CS268889B1 - Halogenated derivatives of diphenylitaconic acid and their preparation - Google Patents

Abstract

The solution relates to new halogenated derivatives of diphenyl itaconic acid of the general formula I p1 ^2 o HOOC COOH 1 2 in which "R denotes hydrogen and R chlorine or R _i RZ bromine, serving as an intermediate stage in the preparation of antineoplastically active halogenated derivatives of benzo(c)fluorene. □Their preparation consists in the Stobbe condensation of 1 to 5 mol equivalents of ethyl succinate in a medium of 1 to 10 mol equivalents of alkali metal alcoholate, preferably sodium methanolate, while boiling the reaction mixture with the corresponding halogenated benzophenones of the general formula l i l 6HHH 9 5 with the above-mentioned meaning of R* and R2.

Description

The invention relates to new halogen derivatives of diphenylitaconic acid of the general formula I

2 12 in which R denotes hydrogen and R denotes chlorine or R and R denotes bromine. The compounds of general formula I with the above-mentioned meanings of R and R are valuable intermediates for the preparation of compounds with interesting biological effects, especially tetracyclic derivatives of benzo(c)fluorene. Benzo(c)fluorene derivatives exhibit significant antitumor, interferonogenic and antibacterial activity (Křepelka et al. Collect. Czech. Chern. Commun. 47, 1258 (1982), 47, 1857 (1982), Vančurová et al. Collect. Czech. Chem. Commun. 47, 1867 (1982), Czechoslovak author's certificate No. 212 669, USA patent No. 4,661,297, Smejkal et al. Acta Virol. 29, 11 (1984)) and compounds of general formula I are important precursors in their synthesis.

2

The compounds of the general formula I with the above-mentioned meanings of R and R are prepared according to the invention from the corresponding halogenated benzophenones of the general formula II.

in which R and R have the above meaning (Koopal: Recueil 34, 153, Lock, Rodiger Chem.

Ber. 72, 861 (1939), Haller et al. □. Am. Chem. Soc. 67, 1591 (1945), Ford-Moore □. Chem. Soc. London 1947, 952, Demuth, Dittrich chem. Ber. 23, 3614 (1890) by the Stobbe condensation, which is known and commonly used in organic chemistry. The compounds of the general formula I, in which R denotes hydrogen and R is chlorine or R and R is bromine, are prepared according to the invention by reacting compounds of the general formula II, in which R denotes hydrogen and R is chlorine or R and R is bromine, with 1 to 5 molar equivalents of ethyl succinate in a medium of 1 to 10 molar equivalents of an alkali metal, preferably sodium, in a medium of a lower alcohol with a straight or branched chain, preferably in methanol, at the boiling temperature of the reaction mixture, after which the resulting mixture is saponified with an excess of sodium hydroxide and acidified with a mineral acid after the reaction has taken place.

More detailed information on the preparation of compounds of general formula I with the above-mentioned meanings of R* and R will result from the following embodiment example, which does not limit the scope of the invention in any way.

Example

3,3'-Dibromo-diphenylitaconic acid

In a three-necked flask equipped with a reflux condenser and a stirrer, 5.1 g of sodium (0.22 mol) was dissolved in 51 ml of methanol and 3,3 ^- dibromobenzophenone was poured into the resulting alcoholate and 16 ml (0.087 mol) of ethyl succinate was added dropwise at room temperature with stirring. The reaction mixture was heated to reflux for 5 hours (reaction mixture temperature 78 °C).

After this time, a solution of 35.5 g (0.88 mol) of sodium hydroxide in 55.5 ml of water was added to the reaction mixture and the reaction mixture was further heated to reflux for 8 hours (temperature of the reaction mixture 84 °C).

CS 268889 Bl

The resulting dark white mass was diluted with water and the solution was acidified with concentrated hydrochloric acid to pH 3. The solution was then extracted three times with approximately 100 ml of chloroform and the chloroform layer was separated and dried with anhydrous sodium sulfate.

After evaporation of chloroform in vacuo and recrystallization of the residue from a mixture of toluene and n-hexane, a dark yellow substance with a melting point of 105-107° C. was obtained. 14.7 g (76%) of product was obtained.

3-Chlorodiphenylitaconic acid was prepared analogously, melting point 63 to 65 °C.

Claims (4)

• SUBJECT OF THE INVENTION 1. Halogen derivatives of diphenylitaconic acid of general formula I (AND). 1 2 1 2 in which R represents hydrogen and R represents chlorine or R and R represent bromine. 2. 3,3'-dibromo-diphenylitaconic acid. 3. 3-Chloro-diphenylitaconic acid. 4. A method for preparing substances according to point 1, of general formula i, characterized in that the corresponding halogenated benzophenones of general formula n (II), 1 2 12 in which R denotes hydrogen and R is chlorine or R ^is bromine, are converted by Stobbe condensation1 2 to compounds of general formula I with the above-mentioned meaning of R and R in such a way that compounds of general formula II with the above-mentioned meaning of R and R are reacted with 1 to 5 molar equivalents of ethyl succinate in the medium of 1 to 10 molar equivalents of an alkali metal, preferably sodium, in the medium of a lower alcohol with a straight or branched chain, preferably in methanol, at the boiling temperature of the reaction mixture, after which the resulting reaction mixture is saponified with an excess of sodium hydroxide and acidified with a mineral acid.