NO801496L - PROCEDURE FOR THE PREPARATION OF PYRAZOLD DERIVATIVES - Google Patents

Description

The present invention relates to a method for producing the compounds specified in claim 11

Pyrazole derivatives of the general formula I according to claim 1 are known from German patent application P 26 33 992, but their production by the known methods is very expensive, and the yields obtained are often unsatisfactory.

The present method, on the other hand, succeeds in preparing the pyrazdl derivatives of the general formula I by a simple synthesis in good yields.

The present method is carried out under conditions known per se (Org. Reactions, ^3, (1946), 83-107; Angew. Chem., 70, (1958), 351-367 and Synthesis (1975), 358-375) .

The present method is carried out in the presence of primary or secondary amines. Suitable amines are e.g. methylamine, ethylamine, dimethylamine, diethylamine, dibutylamine, aniline,

α-, 3- or Y-Picolin' piperidine or especially morpholine and pyrrolidine.

The following exemplary embodiments serve to further illustrate the invention.

Example 1

a) 28.9 g of 4-fluoroaniline is added to 260 ml of 15% hydrochloric acid and 260 g of ice, cooled to -5°C and diazotized with 19.7 g

sodium nitrite in 50 ml of water. With constant stirring and cooling, a solution of 38.4 g of 3-chloro-2,4-pentanedione, 260 ml of ethanol, 260 g of ice water and 350 g of sodium acetate hydrate is added dropwise. The mixture is stirred for a further 3 hours at 0°C, then diluted with water, whereby the compound crystallizes out. The crystal residue is recrystallized from ethanol, and 50 g of 1-chloro-1-(4-fluorophenylhydrazono)-2-propanone with m.p. 148°C.

b) A solution of 19.6 g of 4-bromobenzyl cyanide in 100 ml of toluene is added dropwise to 108 ml at -10°C under nitrogen

of a 20% solution of diisobutylaluminum hydride (Dibah)

in toluene<p>g is then stirred for a further 15 minutes. After carefully adding 35 ml of ethanol, add 250 ml of water and approx. 20 ml of concentrated sulfuric acid (to pH 2), and stir for 15 minutes at 0°C. The toluene phase is then separated, and

the water phase is subsequently extracted with toluene, the combined toluene solutions are washed with water and dried over magnesium sulphate. After filtration, 78 g of morpholine are added to the toluene solution of 4-chlorophenylacetaldehyde, which is slowly evaporated to half the volume in a vacuum and allowed to stand overnight. After evaporation of the solution, the residue is stirred with cyclohexane, whereby crystallization takes place. The crystallisate is then recrystallized from diisopropyl ether, and 12 g of 4-(4-bromo-styryl)-morpholine with m.p. 142°C. c) A solution of 7.2 g of 4-(4-bromostyryl)-morpholine in 30 ml of chloroform is added successively with 2.7 g of triethylamine and a solution of 5.3 g of 1-chloro-1-(4- fluorophenylhydra-zono)-2-propanone in 30 ml of chloroform and stirred overnight at room temperature (alternatively, it can be boiled under reflux for 4 hours). After washing with 2N hydrochloric acid, sodium bicarbonate solution and water, the chloroform phase is dried with magnesium sulphate and evaporated. The residue crystallized from hexane (cyclohexane) (10.5 g) can either be further worked up or recrystallized once more from ethanol; and 3-acetyl-4-(4-bromophenyl)-1-(4-fluorophenyl)-5-morpholino-4,5-dihydropyrazole is obtained with m.p. 148°C. d) A solution of 10 g of the above-mentioned dihydropyrazole in 110 ml of dioxane is boiled with 30 ml of 2N hydrochloric acid for 60-90 minutes

during reflux. It is then evaporated in vacuo, the residue is taken up in ethyl acetate, washed with water, dried with magnesium sulfate and evaporated in vacuum. The residue is crystallized from methanol, and 7.5 g of 3-acetyl-4-(4-bromophenyl)-1-(4-fluorophenyl)-pyrazole with m.p. 185°C.

e) A mixture of 7.2 g of the 3-acetylpyrazole derivative and 0.84 g of sulfur is heated in 9 ml of morpholine for 3-4 hours at

135°C, then pour into 150 ml of ice water and stir well. The aspirated precipitate is crystallized from ethyl acetate and dioxane, and 7.8 g of 4-[4-(4-bromophenyl)-1-(4-fluorophenyl)-3-pyrazolyl-thioacetyl]-morpholine are obtained with m.p. 211°C.

f) A mixture of 7.4 g of the thio-acetylmorpholine derivative prepared according to example 1d in 20 ml of dimethylsulfoxide is added to 6.4 g

sodium hydroxide in 30 ml of water and heated under reflux for 5 hours. After pouring into ice water, the sodium salt crystallizes out, filtered off with suction, washed with methyl chloride and suspended in 2N hydrochloric acid. 5 g of 4-(4-bromophenyl)-1-(4-fluorophenyl)-3-pyrazole-acetic acid with m.p. 175°C.

Example 2

Analogous to example 1, 4-(4-chlorophenyl)-1-(.4-fluorophenyl)-3-pyrazole-acetic acid is obtained with m.p. 148°C (ethanol/water).

The intermediates used are: 4-(4-chlorostyryl)-morpholine with m.p. 102°C (diisopropyl ether) (prepared analogously to example 1b from 4-chlorobenzyl cyanide)

3-acetyl-4-(4-chlorophenyl)-1-(4-fluorophenyl)-5-morpholino-4,5-dihydropyrazole, m.p. 137°C (ethanol)

3- acetyl-4-(4-chlorophenyl)-1-(4-fluorophenyl)-pyrazole, m.p. 181°C (isopropyl alcohol) 4-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl-thio-acetyl]-morpholine, m.p. 213°C (dioxane)

4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazole-acetic acid sodium salt, m.p. 299°C (water).

The production of 3-acetyl-4-(4-chlorophenyl)-1-(4-fluoro-phenyl)-pyrazole can also take place analogously to example 1c from α-dimethylamino-4-chlorostyrene and 1-chloro-1-(4- fluorophenyl-hydrazono)-propan-2-one.

The starting material, α-dimethylamino-4-chlorostyrene, can also be obtained in the following way:

A solution of 8 g of 4-chlorobenzyl chloride in 50 ml of ether is added dropwise to 1.5 g of magnesium shavings (under argon) and then stir for 30 minutes. The solution is then cooled to -15°G and 11 g of pure dimethylformamide and 30 ml of tetrahydrofuran are added dropwise. The reaction mixture is stirred for 3 hours at -15°C, then carefully evaporated in vacuo and 50 ml of 2N ammonium chloride solution as well as ethyl acetate are added. The organic residue is crystallized from methanol, and 5 g of ct-dimethylamino-4-chlorostyrene with m.p. 77°C. Example 3

Analogous to example 1, 1,4-bis-(4-chloro-.phenyl)-3-pyrazole-1-acetic acid is prepared with m.p. 184°C (toluene).

The intermediate products used are:

1-chloro-1-(4-chlorophenylhydrazono)-2-propanone,

m.p. 175°C (ethanol) (prepared analogously to example 1a from 4-chloroaniline).

3-acetyl-1,4-bis-(4-chlorophenyl)-pyrazole, m.p. 190°C

(dioxane)

4-[1,4-bis-(4-chlorophenyl)-3-pyrazolyl-thioacetyl]-morpholine, m.p. 204°C (dioxane)

Example 4

Analogous to example 1, 4-(4-chlorophenyl)-1-(4-methylthiophenyl)-3-pyrazole-acetic acid is prepared with m.p. 169°C (methanol).

The intermediates used are: 1-chloro-1-(4-methylthiophenylhydrazono)-2-propanone, m.p. 110°C (tetrachloromethane); (prepared analogously to example 1a from 4-methylthioaniline).

3- acetyl-4-(4-chlorophenyl)-1-(4-methylthiophenyl)-pyrazole, m.p. 85°C (methanol)

4-[4-(4-chlorophenyl)-1-(4-methylthiophenyl)-3-pyrazolyl-thioacetyl]-morpholine, m.p. 248°C (ethyl acetate)

Example 5

A solution of 1.8 g of 4-(4-chlorophenyl)-1-(4-methylthio-phenyl)-3-pyrazole-acetic acid (prepared according to example 4) in a mixture of 20 ml of chloroform and 20 ml of acetic acid is added to 1 ml hydrogen peroxide (30%) and stirred at room temperature i

1 hour. It is then diluted with water, whereby the compound

crystallizes out. The crystalline compound is filtered off, washed with hot water and recrystallized from methanol, and 1.4 g of 4-(4-chlorophenyl)-1-(4-methylsulfinylphenyl)-3-pyrazole-acetic acid with m.p. 193°C.

Example 6

Analogous to example 1, 4-(4-chlorophenyl)-1-phenyl-3-pyrazole-acetic acid is prepared with m.p. 169°C (toluene).

The intermediates used are: 1-chloro-1-phenylhydrazono-2-propanone, m.p. 136°C

(ethanol)

3- acetyl-4-(4-chlorophenyl)-1-phenyl-pyrazole,

m.p. 101°C (methanol)

4-[4-(4-chlorophenyl)-1-phenyl-3-pyrazblylthioacetyl]-morpholine, m.p. 205°C (dioxane)..

Example 7

A solution of 2 g of 4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazole-acetic acid (prepared according to example 2) in 30 ml of dimethylformamide is added to a solution of 600 mg of copper (II) acetate in 35 ml of dimethylformamide and stirred for 8 hours at room temperature. After distilling off the solvent in vacuum, the oily residue is dissolved in acetone, and the residue is filtered off. After evaporation of the acetone, the salt residue is crystallized from methanol. 1.7 g of 4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazoleacetic acid copper(II) salt monohydrate with m.p. 171°C.

Example 8

Analogous to example 1, 1,4-bis-(4-fluoro-phenyl)-3-pyrazole-acetic acid (m.p. 116°C from tetrachloromethane) is prepared.

Example 9

Analogously to example 1, 4-(2,4-dichlorophenyl)-1-(4-fluorophenyl)-3-pyrazoleacetic acid is prepared (m.p. 133°C from toluene).

Example 10

Analogous to example 1, 1-(2-fluorophenyl)-4-(4-nitrophenyl)-3-pyrazole-acetic acid is prepared (m.p. 208°C from acetic acid ethyl ester).

Example 11

Analogous to example 1, 4-(4-chlorophenyl)-1-(2-fluorophenyl)-3-pyrazole-acetic acid (m.p. 187°C from acetic acid ethyl ester) is prepared.

Example 12

Analogously to example 1, 1-(4-fluorophenyl)-4-(4-nitrophenyl)-3-pyrazole-acetic acid (m.p. 254°C) is prepared from aceto-

4- • nitrile).

Example 13

Analogous to example 1, 4-(3,4-dichlorophenyl)-1-(4-fluorophenyl)-3-pyrazole-acetic acid is prepared (m.p. 178°C from toluene).

Claims (1)

Procedure for the preparation of pyrazole derivatives with - the general formula: where R^ , R2, R^ and R^ are substituents in the ortho-, meta- or para-position and are hydrogen, halogen, alkyl, alkoxy, trifluoromethyl, nitro, amino, alkylthio or alkylsulfonyl, at least one of the substituents R .^ to R^ is different from hydrogen,. and their salts with physiologically acceptable bases, characterized in that a compound of the formula: where , . R 2 , R 1 and R 2 are, as indicated above, reacted with sulfur and an amine with the general formula: where R 2 and R 2 together form a tetramethylene group, a pentamethylene group or, an ethoxyethylene group, or where R 2 is hydrogen or alkyl with 1 - 4 carbon atoms, and R, is alkyl with 1 - 4 carbon atoms, phenyl or pyridyl, and that the obtained compound with the general formula: where R^ to Rg are as indicated above, is hydrolysed with the aid of acids or bases, and the acids obtained are optionally transferred to their salts.