CS268395B1 - Method of 2-/4/2-theonyl/phenyl/-propionic acid production - Google Patents

Abstract

Manufacturing Method 2- (4-Thenoyl-phenyl) - propionic acid of formula I from 4-fluorophenyl-2-thienyl ketone of Formula II by treatment anion generated from diethyl methyl malonite of formula III by treatment with sodium hydride in a dipolar aprotic environment solvents at 80 to 100 ° C is that the molar ratio of ketone of formula II and diethyl methylmalonite of formula III is between 1 and 1.5 to 3, whereupon after the reaction was complete, the reaction mixture was diluted water, extraction with an organic solvent to isolate diethyl (4-12-henoyl) phenyl (-) -methylmalonite of formula IV, which, after hydrolysis and dec arboxylation provides the acid of formula I.

Description

The invention relates to a process for the preparation of 2- (4-12-thenoyl) phenyl] propionic acid of formula I. Said acid of formula I belongs to the group of arylpropionic acids, which represent one of the important classes of non-steroidal anti-inflammatory agents. Farm. 29, 309 119801 /. In addition, it has a significant antipyretic / arsenic. Forschl 3é (959, 965 119861) and analgesic effect (Drugs 3Qz 514 | 1985 |, Curr. Ther. Res. 3éz 245 11984, Arzneim. Forsch. 33, 1327 119831 /. It is used therapeutically to reduce postoperative pain and in some cases has proven to be an effective antipyretic for children.

Conventional processes for the preparation of the acid of the formula I / Arzneim. Forsch. 25 »1495 11975 1, Spanish. pat. files 508 704, 524 225, Europatent 14 440, Jpn. Kokai Tokkyo Koho 79 76 573, 80 104 216, Ger. Offen. 2,746,754 / are based on multistage syntheses which are of little technological, economic and ecological advantage. Also processes that use organometallic reagents in some of the reaction stages. pat. file 363 069, Jpn. Kokai Tokkyo Koho 82 28 709, Belg. 875 059, Neth. Appl. 76 06 830, Arzneim. Forsch. J5, 1495 119751 / did not bring significant progress. From a technological point of view, they are difficult to implement and, in most cases, require the use of highly flammable solvents. There are some improvements in the ways / Arzneim. Forsch. 25 »1495 119751, span. pat. U.S. Pat. Aquemilic amounts of reactants are used in these procedures. The ester obtained is converted to the desired acid of formula I in a conventional manner, i.e. by alkaline hydrolysis and subsequent acid-catalyzed decarboxylation. This results in a significant amount of waste that is difficult to dispose of. Furthermore, it has a significant effect on the overall low acid yield of formula I, which is 23%. For these reasons, the methods mentioned are economically considerably disadvantageous in this embodiment.

These known processes are followed by the process according to the invention, which consists in treating the 4-fluorophenyl-2-thienyl ketone of the formula II with a 1.5 to 3 molar excess of the anion of diethyl methylmalonate generated by the action of sodium hydride in an aprotic dipolar solvent. methyl malonate of formula III at a temperature of 80 to 100 ° C. After completion of the reaction, which is easily monitored by thin layer chromatography, the reaction mixture is diluted with water and the product is extracted into an organic solvent, preferably toluene, chloroform or dichloroethane. After evaporation of the solvents under reduced pressure, the crude thiethyl [4- (2-theonoylphenyl) methyl] malonate obtained of formula IV gives, after alkaline hydrolysis and acid-catalyzed decarboxylation, the desired acid of formula I in good yield of 56% based on the starting ketone of formula II.

The advantage of the process according to the invention is that the yield of 2- (4-2-thenoyl) phenyl / propionic acid of the formula I is substantially increased. The reaction rate and the conversion of the starting ketone of the formula II increase. Furthermore, the reaction time is substantially shortened and the amount of ballast substances is reduced. The one-step process, which does not require complex apparatus, with a minimum consumption of auxiliary chemicals and solvents that can be regenerated, is very advantageous from an economic point of view.

The invention and its effects are demonstrated by several examples, which are illustrative only and do not limit the scope of the invention in any way.

Example 1

To a mixture of 10.6 g of 75% sodium hydride in hexamethylphosphoramide (100 ml) was added dropwise 58.0 g of the malonate of formula III with stirring under a nitrogen atmosphere. After 30 min. 23.0 g of the ketone of formula II were added and the mixture was stirred for 8 h at 90-100 ° C, after cooling it was quenched by the addition of 300 ml of water, extracted with toluene (3 x 150 ml) and toluene solution.

CS 268 395 Bl stream evaporated. The residue was hydrolyzed in a mixture of 44 g of sodium hydroxide, water (300 ml) and ethanol (300 ml). After 8 h the mixture was diluted with water (300 ml), washed with chloroform (3 x 100 ml) and after acidifying the aqueous layer with hydrochloric acid to pH 2 the product of formula I was extracted with toluene (4 x 150 ml) and after evaporation crystallized from acetonitrile to give 16.1 g (56%) of the acid of formula I, m.p. 124-125 ° C.

Example 2

In the same manner as in Example 1, 21.2 g of 75 Z sodium hydride in 250 ml dimethylformamide, 77.3 g of malonate of formula IIX and 46 g of ketone of formula II after hydrolysis of the crude ester of formula IV in a mixture of 59 g of sodium hydroxide, water / 500 ml / and ethanol (500 ml) followed by acidification with hydrochloric acid to give 30.4 g of the acid of formula I (53 Z), m.p. 124-125.5 ° C.

Claims (1)

OBJECT OF THE INVENTION Preparation of 2- / 4 I2 thenoylIfenyl / propionic acid of formula I from 4-fluorophenyl-2-thienylketone formula II with the anion generated from diethyl methyImalonátu formula III CH ₃ CH / COOC ₂ H _5/2/111 / with sodium hydride in a dipolar aprotic solvent medium at a temperature of 80 to 100 ° C, characterized in that the molar ratio of 4-fluorophenyl-2-thienyl ketone of formula II and diethyl methyl malonate of formula III is in the range of 1: 1.5 to 3, then after completion the reaction mixture is diluted with water, extraction with an organic solvent isolates diethyl / 4-2-thenoylphenyl / methylmalonate of formula IV, which after hydrolysis and decarboxylation gives the acid of formula I.