CS269407B1 - Process for producing suprofen - Google Patents

Abstract

The method for producing suprofen of formula I by the action of phenyl-2-thienyl ketone on the anion of diethyl methyl malonate of formula III, which is generated in situ using sodium or sodium hydride in a dipolar aprotic solvent, extraction of the obtained ester of formula IV with an organic solvent and subsequent hydrolysis and decarboxylation consists in that phenyl-2-thienyl ketone of general formula II, where X denotes bromine or a nitro group, is acted on the anion of diethyl malonate of formula III, after which the reaction mixture is diluted with water after completion, extraction with an organic solvent yields the crude ester of formula IV, which is converted into the disodium salt of substituted malonic acid, from which impurities are removed by extraction, after which the aqueous solution of the disodium salt of substituted malonic acid is converted into suprofen of formula I after acidification and heating

Description

The invention relates to a method for producing suprofen of formula I. The substance of formula 1 belongs to the group of non-steroidal anti-inflammatory drugs based on arylalkanoic acids (Cs. Farmacie 29, 309 (1900)). Its analgesic (Drugs 30, 514 (1985), Curr. Ther. Res. 36, 245 (1984), Arzneim. Forsch. 22, 1327 (1983)) and antipyretic effect (Arzneim. Forsch. 36, 959, 965 (1986)) can be used to suppress acute pain, especially in postoperative conditions and as an effective antipyretic in children.

The current method of producing the acid of formula I (Arzneim. Forsch. 25, 1495 (1975), Spart, patent documents 508 704, 524 225, European patent application 14 440, Japanese Kokai Tokkyo Koho 7976 573, 80 104 216, DOS 2 746 754) consists of multi-stage syntheses, which are not very advantageous from an economic, technological and ecological point of view. Other methods using organometallic reagents in one of the reaction stages (Austrian Pat. No. 363,069, Japanese Kokai Koho 82 28 709, British Pat. No. 875,059, German Pat. No. 76 06 830, Arzneim. Forsch. 25, 1495 (1975)) do not bring significant improvements due to the difficulty of handling under technological conditions. Some technologically used methods (Arzneim. Forsch. 25, 1495 (1975), Spart, Pat. No. 485,932, 539,196) protect the aromatic nucleophilic substitution of 4-fluorophenyl-2-thienyl ketone with an anion generated by basic reagents in the environment of dipolar aprotic solvents from diethyl methyl malonate of formula III, with the ratio of reactants being 1:1. The resulting ester of formula IV provides, after alkaline hydrolysis and subsequent acid-catalyzed decarboxylation, the target compound of general formula I. The disadvantage of these processes is not only the low conversion of 4-fluoro-phenyl-2-thienyl ketone and its practically unfeasible regeneration, but also the associated overall low yield of ester of formula IV. Together with the difficult and laborious synthesis of fluorophenone, resulting from the difficult introduction of a fluorine atom into both the aromatic and the ring, these methods also make them economically considerably disadvantageous.

These methods are followed in a positive sense by the method according to the invention, which significantly reduces the above-mentioned disadvantages. The essence of the method according to the invention lies in the fact that | The methyl malonate anion of formula III generated by sodium reagents, preferably sodium or even sodium hydride, in an organic solvent environment, preferably dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide, is reacted with readily available phenyl-2-thienyl ketone (J. Org. Chem. 17, 705 (1952), Rec. Trav. Chim. Pays-Bas 69, 1083 (1953)) of general formula II, where X represents bromine or a nitro group, at a temperature of 40 to 140 °C, preferably 80 to 100 °C, after which, after the reaction is complete, the reaction mixture is diluted with a 5 to 10-fold amount of ice water and the crude diester of formula IV is isolated by extraction with an organic solvent, such as toluene, benzene, xylene, chloroform. After evaporation of the solvent, the crude diester of formula IV is treated with sodium hydroxide to form the disodium salt of substituted malonic acid, from which impurities are removed by extraction with a chlorinated hydrocarbon, for example chloroform, after which the aqueous solution of the disodium salt of substituted malonic acid is converted into the acid of formula I after acidification and heating to 80 to 120 °C, which is purified by crystallization.

The advantage of the process according to the invention is the easy preparation of the ketone of general formula II, where X = Br, NO ₂ and the easy isolation of the pure product.

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

EN 269407 81

Example

To a mixture of 10.6 g, i.e. 0.13 mol of 75% sodium hydride in dimethylformamide (100 ml) was added dropwise under stirring under a nitrogen atmosphere 58.0 g, i.e. 0.33 mol of malonate of formula III, after 0.5 h 25.9 g, i.e. 0.11 mol of phenone of formula II, where X = NO?, were added to the suspension and the mixture was stirred for 8 h at 100 °C. After cooling, it was decomposed with ice water (500 ml), washed with toluene and the toluene solution was evaporated. The residue was hydrolyzed in a mixture of 22 g of sodium hydroxide, water (150 ml) and ethanol (150 ml). After 8 h of heating to boiling, the majority of the ethanol was evaporated, the residue was diluted with water, washed with chloroform and after acidification of the aqueous solution with hydrochloric acid to pH 2, the crude acid of formula I was extracted with toluene. After concentration of the toluene solution, the crude acid of formula I (23%) was purified by simple crystallization from acetonitrile; analytically pure product of formula I was obtained, m.p. 124-125 °C. .

Example 2

In the same manner as in Example 1, from 29.6, i.e. 0.11 mol of ketone of formula II, where X = Br, the acid of formula I was prepared, which after crystallization from acetonitrile gave an analytically pure product, mp 124-125.5 °C.

Example 3

To a mixture of 34.4 g, which is 0.198 mol of malonate of formula III and 50 ml of dimethylformamide, 4.6 g (0.198 mol) of sodium was added in portions under stirring in a nitrogen atmosphere. After 1/2 hour, 25.9 g (0.11 mol) of phenone of formula II, where X = NO? was added to the resulting suspension and the mixture was stirred for 10 h at 80 °C. After cooling, it was poured into 250 ml of a mixture of ice and water, the organic layer was separated and the aqueous phase was washed with toluene. The combined organic fractions were evaporated and the distillation residue was hydrolyzed and treated as in Example 1. 8.6 g (30 µ) of the product of formula I with a melting point of 123 to 125 °C were obtained.

Claims (1)

SUBJECT OF THE INVENTION A method for producing suprofen of formula I by the action of phenyl-2-thienyl ketone on the anion of diethyl methyl malonate of formula III, which is generated in situ using sodium or sodium hydride in a dipolar aprotic solvent, by extraction of the obtained ester of formula IV with an organic solvent and subsequent hydrolysis and decarboxylation, characterized in that phenyl-2-thienyl ketone of general formula II, where X represents bromine or a nitro group, is acted on the anion of diethyl malonate of formula III in a molar ratio of 1:1 to 3 at a temperature of 40 to 140 °C, after which the reaction mixture is diluted with water after completion, extraction with an organic solvent yields the crude ester of formula IV, which is converted by the action of sodium hydroxyl into the disodium salt of substituted malonic acid, from which impurities are removed by extraction with a chlorinated hydrocarbon, for example chloroform, after which the aqueous solution of the disodium salt of substituted malonic acid is acidified and heated to 80 to 120 °C converts it to suprofen of formula I.