Patent ES-335390-A1 (ES)
Title: Derivatives of malonic acid
IPC: C07C59/68
Filed: 1967-01-09
Abstract: Novel bis-phenoxy-malonic acid derivatives of the general formula wherein R is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and either (1) R 3 is a trifluoromethyl, benzyl, benzoyl or phenyl radical or an acylamido radical having from 2 to 4 carbon atoms and R 7 is a hydrogen atom, or a trifluoromethyl, benzyl, benzoyl or phenyl radical or an acylamido radical having from 2 to 4 carbon atoms and each of R 1 , R 2 , R 4 , R 5 , R 6 and R 8 is a hydrogen atom or (2) one or two of the substituents R 1 to R 4 are chlorine, fluorine or bromine atoms and either R 7 is a hydrogen atom or a trifluoromethyl, benzyl, benzoyl or phenyl radical or an acylamido radical having from 2 to 4 carbon atoms, or one or two of the substituents R 5 to R 8 are chlorine, bromine or fluorine atoms, and the remainder of R 1 to R 8 are hydrogen atoms, or (3) R 3 is a chlorine, bromine or fluorine atom and R 1 is a nitro radical or an alkyl radical having from 1 to 4 carbon atoms, and either R 7 is a hydrogen atom, a trifluoromethyl, benzyl, benzoyl or phenyl radical or an acylamido radical having from 2 to 4 carbon atoms, or one or two of the substituents R 5 to R 8 are chlorine, bromine or fluorine atoms, or R 7 is a chlorine, bromine or fluorine atom and R 5 is a nitro radical or an alkyl radical having from 1 to 4 carbon atoms, and the remainder of R 1 to R 8 are hydrogen atoms, with the exception of bis- (4-chlorophenoxy)-malonic acid ethyl ester, are prepared (i) when R is an alkyl group having from 1 to 4 carbon atoms, either by (a) reacting a halo-malonic ester and a phenoxide derivative of the respective formul[mu] wherein Hal is a chlorine or bromine atom, Alk is an alkyl radical having from 1 to 4 carbon atoms and Y is an alkali metal, treating the resulting mono-phenoxy-malonic ester of the formula with a chlorinating or brominating agent to give a phenory-halo-malonic ester of the formula which is then reacted with a phenoxide derivative of the formula or (b) reacting a phenoxide derivative of the sixth formula above with a halo-malonic ester of the second formula above, treating the resulting mono-phenoxy-malonic ester of the formula with a chlorinating or brominating agent to give a phenoxy-halo-malonic ester of the formula which is then reacted with a phenoxide derivative of the third formula above or (c) reacting together a novel bis-phenoxy-malonyl halide and an alcohol or alkoxide of the respective formul[mu] wherein X is hydrogen or an alkali metal or (d), when R 1 , R 2 , R 3 and R 4 are identical to R 5 , R 6 , R 7 and R 8 respectively, reacting at least 2 mols of a phenoxide derivative of the third formula above with 1 mol of a dihalo-malonic ester of the formula (ii) when R is a hydrogen atom, by treating a bis-phenoxy-malonic ester of the first formula above, wherein R is an alkyl group having from 1 to 4 carbon atoms with barium hydroxide or an alkali metal hydroxide and liberating the acid from the resulting salt. The preparation of bis-(4-chlorophenoxy)-malonic acid diethyl ester is also described. Novel bis-phenozy-malonyl halides of the ninth formula above are prepared by treating a bis-phenoxy malonic acid of the first formula above, wherein R is a hydrogen atom, with chlorinating or brominating agent. Pharmaceutical compositions comprising, as active ingredient, a bis-phenoxy-malonic acid derivative of the first formula above and a physiologically acceptable, inert carrier having strong cholesterine blood level and blood fat level lowering effects and may be administered orally.