Patent GB-743106-A (GB)
Title: Basic ethers of aralkyl phenols
Inventor: CHENEY LEE CANNON
IPC: C07D295/092
Filed: 1951-04-25
Abstract: A process for the production of a compound of the formula <FORM:0743106/IV(a)/1> wherein R1 and R3 each represent hydrogen, lower alkyl (i.e. alkyl with not more than 6 carbon atoms), halogen or alkoxy, R2 is hydrogen or methyl, Z is a divalent radical derived from benzene, thiophene, furan or pyridine, B is a dialkylamino, 1-pyrrolidyl, 1-piperidyl or 4-morpholinyl group and A is a polycarboxylic acid being citric, malic, tartaric, succinic, maleic or fumaric acid, and n is an integer from 1 to 3 when A is a tricarboxlic acid or an integer from 1 to 2 when A is a dicarboxylic acid, comprises dissolving an aralkylphenol of the following general formula in which R1, R2, Z and R3 each represent the same atoms or radicals as the corresponding symbols above; <FORM:0743106/IV(a)/2> or an isomeric mixture of the said phenol with its isomer in which the hydroxyl is para to the grouping R2-CH-Z-R3, in an inert, non-aqueous organic solvent, converting the phenol or mixture of isomeric phenols to the corresponding alkali metal phenoxide or phenoxides by the addition of alkali metal hydroxide, removing at least part of the relatively insoluble alkali metal salt of the para-aralkylphenol which may be present when a mixture of isomers is used as a starting material, whereafter the solution of the alkali metal-2-aralkyl phenoxides thus formed is mixed and heated with a toluene solution of a beta-disubstituted aminoethyl chloride having the formula Cl-CH2-CH2-B which solution has been prepared by addition of alkali metal hydroxide to the corresponding hydrochloride dissolved in toluene, until the formation of the orthoaralkylphenolic ether is substantially completed, adding a polycarboxylic acid A and water to the mixture to precipitate the corresponding salt of the basic ether and to dissolve impurities and recrystallizing the precipitated polycarboxylic acid salt from a hydroxylated solvent whereby any para-isomer, which may be present when a mixture of isomers is used as the starting material is efficiently removed by the difference in solubility of the salts of the ethers.  The dihydrogen citrates are the preferred salts.  Other suitable polycarboxylic acids are malic, tartaric, succinic, maleic and fumaric acids.  The acids may be introduced to the reaction mixture as solids or in solution.  Flake sodium hydroxide is the preferred alkali.  It may be replaced by alkali metals, other alkali metal hydroxides, hydrides and amides.  It is unnecessary to remove water formed by the reaction of the alkali metal hydroxide with the phenol. Where a relatively pure ortho-aralkylphenol is used, the reactants required to form the basic ether can be added all together to the reaction vessel.  In examples: (1) a solution in toluene of the sodium derivative of 4-chloro-2-benzyl-phenol is reacted with b -dimethyl-aminoethyl chloride (liberated from its hydrochloride with sodium hydroxide).  Addition of an aqueous solution of citric acid to the mixture precipitates on cooling 4-chloro-2-benzyl-phenyl b -dimethylaminoethyl ether dihydrogen citrate; (2) a mixture of equal amounts of 2- and 4-benzylphenols is refluxed in toluene with flake sodium hydroxide while removing water azeotropically. Insoluble sodium 4-benzylphenoxide is filtered off and the remaining solution of sodium 2-benzylphenoxide is refluxed with b -dimethylaminoethyl chloride.  Addition of an aqueous solution of citric acid results in the precipitation of 2-benzylphenyl b -dimethylaminoethyl ether dihydrogen citrate.