DE897406C - Process for the preparation of pyrazolone compounds - Google Patents

Description

Process for the preparation of pyrazolone compounds Among the numerous compound groups of the pyrazolone series are so far oxyarylpyrazolones of the formula or their derivatives are not of therapeutic importance because they have no advantages over the common representatives of the named group of drugs. Only the p-alkylphenyl ether derivatives i- (p-methylphenyl ether) -2, 3-dimethylpyrazolone (5) and i- (p-ethylphenyl ether) -2, 3-dimethylpyrazolone (5) of the following general formula are known from literature: (See reports of the Deutsche Chem. Ges., Vol. 25, pp. 1664 and 1852). It has now been found that by reacting alkoxyarylhydrazines with at least 3 carbon atoms in the alkyl group or ring-substituted alkoxyarylhydrazines with acetoacetic esters or substituted acetoacetic esters and optionally subsequent alkylation or by etherification of i- (oxyaryl) pyrazolones with corresponding -alkyl or ring-substituted alkyl compounds , e.g. B. their halides, arrives at new pyrazolone compounds, which are characterized by good analgesic and anti-inflammatory properties. The implementation takes place according to the following scheme: X = alkyl with at least 3 carbon atoms or ring-substituted alkyl, R ', R "= H or alkyl. These i-aryl ether pyrazolones can be aminated in the 4-position and the 4-amino derivatives can be alkylated in a manner known per se As long as an unsubstituted hydrogen atom is still present, alkylation products can be reacted with formaldehyde bisulfites or sulfoxylates, just like the free amines The resinous reaction product becomes crystalline on treatment with ethyl acetate .

There by methylation with iodomethyl and methanol at 115 to 12o ° it the z- (p-Isopropylphenyläther) -2, 3-dimethyl-4-isopropylpyrazolon- (5) from F. 85 to 870.

The starting product is obtained z. B. as follows: 740 parts p-benzalaminophenol are in 62o parts g6% alcohol. and 45o parts of 33% sodium hydroxide solution dissolved and boiled with 475 parts of isopropyl bromide with stirring for 10 hours. When cooling down the reaction mass solidifies to a crystal cake, which is triturated and sucked off will; the p-benzalaminophenylisopropyl ether recrystallized with alcohol melts at 86 to gi °.

100 parts of the unpurified p-benzalaminophenyl isopropyl ether are suspended in 100 parts of water and, after addition of 600 parts of 30% sulfuric acid, subjected to steam distillation to recover the benzaldehyde. The distillation residue crystallizes on cooling to form a thick paste of the sulphate of p-aminophenyl isopropyl ether, which is extremely sparingly soluble in water and melts at 85 to 0 °. The sulfate can easily be converted into p-aminophenylisopropyl ether by decomposing it with potash and extracting it with benzene which boils at 125 to 130 'under 5 to 6 mm of mercury pressure; for identification it can be converted into its acetyl derivative, p-acetylaminophenylisopropyl ether, which melts at 129 to 131 °. The p-aminophenyl isopropyl ether is diazotized and the diazo solution is treated with sodium sulfite solution. The resulting solution of sodium p-isopropyletherphenylazosulfonsaurem is reduced in acetic acid solution with zinc dust, and p-isopropyletherphenylhydrazinesulfonic acid is obtained, expediently by soaking with sodium chloride. Sodium.

50 parts of sodium p-isopropyletherphenylhydrazinesulfonic acid are stirred with 240 parts of methanol and 175 parts of concentrated hydrochloric acid. Conversion to p-isopropyletherphenylhydrazine hydrochloride takes place with heat tinting to 4o to 5o0. After good cooling, it is suctioned off; the hydrochloric acid salt was broken down with potash and the hydrazine base was added to benzene. . Example 2 The calculated amount of acetoacetic ester is added to the benzene solution of p-isopropyletherphenylhydrazine and the benzene is distilled off; the residue is heated on the steam bath for a further 1 to 4 hours, during which it solidifies in crystalline form to give i- (p-isopropylphenyl ether) -3-methylpyrazolone- (5). Recrystallized from alcohol, this melts at between 35 and 37 °.

Obtained by methylation with iodomethyl and methanol at 115 to = 20 ° from it the i- (p-Isopropylphenyläther) -2, 3-dimethylpyrazolon- (5), its melting point is 103 to 1o4 °.

Its molecular connection with salicylic acid can also be used for identification serve that consist of a mixture of solutions of molecular amounts of salicylic acid and i- (p-Isopropylphenylether) -2, 3-dimethylpyrazolon- (5) in common solvents crystallizes out and melts at 124 to i25 °.

49.2 parts of i- (p-isopropylphenyl ether) -2, 3-dimethylpyrazolone- (5) are dissolved in 300 parts of water and after the addition of = o parts of concentrated sulfuric acid and 100 parts of ice nitrosated with 34.6 parts of 40% sodium nitrite solution. That Nitrosation mixture is in a solution of = o6 parts of sodium hydrosulfite in 3oo Parts of water are stirred in. The i- (p-isopropylphenyl ether-2, 3-dimethyl-4-nitrosopyrazolons- (5), and the i- (p-isopropylphenyl ether) -2 formed is extracted, 3-dimethyl-4-aminopyrazolone- (5) with benzene. The amino compound melts at 105 up to 1o7 °.

From the i- (p-Isopropylphenylether) -2, 3-dimethyl-4-aminopyrazolone- (5) the i- (p-isopropylphenyl ether) is obtained by reaction with sodium formaldehyde bisulfite - 2, 3 - dimethylpyrazolone - (5) - 4 - aminomethane sodium sulfonate.

With methylating agents, e.g. B. formic acid and formaldehyde there the 4-amino compound i- (p-isopropylphenyl ether) -2, 3-dimethyl-4-dimethylaminopyrazolone- (5) from 71 to 73 °. Example 3 13.7 parts of i- (p-Oxyphenyl) -2, 3-dimethylpyrazolone- (5) are dissolved in = 0.2 parts of 33% sodium hydroxide solution and 20 parts of alcohol and mixed with 15.4 parts of isobutyl bromide boiled for 6 hours. The solution is concentrated to dryness and treated with dilute sodium hydroxide solution and benzene. After narrowing down the benzene Solution, the residue is distilled. The i- (p-isobutylphenyl ether) -2 to be obtained in this way, 3-dimethylpyrazolon- (5) boils at 24o to 245 ° below = 0 mm mercury pressure and soon solidifies crystalline. Recrystallized from a little ether, the substance melts at 52 to 56 °.

The starting product can be obtained as follows: Equimolecular Amounts of p-oxyphenylhydrazine hydrochloride, sodium acetate and acetoacetic ester are expediently in a dilute acetic acid solution, warmed to go ° for 3 hours. The solvent is removed in vacuo and the crystalline residue is recrystallized from methanol. The i- (p-oxyphenyl) -3-methylpyrazolon- (5) thus obtained melts at 23o ° and is identical to that according to "Reports of the German Chemical Society", Vol. 28, P. 638, obtained cleavage product of i- (p-ethylphenyl ether) -3-methylpyrazolons- (5).

Methylation converts it to i- (p-oxyphenyl) -2, 3-dimethylpyrazolone- (5) with a melting point of 2o7 to -2o8 °. Example 4 15.1 parts of i- (p-Oxyphenyl) -2, 3-dimethylpyrazolone- (5) are dissolved in 11.4 parts of 33% sodium hydroxide solution and 25 parts of alcohol and mixed with 11.9 parts of benzyl chloride boiled for 5 hours. The reaction product is released from the solvent freed and treated with dilute sodium hydroxide solution and benzene. The benzene solution is concentrated and the crystalline residue is recrystallized from benzene. That i- (p-Benzylphenylether) -2, 3-dimethylpyrazolone- (5) melts at 159 to 163 °.

Claims (1)

PATENT CLAIM: Process for the production of pyrazolone compounds, characterized in that one alkoxyarylhydrazines with at least 3 carbon atoms in the alkyl group or ring-substituted alkoxyarylhydrazines with acetoacetic ester or substituted acetoacetic esters and the products of the process, if appropriate then alkylated or that i- (oxyaryl) pyrazolones with corresponding alkyl or ring-substituted alkyl compounds, e.g. B. their halides, etherified.