CS215372B1 - Process for preparing 4,4-bis (4-ethylphenyl) -2,3-dibroin-2-butenoic acid - Google Patents

Abstract

The invention relates to a new method for the preparation of antineoplastically active 4,4-bis(4-ethylphenyl)-2,3-dibromo-2-butenoic acid, which consists in introducing mucobromic acid into an excess of ethylbenzene, after which aluminum chloride is added under cooling so that the temperature of the reaction mixture does not exceed 20 °C, and after completion of condensation, the reaction mixture is treated in a manner customary for this type of reaction.

Description

The invention relates to a process for the preparation of 4,4-bis (4-ethylphenyl) -2,3-dibromo-2-butenoic acid of the formula I,

Br Br

CH — C = C — COOH (I)

by reacting ethylbenzene with mucobromic acid in the presence of anhydrous aluminum chloride.

The compound of formula I has shown a remarkable anti-neoplastic effect in animals with experimental tumors and can be considered to be a suitable chemotherapeutic agent for certain human cancers based on clinical experience to date (cf. US Patent Nos. 143,847 and 165,753).

According to MS. No. 165,753, the compound of formula I is produced by reacting ethylbenzene with mucobromic acid in the presence of anhydrous aluminum chloride, the reaction being conducted in two temperature phases, the first of which is carried out at 0-15 ° C, preferably at 10-13 ° C, and the other at a temperature of 20 to 50 ° C, preferably at 20 to 25 ° C, after which the reaction mixture is worked up in the manner customary in organic chemistry for this type of reaction. The condensation of the reactants consists in the gradual addition of mucobromic acid to a stirred suspension of granulated aluminum chloride in ethylbenzene. The above-mentioned temperature regime, together with the use of granular aluminum chloride, limits the application of undesirable disproportionation reactions of ethylbenzene, but is technologically difficult because constant temperature control over the entire reaction vessel by efficient cooling equipment is energy intensive, requires perfect homogeneity of the reaction mixture. perfect mixing, and also places great demands on the operator.

Said process further requires the use of coarse granulated aluminum chloride. However, catalyst granules have different granule sizes, different active catalytic area, disintegration, catalytic promoter admixtures, and a number of other physicochemical variables depending on the method of manufacture, age, storage, etc., depending on the provenance, and thus hardly reproducible and uniform reaction. These disadvantages are particularly evident when operating on a technical scale, where reproducible yields and consistent product quality for pharmaceutical purposes cannot be ensured.

Based on these facts and unlike the nature of the measures in the subject of MS. No. 165,753, the inventors have found that the disproportionation reactions of ethylbenzene can be substantially reduced by the use of an inverse addition of aluminum chloride, both granulated and powdered, i.e. regardless of the particle size of the catalyst to be added. Thus, the yield of the compound of the formula I is substantially increased, not only by increasing the yield of the crude product, but mainly by its easier purification.

The invention therefore relates to a process for the preparation of 4,4-bis- (4-ethylphenyl) -2,3-dibromo-2-butenoic acid of the formula I by reacting ethylbenzene with mucobromic acid in the presence of aluminum chloride. Mucobromic acid is added to an excess of ethylbenzene of not more than 10 to 12 mol equivalents, followed by the addition of aluminum chloride in an amount of 1.2 to 2.2 mol equivalents relative to the starting acid of the formula I to the mixture cooled to 0 to 10 ° C. The reaction mixture is maintained at a temperature of not more than 20 ° C and, after completion of the condensation, the acid of formula (I) is isolated from the reaction mixture, preferably by the method customary for this type of reaction.

The process according to the invention allows the condensation reaction to be carried out on an industrial scale, while ensuring reproducible yields and a standard product quality which is obtained in yields above 90% of the theory, i.e. about 15% higher than according to the process disclosed in U.S. Pat. No. 165,753, which contains fewer reaction by-products, especially colored, and is easier to clean for therapeutic use.

The process according to the invention is described in detail in the following non-limiting example: 4,4-bis (4-ethylphenyl) -2,3-dibromo-2-butenoic acid

To 7,088 ml of ethylbenzene (66 mol) was added with stirring 1,800 g (6.95 mol) of mucobromic acid and the mixture was cooled to 5 ° C. Then it was added

278 g (9.6 mol) of aluminum chloride at a rate such that the temperature did not exceed 20 ° C during the addition. After removing the cooling bath, the reaction mixture was poured into a mixture of 8,010 g of ice and 2,400 ml of conc. hydrochloric acid and stirred for 30 minutes. To the separated organic phase was added 8,010 ml of water at 50 ° C and 810 ml of ethanol, and the mixture was thoroughly mixed. The organic phase was separated and the aqueous phase was shaken with 1200 ml of chloroform. The combined organic fractions were filtered and evaporated at 50 ° C, under vacuum approximately

500 Pa and the residue was allowed to crystallize. The crude product was recrystallized from carbon tetrachloride to give the pure product, mp 137-138 ° C, yield 90-92%.

Claims (1)

A process for the preparation of 4,4-bis (4-ethylphenyl) 2,3-dibromo-2-butonic acid of the formula I CH - C = C - COOH (I) by reaction of ethylbenzene with mucobromic acid, OF THE INVENTION in the presence of anhydrous aluminum chloride, characterized in that the mucobromic acid is first introduced into an excess of ethylbenzene of not more than 10 to 12 mol equivalents, followed by addition of aluminum chloride in an amount of 1.2 to 2, 2 moles of valent, based on the starting acid of formula I, maintaining the temperature of the reaction mixture at a maximum of 20 ° C and isolating the acid of formula I from the reaction mixture after completion of the condensation.