CS208825B1 - Process for preparing 1,2-diphenyl-3,5-dioxopyrazolidine derivatives - Google Patents

Abstract

Method for preparing 1,2-diphenyl-3,5-dioxopyrazolidine derivatives. The invention relates to the production of pharmaceutical substances and solves a new method for the preparation of active 1,2-diphenyl-3,5-dioxopyrazolidine derivatives. The purpose of the invention is to prevent the formation of by-products, which are partly strongly colored and often, even in trace amounts, make it difficult to perform an effective purification operation. The stated purpose is achieved by adding L-ascorbic acid or D-isoascorbic acid or its derivatives, which have a significant stabilizing effect and help prepare products of the desired quality. The invention relates to the preparation of chemical compounds characterized by the general formula In which R denotes hydrogen or the groups n-butyl, 3-oxobutyl, 3-chlorocrotyl or 4,4-dimethyl-3-oxopentyl.

Description

(54) Preparation of 1,2-diphenyl-3,5-dioxopyrazolidine derivatives

A process for the preparation of 1,2-diphenyl-3,5-dioxopyrazolidine derivatives. The present invention relates to the manufacture of pharmaceutical substances and to a novel process for the useful 1,2-diphenyl-3,5-dioxopyrazolidine derivatives. This is achieved by adding L-ascorbic acid or D-isoascorbic acid or derivatives thereof, which have a significant stabilizing effect and assist in the preparation of the products of the desired quality. The invention relates to the preparation of chemical compounds characterized by the general formula

Wherein R is hydrogen or n-butyl, 3-oxobutyl, 3-chlorocrotyl or 4,4-dimethyl-3-oxopentyl.

206,825 i

The invention relates to a process for the preparation of compounds of the general formula

R — C K

-WHAT

V - ^C 6 ^H 5

CO-N -C ₈ H ₅ (I) wherein R represents hydrogen or n-butyl, 3-oxobutyl, 3-chlorocrotyl or 4,4-dimethyl-3-oxopentyl groups. These compounds may be present during synthesis in the form of the appropriate acid, in the form of a salt such as an alkali metal salt, a divalent metal cation such as an ammonium salt and the like.

These compounds are drugs with significant anti-inflammatory effects (eg Ketazone, Tribuzone) or intermediates for the preparation of these drugs.

The above compounds are generally prepared by condensation of the corresponding malonic esters with hydrazobenzene or by reaction of the respective components with 1,2-diphenyl-3,5-dioxopyrazolidine or derivatives thereof. (U.S. Patent 85569 (1956), U.S. Patent No. 136647 (1970), U.S. Patent No. 112958 (1964), Ruhkopf, H., Ber. 820 (1940)).

In the preparation of said 1,2-diphenyl-3,5-dioxopyrazolidine derivatives, a number of by-products are formed, the formation of which, inter alia, results from the lability of the dioxopyrazolidine ring and the reactivity of the other components used. The presence of hydrazobenzene, which is always present in larger or smaller amounts in the reaction medium in the presence of 1,2-diphenyl-3,5-dioxopyrazolidine derivatives, also has a negative effect on stability. (Sokolova, V.N. and Magidzon, O. Ju .: ŽOCH 26 604 (1956)). The resulting accompanying compounds are in part strongly colored and often make it difficult to perform an effective cleaning operation even in trace amounts. Even if non-color by-products are formed, they are the cause of the formation of opalescence in the solutions under difficult analytical evaluations according to pharmacopoeias and other conditions.

It has been found that although these are oxidation reactions in part, the use of strong reducing agents such as sodium dithionite is not fully addressed. Decomposition of 1,2-diphenyl-3,5-dioxopyrazolidine derivatives, resp. conventional antioxidants, such as 2,6-di-tert-butyl-4-methylphenol, glucose and the like, do not prevent the formation of other by-products to the extent necessary. In many cases, the use of these reagents may result in subsequent product recovery.

It has now surprisingly been found that the addition of L-ascorbic acid or its derivatives (esters, salts) has a remarkable stabilizing effect and aids in the preparation of intermediate and final products of the desired quality. The addition of L-ascorbic acid and its derivatives can be used already at the stage of the production process itself, especially in the isolation and purification operations. The addition of D-isoascorbic acid or derivatives thereof has a similar effect.

The 1,2-diphenyl-3,5-dioxopyrazolidine derivatives of formula (I) are isolated from water, a mixture of water and organic solvents, organic solvents or mixtures thereof. In similar solvent systems, refining or proprietary product preparation technology is also performed. In the preparation of the 1,2-diphenyl-3,5-dioxopyrazolidine derivatives of the formula I as well as in the isolation purification processes, these compounds can also be present in the form of salts. In some cases, salt formation is utilized in the purification process * (U.S. Patent No. 102406 (1962)).

The following examples illustrate but do not limit the scope of the invention.

Examples;

Example 1

0.5 g of L-ascorbic acid, 70.0 g of 1,2-diphenyl-3,5-dioxo-4- (3-oxobutyl) pyrazolidine sodium salt and 0,5 g of sodium dithionite are gradually dissolved in 530 ml of distilled water. .

The reaction mixture is filtered with 5.0 g of carborafine, the filtrate is diluted with 300 ml of methanol and, cooled to 14-16 ° C, is precipitated with 18 ml of acetic acid. The 1,2-diphenyl-3,5-dioxo-4- (3-oxobutyl) pyrazolidine suspension is suctioned off after cooling to 0 DEG C. and stirred in a mixture of 110 ml of methanol and 290 ml of water in which 0.2 g of L- ascorbic. After aspiration, washing and drying, 63.0 g of white 1,2-diphenyl-3,5-dioxo-4- (3-oxobutyl) pyrazolidine (96.1% th.) Are obtained, m.p. 126-128 ° C. . The product meets pharmacopoeial requirements.

Example 2

In a butanolic solution of sodium butylate, prepared by dissolving 6.5 g of sodium (0.283 mol) in 300 ml of n-butanol, 70.0 g of 1,2-diphenyl-3,5-dioxopyrazolidine (0.277 mol) and 41% are gradually dissolved. 0 g of 2,2-dimethyl-3-oxo-5-dimethylaminopentane (0.261 mol) at 65 ° C. The reaction mixture is then heated to boiling and boiled for 3 hours. It is then cooled to 45-50 ° C, 0.86 g of L-ascorbic acid is added and acidified with ca. 55 ml of conc. of hydrochloric acid to congo. The precipitated suspension is cooled to 0 ° C, filtered off with suction, washed with 150 ml of cold methanol. lu and approx. 1000 ml dest. water. After drying, 91.1 g of off-white, crude 1,2-diphenyl-3,5-dioxo-4- (4,4-dimethyl-3-oxopentyl) pyrazolidine is obtained, i.e. 95.9% th., Mp 144 Mp, 0-146.0 ° C.

91.1 g of crude 1,2-diphenyl-3,5-dioxo-4- (4,4-dimethyl-3-oxopentyl) pyrazolidine is dissolved at 60 ° C in 990 ml of methanol containing 1.2 g of L- Ascorbic acid, 4.5 g of carboraffin mixed in saturated sodium dithionite solution is added to the solution, and the reaction mixture is filtered. The filtrate is cooled to 0 ° C, the crystalline product is filtered off with suction, washed with 100 ml of methanol and dried.

82.0 g of 1,2-diphenyl-3,5-dioxo-4- (4,4-dimethyl-3-oxopentyl) pyrazolidine are obtained, i.e. 90% of the batch; mp 144.5-145.5 ° C. The product is white and meets pharmacopoeial requirements.

Example 3

To a methanolic solution of sodium methylate prepared by dissolving 1.9 g of sodium (0.083 mol) in 22.0 ml of methanol is added a suspension of 11.2 g of hydrazobenzene. (0.061 mol) and 10.0 ml of n-butanol, and 11.2 g of ethyl malonate (0.070 mol). Reaction mixture. The mixture was heated to boiling and a mixture of methanol and n-butanol was distilled off over 6 hours, raising the temperature to 175 ° C. The resulting 1,2-diphenyl-3,5-dioxopyrazole sodium salt was collected; it is dissolved in 160 ml of water in which 1.0 g of D-isoascorbic acid has previously been dissolved and the mixture is filtered with 0.7 g of carboraffin.

The light yellow filtrate was acidified with ca. 7 ml conc. hydrochloric acid to pH 3 and after cooling to 5 ° C the suspension is filtered off with suction, washed with water until neutral and dried. 14.2 g of pale yellow 1,2-diphenyl-3,5-dioxo-pyrazolidine, i.e. 92.6% of m.p. 165 DEG-172 DEG C., is obtained. The product is chromatographically uniform.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 1,2-diphenyl-3,5-dioxopyrazolidine derivatives of the general formula I-CO 2 - C ₆ H ₅ R-Ch '(I),' CO-N C ₈ H ₅ wherein R represents hydrogen or n-butyl, 3-oxobutyl, 3-chlorocrotyl or 4,4-dimethyl-3-oxopentyl groups by condensation of malonic esters with hydrazobenzene or by reaction of appropriate a component with 1,2-diphenyl-3,5-dioxopyrazolidinenyl or derivatives thereof in an aqueous medium or in mixtures of water with organic solvents or in organic solvents or mixtures thereof, characterized in that the respective operation is carried out with the addition of L-ascorbic acid or D isoascorbic acids and / or derivatives of these acids with a preferred salt or ester.