Patent GB-709482-A (GB)
Title: Polyethylene glycol derivatives and method of making same
IPC: C08G65/329
Filed: 1951-06-05
Abstract: The invention comprises compounds of the general formula RO(CH2CH2O)nCH2 CH2.  ZCOOH- in which R stands for an alkyl, cycloalkyl, aryl or aralkyl radical containing at most 7 carbon atoms, n for an integer from 6 to 50 p  inclusive and Z for one of the groupings -CH2-, <FORM:0709482/IV (a)/1> , -S.CH2-, and -O. arylene-and Y is an alkyl group containing at most 7 carbon atoms. Such compounds are obtained by condensing a reactive ester of the formula CH2(COOY)2, CH3COCH2COOY, NHY.CN2COOY, HS.CH2.COOY, HO.Ar. COOY (where Ar is arylene) or CN.CH2. COOY (where Y is an alkyl radical containing at most 7 carbon atoms) with a polyethylene glycol derivative of a formula RO(CH2CH2O)n CH2CH2X where X is halogen or the residue of a strong, monobasic organic acid (e.g. as prepared in Specification 709,478) followed by hydrolysis of the ester produced to the free acid and (where the resulting product is an a - substituted malonic acid) by the splitting off of carbon dioxide to give the monocarboxylic acid.  The products are of use in medicines. In an example (1) p-hydroxy methyl benzoate is reacted in the presence of sodium methoxide with the bromide of a polyethylene glycol monomethyl ether of average weight 414.  The product of formula CH3O(CH2CH2O)n CH2CH2O-pC6H4 .COOCH3 (average value of n is about 6) is hydrolysed to the free acid.  Salicylic ester, isopropyl 2-hydroxy-5-methyl benzoate or methyl 4-hydroxy -1- naphthoate may be used in place of the methyl p-hydroxybenzoate.  In a similar manner there are produced (2) from polyethylene glycol monoisopropyl ether (molecular weight 900), the compound of the formula iso- C3H7O (Ch2 CH2O) nCH2CH2O-p-C6H4 .COOC4H9 (n has average value 15), which is hydrolysed to the free acid. As starting material may be used instead the p-toluene sulphonic acid ester of polyethylene glycol monobenzyl ether (molecular weight 2000); (3) from diisopropylmalonate and the p-toluene sulphonic acid ester of polyethylene glycol monophenyl ether (molecular weight 650), a compound C6H5O <FORM:0709482/IV (a)/2> is produced, which is hydrolysed to the dicarboxylic acid and the latter is decarboxylated to the monocarboxylic acid (n is about 8).  Analagously the benzene sulphonic acid ester of polyethylene glycol monocyclopentyl ether (molecular weight 500) is employed; (4) from thioglycolic acid ethyl ester and the benzene or methane sulphonic acid ester of polyethylene glycol monomethyl ether (molecular weight 690 or 628) a thioether of formula CH3O <FORM:0709482/IV (a)/3> is obtained (n is about 11) which is saponified to the free acid; (5) from sarcosine ethylester and the iodide or benzene sulphonate of polyethylene glycol monomethyl ether (molecular weight 690) an ester of formula <FORM:0709482/IV (a)/4> is obtained and is hydrolysed to the free acid (n being about 11). The acid products of (2) and (4) may be recovered by absorption on a basic exchange resin and elution therefrom.ALSO:The invention comprises compounds of the general formula  RO(CH2CH2O)nCH2CH2.Z.COOH in which R stands for an alkyl, cycloalkyl, aryl or aralkyl radical containing at most 7 carbon atoms, n for an integer from 6 to 50 inclusive, and Z for one of the groupings -CH2-, <FORM:0709482/IV (b)/1> -S.CH2-, and -O-arylene-, and Y is an alkyl group containing at most 7 carbon atoms.  Such compounds are obtained by condensing a reactive ester of the formula CH2(COOY)2, CH3COCH2COOY, NHY.CH2.COOY, HS.CH2.COOY,  HO . Ar . COOY (where Ar is arylene), or CN . CH2 . COOY (where Y is an alkyl radical containing at most 7 carbon atoms), with a polyethylene glycol derivative of formula RO(CH2CH2O)nCH2CH2X, where X is halogen or the residue of a strong, monobasic organic acid (e.g. as prepared in Specification 709,478), followed by hydrolysis of the ester produced to the free acid and (where the resulting product is an a -substituted malonic acid) by the splitting off of carbon dioxide to give the monocarboxylic acid.  The products are of use in medicines.  In an example: (1) p-hydroxy methyl benzoate is reacted in presence of sodium methoxide with the bromide of a polyethylene glycol monomethyl ether of average molecular weight of 414.  The product, of formula CH3O(CH2CH2O)nCH2CH2O . pC6H4 . COOCH3 is hydrolysed to the free acid (n is about 6).  Salicylic ester, isopropyl 2-hydroxy-5-methyl benzoate or methyl-4-hydroxy-1-naphthoate may replace the methyl p-hydroxybenzoate.  In a similar manner are obtained (2) from polyethylene glycol mono-isopropyl ether (molecular weight 900), the compound iso-C3H7O(CH2 <FORM:0709482/IV (b)/2> , which is hydrolysed to the free acid (n is about 15).  As starting material may be used instead the p-toluene sulphonic acid ester of polyethylene glycol monobenzyl ether (molecular weight 2000); (3) from diiscpropylmalonate and the p-toluene sulphonic acid ester of polyethylene glycol monophenyl ether (molecular weight 650), a compound <FORM:0709482/IV (b)/3> is produced which is hydrolysed to the dicarboxylic acid and the latter is decarboxylated to the monocarboxylic acid (n is about 8).  Analogously, ethyl aceto-acetate is alkylated with polyethylene glycol monocyclopentyl ether and the product is saponified; (4) from thioglycolic acid ethyl ester and the benzene sulphonic acid ester of polyethylene glycol mono-methyl ether (molecular weight 690) or the methane sulphonic acid ester of polyethylene glycol monomethyl ether (molecular weight 628), a thioether CH3O(CH2CH2O)n . CH2CH2S . CH2COOC2H5 is obtained which is hydrolysed to the acid (n is about 11); (5) from sarcosine ethyl ester and polyethylene glycol monomethyl ether benzene sulphonate or iodide, an ester of formula <FORM:0709482/IV (b)/4> is obtained and is hydrolysed to the free acid (n having an average value of about 11).  The acid products of (2) and (4) may be recovered by adsorption on a basic exchange resin and elution therefrom.