CS199667B2 - Method of producing 2-/4-/3-thenoyl/phenyl/propionic acid - Google Patents

Abstract

The present invention concerns a process of preparation of a novel substituted propionic acid. This compound, which is the 2-¢4-(3-thenoyl)-phenoyl!-propionic acid, is obtained by the intermediary of the ethyl 2-methyl-2-¢4-(3-thenoyl)-phenyl! malonate and fluorophenylthenyl methanone. This compound is of particular interest as an analgesic anti-inflammatory agent and anti-aggregating agent for blood platelets.

Description

The present invention relates to a process for the preparation of 2- [4- (3-thenoyl) phenyl] propionic acid of the formula I:

crystallizing the obtained salts with an optically active base.

This acid can be obtained by alkylating the fluorophenylthenylmethanone with ethyl 2-methylmalonate in an aprotic solvent such as hexamethylphosphoric triamide in the presence of a strong base such as sodium hydride at room temperature. After the addition of fluorophenylthenylmethanone, the temperature of the reaction medium is maintained at 100 ° C for about ten hours. The alkylation of 2-methyl-2 - [(4- (3-thenoyl) phenyl) malonate of the formula (II _{) -} COOC _X W ₅ ζΓ 3 cooc _of w ₅ (Ю) is subjected to alkaline ihydrolysis, for example with sodium hydroxide at reflux temperature. for several hours, of the order of six, and decarboxylation to give 2- [4- (3-thenoyl) phenyl] propionic acid.

The above fluorophenylthenylmethanone of formula III

This compound contains asymmetric carbon and can therefore be separated by methods known to those skilled in the art, for example

More preferably, the 3-thenoyl chloride can be condensed with fluorobenzene with the gradual addition of aluminum chloride, stirring continuously so that the temperature does not exceed 10 ° C with a later temperature rise to the reflux temperature of the reaction mixture and maintained at that temperature. about 15 minutes.

It has been found that 2- [4- (3-thenoyl) phenyl] propionic acid has a particular analgesic, anti-inflammatory and anti-platelet aggregation effect.

The analgesic effect was demonstrated by the acetic acid test in mice [Siegmund method, modified according to Koster, Anderson and Deeber]. The effective dose, expressed as a concentration in mg / kg, which causes a reduction in pain sensitivity equal to or greater than 50% / o, in the case of analgesic action, is 9 for 2- [4- (3'thenoyl) phenyl] propionic acid, while aspirin (acid) acetylsalicyl) has an effective dose of 130 in this test, pyramidone (phenyldimethylaminodimethylpyrazolone) has 32 and pethidine (ethyl [1-methyl-4-phenyl-4-piperidinecarboxylate] hydrochloride] has a dose of 17.

The anti-inflammatory effect has been demonstrated inter alia by poAspirin

Fenergan [10- (2-dimethylaminopropyl) phenothiazine]

2- [4- (3-thenoyl) phenyl] propionic acid

Pharmaceutical compounds containing, as an active ingredient, an acid of the invention and a carrier or solvent physiologically acceptable in solid or liquid form allow administration of daily doses of active ingredient between 20 and 1000 mg.

Next, an example is given which illustrates, without limiting the scope of the present invention, the different stages of the process for producing a new acid.

Example

Stage 1:

(4-Fluorophenyl) -3-thenylmethanone (Formula III)

C11H7FOS Molecular Weight = 206.17

To a solution of 42.5 g (0.29 mol) of 3-thiophenecarbonyl chloride in 315 ml of fluorobenzene is added while stirring and cooling by the carrageenan swelling test in the rat (Winter and Coli, Proc. Soc. Exp. Biol. Med. 1972 III, The effective dose, expressed as a concentration in mg / kg, which inhibits carrageenin swelling equal to or greater than 30%, is 2- [4- (3-thenoyl) phenylpropionic acid 5, phenylbutazone (1,2-diphenyl-3,5-dioxo-4n-butylpyrazolidine) 50 and pyramidone 82.

Inhibition of UV-induced erythema in guinea pigs [Winder С. V. Wax. J. Burr. V. et al., Arch. Int. Pharm. (1958), 116-261] is thirty times greater than aspirin for 2- [4- (3-thenoyl) phenol] propionic acid. At 5 mg / kg the protection of the animal is complete and of the same size as indomethacin [1- (4-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid] or ketoprofen [2'- (3- benzoylphenyl) propionic acid].

2- [4- (3-thenoyl) phenyl] propionic acid has the ability to inhibit in vitro and in vivo platelet clotting in rabbits induced by 5-adenosine diphosphate (ADP) and collagen. To demonstrate this pharmacological property, a method based on the method described by Born (Journal of Physiology) and with a Mustard coagulation meter was used. The result is expressed as a coefficient that expresses the ratio of the weakest effective concentration (in micromoles) of the etalon to the weakest effective concentration of the product. (An effective concentration is called a concentration that causes a clotting inhibition equal to or greater than 50%).

ADP Collagen

60 in an ice bath of 57 g (0.42 mol) of anhydrous aluminum chloride in small portions. The reaction is slightly exothermic and the temperature rises up to 10 ° C. The temperature is then maintained at 60 ° C for 45 minutes and then refluxed for 15 minutes. Cool and pour into ice water. Extract into chloroform. The organic phase is washed with 5% sodium bicarbonate solution and dried over sodium sulfate. After evaporation of the solvent and distillation under vacuum, 18.3 g are obtained.

Yield 30%.

Boiling point 125-130 ° C / 33 Pa, m.p. (hexane) 74 ° C.

IR:

in _CeO 1660СШ ^'first

Stage 2:

2-Methyl-2- [4- (3-thenoyl) phenyl] ethyl malonate (Formula II).

C19H20O5S molecular weight 360.35

To a suspension of sodium hydride [4 g of a 50% suspension (0.083 mol) in 83 ml of freshly distilled hexamethylphosphoric triamide] was added dropwise at room temperature 14.4 g (0.083 mol) of ethyl 2-methylmalonate. 17.1 g (0.083 mol) of 4-fluorophenyl-3-then-methanone in small portions and held at 100 DEG C. for 10 hours, then dissolved in 300 ml of benzene, washed with water and dried over sodium sulfate. to give a yellow oil, total 12.1 g.

Yield 40.6%.

Boiling point 190-200 ° C / 33 Pa.

IR:

vc = o 1660СЩУ ¹ · (ketone) in _c = -o 1750 cm ¹ (esters)

NMR (CCU):

(ppm):

protons at 1.25 (triplet J = 7cps) protons at 1.95 (singlet) protons at 4.3 (quadruplet J = 7cps) protons from 7.3 to 8 (massif)

Stage 3:

2- [4- (3-thenoyl) phenyl] propionic acid (Formula I)

C 11 H 12 O 3 S molecular weight = 260.30

12.1 g (0.033 mole) of 2-methyl-2- [4-thrnoyl) phenyl] ethyl malonate and 80 ml of a 5% aqueous soda solution are kept at reflux for 6 hours. After cooling and washing the solution in benzene, the aqueous bath was acidified with hydrochloric acid. The oil thus obtained was extracted with chloroform. After drying with sodium sulfate and evaporation of the solvent, 9 g of a thick oil is obtained which is recrystallized.

This gave 3.4 g of a white solid having the following characteristics:

Melting point 99-105 ° C.

Yield 39.5%

IR:

i * c = 0 1650 cm- ¹ (ketone) vc = 0 1730 cm1 (acid)

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of 2- [4- (3-teenoyl) phenyl] propionic acid of formula 1 O (1 1 —CH — COOH CH (0) characterized by condensing 3-thenoyl cellulose with fluorobenzene in the presence of aluminum chloride added successively so that the temperature does not exceed 10 ° C, the obtained fluorophenylthenylmethanone is alkylated with ethyl 2-butylalmalonate in an aprotic solvent such as hexamethylphosphorri triamide, in the presence of a strong base such as sodium hydride at room temperature, and after completion of the reaction, the reaction mixture is heated to 100 degrees Celsius for 10 hours, after which 2-methyl-2- [4- (3-thenoyl) phenyl Ethyl malonate is subjected to alkaline hydrolysis, for example with sodium hydroxide at reflux, and then decarboxylated.