FI57584C - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC ANALYSIS 5-CHLORO-ELLER 5-BROMO-1,3-DIPHENYLPYRAZOLE-4-ACETIC XYRIDES - Google Patents

Description

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National Board of Patents and Registration (44) Date of publication and date of publication. -

Patent and registration authorities An * eion utfcjd «* utUkrtfton pubifcond 30.05.80, (32) (33) (31) Pyy4 * tty etuolkeu * —8ogird priorltut 16.08.73

Luxembourg (LU) 68238 (71) Byk Guiden Lomberg Chemische Fabrik GmbH, Byk-Gul den-St r as se 2, D-7750 Konstanz, Federal Republic of Germany Förbundsrepubliken Tyskland (DE) (72) Georg Rainer, Konstanz, Richard Riedel, Konstanz, Federal Republic of Germany Förbundsrepubliken Tyskland (DE) (TU) Oy Kolster Ab (5U) Method for the preparation of therapeutically useful 5 ~ chloro or 5 ~ bromo-1,3-diphenylpyrazole-U-ethanic acid derivatives - Förfarande för fram-ställning from therapeutically active compounds 5 ~ chloro- or 5-Bromo-1,3-diphenylpyrazole-U-acetic acid derivatives

The invention relates to a process for the preparation of pharmaceutically valuable halopyrazole sol derivatives.

BE Patent Publication No. 755 92U describes pyrazole-U-acetic acid derivatives having the general formula: R1 * 2 '

R CH-A

νηΤ i '2 57584 1 2. 3. . ....

wherein R, R and R, which may be the same or different, are a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic or cycloaliphatic hydrocarbon radical having 1 to 7 carbon atoms, or an optionally substituted aryl or heteroaryl group in which has 12 carbon atoms, with the simultaneous 2. . 3. . . R cannot be a hydrogen atom and R is a hydrogen atom, or are a methyl group, and R can further be a benzyl group which may be substituted by a halogen atom or an alkoxy group having 1 to U carbon atoms, R 1 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, COOH, COOR '*, CONR 1 R 4, CN or C (= NOH) OH, wherein R' * represents an alkyl group having 1-h carbon atoms, a benzyl group, a phenyl group or a 2- a carboxyphenyl group, and

6 V

R and R in each case represent a hydrogen atom and / or an alkyl group having 1 to U carbon atoms or, together with a nitrogen atom, form a pyrrolidine, piperidine or morpholine group.

The described group of compounds has an anti-inflammatory, analgesic and antipyretic effect.

A new class of pyrazole acetic acid derivatives has now been invented, which are substituted in a completely new type in which the halogen atom is directly attached to the pyrazole ring. It was further found that compounds of such a group have particularly advantageous pharmacological effects. In particular, the invention is based on the finding that pyrazole-1 + -acetic acids substituted in the 5-position of the pyrazole ring by halogen have very strong and specific pharmacological effects. The compounds according to the invention have a special anti-inflammatory effect, but also as antipyretics and analgesics.

The invention relates to a process for the preparation of therapeutically useful 5-chloro or 5-bromo-1,3 * -diphenylpyrazole-U-acetic acid derivatives of the general formula I

Ph CH COOH

n.

halogen ό 3,57584 wherein Ph represents phenyl, halophenyl, p-alkoxyphenyl having 1-U carbon atoms in the alkoxy moiety, or p-alkylphenyl having 1-U carbon atoms in the alkyl moiety, and halogen represents a chlorine or bromine atom, or for the preparation of their salts with organic or inorganic bases.

Preferred pyrazole-U-acetic acid derivatives of the formula I and their salts with inorganic or organic bases are those in which Ph is unsubstituted phenyl, p-chlorophenyl or p-bromophenyl and the halogen is chlorine.

A particularly preferred group of pyrazole acetic acid derivatives of the formula I and their salts are those in which Ph is an unsubstituted phenyl, p-chlorophenyl, p-methoxyphenyl or p-isobutylphenyl residue and halogen is chlorine or bromine.

The compounds of general formula I have particularly valuable pharmacological properties

Ph'n, _✓ CH_COOH.

1 2 N '^ N Λΐ X * ό where

Ph 'is unsubstituted phenyl or p-chlorophenyl, and their salts with inorganic or organic bases.

The following compounds have particularly advantageous pharmacological properties in the form of the free acids or their salts 5-chloro-1,3-diphenylpyrazole-1 + -acetic acid 5-chloro-3-p-chlorophenyl-1-phenylpyrazole -U-acetic acid 5-chloro-3-m-chlorophenyl-1-phenyl-pyrazole-U-acetic acid 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-U-acetic acid 5-chloro-1-phenyl -3-p-tolyl-pyrazole-U-acetic acid 5-chloro-3-p-isobutyl-phenyl-1-phenyl-pyrazole-U-acetic acid 5-bromo-1,3-diphenyl-pyrazole-U-acetic acid.

11 57584

Representative compounds of formula I further include the following acids and their salts: 3-p-bromophenyl-5-chloro-1-phenyl-pyrazole-U-acetic acid 5-chromium-3-p-chlorophenyl-1-phenyl-pyrazole-U -acetic acid 5-bromo-3-p-methoxyphenyl-1-phenyl-pyrazole-U-acetic acid 5-bromo-3-p-isobutylphenyl-1-phenyl-pyrazole-U-acetic acid 5-chloro-3-p-butoxy phenyl -1-phenyl-pyrazole-U-acetic acid.

Of the salts of the compounds of formula I, pharmacologically acceptable are the most preferred. The cations used for salt formation are, in particular, the cations of the alkali metal, alkaline earth metal and earth metal ions, or also the ammonium ion, but also the corresponding cationic acids of the corresponding 1- or more-acid organic nitrogen bases, in particular organic amines. ~ -

For example, lithium, sodium, potassium, magnesium, calcium, and aluminum cations and ethanolamine, diethanolamine, triethanolamine, ethylenediamine, dimethylamine, diethylamine, morpholine, piperine, methylcyclohexylamine, glucosamine, N-methylglycine, N-methylglucine, N-methyl further cationic acids of tert-butylamine, dibutylamine, diisopropylamine, triethylamine, isopropylamine, quinoline and ammonia.

The process according to the invention is characterized in that the compound of general formula II

_ <r * · * f

M yK halogen II

wherein Ph and halogen are as defined above, and B represents a hydrolyzable derivative of an acetic acid functional group, is hydrolysed, and the obtained compound of general formula I is optionally converted into a salt, or if desired, the compound of general formula I obtained in salt form is converted to the free acid.

5,57584

By a functional derivative of an acetic acid group is meant a derivative of an acetic acid group (-CH 2 COOH) which is chemically close to the acetic acid group and can be converted by hydrolysis into a free acetic acid group. Typical functional derivatives of the acetic acid group are described in more detail below.

According to a preferred embodiment, a pyrazole-1 '-acetic acid derivative of the general formula * 11' is hydrolyzed.

Ph B '1 X n * \ N ^ halogen ό where

Ph and halogen have the same meaning as above, B 'is a group -CH 2 CN or a group -CH 2 -C 1 y in which X is an oxygen or sulfur atom or a substituted nitrogen atom, in particular an imino, alkylimino or hydroxyimino group and Y is a hydroxy group or a monovalent removable electrophilic residue, in particular a free or substituted amino group, preferably a monoalkyl or dialkyl or arylamino group, a hydroxyamino or hydrazine group, a hydrobasyl group, a 2-hydroxyethylamino group, a free or substituted a mercapto group, preferably an alkylthio group, a substituted hydroxy group, preferably an alkoxy group, or an azide, chlorine or chromium residue, a morpholine group or a piperidine group, wherein Y is not a hydroxy group when X is an oxygen atom.

An alkyl residue of an alkylimino, monoalkylamino, dialkyl amino, alkylthio and alkoxy group means an alkyl residue having up to six carbon atoms, an aryl residue of an arylamino group means an aryl 57584 6 residue having up to 10 carbon atoms.

In another preferred embodiment of the hydrolysis, functional pyrazole-4-acetic acid derivatives of general formula II 'are used, in which B' represents a group -CH 2 CN or a group -CH 2 -C 2 wherein X is an oxygen atom, a sulfur atom or an imino group and Y is amino, monoalkylamino, dialkylamino, phenylamino, alkoxy, alkylthio, chloro or bromo residue *

In a particularly preferred embodiment of the hydrolysis, the starting materials are pyrazole-4-acetic acid nitriles, pyrazole-4-acetic acid amides and pyrazole-4-acetic acid alkyl esters of the general formula II *.

The process can also be carried out by using a pyrazole derivative which sometimes forms a pyrazole derivative of the general formula II or II ', which is then converted into the desired pyrazole-4-acetic acid derivative of the general formula I by means of a water-donating medium. In many cases, the hydrolysis takes place in several stages and, by suitably controlling the course of the reaction, the intermediate stages can also be isolated. Thus, for example, the hydrolysis of nitriles, thioamides, amidines and imidazolines takes place via the corresponding amides or the hydrolysis of imidic acid esters via caconic acid esters. Reaction of unsubstituted amides with nitric oxide yields as intermediates acyldiazonium compounds which are readily hydrolysed to carboxylic acids. Examples of such functional carboxylic acid derivatives are: alkyl ester, phenyl ester, benzyl ester, alkoxyalkyl ester, dialkylaminoalkyl ester, amides, N monoalkylamides, N, N-dialkylamides, morpholides, piperidides, piperidides, piperidides, piperidides , hydrazides, azides, monothiocarboxylic acids, monothiocarboxylic acid alkyl esters, thionicarboxylic acid alkyl esters, thioamides, thiomorphols, imidic acid esters, amidines, hydrazidines, oxazoline, imidazoline, thiazoline, acid chlorides, acid chlorides, acid chlorides, acid chlorides

However, particularly important starting materials are those compounds whose

The preparation of Yi 7 57584 makes technical and economic sense and which best correspond to the general formula II '. However, if residues X and Y are removed during the hydrolysis, their chemical structure has a negligible effect. In addition, it should be noted that some compounds due to possible tautomerism (e.g., amide-imidic acid) may be represented in two different ways.

For the hydrolysis of the functional carboxylic acid derivatives of the general formula II or II ', a water-donating medium consisting wholly or partly of water or water-donating substances under hydrolysis conditions is used. The reaction may be carried out as a homogeneous reaction, in which case it is generally carried out in the presence of a polar organic solvent or solvent. Preferred solvents are, for example, lower alcohols, dioxane, acetone, small carboxylic acids, N-methylpyrrolidone, sulfolane or dimethyl sulfoxide. However, the hydrolysis can also be performed as a heterogeneous reaction. The pH of the water-donating medium depends on the chemical nature of the pyrazole-U-acetic acid derivative used, but also on the nature of the desired compound of general formula I, which may be neutral, acidic or basic. The pH is adjusted to the desired value with acids, bases or buffers.

The hydrolysis temperatures range from 0 ° C to the boiling point of the water-donating medium and are generally from 0 to 150 ° C, in particular from 20 to 120 ° C. In more detail, the hydrolysis temperatures also depend on whether working under pressure or without pressure. Reaction times are from 10 minutes to 20 hours, depending on the respective batches, reaction temperatures and other reaction parameters. After completion of the hydrolysis, the pyrazole-U-acetic acids are isolated according to customary methods, for example by recrystallization or acidification of their solutions, possibly by evaporation of these solutions. To purify them, their alkaline solution can be extracted as an organic solvent which is immiscible with the alkaline solution, for example, ether, benzene, chlorobenzene, chloroform or methylene chloride.

δ 57584

The conversion of pyrazole-U-acetic acids of the general formula I or I * to their salts can take place by direct alkaline hydrolysis of the pyrazole-U-acetic acid derivatives of the general formula II or II '.

As the alkaline reaction partner, the inorganic or organic bases whose salts are desired are used. However, salts are also obtained by reacting pyrazole-U-acetic acids of general formula I with a stoichiometrically equivalent amount of the corresponding base or by converting readily soluble salts into sparingly soluble salts by a double reaction or by converting optional salts into pharmacologically tolerable salts.

The pyrazole-H-acetic acid derivatives of the general formula II or II 'are obtained in principle by halogenation of the 2-pyrazolin-5-ones of the general formula III and IV, which are obtained by known or per se known methods, in the 5-position

Ph ^ Ph ^ 1 1 ^ t

AA

I N

ό ό

III IV

9,57584 using, for example, reactive halides of groups V and VI of the Periodic Table of the Elements, or reactive carboxylic acid halides, carboxylic acid imide halides or Vilsmeier reagents, and optionally by other process steps known per se.

In a preferred process variant, the compound of general formula III is converted with at least two molar equivalents of a Vilsmeier reagent prepared from dialkyl or alkylarylformamide and an acid halide in situ before or during the reaction into the corresponding 5-halo-4-pyrazolyl-methylene-dimethylammonium To 4-carboxaldehydes of general formula V.

Ph v CH-0

N-S

li

^ N

halogen

I V

O

Examples of dialkylformamides are dimethylformamide, diethylformamide, diisopropylformamide, N-formylpiperidine, N-formylpiperazine, Ν, Ν-diformylpiperazine or N-formylmorpholine. As the alkylarylformamide, for example, N-methyl-N-phenylformamide or N-ethyl-N-tolylformamide is used. Suitable acid halides are, for example, phosphorus oxytrichloride, phosphorus oxytribromide, phosgene and thionyl chloride. By this method, the reaction is conveniently carried out by controlling not only the formylation at the 4-position but also the halogenation of the pyrazole at the 4-position with excellent yield. Reaction temperatures are generally in the range of 10 to 100 ° C and reaction times of 15 minutes to 30 hours.

Another method is the exchange of halogen from compounds of the general formula V, for example the replacement of chlorine by bromine or fluorine with halides or hydrohalic acids, possibly at elevated temperature and in a pressure vessel.

With the exception of 5-chloro-1,3-diphenylpyrazole-4-carboxaldehyde, the compounds of general formula V are novel compounds.

The compound 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-carboxaldehyde forms a key intermediate because through it the compound 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid and its salts can be prepared and these final compounds have particularly valuable pharmacological properties.

10 57584

The obtained compounds of the general formula V are converted into the most known * per se from Belgian patent no. 733,924 by known methods via a series of intermediates to give pyrazole-4-acetic acid derivatives of general formula II. First, the carbonyl group is reduced under mild conditions to a hydroxymethyl group, converted to a halomethyl or trialkylammonium methyl group, and reacted with a cyanide to form nitriles of general formula II. The reduction can be carried out, for example, with sodium borohydride in anhydrous or aqueous solvents between 0 and 50 ° C. Halogenethyl compounds are obtained from hydroxymethyl compounds, for example, by reaction with sulfur or phosphorus halides or with carboxylic acid halides, such as phosgene *, but also by reaction with hydrohalic acids and their concentrated aqueous solutions, in which case any inert solvents can be used. The reaction of 4-halomethyl-5-halopyrazoles to nitriles of general formula II can be carried out in Belgian patent no. 755,925 according to the methods described for similar compounds * preferably in aprotic * dipolar solvent temperatures between 0-80 ° C.

Pyrazole-4-acetic acid esters * of general formula II are readily obtained from other reactive pyrazole-4-acetic acid derivatives of general formula II by known methods * e.g. acid halides * from acid anhydrides and nitriles by alcoholysis * further from pyrazole-4-acet is the general formula I by reaction with alcohols under water-separating conditions or by reacting acids and salts with alkylating agents *, for example, a benzyl ester from the reaction of alkali salts with benzyl halides.

Unsubstituted amides of general formula II can be prepared by hydrolysis of the corresponding nitriles. Aminolysis of reactive carboxylic acid derivatives such as acid halides or esters with ammonia * mono- and di-alkylamines * arylated * cyclic amines »such as piperidine, morpholine and pperazine * hydroxylamine or optionally substituted with H-alkylate-O-alkyl-hydroxylamine and optionally substituted amides * piperidides, morpholides, piperazides further hydroxamic acids * O-alkylamides and optionally H-alkyl- or aryl-substituted hydrazides of the general formula II.

Thioamides of general formula II can be prepared, for example, by reacting nitriles with hydrogen sulfide in the presence of bases or by sulfurizing amides * with, for example, phosphorus pentasulfide.

The nitriles of the general formula I are further attached to the alcohol as acid-catalyzed corresponding imidic acid esters * to arylamines basically 11,57584-catalyzed to the corresponding amidines, and to mercaptans or mercaptoacetic acid to the corresponding thioimidic acid esters.

For example, amidines can be prepared from amide acid esters of the general formula II with amines, oxazoline with amino alcohols and imidazolines with diamines,

The acid halides of the general formula II can be prepared in a known manner from the compounds of the formula I by means of halides of phosphoric or sulfuric acid and the ketenes from the acid halides by dehydrohalogenation with tertiary bases.

Experience has shown that in many cases no special purification measures were required for intermediates II or II 'and their precursors, but could be used in the next process step without a subsequent purification step.

Surprisingly, it was found that the compounds of the general formula I and their salts - with relatively low toxicity - had excellent anti-inflammatory as well as analgesic and antipyretic properties.

The anti-inflammatory effect could be demonstrated after both single and multiple use in acute and chronic inflammatory cases. Compared to the commercial drug phenylbutazone (i), the compounds prepared according to the invention, such as 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid (II) and 5-chloro-1,3-diphenyl- pyrazole-4-acetic acid (II) is clearly superior to the prior art compounds.

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In addition, in other pharmacological studies, the compounds according to the invention proved to be specific and superior to standard preparation I, as shown in Table 2 for the following compounds: 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-U-acetic acid (II), 5- chloro-η-1,3-diphenyl-pyrazole-U-acetic acid (lii) and 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-it-acetic acid (IV).

Table 2

Anti-inflammatory effect, acute toxicity and therapeutic quotient of halogen-pyrazole derivatives:

Q

Compound Inhibitory effect of carrageenan edema in LD mouse rats / ED J, 5 ° to 50 μ 25 / mg / kg / p.o.

/ mg / kg7 p.o. rel. effect I 10 1.0 635 63.5 II 1.5 6.7 530 353 III 1.0 10.0 1200 1200 IV 12 0.8 1100 91.7

The anti-inflammatory effect of the standard compound compared to the effects of the compounds according to the invention was studied for the inhibitory effect of the substances on the hind legs of carrageenan edema in rats / Winter et. Oh. Proc. Soc. exp. Biol. Med. 111 (1962) 5 * + * i7j wherein in each case of Table 2 doses were administered which, after administration of a single dose of 3 and 5 hours, give an average puffiness of 25 ~ #; for the prevention of ultraviolet redness in the back of the guinea pigs Winder et. Oh. Arch. int. Pharmacodyn. 116 (195Ö) 2Ö1, with the doses given in Table 1 5 hours after irradiation each reducing erythema by 25% in the case of chronic inflammation (water grain tumor), in which case Winter et. Oh. J. Pharmacol. exp. Therap. 1 h 1 (1963) 369, the effect of the compounds on bladder tissue formation once daily for 7 consecutive days after subcutaneous vesicle implantation in rats; Table 1 shows the doses that inhibit vesicle tissue formation by 20 μl (ED2Q).

Lethal doses were expressed in the usual manner. LD50 refers to doses at which, once or within 7 days, 50% (mouse) or 5% (rat) of animals died within 10 days.

* 57584

The compounds prepared according to the invention were compared with pyrazole-1 + acetic acid derivatives known from BE patent 755 92k. The results are shown in the following Tables 3 and 1+.

Table 3

Anti-inflammatory effect in an anti-granuloma test in rats.

Compound ED ^ q Therapeutic quotient Lethal dose 7 days, after oral administration mg / kg / day 57 20 keen mg / kg / day II '3.5 5.0 18 1' 8.0 12.5 100 A 0.7 1.6 1.1 B 25.0 1.0 25 C 20.0 1.0 20 D 80.0 1.3 100

Table 4

Analgesic effect as measured in an inflamed foot torsion test in rats

Compound Animal number Analgesic effect, Relative effect ED ™ mg / kg p.o. calculated with respect to N N = 1.0 1 '30 10.0 1.7 II' 90 7.1 2.1+ III '20, -10.0 r-1.7 IV 20 7.5 2.3 V 50 6.0 2.8 0 20 50.0 0.3 L 1 + 0 28.0 0.6 M 30 20.0 0.9 N 80 17.0 1.0 Q 1 + 0 00.0 * 0.3 is 57584

The Roman numerals in the tables refer to the following compounds prepared according to the invention: I ': 5-chloro-1,3-diphenylpyrazole-U-acetic acid II': 5-chloro-3-p-chlorophenyl-1-phenylpyrazole-U-acetic acid III ': 5-chloro-3-p-methoxyphenyl-1-phenylpyrazole-U-acetic acid IV: 5-chloro-3-p-isobutylphenyl-1-phenylpyrazole acetic acid V: 5-bromo-1,3-diphenylpyrazole-U-acetic acid By letters AD and The compounds shown in LQ are the most active reference compounds from BE Patent 755 92k.

Compounds AD (anti-inflammatory effect): - A: 1,3,5-triphenylpyrazole-N-acetic acid B: 1-phenyl-3,5-di- (2-furyl) -pyrazole-U-acetic acid C: 3,5- Diphenyl-1- (3-pyridyl) -pyrazole-U-acetic acid D: 1-Phenyl-3- (p-chlorophenyl) -pyrazole-U-acetic acid Compounds LQ (analgesic effect): L: 3.5 “d.phenyl -1- (p-Chlorophenyl) -pyrazole-U-acetic acid N: 1-phenyl-N-this-ip-chlorophenyl) -pyrazole-1 * -acetic acid N: 1-phenyl-3,5-bis- (m -methoxyphenyl) -pyrazole-U-acetic acid 0: 3,5-Diphenyl-1- (of, -trifluoro-m-tolyl) -pyrazole-U-acetic acid ethyl ester Q: 3,5-Dimethyl-1-phenylpyrazole-U -acetonitrile.

Tables 3 and show that the compounds according to the invention have a significantly better anti-inflammatory and analgesic effect than the reference compounds. The compounds according to the invention have a strong anti-inflammatory (antiproliferative) effect, for example, in the wadding granule test, as can be seen from Table 3. The lethal doses required to calculate the therapeutic quotient were determined in the usual manner. It can be seen from Table * + that the compounds according to the invention also have a clearly better analgesic effect than the compounds known from said BE patent used for comparison. The study of the analgesic effect was performed according to the method described by Hoffmeister et al., Arzneimittelforschung 2k_, 600 (197 * 0), in which the inflamed (AgNO 2) treatment of the rat's foot was twisted and the effect of the compounds on pain was monitored. better than the reference compounds.

57584 16

The compounds according to the invention are thus suitable for the treatment of various conditions in which inflammation, pain and fever occur.

The compounds of the invention may be formulated into pharmaceutical preparations containing one or more of the novel active ingredients.

The pharmaceutical preparations contain, in unit doses, from 1 to 1000 mg, particularly preferably from 5 to 500 mg or from -10 to 250 mg of active ingredient. Therapeutic use of these pharmaceutical preparations can take place 1 to 4 times a day, e.g. after meals and / or in the evening.

The following examples further illustrate the invention.

Example 1 5-Chloro-1,3-diphenyl-pyrazole-4-acetic acid 19.1 g of 5-chloro-1,3-diphenyl-pyrazole-U-acetonitrile are heated in 96 g of 63 # sulfuric acid for 1 hour at 115 °. C. Cool, precipitate the acid by diluting with 50 ml of water, wash with water and recrystallize from ethanol / water. An aqueous crystalline product is obtained which is dehydrated after dissolving in benzene and evaporating the solution. Yield: 91% yield of 5-chloro-1,3-diphenylpyrazole-4-acetic acid; mp. 151-152 ° C.

Example 2 5-Chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid 30 g of 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-k-acetonitrile and a mixture of 46 ml of concentrated sulfuric acid and 55 nil of water are heated with stirring at 100 ° C for 2.5 hours. It is then diluted with 700 ml of water, the precipitate is filtered off with suction and washed with water. The filter cakes are dissolved in dilute Na-OH solution, clarified with activated carbon and precipitated with acid-dilute hydrochloric acid. Yield $ 95 yields 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid; mp. 179-5 ° C (from methanol).

From the corresponding pyrazole-4-acetonitriles, 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetonitrile, 5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-4-acetonitrile, 5-bromo-1 3-Diphenyl-pyrazole-4-acetonitrile in a similar manner gives 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid (m.p. 166.5-167.5 ° C), 5-chloro- 3-p-isobutylphenyl-1-phenylpyrazole-4-acetic acid, (m.p. 110-110.5 ° C) and 5-bromo-1,3-diphenylpyrazole-4-acetic acid, (m.p. 187.5 -188.5 ° C).

17 57584

Example 3 5-Chloro-3-β-chloro-phenyl-1-phenyl-pyrazol-4-acetic acid 3.8 g of 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid ethyl ester, 13 ml of ethanol. and 1.0 g of sodium hydroxide in 13 ml of water is heated to boiling for 1 inch. At pH 10 it is stopped, the alcohol is distilled off in vacuo, the aqueous solution is shaken with ether and clarified with activated carbon. Acidification with dilute hydrochloric acid gives 5-yield of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid, m.p. 179 »5-181 ° C.

In a similar manner, 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid methyl ester is obtained from 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid n-butyl ester. , 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid-n-hexyl ether, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid benzyl ether, 5-Chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid phenyl ether, 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid-3-ethoxy-ethyl ester, 5- chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid-3-dimethylamino-ethyl ether, alkaline hydrolysis of 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-thioacetic acid ethyl ester -3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid (m.p. 179-5-181 ° C).

In a similar manner, 5-chloro-1,3-diphenyl-pyrazole-4-acetic acid ethyl ester, 5-chloro-3-p-methoxy-phenyl-1-phenyl-pyrazole-4-acetic acid methyl ether, 5-bromo-1,3-diphenyl-pyrazole From 4-acetic acid methyl ester by early hydrolysis, 5-chloro-1,3-diphenyl-pyrazole-4-acetic acid (m.p. 151-152 ° C), 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4- acetic acid (m.p. 166.5-167.5 °), 5-bromo-1,3-diphenylpyrazole-4-acetic acid (m.p. 187.5-188.5 ° C).

Example 4 5-Chloro-3 ', p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid 1.8 g of 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetonitrile, 10 ml of ethanol and 1.4 g of sodium hydroxide is heated to boiling for 4 hours until the evolution of ammonia ceases. The alcohol is distilled off in vacuo, extracted into ether, clarified with activated carbon and acidified with aqueous hydrochloric acid to pH 3. Yield 95-yield of 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid; mp. * 179 5-181 ° C.

Example 5 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazol-4-acetic acid 2.0 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide and 10 g of 63 Sulfuric acid is heated for 1.3 hours at 100 ° C * and then post-treated according to Example 2. 3-Chloro-3-β-chlorophenyl-1-phenyl-pyratole-4-acetic acid is obtained; 179.5 to 181 ° C.

In a similar manner, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid-n-butylamide, 3-chloro-3'-P-chlorophenyl-1-phenyl-pyrazol-4-acetic acid from diethylamide, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrateol-4-acetorpholidide, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetylpiperidide, 5-chloro-3-p- -chlorophenyl-1-phenyl-pyrazole-4-acetpyrrolidide, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetanilide, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4 -acetic acid N-methylanilide, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acethydroxamic acid, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamidoxime, 5 -Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acethydrate, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamidine hydrochloride by sulfuric acid hydrolysis 5 ** chloro-3'-P- chlorophenyl-1-phenyl-pyrazole-4-acetic acid (m.p. 179-5-181 ° C).

Example 6 5-Chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid 0.3 g of 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-thioacet-morpholide and 6 ml of 20 # hydrochloric acid is heated to boiling until the evolution of hydrogen sulphide ceases. 5-Chloro-3-p-chlorophenyl-1 ** phenyl-pyrazole-4-acetic acid m.p. 179 »5-181¾.

In a similar manner, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamic acid ethyl ester hydrochloride, 2 - [(5-chloro-3-p-chlorophenyl-1-phenyl-4-pyrazolyl) -methyl, is obtained. ] -oxazelin, 2 - [(5-chloro-3-p-chlorophenyl-1-phenyl-4-pyrazolyl) -methyl] -thiazoline, 1-methyl-2 - [(5-chloro-3- From p-chlorophenyl-1-phenyl-4-pyrazolylmethyl] -imidazoline by hydrochloric acid by hydrolysis of 5-chloro-3-p-chlorophenyl-1-1957584 phenylpyrazole-U-acetic acid (m.p. 1T9.5 ~ 131 ° C).

Example 7 5-Chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-14-acetic acid 3.5 g of 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-1-acetamide are dissolved in 15 ml of 90 % hydrochloric acid and is added dropwise with stirring at 20-30 ° C underground to a solution of 0.7 g of sodium nitrite in a little water. Heat gently until gas evolution ceases and pour into ice water. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-U-acetic acid is obtained; mp. 179> 5-181 ° C.

Example 8 Sodium salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-α-acetic acid

Dissolve 3.5 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-β-acetic acid in 10 ml of 1/10 N NaOH solution, evaporate the solution to dryness in vacuo and triturate the residue with ether. The sodium salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-U-acetic acid is obtained; mp. 275-279 ° C.

Example 9 Calcium salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-U-acetic acid

A solution of 3.5 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-1-acetic acid in an equivalent amount of dilute NaOH is heated dropwise to a solution of 1.6 g of calcium chloride hexahydrate in 12 ml of water. The precipitate is washed with dilute calcium chloride solution and ice-cold water. A calcium salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained in a quantitative amount; mp. 302-307 ° C (decomposes).

Example 10 Morpholine salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid

To a solution of 1.0 g of 5-chloro-3-p-chlorophenyl-1-phenylpyrazole-4-acetic acid in 1 + 5 ml of ether is added dropwise 0.25 g of morpholine. The morpholine salt of 5-chloro-3-p-chlorophenyl-1-phenylpyrazole-1 + -acetic acid is obtained in 87% yield; mp. L4K-lU5,5 ° C.

Example 11 5-Chloro-1,3-diphenyl-pyrazole-N-carboxaldehyde 92.7 g of dimethylformamide are added dropwise at 5-10 ° C to 97.3 g of phosphorus oxychloride and stirred for 30 minutes to complete the formation of the complex. 30 g of 1,3-diphenyl-2-pyrazolin-5-one are then added and the mixture is heated with stirring for 1 hour at 55 [deg.] C. and for 20 hours at 70 [deg.] C. Pour on 20 575 84 about 600 g of ice, adjust to pH 3-4 with concentrated NaOH solution, suction filter and wash with water. Yield: 5-chloro-1,3-diphenylpyrazole-β-carboxaldehyde in 93% yield; mp. 109-110 ° C (from petroleum ether).

Example 12 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-cart) oxaldehyde a) 270 g of dimethylformamide are added dropwise at 5-10 ° C over 90 minutes, 28 g of phosphorus oxychloride, stirred for 30 minutes at 15 ° C and then 100 g of 3-p-chlorophenyl-1-phenyl-2-pyrazol-5-one are added. Heat for 1.5 hours at 50 ° C and 21 hours at 70 ° C, pour into 2 kg of ice, adjust the pH to 3 - * + with 20 ml of NaOH solution and filter the precipitate. 99% yield gives 5-chloro-3-p-chlorophenyl-1-phenylpyrazole-1 + -carboxaldehyde, m.p. 169 »5 ~ 1T1 ° C (acetone).

In a similar manner, according to a), the corresponding 2-pyrazolin-5-ones are obtained: 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-1-carboxaldehyde (m.p. 108-110 ° C), η 5 -chloro-3- m-chlorophenyl-1-phenyl-pyrazole-1 + -carboxaldehyde, 5-chloro-1-phenyl-3-p-tolyl-pyrazole-U-carboxaldehyde, 5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole- 1 * -carboxaldehyde (m.p. 56.5-57 ° C), 5-chloro-3'-P-fluorophenyl-1-phenyl-pyrazole-U-carboxaldehyde, 3-p-bromophenyl-5'-chloro-1-phenyl-pyrazole-1 - carboxaldehyde.

b) The starting 3-p-chloro-phenyl-1-phenyl-2-pyrazolin-5-one is obtained as follows: 50.8 g of p-chlorobenzoylacetic acid ethyl ester (prepared, for example, from p-chloroacetophenone, carbonic acid diethyl ester and sodium hydride in 72% strength) catch), 29 g of phenylhydrazine, 5 ml of glacial acetic acid and 150 ml of ethanol are heated at reflux under nitrogen for 1 hour. After cooling in an ice bath, 3-p-chlorophenyl-1-phenyl-2-pyrazolin-5-one is obtained in a yield of 8%; mp. 160,5_161,5 ° C. In a similar manner, the following 2-pyrazolin-5-ones are obtained according to b): 3-p-methoxyphenyl-1-phenyl-2-pyrazolin-5-one (m.p. 137-138 ° C), 3-chlorophenyl-1-one phenyl-2-pyrazolin-5-one, 1-phenyl-3-p-tolyl-2-pyrazolin-5-one, 3-p-isobutylphenyl-1-phenyl-2-pyrazolin-5-one (m.p. 12 ^ , 5-125 ° C), 3-p-fluorophenyl-1-phenyl-2-pyrazolin-5-one, 3-p-bromophenyl-1-phenyl-2-pyrazolin-5-one.

21 575 8 4

Example 13 β-Bromo-1,3-diphenylpyrazole-U-carboxaldehyde

175 g of molten phosphorus oxytribromide are allowed to drop to 306 g of dimethylformamide at 10-16 ° C under stirring and cooling over a period of 75 minutes. To the crystal suspension of the Vilsmeier complex is added 29 g of 1,3-diphenyl-2-pyrazolin-5-one and then heated at 65-70 ° C for 20 hours. Pour into 850 g of ice, make up to pH J + -5 with 2N NaOH solution, suction filter and wash the precipitate well with water. Yield 85% of crude 5-bromo-1S-diphenylpyrazole-N-carboxaldehyde, which is purified using silica gel and chloroform solution; mp. 128 to 128.5 ° C.

In a similar manner, 5-bromo-3-p-chlorophenyl-1-phenyl-2-pyrazolin-5-one, 3-p-methoxyphenyl-1-phenyl-2-pyrazolin-5-one and Vilsmeier complex are obtained from phosphorus oxytribromide and dimethylformamide. p-chlorophenyl-1- "phenyl-pyrazole-1 + -carboxaldehyde (m.p. 178-179.5 ° C) and 5-bromo-3-p-methoxyphenyl-1-phenyl-pyrazolecarboxaldehyde.

Example lU

5-chloro-D-hydroxymethyl-1,3-diphenyl-pyrazole

To a solution of 21 g of 5-chloro-1,3-diphenylpyrazole-k-carboxaldehyde in 80 ml of dioxane is added dropwise at 23-27 ° C a solution of 1.11 g of sodium borohydride in 35 ml. in water. The resulting suspension is stirred for a further 30 minutes and, by adding 200 ml of water, 5-chloro-1 + -hydroxymethyl-1,3-diphenylpyrazole is precipitated in a yield of 99%; mp. 1UO, 5-1 ± + 1.5 ° C (from toluene).

Example 15 5-Chloro-3-p-chlorophenyl-U-hydroxymethyl-1-phenylpyrazole

To a suspension of 6 g of 5-chloro-3-p-chlorophenyl-1-phenylpyrazole-β-carboxaldehyde in 700 ml of dimethylformamide and 100 ml of water is added 2.8 g of sodium borohydride, which may increase the temperature to 35 ° C: C. After 30 minutes, clarify with activated carbon, precipitate with 100 ml of water and wash well. 95% yield yields 5-chloro-3-p-chlorophenyl-1-hydroxymethyl-1-phenylpyrazole; mp. 152.5 ~ 153.5 ° C (from acetone).

Similarly, from pyrazole-U-carboxaldehydes, 5-chloro-1-hydroxymethyl-3-p-methoxyphenyl-1-phenyl-pyrazole (m.p. 126-127 ° C), 5-chloro-U-hydroxymethyl-1-phenyl, is obtained -3-p-tolylpyrazole, β-chloro-3-m-chlorophenyl-1-hydroxymethyl-1-phenylpyrazole, 5-chloro-1 + hydroxymethyl-3-p-isobutylphenyl-1-phenylpyrazole (m.p. 1U0-1U0.5 ° C), 22 5 7 5 8 4 5-bromo-4-hydroxymethyl-1,3-diphenylpyrazole (m.p. 134-135 ° C), 5-bromo-3-P-chlorophenyl -4-hydroxymethyl-1-phenylpyrazole, 5-bromo-4-hydroxymethyl-3-p-methoxyphenyl-1-phenylpyrazole, 3-p-bromophenyl-5-chloro-4-hydroxymethyl-1-phenylpyrazole .

Example 16 5-Chloro-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyrazole To a suspension of 45S 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenyl-pyrazole 45 ml in benzene, 17 * 6 g of thionyl chloride are added dropwise, whereupon strong gas evolution and dissolution are observed. It is then heated to complete the reaction for 30 minutes and heated to boiling for 30 minutes. The solvent is distilled off in vacuo and this delivery is repeated by adding benzene. The residue is crystallized from petroleum ether to give 98.5% of 5-chloro-4-chloromethyl-3-p-chlorophenyl-1-phenylpyrazole} m.p. 96.5-97 ° C: "

In a similar manner, the following 4-chloromethylpyrazoles are obtained from the corresponding 4-hydroxymethylpyrazoles: 5-chloro-4-chloromethyl-1,3-diphenylpyrazole (m.p. 67.5-68.5 °). 4-chloromethyl-3-p-methoxyphenyl-1-phenylpyrazole (m.p. 129-129.5 ° C), 5-chloro-4-chloromethyl-1-phenyl-3-p-tolylpyrazole, 5-chloro -4-chloromethyl-3-m-chlorophenyl-1-phenylpyrazole, 5-chloro-4-chloromethyl-3-p-isobutyl-phenyl-1-phenyl-pyrazole (87-87.3 ° C), 5- bro-4-chloromethyl-1,3-diphenylpyrazole (m.p. 83.5-84 ° C), 5-bromo-4-chloromethyl-3-p-chlorophenyl-1-phenylpyrazole, 5-bromo-4 -chloromethyl-3-p-methoxyphenyl-1-phenylpyrazole, 3-p-bromophenyl-5-chloro-4-chloromethyl-1-phenylpyrazole.

4-Chloro-4-chloroethyl-3-β-chlorophenyl-1-phenyl-pyrazole To a mixture of 15 g of 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenyl- pyrazole and 25 ml of concentrated hydrochloric acid, hydrogen chloride gas and heated at reflux for 4 hours, then 25 ml of toluene are added, the layers are separated and the aqueous phase is shaken off with toluene. chloro-4-chloromethyl-3-p-chlorophenyl-1-phenylpyrazole} mp 96.5-97 ° C (from petroleum ether).

57584 23

Example 18 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile

To a mixture of 6.15 g of sodium cyanide in 150 ml of dimethyl sulfoxide is introduced, with stirring and gentle cooling at 25 ° C, 35 g of 5 'chloro-t-chloromethyl-3-p-chlorophenylpyrazole. Stirring is continued for another 2-5 hours at this temperature until the reaction is complete. 200 ml of water and 200 ml of trichlorethylene or benzene are added, the layers are separated, washed with an organic solvent, dried over sodium sulfate and the organic phase is clarified with clay silicate. Evaporation in vacuo gives a yield of $ 99 from the theoretical 5 'chloro-3-p-chlorophenyl-1-phenyl-pyrazole-t-acetonitrile; mp. 129.5-130.5 ° C - (from acetonitrile).

In a similar manner, the following pyrazole-U-acetonitriles are obtained from the corresponding U-chloromethylpyrazoles: 5-chloro-1,3-diphenyl-pyrazole-1-acetonitrile (m.p. 78.5-79.5 ° C), 5-chloro -3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetonitrile (m.p. 91.5-92.5 ° C), 5-chloro-1-phenyl-3-p-tolyl-pyrazole-U-acetonitrile, 5-chloro-m-chlorophenyl-1-phenyl-pyrazole-h-acetonitrile, 5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-1 + -acetonitrile (m.p. 98-96.5 ° C), 5-bromo-1,3-diphenyl-pyrazole-U-acetonitrile (m.p. 99-100.5 ° C), 5-bromo-3-p-chlorophenyl-1-phenyl-pyrazole-1 + -acetonitrile, 5-bromo -3-p-methoxyphenyl-1-phenyl-pyrazole-14-acetonitrile, 3-p-bromophenyl-5-chloro-1-phenyl-pyrazole-1H-acetonitrile.

Example 19 5-Chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-U-acetic acid ethyl ester 10 g of 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-U-acetonitrile, 100 ml of ethanol, 1.5 ml of water and 15 ml of concentrated sulfuric acid are heated to reflux for 16 hours. Pour onto ice, make alkaline with sodium bicarbonate solution, shake with ether and evaporate. After recrystallization from ethanol and water, 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-t-acetic acid ethyl ester is obtained in 69% yield; mp 51.5-52.5 ° C (from ether / petroleum ether) .

In a similar manner, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-h-acetic acid methyl ester (m.p. 66-67.5 ° C), 5-chloro-3-p-chlorophenyl-1-phenyl, can be prepared with the corresponding alcohols. -pyrazole-h-acetic acid-n-butyl ester (b.p. 0.0001 210-215 ° C), 24,57584 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid-n-hexyl ester. Example 20 5-Chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid ethyl ester 6.9 g of 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid, 70 ml of ethanol and 4 g of concentrated sulfuric acid are heated at reflux for 8 hours. Evaporate) pour into ice water, extract with ether) wash with sodium carbonate solution, dry the organic solution and evaporate. 85% of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid ethyl ester is obtained} m.p. 51.5 to 52.5 ° C.

Example 21 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide 5 g of 5-chloro-3-β-chlorophenyl-1-phenylpyrazole-4-acetonitrile __ and 10 ml of $ 96 sulfuric acid are mixed at room temperature for 4 hours.

The mixture is poured into 50 g of ice *, the precipitate is filtered off with suction and washed with water. Yield 99-tn of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide; mp. 192-193 ° C.

Example 22 5-Chloro-3-β-chlorophenyl-1-phenyl-pyrazole-4-acetyl (a) 1.1 g of 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid, 15 g. ml of benzene and 0.5 g of phosphorus oxychloride are heated at reflux for 2 hours to give 5-chloro-3-p-chlorophenyl-1-phenylpyrazole-4-acetyl chloride.

b) 0.31 ml of aniline are added dropwise to the benzene solution of the acid chloride and stirred at room temperature for 1 hour. Filter and recrystallize. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetanilide is obtained, m.p. 201-202 ° C.

In a similar manner, 5-chloro-3'-p-chloro-5-chloro-3-p-chloro-phenyl-1-phenylpyrazole-4-acetyl chloride and ammonia, morpholine, piperidine, ethylamine, 2-aminoethanol and phenylhydrazine are obtained. -phenyl-1-phenyl-pyrateole-4-acetamide m.p. 192-105 ° C. 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetmorpholide diff. 182-183 ° C, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetpiperidide, 5-chloro-3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid-ethylamide, 5- chloro-3-p-chlorophenyl-1-phenyl-pyrateole-4-acetic acid (2-hydroxyethyl) -amide, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid-2, - phenyl-hydrazide.

25 5 75 8 4

Example 23 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-N-thioacetmorpholide 1.5 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-U-acetmorpholide, 8 ml of pyridine and 0 .8 g of phosphorus pentasulfide are refluxed for 5 hours. 30 g of ice are then added to the solution and the precipitate is filtered off with suction. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-U-thioacetmorpholide is obtained; mp. 20 DEG-205.5 DEG C. (dimethylformamide).

Example 2b 5-Chloro-3-β-chlorophenyl-1-phenyl-pyrazole-U-acetamidoxime

To a solution of 1.0 g of 5-chloro-3-p-chlorophenyl-1-phenylpyrazole-β-acetonitrile in 75 ml of ethanol is added to a solution of 1.0 g of hydroxylamine hydrochloride in 6.05 ml. 1 N sodium bicarbonate solution, and reflux for 11 hours. Evaporate to dryness and recrystallize from methanol / water. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-1-acetamidoxime is obtained 86 g; mp. 18U-186 ° C (from toluene).

Claims (2)

26 5 7 5 8 4 Patent claim *: A process for the preparation of therapeutically useful 5-chloro or 5'-bromo-1,3-diphenyl-pyrazole-U-acetic acid derivatives of the general formula I Ph CELCOOH v-r 2 N JL '' vN halogen ^ ό wherein Ph represents phenyl, halophenyl, p-alkoxyphenyl having 1-U carbon atoms in the alkoxy moiety, or p-alkylphenyl having 1-k carbon atoms in the alkyl moiety, and halogen means chlorine or bromine atom, or salts thereof with orgasmic or inorganic bases, characterized in that the compound of general formula II phwB NI ^ N ^^ halogen II ό wherein Ph and halogen have the same meaning as above, and B represents a hydrolyzable acetic acid functional derivative is hydrolyzed , and the compound of general formula I obtained is optionally converted into a salt, or, if desired, the compound of general formula I obtained in the form of a salt is converted into the free acid.