desired product is obtained by concentrating the aqueous mother liquor and adding isopropanol; or (b) by boiling 4 - amino - 2 - hydroxybenzoic acid with diethylaminoethyl chloride and isopropanol under reflux, adding ammonia, extracting with isopropyl chloride, converting the extracted products to hydrochlorides and separating as described under (a) (4).ALSO:A pharmaceutical composition comprises an ester of 4-amino-2-hydroxy-benzoic acid mono-substituted at the nitrogen atom and having the general formula <FORM:0765591/VI/1> in which X is an organic radical, Y is a straight or branched aliphatic carbon chain containing from 1 to 10 carbon atoms, and Z1 and Z2 are the same or different alkyl groups each of which contains from 1 to 6 carbon atoms, or Z1 is a hydrogen atom and Z2 is an alkyl group containing from 1 to 6 carbon atoms or the grouping <FORM:0765591/VI/2> is a nitrogen-containing heterocyclic radical.  The ester may be present in the form of a salt of an acid, e.g. a mono- or dihydrochloride.  The radical X may be methyl, ethyl, butyl, secondary amyl, benzyl, 3-(p-nitrophenyl)-propyl, p-tolyl, 3-hydrophenyl, beta-dimethylaminoethyl, beta-diethylaminoethyl, beta - ethalaminoethyl, beta - isopropylaminoethyl, 1-methyl-2-methyl-3-diethylaminopropyl, beta - piperidinoethyl and beta-thiazolindinoethyl groups.  Z1 and Z2 may be alkyl or isoalkyl groups.  When the grouping <FORM:0765591/VI/3> is a heterocyclic group this may be piperidino, morpholino, thiazolino or pyrnolidino. Aqueous solutions of alkyl esters of 4-(diethylaminoethylamino) - 2 - hydroxybenzoic acid in which the alkyl group of the ester contains not more than 4 carbon atoms, and the beta-dimethyl- and beta-diethylaminoethyl esters of 4-(diethyl-aminoethylamino)-2-hydroxybenzoic acid or salts thereof are employed as local anaesthetics.