CS212636B1 - Process for preparing 4-aryl-2r3-dicyano-1-naphthol derivatives - Google Patents

Abstract

The invention relates to a new process for the production of 4-aryl-2,3-dicyeno-1-naphthol derivatives of the general formula I, in which R represents a hydrogen atom, a methyl or ethyl group. The production process consists in the demethylation of the corresponding 4-aryl-2,3-dicyeno-1-methoxynaphthalenes by the action of anhydrous aluminum chloride in an inert solvent, preferably in dichloroethane, at a temperature range from 20 °C to the boiling point of the reaction mixture.

Description

The invention relates to a process for the preparation of 4-aryl-2,3-dicyano-1-naphthol derivatives of the general formula I,

wherein R is hydrogen, methyl or ethyl.

4-Aryl-2,3-dicyano-1-naphthol derivatives can be structurally regarded as intermediates for model synthesis, structurally related to podophyllic acid derivatives, podophyllotoxin, and related lignans found in plant species of the genus Berberidaceae. • Podophyllotoxin-type lignans are known to have antineoplastic activity and some of them are used in the combination therapy of human cancers (eg SPG, SPI, VP-16, VM-26).

4-Aryl-2,3-dicyano-1-naphthol derivatives are useful intermediates for the synthesis of a number of pharmacologically active structures useful in the chemotherapy of various diseases, particularly tumor diseases.

According to the invention, the compounds of the formula I with the above-mentioned meaning of R 1 are prepared by demethylation of the compounds of the formula II,

wherein R is as defined for formula (I), using 3 to 6 mol equivalents of anhydrous aluminum chloride, in an inert medium, preferably dichloroethane, in the temperature range of 20 ° C to the boiling point of the reaction mixture.

After the reaction, the reaction mixture is worked up as required, e.g. after distilling off the reaction medium on a vacuum evaporator, the residue is stirred in a mixture of ice and hydrochloric acid, the precipitate is filtered off with suction, washed with water and recrystallized from a suitable solvent or mixture.

Any inert solvent to which the aluminum chloride does not react and which is not the reaction component for Friedel-Crafts-type reactions can be used as the reaction medium for performing the demethylation. Particularly suitable are chlorinated solvents, of which dichloroethane or aromatic solvents (chlorobenzene, bromobenzene, nitrobenzene), carbon disulphide or nitromethane seem to be the most preferred.

It is necessary to use aluminum chloride in excess, i.e. in an amount of 3 to 6 mol equivalents, to ensure a quantitative yield, and it does not matter whether it is used in powder or granular form.

According to the literature, the demethylation of arylmethyl ethers can be carried out in a variety of ways using acidic or alkaline reagents in a variety of environments. However, the presence of nitrile groups in the arylmethyl ether molecule precludes the use of alkaline and acidic agents in a polar environment, since in such cases, in addition to the demethylation reaction, 1 hydrolysis and elimination reactions take place. The course of demethylation using alkaline reagents in a non-aqueous medium is very slow and disadvantageous in yield. The use of aluminum chloride in an inert environment obviates the above problems, is economically advantageous, e.g. compared to using boron-derived Lewis acids (BCl4, BBr4), and additionally provides the desired products in high yields.

The compound of formula (I) wherein R is ethyl is already a known compound prepared according to U.S. Pat. No. 194,589, by isolation from the reaction mixture, as a by-product in the preparation of 7-ethyl-4- (4-ethylphenyl) -2,3-dicyano-1-methoxynaphthalene.

The compounds of formula (II), as defined above for R, are known and readily prepared according to U.S. Pat. No. 94,589 and S. 200,094. For further details on the preparation of the compounds of formula (I), as defined above, R will be apparent from the following non-limiting example. The melting points of the substances were determined on the Kofler block and are not corrected.

4-Penyl-2,3-dicyano-1-naphthol

To a solution of 28.4 g (10 mmol) of 4-phenyl-2,3-dicyano-1-methoxynaphthalene in 600 ml of dichloroethane was added portionwise 39.9 g (30 mmol) of anhydrous aluminum chloride with stirring, and the reaction mixture was stirred for 3 hours, at 20-25 ° C. After evaporation of the solvent in a water-jet vacuum, the dry residue is stirred in a mixture of 200 g of ice and 50 ml of concentrated hydrochloric acid, the product precipitate is stirred, suctioned off, washed with warm water and dried. The crude product after crystallization from chloroform gave a melting point of 268-270 ° C.

In an analogous manner using 7-methyl-4- (4-methylphenyl) -2,3-dicyano-1-methoxynaphthalene as a starting material, 7-methyl-4- (4-methylphenyl) -2,3-dicyano-1- naphthol, m.p. 278 DEG-280 DEG C. (benzene-ethanol), and using 7-ethyl-4- (4-ethylphenyl) -2,3-dicyano-1-methoxynaphthalene, 7-ethyl-4- / 4- 234 DEG-236 DEG C. (chloroform), ethylphenyl / -2,3-dicyano-1-naphthol.

Claims (2)

A process for the preparation of 4-aryl-2,3-dicyano-1-naphthol derivatives of the general formula I, in which R represents a hydrogen atom, a methyl or ethyl group, characterized in that the compounds of the general formula II, H is the same as in Formula I, demethylated with anhydrous aluminum chloride used in an amount of 3 to 6 mol equivalents in an inert medium. 2. A process according to claim 1, wherein the reaction is carried out in a dichloromethane medium at a temperature of from 20 DEG C. to the boiling point of the reaction mixture.