CZ341391A3 - process for preparing 4-(2,4-difluorobiphenylyl)-2-4-oxobutanoic acid - Google Patents

Abstract

The process of preparing the given compound is based on the reaction of 2,4-difluorobiphenyl with itaconic acid anhydride under the conditions of the Friedel-Crafts' reaction and following hydrogenation of the produced 4-(2,4-difluorobiphenylyl)-2-methylene-4-oxobutanoic acid. The material has significant anti-inflammatory effect, immunomodulative activity and low gastrotoxicity.<IMAGE>

Description

Technical field

The invention relates to a process for preparing 4- (2,4-difluorobiphenylyl) -2-methyl-4-oxobutanoic acid.

BACKGROUND OF THE INVENTION

Monohalogen derivatives of 4-biphenylyl-2-methyl-4-oxo-butanoic acid (Swiss Patent No. 628014) are known to have a significant anti-inflammatory effect. Later synthesized double halide-substituted acids exhibited a prolonged anti-inflammatory effect lasting longer than 24 hours (cf. Aut. No. 243570), especially for 4- (2,4-difluorobiphenylyl) -2-methyl-4-oxobutanoic acid.

Said acids may be prepared by reacting biphenyl or a suitable halogenated derivative thereof with methylsuccinic anhydride in an inert organic solvent in the presence of a suitable catalyst, for example aluminum chloride, under Priedel-Crafts realce conditions. This reaction produces, in addition to the desired 4-biphenyl-2-methyl-4-oxobutyric acid, a 3-methylisoinomer, the separation of which is associated with a decrease in the yield of the desired product.

SUMMARY OF THE INVENTION

The essence of the regioselective process for preparing 4- (2,4-difluorobiphenylyl) -2-methyl-4-oxobutanoic acid of formula I

C0CH _o CHCOOH

The CH, (I) which is not contaminated with the 3-methylisomer, consists in reacting 2,4-difluorobiphenyl with itaconic anhydride in an inert solvent, preferably dichloromethane, dichloroethane, nitromethane or carbon disulphide, in the presence of of a suitable catalyst, preferably aluminum chloride, at 0-80 ° C, preferably at 10-30 ° C, to give 4- (2,4-difluorobiphenylyl) -2-methylene-4-oxobutanoic acid in which: the 3-methylisomer content is less than 2%. This acid is subjected to hydrogenation in the presence of a suitable catalyst, for example Pd or pTa and activated carbon under a hydrogen pressure of 0.1 to 1.0 MPa, preferably at 0 to 0.5 MPa in a suitable solvent, preferably dioxane. or acetic acid at a temperature of 20-40 ° C. If desired, the alkali metal salt of 4- (2,4-difluorobiphenylyl) -2-methylene-4-oxobutanoic acid in a suitable solvent, preferably water, may be used for the hydrogenation; the resulting salt is converted to the free acid by acidification. After isolation from the reaction medium, the crude product is purified by crystallization from a suitable solvent, preferably acetic acid or aqueous methanol. 4- (2,4-Difluorobiphenylyl) -2-methyl-4-oxobutanoic acid (I) is obtained. which contains no 3-methylisomsr.

Itaconic anhydride is prepared from itaconic acid by conventional dehydration methods, e.g. boiling with acetic anhydride.

DETAILED DESCRIPTION OF THE INVENTION

The details of the synthesis are evident from the examples which illustrate the preparation but do not limit it in any way.

Example 1

4- (2,4-Difluorobiphenylyl) -2-methylene-4-oxobutanoic acid

To a solution of 76.7 g of 2,4-difluorobiphenyl in 100 ml of dichloromethane is added a solution of 45.1 g of itaconic anhydride in 200 ml of dichloromethane. The mixture is cooled to 5 ° C and aluminum chloride is gradually added at a temperature of up to 10 ° C. The reaction mixture was then kept under stirring at 10 ° C for 4 hours, then allowed to rise to 20 ° C and stirred for 1 hour. After standing at 20 ° C for 12 hours, the reaction was quenched by pouring onto 800 g of ice. and 260 ml conc. hydrochloric acid. The precipitated, creamy yellow product is filtered off with suction and washed on the filter with dichloromethane and water. After drying, the crude product is stirred under boiling in 610 ml of 80% methanol and the suspension is filtered off with suction. 72.7 g of a first crop of product are obtained.

Upon cooling the filtrate to 5 ° C, more product precipitated.

After suctioning, 13.1 g of a second crop are obtained. The HPLC impurity content is 1. share 0.3 - 0.85% and in share 2 0.8 -1.2% é>

i.e·

Thus, the total yield of 100% product is 85.0 -> 85.5 70.7% of theory to the starting 2,4-difluorobiphenyl.

4- (2,4-Difluorobiphenyl) -2-methyl-4-oxobutanoic acid

The autoclave was charged with 15.1 g of the previous 2-methylene-4-oxobutanoic acid, 1.0 g of catalyst. Pd / C (3% Pd on dry basis) and 70 mL dioxane. After closing and flushing with nitrogen and hydrogen, the autoclave is filled with hydrogen to 0.5 MPa at 40 ° C and the reduction is continued until about 40 min. The hydrogen consumption ceases (hydrogen consumption is about 1.4 L). The autoclave was degassed, purged with nitrogen, and the reaction mixture was freed from the catalyst by filtration. The filtrate was concentrated in a water pump vacuum and the thick suspension was dissolved in 45 mL acetic acid after heating to 95 ° C. The solution is cooled to 10 ° C with stirring, left at this temperature for 2 hours and then the crystalline product is filtered off with suction. The filter was washed with acetic acid and dried in vacuo at 40 ° C to give 12.1 g of crude product. This was crystallized by dissolving in 90 ml of 90% acetic acid at boiling. The slightly turbid solution was filtered and the filtrate was cooled to 5 ° C. After 5 hours of cooling, the precipitated crystalline product is filtered off with suction, washed on the filter with 25 ml of 80% aqueous methanol and 3 x 20 ml of water. ) with tt Mp 158-159 ° C.

Example 2.

4- (2,4-Difluorobiphenylyl) -2-methyl-4-oxobutanoic acid

14.0 g of 4- (2,4-difluorobiphenylyl) are charged into the autoclave

-2-methylene-4-oxobutanoic acid, 0.7 g of Pd / C catalyst (3: with Pd on dry basis) in 70 ml of acetic acid. After capping and being purged with nitrogen, the autoclave is filled with hydrogen at a pressure of 0.5 MPa and the mixture is heated at a temperature of 80 ° C. The hydrogenation is continued until the theoretical consumption of hydrogen, then cooled to 20 ° C, the autoclave is degassed, purged with nitrogen, and after heating to 50 ° C the catalyst is filtered off. After concentration in a water pump vacuum to 45 ml and cooling to 10 DEG C., the crystalline product is suctioned off. Purification and crystallization in the same manner as in Example 1 afforded 10.0 g of the product (70.5% th.), M.p. Mp 158-159 ° C.

Example 3

The autoclave is charged with a solution prepared from 6.05 g of 4- (2,4-difluorobiphenylyl) -2-methylene-4-oxobutanoic acid in 190 ml of water by alkalization with the calculated amount of 25% NaOH (final pH 10.5), 1.0 g of Pd / C catalyst (3% Pd in dry matter). The hydrogenation was carried out at a hydrogen pressure of 0.5 MPa and a temperature of 40 ° C for 1 hour. After cooling to 20 ° C, the autoclave is degassed, purged with nitrogen and the contents filtered and the filtrate acidified with dilute hydrochloric acid (1: 1) to pH 3. The precipitated 4- (2,4-difluorobiphenylyl) -2-methyl-4-oxobutanoic acid (5.75 g, 94.3% th.) Was crystallized by dissolving in 115 mL of 80% methanol at boiling. After filtration, the filtrate is cooled to 5 DEG C. and after 5 hours of cooling, the precipitated crystalline product is filtered off with suction and washed on the filter with 2.times.20 ml 80% methanol and 2.times.20 ml water. 4.7 g (77.3% of th.) Of the product with m.p. 157-159 ° G.

Industrial applicability

The present invention provides a process of preparing 4- (2,4-difluorobiphenylyl) -2-methyl-4-oxobutanoic acid in high purity without the addition of the positional isomer, i.e. 4- (2,4-difluorobiphenylyl) - 3-methyl-4-oxobutane. 4- (2,4-Difluorobiphenylyl) -2-methyl-4-oxobutanoic acid has significant anti-inflammatory activity (cf. No. 243570) and maximum achievable purity is an essential requirement for its use as a medicament ·

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Claims (1)

O Ξ Ξ Ξ-K K - Preparation of 4- (2, 4-difluorobiphenylyl) -2-methy1-4-oxo-butyric acid of formula I ^f QQ C0CH _o CHCOOH CH3 (I) characterized in that it is an anhydride. Itaconic acids are reacted with 2,4-difluorobiphenyl under Friedel-Crafts reaction conditions and the resulting 4- (2,4-difluorobiphenylyl) -2-methylene-4-oxobutanoic acid is subjected to hydrification in the presence of a suitable catalyst. (a) it is a suitable solvent, preferably acetic acid or non-aqueous methanol.