Patent GB-620657-A (GB)
Title: Improvements in or relating to the preparation of para-aminobenzoic acid esters
Filed: 1944-10-04
Abstract: p-Aminobenzoic acid esters of mono-sec.-alkyl- and -cycloalkyl-amino-propanols and -butanols, of the general formula <FORM:0620657/IV (b)/1> (wherein R represents a sec.-alkyl or cycloalkyl group containing 5-9 carbon atoms and R1 a propylene or butylene group), and their salts, are manufactured by the interaction, in a water-immiscible reaction medium, of p-nitrobenzoic acid anhydride or a p-nitrobenzoyl halide (e.g. chloride or bromide) with a salt of a mono-sec.-alkyl-or-cycloalkyl-amino-propanol or -butanol, and reduction of the resulting nitrobenzoic ester or salt thereof.  The initial reaction is advantageously effected by dissolving the alkanolamine in an inert solvent such as a chlorinated lower paraffin, converting it into its salt, adding an equimolecular proportion of p-nitrobenzoyl halide dissolved in an equal quantity of the same solvent, refluxing (preferably at 50-60 DEG  C.), cooling and removing the solvent under vacuum.  The nitro-ester may then be reduced, by catalytic hydrogenation or otherwise, in the form of the salt so obtained or as the base liberated by the action of alkali. When the alkanolamine contains a tertiary alcohol group, the process is preferably modified by treating the alkanolamine (free base) with a substantial (e.g. 50 per cent) excess of p-nitrobenzoic acid anhydride or halide to form the N-p-nitrobenzoyl derivative and rearranging this to the nitrobenzoic ester salt by treatment with acid prior to reduction of the nitro group.  When the aminobenzoic ester is obtained in the form of a salt, it may be converted, by the action of excess of alkali on an aqueous suspension thereof, into the free base, which may be extracted with benzene and may be converted into other salts by treating a solution thereof (e.g. in benzene) with the stoichiometric proportion of the acid and evaporating the solvent.  The products, especially those in which the alkylated amino group and the esterified hydroxy group are attached to adjacent carbon atoms, are useful as local an sthetics, preferably in the form of their salts, e.g. hydrochlorides, sulphates, sulphamates, tartrates or glycolates.  In examples: (1) a solution of 2-(41-heptylamino)-1-propanol in chloroform is saturated with dry hydrogen chloride and refluxed with a solution of p-nitrobenzoyl chloride in chloroform, the solvent is then evaporated and the p-nitrobenzoate hydrochloride is reduced with hydrogen in aqueous suspension at room temperature in the presence of pallidinised charcoal; (2) 2 - [41 - (21 : 61 - dimethylheptyl) - amino] - 1 - butanol is similarly treated, as also may be 1-[41-(21 : 61-dimethylheptyl)-amino]-2-propanol 2- or 3 - (31 - pentylamino) - 1 - propanol, 2- or 3-[41-(21 : 61-dimethylheptyl)-amino]-1-propanol 1-(31-pentyl-, 41-heptyl- or 51-nonyl-amino)-2 - propanol, 2 - (51-nonylamino) - 1 - propanol, 1 - [21 - (41 - methylpentyl) - amino] - 2 - propanol, 3-(21- or 41-heptyl- or 21-octyl-amino)-1-propanol, 2-(31 - pentyl-, 41 - heptyl- or 51 - nonylamino) - 1 - butanol or 2-(21 - heptylamino) - 2 - methyl - 1 - propanol; (3) 2-cyclohexylamino - 1 - butanol is treated as in (1); (4) 1-cyclohexylamino-2-methyl-2-propanol is suspended in aqueous caustic soda and heated with a solution of excess of p-nitrobenzoyl chloride in methylene chloride, the methylene chloride layer is separated and evaporated, the N-p-nitrobenzoyl compound obtained is boiled with aqueous alcoholic hydrochloric acid, and the resulting p-nitrobenzoic ester hydrochloride is hydrogenated as in (1); other cycloalkylaminoalkanols which may be treated as in (3) are 1-cyclohexyl- and -cyclopentyl-amino-2-propanol, 1-(41-methylcyclohexyl)-amino-2-propanol, 2-cyclohexyl- and -cyclopentyl-amino-2-methyl-1-propanol, 2- and 3-cyclohexyl- and -cyclopentyl-amino - 1 - propanol, 1 - (31 - ethyl - cyclopentyl and 41-ethylcyclohexyl) - amino - 2 - propanol, 2 - cyclopentylamino - 1 - butanol and 2 - (41 - methylcyclohexyl) - amino - 1 - butanol; other sec.-alkyl- or cycloalkyl-aminoalkanols containing a tertiary alcohol group, which may be treated as in (4), are 1-(31-pentyl-, 21-heptyl-and 21-octyl-amino)-and 1-cyclopentylamino-2-methyl-2-propanol.  The hydrogenation step may be carried out in other liquid media, e.g. mixtures of water and alcohol or of acetic acid and water, and with other hydrogenation catalysts, e.g. platinum, copper chromites or nickel.  Specifications 533,012 and 551,753 are referred to.  Alkanolamines of the kind defined are obtainable by condensing a ketone with a primary aminoalcohol with simultaneous or subsequent reduction.  The Specification as open to inspection under Sect. 91 comprises also the manufacture of benzoic esters as described in Specification 632,561, the manufacture of p-aminobenzoic esters of the general formula above in which R may contain fewer than 5 or more than 9 carbon atoms and R1 may contain substituents (e.g. alkyl groups, which may bring the total number of carbon atoms above 4), and the use of the free aminoalkanols in the direct esterification process.  Additional starting materials specified are 1-isopropylamino-2-methyl-2-propanol (further example), 2-isopropylamino-1-butanol and 2-sec.-butylamino-2-methyl-1-propanol.  This subject-matter does not appear in the Specification as accepted.