HU195489B - Process for producing 1,2-diphenyl-4 brackets open /2-phenyl-sulfinyl/-ethyl brackets closed-3,5-pyrazolidindione - Google Patents

Abstract

The present invention relates to a process for the preparation of 1,2-diphenyl-4 - [(2-phenylsulfinyl) ethyl] -3,5-pyrazolidinedione in 1,2-diphenyl-4 - [(2-phenylthio) ethyl]. ] By oxidation of hydrogen peroxide in the presence of acetic acid, in the presence of acetic acid in the presence of pK = 0-3 as the catalyst in aliphatic alcohol, chlorinated or aromatic hydrocarbon at 0 ° C to 20 ° C. temperature. The product obtained by this process, sulfinpyrazone, is an active ingredient of

Description

The present invention relates to a new process for the preparation of 1,2-diphenyl-4 - [(2-phenylsulfonyl) ethyl] -3,5-pyrazolidinedione, hereinafter referred to as sulfinpyrazone, 1,2-diphenyl-4 - [(2-phenylthio) - by oxidation of ethyl] -3,5-pyrazolidinedione with hydrogen peroxide in the presence of acetic acid.

Sulfinpyrazone is an active ingredient in pharmaceuticals for the treatment of gout and, more recently, for the prevention of thrombus formation.

The most obvious method for the preparation of the compound was the oxidation of the corresponding "phenylthioethyl" derivative. This was solved in previous processes by acid oxidation.

Other known methods, e.g. The synthesis described in the Swiss patent, which consists of 7 steps, is cumbersome and cumbersome.

No. 179,575. The authors of Hungarian Patent No. 5,123,121, issued a request to further develop the original Pfister process (Helv. Chim. Acta 44, 232 (1961)) by oxidizing peracetic acid in the presence of sulfur-containing additives. The original process did not prove to be sufficiently selective, and the product was only obtained by evaporation from the reaction mixture. This had the disadvantage that any unreacted hydrogen peroxide, when oxidized to acetic acid peracetate, posed a serious explosion hazard.

According to the above-mentioned Hungarian patent, the efficiency of oxidation in the presence of a thioether or sulfoxide type solvent was improved, and even the presence of a by-product could be reduced, but in the meantime the ever-stricter prescription requirements had already limited all possible by-products. Thus, for example, the product obtained by the above procedure no longer complied with the requirements of the British Pharmacopoeia in of the quality described in the 1985 edition of the US Pharmacopoeia.

The industrial implementation of the above process has further disadvantages. The oxidation had to be carried out at 50 ° C, whereby the exothermic reaction was very difficult to control, thus often overoxidation, thus a harmful side reaction occurred. In addition, the removal or removal of extremely high levels of acid by-products. its destruction has also caused significant problems, including environmental problems.

It is therefore an object of the present invention to provide a chemical process which is well practicable on an industrial scale to eliminate the above disadvantages and to obtain the desired product in a simple, pure manner.

In our experiments we found that oxidation is much more dependent on pH than expected. Surprisingly, it has been found that by carrying out the reaction in the presence of a catalytic amount of pK = 0-3 acid, very favorable conditions can be achieved at a reaction temperature of 0 ° C to 20 ° C. In this case, the side reactions are significantly suppressed and a substantially pure, uniform product can be obtained. It has also been found that using different acids instead of the previously used sulfoxide-type compounds, the use of previously unfavorable aromatic or chlorinated hydrocarbons as a solvent for the cut aliphatic alcohols proves to be surprisingly advantageous.

Thus, the present invention is based on the discovery that another type of chemical oxidation is better and more effectively used than less controllable peracid oxidation.

Accordingly, the present invention relates to a process for the preparation of 1,2-diphenyl-4 - [(2-phenylsulfonyl) ethyl] -3,5-pyrazolidinedione, 1,2-diphenyl-4 - [(2-phenylthio) ethyl ] -3,5-pyrazolidinedione by hydrogen peroxide oxidation in the presence of acetic acid, which is carried out in the presence of a pK-0-3 acid used as a catalyst in an aliphatic alcohol, chlorinated or aromatic hydrocarbon at a temperature of 0 ° C to 20 ° C.

In a preferred embodiment of the invention, the reaction comprises reacting an acid pK = 1 to 2, such as p-toluenesulfonic acid, oxalic acid, fumaric acid, salicylic acid, benzene, toluene, chloroform, dichloroethane, aliphatic as aromatic or chlorinated hydrocarbon. and the alcohol used is methanol and ethanol.

Alternatively, from 0.001 to 0.1 parts by weight of oxalic acid may be selected from the particular acid, e.g., p-toluenesulfonic acid, relative to 1 part by weight of the starting material.

The reaction temperature is preferably from 15 ° C to 20 ° C, but favorable results have also been obtained at lower temperatures. It is expedient to use a very small excess (0-5 mol · #) of hydrogen peroxide as the oxidizing agent.

The reaction according to the invention is carried out in a simple mixing apparatus, in which the starting pyrazolidinedione derivative, the desired solvent, concentrated hydrogen peroxide and the acid or acid mixture used as catalyst are pre-measured. The components are reacted with stirring, and the mixture is worked up. In the case where the solvent is immiscible with water, the work-up is treated with an aqueous wash, the resulting phases are separated, the organic phase is dried, the solvent is evaporated and the product is crystallized.

If a water-miscible solvent is used, the resulting mixture is simply crystallized.

The most important advantage of the process according to the invention is that the oxidation takes place in a highly selective manner, according to our measurements, the amount of undesired oxidation by-products can be reduced to less than 0.01% by weight and all other = impurities to less than 0.05% by weight.

It is also advantageous that prior art procedures often show discoloration, which has also called into question the medical use. This unknown dye was only very difficult to dispose of by recrystallization gj'akran several times, whereas this type of dye does not occur in the present process.

It is also a significant advantage that the process can be carried out on an industrial scale in a simple manner with high security. Regeneration of the solvents used can be easily solved, while the mother liquors formed in prior art processes have been a serious environmental problem.

The crude product obtained can, if desired, be purified by simple recrystallization.

The invention is illustrated by the following examples, without, however, limiting the invention thereto.

Example 1

Weigh 20 g (51 g) into a 200 ml glass reactor

195,489 mmol) 1,2-diphenyl-4 - [(2-phenylthio) ethyl] pyrazolidine-3,5-dione, 40 ml chloroform, 30 ml methanol, 10 ml glacial acetic acid, 40 mg salicylic acid and 9 ml liidrogén peroxide. The mixture was stirred at 20 ° C for 8 hours and then extracted with water (2 x 50 ml) at 20 ° C, and the organic phase 5 was stripped of solvent.

Product weight: 40.4 g (97.177).

The residue was recrystallized from absolute ethanol to give 37.4 g (89,877) of pure product, which was 1,2-diphenyl-4 - [('2-phenylsulfinyl) ethyl] -3,5-dione-pyrazolidine -tar- 10 Talma: 99,577.

Example 2

All were carried out as described in Example 1 except that fumaric acid was used instead of salicylic acid and ethanol was used instead of methanol. The resulting reaction mixture was cooled to 10 ° C, and the precipitated 1,2-diphenyl-4 - [(2-phenylsulfinyl) ethyl] -3,5-dione pyrazolidine was crystallized, filtered and dried. Weight: 38.2%

g. Yield: 91.777. Active ingredient content: 99.8%.

Example 3

With a 250 ml stirrer, place 20 g of 1,2-diphenyl-4 - [(2-phenylthio) ethyl] -3,5-pyrazolidinedione in a thermos flask. 60 ml of toluene, 5 ml of acetic acid and 7 ml of hydrogen peroxide and 300 mg of oxalic acid. The reaction mixture was stirred at 15 ° C for 2 hours and then diluted with water (100 mL). The organic layer was separated, washed with water (20 mL), and evaporated in vacuo. Weight: 20.5 g (987-). which is crystallized from 92 ml of absolute ethanol. Yield: 18.5 g (89%) Active ingredient: 99.777.

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Example 4

A 2000 L duplicator was charged with 300 L dichloroethane, 300 L acetic acid, 150 kg (386.5 mol) 1,2-diphenyl-4 - [(2-phenylthio) ethyl] -3,5-dione pyrazolidine and 300 g of p-40

toluenesulfonic. The solution was cooled to 15 ° C and 41 kg (398 moles) of hydrogen peroxide were added and stirred at 15 ° C for 2 hours. After the oxidation is complete, the organic phase is extracted with 2 x 500 L of water and the dichloroethane is distilled off in vacuo, which can be reused without further regeneration. The distillation residue was dissolved in 700 L of absolute ethanol, cooled, and the resulting 1,2-diphenyl-4 - [(2-phenylsulfonyl) ethyl] -3,5-dione pyrazolidine was crystallized, filtered by centrifugation and dried. Weight: 142 kg. yield: 90.977. Active ingredient content: 99.65%.

Claims (6)

A process for the preparation of 1,2-diphenyl-4 - [(2-phenylsulfinyl) ethyl] -3,5-pyrazolidinedione, 1,2-diphenyl-4 - [(2-phenylthio) ethyl] - 3.5-pyrazolidinedione by hydrogen peroxide oxidation in the presence of acetic acid, characterized in that the oxidation was used as a catalyst. in the presence of an acid of pK = 0-3, aliphatic alcohol, chlorinated or aromatic hydrocarbon at a temperature of 0 ° C to 20 ° C. 2. The process according to claim 1, wherein the acid is pK = 1-2, preferably p-toluenesulfonic acid or fumaric acid. Process according to claim 1 or 2, characterized in that the solvent is methanol, benzene, toluene, dichloroethane or chloroform. 4. A process according to any one of claims 1 to 4, wherein the p-toluenesulfonic acid or fumaric acid is used in an amount of 0.0001-0.1 parts by weight relative to 1 part by weight of the starting material. 5. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out at a temperature of 15 to 20 ° C. 6. Process according to any one of claims 1 to 3, characterized in that the hydrogen peroxide used for the oxidation is used in an excess of 0-5 mol77.