HU195955B - Process for producing 1,2-diphenyl-4-n-butyl-3,5-dioxo-pyrazolidine - Google Patents

Abstract

The present invention relates to a process for the preparation of 1,2-diphenyl-4-n-butyl-3,5-dioxopyrazolidine by condensation of hydroxybenzene in the presence of sodium alcoholate with an alkyl ester of n-butyl malonic acid. The process consists of reacting the reaction with 0.5-1.5 moles of n-butanol per b-benzene, and then, after the condensation reaction has ended, with water and n-water (precipitation). The volume ratio of .anol to 100: 1 to 20: 1 is preferably set at 25: 1. The compound produced by the process is known to be an active ingredient in anti-inflammatory compositions. 195955 -1-

Description

Λ subject of the invention; » new process in the presence of 1,2-difc11 i 1 - 1 - n-bu I. z-I-3,5-cl ioxoporazolid in the presence of a shaker in the presence of zol n-rialium in the presence of by condensation of their n-butyl malonic acid slides with an ester.

It is known that 1,2-diphenyl-4-n-butyl-3,5-dioxopyrazolidine, hereinafter internationally known as phenylbutazone, is an important active ingredient in pharmaceuticals for the treatment of inflammatory and rheumatic diseases.

It is also known that various 3,5-dioxopyrazolidines were substituted with malonic acid and hydra derivatives by sodium alcoholate condensation as early as 1906 [Bér. 39, 2282 (1906)]. This method was further developed by Ruhkopf [Bér. 73, 820 (1940)] by condensing in the presence of methanol or ethanol and letting the solvent begin at the beginning of the reaction. According to the procedure, the reaction mixture was then maintained at 100-200 ° C at atmospheric pressure and the reaction was terminated in vacuo.

Λ The main disadvantage of the above condensation reaction was that due to the high condensation temperature, a thermal decomposition occurred. For example, it is known that hydrazobenzene melts at 130-131 ° C with decomposition. The contaminated product was only recoverable, with relatively poor production.

Λζ In the 1950s, for these reasons, other pathways were sought to produce phenylbutazone, such as the subsequent 4-alkylation or 4-acylation of the resulting pyrazolidine ring followed by the reduction of the acylated product (No. 336,398 and 806,759 and British Patent Nos. 812,339). However, these processes could not be successful in industrial production requiring a high quality, high quality end product.

That is why they came back with the no. The authors of U.S. Patent No. 4,123,123 to the United Kingdom patent for dialkyl ester condensation of malonic acid, recognizing that the reaction must be carried out in a solvent which does not or only slightly dissolve the alkali metal salt of the condensation product. Benzene α was found to be such a solvent, but methyl and ethyl alcohol were also used. The process yielded a truly high quality product, but the yield was far below the level expected in such a high volume industrial production. A further disadvantage of the process is that the unreacted starting material and the by-products formed have a detrimental effect on health and their separation and disposal have caused serious environmental problems.

The wise method was implemented by the 172,100. Hungarian patent, which discloses that inalonic acid dialkyl esters are buffered in situ and then condensed in the same mixture containing xylene or gasoline. The reaction temperature was maintained between 115 and 135 ° C, yielding a yield of about 70%, which was also below the required economical result.

It is therefore an object of the present invention to provide a process for obtaining phenylbutazone of unimpaired quality by simple but high-volume technology that minimizes environmental contamination in a short reaction time of at least 90% yield.

In our experiments, it has surprisingly been found that the desired object can be perfectly achieved if, when the condensation is carried out in a certain amount of n-butanol, and after completion of the condensation reaction, -n-butanol ratios are obtained.

Our recognition has overcome a long-standing technical bias in the reaction literature. 172,106, cited above, which summarizes the state of the art. For example, the Hungarian description reads as follows (column 4, lines 14-18): .The alcoholic medium is particularly disadvantageous from the point of view of equilibrium, since ethyl alcohol is formed as a by-product of the condensation, which affects the chemical reaction in the opposite direction. In contrast, it has been found that condensation in the n-butanol medium is excellent, in a surprisingly short time.

Accordingly, the present invention provides a process for the preparation of 1,2-diphenyl-4-n-butyl-3,5-dioxopyrazolidine by condensation of hydrazobenzene with a dialkyl ester of n-butyl malonic acid in the presence of sodium alcoholate. the reaction is carried out in 0.5-1.5 moles of n-butanol based on hydrazobenzene and then, after completion of the condensation reaction, the volume ratio of water to n-butanol is 100: 1-20: 1. , preferably 25: 1.

In a preferred embodiment of the invention, 1.05 mol of 9-10% sodium methylate and 1.05 mol of n-butanol are added to the reactor per mole of hydrazobenzene. The mixture was heated to reflux and 1.05 moles of n-butyl malonic acid dialkyl ester, preferably n-buLyl malonic acid methyl ester, were added to the reaction mixture with stirring, followed by continuous distillation of the methanol in water for 2-4 hours. and the aqueous butanolic solution is extracted with a water immiscible organic solvent, preferably toluene. The aqueous phase obtained is clarified as desired and the final product is precipitated by acid treatment. The precipitated material is filtered off and, if desired, subjected to VAT crystallization with ethanol.

-2ί95955

The advantages of the process according to the invention can be summarized as follows:

- we have a well-controlled, homogeneous system both in the condensation reaction and in the processing of the reaction mixture,

- as a result of these, the reaction is much shorter compared to the prior art processes, without the need for overpressure,

- the methanol produced in the reaction can be easily distilled from the system but, at the same time, the n-butanol present does not give an azeotrope,

- the presence of n-butanol during processing favors the crystallization of the excellent material and eliminates the need for the high dilutions previously used,

- the reaction is almost 100% complete, which results in much less by-product than other processes at the end of the reaction,

- the process generates less waste than any previously known method, thus eliminating the serious environmental problems previously encountered,

- due to the above advantages, our process can be easily adjusted to a production of 200 tons / year.

The process of the invention is illustrated by the following examples:

Example 1

Weigh into a 250 ml flask (distillation stopper, thermometer, stirrer)

36.8 g (0.2 gmol) of hydrazobenzene, 50 g (0.21 gmol) of 9.7% sodium melylate, 16 g of nbulanol. The mixture was heated to 70 ° C and n-butylmalonic acid dimethyl ester (39.5 g, 0.21 gmol) was added with stirring or methanol distillation. The mixture is refluxed for 3 to 4 hours, with ca. 70 ml of methanol were distilled off. The end of the reaction is indicated by the end of distillation.

The dense fluid remaining in the apparatus was dissolved in 150 mL of water and extracted with 2 x 30 mL of toluene. To the aqueous phase was added 0.3 g of Na-diphionite, 150 ml of water and 2.0 g of decolorizing agent. After stirring for 30 minutes, the carbon was washed with 20 ml of water. The filtrate was diluted with water (300 mL) and the product precipitated to pH 5 with 1: 4 bigipic sulfuric acid. The precipitate was filtered off and washed with water (2 x 50 mL). The product thus obtained is dried. Weight: 57.5 g. Yield: 93.3% (if desired, recrystallized from ethyl alcohol). Drug total: 99.5% (0.1 N NaOH in acetone, phenolphthalein).

Example 2

In all cases, the procedure of Example 1 was followed except that the reaction mixture was worked up. as follows:

Λ reaction mixture at 40 ° C for 500 m! water, to which 1 g of <RTI ID = 0.0> ulylimil </RTI> diluolite has been added previously, is extracted with 50 ml of dichloroethylene. Add 2 g of carbon to the aqueous phase and allow to stand under a gentle vacuum at 20 ° C for 30 minutes and then filter. The filtrate was added with stirring to a mixture of 500 mL of water and 13 g of glacial acetic acid to precipitate the product. The precipitate was filtered off, washed with water (2 x 50 ml) and dried under an infrared lamp. The resulting 1,2-diphenyl-4-n-bulyl-3,5-dioxopyrazolidine weighed 58.7 g.

Yield: 95.2%.

a laa n yag La rtalont: 99.4%.

(Total coloring by-products: less than 0,2%).

Example 3 461 kg (2.00 kmol) (10%) of sodium melylate, 152 kg (2.05 mol) of n-bulanol, 350 kg (1.90 kmol) of bridazobenzene are charged into a 2000 l reactor. . The apparatus was subjected to distillation and 370 kg (2.00 kmol) of n-builyl malonate v-dime imester were added to the reaction mixture by continuous methanol distillation. After addition, distillation was continued and 670 kg of methanol (containing 30 kg of n-butanol) was distilled off over 5-6 hours. The reaction mixture was then cooled to 60 ° C, and 1400 L of water was added to dissolve the resulting Nn salt. The aqueous solution was extracted with 2 x 300 L of toluene, then diluted to 4,000 L with water and clarified with 10 kg of charcoal in the presence of 3 kg of sodium dithiolite for 0.5 h at 20 ° C. Filter through a Carlson filter and adjust the pL of the solution to 5 with 1: 5 sulfuric acid while the desired final product crystallizes. The crystal slurry was filtered through a filter centrifuge, washed with water to pH 6 and dried.

Product weight: 530 kg.

Yield: 90.5%.

Volatile Toluene: 98.8%.

Claims (2)

PATENT CLAIMS A process for the preparation of 1,2-diphenyl-4-n-bulyl-3,5-dioxopyrazolidine by condensing hydrazobenzene with an acid alkyl ester of n-butylmalonium in the presence of sodium alcoholate, characterized in that the reaction is hydrazo 0.5-1.5 inches of n-3ϋ • bullet based on benzene, is carried out in anol, and then, after the condensation reaction is completed, the volume ratio of water to n-butnnol is 100: 1-20: 1, preferably 25: 1. 2. A process according to claim 1, wherein the n-butylnialric acid dimethyl ester of its n-butylnialric acid diluent is used.