CS216205B2 - Method of making the derivatives of the 1,4-diphenylpyrazole - Google Patents

Abstract

New pyrazole derivs. are of formula (I) (where n = 1-4; R1-4 are H, halogen, alkyl, alkoxy, CF3, NO2 or NH2; and X is CN, aminocarbonyl, lower alkoxy, carbonyl or carboxyl). (I) and their salts have low toxicity and do not cause stomach disorders. Typical cpds. include (I; n = 1, X is CN; R1-4 are H). They may be prepd. from (I; X is halogen) by reaction with an alkali metal cyanide, opt. followed by hydrolysis or redn. In an example, 2.81g (I; X is Br; n = 1; R1-4 are H) was treated with 1.17g KCN and 300 mg 18-dibenzo-6-crown (catalyst) in acetonitrile at 40 degrees C to give (I: X is CN; n = 1; R1-4 are H).

Description

The invention relates to a process for the preparation of derivatives

1,4-diphenylpyrazole of formula I

in which

R1, R2, R3 = Rd are substituents in the ortho position, or para a denotes hydrogen, fluorine, chlorine and bromine, methyl, methoxy, trifluoromethyl, nitro or amino,

X represents a cyano group, an aminocarbonyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy radical, a carboxyl group, n denotes a number 1, 2, 3 or 4 or their physiologically acceptable salts.

Low alkoxycarbonyl derived from low 31 carbon atoms containing up to about 6 carbon atoms is, for example, methoxy, ethoxy ^, naphtha, propyloxy, isopropyloxy, butyloxy, tert-butyloxy, pentyl or hexyl.

Physiologically acceptable salts are, for example, the alkali metal and alkaline earth metal salts, such as sodium, lithium, calcium or magnesium salts, copper or amine salts, such as N-methoxyfluoric salts, salts of Ν, dimethyl-dimethylgiucamine, ethanolamine salts, diethanol amine salts or morpholine salts.

A process for the preparation of the novel 1,4-diphenylprazole derivatives of the general formula. I is characterized in that the pyrazole derivative of general formula II

\ z <<10

4 in which

R 1, R 2, R 1, R 1 and n are as previously defined

Y represents a hydrogen, fluorine, chlorine and .bromu reacted -s cyanide · -alkalického ^one metal and optionally the obtained saponified cyanides present reducing nitro and the resulting carboxylic acids -with 'Velim converted into its salt, or esterified with an alcohol -S 1 to 6 carbon atoms.

The process according to the invention can be carried out under the conditions usually used to exchange a halogen atom with a cyano group.

For this process, compounds having a chlorine, bromine or iodine atom are preferably used as starting compounds of formula II.

The reaction is preferably carried out in a dipolar, aprotic solvent (such as dimethylformamide, N-methylacetamide, N-methylpyrrolidone, acetonitrile, dirylsulfoxide or hexamethylphosphoric triamide).

Preferred alkali metal cyanides for this reaction are sodium cyanide or sodium cyanide; potassium cyanide.

The reaction can be significantly accelerated when carried out in the presence of a crown-elther.

The reaction can be significantly accelerated when performed in the presence

The possible subsequent hydrolysis of the cyano compounds of the formula I is also carried out under conditions known to those skilled in the art. Thus, for example, nitriles - may be partially hydrolyzed to the corresponding amides by strong mineral acids (such as hydrochloric acid - or sulfuric acid) - or, under sharpened conditions, completely hydrolyzed to the corresponding carboxylic acids.

Possible subsequent conversion of the carboxylic acids into the corresponding neto amides. The nitriles are also carried out by known working methods.

For example, acid chlorides, mixed anhydrides or esters corresponding to carboxylic acids can be converted into the corresponding amides under known conditions under the action of ammonia.

The possible subsequent conversion into nitriles is carried out, for example, by treating the corresponding aminocarbonyl compounds under known conditions with water-absorbing agents such as dicyclohexylcarbodiimide, carbonyldiimidazole, polyphosphoric acid, thionyl chloride or phosphorous oxychloride.

The possible esterification of the free acids is also carried out by methods known per se. Thus, for example, the acids can be reacted with diazethane or diazoethane to give the corresponding methyl or ethyl esters. A generally applicable method is the reaction of acids with alcohols in the presence of carbonyldiimidazole or dicyclohexylcarbodiimide.

It is furthermore possible, for example, to react the acids with the alkyl halides in the presence of cuprous oxide or silver oxide.

A further method is to convert the free acids into dimethylformamide-acetyl acetals into the corresponding alkyl esters of the acids. Furthermore, the acids or esters of low alkanecarboxylic acids and alcohols may be reacted in the presence of strongly acidic catalysts such as hydrogen chloride, sulfuric acid, perchloric acid, trifluoromethylsulfonic acid or p-toluenesulfonic acid.

However, it is also possible to convert-carboxylic acids into acid chlorides or mixed acid anhydrides and to react with alcohols in the presence of basic catalysts such as pyridine, collidine, lutidine or 4-dimethylaminopyridine.

Salts of carboxylic acids are formed, for example, in the saponification of the esters by means of Basel catalysts or in the neutralization of acids with physiologically acceptable bases.

The following pyrazole derivatives of the general formula I can be prepared by the process according to the invention:

(1,4-diphenyl-3-pyrazolyl) -acetic acid, 3- (1,4-diphenyl-3-pyrazolyl) -propionic acid, 4- (1,4-diphenyl-3-pyrazolyl) -butyric acid, 5- (1,4-diphenyl-3-methyl-1-yl) -valeric acid, and their amides, nitriles, sodium salts, methyl esters, ethyl esters, propyl esters and butyl esters.

The novel 1,4-diphenynylpyrazole derivatives of the formula I are pharmacologically active substances which, in particular, are distinguished by their excellent anti-inflammatory activity and good gastric compatibility. they have only relatively low toxicity. In addition, these compounds are characterized by rapid-onset action, high intensity of action and long-term action, have a favorable resorbability and relatively good stability in galenic formulations.

The pyrazole derivatives of the general formula (I) are metabolized in the body in a manner other than known yrotizinflammatory substances.

The novel compounds in combination with carriers customary in galenic pharmacy are suitable for treatment, for example

(a) locally:

contact dermatitis, eczema of various species, neurodermitis, erythihroderma, grade 1 burns, Pruritus vulvae et ani, Rosacea, Erythematodes curaneus, Psoriasis, Lichen ruber planus and verrucosus;

(b) orally:

• acute and chronic polyarthritis, neurodermitis, bronchial asthma, hay fever, and others.

The preparation of the medicaments is carried out in the usual manner by converting the active ingredient with suitable additives, carriers and flavoring agents into the desired dosage forms, such as tablets, dragees, capsules, solutions, ointments, inhalants, etc.

For oral use, fines of tablets, dragees and capsules are suitable which contain, for example, 1 to 2-5 mg of the active ingredient and 50 mg to 2 g of a pharmacologically inactive carrier such as lactose, amylose, talc, gelatin, magnesium stearate and the like. as well as conventional additives. Powders, ointments, aerosols and the like are suitable for topical use and preferably contain from 0% to 1% by weight of the active ingredient.

The efficacy of the compounds according to the invention is apparent from the following experimental results and from the attached table.

1. Carragenin paw edema test (cf. Proc. Soc. Exptl. Biol. Med. 111, 1962, 544)

Acute exudative inflammation was induced in the rat by injection of Carragenin. This inflammation is suppressible by anti-inflammatory agents. Edema is measured vol-umetrically.

Male Wistar rats (SPF) weighing 120 to 140 g are used. 16 hours prior to oral administration of the animals, the animals are removed from the feed, receiving water ad libitum.

Carragenine is the edema-inducing agent. 10 mg / ml carrageenin is taken up in 0.9% saline, 0.1 ml is injected into a rat paw.

A single dose of the test substance is administered to the test animal an hour before edema induction in 0.5 ml of binder per 100 g body weight. The binder is a physiological table salt solution; for water-insoluble substances, prepare a micro-suspension in physiological saline with Myrj 53 (85 mg / 1 to 100 ml).

Experimental Handle:

5 animals are taken per dose group. After plethysmography by right volume of the right hind paw, the substances are administered orally; after one hour, inflammation is induced by intraplantar injection of 0.1 ml of the edema-inducing substance. After a further 3 hours, the volumes of the levers are measured again and the suppression of inflammation is calculated.

Evaluation ··% suppression = 100 - ' ¹ -

Y = mean difference in volume of the levers in the treatment group

Z = mean difference in volume of levers in the control group

2. Adjuvant arthritis test (cf. Brit.]. Pharmacol., 21, 1963, 127]

After injection of Freund's adjuvant. (M. butyricum) rats develop polyarthritis within about two weeks, which can be suppressed by anti-inflammatory agents.

Male and male animals are used ^; Lewis (LEW) female rats weighing 110-190 g. The animals receive drinking water and pressed alitromm ad libitum.

Ten rats are used for each dosing group. Mycobacterium butyricum from Difko, Detroit, is used as the edema-inducing agent. A 0.5 mg suspension of M. butyricum in 0.1 ml of sparse liquid paraffin (DAB 7) is injected into the right hind paw.

The test substances were administered orally daily for 4 days from day 11. The substances are applied as a clear aqueous solution or as a crystal suspension with the addition of Myrj 53 (85 mg%) in isotonic sodium chloride solution.

Experimental Handle:

The rats are divided into different groups as far as possible relative to body weight. After plethymographic measurement of the volume of the right and left hind paws, a subplantar injection of 0.1 ml of adjuvant is injected into the right hind paw. Right rear paws are measured from 1.4. until the end of the experiment. Also, measurement of the non-irritated left hind paws is performed from the 14th day of the experiment. The duration of the experiment is 3 weeks.

Evaluation:

% suppression = 100 - у .100 у == mean volume difference of the paw volume of the treated group z - mean volume difference of the paw volume of the control group

3, Gastric wall damage test (cf. Arch. Int. Pharmacodys. 192, 1971, 370 'ff.)

Gastric ulcers are a common complication in non-steroidal anti-inflammatory therapy. This side effect can be demonstrated by animal experiments.

Male Wistar rats (SPF) are used. The animals are in a weight range of 13 ± 10 g. 16 hours prior to the start of the experiment, the animals are withdrawn from feeding; receive water ad libitum.

5 animals are used per dose. The substances are applied once orally dissolved in sodium chloride or as a suspension with the addition of 85 mg% Myrj 53.

hours after the administration of the substances, 1 ml of a 3% diphenyl blue dye solution is injected intravenously and the animal is killed. The stomach is resected and examined microscopically for the number and size of forests in the epithelium and ulcer exiting the dye enrichment.

Evaluation of experiments:

The table below shows that the substances 1 and 2 according to the invention are stronger than the previously known structurally analogous compounds 3, 4 and 5, since they have a stronger anti-inflammatory effect and / or induce smaller gastric ulcers.

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The hitherto unknown starting compound of formula II can be prepared from the corresponding carboxylic acids by reducing them, for example, with lithium aluminum hydride to the corresponding carbiniols, as described, for example, in the synthesis of 3-bromomethyl-1,4-diphenylpyrazole:

(a) 3 g of tiriethylamine and a solution of 6,78 g of ethyl (2-chloro-2-phenylhydrazono) acetic acid in 20 ml of dry are gradually added at room temperature to 5,67 g of α-morpholinostyrene in 35 ml of dry, ethanol-free ethanol; of chloroform-free ethanol. The reaction mixture was stirred at 40 ° C for 1 hour and at room temperature for 16 hours, washed with dilute hydrochloric acid, dilute sodium carbonate solution and water, dried and concentrated in vacuo. The residue was digested with hexane, recrystallized from ethanol-hexane to give 4-morpholino-3-phenyl-2-phenylhydraisono-3-butenoic acid ethyl ester, m.p. 130 DEG-13 DEG.

(b) To 33 g of 4-morpholino-3-phenyl-2-phenylhydrazono-3-butenoic acid ethyl ester are added 330 ml of dioxane and 100 ml of 2 N hydrochloric acid and heated under reflux for 45 minutes. The reaction mixture is then concentrated in vacuo, the residue is dissolved in chloroform, the chloroform solution is washed, dried and concentrated in vacuo. The residue was recrystallized from ethanol-hexane to give 21.15 grams of 1,4-diphenylpyrazole-3-carboxylic acid ethyl ester, m.p. 103-104 ° C.

4.73 g of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran was added dropwise under nitrogen at 0 ° C to a solution of 17.2 g of 1,4-diphenylpyrazole-3-carboxylic acid ethyl ester in 80 ml of absolute! tetrahydirofuran.

The reaction mixture was stirred for a further 30 minutes, 40 mL of saturated aqueous sodium chloride solution was added, acidified with dilute hydrochloric acid and extracted with ether. The organic phase is concentrated, digested with hexane to give 14.6-5 g of 3-hydroxymethyl-1,1-diphenylpyrazole as a crude product, m.p. 1014-110 ° C.

d) To 1.3.2 g of crude 3-hydroxymethyl-1,4-diphenylpyrazole was added 130 ml of 63% hydrobromic acid and heated at 50 ° C for 4 hours.

The reaction mixture is then concentrated in vacuo, excess hydrogen bromide is removed several times by removing the residue with toluene and concentrating in vacuo. The residue was recrystallized from isopropanol to give 10.8 g of 3-bromomethyl-1,4-diphenylpyrazole, m.p. 99 ° C.

The following examples serve to explain the production method of the invention.

Example 1

a) 2.81 g of 3-bromoethyl-1,4-diphenylpyrazole was stirred in 30 ml of absolute acetonitrile with 1.17 g of potassium cyanide and 300 mg of dibenzo-18-crown-6 for 10 hours at 40 ° C.

The reaction mixture is then concentrated in vacuo, water is added, extracted with methylene chloride, the organic phase is washed, dried and concentrated in vacuo. 2.6 g of (1,4-diphenyl-3-pyrazolyl) acetonitrile are thus obtained as a crude product.

b) 2.6 g of crude (1,4-diphenyl-3-pyrazolyl) acetonitrile were stirred with 20 ml of concentrated hydrochloric acid at 50 DEG C. for 1 hour, then diluted with water, extracted with methyl isobutyl ketone, the organic phase It is washed, concentrated in vacuo to give 2.3 g of (1,4-diphenyl-3-pyrazolyl) -acetate as a crude product.

(c) 2.3 g of (1,4-diphenyl-3-pyrazolyl) -acetamide (the crude product is heated to reflux with 40 ml of 10% aqueous sodium hydroxide solution for 30 minutes under argon) and then cooled in an ice bath, It is acidified with 2N hydrochloric acid, extracted with methylene chloride, the methylene chloride phase is washed, dried and concentrated in vacuo.

The crude product obtained is recrystallized from toluene to give 1.25 g of (1, 4-diphenyl-3-pyrazolyl) -acetic acid, m.p. 131-133 ° C.

Example 2

a] A mixture of 2.6 g of crude (1,4-diphenyl-3-pyrazolyl) acetonitrile (prepared according to Example 1a) and 15 ml of 80% sulfuric acid was heated to 120 ° C and stirred at this temperature for 2 hours. The reaction mixture is then poured into ice water, extracted with methylene chloride, the methylene chloride phase is washed, dried and concentrated in vacuo.

The residue was dissolved in 5% aqueous sodium carbonate solution, precipitated with 10% hydrochloric acid, filtered, washed and dried at 60 ° C in vacuo. It was crystallized from toluene to give 1.6 g of (1,4-diphenyl-3-pyrazolyl) -acetic acid, m.p. 131-133 ° C.

1 ϋ 2 О 3

(b) 200 mg of (1,4-diphenyl-3-pyrazolyl) -acetic acid are dissolved in 10 ml of absolute ethanol, 7.6 ml of 0.1 N aqueous sodium hydroxide solution are added to the solution and concentrated in vacuo.

The residue is taken up in 10 .mu.M of absolute ethanol and again concentrated in vacuo.

The crude product obtained was dissolved in a small amount of absolute ethanol, diethyl ether was added thereto, and sodium (1,4-diphenyl-3-pyrazolyl) -acetate was obtained as an amorphous powder.

Example 3

(a) A solution of 15.2 g of sodium nitrite in 40 ml of water is added dropwise to a solution of 21.4 g of p-toluidine and 400 ml of 7.5% hydrochloric acid, cooled to 0 ° C. The thus obtained p-toluenediazonium chloride suspension is added dropwise to a mixture of 36.2 g of ethyl 2-chloroacetate, 4Ш ml of 5% ethanol and 164 g of sodium acetate cooled to 5 ° C. Then; The mixture is stirred at 20 DEG C. for 3 hours, extracted with ethyl acetate, the organic phase is concentrated, the residue is treated with petroleum ether and 41 g of 2-chloro-2- (4-methylphenylhydrazono) -acetic acid ethyl ester of melting point are obtained. 100 to 101 ^q C.

b) R-ztok 24.7 g of ethyl 2-chloro-2- ^{(4-methylfenylhydriazono)} -acetate in 103 ml chloirotormu was added dropwise to a solution of 18.9 g α-morfoilinostyrenu in 100 ml of chloroform and 13.8 g of triethylamine . The reaction mixture was allowed to stand for one hour at 50 ° C and for 16 hours at 20 ° C, washed with 2 N hydrochloric acid and then with saturated sodium bicarbonate solution. The chloroform solution was concentrated in vacuo and the residue treated with petroleum ether to give 27.6 g of 2- (4-methylphenyllihydrazono) -3-morpholino-methylene-3-phenylpionic acid ethyl ester, m.p. 131-13 ^: 2 ° C. = C.

(c) 260 ml of dioxane and 80 ml of 2 N hydrochloric acid are added to 27,6 g of ethyl 2- (4-methylphenylhydroxy-zino) -1,3-, moirfolino-methyl-3-phenyl-propioinoic acid, and heated under reflux for 45 minutes. cooler. The reaction mixture was allowed to cool, concentrated in vacuo and the residue taken up in chloroform. The chloroform phase is washed with water, concentrated in vacuo, the residue is treated with p-eetrolether to give 17.1 g of 4-phenyl-1- (4-tolyl) -3-pyrazolecarboxylic acid ethyl ester, m.p. 115 DEG-1.17 DEG. C.

d) A solution of 16.8 g of 4-phenyl-1- (4-tolyl) -3-pyrazolylcarboxylic acid ethyl ester was added dropwise to a suspension of 4.3 g of lithium aluminum hydride in 100 ml of tetrahydrofuran cooled to 0 ° C. The mixture was stirred for an additional hour, 26 ml of saturated sodium chloride solution and then 63 ml of 201% hydrochloric acid were added. Then, the reaction mixture is extracted with ether, the ether phase is concentrated in vacuo, the residue is treated with petroleum ether and ¹ g of 4-phenyl-1- (4-tolyl) -3-pyrazolylmethanol is obtained, m.p. 125 ° C.

e) 2.65 g of 4-phenyl-1- (4-tolyl) -3-pyrazolylmethaniol are heated at 90 DEG C. for 5 hours in 60 ml of 63% hydrobromic acid, then the reaction mixture is diluted with water, the precipitated product is filtered off with suction, crystallized from isopropanol to give 2.9 g of 3-bromo-methyl-4'-phenyl-1- (4-10-allyl) -pyrazoil, m.p. 98 ° C.

f) К 5 _; 9 g of 3-bromomethyl-4-phenyl-1- (4-tolyl) -pyrazole are added 4.7 g of potassium cyanide, 70 ml of acetonitrile and 500 mg of dibenzo-18-crown-6 and stirred for 10 hours at 40 ° C. The reaction mixture was concentrated in vacuo, water was added to the residue and extracted with methylene chloride. The methylene chloride phase is washed, concentrated and the residue is recrystallized from methanol to give 4.7 g of 4-phenyl-1- (4-tolyl) -3-pyrazolylacetic acid nitrile, m.p. 31-92 ° C.

g) 4.7 g of 4-phenyl-1- (4-tolyl) -3-pyrazolylacetic acid nitrile were heated at 120 ° C in 27 ml of 80% sulfuric acid for 2 hours. The reaction mixture was allowed to cool, diluted with lure and extracted with methylene chloride. The organic phase is washed, concentrated and the residue is recrystallized from toluene to give 3.2 g of 4-phenyl-1- (4-tolyl) -3-pyrazolylacetic acid, m.p. 124-125 ° C.

Example 4

a) 2.5 g of 4-phenyl-1- [4-tolyl) -3-pyrazolylacetic acid nitrile was stirred with 20 ml of concentrated hydrochloric acid at 50 ° C for 1 hour. Then the reaction mixture is diluted with water, extracted with methyl isobutyl ketone, the organic phase is washed, concentrated in vacuo to give 1.9 g of 4-phenyl-1- (4-tolyl) -3-pyrazolylacetic acid amide as a crude product.

b) 1.9 g of crude carboxylic acid 4-phenyl-l- (4-tolyl) -3-pyrazolyloctové under argon ^3G: minutes heated under reflux in 40 ml of 10% aqueous sodium hydroxide solution. The reaction mixture was cooled in an ice bath, acidified with 2N hydrochloric acid, extracted with methylene chloride, the methylene chloride phase was washed, dried, and concentrated in vacuo. The crude product obtained is recrystallized from toluene to give 0.95 mg of 4-phenyl-1- (4-tolyl) -3-pyrazolylacetic acid, m.p.

Example 5

a) Under the conditions of Example 3a, re-ar is allowed

The o-tolidine was converted to ethyl 2-chloro-2- (4-methylphenylhydrazone) acetic acid, m.p. 72 ° C.

b) The product obtained is reacted according to Example 3b to 2- (2-methylphenylhydrazono) -3-amino-thiomeomeithylene-3'-phenylpropionic acid ethyl ester, m.p. 109 ° C.

c) Under the conditions of Example 3c, the obtained compound was converted into 4-phenyl-1- (2-tolyl) -S-pyrazolecarboxylic acid ethyl ester, m.p. 80HC.

d) The product obtained according to the method described above. in Example 3d ' reduces 4-phenyl-4- (2-tolyl) -3-pyrais (olylmethyl) ethanol, m.p. 121 [deg.] C.

e) bromination of the compound of Example 3e gives 3-b) 4-rommιethy.l fenylll- (2 · tolylj -pyrazole of melting point 67 C ^q.

(f) The bromide shall be replaced by:. under the conditions of Example 31 was converted into the 4-phenynyl-1- (2-tolyl) -3-pyrazoleic acid nitrile, m.p. 23 DEG.

g) The nitrile thus obtained was saponified as described in Example 3g to give 4-phenyl-1- (21-tolyl) -3-pyrazol-4-ylacetic acid, m.p. 177 ° C.

Example 6

a.) c-chloroaniline; in the manner described in Example 3a was converted to the acid ethyl ester

2-Coior-2 '- (2-chlorophenylhydrazonioacetate) m.p. 92 ° C.

b). The resulting compound - is converted as described in Example 3b into the 2- (2-chlorophenylhydrazono) -3-fluorolino-4-ol. m.p. 122 ° C.

c) Under the conditions of the example. 3c, the product obtained is converted to the 4-phenyl-1- (2-η1-γ1-β-γ-1) -3-pyrazococarboxylic acid othyiospore, m.p. 109 ° C.

d) Reduction této- compound as described in Example 3d poskytuje- 4-benzenesulfonyl-l- (2-chlΌιrfoayl) -3-pyrazol ^l zO'lyl mothanol · m.p. 132 ° C.

o) Bromoacid alcohol as described in Example 3e, water to 3-bromomethyl-4-phenyl-1- (2-thiolfoayl) -pyrazole, m.p. 91 ° C.

The bromide was converted to 4-phenylil- (2-chlorophenyl) -3-pyrazolyl acetic acid nitrile under the conditions of Example 3f, m.p. 62 ° C.

g) The nitrile thus obtained was converted as described in Example 3f to 4-phenyl-1- (2-chlorophonyl) -3-pyrazolyl acetic acid at a melting point of 146 ° C.

Example 7

From 4-chloroaniline with the conditions of Example 3a to 3f prepared acid nitrile 4-phenyl-l- (4-chlorophenyl) -3-pyrazolyloOtoté a · ^q mp 121 DEG, which was - zmýdolní acid 4-phenyl-l- (4-chlorophonyl) -3-pyrazolyl acetic acid as described in Example 3g, mp 137 ° C.

The intermediates obtained in the production of aitrile have the following physical values:

2- (Chloro-2- (4-chloro-phenynyl) -azonium iodoate, ethyl ester, m.p. 15.0 ° C.

2- (4-Chlorophosphorylhydrazono) -S-mono-amino-methylene-5-phenyl-propionic acid, m.p. 164 ° C.

4-Methyl- (4-chlorophenyl) -3-pyrazolecarboxylic acid ethylostor, m.p. 91 ° C.

4-Phenyl-1- (4-chlorophenyl) -3-pyrazolylmethanol, m.p.

3-Bromomethyl-4-phenyl-4- (4-chlorophonyl) -pyrazole, m.p. 125 ° C.

Example 8

4-Phonyl-1- (3, (4-11-1) -co-phenyl) -3-pyrazdlylacetic acid nitrile was prepared from 3,4-di-chloroaniline as described in Example 3a to 3f. m.p. 131 [deg.] C, which is saponified to 4-methyl-1- (3,4-dichlorophenyl) -3-pyrazoleic acid under the conditions of Example 3.g, m.p. 158 [deg.] C.

The intermediates which are obtained in the production of nitriles have the following physical properties:

R-Chloro-r- (3,4f-dichlorophenyl-hydrazo) -acetic acid ethyl ester, m.p. = 154 ° C.

2- (3,4-Dichloro-phenyl-cyrazone) -4-morpholino-methylene-β-phenylpropioate, m.p. 141 ° C.

4-Phenylil- (3,4-dichlorophonyl) -3-pyrazolecarboxylic acid ethyl ester, m.p. 117 ° C.

4-Phonyl-1- (3,4-dichlorophenyl) -3-pyrazolylmethaniol, m.p. 12.1 ° C.

3-Brornineth-4-Methyl-1- (3,4-db chlorophenyl) pyrazole, m.p. 108 ° C.

Example 9

Example 11

Among the para-fluoroaniline in the same conditions as described in Example 3a to 3f, to give a nitrile ester ^4-fe NYM (4-fiiuorfenyl) -3-pyrazolylioctclvé · m.p. about 79 ° C, ₅ which, as described in Example 3g, saponified to 4-phenyl-1- (4-fluorophenyl) -3-pyrazolyl acetic acid, m.p. 171 ° C.

The intermediates obtained in the nitrile production have the following physical values:

2-Chloro-2- (4-fluorophenylhydrazono) acetic acid ethyl ester, m.p. 109 ° C.

2- (4-fluorfenyIhydraizono] -3 ^{J moifolinomiethyle,} N-3-fe'nylpropionová, mp 191 DEG C. ^q

4-Phenyl-1- (4-fluorophenyl) -3-pyrazolecarboxylic acid ethyl ester, m.p. 125 ° C.

4-Phenyl-1- (4-fluorophenyl) -3-pyrazolylmethanol, m.p. 14: 6 ° C.

3- Bromomethyl-4-phenyl-1- (4-fluorophenyl) -pyrazole, m.p. 89 ° C.

Example 10 '

From o-fluoroaniline under the conditions described in Example 3a; 4-phenyl-1- (2-fluorophenyl) -3-pyrazolylacetic acid nitrile having a melting point of 70 ° C is prepared, which, as described in Example 3g, is saponified to 4-phenyl-1- ( 154 DEG C. 2-fluorophenyl) -3-pyrazolylacetic acid, m.p.

The intermediates obtained in the nitrile production have the following physical values:

2rChilor-2- (2-) ethyl ester

-fluorophenylhydroxyacetic acid, m.p. 70 ° C.

2- (2-Fluorophenylhydrazenoic acid) -

3-morpholinomethyl-3-phenyl-propionic acid, m.p. 99 ° C.

4-Phenyl-1- (2-fluorophenyl) -3-pyrazolecarboxylic acid ethyl ester, m.p. 62 ° C.

4-Phenyl-1- (2-fluorophenyl) -3-pyrazolylmethanol, m.p. 109 ° C.

3-Bromomethyl-4-phenyl-1- (2-fluorophenyl) -pyyrazole, m.p. 102 ° C.

4-Phenyl-1- (3-fluorophenyl) -3-pyrazolylacetic acid nitrile, m.p. 74 DEG C., prepared as described in Example 3g, was prepared from m-fluoroaniline under the conditions described in Examples 3a and 3f. saponified to 4-phenyl-1- (3-fluorophenyl) -3- ^, pyraisolylocetic acid, m.p. 159 DEG C .;

The intermediates obtained in the nitrile production have the following physical values.

2-Chloro-2- (3-fluoro-phenyl-azono) -acetic acid ethyl ester, m.p. 111 ° C.

2- (3-Fluorophenylhydrazono) -3-morpholinylmethylene-3-phenylpionic acid, m.p. 110 DEG.

4-Phenyl-1- (3-fluorophenyl) -3-pyrazolecarboxylic acid ethyl ester, m.p. 81 ° C.

4-Phenyl-1- (3-fluorophenyl) -3-pyrazolylmethanol, m.p. 74 ° C.

3- Bromomethyl-4-phenyl-1- (3-fluorophenyl) -pyrazole, m.p. 7.5 ° C.

Example 1 a d 12

From m-trifluoromethylaniline, 4-phenyl-1- (3-trifluoromethylphenyl) -3-pyrazolyl-acetonitiril was produced from m-trifluoromethylaniline, m.p. 3 g saponified to give 4-phenyl-l- (3-trifluormethylfenylj-and-pyrazolyloctovou mp 169 C ^Q

The intermediates obtained in the nitrile production have the following physical values:

2-Chloro-2- (3-trifluoromethyl-phenylhydrazono) -acetic acid ethyl ester, m.p. 131 ° C.

2- (3-Trifluoromethyl-phenylhydrazino) -3-morpholinomethylene-3-phenylpiropionic acid, m.p. 125 ° C.

4-Phenyl-1- (3-trifluoromethyl-phenyl) -3-pyrazolecarboxylic acid ethyl ester, m.p. 66 ° C.

4-Phenyl-1- (3-trifluoromethyl-phenyl) -3-pyrazolylmethanol, m.p. 94 ° C.

3-Borate ethyl. _{L-4-phenyl-l-} (3-tri-f-1 luormethy 1 phenyl) pyrazole, mp 120 ° C.

Example 13

a) Under the conditions of Example 3b, 22.7 g of .alpha.-dimethylamino-ethylene nitrile was reacted with 19.2 g. 33 gralmů give ethyl 3-methylimidazol! Mia ^o ·· methy'lein-3- (4-nitrophenyl) -2-fenylhydrhzono-propionic acid, m.p. 139 ° C.

b) The compound thus obtained is cyclized to the conditions described in Example 3c in 1-phenyl-4- (4-nitrophenyl) -3-

-pyrazolecarboxylic acid, m.p. 143 DEG C. (yield 27 g).

(c) Dissolve 24 g of the compound obtained in (b) in 500 ml of ethanol, add 5 g of Raney nickel and hydrogenate at room temperature at atmospheric pressure. The catalyst was filtered off, the filtrate was concentrated in vacuo, the residue crystallized from methanol to give 20 g of 4- (4-aminophenyl) -1-phenyl-3-pyrazolylcarboxylic acid ethyl ester, m.p. 142 ° C.

(d) To 3.1 g of 4- (4-aminophenyl) -1-phenyl-3-pyrazolecarboxylic acid ethyl ester in 13 ml of 15% hydrochloric acid, at -5 ° C, add a solution of 760 mg of sodium nitrite in 1,5 Then, 25 ml of 3% hydrochloric acid was added to the mixture, and the mixture cooled to -5 ° C was added dropwise to a solution of 1.5 g of copper (I) chloride in 30 ml of 12% hydrochloric acid heated to 60 ° C. Allow to stand at 60% for a further 10 minutes, cool, extract with ethyl acetate, concentrate the extract, remove the residue in toluene, filter through a silica gel column, concentrate the solution to obtain 2.47 g of ethyl ester 4 - (4-chlorophenyl) -1-phenyl-3-pyrazolecarboxylic acid, m.p. 96 ° C.

e) Under the conditions of Examples 3d to 3g, 4- (4-chlorophenyl) -1-phenyl-3-pyrazolecarboxylic acid ethyl ester was converted to 4- (4-chlorophenyl) -1-phenyl-3-pyrazolyl acetic acid. mp 142 ° C.

The intermediates obtained in the synthesis of this compound have the following physical constants:

4- (4-Chlorophenyl) -1-phenyl-3-pyrazolylmethanol, m.p. 145 ^DEG C.

3-B.romomethyl-4- (4-chlorophenyl) -118

-phenylpyrazole, m.p.

4- ^(4-Chl! Orf) -1-phenyl-pyrazolylacetonitril, temperature, mp 97 ° C.

Example 1 4

a) · To 2.4 g of 4- (4-aminophenyl) -1-phenyl-3-pyrazolecarboxylic acid ethyl ester, add 28 ml of 1 N hydrochloric acid, cool to 0 ° C and slowly diazotize with a solution of 830 mg. sodium nitrite in 5 ml of water. The mixture is then diluted with 10 ml of water and stirred for 15 minutes at 0 DEG. Then 953 mg of zinc chloride are added to the mixture and allowed to stand for 30 minutes. The precipitate formed is filtered off with suction, dried, taken up in 50 ml of methanol and left to stand at room temperature for 16 hours and refluxed for one hour. The mixture is concentrated in vacuo, the residue is taken up in benzene, the benzene phase is washed and concentrated in vacuo. To the residue were added 2 equivalents of sodium hydroxide and 2.02 g of dimethyl sulfate and heated at 80 ^° C for 30 minutes. After cooling, dilute with water, extract with methylene chloride, concentrate the organic phase, g of 4- (4-methoxyphenyl) -1-phenyl-3-pyrazolecarboxylic acid ethyl ester, m.p. 94 DEG C., is added.

b) Under the conditions of Examples 3d to 3g, 4- (4-methoxyphenyl) -1-phenyl-3-pyrazolecarboxylic acid ethyl ester is converted to 4- (4-methoxyphenyl) -1-phenyl-3-pyrazolylic acid, m.p. 170 Deň: 11 ° C.

The intermediates obtained in the synthesis of this compound have the following constants:

4- (4-Methoxyphenyl) -1-phenyl-3-pyrazolylmethanol, m.p.

3-Chloromethyl-4- (4-methoxyphenyl) -1-phenylpyrazole, m.p. 125 ° C (the compound is obtained from said compound by treatment with 1.1 equivalents of phosphorus pentachloride in ether-tetra-tetrahydrofuran at 0 ° C) .

4- (4-Methoxyphenyl) -1-phenyl-3-pyrazolylacetic acid nitrile, m.p. 83 ° C.

n is 1, 2, 3; or 4, or a physiologically acceptable salt thereof, characterized in that the pyrazole derivative of the general formula (I):

Claims (1)

Subject A process for the preparation of 1,4-diyl-pyrazole derivatives of the general formula I according to the invention T-U- 7 ^<I! ''! (II) in which R 1, R 2, R 3, and R 1 are substituents in the ortho, meta or para position and denote hydrogen, fluorine, chlorine and bromine, methyl, methoxy, trifluoromethyl, and lower alkyl; ] ^ inu or amlnoispline, X represents a cyano group, an aminocarbonyl group, an alkoxycarboinyl group having from 1 to 6 carbon atoms in the alkoxy radical, a carboxyl group in which R1, R2, R1, Ro and n are as previously defined, Y is fluorine, chlorine and bromine, reacted with an alkali metal cyanide, and optionally the resulting cyanides are saponified, the nitro groups present are reduced, and the carboxylic acids formed are converted in their salts or esterified with a C1 -C6 -alcohol.