Patent GB-736960-A (GB)
Title: Esters of n-monoalkyl and n-monoalkoxyalkyl aminohydroxybenzoic acids
IPC: C07C233/12
Filed: 1952-01-21
Abstract: The invention comprises as new compounds esters of N-substituted aminohydroxybenzoic acids having the formula (R)(H)N.C6H3(OH).COO-A-N(R1)(R2) in which R is an alkyl group or an alkoxyalkyl group, A is an aliphatic hydrocarbon radical having a straight, branched, or substituted chain, the whole radical containing from 2 to 12 carbons, and N(R1)(R2) is a nitrogen - containing hydrogenated or saturated heterocyclic ring, or R1 and R2 are the same or different alkyl, aryl, aralky or alkaryl groups containing not more than 10 carbon atoms per group or one of the radicals R1 and R2 is a hydrogen atom and the other is an alkyl, aryl, aralkyl or alkaryl group containing not more than 10 carbon atoms.  The esters may be obtained by several methods, e.g. by reacting an appropriate N-monoalkyl or N-monoalkoxy-alkylaminohydroxybenzoic acid with an appropriate N-substituted amino alcohol in the presence of a strong mineral acid, e.g. concentrated sulphuric acid, hydrochloric acid, or phosphoric acid, or an aryl sulphonic acid, e.g. benzene- or p-toluene-sulphonic acid.  Specified substituted benzoic acids are 4 - amino - 2-hydroxybenzoic acid monosubstituted at the nitrogen atom by a methyl, ethyl, propyl (including isopropyl), butyl (including sec.-butyl), methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl group.  Analogous derivatives of other aminohydroxybenzoic acids, e.g. of 3-amino-2-hydroxy-, 5-amino-2-hydroxy- and 6 - amino - 3 - hydroxy - benzoic acids may also be used.  The amino alcohols used have the general formula HO-A-N(R1)(R2) and examples of the groups R1 and R2 are methyl, ethyl, propyl, isopropyl, n-butyl, hexyl, decyl, phenyl, benzyl, phenylethyl, tolyl, and xylyl groups.  The radical A may be substituted by an aliphatic or aromatic hydrocarbon group, e.g. by a methyl or phenyl group or by a halogen atom such as bromine.  Suitable amino alcohols include dimethyl-, diethyl-, di-isopropyl-, methylethyl-, ethyl-isopropyl-, methyl-, ethyl-, hexyl-, diphenyl-, benzyl-, di-(phenyl ethyl)-, o-nitrophenyl-, di-(p-tolyl)-, di-(p-ethyl-phenyl)-, piperidino-, pyrrolidino-, and thiazolidino-aminoethanols, and the analogously substituted amino-propanols, -butanols, -pentanols, and -hexanols as well as higher aminoalcohols and isomers with branched or substituted chains, e.g. 1-methyl-2-(diethylaminoethanol), 2 - phenyl - 3 - (isopropylamino)-propanol, and 2-bromo-3-(diethylamino)-propanol. The esterification is preferably effected at between 0 DEG  and 200 DEG  C. and an inert water-insoluble liquid such as benzene, toluene, xylene, carbon tetrachloride, or hexane, which forms an azeotrope with water may be added to the reaction mixture to assist in the removal of the water formed.  Another method of preparing the products is to heat an appropriate N - mono - substituted aminohydroxy benzoic acid with an halogenated alcohol M.A.OH, wherein M is a halogen atom, in the presence of a strong mineral acid or an aryl sulphonic acid to yield an halogen ester NHR.C6H3(OH) COO.A.M which is then reacted with an appropriate primary or secondary amine or with a nitrogen-containing hydrogenated or saturated heterocyclic compound.  Specified halogenated alcohols are ethylene-chlorhydrin, 3-bromopropanol, and 3-chloro-2-phenyl-propanol.  Suitable amines include p  diethylamine, phenylethylamine, benzylamine, di - (p - tolyl)-amine, piperidine, and thiazolidine.  The reaction of the halogenated ester with the amine can be effected in the presence of an inert liquid in which the reactants are dissolved, suspended or emulsified, and increased pressure may be used.  The products may also be obtained by reacting a metal salt of the N-mono-substituted aminohydroxybenzoic acid with a halide of the formula M.A.N.(R1)(R2) in which M is a halogen atom. The metal salts are preferably alkali metal or alkaline earth metal salts.  Suitable halides include 1-chloro-2 - diethylamino ethane, 1 - chloro - 3 - benzylaminopropane, and 1 - bromo - 2 - phenyl - 3-(phenyl - ethyl - amino) - propane.  The reaction may be carried out in the presence of an anhydrous solvent, if desired under pressure.  Specified solvents are ethyl acetate, isopropanol, butanol, and nitrobenzene.  The products may also be obtained by subjecting an ester of a N-monoalkyl or N-monoalkoxy alkylaminohydroxybenzoic acid to alcoholysis with the N-substituted amino alcohol, the alcohol component of the ester being derived from an aliphatic alcohol, e.g. methanol or ethanol, having a lower boiling point than the N-substituted amino alcohol. The alcoholysis may be effected by heating at 80-150 DEG  C. for several hours and a small quantity of an alkoxide such as sodium ethoxide may be added to the mixture.  Examples are given for the production of (1) diethylaminoethyl ester of 4 - n - butylamino - 2 - hydroxy - benzoic acid; (2) dimethylaminoethyl-4-b -methoxyethylamino - 2 - hydroxy - benzoate; (3) diethylaminoethyl - 4 - isopropylamino - 2-hydroxy - benzoate; (4) piperidinoethyl ester of 4 -n butyl - amino - 2 - hydroxy - benzoic acid; (5) diethylaminoethyl ester of 4-b -methoxyethylamino - 2 - hydroxybenzoic acid; (6) dimethylaminoethyl ester of 4-sec-butylamino - 2 - hydroxy - benzoic acid; (7) diethylaminoethyl ester of 4-n-propylamino-2-hydroxy-benzoic acid; (8) diethylaminoethyl ester of 5 - n - butylamino - 2 - hydroxybenzoic acid; (9) dimethylaminoethyl ester of 4 - n - butylamino - 2 - hydroxy - benzoic acid; (10) dimethylaminoethyl ester of 4-isopropylamino - 2 - hydroxy - benzoic acid; (11) piperidino-ethyl ester of 4-(b -methoxyethylamino) - 2 - hydroxy - benzoic acid; (12) diethylaminoethyl ester of 4-n-propylamino-2-hydroxy - benzoic acid; (13) diethylaminoethyl ester of 4-sec.-butylamino-2-hydroxybenzoic acid; (14) diethylaminoethyl ester of 5 - n - propylamino - 2 - hydroxy - benzoic acid.  In (1) to (3) the ester is produced by reacting the amino alcohol with the N-substituted acid; in (4) to (6) the N-substituted acid is first esterified with a halogenated alcohol and the resulting ester reacted with the appropriate amino or heterocyclic compound; in (7) to (11) a salt of the N-substituted acid is reacted with a chloride of the amino alcohol and in (12) to (14) a low molecular ester of the N-substituted acid is reacted with the amino alcohol. Reference is also made to the hydrochlorides of products (1), (4), (7) to (9), (12) and (14) and to the picrates of products (2), (3), (5), (6), (10), (11) and (13).  The ester products are stated to have powerful local anaesthetic action.