DE1135478B - Process for the preparation of 3, 5-dioxo-1, 2, 4-triazolidines - Google Patents

Description

Process for the production of 3,5-dioxo-1,2,4-triazolidines of therapeutically effective triazolidines of the general formula (I) where R1 is a phenyl radical in which a hydrogen atom can optionally be substituted by a halogen atom or a low molecular weight alkyl or alkoxy group, and R2 is a phenyl radical in which a hydrogen atom is substituted by a hydroxyl group, an acylamino group, a low molecular weight alkoxy group or a halogen atom , by ring closure reaction from phenyl hydrazine derivatives by, in a manner known per se, a) reactive derivatives of semicarbazide-carboxylic acids of the general formulas (II) and (IIa) RIN - NHCONHR2 (II) COOH or HOOC-NH-N-CONH-R2 (IIa) R1 treated with alkaline agents or heated in the absence of alkaline agents; or b) semicarbazides of formulas (III) and (IIIa) R1-NH-NH-CONH-R2 (III) respectively with reactive derivatives of carbonic acid or c) reactive derivatives of phenylhydrazine-N1, N2-dicarboxylic acids of the formula (IV) reacts with amines of the formula R2 - N H2 or d) reactive derivatives of phenylhydrazine-N1- or -N2-monocarboxylic acids of the formulas (V) and (V a) or R1-NH-NH (Va) COOH is reacted with reactive derivatives of carbanilic acid and, if appropriate, the compounds obtained are converted into the corresponding salts with the aid of inorganic or organic bases.

In the further processing of this work area it was found that that the triazolidines of the general formula (I) can also be obtained if 1 mol of a phenylhydrazine of the general formula R1 - N H - N H2 with 1 mol of one Amine of the formula R2 - NR2 and with 2 moles of a reactive derivative of carbonic acid Reacts at elevated temperature.

As starting materials for the method according to the invention, for. B. following the general formula R1 - NR - NR2 corresponding phenylhydrazines in Consideration: phenylhydrazine, 2-, 3- or 4-chlorophenylhydrazine, 2-, 3- or 4-bromo-phenylhydrazine, 4-fluoro-phenylhydrazine, 3-iodo-phenylhydrazine, 4-methoxyphenylhydrazine, 2-, 3- or 4-methyl-phenylhydrazine, 4-n-butoxyphenylhydrazine, 2-, 3- or 4-propylphenylhydrazine, 4-tert. -Butyl-phenylhydrazine.

As amines of the formula R2-NH2, which react with reactive derivatives of Carbonic acid and phenylhydrazines of the formula R1-NH-NH2 to the triazolidines of the formula (1) can be implemented, z. B. 2-, 3- or 4-methoxy- or ethoxyaniline, 2-, 3- or 4-chloro- or bromo-aniline, 4-fluoroaniline, 4-amino-acetanilide, 4-hydroxy-aniline, 4-isopropoxy- or n-butoxy-aniline or 4-n-propoxyaniline.

Of the reactive derivatives of carbonic acid that come with the starting materials can be converted to triazolidines of the type mentioned above, is particularly suitable Urea, but other carbonic acid derivatives such as carbonic acid diethyl ester, Phenyl carbonate, chlorocarbonate, carbamic acid ester or carbamic acid chloride be used.

The process according to the invention can be varied within wide limits and be adapted to the respective conditions. For example, you can see the reaction in the presence or absence of a solvent and optionally in the closed Carry out the vessel. To achieve favorable reaction rates, it is advisable to to work at temperatures above 150 "C. When using urea as a reaction component the reaction is advantageously carried out in the melt; the reactants are heated as long as elevated temperatures, e.g. B. to temperatures between 180 and 220 "C, until the evolution of ammonia has ended. Instead of the free phenylhydrazines and Amines can also use corresponding salts of inorganic or organic acids will. When using halogen-containing carbonic acid derivatives, the amine is used of the formula R2-NH2 expediently in excess amounts or uses others basic agents as hydrogen halide. In the case of using carbonic acid esters can the reaction by catalytic amounts of alkali, z. B sodium alcoholate, be promoted. The reaction products are made up of neutral by-products or starting material still present, advantageously by treating the reaction mixture with aqueous or aqueous-alcoholic alkali, in which the 3,5-dioxo-1,2,4-triazolidines are mostly easily soluble, separated. From the alkaline solution is obtained at Acidification with inorganic or organic acids, the free dioxo-triazolidines, which are usually obtained in crystalline form and in the usual way, for. B. by Recrystallization from a suitable solvent, e.g. B. alcohol, be cleaned can.

The 3,5-dioxo-l obtainable by the process according to the invention 2,4-triazolidines are compounds of acidic character that are created with the help of inorganic and organic bases can be converted into corresponding salts. With regard to The alkali and alkaline earth salts, in particular, have benefited from their use as medicinal products Meaning, which in most cases are soluble in water and their solutions unite have a physiological Px value.

The products of the process are valuable remedies.

They show in particular anti-inflammatory properties but also z. B. analgesic and antihypertensive effectiveness and are generally characterized by their good physiological tolerance the end. So shows z. B. the 1-phenyl-4- (p-ethoxyphenyl) -3,5-dioxo-1,2,4-triazolidine sodium salt in the aerosil test on the rat paw a dosage of 500 mg / kg s. c. a clear one. long-lasting anti-inflammatory effect. The LD50 in the mouse is intravenous Application about 800mg / kg, from which compared to already known anti-inflammatory effective compounds, e.g. B. compared to sodium salicylate and l-phenyl-2,3-dimethyl-4-dimethylamino-pyrazolone- (5) results in a greater therapeutic index, which is clinically essential Means progress in the treatment of rheumatic diseases.

Example 1 A mixture of 10.8 g phenylhydrazine, 16 g p-methoxyaniline hydrochloride and 12 g of urea is gradually heated to 190 "C and 5 hours at this temperature held. After cooling, the reaction mixture is washed with 200 ccm of 2N sodium hydroxide solution and 200 cc of benzene shaken until two clear layers are present. Man separates the aqueous phase, diluted with water and clarified by suction Addition of activated carbon. Upon acidification, the l-phenyl-4- (p-methoxyphenyl) -3,5-dioxo- 1,2,4-triazolidine in the form of an almost colorless precipitate, which is sucked off, washed with water and dried. Yield: 9.3 g. Melting point 222 to 225 "C (from ethanol).

Example 2 A mixture of 14.5 g of phenylhydrazine hydrochloride is heated 15 g urea and 14 g phenetidine at 180 to 210 "C until no ammonia development is more detectable. After cooling to about 80 "C, the reaction mixture will dissolved in a mixture of 400 cc of ln sodium hydroxide solution and 250 cc of ethanol and the water is added to the cloudy solution until a sample is underneath after suction Addition of charcoal remains clear with further addition of water. Then the whole Approach treated with charcoal and suctioned off. After acidification, 15.4 g of 1 are obtained -Phenyl-4- (p-ethoxyphenyl) -3,5-dioxo- 1, 2,4-triazolidine, which is obtained from ethanol in the form thin needles with a melting point of 192 to 1950 C crystallized.

Example 3 11 g of phenylhydrazine and 16.5 g of p-n-butoxyaniline are used with 23 g of diphenyl carbonate and 0.5 g of potassium phenolate in a nitrogen atmosphere first 3 hours at 150 "C and then for some time at 190 to 220" C heated. A dark colored reaction mixture is obtained which corresponds to the in Example 1 described method is worked up. The l-phenyl-4- (p-butoxyphenyl) -3,5-dioxo-1,2,4-tetrazolidine thus obtained (7.7 g) melts at 158-160 "C after recrystallization from methanol.

Example 4 A solution of 14.3 g of p-chlorophenyl hydrazine and 12.8 g p-chloroaniline in 250 ccm xylene is in the shaking autoclave after adding 12 g finely pulverized 19 g of methyl chlorocarbonate are added to anhydrous sodium carbonate and the reaction mixture is then slowly heated to 200 ° C. The temperature is maintained several hours at this height, then allowed to cool and sucked the reaction product away.

The residue obtained is in a mixture of 250 cc of ethanol and 100 ccm of dilute sodium hydroxide solution dissolved with warming and the solution accordingly the treated in Example 2 procedure specified. 9.4 g of 1,4-bis (p-chlorophenyl) -3,5-dioxo-1 are obtained , 2,4-triazolidine, which after recrystallization from dimethylformamide / ethanol at Melts from 304 to 308 "C. By dissolving in the calculated amount of methanolic sodium methylate solution and addition of ether, the sodium salt is obtained as a colorless powder, which in Water is soluble with a nearly neutral reaction.

Claims (1)

PATENT CLAIM: Process for the preparation of 3,5-dioxo-1,2,4-triazolidines of the general formula (1) where R1 is a phenyl radical in which a hydrogen atom can optionally be substituted by a halogen atom or a low molecular weight alkyl or alkoxy group, and R2 is a phenyl radical in which a hydrogen atom is substituted by a hydroxyl group, an acylamino group, a low molecular weight alkoxy group or a halogen atom , and their salts, characterized in that in a further embodiment of the process according to patent application F 30680 IVd / l2p (German Auslegeschrift 1129498) 1 mol of a phenylhydrazine of the general formula R1-NH-NH2 with 1 mol of an amine of the formula R2-NH and with 2 moles of a reactive derivative of carbonic acid at elevated temperature, where R1 and R2 are as defined, and optionally converting the compounds obtained into the corresponding salts with the aid of inorganic or organic bases.