Patent GB-1177841-A (GB)
Title: Novel Bis-Phenoxy-Malonic Acid Derivatives and Process for the Preparation thereof
Inventor: GRIOT RUDOLF GUSTAV
IPC: C07C59/90
Filed: 1967-01-05
Abstract: 1,177,841. Bis-phenoxy-malonic acid derivatives. SANDOZ Ltd. 5 Jan., 1967 [10 Jan., 1966; 25 Feb., 1966; 5 May, 1966; 2 Aug., 1966 (2); 8 Aug., 1966], No. 684/67. Heading C2C. 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 formulµ 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 formulµ 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.