Patent GB-741982-A (GB)
Title: Basic ethers of aralkyl phenols
Inventor: CHENEY LEE CANNON
IPC: C07D295/092
Filed: 1951-04-25
Abstract: A compound having the general formula <FORM:0741982/IV(a)/1> wherein R1 and R3 each represent hydrogen, lower alkyl (i.e. 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 tricarboxylic acid or an integer from 1 to 2 when A is a dicarboxylic acid, is prepared by a process which comprises dissolving an aralkylphenol of the formula <FORM:0741982/IV(a)/2> or a mixture of said phenol with its isomer in which the hydroxyl group is para to the grouping R2-CH-Z-R3 in an inert, non-aqueous organic solvent, converting the phenol or isomeric mixture of phenols to the corresponding alkali metal phenoxide or phenoxides by the addition of an 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 the starting materials, heating the solution containing the alkali metal salt of the orthoaralkylphenol with a beta-disubstituted aminomethyl hydrochloride in the presence of an alkali metal hydroxide or carbonate until the formation of the aralkyl phenolic basic ether is substantially complete, adding a polycarboxylic acid and water to the mixture to precipitate the corresponding salt of the basic ethers 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 removed by the difference in solubility of the salts of the ethers.  Where a relatively pure o-aralkyl phenol is used, all the reactants required to form the basic ether can be added at one time to the reaction vessel.  As a modification a b -haloethyl o-aralkyl phenyl ether can be prepared as an intermediate which can then be reacted with the appropriate secondary amine to form the basic ether.  In example (1) a mixture of o- and p-benzyl phenols in toluene is heated with solid sodium hydroxide.  Some of the salt of the p-isomer is filtered off. To the filtrate containing sodium ortho-benzylphenoxide with some p-isomer are added solid sodium hydroxide and b -dimethylaminoethyl chloride hydrochloride. After refluxing the mixture is treated with aqueous citric acid. The dihydrogen citrate obtained is filtered off and recrystallized to remove p-isomer giving 2-benzylphenyl b -dimethylaminoethyl ether dihydrogen citrate.  The sodium p-benzylphenoxide separated after the first stage is acidified in aqueous solution to give p-benzylphenol.  In example (13) o-benzyl p-chlorophenol, b -dimethyl aminoethyl chloride hydrochloride and solid sodium hydroxide are heated in toluene, aqueous citric acid is added and after heating the toluene layer is discarded and 2-benzyl-4-chlorophenyl-b -dimethylaminoethyl ether dihydrogen citrate is obtained from the aqueous layer.  In example (22) a toluene solution of sodium o-benzylphenoxide with some sodium p-benzyl-phenoxide, prepared as in the first part of example (1) is heated with ethylene dichloride and solid sodium hydroxide. After removal of solvent and excess ethylene dichloride the residue, dissolved in toluene, is heated under pressure with dimethylamine. After removal of excess dimethylamine by washing with water, the toluene solution is treated with aqueous citric acid to give 2-benzylphenyl-b -dimethylaminoethyl ether dihydrogen citrate. Similarly to (1) there are prepared from the appropriate reactants (2) b -dimethylaminoethyl 2-(21-thenyl)-phenyl ether dihydrogen citrate; (3) b -dimethylaminoethyl 2-furfurylphenyl ether dihydrogen citrate; (4) 2-benzylphenyl b -dimethylaminoethyl ether acid DL-malate; (5) 2-benzylphenyl b -diethylaminoethyl ether dihydrogen citrate; (6) 2-benzylphenyl b -(1-pyrrolidyl)-ethyl ether dihydrogen citrate; (7) 2-benzylphenyl b -(1-piperidyl)-ethyl ether dihydrogen citrate; (8) 2-benzylphenyl b -(4-morpholinyl)-ethyl ether dihydrogen citrate; (9) to (12) the acid D-tartrate, acid succinate, acid maleate and acid fumarate respectively of 2-benzylphenyl b -dimethylaminoethyl ether.  Similarly to (13) there are prepared (14) 2-benzyl - 4 - ethoxyphenyl b  - diethylaminoethyl ether dihydrogen citrate; (15) b -diethylaminoethyl 2 - (a  - methyl - benzyl) - phenyl ether dihydrogen citrate; (16) b  - diethylaminoethyl 2 - (2 - methylbenzyl) - 4 - methylphenyl ether dihydrogen citrate; (17) b -dimethylaminoethyl 2-(21-pyridylmethyl)-phenyl dihydrogen citrate; (18) 2-(41-bromobenzyl)-phenyl b  - dimethylaminoethyl ether acid malate; (19) b  - diethylaminoethyl 2 - (41-isopropylbenzyl) - phenyl ether dihydrogen citrate; (20) b  - dimethylaminoethyl 2 - (41-methoxybenzyl) - phenyl ether acid maleate and (21) b  - dimethylaminoethyl 2 - (31-thenyl) - phenyl ether dihydrogen citrate.