CS219280B2 - Method of making the pyrazol derivatives - Google Patents

Abstract

1. Process for the manufacture of pyrazole derivatives of the general formula I see diagramm : EP0022906,P6,F2 in which R1 , R2 , R3 and R4 are substituents in the ortho-, meta- or para-positions and represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a nitro group, an amino group, an alkylthio group or an alkylsulphonyl group, with the proviso that at least one of the substituents R1 to R4 is other than hydrogen, characterized in that a compound of the general formula II see diagramm : EP0022906,P6,F3 in which R1 , R2 , R3 and R4 have the above-mentioned meanings, is reacted with sulphur and an amine of the general formula III see diagramm : EP0022906,P6,F4 in which R5 and R6 together represent a tetramethylene group, a pentamethylene group or an ethoxyethylene group, or in which R5 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R6 represents an alkyl group having from 1 to 4 carbon atoms, a phenyl group or a pyridyl group, and the resulting compound of the general formula IV see diagramm : EP0022906,P7,F1 in which R1 to R6 have the above-mentioned meanings, is hydrolysed using acids or bases.

Description

The invention relates to a process for the preparation of pyrazole derivatives of the general formula I

<1) wherein R 1, R 2, R 3 and R 1 are ortho-, para- or meta- and denote a hydrogen atom, a halogen atom, a nitro group or a methylthio group, with the proviso that at least one of R 1 to R 4 is different from hydrogen, and their salts with physiologically harmless bases.

The pyrazole derivatives of the formula I are known from DOS 26 33 992. However, their preparation according to the known process is very expensive and the yields obtained are often unsatisfactory.

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a novel process for the preparation of the pyrazole derivatives of the general formula I which is simple and satisfactory.

According to the invention, this object has been solved by finding a novel process which comprises reacting a compound of the formula II

wherein R 1, R 2, R 3 and R 4 are as defined above, with sulfur and morpholine and the obtained compounds of formula IV

S II

wherein R 1, R 2, R 3 and R 4 are as defined above are then hydrolyzed with acids or bases and the resulting acids are converted into their salts.

The method of the invention is carried out under generally known conditions (Org. Reactions, 3, 1946, 83-107; Angew. Chem., 70, 1958, 331-367 and Synthesis, 1975, 338-373).

The process according to the invention is carried out in the presence of primary or secondary amines. Suitable amines are, for example, methylamine, ethylamine, dimethylamine, dlethylamine, dibutylamine, aniline, alpha-, beta- or gamma-picoline, piperidine or especially morpholine and pyrrolidine.

The following examples serve to illustrate the process of the invention in more detail.

Example 1

a] 28.9 g of 4-fluoroaniline are mixed with 260 ml of 13% hydrochloric acid and 260 g of ice, cooled to -8 DEG C. and diazotized with 19.7 g of sodium nitrite in 30 ml of water. While stirring and cooling, a solution of 38.4 g of 3-chloro-2,4-pentadione, 260 ml of ethanol and 330 g of sodium acetate hydrate is added dropwise to this reaction solution. The reaction mixture is stirred for a further 3 hours at 0 [deg.] C., then diluted with water and the substance crystallizes. The crystalline residue was recrystallized from ethanol to give 30 g of 1-chloro-1- [4-fluorophenylhydrazono] -2-propanone.

Melting point: 148 ° C,

b] A solution of 19.6 g of 4-bromobenzyl cyanide in 100 ml of toluene was treated dropwise with 10 ml of a 20% solution of diisobutylaluminum hydride in toluene at -10 DEG C. under nitrogen and then stirred for 16 minutes. After careful addition of 33 ml of ethanol, this mixture was mixed with 230 ml of water and about 20 ml of concentrated sulfuric acid (until pH 2) and the reaction mixture was stirred for 13 minutes at 0 ° C.

The toluene phase is separated, the aqueous phase is extracted once more with toluene, the combined toluene extracts are washed with water and dried over magnesium sulphate. After filtration, the toluene solution of 4-chlorophenylacetaldehyde was treated with 87 g of morpholine and slowly concentrated in half in vacuo and the reaction mixture was allowed to stand overnight. After concentrating the solution in half, the residue is stirred with cyclohexane to crystallize. The crystallizate is then recrystallized from diisopropyl ether to give 12 g of 4- (4-bromostyryl) -morpholine, m.p. 142 ° C.

c] A solution of 7.2 g of 4- (4-bromostyryl) morpholine in 30 ml of chloroform is treated successively with 2.7 g of triethyleneamine and a solution of 3.3 g of 1-chloro-1- (4-fluorophenylhydrazono) -2-propa5.

219 NONO in 30 ml chloroform. The reaction mixture is stirred overnight at room temperature (alternatively, it can be refluxed for 4 hours.) After washing with 2N hydrochloric acid, sodium bicarbonate solution and water, the chloroform phase is dried over magnesium sulfate and concentrated from hexane (cyclohexane). ) the crystallizing residue (10.5 g] can be further processed or recrystallized from ethanol to give 3-acetyl-4- (4-bromophenyl) -1- (4-fluorophenyl) -5-morpholino-4 5-dihydropyrazole, m.p. 148 ° C.

(d) A solution of 10 g of 3-acetyl-4- (4-bromophenyl) -1- (4-fluorophenyl) -5-morpholino-4,5-dihydropyrazole in 110 ml of dioxane is refluxed with 30 ml of 2 N hydrochloric acid. The reaction mixture is concentrated in vacuo, the residue is taken up in ethyl acetate, washed with water, dried over magnesium sulphate and concentrated in vacuo, and the residue is crystallized from methanol and 7.5 g of 3 are obtained. -acetyl-4- (4-bromophenyl) -1- (4-fluorophenyl) -pyrazole.

Melting point: 185 ° C.

e) A mixture of 7.2 g of S-acetyl-4- (4-fluorophenyl) -1- (4-fluorophenyl) pyrazole and 0.84 g of sulfur in 9 ml. The morpholine is heated for 3 to 4 hours at 135 ° C, then poured into 150 ml of ice-water and mixed well, the precipitate formed is filtered off with suction, crystallized from a mixture of ethyl acetate and dioxane and 7.8 is obtained. g of 4- [4- (4-bromophenyl) -1- (4-fluorophenyl) -3-pyrazolyl-thioacetyl] morpholine.

Melting point: 211 ° C.

f) - A mixture of 7.4 g of 4- [4-orphenyl] -3-pyrazolyl-thioacetyl] morpholine in 20 ml of dimethylsulfoxide is mixed with 6.4 g of sodium hydroxide in 30 ml of water and the reaction mixture is refluxed for for 5 hours. After pouring into ice water, the sodium salt crystallizes; the salt is filtered off with suction, washed with methylene chloride and suspended in 2 N hydrochloric acid. 5 g of 4- (4-bromophenyl) -1- (4-fluorophenyl) -3-pyrazoloacetic acid are obtained.

Melting point: 175 ° C.

Example 2

Analogously to Example 1, 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid, m.p. 148 DEG C. (ethanol / water), is obtained.

The intermediates used are as follows:

4- (4-chlorostyryl) -morpholine, m.p. 102 DEG C. (from diisopropylethyl) (obtained analogously to Example 1b from 4-chlorobenzyl cyanide);

3-acetyl-4- (4-chlorophenyl 1) -1- (4-fluorophenyl] _{-5-morpholino-4-one} 5 dihydropyi'azol, mp 137 DEG 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-thioacetyl] -molfoline, m.p. 213 DEG C. (dioxane);

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

The recovery of 3-acetyl-4- (4-chlorophenyl) -1- (4-fluorophenyl) -pylazole can proceed analogously to Example 1c from alpha-dimethylamino-4-chlorostyrol and 1-chloro-1- (4-fluorophenylhydrazo). 1'-Propan-2-one.

The alpha-dimethylamino-4-chlorostyrol starting material can be obtained as follows:

A solution of 8 g of 4-chlorobenzyl chloride in 50 ml of ethyl ether is added dropwise to 1.5 g of magnesium shavings under argon and the mixture is stirred for 30 minutes. The solution was cooled to -15 ° C and treated dropwise with 30 mL of tetrahydrofuran and 11 g of pure dimethylformamide. The reaction mixture is stirred for 3 hours at -15 ° C, then concentrated carefully in vacuo and treated with 50 ml of 2 N ammonium chloride solution and ethyl acetate. The organic residue was crystallized from methanol to give 5 g of alpha-dimethylamino-4-chlorostylol.

Melting point: 77 ° C.

Example 3

Analogously to Example 1, 1,4-bis (4-chlorophenyl) -3-pyrazole acetic acid with a melting point of 184 ° C (toluene) is obtained.

The intermediates used are as follows:

1-chloro-1- (4-chlorophenylhydrazono) -2-propanone; mp 175 ° C; (ethyl alcohol); (obtained analogously to Example 1a from Achloraniim);

3-Acetyl-1,4-bis (4-chlorophenyl) pyrazole; mp 190 ° C (dioxar) ¹ ;

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

Example 1 a d 4

Analogously to Example 1, 4- (4-chlorophenyl) -1- (4-methylthiophenyl) -3-pyrazole acetic acid is obtained, m.p. 169 DEG C. (methanol).

The intermediates used are as follows:

1-chloro-1- (4-methyl-thiophenylhydrazone) -2-propane, m.p. 110 DEG C. (carbon tetrachloride) (obtained analogously to Example 1a from 4-methylthioaniline);

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

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

Example 5

Analogously to Example 1, 4- (4-chlorophenyl-1-phenyl-3-pyrazole-acetic acid) with a melting point of 169 ° C (toluene) is obtained.

The intermediates used are as follows:

1-chloro-1-phenylhydrazono-2-propane; mp 136 ° C (ethyl alcohol);

3-Acetyl-4- (4-chlorophenyl) -1-phenyl-pyrazole; mp 101 ° C (methanol);

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

Example 6

A solution of 2 g of 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid (obtained according to Example 2 ') in 30 ml of dimethylformamide is mixed with a solution of 600 mg of copper acetate in 35 ml of dimethylformamide. and the reaction mixture is stirred for 8 hours at room temperature. After distilling off the solvent in vacuo, the oily residue was dissolved in acetone and filtered off from the other residues. After evaporation of the acetone, the residual salt is crystallized from acetone. 1.7 g of copper (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid monohydrate are obtained.

Melting point: 171 ° C.

Example 7

Analogously to Example 1, 1,4-bis () -3-pyrazole-acetic acid was prepared; 116 ° C (carbon tetrachloride).

Example 8

Analogous to. in Example 1, 4- (2,4-dichlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid was prepared; melting point: 133 ° C (toluene).

Example 9

Analogously to Example 1, 1- (2-fluorophenyl) -4- (4-nitro-phenyl) -3-pyrazole acetic acid was prepared; mp: 208 ° C (ethyl acetate).

Example 10

Analogously to Example 1, 4- (4-chlorophenyl) -1- (2-fluorophenyl) -3-pyrazole acetic acid was prepared; mp: 187 ° C (ethyl acetate).

Example 11

Analogously to Example 1, 1- (4- (4-nitrophenyl) -3- (4-nitrophenyl) -3-pyrazole acetic acid) was prepared; 254 ° C (acetonitrile).

Example 12

Analogously to Example 1, 4- (3,4-dichlorophenyl) -1- (4-fluorophenyl) -3-pyrazole acetic acid was prepared; melting point: 178 ° C (toluene).

Claims (1)

THE PRBDMET OF THE INVENTION Process for the preparation of pyrazole derivatives of the general formula I and their physiologically acceptable salts, characterized in that a compound of the general formula II is reacted with R 1, R 2, R 3 and R 4 are hydrogen, halogen, nitro or methylthio, with the proviso that at least one of R 1 to R 6 is other than hydrogen, wherein R 1, R 2, R ₃ and R 4 are ortho- , meta- or para- in which they have R 1, R 2, R 3 and R 6, as defined above, with sulfur and morpholine, and the obtained compound of formula IV wherein they have R 1, R 2, R 3 and R 4 as defined above are hydrolyzed with acids or bases and the resulting acids are converted into their physiologically acceptable salts.