Patent GB-788100-A (GB)
Title: Manufacture of polyethylene-glycol esters of substituted p-aminobenzoic acids
Filed: 1954-05-04
Abstract: The invention comprises compounds of the formula <FORM:0788100/IV (b)/1> in which R is an alkyl, cycloalkyl or oxa-alkyl residue containing 4-7 carbon atoms, R1 represents hydrogen or a lower alkyl residue of up to 6 carbon atoms such as a methyl group and n is a whole number from 8 to 12 or has an average value between 8 and 12, and acid addition salts of these compounds.  The compounds are made by reacting a benzoic acid of the formula <FORM:0788100/IV (b)/2> or a reactive derivative thereof with a polyethylene glycol of the formula HO-(CH2-CH2-O)n-R1 or a reactive derivative thereof. Suitably the benzoic acid or its halide, anhydride or ester with a volatile alcohol is reacted with the polyglycol in the presence of a basic condensing agent or a metal salt of the benzoic acid is reacted with an ester of the glycol.  Preferred products include the p-n-butylamino-benzoic acid esters of octa-ethylene glycol monomethyl ether, nona-ethylene glycol monomethyl ether, undeca-ethylene glycol monomethyl ether and nona-ethylene glycol.  Examples describe the preparation of esters of p-aminobenzoic acids in which R is chosen from n-hexyl, 3-methoxybutyl, 4-methoxybutyl, n-heptyl, n-butyl, sec.-butyl isoamyl, butoxyethyl, cyclohexyl and cyclopentyl radicals and the esterifying group is derived from octa-ethylene glycol monomethyl ether, undeca - ethylene glycol monomethyl ether, octa - ethylene glycol, nona - ethylene glycol, nona-ethylene glycol monomethyl ether or mixtures of polyethylene glycols or their methyl esters in which n has an average value between 8 and 12.  Glycols. Polyethylene glycols and ethers thereof used in the esterification of the p-aminobenzoic acids are made by known methods.  For example, octaethylene glycol monomethyl ether is made by reacting diethylene glycol monomethyl ether benzene sulphonate with triethylene glycol to give pentaethylene glycol monomethyl ether, treating this with benzene sulphonyl chloride to give the benzene sulphonate and reacting this with triethylene glycol to give octaethylene glycol; undecaethylene glycol monomethyl ether is made by treating octaethylene glycol monomethyl ether with benzene sulphonyl chloride to give the corresponding benzene sulphonate which is reacted with triethylene glycol; octaethylene glycol is made by treating diethylene glycol with benzene sulphonyl chloride and reacting the resulting bis-benzenesulphonate with two mols. of triethylene glycol; nonaethylene glycol is made by reacting triethylene glycol bis-benzenesulphonate with two mols. of triethylene glycol and nonaethylene glycol monomethyl ether is made by converting octaethylene glycol monomethyl ether into its monobenzene sulphonate and reacting this with ethylene glycol, or by converting nona-ethylene glycol to its monobenzenesulphonate which is reacted with methyl alcohol, or by treating the monobenzene sulphonate of triethylene glycol with triethylene glycol monomethyl ether with triethylene glycol monobenzenesulphonate.  Aromatic acids.  p - Aminobenzoic acid derivatives used to esterify polyethylene glycols are made by known methods.  For example, the ethyl esters of p-hexylaminobenzoic acid, p-heptylaminobenzoic acid and p-cyclohexylaminobenzoic acid are made by treating ethyl p-aminobenzoate with the appropriate alkyl or cycloalkyl bromide and p-(2-butoxyethylamino) benzoic acid ethyl ester is made by treating p-aminobenzoic acid with ethylene glycol monobutyl ether benzene sulphonate.  The Provisional Specification also describes processes for the preparation of compounds of formula I in which an alcohol of the formula <FORM:0788100/IV (b)/3> or its metal salt or reactive ester is reacted with an alcohol of the formula HO-(CH2-CH2-O)p-R1 or its metal salt or reactive ester, m and p being whole numbers such that m+p=n; or in which the group R1 in a compound of the formula <FORM:0788100/IV (b)/4> is converted into the group R-NH-, R1 being a convertible group such as a primary amino group.  Specification 728,583 is referred to.ALSO:Pharmaceutical preparations suitable for parenteral or oral administration in the treatment of coughs comprise a compound of the formula <FORM:0788100/VI/1> in which R is an alkyl, cycloalkyl or oxa-alkyl group of 4-7 carbon atoms, R1 is hydrogen or an alkyl radical of 1-6 carbon atoms and n is an integer from 8 to 12 or has an average value from 8 to 12 (see Group IV (b)), plus a pharmaceutical carrier.  Examples include a syrup containing nona - ethylene - glycol - mono - methyl ether p-n-butylaminobenzoate or undeca-ethylene-glycol-monomethyl ether p-butylaminobenzoate, sugar, p-hydroxybenzoic acid ester, sodium carboxymethyl cellulose, citric acid, oil of lemon, vanillin, banana essence, "Tween" (Registered Trade Mark) and water; ampoules containing the octaethylene-glycol-monomethyl ether or nonaethylene-glycol-monomethyl ether ester of p-butylaminobenzoic acid, sodium chloride and water and capsules containing the same active ingredient optionally mixed with propylene glycol or stearic acid.  Specification 728,583, [Group IV (b)], is referred to.