DE959095C - Process for the preparation of pyridazone derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

ISSUED FEBRUARY 28, 1957

GERMAN PATENT OFFICE

PATENT LETTERING

CLASS 12p GROUP 10
INTERNAT. CLASS C07d

B 35661 IVb 112 ρ

Dr. Käthe Bartram, Ludwigshafen / Rhine

has been named as the inventor

Badische Anilin- & Soda-Fabrik Aktiengesellschaft, Ludwigshafen / Rhein

Process for the preparation of pyridazone derivatives

Patented in the territory of the Federal Republic of Germany on May 8, 1955

Patent application published August 30, 1956

Patent issued on February 7, 1957

It has been found that new, therapeutically valuable pyridazone derivatives are obtained if converts j'-propionylpropionic acid with phenylhydrazine, the resulting 2-phenyl-6-ethylpyridazi-

non- (3) treated with halogenating agents and the 4-halo-2-phenyl-6-äthylpyridazon- (3) obtained in this way secondary amines can act.

The implementation can be formulated as follows:

CH ₂ CH ₂

\ + H ₂ N-NH-C ₆ H ₅ / \

xooH -L-l i-4 Η ₂ σ co _>

CO H ₅ C ₂ -C NC ₆ H ₅ 3o

H ₅ C ₂ ^N

Hal NR ₂

I! 35

* 5 C C

Halogen HC ^ ^X CO HNR ₂ HC ^V CO

H ₅ C ₂ -C NC ₆ H ₅ H ₅ C ₂ -C NC ₆ H ₅ 40

The secondary amines HNR ₂ can be ζ. Β. Use dimethyl, diethyl, methyl ethyl or diisopropylamine, pyrrolidine, piperidine, morpholine or hexamethyleneimine. The y-propionylpropionic acid used as the starting material is technically accessible by catalytic reaction of 2 moles of ethylene with 2 moles of carbon oxide and ι moles of water.

The implementation of this y-keto acid with phenyl-ίο hydrazine is carried out by heating approximately equimolecular amounts of the components, expediently in an inert solvent such as benzene, toluene or chlorobenzene. An addition of alkaline Agents such as triethanolamine favor the reaction and increase the yield of 2-phenyl-6-äthylpyridazinon- (3).

This compound is now, expediently, in an inert diluent such as chlorobenzene or phosphorus oxychloride treated with halogenating agents, with dehydrogenative halogenation he follows. Suitable halogenating agents are, for. B. free chlorine or bromine in the presence of catalytic Amounts of phosphorus pentachloride or bromide or an excess of the phosphorus halides mentioned, z. B. 3 to 5 moles thereof. It is expedient to use aluminum halide, z. B. 0.5 mol. You can use the 2-phenyl-6-ethylpyridazinone- (3) also first z. B. with chlorine, bromine or sulfuryl chloride without the addition of phosphorus pentahalide to dehydrate 2-phenyl-6-äthylpyridazon- (3) and then subsequently halogenating substitution, ζ. Β. less with phosphorus pentachloride or with chlorine in the presence Amounts of phosphorus pentachloride.

The implementation of the 4-halo-2-phenyl-6-äthylpyridazons- (3) thus obtained with the secondary amines mentioned takes place quickly and smoothly even at ordinary temperature. One works expediently in a solvent such as methanol. For binding the split off hydrogen halide if a basic agent such as triethylamine or pyridine is added; you can also do one Use excess secondary amine.

Draw the pyridazone derivatives accessible in good yields on the route described are characterized by high analgesic, anti-inflammatory and spasmolytic effects.

It is already known that by reacting another γ-keto acid of levulinic acid with 'Phenylhydrazine contains 2-phenol-6-methylpyridazinone- (3) (cf. E. Fischer, Liebigs Ann. Chem., 236, p. 147); only yields of about 60% of theory were obtained. From the 2-Phenyl-6-methylpyridazinone- (3) is obtained by melting it with phosphorus pentachloride in a yield of 25 to 30% of theory 4-chloro-2-phenyl-6-methylpyridazon- (3) prepared (cf. Ach, Liebigs Ann. Chem., 253, p. 47), the one with dimethylamine to 4-dimethylamino-2-phenyl-6-methylpyridazon- (3) implemented (see British patent specification 656228). The present The process which starts from the technically more easily accessible y-propionylpropionic acid provides the previously unknown 6-ethyl-4-amino-2-phenylpyridazone- (3) in better yields; the pharmacological Properties of the new pyridazone derivatives are superior to those of the known product.

The parts mentioned in the examples are parts by weight.

example 1

65 parts of propionylpropionic acid, 80 parts of toluene and 53 parts of phenylhydrazine are heated to 60 ° for 2 hours with the addition of 3 parts of triethanolamine. The toluene and the water formed are then distilled off and the residue is heated to 160 ° C. under reduced pressure for 2 hours, about 8 parts of water still distilling off. After cooling, dilute with ether and wash the ethereal solution with water. After evaporation of the ether, fractional distillation is carried out under reduced pressure. The main fraction passes from 165 to 171 ⁰ under 2 mm pressure. 75 parts of 2-phenyl-6-ethylpyridazinone- (3) are obtained.

A solution of 300 parts of this product in 330 parts of chlorobenzene is added, with stirring, in a 70 to ^8ο ό heated suspension of 1500 parts of phosphorus pentachloride in 550 parts of chlorobenzene. The mixture is heated over 30 minutes to 120 ^0, where about 300 parts of phosphorus trichloride are distilled off. The reaction mixture is then poured onto about 4000 parts of ice and extracted with ether. The residue remaining after the ether and the chlorobenzene have been distilled off is boiled with cyclohexane. When the cyclohexane solution cools, the 2-phenyl-6-ethyl ~ 4-chloropyridazon- (3) crystallizes out; it can be purified by recrystallization from cyclohexane or from a water-alcohol mixture. It melts at 79 to 80 degrees. The yield is 220 parts (64% of theory).

145 parts of 2-phenyl-4-chloro-6-äthylpyridazon- (3) are refluxed with 90 parts of pyrrolidine in 350 parts of toluene for 24 hours. To. After cooling, the precipitated pyrrolidine hydrochloride is filtered off with suction and the toluene is distilled off under reduced pressure. The residue is washed with water and distilled. The 2-phenyl-4-pyrrolidino-6-äthylpyridazon- (3) is 4 mm under pressure at 215-220 ⁰ over. It solidifies to form crystals with a melting point of 58 to 59 ⁰ . The yield is 110 parts.

Example 2

30 parts of the 2-phenyl-4-chloro-6-äthylpyridazons- (3) obtained according to Example 1 are left to stand for about 20 hours at ordinary temperature with a solution of 250 parts of dimethylamine in 200 parts of methanol. Heated to complete the reaction, iao further 3 hours at 45 to 50 ^0th After the solvent and the excess dimethylamine have been distilled off, a residue remains which is taken up in ether. The dimethylamine hydrochloride which separates out is suctioned off and the ether is evaporated. Of the

Residue from 2-PhenyI-4-dimethylamino-6-äthylpyridazon- (3) consists, yields on recrystallization from cyclohexane or an alcohol-water mixture Crystals with a melting point of 52 to 53 °.

The 2 - phenyl - 4 - dimethylamino - 6 - ethylpyridazon- (3) was in its analgesic and antipyretic effect with that of Example 2 of British patent specification 656 228 known 2-phenyl-4-dimethylamino-6-methylpyridazon- (3) compared.

When examining the reaction time of the mouse in the heat stimulus test, it was normal reaction time extended by the following values:

Dose 100 mg / kg I dose 80 mg / kg

6-ethyl-.
6-methyl-

75! ° / »(20 mice) 58ί ° / οι (19 mice)

65 »/ egg (17 mice) 31% (14 mice)

Six rabbits each were artificially fevered in the usual way. At the same time intravenous injection of 50 mg / kg each of a solution of the pyridazone derivatives to be compared the following relative fall in fever was observed at the time of the peak of the fever:

With 6-ethyl- 1.95 °

with 6-methyl-0.8 °

The 2-phenyl-4-dimethylamino-6-äthylρyridazon- (3) obtainable by the present process is therefore the well-known 6-methyl analog both in the analgesic as well as in the antipyretic Effect unexpectedly superior.

Example 3

The 2-phenyl-4-chloro-6-äthylpyridazon- (3) obtained according to Example 1 is reacted as in Example 1 with hexamethyleneimine. This gives 2-phenyl-4-hexamethyleneimino-6-ethylpyridazone (3) with a b.p. _t 204 to 206 ⁰ .

The 2-phenyl-4-morpholino-6-äthylpyridazon- (3) prepared in an analogous manner using morpholine forms crystals with a melting point of 78 to 79 °.

Example 4

A solution of 75 parts of 2-phenyl-6-äthylpyridazinon- (3) in 120 parts of tetrachloroethane is allowed to flow into a suspension of 250 parts of phosphorus pentachloride and 35 parts of aluminum chloride in parts of tetrachloroethane. The reaction mixture is heated to 120 ^0, wherein a portion of the phosphorus trichloride formed distilled off. It is then evaporated under reduced pressure and the residue is decomposed with ice. After standing for a while, the mass turns into a stiff crystal slurry of 2-phenyl-4-chloro-6-äthylpyridazon- (3), which is filtered off with suction and washed out with water. The yield is 75 parts. The reaction with amines takes place as in the previous examples.

Claims (3)

Godfather tan s PK ugh E: 1. Process for the preparation of pyridazone derivatives by reacting a γ-keto acid with phenylhydrazine, halogenation of the pyridazinone obtained (3) and exchange of the Halogen through a secondary amine, dadu -ch characterized in that γ-propionylpropionic acid is used as the starting material. 2. The method according to claim 1, characterized in that that the reaction of γ-propionylpropionic acid with phenylhydrazine in The presence of a base. 3. The method according to claim 1, characterized in that that the dehydrogenative halogenation of 2-phenyl-6-äthylpyridazinons- (3) to the 4-halo-2-phenyl ~ 6-äthylpyridazon- (3) in an inert diluent with about 3 to 5 moles of phosphorus pentahalide, expediently in the presence of aluminum halide, or with chlorine in the presence of catalytic Quantities of phosphorus pentachloride. Papers considered: British Patent No. 656 228. © 609 616/463 8.56 (609 809 2.57}