CA1077049A - Pyrazole derivatives and their manufacture and use - Google Patents
Pyrazole derivatives and their manufacture and useInfo
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- CA1077049A CA1077049A CA271,158A CA271158A CA1077049A CA 1077049 A CA1077049 A CA 1077049A CA 271158 A CA271158 A CA 271158A CA 1077049 A CA1077049 A CA 1077049A
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Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides a pyrazole derivative of the general formula I
(I)
The present invention provides a pyrazole derivative of the general formula I
(I)
Description
107'70~9 The present invention relates to pyrazolederivatives and with their manufacture and use.
The present invention provides pyrazole derivatives of the general formula I
C112 ) nX
R2 - N ~ (I) ~ ~3 in which 4 _ represents 1, 2, 3 or 4, Rl, R2, R3 and R4 each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a trifluoro-methyl group, a nitro group or an amino group, the atom or group represented by each of the symbols Rl, R2, R3 and R4 being in the ortho-, meta- or para-position, and X r~presents a cyano group, an aminocarbonyl group, a ~.
lower alkoxycarbonyl group or a carboxyl group, ~
and physiologically tolerable salts of such compounds in which ~.
X represents a carboxyl group.
As a lower alkoxycarbonyl group there is to be under-stood preferably such a group in which the alkoxy part contains 1 to 6 carbon atoms, (for example a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert.-butoxy yroup~ a pentyloxy group or a hexyloxy group). t As physiologically tolerable salts there are to be understood, for example, alkali metal salts or alkaline earth metal salts, for example sodium salts, lithium salts, calcium salts or magnesium salts, copper salts or amine salts, for - 1 - @
.. , . _ _ . . . . . .
~ , . :
107'7049 example M-methylglucamine salts, N,N-dimethylglucamin~ salts, ethanolamine salts, diethanolamine salts or morpholine salts.
As an alkyl group represented by each of the symbols R1, R2, R3 and R4 there is to be understood preferably a group containin~ 1 to 4 carbon atoms, for example an ethyl group, a propyl group, an isopropyl qroup, a butyl group, a tert.-butyl group or especially a methyl group.
As an alkoxy group represented by each of the symbols Rl, R2, R3 and R4 there is to be understood preferably a group containing 1 to 4 carbon atoms. Examples of suitable alkoxy groups are ethoxy, propoxy, butoxy or especially methoxy groups.
As a halogen atom represented by each of the symbols Rl, R2, R3 and R4 there is to be understood especially a fluorine atom or a chlorine atom.
The present invention also provides a process for the manufacture of the new pyrazole derivatives and the aforesaid new physiologically tolerable salts, wherein ~ ;
(a) a pyrazole derivative of the general formula II
The present invention provides pyrazole derivatives of the general formula I
C112 ) nX
R2 - N ~ (I) ~ ~3 in which 4 _ represents 1, 2, 3 or 4, Rl, R2, R3 and R4 each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a trifluoro-methyl group, a nitro group or an amino group, the atom or group represented by each of the symbols Rl, R2, R3 and R4 being in the ortho-, meta- or para-position, and X r~presents a cyano group, an aminocarbonyl group, a ~.
lower alkoxycarbonyl group or a carboxyl group, ~
and physiologically tolerable salts of such compounds in which ~.
X represents a carboxyl group.
As a lower alkoxycarbonyl group there is to be under-stood preferably such a group in which the alkoxy part contains 1 to 6 carbon atoms, (for example a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert.-butoxy yroup~ a pentyloxy group or a hexyloxy group). t As physiologically tolerable salts there are to be understood, for example, alkali metal salts or alkaline earth metal salts, for example sodium salts, lithium salts, calcium salts or magnesium salts, copper salts or amine salts, for - 1 - @
.. , . _ _ . . . . . .
~ , . :
107'7049 example M-methylglucamine salts, N,N-dimethylglucamin~ salts, ethanolamine salts, diethanolamine salts or morpholine salts.
As an alkyl group represented by each of the symbols R1, R2, R3 and R4 there is to be understood preferably a group containin~ 1 to 4 carbon atoms, for example an ethyl group, a propyl group, an isopropyl qroup, a butyl group, a tert.-butyl group or especially a methyl group.
As an alkoxy group represented by each of the symbols Rl, R2, R3 and R4 there is to be understood preferably a group containing 1 to 4 carbon atoms. Examples of suitable alkoxy groups are ethoxy, propoxy, butoxy or especially methoxy groups.
As a halogen atom represented by each of the symbols Rl, R2, R3 and R4 there is to be understood especially a fluorine atom or a chlorine atom.
The present invention also provides a process for the manufacture of the new pyrazole derivatives and the aforesaid new physiologically tolerable salts, wherein ~ ;
(a) a pyrazole derivative of the general formula II
2 b ~ - (C~12)nY ~II), ~ R3 L
4 \-~in which _, Rl, R2, R3 and R4 have the meanings given above and Y represents a halogen atom, is reacted with an alkali metal cyanide and, if desired, the resulting compound of the general formula I, in which X represents a cyano group, is hydrolysed to form acompound of the general formula I, in which X represents an amino-carbonyl or a carboxyl group, and/or any nitro group present is reduced to form an amino group and/or any resulting carboxylic acid is converted into a physiologically tolerable 1()770~9 salt thereof or esterified to form a lower alkyl ester thereof, or 3 (b) a pyrazole derivative of the aeneral formula III
( C ~ 2 ) n - l Y ( I I I ) ~--R3 L
in which n, R2, R3, R4 and Y have the meanings given above, is reacted in the presence of a deprotonizing agent with a malonic acid dialkyl ester or a cyanoacetic acid alkyl ester and the resulting reaction product is hydrolysed and decarboxylated to form a compound of the general formula I, in which X represents a carboxyl group or a cyano group (depending on whether a malonic acid dialkyl ester or a cyanoacetic acid alkyl ester, respectively, is used as starting material), and, if desired, any nitro `' group present is reduced to form an amino group and/or any resulting carboxylic acid is converted into a physiologically tolerable salt thereof or esterified to form a lower alkyl ester thereof, or (c) a pyrazole derivative of the general formula II ,~
( CH 2 ) nY L
~ (II), in which n, Rl, R2, R3, R4 and Y have the meanings given above, 30 iS reacted, if appropriate in the presence of an ether, with magnesium or lithium and the resulting organo-metal compound is treated with carbon dioxide and, if desired, any nitro group 1(~7704~
present is reduced to form an amino group and/or the ~esulting carboxylic acid is converted into a physiologically tolerable salt thereof, a corresponding amide or nitrile or a lower alkyl ester thereof, or (d) a pyrazole derivative of the general formula IV
(CH2)n-1CCl L
~ R3 (IV), in which n, ~1~ R2~ R3 and R4 have the meanings given above, is reacted with diazomethane and the resulting diazoketone is rearranged in the presence of water, ammonia or a lower alcohol to form a compound of the general formula I, in which X represents a carboxyl, aminocarbonyl or lower alkoxycarbonyl group, respectively, and, if desired, any nitro group present is reduced to form an amino group and/or any ester group present is hydrolysed to form a carboxyl group or any aminocarbonyl group present is dehydrated to form a cya~o group and/or any resulting carboxylic acid is converted into a physiologically tolerable salt thereof. ~' Variant (a) of the process according to the present invention may be carried out under the conditions usually employed to replace halogen atoms by a cyano group.
For this variant of the process, there are preferably used as the starting compounds of the general formula II those that carry a chlorine, bromine or iodine atom (~epresented by the symbol Y).
This reaction is prefexably carried out in a dipolar, aprotic solvent (for example dimethylformamide, N-methylacet-amide, N-methylpyrrolidone, acetonitrile, dimethyl sulphoxide 1~77~)49 or hexamethylphosphoric acid triamide). Sodium cyanide or potassium cyanide is preferably used as the alkali metal cyanide for this reaction.
In this reaction, the rate of reaction can be acceler-ated significantly by carrying out the reaction in the presence of a coronene ether.
Variant (b) of the process according to the present invention may be carriedout in a manner known per se, by reacting the cyanoacetic acid esters (for example cyanoacetic acid methyl ester or cyanoacetic acid ethyl ester) or the malonic acid dialkyl esters (for example malonic acid dimethyl ester or malonic acid diethyl ester), in an inert solvent, with a deprotonizing agent and then with a pyrazole derivative of the general formula III (preferably a chloride, bromide or iodide).
Suitable inert solvents for this reaction are, for example, hydrocarbons (for example benzene, xylene or toluene) or ethers (for example dioxan, tetrahydrofuran or glycol dimethyl ether). The deprotonizing agents used for this reaction are alkali metal alcoholates (for example sodium methylate or potas,sium te,rt,-butylate), alkali metal hydrides (for example j~;
sodium hydride or potassium hydride), alkali metal amides (for example sodium amide or potassium amide) or thallium-alkyl compounds (for example thallium ethylate).
After the reaction has been carried out, the esters formed are hydrolysed in a manner known per se (for example by reaction with bases, for example sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate or potassium bicarbonate, in the presence of water) and are decarboxylated by heating.
The decarboxylation can be carried out in the absence of solvents or in the presence of a high-boiling solvent (for example xylene, chlorobenzene or decalin).
Variant (c) of the process according to the present ~077049 invention may be carried out in a manner known ~r se, for example by reacting the compounds of the general formula II
(preferably the chlorides, bromides and iodides) with magnesium or lithium in a suitable solvent (for example diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran or, where appropriate, benzene) and treating the organo-metallic compounds so prepared with solid carbon dioxide.
Variant (d) of the process according to the present invention may be carried out under the conditions that are usually employed in Arndt-Eistert syntheses. Thus, the compounds of the general formula IV (manufactured by reacting the corresponding carboxylic acids with a chlorinating agent, for example thionyl chloride, phosphorus oxychloride or phosphorus pentachloride) can be reacted with a solution of diazomethane in ether, and the resulting diazoketones can be reacted in water, a lower alcohol or an ammonia solution, in the presence of colloidal copper, silver, silver oxide or silver ~:
nitrate, to give the acids, acid esters or acid amides of the general formula I. ~' The optional subsequent hydrolysis of cyano compounds r;
of the general formula I may also be carried out under conditions that are well known to those skilled in the art. Thus, for ~;
example, the nitriles can be hydrolysed, for example with strong mineral acids (for example hydrogen chloride or sulphuric acid), either partially to the corresponding amides or, under more severe conditions, completely, to the corresponding carboxylic acids.
The optional subsequent conversion of the carboxylic acids to the corresponding amides or nitriles may also be carried out with the aid of well-known methods of working.
Thus, for example, it is possible to convert the acid chlorides, mixed anhydrides or esters, corresponding 1C~77~)49 to the carboxylic acids, into the corresponding a~ides ~y treatment with ammonia under the known conditions.
The optional measure of subsequent conversion to nitriles may be carried out, for example, by treating the corresponding aminocarbonyl compounds, under the known conditions, with dehydrating agents, for example dicyclohexyl-carbodiimide, carbonyldiimidazole, polyphosphoric acid, thionyl chloride or phosphorus oxychloride.
The optional subsequent esterification of the free acids may also be carried out in accordance with methods of working known per se. Thus, for example, the acids can be reacted with diazomethane or diazoethane, and the corresponding methyl esters or ethyl esters are obtained. A generally applic-able method is to react the acids with the alcohols in the presence of carbonyldiimidazole or dicyclohexylcarbodiimide.
Further it is possible, for example, to react the acids with alkyl halides in the presence of copper-(I) oxide or silver oxide.
A further method is to convert the free acids into the ~r~
corresponding alkyl esters of the acids by means of the corres-ponding dimethylformamide alkyl-acetals. Furthermore, the acids can be reacted with the alcohols or the lower alkanecarboxy- sP
lic acid esters of the alcohols in the presence of strongly acidic catalysts, for example hydrogen chloride, sulphuric acid, perchloric acid, trifluoromethylsulphonic acid or p-toluene-sulphonic acid.
~ owever, it is also possible to convert the carboxylic acids into the acid chlorides or mixed acid anhydrides and to react these with the alcohols in the presence of basic catalysts, for example pyridine, collidine, lutidine or 4-dimethylamino-pyridine.
~077~)49 The salts of the carboxylic acids are produced, for example, by saponifying the esters by means of basic catalysts, or by neutralizing the acids with bases capable of forming physiologically tolerable salts.
Using the process of the present invention it is possible, for example, to manufac~ure the following pyrazole derivatives of the general formula I and salts thereof namely L(1,4-diphenyl-3-pyrazolyl)-acetic acid, 3-(1,4-diphenyl-3-pyrazolyl)-propionic acid, 4-(1,4-diphenyl-3-pyrazolyl)-butyric acid and 5-(1,4-diphenyl-3-pyrazolyl)-valeric acid and their r amides, nitriles, sodium salts, methyl esters, ethyl esters, propyl esters and butyl esters. ~ -The new pyrazole derivative of the general formula I
and the aforesaid physiologically tolerable salts are pharmaco-loqically active substances which are distinguished more especially by the fact that they possess a pronounced anti- t inflammatory activity, are well tolerated by the stomach and have only a relatively low toxicity. In addition, these compounds are frequently distinguished by the fact that their action commences rapidly and is of high intensity and of long duration;
they also have a favourable resorbability, and a relatively good stability in galenical formulations.
The pyrazole derivatives of the general formula I and the aforesaid salts are metabolized in the body in a different way from known anti-inflammatory compounds.
The new compounds are suitable, in combination with the carrier materials customarily used in, for example, galenical pharmacy, for the treatment of, for example, the following conditions a) local treatment: contact dermatitis, eczemas of a very wide variety of types, neurodermitis, erythrodermia, first-degree burns, pruritus vulvae et ani, rosacea, erythematodes - 8 - ..
1C~77049 cutaneus, psoriasis and lichen ruber planus et Verruco~us;
b) oral treatments acute and chronic polyarthritis, neurodermitis, bronchial asthma and hay fever.
The present invention accordingly further provides a pharmaceutical preparation which comprises a compound of the general formula I or a physiologically tolerable salt of such acompound in which X represents a carboxyl group, in admixture or conjunction with a pharmaceutically suitable carrier.
The pharmaceutical preparations may be prepared in the usual manner by converting the active substances, with suitable additives, excipients and flavour correctants, into the desired forms for administration, for example tablets, dra~ées, capsules, solutions, powders, salves, aerosols and inhalant preparations.
For oral use, tablets, dragées and capsules are especially suitable, which contain, for example, 1 - 250 mg of active substance and 50 mg - 2 g of a pharmacologically inactive excipient, for example lactose, amylose, talc, gelatine or magnesium stearate, as well as the customary additives. -Powders, salves, aerosols and similar preparations, which preferably contain 0.01 to 2~ by weight of the active substance, are suitable for topical application.
The starting compounds of the general formulae II and III, which have not previously been known, can be prepared from the corresponding carboxylic acid esters by, for example, reducing these with lithium aluminium hydride to form the corresponding carbinols and replacing the hydroxyl group of the latter by a halogen atom, as is described below, by way of example, for the synthesis of 3-bromomethyl-1,4-diphenyl-pyrazole;
a) 3 g of triethylamine and a solution of 6~78 g of (2-chloro-2-phenylhydrazono)-acetic acid ethyl ester in 20 ml of dry, ethanol-free chloroform were added successively, at room temperature, to 5.67 g of ~,morpholinostyrene in 35 ml of dry ethanol-free chloroform. The reaction mixture was stirred for one hour at 40C and 16 hours at room temperature and was washed with dilute hydrochloric acid, a dilute sodium carbonate solution and water, dried and concentrated ln _cuo.
The residue was digested with hexane and recrystallized from ethanol-hexane, and 7.3 g of 4-morpholino-3-phenyl-2-phenylhydrazono-3-butenoic acid ethyl ester melting at 130 -131C were obtained.
b) 33 g of 4-morpholino-3-phenyl-2-phenylhydrazono-3-butenoic acid ethyl ester were mixed with 330 ml of dioxan and 100 ml of 2N hydrochloric acid and the mixture was heated for 4S minutes under reflux. The reaction mixture was then concentra-ted ln vacuo, the residue was dissolved in chloroform, and the chloroform solution was washed, dried and concentrated ln vacuo.
The residue was recrystallized from ethanol-hexane and 21.15 g of 1,4-diphenyl-pyrazole-3-carboxylic acid ethyl ester melting at 103 - 104C were obtained.
c) A solution of 17.2 g of 1,4-diphenyl-pyrazole-3-carboxylic acid ethyl ester in 80 ml of absolute tetrahydrofuran was added ~.
dropwise, at 0C, to 4.63 g of lithium aluminium hydride in 100 ml of absolute tetrahydrofuran, under nitrogen. , The reaction mixture was stirred for a further 30 minutes, 40 ml of a saturated aqueous sodium chloride solution were added, and the batch was acidified with dilute hydrochloric acid and extracted with ether. The organic phase was concentrated, !
the residue was digested with hexane and 14.65 g of 3-hydroxy-methyl-1,4-diphenyl-pyrazole crude product melting at 104-105C
were obtained.
d) 130 ml of 63~ strength hydrobromic acid were added to 13.2 g of 3-hydroxymethyl-1,4-diphenyl-pyrazole crude product and the r mixture was heated at 90C for 4 hours.
The reaction mixture was then concentrated ln vacuo the excess hydrogen bromide was removed by repeatedly taking up the residue in toluene and concentrated _n vacuo.
The residue was recrystallized from isopropanol and 10.8 g of 3-bromomethyl-1,4-dipheny~pyrazole melting at 99C
were obtained.
The following Examples illustrate the invention:- ;
Example 1 a) 2.81 q of 3-bromomethyl-1,4-diphenylpyrazole in 30 ml of absolute acetonitrile were stirred with 1.17 y of potassium cyanide and 300 mg of dibenzo-18-coronene-6 for 10 hours at 40C.
The reaction mixture was then concentrated in vacuo, mixed with water and extracted with methylene chloride, and the organic phase was washed, dried and concentrated in vacuo.
2.6 g of (1,4-diphenyl-3-pyrazolyl)-acetonitrile were thus obtained as a crude product.
b) 2.6 g of (1,4-diphenyl-3-pyrazolyl)-acetonitrile crude product were stirred with-20 ml of concentrated hydro-chloric acid for one hour at a reaction temperature of 50C. h The reaction mixture was then diluted with water and extracted with methyl isobutyl ketone, the organic phase was washed and - concentrated ln vacuo, and 2.3 g of (1,4-diphenyl-3-pyrazolyl)- ~;
acetamide were obtained as a crude product.
c) 2.3 g of (1,4-diphenyl-3-pyrazolyl)-acetamide crude product and 40 ml of a 10~ strength aqueous sodium hydroxide solution were heated under reflux for 30 minutes, under argon.
The reaction mixture was then cooled in an ice bath, acidified with 2N hydrochloric acid and extracted with methylene chloride, r-and the methylene chloride phase was washed, dried and concentra-ted ln vacuo.
The resulting crude product was recrystallized from toluene and 1.25 g of (l,4-diphenyl-3-pyrazolyl)-acetic acid 10~7049 melting at 131 - 133C were obtained. ~ ;
Example 2 a) A mixture of 2 6 g of (1~4-diphenyl-3-pyrazolyl)-acetonitrile crude product [prepared as described in Example l(a)]
and 15 ml of 80% strength sulphuric acid was heated to 120C
and stirred for 2 hours at this temperature. The reaction mixture was then poured into ice water and extracted with methylene chloride, and the methylene chloride phase was washed, dried and concentrated 1n vacuo.
The residue was dissolved in a 5% strength aqueous sodium carbonate solution and the product was precipitated with 10~ strength hydrochloric acid, filtered off, washed and dried _ vacuo at 60C. It was then recrystallized from toluene and 1.6 g of (1,4-diphenyl-3-pyrazolyl)-acetic acid melting at 131 -133C were obtained.
b) 200 mg of ~1,4-diphenyl-3-pyrazolyl)-acetic acid were dissolved in 10 ml of absolute ethanol, 7.6 ml of a O.lN aqueous sodium hydroxide solution were added to the ethanol solution, and the ~;
mixture was concentrated in vacuo. ~' The residue was again taken up in 10 ml of absolute ~!
ethanol and again concentrated ln vacuo.
The resulting crude product was dissolved in a small amount of absolute ethanol, absolute diethyl ether was added to the solution and sodium (1,4-diphenyl-3-pyrazolyl)-acetate was obtained as an amorphous powder. F
Example 3 a) 3.84 g of malonic acid diethyl ester and 4.7 g of 3-bromomethyl-l~4-diphenyl-pyrazole were added successively to a solution of 5.6 g of thallium ethylate in 120 ml of absolute benzene, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was then diluted with diethyl ether and 100 ml of ice water were added. The organic phase was 1~77049 separated off, washed, dried and concentrated in _acuo. 5.3 g of 2-(1,4-diphenyl-3-pyrazolyl.methyl)-malonic acid diethyl ester were thus obtained as a crude product.
b) To 6 9 g of the resulting 2-(1,4-diphenyl-3-pyrazolyl-methyl)-malonic acid diethyl ester crude product were added 2.7 g of sodium hydroxide -dissolved in 30 ml of water - and 30 ml of dioxane, and the mixture was heated for 3 hours under reflux.
The reaction mixture was then substantially evaporated ln vacuo, the residue was diluted with 100 ml of water, the mixture was extracted with diethyl ether, the aqueous phase was acidified to a pH-value of 1 with concentrated hydrochloric acid andthe oily crude product which had separated out was isolated~ -The resulting crude product was dissolved in diethyl ether and the solution was washed with water, dried and concentrated in vacuo.
4.25 g of 2-(1,4-diphenyl-3-pyrazolyl-methyl)-malonic acid melting at 172C were thus obtained.
c) 4.1 g of 2-(1,4-diphenyl-3-pyrazolyl-methyl)-malonic acid were slowly heated to 200C. The reaction temperature was maintained at 200C for a further 20 minutes, it was then allowed to cool, the resulting product was crystallized from toluene and 2.9 g of 3-(1,4-diphenyl-3-pyrazolyl)-propionic acid melting at 128 - 129C were obtained.
d) 200 mg of 3-(1,4-diphenyl-3-pyrazolyl)-propionic acid were converted into amorphous sodium 3-(1,4-diphenyl-3-pyrazolyl)-propionate under the conditions described in Example 2(bJ.
Example 4 a) 10 ml of thlonyl chloride, which had been distilled over linseed oil, were added to 2.7 g of 3-(1,4-diphenyl-3-pyrazolyl)-propionic acid andthe mixture was heated for two hours under reflux. The reaction mixture was then concentrated 1~77~49 in vacuo, 25 ml of absolute benzene were added to the residue, the mixture was again concentrated ln _cuo and 2.6 g of 3-(1,4- !
diphenyl-3-pyrazolyl) propionyl chloride were obtained as a crude product.
b) 5 ml of absolute benzene and 5 ml of absolute ethanol were added to 50 mg of 3-(1,4 diphenyl-3-pyrazolyl)-propionyl chloride crude product. 0 2 ml of pyridine was added dropwise to the mixture which was then allowed to stand for 16 hours at room temperature, and diluted with 20 ml of benzene; the reaction mixture was then washed with water, dilute hydrochloric acid and water, dried and concentrated ln vacuo. The residue was recrystallized from acetone-hexane and 38 mg of 3-(1,4-diphenyl-3-pyrazolyl)-propionic acid ethyl ester melting at 95.5 - 98.5C were obtained.
Example 5 a) A solution of diazomethane in ether, prepared from 3.5 g of nitrosomethylurea, 50 ml of anhydrous ether and 11 ml of a 50~ strength aqueous potassium hydroxide solution, was added to ~;1.9 g of 3-(1,4-diphenyl-3-pyrazolyl)-propionyl chloride crude product in 20 ml of absolute ether and the mixture was allowd to stand for 4 hours at room temperature.
The reaction mixture was then concentrated in vacuo, 40 ml of ethanol were added, the mixture was heated to 60C, .
0.2 g of freshly prepared silver oxide was added and the batch was heated until the evolution of nitrogen had ceased.
The reaction mixture was then clarified with active charcoal, filtered and concentrated ln vacuo, and 1.7 g of 4-(1,4-diphenyl-3-pyrazolyl)-butyric acid ethyl ester were r obtained as a crude product.
b) 1.7 g of 4-(1,4-diphenyl-3-pyrazolyl)-butyric acid ethyl ester were dissolved in 20 ml of ethanol, 5 ml of a 10% strength sodium hydroxide solution were added and the mixture was heated ~,.
107704~
for two hours under reflux. The ethanol was then removed ln vacuo, the residue was diluted with 10 ml of water and acidified with hydrochloric acid to a pH-value of 1, and the product which had separated out was filtered off.
The resulting crude product was washed with water, dried ln _cuo at 60C and recrystallized from toluene, and 1.05 g of 4-(1,4-diphenyl-3-pyrazolyl)-butyric acid melting at 107 -109C were obtained.
Example 6 a) A solution of 15.2 g of sodium nitrite in 40 ml of water was added dropwise to a solution, at 0C, of 21.4 g of _-toluidine and 400 ml of 7.5~ strength hydrochloric acid. The p-toluene-diazonium chloride suspension so obtained was added dropwise to a mixture, at 5C, of 36.2 g of 2-chloroacetoacetic acid ethyl ester, 400 ml of 50~ strength ethanol and 164 g of sodium acetate. The mixture was then stirred for 3 hours at 20C and was extracted with ethyl acetate, the organic phase was concentra-ted, the residue was treated with petroleum ether, and 41 g of 2-chloro-2-(4-methylphenylhydrazono~acetic acid ethyl ester melting at 100 - 101C were obtained.
b) A solution of 24.7 g of 2-chloro-2-(4-methylphenyl-hydrazono)-acetic acid ethyl ester in 100 ml of chloroform was added dropwise to a solution of 18.9 g of ~-morpholinostyrene in 100 ml of chloroform and 13.8 g of triethylamine. The reaction 5 mixture was allowed to stand for one hour at 50C and 16 hours F !
at 20C and was washed with 2N hydrochloric acid and then with a saturated sodium bicarbonate solution. The chloroform solution was then concentrated ln vacuo, the residue was treated with petroleum ether, and 27.6 g of 2-(4-methylphenylhydrazono)-3-morpholino-methylene-3-phenylpropionic acid ethyl ester melting t at 131 - 132C were obtained, c) 260 ml of dioxareand 80 ml of 2N hydrochloric acid 1~77049 were added to 27.6 g of 2.(4-methylphenylhydrazono)-3~morpholino-methylene.3-phenylpropionic acid ethyl ester and the mixture was heated for 45 minutes under reflux. The reaction mixture was allowed to cool and was concentrated ln vacuo, and the residu~ was taken up in chloroform. The chloroform phase was washed with water and concentrated in vacuo, the residue was treated with petroleum ether, and 17.1 g of 4-phenyl-1-(4-tolyl)-
4 \-~in which _, Rl, R2, R3 and R4 have the meanings given above and Y represents a halogen atom, is reacted with an alkali metal cyanide and, if desired, the resulting compound of the general formula I, in which X represents a cyano group, is hydrolysed to form acompound of the general formula I, in which X represents an amino-carbonyl or a carboxyl group, and/or any nitro group present is reduced to form an amino group and/or any resulting carboxylic acid is converted into a physiologically tolerable 1()770~9 salt thereof or esterified to form a lower alkyl ester thereof, or 3 (b) a pyrazole derivative of the aeneral formula III
( C ~ 2 ) n - l Y ( I I I ) ~--R3 L
in which n, R2, R3, R4 and Y have the meanings given above, is reacted in the presence of a deprotonizing agent with a malonic acid dialkyl ester or a cyanoacetic acid alkyl ester and the resulting reaction product is hydrolysed and decarboxylated to form a compound of the general formula I, in which X represents a carboxyl group or a cyano group (depending on whether a malonic acid dialkyl ester or a cyanoacetic acid alkyl ester, respectively, is used as starting material), and, if desired, any nitro `' group present is reduced to form an amino group and/or any resulting carboxylic acid is converted into a physiologically tolerable salt thereof or esterified to form a lower alkyl ester thereof, or (c) a pyrazole derivative of the general formula II ,~
( CH 2 ) nY L
~ (II), in which n, Rl, R2, R3, R4 and Y have the meanings given above, 30 iS reacted, if appropriate in the presence of an ether, with magnesium or lithium and the resulting organo-metal compound is treated with carbon dioxide and, if desired, any nitro group 1(~7704~
present is reduced to form an amino group and/or the ~esulting carboxylic acid is converted into a physiologically tolerable salt thereof, a corresponding amide or nitrile or a lower alkyl ester thereof, or (d) a pyrazole derivative of the general formula IV
(CH2)n-1CCl L
~ R3 (IV), in which n, ~1~ R2~ R3 and R4 have the meanings given above, is reacted with diazomethane and the resulting diazoketone is rearranged in the presence of water, ammonia or a lower alcohol to form a compound of the general formula I, in which X represents a carboxyl, aminocarbonyl or lower alkoxycarbonyl group, respectively, and, if desired, any nitro group present is reduced to form an amino group and/or any ester group present is hydrolysed to form a carboxyl group or any aminocarbonyl group present is dehydrated to form a cya~o group and/or any resulting carboxylic acid is converted into a physiologically tolerable salt thereof. ~' Variant (a) of the process according to the present invention may be carried out under the conditions usually employed to replace halogen atoms by a cyano group.
For this variant of the process, there are preferably used as the starting compounds of the general formula II those that carry a chlorine, bromine or iodine atom (~epresented by the symbol Y).
This reaction is prefexably carried out in a dipolar, aprotic solvent (for example dimethylformamide, N-methylacet-amide, N-methylpyrrolidone, acetonitrile, dimethyl sulphoxide 1~77~)49 or hexamethylphosphoric acid triamide). Sodium cyanide or potassium cyanide is preferably used as the alkali metal cyanide for this reaction.
In this reaction, the rate of reaction can be acceler-ated significantly by carrying out the reaction in the presence of a coronene ether.
Variant (b) of the process according to the present invention may be carriedout in a manner known per se, by reacting the cyanoacetic acid esters (for example cyanoacetic acid methyl ester or cyanoacetic acid ethyl ester) or the malonic acid dialkyl esters (for example malonic acid dimethyl ester or malonic acid diethyl ester), in an inert solvent, with a deprotonizing agent and then with a pyrazole derivative of the general formula III (preferably a chloride, bromide or iodide).
Suitable inert solvents for this reaction are, for example, hydrocarbons (for example benzene, xylene or toluene) or ethers (for example dioxan, tetrahydrofuran or glycol dimethyl ether). The deprotonizing agents used for this reaction are alkali metal alcoholates (for example sodium methylate or potas,sium te,rt,-butylate), alkali metal hydrides (for example j~;
sodium hydride or potassium hydride), alkali metal amides (for example sodium amide or potassium amide) or thallium-alkyl compounds (for example thallium ethylate).
After the reaction has been carried out, the esters formed are hydrolysed in a manner known per se (for example by reaction with bases, for example sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate or potassium bicarbonate, in the presence of water) and are decarboxylated by heating.
The decarboxylation can be carried out in the absence of solvents or in the presence of a high-boiling solvent (for example xylene, chlorobenzene or decalin).
Variant (c) of the process according to the present ~077049 invention may be carried out in a manner known ~r se, for example by reacting the compounds of the general formula II
(preferably the chlorides, bromides and iodides) with magnesium or lithium in a suitable solvent (for example diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran or, where appropriate, benzene) and treating the organo-metallic compounds so prepared with solid carbon dioxide.
Variant (d) of the process according to the present invention may be carried out under the conditions that are usually employed in Arndt-Eistert syntheses. Thus, the compounds of the general formula IV (manufactured by reacting the corresponding carboxylic acids with a chlorinating agent, for example thionyl chloride, phosphorus oxychloride or phosphorus pentachloride) can be reacted with a solution of diazomethane in ether, and the resulting diazoketones can be reacted in water, a lower alcohol or an ammonia solution, in the presence of colloidal copper, silver, silver oxide or silver ~:
nitrate, to give the acids, acid esters or acid amides of the general formula I. ~' The optional subsequent hydrolysis of cyano compounds r;
of the general formula I may also be carried out under conditions that are well known to those skilled in the art. Thus, for ~;
example, the nitriles can be hydrolysed, for example with strong mineral acids (for example hydrogen chloride or sulphuric acid), either partially to the corresponding amides or, under more severe conditions, completely, to the corresponding carboxylic acids.
The optional subsequent conversion of the carboxylic acids to the corresponding amides or nitriles may also be carried out with the aid of well-known methods of working.
Thus, for example, it is possible to convert the acid chlorides, mixed anhydrides or esters, corresponding 1C~77~)49 to the carboxylic acids, into the corresponding a~ides ~y treatment with ammonia under the known conditions.
The optional measure of subsequent conversion to nitriles may be carried out, for example, by treating the corresponding aminocarbonyl compounds, under the known conditions, with dehydrating agents, for example dicyclohexyl-carbodiimide, carbonyldiimidazole, polyphosphoric acid, thionyl chloride or phosphorus oxychloride.
The optional subsequent esterification of the free acids may also be carried out in accordance with methods of working known per se. Thus, for example, the acids can be reacted with diazomethane or diazoethane, and the corresponding methyl esters or ethyl esters are obtained. A generally applic-able method is to react the acids with the alcohols in the presence of carbonyldiimidazole or dicyclohexylcarbodiimide.
Further it is possible, for example, to react the acids with alkyl halides in the presence of copper-(I) oxide or silver oxide.
A further method is to convert the free acids into the ~r~
corresponding alkyl esters of the acids by means of the corres-ponding dimethylformamide alkyl-acetals. Furthermore, the acids can be reacted with the alcohols or the lower alkanecarboxy- sP
lic acid esters of the alcohols in the presence of strongly acidic catalysts, for example hydrogen chloride, sulphuric acid, perchloric acid, trifluoromethylsulphonic acid or p-toluene-sulphonic acid.
~ owever, it is also possible to convert the carboxylic acids into the acid chlorides or mixed acid anhydrides and to react these with the alcohols in the presence of basic catalysts, for example pyridine, collidine, lutidine or 4-dimethylamino-pyridine.
~077~)49 The salts of the carboxylic acids are produced, for example, by saponifying the esters by means of basic catalysts, or by neutralizing the acids with bases capable of forming physiologically tolerable salts.
Using the process of the present invention it is possible, for example, to manufac~ure the following pyrazole derivatives of the general formula I and salts thereof namely L(1,4-diphenyl-3-pyrazolyl)-acetic acid, 3-(1,4-diphenyl-3-pyrazolyl)-propionic acid, 4-(1,4-diphenyl-3-pyrazolyl)-butyric acid and 5-(1,4-diphenyl-3-pyrazolyl)-valeric acid and their r amides, nitriles, sodium salts, methyl esters, ethyl esters, propyl esters and butyl esters. ~ -The new pyrazole derivative of the general formula I
and the aforesaid physiologically tolerable salts are pharmaco-loqically active substances which are distinguished more especially by the fact that they possess a pronounced anti- t inflammatory activity, are well tolerated by the stomach and have only a relatively low toxicity. In addition, these compounds are frequently distinguished by the fact that their action commences rapidly and is of high intensity and of long duration;
they also have a favourable resorbability, and a relatively good stability in galenical formulations.
The pyrazole derivatives of the general formula I and the aforesaid salts are metabolized in the body in a different way from known anti-inflammatory compounds.
The new compounds are suitable, in combination with the carrier materials customarily used in, for example, galenical pharmacy, for the treatment of, for example, the following conditions a) local treatment: contact dermatitis, eczemas of a very wide variety of types, neurodermitis, erythrodermia, first-degree burns, pruritus vulvae et ani, rosacea, erythematodes - 8 - ..
1C~77049 cutaneus, psoriasis and lichen ruber planus et Verruco~us;
b) oral treatments acute and chronic polyarthritis, neurodermitis, bronchial asthma and hay fever.
The present invention accordingly further provides a pharmaceutical preparation which comprises a compound of the general formula I or a physiologically tolerable salt of such acompound in which X represents a carboxyl group, in admixture or conjunction with a pharmaceutically suitable carrier.
The pharmaceutical preparations may be prepared in the usual manner by converting the active substances, with suitable additives, excipients and flavour correctants, into the desired forms for administration, for example tablets, dra~ées, capsules, solutions, powders, salves, aerosols and inhalant preparations.
For oral use, tablets, dragées and capsules are especially suitable, which contain, for example, 1 - 250 mg of active substance and 50 mg - 2 g of a pharmacologically inactive excipient, for example lactose, amylose, talc, gelatine or magnesium stearate, as well as the customary additives. -Powders, salves, aerosols and similar preparations, which preferably contain 0.01 to 2~ by weight of the active substance, are suitable for topical application.
The starting compounds of the general formulae II and III, which have not previously been known, can be prepared from the corresponding carboxylic acid esters by, for example, reducing these with lithium aluminium hydride to form the corresponding carbinols and replacing the hydroxyl group of the latter by a halogen atom, as is described below, by way of example, for the synthesis of 3-bromomethyl-1,4-diphenyl-pyrazole;
a) 3 g of triethylamine and a solution of 6~78 g of (2-chloro-2-phenylhydrazono)-acetic acid ethyl ester in 20 ml of dry, ethanol-free chloroform were added successively, at room temperature, to 5.67 g of ~,morpholinostyrene in 35 ml of dry ethanol-free chloroform. The reaction mixture was stirred for one hour at 40C and 16 hours at room temperature and was washed with dilute hydrochloric acid, a dilute sodium carbonate solution and water, dried and concentrated ln _cuo.
The residue was digested with hexane and recrystallized from ethanol-hexane, and 7.3 g of 4-morpholino-3-phenyl-2-phenylhydrazono-3-butenoic acid ethyl ester melting at 130 -131C were obtained.
b) 33 g of 4-morpholino-3-phenyl-2-phenylhydrazono-3-butenoic acid ethyl ester were mixed with 330 ml of dioxan and 100 ml of 2N hydrochloric acid and the mixture was heated for 4S minutes under reflux. The reaction mixture was then concentra-ted ln vacuo, the residue was dissolved in chloroform, and the chloroform solution was washed, dried and concentrated ln vacuo.
The residue was recrystallized from ethanol-hexane and 21.15 g of 1,4-diphenyl-pyrazole-3-carboxylic acid ethyl ester melting at 103 - 104C were obtained.
c) A solution of 17.2 g of 1,4-diphenyl-pyrazole-3-carboxylic acid ethyl ester in 80 ml of absolute tetrahydrofuran was added ~.
dropwise, at 0C, to 4.63 g of lithium aluminium hydride in 100 ml of absolute tetrahydrofuran, under nitrogen. , The reaction mixture was stirred for a further 30 minutes, 40 ml of a saturated aqueous sodium chloride solution were added, and the batch was acidified with dilute hydrochloric acid and extracted with ether. The organic phase was concentrated, !
the residue was digested with hexane and 14.65 g of 3-hydroxy-methyl-1,4-diphenyl-pyrazole crude product melting at 104-105C
were obtained.
d) 130 ml of 63~ strength hydrobromic acid were added to 13.2 g of 3-hydroxymethyl-1,4-diphenyl-pyrazole crude product and the r mixture was heated at 90C for 4 hours.
The reaction mixture was then concentrated ln vacuo the excess hydrogen bromide was removed by repeatedly taking up the residue in toluene and concentrated _n vacuo.
The residue was recrystallized from isopropanol and 10.8 g of 3-bromomethyl-1,4-dipheny~pyrazole melting at 99C
were obtained.
The following Examples illustrate the invention:- ;
Example 1 a) 2.81 q of 3-bromomethyl-1,4-diphenylpyrazole in 30 ml of absolute acetonitrile were stirred with 1.17 y of potassium cyanide and 300 mg of dibenzo-18-coronene-6 for 10 hours at 40C.
The reaction mixture was then concentrated in vacuo, mixed with water and extracted with methylene chloride, and the organic phase was washed, dried and concentrated in vacuo.
2.6 g of (1,4-diphenyl-3-pyrazolyl)-acetonitrile were thus obtained as a crude product.
b) 2.6 g of (1,4-diphenyl-3-pyrazolyl)-acetonitrile crude product were stirred with-20 ml of concentrated hydro-chloric acid for one hour at a reaction temperature of 50C. h The reaction mixture was then diluted with water and extracted with methyl isobutyl ketone, the organic phase was washed and - concentrated ln vacuo, and 2.3 g of (1,4-diphenyl-3-pyrazolyl)- ~;
acetamide were obtained as a crude product.
c) 2.3 g of (1,4-diphenyl-3-pyrazolyl)-acetamide crude product and 40 ml of a 10~ strength aqueous sodium hydroxide solution were heated under reflux for 30 minutes, under argon.
The reaction mixture was then cooled in an ice bath, acidified with 2N hydrochloric acid and extracted with methylene chloride, r-and the methylene chloride phase was washed, dried and concentra-ted ln vacuo.
The resulting crude product was recrystallized from toluene and 1.25 g of (l,4-diphenyl-3-pyrazolyl)-acetic acid 10~7049 melting at 131 - 133C were obtained. ~ ;
Example 2 a) A mixture of 2 6 g of (1~4-diphenyl-3-pyrazolyl)-acetonitrile crude product [prepared as described in Example l(a)]
and 15 ml of 80% strength sulphuric acid was heated to 120C
and stirred for 2 hours at this temperature. The reaction mixture was then poured into ice water and extracted with methylene chloride, and the methylene chloride phase was washed, dried and concentrated 1n vacuo.
The residue was dissolved in a 5% strength aqueous sodium carbonate solution and the product was precipitated with 10~ strength hydrochloric acid, filtered off, washed and dried _ vacuo at 60C. It was then recrystallized from toluene and 1.6 g of (1,4-diphenyl-3-pyrazolyl)-acetic acid melting at 131 -133C were obtained.
b) 200 mg of ~1,4-diphenyl-3-pyrazolyl)-acetic acid were dissolved in 10 ml of absolute ethanol, 7.6 ml of a O.lN aqueous sodium hydroxide solution were added to the ethanol solution, and the ~;
mixture was concentrated in vacuo. ~' The residue was again taken up in 10 ml of absolute ~!
ethanol and again concentrated ln vacuo.
The resulting crude product was dissolved in a small amount of absolute ethanol, absolute diethyl ether was added to the solution and sodium (1,4-diphenyl-3-pyrazolyl)-acetate was obtained as an amorphous powder. F
Example 3 a) 3.84 g of malonic acid diethyl ester and 4.7 g of 3-bromomethyl-l~4-diphenyl-pyrazole were added successively to a solution of 5.6 g of thallium ethylate in 120 ml of absolute benzene, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was then diluted with diethyl ether and 100 ml of ice water were added. The organic phase was 1~77049 separated off, washed, dried and concentrated in _acuo. 5.3 g of 2-(1,4-diphenyl-3-pyrazolyl.methyl)-malonic acid diethyl ester were thus obtained as a crude product.
b) To 6 9 g of the resulting 2-(1,4-diphenyl-3-pyrazolyl-methyl)-malonic acid diethyl ester crude product were added 2.7 g of sodium hydroxide -dissolved in 30 ml of water - and 30 ml of dioxane, and the mixture was heated for 3 hours under reflux.
The reaction mixture was then substantially evaporated ln vacuo, the residue was diluted with 100 ml of water, the mixture was extracted with diethyl ether, the aqueous phase was acidified to a pH-value of 1 with concentrated hydrochloric acid andthe oily crude product which had separated out was isolated~ -The resulting crude product was dissolved in diethyl ether and the solution was washed with water, dried and concentrated in vacuo.
4.25 g of 2-(1,4-diphenyl-3-pyrazolyl-methyl)-malonic acid melting at 172C were thus obtained.
c) 4.1 g of 2-(1,4-diphenyl-3-pyrazolyl-methyl)-malonic acid were slowly heated to 200C. The reaction temperature was maintained at 200C for a further 20 minutes, it was then allowed to cool, the resulting product was crystallized from toluene and 2.9 g of 3-(1,4-diphenyl-3-pyrazolyl)-propionic acid melting at 128 - 129C were obtained.
d) 200 mg of 3-(1,4-diphenyl-3-pyrazolyl)-propionic acid were converted into amorphous sodium 3-(1,4-diphenyl-3-pyrazolyl)-propionate under the conditions described in Example 2(bJ.
Example 4 a) 10 ml of thlonyl chloride, which had been distilled over linseed oil, were added to 2.7 g of 3-(1,4-diphenyl-3-pyrazolyl)-propionic acid andthe mixture was heated for two hours under reflux. The reaction mixture was then concentrated 1~77~49 in vacuo, 25 ml of absolute benzene were added to the residue, the mixture was again concentrated ln _cuo and 2.6 g of 3-(1,4- !
diphenyl-3-pyrazolyl) propionyl chloride were obtained as a crude product.
b) 5 ml of absolute benzene and 5 ml of absolute ethanol were added to 50 mg of 3-(1,4 diphenyl-3-pyrazolyl)-propionyl chloride crude product. 0 2 ml of pyridine was added dropwise to the mixture which was then allowed to stand for 16 hours at room temperature, and diluted with 20 ml of benzene; the reaction mixture was then washed with water, dilute hydrochloric acid and water, dried and concentrated ln vacuo. The residue was recrystallized from acetone-hexane and 38 mg of 3-(1,4-diphenyl-3-pyrazolyl)-propionic acid ethyl ester melting at 95.5 - 98.5C were obtained.
Example 5 a) A solution of diazomethane in ether, prepared from 3.5 g of nitrosomethylurea, 50 ml of anhydrous ether and 11 ml of a 50~ strength aqueous potassium hydroxide solution, was added to ~;1.9 g of 3-(1,4-diphenyl-3-pyrazolyl)-propionyl chloride crude product in 20 ml of absolute ether and the mixture was allowd to stand for 4 hours at room temperature.
The reaction mixture was then concentrated in vacuo, 40 ml of ethanol were added, the mixture was heated to 60C, .
0.2 g of freshly prepared silver oxide was added and the batch was heated until the evolution of nitrogen had ceased.
The reaction mixture was then clarified with active charcoal, filtered and concentrated ln vacuo, and 1.7 g of 4-(1,4-diphenyl-3-pyrazolyl)-butyric acid ethyl ester were r obtained as a crude product.
b) 1.7 g of 4-(1,4-diphenyl-3-pyrazolyl)-butyric acid ethyl ester were dissolved in 20 ml of ethanol, 5 ml of a 10% strength sodium hydroxide solution were added and the mixture was heated ~,.
107704~
for two hours under reflux. The ethanol was then removed ln vacuo, the residue was diluted with 10 ml of water and acidified with hydrochloric acid to a pH-value of 1, and the product which had separated out was filtered off.
The resulting crude product was washed with water, dried ln _cuo at 60C and recrystallized from toluene, and 1.05 g of 4-(1,4-diphenyl-3-pyrazolyl)-butyric acid melting at 107 -109C were obtained.
Example 6 a) A solution of 15.2 g of sodium nitrite in 40 ml of water was added dropwise to a solution, at 0C, of 21.4 g of _-toluidine and 400 ml of 7.5~ strength hydrochloric acid. The p-toluene-diazonium chloride suspension so obtained was added dropwise to a mixture, at 5C, of 36.2 g of 2-chloroacetoacetic acid ethyl ester, 400 ml of 50~ strength ethanol and 164 g of sodium acetate. The mixture was then stirred for 3 hours at 20C and was extracted with ethyl acetate, the organic phase was concentra-ted, the residue was treated with petroleum ether, and 41 g of 2-chloro-2-(4-methylphenylhydrazono~acetic acid ethyl ester melting at 100 - 101C were obtained.
b) A solution of 24.7 g of 2-chloro-2-(4-methylphenyl-hydrazono)-acetic acid ethyl ester in 100 ml of chloroform was added dropwise to a solution of 18.9 g of ~-morpholinostyrene in 100 ml of chloroform and 13.8 g of triethylamine. The reaction 5 mixture was allowed to stand for one hour at 50C and 16 hours F !
at 20C and was washed with 2N hydrochloric acid and then with a saturated sodium bicarbonate solution. The chloroform solution was then concentrated ln vacuo, the residue was treated with petroleum ether, and 27.6 g of 2-(4-methylphenylhydrazono)-3-morpholino-methylene-3-phenylpropionic acid ethyl ester melting t at 131 - 132C were obtained, c) 260 ml of dioxareand 80 ml of 2N hydrochloric acid 1~77049 were added to 27.6 g of 2.(4-methylphenylhydrazono)-3~morpholino-methylene.3-phenylpropionic acid ethyl ester and the mixture was heated for 45 minutes under reflux. The reaction mixture was allowed to cool and was concentrated ln vacuo, and the residu~ was taken up in chloroform. The chloroform phase was washed with water and concentrated in vacuo, the residue was treated with petroleum ether, and 17.1 g of 4-phenyl-1-(4-tolyl)-
3-pyrazolylcarboxylic acid ethyl ester melting at 115 - 117C
were obtained.
d) A solution of 16.8 g of 4-phenyl-1-(4-tolyl)-3-pyrazolyl-carboxylic acid ethyl ester in 100 ml of tetrahydro-furan was added dropwise to a suspension, cooled to 0C, of
were obtained.
d) A solution of 16.8 g of 4-phenyl-1-(4-tolyl)-3-pyrazolyl-carboxylic acid ethyl ester in 100 ml of tetrahydro-furan was added dropwise to a suspension, cooled to 0C, of
4.3 g of lithium aluminium hydride in 100 ml of tetrahydrofuran.
The mixture was stirred for a further hour, and 25 ml of a saturated sodium chloride solution were added, followed by 63 ml of 20~ strength hydrochloric acid. The reaction mixture was then extracted with ether, the ether phase was concentrated ln vacuo, the residue was treated with petroleum ether, and 12 g ~' of 4-phenyl-1-(4-tolyl)-3-pyrazolylmethanol melting at 125C
were obtained. ;e) 2.65 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylmethanol in '~
60 ml of 63~ strength hydrobromic acid were heated at 90C for ,
The mixture was stirred for a further hour, and 25 ml of a saturated sodium chloride solution were added, followed by 63 ml of 20~ strength hydrochloric acid. The reaction mixture was then extracted with ether, the ether phase was concentrated ln vacuo, the residue was treated with petroleum ether, and 12 g ~' of 4-phenyl-1-(4-tolyl)-3-pyrazolylmethanol melting at 125C
were obtained. ;e) 2.65 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylmethanol in '~
60 ml of 63~ strength hydrobromic acid were heated at 90C for ,
5 hours. The reaction mixture was then diluted with water, ,~
the product which had separated out was filtered off with suction and recrystallized from isopropanol, and 2.9 g of 3-bromomethyl~-phenyl-l-(4-tolyl)-pyrazole melting at 98C were obtained.
f) 4.7 g of potassium cyanide, 70 ml of acetonitrile and 500 mg of dibenzo-18-coronene-6 were added to 5.9 g of 3-bromo-methyl-4-phenyl-1-(4-tolyl)-pyrazole and the mixture was stirred for 10 hours at 40C, The reaction mixture was then concentrated n vacuo, the residue was mixed with water and the mixture was .. . ... ~
. - ~-; ~. , .
. .. ;' : :-1~771~49 extracted with methylene chloride. The methylene chloride phase was washed and concentrated, the residue was recrystallized from methanol, and 4.7 g o~ 4~phenyl 1-(4-tolyl)-3-pyrazolyl-acetonitrile melting at 91 - 92aC were obtained.
g) 4.7 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetonitrile in 27 ml of 80~ strength sulphuric acid were heated for 2 hours at 120C. The reaction mixture was allowed to cool and was diluted with water and extracted with methylene chloride. The organic phase was washed and concentrated, the residue was recrystallized from toluene, and 3.2 g of 4-phenyl-1-(4-tolyl)- r 3-pyrazolylacetic acid melting at 124 - 125C were obtained.
Example 7 a) 2.5 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetonitrile were stirred for one hour with 20 ml of concentrated hydrochloric acid at a reaction temperature of 50C. The reaction mixture was then diluted with water and extracted with methyl isobutyl ketone, the organic phase was washed and concentrated in vacuo, and 1.9 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetamide were obtained as a crude product.
b) 1.9 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetamide ,~
crude product in 40 ml of a 10~ strength aqueous sodium hydroxide ~' !
solution were heated under reflux for 30 minutes, under argon. ~;
The reaction mixture was then cooled in an ice bath, acidified ~' with 2N hydrochloric acid and extracted with methylenechloride, and the methylene chloride phase was washed, dried and concen- F
trated ln vacuo. The resulting crude product was recrystallized from toluene and 0.95 g of 4-phenyl-1-(4-tolyl)-3-pyrazolyl-acetic acid melting at 124.5 - 126C were obtained. ~F;
Example 8 a) 10 ml of thionyl chloride, which had been distilled over linseed oil,were added to 2.5 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetic acid, and the mixture was heated for 2 hours ,- .: .: - -1C~7~)49 under reflux. The reaction mixture was then concentrated in vacuo, 25 ml of absolute benzene were added to the residue, the mixture was again concentrated in va uo, and 2 2 g of 4-phenyl-l-(4-tolyl)-3-pyrazolylacetyl chloride were obtained as a crude product.
b) 5 ml of absolute benzene and 5 ml of absolute ethanol were added to 2.2 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetyl chloride crude product. 0.2 ml of pyridine was added dropwise to the mixture which was allowed to stand for 16 hours at room temperature, and diluted with 20 ml of benzene, and the reaction mixture was then washed with water, dilute hydrochloric acid and water, dried and concentrated in vacuo. The residue was recrystallized from acetone/hexane and 1.7 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetic acid ethyl ester melting at 76 - 79C
were obtained.
Example 9 a) o-Toluidine was reacted to form 2-chloro-2-(2-methyl-phenyl-hydrazono)-acetic acid ethyl ester, melting at 72C, under the conditions described in Example 6(a). t,' b) The resulting product was reacted, as described in ,~
Example 6(b), to form 2-(2-methylphenylhydrazono)-3-morpholino-methylene-3-phenylpropionic acid ethyl ester melting at 109C. ;~
c) The resulting compound was converted into 4-phenyl-1- L
(2-tolyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 80C, under the conditions described in Example 6(c).
d) The resulting product was reduced, as described in Example 6(d), to form 4-phenyl-1-(2-tolyl)-3-pyrazolylmethanol melting at 121C.
e) The bromination of this compound, as described in Example -30 6(e), yielded 3-bromomethyl-4-phenyl-1-(2-tolyl)-pyrazole melting at 67C~
f) The bromide was converted into 4-phenyl-1-(2-tolyl)-3-pyrazolylacetonitrile, melting at 23C, under the conditions described in Example 6~f).
g) The resulting nitrile was hydrolysed as described in Example 6(g) and 4-phenyl-1~(2-tolyl)-3-pyrazolylacetic acid, melting at 177C, was obtained.
Examplè 10 a) _-Chloroaniline was converted into 2-chloro-2-(2-chloro-phenylhydrazono)-acetic acid ethyl ester, melting at 92C, as described in Example 6(a).
b) The resulting compound was converted into 2-(2-chloro- ¦
phenylhydrazono) -3-morpholinomethylene-3-phenylpropionic acid ethyl ester, melting at 122C, as described in Example 6(b).
c) The resulting product was converted into 4-phenyl-1-(2-chlorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 109C, under the conditions described in Example 6(c).
d) The reduction of this compound, as described in Example
the product which had separated out was filtered off with suction and recrystallized from isopropanol, and 2.9 g of 3-bromomethyl~-phenyl-l-(4-tolyl)-pyrazole melting at 98C were obtained.
f) 4.7 g of potassium cyanide, 70 ml of acetonitrile and 500 mg of dibenzo-18-coronene-6 were added to 5.9 g of 3-bromo-methyl-4-phenyl-1-(4-tolyl)-pyrazole and the mixture was stirred for 10 hours at 40C, The reaction mixture was then concentrated n vacuo, the residue was mixed with water and the mixture was .. . ... ~
. - ~-; ~. , .
. .. ;' : :-1~771~49 extracted with methylene chloride. The methylene chloride phase was washed and concentrated, the residue was recrystallized from methanol, and 4.7 g o~ 4~phenyl 1-(4-tolyl)-3-pyrazolyl-acetonitrile melting at 91 - 92aC were obtained.
g) 4.7 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetonitrile in 27 ml of 80~ strength sulphuric acid were heated for 2 hours at 120C. The reaction mixture was allowed to cool and was diluted with water and extracted with methylene chloride. The organic phase was washed and concentrated, the residue was recrystallized from toluene, and 3.2 g of 4-phenyl-1-(4-tolyl)- r 3-pyrazolylacetic acid melting at 124 - 125C were obtained.
Example 7 a) 2.5 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetonitrile were stirred for one hour with 20 ml of concentrated hydrochloric acid at a reaction temperature of 50C. The reaction mixture was then diluted with water and extracted with methyl isobutyl ketone, the organic phase was washed and concentrated in vacuo, and 1.9 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetamide were obtained as a crude product.
b) 1.9 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetamide ,~
crude product in 40 ml of a 10~ strength aqueous sodium hydroxide ~' !
solution were heated under reflux for 30 minutes, under argon. ~;
The reaction mixture was then cooled in an ice bath, acidified ~' with 2N hydrochloric acid and extracted with methylenechloride, and the methylene chloride phase was washed, dried and concen- F
trated ln vacuo. The resulting crude product was recrystallized from toluene and 0.95 g of 4-phenyl-1-(4-tolyl)-3-pyrazolyl-acetic acid melting at 124.5 - 126C were obtained. ~F;
Example 8 a) 10 ml of thionyl chloride, which had been distilled over linseed oil,were added to 2.5 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetic acid, and the mixture was heated for 2 hours ,- .: .: - -1C~7~)49 under reflux. The reaction mixture was then concentrated in vacuo, 25 ml of absolute benzene were added to the residue, the mixture was again concentrated in va uo, and 2 2 g of 4-phenyl-l-(4-tolyl)-3-pyrazolylacetyl chloride were obtained as a crude product.
b) 5 ml of absolute benzene and 5 ml of absolute ethanol were added to 2.2 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetyl chloride crude product. 0.2 ml of pyridine was added dropwise to the mixture which was allowed to stand for 16 hours at room temperature, and diluted with 20 ml of benzene, and the reaction mixture was then washed with water, dilute hydrochloric acid and water, dried and concentrated in vacuo. The residue was recrystallized from acetone/hexane and 1.7 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetic acid ethyl ester melting at 76 - 79C
were obtained.
Example 9 a) o-Toluidine was reacted to form 2-chloro-2-(2-methyl-phenyl-hydrazono)-acetic acid ethyl ester, melting at 72C, under the conditions described in Example 6(a). t,' b) The resulting product was reacted, as described in ,~
Example 6(b), to form 2-(2-methylphenylhydrazono)-3-morpholino-methylene-3-phenylpropionic acid ethyl ester melting at 109C. ;~
c) The resulting compound was converted into 4-phenyl-1- L
(2-tolyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 80C, under the conditions described in Example 6(c).
d) The resulting product was reduced, as described in Example 6(d), to form 4-phenyl-1-(2-tolyl)-3-pyrazolylmethanol melting at 121C.
e) The bromination of this compound, as described in Example -30 6(e), yielded 3-bromomethyl-4-phenyl-1-(2-tolyl)-pyrazole melting at 67C~
f) The bromide was converted into 4-phenyl-1-(2-tolyl)-3-pyrazolylacetonitrile, melting at 23C, under the conditions described in Example 6~f).
g) The resulting nitrile was hydrolysed as described in Example 6(g) and 4-phenyl-1~(2-tolyl)-3-pyrazolylacetic acid, melting at 177C, was obtained.
Examplè 10 a) _-Chloroaniline was converted into 2-chloro-2-(2-chloro-phenylhydrazono)-acetic acid ethyl ester, melting at 92C, as described in Example 6(a).
b) The resulting compound was converted into 2-(2-chloro- ¦
phenylhydrazono) -3-morpholinomethylene-3-phenylpropionic acid ethyl ester, melting at 122C, as described in Example 6(b).
c) The resulting product was converted into 4-phenyl-1-(2-chlorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 109C, under the conditions described in Example 6(c).
d) The reduction of this compound, as described in Example
6(d), yielded 4-phenyl-1-(2-chlorophenyl)-3-pyrazolylmethanol t melting at 132C.
2Q e) The bromination of the alcohol, as described in Example '' 6(e), yielded 3-brom~thyl-4-phenyl-1-(2-chlorophenyl)-pyrazole melting at 91C.
f) The bromide was converted into 4-phenyl-1-(2-chloro- I, phenyl)-3-p~razolylacetonitrile, melting at 62C, under the conditions described in Example 6(f).
g) The resulting nitrile was converted into 4-phenyl-1-(2-chlorophenyl)-3-pyrazolylacetic acid melting at 146C, as described in Example 6(g).
Example 11 4-Phenyl-1-(4-chlorophenyl)-3-pyrazolylacetonitrile, melting at 121C, was prepared from 4-chloroaniline under the conditions described in Example 6(a) to 6(f), and was hydrolysed, 1~77~49 as described in Example 6(g), to form 4-phenyl-1-(4-chlorophenyl)-3-pyrazolylacetic acid melting at 137C.
The intermediate products obtained in the course of the preparation of the nitrile had the following physical data:
2-chloro-2-(4-chlorophenylhydrazono)-acetic acid ethyl ester, melting at 150C, 2-(4-chlorophenylhydrazono)-3-morpholinomethylene-3-phenylpropionic acid ethyl ester, melting at 164C, 4-phenyl-1-(4-chlorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 91C, 4-phenyl-1-(4-chlorophenyl)-3-pyrazolylmethanol, melting at 117C, and 3-bromomethyl-4-phenyl-1-(4-chlorophenyl)-pyrazole, melting at 125C.
Example 12 4-Phenyl-1-(3,4-dichlorophenyl)-3-pyrazolylacetonitrile melting at 131C, was prepared from 3,4-dichloroaniline, as ~' described in Example 6(a) to 6(f), and was hydrolysed to form 4-phenyl-1-(3,4-dichlorophenyl)-3-pyrazolylacetic acid, melting t~
at 158C, ~nder the conditions described in Example 6(g).
The intermediate products which were obtained in the course of the preparation of the nitrile had the following physical data:
2-chloro-2-(3,4-dichlorophenylhydrazono)-acetic acid ethyl ester, melting at 154C, 2-(3,4-dichlorophenylhydrazono) -3-morpholinomethylene-3-phenylpropionic acid ethyl ester, melting at 141C, 4-phenyl-1-(3,4-dichlorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 117C, 4-phenyl-1-(3,4-dichlorophenyl)-3-pyrazolylmethanol, melting at 121C, and 3-bromomethyl-4-phenyl-1-(3,4-dichlorophenyl)-pyrazole, melting at 108C.
Example 13 4-Phenyl-1-(4-fluorophenyl)-3-pyrazolylacetonitrile, meltinq at 79C, was prepared from ~-fluoroaniline under the same conditions as those described in Example 6(a) - 6(f) ! and was hydrolysed to form q-phenyl-1-(4-fluorophenyl)-3-pyrazolyl-acetic acid, melting at 171C, as described in Example 6(g).
The intermediate products which were obtained in the course of the preparation of the nitrile had the following physical data:
2-chloro-2-(4-fluorophenylhydrazono)-acetic acid ethyl ester, melting at 109C, 2-(4-fluorophenylhydrazono)-3-morpholinomethylene-3-phenylpropionic acid ethyl ester, melting at 161C, 4-phenyl-1-(4-fluorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 125C, 4-phenyl-1-(4-fluorophenyl)-3-pyrazolylmethanol, melting at 146C, and ~r 3-bromomethyl-4-phenyl-1-(4-fluorophenyl)-pyrazole, melting at 89C. -Ex _ple 14 4-Phenyl-1-(2-fluorophenyl)-3-pyrazolylacetonitrile, melting at 70C, was prepared from _-fluoroaniline under the conditions described in Example 6(a) to 6(f), and was hydrolysed to form 4-phenyl-1-(2-fluorophenyl)-3-pyrazolylacetic acid, melting at 154C, as described in Example 6(g). ?
The intermediate products which were obtained in the course of the preparation of the nitrile had the following r physical data:
2-chloro-2-(2-fluorophenylhydrazono)-acetic acid ethyl ester, melting at 70C, 2-(2-fluorophenylhydrazono)-3-morpholinomethylene-3-1~77~49 phenyl-propionic acid ethyl ester, melting at 99C !
4-phenyl-1-12~fluorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 62C~
4-phenyl-1-(2-fluorophenyl)-3-pyrazolylmethanol, melting at 109C, and 3-bromomethyl-4-phenyl-1-(2-fluorophenyl)-pyrazole, melting at 102C. E
Example 15 4-Phenyl-1-(3-fluorophenyl)-3-pyrazolylacetonitrile, 10melting at 74C, was prepared from _-fluoroaniline under the conditions described in Example 6(a) to 6(f) and was hydrolysed to form 4-phenyl-1-(3-fluorophenyl)-3-pyrazolylacetic acid, melting at 159C, as described in Example 6(g).
The intermediate products which were obtained in the course of the preparation of the nitrile had the following physical data:
2-chloro-2-(3-fluorophenylhydrazono)-acetic acid ethyl ester, melting at 111C, 2-(3-fluorophenylhydrazono)-3-morpholinomethylene-3-20phenyl-propionic acid ethyl ester, melting at 110C, 4-phenyl-1-(3-fluorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 81C, 4-phenyl-1-(3-fluorophenyl)-3-pyrazolylmethanol, melting at 74C, and ` 3-bromomethyl-4-phenyl-1-(3-fluorophenyl)-pyrazole, melting at 75C.
Example 16 4-Phenyl-1-(3-trifluoromethylphenyl)-3-pyrazolylaceto-nitrile, melting at 76C, was prepared from m-trifluoromethyl-aniline under the conditions described in Example 6(a) to 6(f) and was hydrolysed to form 4-phenyl-1-(3-trifluoromethylphenyl)-3-pyrazolylacetic acid, melting at 169C, under the conditions described in Fxample 6(g), The intermediate products which were obtained in the course of the preparation of the nit:rile had the following physical data:
2-chloro-2,(3~trifluoromethyl-phenylhydrazono)-acetic acid ethyl ester, melting at 131C, 2-(3-trifluoromethyl-phenylhydrazono)-3-morpholino-methylene-3-phenylpropionic acid ethyl ester, melting at 125C, 4-phenyl-1-(3-trifluoromethyl-phenyl)-3-pyrazolyl-1~ carboxylic acid ethyl ester, melting at 66C, 4-phenyl-1-(3-trifluoromethyl-phenyl)-3-pyrazolyl-methanol, melting at 94C, and 3-bromomethyl-4-phenyl-1-(3-trifluoromethyl-phenyl)-pyrazole, melting at 120C.
Example 17 a) Under the conditions described in Example 6(b) 22.7 g of ~-dimethylamino-4-nitrostyrene were reacted with 19.2 g ~!
of 2-chloro-2-phenylhydrazonoacetic acid ethyl ester and worked up. 3-Dimethylaminomethylene-3-(4-nitrophenyl)-2-phenylhydrazono- e propionic acid ethyl ester melting at 139C was obtained. -~
b) The resulting compound was cyclized under the conditions described in Example 6(c) to form 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylcarboxylic acid ethyl ester melting at 143C.
c) 24 g of the compound obtained as described in Example 17(b) were dissolved in 500 ml of ethanol, 5 g of Raney nickel were added and the compound was hydrogenated at room temperature under normal pressure. The catalyst was then filtered off, the filtrate was concentrated in vacuo, the residue was recrystallized from methanol and 20 g of 4-(4-aminophenyl)-1-phenyl-3-pyrazolyl-carboxylic acid ethyl ester melting at 142C were obtained.
d) A solution of 760 mg of sodium nitrite in 1.5 ml of water was added to 3.1 g of 4-(4-aminophenyl)-1-phenYl-3-pyrazolylcarboxylic acid ethyl ester in 13 ml of 15% strength ~ .
hydrochloric acid at -5C, 25 ml of 3~ strength hydrochloric acid were then also added to the mixture and the whole, at -5, was added dropwise to a warm solution, at 60C, of 1,5 g of copper-(II) chloride in 30 ml of 12~ strength hydrochloric acid. The mixture was allowed to stand for a further 10 minutes at 60C and was then cooled and extracted with ethyl acetate, the extract was concentrated, the residue was taken up in toluene, the solution was filtered through a silica gel column and was concentrated, and 2.47 g of 4-(4-chlorophenyl)-1-phenyl-3-pyrazolylcarboxylic acid ethyl ester melting at 96C
were obtained.
e) 4-(4-Chlorophenyl)-l-phenyl-3-pyrazolylcarboxylic acid ethyl ester was converted into 4-(4-chlorophenyl)-1-phenyl-3-pyrazolylacetic acid, melting at 142C, under the conditions described in Example 6(d) to 6(g).
The intermediate products obtained in the course of the synthesis of this compound had the following physical constants:
4-(4-chlorophenyl)-1-phenyl-3-pyrazolylmethanol, melting at l45C, 3-bromomethyl-4-(4-chlorophenyl)-1-phenylpyrazole, F~
melting at 110C, and r, 4-(4-chlorophenyl)-1-phenyl-3-pyrazolylacetonitrile, i~
melting at 97C.
Example 18 a) 28 ml of lN hydrochloric acicl were added to 2.4 g of 4-(4-aminophenyl)-~phenyl-3-pyrazolylcarboxylic acid ethyl ester, the mixture was cooled to 0C and the ester was slowly diazotized with a solution of 830 mg of sodium nitrite in 5 ml of water, The mixture was diluted with 10 ml of water and was stirred for 15 minutes at 0C. 953 mg of zinc chloride were then added to the mixture ! which was allowed to stand for ~U77049 30 minutes. The precipitate which had separated out wa~ filter~d off with suction, dried and taken up in 50 ml of methanol, and the solution was allowed to stand for 16 hours at room temperature and was then heated for one hour under reflux. The reaction mixture was concentrated in vacuo, the residue was taken up in benzene and the benzene phase was washed and concentrated in vacuo.
2 equivalents of sodium hydroxide solution and 2.02 g of dimethyl ~ , sulphate were added to the residue and the mixture was heated for 30 minutes at 80C. After it had cooled, the mixture was extracted with methylene chloride, the organic phase was concen-trated, the residue was recrystallized from isopropanol and 1.92 g of 4-(4-methoxyphenyl)-1-phenyl-3-pyrazolylcarboxylic acid ethyl ester melting at 94C were obtained.
b) 4-(4-Methoxyphenyl~-l-phenyl-3-pyrazolylcarboxylic acid ethyl ester was converted into 4-(4-methoxyphenyl)-1-phenyl-3-pyrazolylacetic acid, melting at 170C, under the conditions described in Example 6(d) to 6(g).
The intermediate products obtained in the course of the synthesis of this compound had the following physical constants:
4-(4-methoxyphenyl)-l-phenyl-3-pyrazolylmethan melting at 101C, 3-chloromethyl-4-(4-methoxyphenyl)-1-phenyl-pyrazole, j~,melting at 125C (the compound was obtained from the immediately preceding compound by reaction with 1.1 equivalents of methane-sulphonyl chloride in pyridine at -15C), and 4-(4-Methoxyphenyl)-l-phenyl-3-pyrazolylacetonitrile, melting at 83C.
Example 19 a) 70 ml of isopropanol and 15 ml of a 40% strength L
potassium hydroxide solution were added to 2 g of 4-(4-nitro-phenyl)-l-phenyl-3-pyrazolylcarboxylic acid ethyl ester and the mixture was heated for 2 hours under reflux. The reaction 1C~77049 mixture was then concentrated ln vacuo to a far reaching extent, the crystals which had separated out were filtered off with suctlon, and 1.67 g of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylcarboxylic acid melting at 273C were obtained.
b) 0,5 mlof dimethylformamide and 10 ml of thionyl chloride were added to the carboxylic acid and the mixture was heated for 14 hours under reflux. The reaction mixture was concentrated ln vacuo and 1.55 g of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylcarboxylic acid chloride melting at 226C
were obtained.
c) 25 ml of dioxa~ and 5 ml of ether were added to the acid chloride and the mixture was cooled to lO~C. 3 equivalents of a solution of diazomethane in etherwere then added to the mixture, which was allowed to stand for 2 hours at 10C. The reaction mixture was concentrated in vacuo, 80 ml of isoamyl alcohol were added to the residue, and the mixture was filtered.
A solution of 4.4 g of silver benzoate in 45 ml of triethylamine `
was added dropwisè to the solution so obtained, and the mixture was allowed to stand for 72 hours. It was then filtered and the ~'~
filtrate was washed with an aqueous sodium carbonate solution and concentrated in vacuo. The residue was purified by chromato-graphy over a silica gel column, using cyclohexane/ethyl acetate, and 395 mg of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylacetic acid isoamyl ester melting at 81C were obtained.
d) The resulting ester was hydrolysed as described in Example 19(a) and 145 mg of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylacetic acid melting at 306C were obtained.
Example 20 ..
20 ml of glycol monomethyl ether and 1 g of Raney nickel were added to 210 mg of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolyl-acetic acid, and the acid was hydrogenated at room temperature under normal pressure. The reaction mixture was ., 1~77049 worked up as described in Example 17(c) and 4-(4-aminophenyl)-1-phenyl-3-pyrazolylacetic acid was obtained.
Example 21 4-Phenyl-1-(3-chloro-4-fluorophenyl)-3-pyrazolylacetic acid was prepared from 3-chloro-4-fluoroaniline under the conditions described in Example 6(a) to 6(g).
Example 22 4-Phenyl-(4-trifluoromethyl-phenyl)-3-pyrazolylacetic acid was prepared from 4-trifluoromethylaniline under the conditions described in Example 6(a) to 6(g).
Example 23 3-Methoxy-~-morpholinostyrene and 2-chloro-2-phenyl-hydrazonoacetic acid ethyl ester were reacted as described in Example 6(b) to 6(g) to yield 4-(3-methoxyphenyl)-1-phenyl-3-pyrazolylacetic acid.
Example 24 !
a) ~-Dimethylamino-4-nitrostyrene was reacted with 2-chloro-2-(4-fluorophenylhydrazono)-acetic acid under the conditions described in Example 17(a) to 17(c), and 4-(4-aminophenyl)-1- ~:
(4-fluorophenyl?-3-pyrazolylcarboxylic acid ethyl ester was obtained.
b) The resulting compound was converted into 4-(4-chloro- 's phenyl)-1-(4-fluorophenyl)-3-pyrazolylacetic acid as described in Example 17(d) and 17(e).
Example 25 4-(4-Aminophenyl)-1-(4-fluorophenyl)-3-pyrazolylcarboxy-lic acid ethyl ester was converted into 4-(4-methoxyphenyl)-1-(4-fluorophenyl)-3-pyrazolylacetic acid under the conditions described in Example 18(a) and 18(b).
2Q e) The bromination of the alcohol, as described in Example '' 6(e), yielded 3-brom~thyl-4-phenyl-1-(2-chlorophenyl)-pyrazole melting at 91C.
f) The bromide was converted into 4-phenyl-1-(2-chloro- I, phenyl)-3-p~razolylacetonitrile, melting at 62C, under the conditions described in Example 6(f).
g) The resulting nitrile was converted into 4-phenyl-1-(2-chlorophenyl)-3-pyrazolylacetic acid melting at 146C, as described in Example 6(g).
Example 11 4-Phenyl-1-(4-chlorophenyl)-3-pyrazolylacetonitrile, melting at 121C, was prepared from 4-chloroaniline under the conditions described in Example 6(a) to 6(f), and was hydrolysed, 1~77~49 as described in Example 6(g), to form 4-phenyl-1-(4-chlorophenyl)-3-pyrazolylacetic acid melting at 137C.
The intermediate products obtained in the course of the preparation of the nitrile had the following physical data:
2-chloro-2-(4-chlorophenylhydrazono)-acetic acid ethyl ester, melting at 150C, 2-(4-chlorophenylhydrazono)-3-morpholinomethylene-3-phenylpropionic acid ethyl ester, melting at 164C, 4-phenyl-1-(4-chlorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 91C, 4-phenyl-1-(4-chlorophenyl)-3-pyrazolylmethanol, melting at 117C, and 3-bromomethyl-4-phenyl-1-(4-chlorophenyl)-pyrazole, melting at 125C.
Example 12 4-Phenyl-1-(3,4-dichlorophenyl)-3-pyrazolylacetonitrile melting at 131C, was prepared from 3,4-dichloroaniline, as ~' described in Example 6(a) to 6(f), and was hydrolysed to form 4-phenyl-1-(3,4-dichlorophenyl)-3-pyrazolylacetic acid, melting t~
at 158C, ~nder the conditions described in Example 6(g).
The intermediate products which were obtained in the course of the preparation of the nitrile had the following physical data:
2-chloro-2-(3,4-dichlorophenylhydrazono)-acetic acid ethyl ester, melting at 154C, 2-(3,4-dichlorophenylhydrazono) -3-morpholinomethylene-3-phenylpropionic acid ethyl ester, melting at 141C, 4-phenyl-1-(3,4-dichlorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 117C, 4-phenyl-1-(3,4-dichlorophenyl)-3-pyrazolylmethanol, melting at 121C, and 3-bromomethyl-4-phenyl-1-(3,4-dichlorophenyl)-pyrazole, melting at 108C.
Example 13 4-Phenyl-1-(4-fluorophenyl)-3-pyrazolylacetonitrile, meltinq at 79C, was prepared from ~-fluoroaniline under the same conditions as those described in Example 6(a) - 6(f) ! and was hydrolysed to form q-phenyl-1-(4-fluorophenyl)-3-pyrazolyl-acetic acid, melting at 171C, as described in Example 6(g).
The intermediate products which were obtained in the course of the preparation of the nitrile had the following physical data:
2-chloro-2-(4-fluorophenylhydrazono)-acetic acid ethyl ester, melting at 109C, 2-(4-fluorophenylhydrazono)-3-morpholinomethylene-3-phenylpropionic acid ethyl ester, melting at 161C, 4-phenyl-1-(4-fluorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 125C, 4-phenyl-1-(4-fluorophenyl)-3-pyrazolylmethanol, melting at 146C, and ~r 3-bromomethyl-4-phenyl-1-(4-fluorophenyl)-pyrazole, melting at 89C. -Ex _ple 14 4-Phenyl-1-(2-fluorophenyl)-3-pyrazolylacetonitrile, melting at 70C, was prepared from _-fluoroaniline under the conditions described in Example 6(a) to 6(f), and was hydrolysed to form 4-phenyl-1-(2-fluorophenyl)-3-pyrazolylacetic acid, melting at 154C, as described in Example 6(g). ?
The intermediate products which were obtained in the course of the preparation of the nitrile had the following r physical data:
2-chloro-2-(2-fluorophenylhydrazono)-acetic acid ethyl ester, melting at 70C, 2-(2-fluorophenylhydrazono)-3-morpholinomethylene-3-1~77~49 phenyl-propionic acid ethyl ester, melting at 99C !
4-phenyl-1-12~fluorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 62C~
4-phenyl-1-(2-fluorophenyl)-3-pyrazolylmethanol, melting at 109C, and 3-bromomethyl-4-phenyl-1-(2-fluorophenyl)-pyrazole, melting at 102C. E
Example 15 4-Phenyl-1-(3-fluorophenyl)-3-pyrazolylacetonitrile, 10melting at 74C, was prepared from _-fluoroaniline under the conditions described in Example 6(a) to 6(f) and was hydrolysed to form 4-phenyl-1-(3-fluorophenyl)-3-pyrazolylacetic acid, melting at 159C, as described in Example 6(g).
The intermediate products which were obtained in the course of the preparation of the nitrile had the following physical data:
2-chloro-2-(3-fluorophenylhydrazono)-acetic acid ethyl ester, melting at 111C, 2-(3-fluorophenylhydrazono)-3-morpholinomethylene-3-20phenyl-propionic acid ethyl ester, melting at 110C, 4-phenyl-1-(3-fluorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 81C, 4-phenyl-1-(3-fluorophenyl)-3-pyrazolylmethanol, melting at 74C, and ` 3-bromomethyl-4-phenyl-1-(3-fluorophenyl)-pyrazole, melting at 75C.
Example 16 4-Phenyl-1-(3-trifluoromethylphenyl)-3-pyrazolylaceto-nitrile, melting at 76C, was prepared from m-trifluoromethyl-aniline under the conditions described in Example 6(a) to 6(f) and was hydrolysed to form 4-phenyl-1-(3-trifluoromethylphenyl)-3-pyrazolylacetic acid, melting at 169C, under the conditions described in Fxample 6(g), The intermediate products which were obtained in the course of the preparation of the nit:rile had the following physical data:
2-chloro-2,(3~trifluoromethyl-phenylhydrazono)-acetic acid ethyl ester, melting at 131C, 2-(3-trifluoromethyl-phenylhydrazono)-3-morpholino-methylene-3-phenylpropionic acid ethyl ester, melting at 125C, 4-phenyl-1-(3-trifluoromethyl-phenyl)-3-pyrazolyl-1~ carboxylic acid ethyl ester, melting at 66C, 4-phenyl-1-(3-trifluoromethyl-phenyl)-3-pyrazolyl-methanol, melting at 94C, and 3-bromomethyl-4-phenyl-1-(3-trifluoromethyl-phenyl)-pyrazole, melting at 120C.
Example 17 a) Under the conditions described in Example 6(b) 22.7 g of ~-dimethylamino-4-nitrostyrene were reacted with 19.2 g ~!
of 2-chloro-2-phenylhydrazonoacetic acid ethyl ester and worked up. 3-Dimethylaminomethylene-3-(4-nitrophenyl)-2-phenylhydrazono- e propionic acid ethyl ester melting at 139C was obtained. -~
b) The resulting compound was cyclized under the conditions described in Example 6(c) to form 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylcarboxylic acid ethyl ester melting at 143C.
c) 24 g of the compound obtained as described in Example 17(b) were dissolved in 500 ml of ethanol, 5 g of Raney nickel were added and the compound was hydrogenated at room temperature under normal pressure. The catalyst was then filtered off, the filtrate was concentrated in vacuo, the residue was recrystallized from methanol and 20 g of 4-(4-aminophenyl)-1-phenyl-3-pyrazolyl-carboxylic acid ethyl ester melting at 142C were obtained.
d) A solution of 760 mg of sodium nitrite in 1.5 ml of water was added to 3.1 g of 4-(4-aminophenyl)-1-phenYl-3-pyrazolylcarboxylic acid ethyl ester in 13 ml of 15% strength ~ .
hydrochloric acid at -5C, 25 ml of 3~ strength hydrochloric acid were then also added to the mixture and the whole, at -5, was added dropwise to a warm solution, at 60C, of 1,5 g of copper-(II) chloride in 30 ml of 12~ strength hydrochloric acid. The mixture was allowed to stand for a further 10 minutes at 60C and was then cooled and extracted with ethyl acetate, the extract was concentrated, the residue was taken up in toluene, the solution was filtered through a silica gel column and was concentrated, and 2.47 g of 4-(4-chlorophenyl)-1-phenyl-3-pyrazolylcarboxylic acid ethyl ester melting at 96C
were obtained.
e) 4-(4-Chlorophenyl)-l-phenyl-3-pyrazolylcarboxylic acid ethyl ester was converted into 4-(4-chlorophenyl)-1-phenyl-3-pyrazolylacetic acid, melting at 142C, under the conditions described in Example 6(d) to 6(g).
The intermediate products obtained in the course of the synthesis of this compound had the following physical constants:
4-(4-chlorophenyl)-1-phenyl-3-pyrazolylmethanol, melting at l45C, 3-bromomethyl-4-(4-chlorophenyl)-1-phenylpyrazole, F~
melting at 110C, and r, 4-(4-chlorophenyl)-1-phenyl-3-pyrazolylacetonitrile, i~
melting at 97C.
Example 18 a) 28 ml of lN hydrochloric acicl were added to 2.4 g of 4-(4-aminophenyl)-~phenyl-3-pyrazolylcarboxylic acid ethyl ester, the mixture was cooled to 0C and the ester was slowly diazotized with a solution of 830 mg of sodium nitrite in 5 ml of water, The mixture was diluted with 10 ml of water and was stirred for 15 minutes at 0C. 953 mg of zinc chloride were then added to the mixture ! which was allowed to stand for ~U77049 30 minutes. The precipitate which had separated out wa~ filter~d off with suction, dried and taken up in 50 ml of methanol, and the solution was allowed to stand for 16 hours at room temperature and was then heated for one hour under reflux. The reaction mixture was concentrated in vacuo, the residue was taken up in benzene and the benzene phase was washed and concentrated in vacuo.
2 equivalents of sodium hydroxide solution and 2.02 g of dimethyl ~ , sulphate were added to the residue and the mixture was heated for 30 minutes at 80C. After it had cooled, the mixture was extracted with methylene chloride, the organic phase was concen-trated, the residue was recrystallized from isopropanol and 1.92 g of 4-(4-methoxyphenyl)-1-phenyl-3-pyrazolylcarboxylic acid ethyl ester melting at 94C were obtained.
b) 4-(4-Methoxyphenyl~-l-phenyl-3-pyrazolylcarboxylic acid ethyl ester was converted into 4-(4-methoxyphenyl)-1-phenyl-3-pyrazolylacetic acid, melting at 170C, under the conditions described in Example 6(d) to 6(g).
The intermediate products obtained in the course of the synthesis of this compound had the following physical constants:
4-(4-methoxyphenyl)-l-phenyl-3-pyrazolylmethan melting at 101C, 3-chloromethyl-4-(4-methoxyphenyl)-1-phenyl-pyrazole, j~,melting at 125C (the compound was obtained from the immediately preceding compound by reaction with 1.1 equivalents of methane-sulphonyl chloride in pyridine at -15C), and 4-(4-Methoxyphenyl)-l-phenyl-3-pyrazolylacetonitrile, melting at 83C.
Example 19 a) 70 ml of isopropanol and 15 ml of a 40% strength L
potassium hydroxide solution were added to 2 g of 4-(4-nitro-phenyl)-l-phenyl-3-pyrazolylcarboxylic acid ethyl ester and the mixture was heated for 2 hours under reflux. The reaction 1C~77049 mixture was then concentrated ln vacuo to a far reaching extent, the crystals which had separated out were filtered off with suctlon, and 1.67 g of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylcarboxylic acid melting at 273C were obtained.
b) 0,5 mlof dimethylformamide and 10 ml of thionyl chloride were added to the carboxylic acid and the mixture was heated for 14 hours under reflux. The reaction mixture was concentrated ln vacuo and 1.55 g of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylcarboxylic acid chloride melting at 226C
were obtained.
c) 25 ml of dioxa~ and 5 ml of ether were added to the acid chloride and the mixture was cooled to lO~C. 3 equivalents of a solution of diazomethane in etherwere then added to the mixture, which was allowed to stand for 2 hours at 10C. The reaction mixture was concentrated in vacuo, 80 ml of isoamyl alcohol were added to the residue, and the mixture was filtered.
A solution of 4.4 g of silver benzoate in 45 ml of triethylamine `
was added dropwisè to the solution so obtained, and the mixture was allowed to stand for 72 hours. It was then filtered and the ~'~
filtrate was washed with an aqueous sodium carbonate solution and concentrated in vacuo. The residue was purified by chromato-graphy over a silica gel column, using cyclohexane/ethyl acetate, and 395 mg of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylacetic acid isoamyl ester melting at 81C were obtained.
d) The resulting ester was hydrolysed as described in Example 19(a) and 145 mg of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylacetic acid melting at 306C were obtained.
Example 20 ..
20 ml of glycol monomethyl ether and 1 g of Raney nickel were added to 210 mg of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolyl-acetic acid, and the acid was hydrogenated at room temperature under normal pressure. The reaction mixture was ., 1~77049 worked up as described in Example 17(c) and 4-(4-aminophenyl)-1-phenyl-3-pyrazolylacetic acid was obtained.
Example 21 4-Phenyl-1-(3-chloro-4-fluorophenyl)-3-pyrazolylacetic acid was prepared from 3-chloro-4-fluoroaniline under the conditions described in Example 6(a) to 6(g).
Example 22 4-Phenyl-(4-trifluoromethyl-phenyl)-3-pyrazolylacetic acid was prepared from 4-trifluoromethylaniline under the conditions described in Example 6(a) to 6(g).
Example 23 3-Methoxy-~-morpholinostyrene and 2-chloro-2-phenyl-hydrazonoacetic acid ethyl ester were reacted as described in Example 6(b) to 6(g) to yield 4-(3-methoxyphenyl)-1-phenyl-3-pyrazolylacetic acid.
Example 24 !
a) ~-Dimethylamino-4-nitrostyrene was reacted with 2-chloro-2-(4-fluorophenylhydrazono)-acetic acid under the conditions described in Example 17(a) to 17(c), and 4-(4-aminophenyl)-1- ~:
(4-fluorophenyl?-3-pyrazolylcarboxylic acid ethyl ester was obtained.
b) The resulting compound was converted into 4-(4-chloro- 's phenyl)-1-(4-fluorophenyl)-3-pyrazolylacetic acid as described in Example 17(d) and 17(e).
Example 25 4-(4-Aminophenyl)-1-(4-fluorophenyl)-3-pyrazolylcarboxy-lic acid ethyl ester was converted into 4-(4-methoxyphenyl)-1-(4-fluorophenyl)-3-pyrazolylacetic acid under the conditions described in Example 18(a) and 18(b).
Claims (100)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of a pyrazole derivative of the general formula I
(I) in which n represents 1, 2, 3 or 4, R1, R2, R3 and R4 each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a nitro group or an amino group, the atom or group represented by each of the symbols R1, R2, R3 and R4 being in the ortho-, meta- or para-position, and X represents a cyano group, an aminocarbonyl group, a lower alkoxycarbonyl group or a carboxyl group, or a physiolog-ically tolerable salt of such a compound in which X represents a carboxyl group, wherein (a) A pyrazole derivative of the general formula II
(II) , in which n, R1, R2, R3 and R4 have the meanings given above and Y represents a halogen atom, is reacted with an alkali metal cyanide and when required the resulting compound of the general formula I, in which X represents a cyano group, is hydrolyzed to form a compound of the general formula I, in which X repres-ents an aminocarbonyl or a carboxyl group, and when required any nitro group present is reduced to form an amino group and when required any resulting carboxylic acid is converted into a physiologically tolerable salt thereof or esterified to form a lower alkyl ester thereof, or (b) a pyrazole derivative of the general formula III
(III) , in which n, R1, R2, R3, R4 and Y have the meanings given above, is reacted in the presence of a deprotonizing agent with a malonic acid dialkyl ester or a cyanoactic acid alkyl ester and the re-sulting reaction product is hydrolyzed and decarboxylated to form a compound of the general formula I, in which X represents a carboxyl group or a cyano group, and when required any nitro group present is reduced to form an amino group and when required any resulting carboxylic acid is converted into a physiologically tolerable salt thereof or esterified to form a lower alkyl ester thereof, or (c) a pyrazole derivative of the general formula II
(II) , in which n, R1, R2, R3, R4 and Y have the meanings given above, is reacted with magnesium or lithium and the resulting organo-metal compound is treated with carbon dioxide and, when required any nitro group present is reduced to form an amino group and when required the resulting carboxylic acid is converted into a physiologically tolerable salt thereof, a corresponding amide or nitrile or a lower alkyl ester thereof, or (d) a pyrazole derivative of the general formula IV
(IV) , in which n, R1, R2, R3 and R4 have the meanings given above, is reacted with diazomethane and the resulting diazoketone is re-arranged in the presence of water, ammonia or a lower alcohol to form a compound of the general formula I, in which X represents a carboxyl, aminocarbonyl or lower alkoxycarbonyl group, res-pectively, and, when required any nitro group present is reduced to form an amino group and when required any ester group present is hydrolysed to form a carboxyl group or any aminocarbonyl group present is dehydrated to form a cyano group and when required any resulting carboxylic acid is converted into a physiologically tolerable salt thereof.
(I) in which n represents 1, 2, 3 or 4, R1, R2, R3 and R4 each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a nitro group or an amino group, the atom or group represented by each of the symbols R1, R2, R3 and R4 being in the ortho-, meta- or para-position, and X represents a cyano group, an aminocarbonyl group, a lower alkoxycarbonyl group or a carboxyl group, or a physiolog-ically tolerable salt of such a compound in which X represents a carboxyl group, wherein (a) A pyrazole derivative of the general formula II
(II) , in which n, R1, R2, R3 and R4 have the meanings given above and Y represents a halogen atom, is reacted with an alkali metal cyanide and when required the resulting compound of the general formula I, in which X represents a cyano group, is hydrolyzed to form a compound of the general formula I, in which X repres-ents an aminocarbonyl or a carboxyl group, and when required any nitro group present is reduced to form an amino group and when required any resulting carboxylic acid is converted into a physiologically tolerable salt thereof or esterified to form a lower alkyl ester thereof, or (b) a pyrazole derivative of the general formula III
(III) , in which n, R1, R2, R3, R4 and Y have the meanings given above, is reacted in the presence of a deprotonizing agent with a malonic acid dialkyl ester or a cyanoactic acid alkyl ester and the re-sulting reaction product is hydrolyzed and decarboxylated to form a compound of the general formula I, in which X represents a carboxyl group or a cyano group, and when required any nitro group present is reduced to form an amino group and when required any resulting carboxylic acid is converted into a physiologically tolerable salt thereof or esterified to form a lower alkyl ester thereof, or (c) a pyrazole derivative of the general formula II
(II) , in which n, R1, R2, R3, R4 and Y have the meanings given above, is reacted with magnesium or lithium and the resulting organo-metal compound is treated with carbon dioxide and, when required any nitro group present is reduced to form an amino group and when required the resulting carboxylic acid is converted into a physiologically tolerable salt thereof, a corresponding amide or nitrile or a lower alkyl ester thereof, or (d) a pyrazole derivative of the general formula IV
(IV) , in which n, R1, R2, R3 and R4 have the meanings given above, is reacted with diazomethane and the resulting diazoketone is re-arranged in the presence of water, ammonia or a lower alcohol to form a compound of the general formula I, in which X represents a carboxyl, aminocarbonyl or lower alkoxycarbonyl group, res-pectively, and, when required any nitro group present is reduced to form an amino group and when required any ester group present is hydrolysed to form a carboxyl group or any aminocarbonyl group present is dehydrated to form a cyano group and when required any resulting carboxylic acid is converted into a physiologically tolerable salt thereof.
2. A pyrazole derivative of the general formula I
(I) in which n represents 1, 2, 3 or 4, R1, R2, R3 and R4 each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a nitro group or an amino group, the atom or group represented by each of the symbols R1, R2, R3 and R4 being in the ortho-, meta- or para-position, and X represents a cyano group, an aminocarbonyl group, a lower alkoxycarbonyl group or a carboxyl group or a physiologically tolerable salt thereof when prepared by the process as claimed in claim 1 or an obvious chemical equivalent thereof.
(I) in which n represents 1, 2, 3 or 4, R1, R2, R3 and R4 each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a nitro group or an amino group, the atom or group represented by each of the symbols R1, R2, R3 and R4 being in the ortho-, meta- or para-position, and X represents a cyano group, an aminocarbonyl group, a lower alkoxycarbonyl group or a carboxyl group or a physiologically tolerable salt thereof when prepared by the process as claimed in claim 1 or an obvious chemical equivalent thereof.
3. A process as claimed in claim 1, in which in the reactant the halogen atom is a fluorine or chlorine atom.
4. A compound of formula I given in claim 1, in which n, R1,R2,R3,R4 and X are as in claim 1 or a physiologically tolerable salt thereof and wherein the halogen atom is a fluorine or chlorine atom when prepared by the process as claimed in claim 3 or an obvious chemical equivalent thereof.
5. A process as claimed in claim 3, in which in the reactants the alkyl group contains 1 to 4 carbon atoms.
6. A compound of formula I given in claim 1, in which n,R1,R2,R3,R4 and X are as in claim 1 or a physiologically tolerable salt thereof and wherein the halogen is fluorine or chlorine and the alkyl group contains 1 to 4 carbon atoms when prepared by the process as claimed in claim 5 or an obvious chemical equivalent thereof.
7. A process as claimed in claim 5, in which in the reactants the alkyl group is methyl,
8. A compound of formula I given in claim 1, in which n, R1, R2, R3, R4 and X are as in claim 1 or a physiologically tolerable salt thereof and wherein the halogen atom is fluorine or chlorine and the alkyl group is a methyl group when prepared by the process as claimed in claim 7 or an obvious chemical equivalent thereof.
9. A process as claimed in claim 5, in which in the reactants the alkoxy group represented by the symbols R1, R2, R3 and R4 has 1 to 4 carbon atoms.
10. A compound of formula I given in claim 1, in which n, R1, R2, R3, R4 and X are as in claim 1 or a physiologically tolerable salt thereof and wherein the halogen atom is fluorine or chlorine, the alkyl group contains 1 to 4 carbon atoms and the alkoxy group represented by the symbols R1, R2, R3 and R4 has 1 to 4 carbon atoms when prepared by the process as claimed in claim 9 or an obvious chemical equivalent thereof.
11. A process as claimed in claim 7, in which in the reactants the alkoxy group represented by the symbols R1, R2, R3 and R4 is methoxy.
12. A compound of formula I given in claim 1, in which n, R1, R2, R3, R4 and X are as in claim 1 or a physiologically tolerable salt thereof and wherein the alkoxy group represented by each of the symbols R1, R2, R3 and R4 is a methoxy group, the alkyl group is a methyl group and the halogen atom is a fluorine or chlorine atom when prepared by the process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process as claimed in claim 9, in which in the reactants the alkoxy part of the lower alkoxycarbonyl group contains 1 to 6 carbon atoms.
14. A compound of formula I given in claim 1, in which n, R1, R2, R3, R4 and X are as in claim 1 or a physiologically tolerable salt thereof and wherein the alkoxy part of the lower alkoxycarbonyl group contains 1 to 6 carbon atoms, the halogen atom is fluorine or chlorine, the alkyl group contains 1 to 4 carbon atoms and the alkoxy group represented by each of the symbols R1, R2, R3 and R4 contains 1 to 4 carbon atoms when prepared by the process as claimed in claim 13 or an obvious chemical equivalent thereof.
15. A process as claimed in claim 1, in which the product obtained in which X is carboxyl is converted to an alkali metal salt, an alkaline earth metal salt, a copper salt or an amine salt.
16. A compound of formula I given in claim 1, in which n, R1, R2, R3, R4 and X are as in claim 1 or a physiologically tolerable salt thereof and in the form of an alkali metal salt, an alkaline earth metal salt, a copper salt or an amine salt thereof when prepared by the process as claimed in claim 15 or an obvious chemical equivalent thereof.
17. A process as claimed in claim 1, in which in the reactants, n is 1, 2 or 3, X is cyano, aminocarbonyl, carboxyl ethoxylcarbonyl, iso-amyloxy or carboxyl, R2 is hydrogen, R4 is hydrogen, chlorine or fluorine, R1 is hydrogen chlorine, methoxy, nitro or amino and R3 is hydrogen, methyl, chlorine, fluorine or trifluoro methyl and when required, when X is carboxyl, converting the product obtained into the sodium salt.
18. A compound of formula I given in claim 1, in which n, X, R1, R2, R3 and R4 are as in claim 15 or a sodium salt thereof when prepared by the process as claimed in claim 17 or an obvious chemical equivalent thereof.
19. A process as claimed in claim 1 which comprises reacting 3-bromo methyl-1,4-diphenyl pyrazole in absolute acetonitrile with potassium cyanide in the presence of dibenzo-18-coronene.
20, (1,4-Diphenyl-3-pyrazolyl)-acetonitrile when prepared by the process as claimed in claim 19 or an obvious chemical equivalent thereof.
21. A process as claimed in claim 19, in which the (1,4-diphenyl-3-pyrazolyl) -acetonitrile is hydrolysed with concentrated hydrochloric acid,
22. (1,4-Diphenyl-3-pyrazolyl)-acetamide when prepared by the process as claimed in claim 21 or an obvious chemical equivalent thereof.
23. A process as claimed in claim 21, in which the (1,4-diphenyl-3-pyrazolyl)acetamide is treated under reflux in aqueous sodium hydroxide in an argon atmosphere.
24. A process as claimed in claim 19, which comprises heating the (1,4-diphenyl-3-pyrazolyl)-acetonitrile so obtained with sulphuric acid.
25. (1,4-Diphenyl-3-pyrazolyl)-acetic acid when prepared by the process as claimed in claim 23 or 24 or an obvious chemical equivalent thereof.
26. A process as claimed in claim 24, in which the acid obtained in absolute ethanol is reacted with aqueous sodium hydroxide.
27. Sodium (1,4-diphenyl-3-pyrazolyl)-acetate when prepared by the process as claimed in claim 26 or an obvious chemical equivalent thereof.
28. A process as claimed in claim 1 which comprises reacting 3-bromomethyl-1,4-diphenyl-pyrazole with malonic acid diethyl ester in absolute benzene in the presence of thallium ethylate, hydrolysing the resulting 2-(1,4-diphenyl-3-pyrazolyl- methyl)-malonic acid diethyl ester with sodium hydroxide in dioxane under reflux and heating the 2-(1,4-diphenyl-3-pyrazolyl-methyl)malonic acid to effect decarboxylation thereof.
29. 3-(1,4-Diphenyl-3-pyrazolyl)-propionic acid when prepared by the process as claimed in claim 28 or an obvious chemical equivalent thereof.
30. A process as claimed in claim 28 in which the acid obtained in absolute ethanol is reacted with aqueous sodium hydroxide.
31. Sodium 3-(1,4-diphenyl-3-pyrazolyly)-propionate when prepared by the process as claimed in claim 30 or an obvious chemical equivalent thereof.
32. A process as claimed in claim 28, in which the acid obtained is heated under reflux with thionyl chloride and the resulting chloride reacted with ethanol in benzene and in the presence of pyridine.
33. 3-(1,4-Diphenyl-3-pyrazolyl)-propionic acid ethyl ester when prepared by the process as claimed in claim 32 or an obvious chemical equivalent thereof.
34. A process as claimed in claim 28, in which the acid obtained is heated under reflux with thionyl chloride, the resulting chloride treated with diazomethane in ether and the product obtained heated with ethanol in the presence of silver oxide.
35. 4-(1,4-Diphenyl-3-pyrazolyl)-butyric acid ethyl ester when prepared by the process as claimed in claim 34 or an obvious chemical equivalent thereof.
36. A process as claimed in claim 34, in which the ester obtained is heated under reflux with ethanolic sodium hydroxide.
37. 4-(1,4-Diphenyl-3-pyrazolyl)-butyric acid when prepared by the process as claimed in claim 36 or an obvious chemical equivalent thereof.
38. A process as claimed in claim 1 which comprises heating 3-bromomethyl-4-phenyl-1-(4-tolyl)-pyrazole with potassium in cyanide in acetonitrile and in the presence of dibenzo-18-coronene-6.
39. 4-Phenyl-1-(4-tolyl)-3-pyrazolylacetonitrile when prepared by the process as claimed in claim 38 or an obvious chemical equivalent thereof.
40. A process as claimed in claim 38, in which the nitrile so obtained is heated with concentrated hydrochloricacid.
41. 4-Phenyl-1-(4-tolyl)-3-pyrazolylacetamide when prepared by the process as claimed in claim 40 or an obvious chemical equivalent thereof.
42. A process as claimed in claim 38, in which the nitrile so obtained is heated with sulphuric acid.
43. A process as claimed in claim 40, in which the acetamide so obtained is refluxed with sodium hydroxide under argon.
44. 4-Phenyl-1-(4-tolyl)-3-pyrazolylacetic acid when prepared by the process as claimed in claim 42 or 43 or an obvious chemical equivalent thereof.
45. A process as claimed in claim 42, in which the acid obtained is heated under reflux with thionyl chloride and the resulting chloride reacted with ethanol in benzene and in the presence of pyridine.
46. 4-Phenyl-1-(4-tolyl)-3-pyrazolylacetic acid ethyl ester when prepared by the presence of claim 45 or an obvious chemical equivalent thereof.
47. A process as claimed in claim 1, which comprises heating 3-bromomethyl-4-phenyl-1-(2-tolyl)-pyrazole with potassium cyanide in acetonitrile and in the presence of dibenzo-18-coronene-6.
48. 4-Phenyl-1-(2-tolyl)-3-pyrazolylacetonitrile when prepared by the process as claimed in claim 47 or an ohvious chemical equivalent thereof.
49. A process as claimed in claim 47, in which the nitrile so obtained is heated with sulphuric acid.
50. 4-Phenyl-1-(2-tolyl)-3-pyrazolylacetic acid when prepared by the process as claimed in claim 49 or an obvious chemical equivalent thereof.
51. A process as claimed in claim 1, which comprises heating3-bromomethyl-4-phenyl-1-(2-chlorophenyl)-pyrazolee with potassium cyanide in acetonitrile and in the presence of dibenzo-18-coronene-6.
52. 4-Phenyl-1-(2-chlorophenyl)-3-pyrazolylacetonitrille when prepared by the process as claimed in claim 51 or an obvious chemical equivalent thereof.
53. A process as claimed in claim 51, in which the nitrile so obtained is heated with sulphuric acid.
54. 4-Phenyl-1-(2-chlorophenyl)-3-pyrazolylacetic acid when prepared by the process as claimed in claim 53 or an obvious chemical equivalent thereof.
55. A process as claimed in claim 1 which comprises heating3-bromomethyl-4-phenyl-1-(4-chlorophenyl)-pyrazolee with potassium cyanide in acetonitrile and inthe presence of dibenzo-18-coronene-6.
56. 4-Phenyl-1-(4-chlorophenyl)-pyrazolylacetonitrile when prepared by the process as claimed in claim 55 or an obvious chemical equivalent thereof.
57. A process as claimed in claim 55, in which the nitrile so obtained is heated with sulphuric acid.
58. 4-Phenyl-1-(4-chlorophenyl)-pyrazolylacetic acid when prepared by the process as claimed in claim 57 or an obvious chemical equivalent thereof.
59. A process as claimed in claim 1, which comprises heating3-bromomethyl-4-phenyl-1-(3,4-dichlorophenyl)-pyraazole with potassium cyanide in acetonitrile and in the presence of dibenzo-18-coronene-6.
60. 4-Phenyl-1-(3,4-dichlorophenyl)-pyrazolylaceto-nitrile when prepared by the process as claimed in claim 59 or an obvious chemical equivalent thereof.
61. A process as claimed in claim 59, in which the nitrile so obtained is heated with sulphuric acid.
62. 4-Phenyl-1-(3,4-dichlorophenyl)-pyrazolylacetic acid when prepared by the process as claimed in claim 61 or an obvious chemical equivalent thereof.
63. A process as claimed in claim 1, which comprises heating3-bromomethyl-4-phenyl-1-(4-fluorophenyl)-pyrazolee with potassium cyanide in acetonitrile and in the presence of dibenzo-18-coronene-6.
64. 4-Phenyl-1-(4-fluorophenyl)-pyrazolylacetonitrile when prepared by the process as claimed in claim 63 or an obvious chemical equivalent thereof.
65. A process as claimed in claim 63, in which the nitrile so obtained is heated with sulphuric acid.
66. 4-Phenyl-1-(4-fluorophenyl)-pyrazolylacetic acid when prepared by the process as claimed in claim 65 or an obvious chemical equivalent thereof.
67. A process as claimed in claim 1, which comprises heating3-bromomethyl-4-phenyl-1-(2-fluorophenyl)-pyrazolee with potassium cyanide in acetonitrile and in the presence of dibenzo-18-coronene-6.
68. 4-Phenyl-1-(2-fluorophenyl)-pyrazolylacetonitrile when prepared by the process as claimed in claim 67 or an obvious chemical equivalent thereof.
69. A process as claimed in claim 67, in which the nitrile so obtained is heated with sulphuric acid.
70. 4-Phenyl-1-(2-fluorophenyl)-pyrazolylacetic acid when prepared by the process as claimed in claim 69 or an obvious chemical equivalent thereof.
71. A process as claimed in claim 1, which comprises heating3-bromomethyl-4-phenyl-1-(3-fluorophenyl)-pyrazolee with potassium cyanide in acetonitrile and in the presence of dibenzo-18-coronene-6.
72. 4-Phenyl-1-(3-fluorophenyl)-pyrazolylacetonitrile when prepared by the process as claimed in claim 71 or an obvious chemical equivalent thereof.
73. A process as claimed in claim 71, in which the nitrile so obtained is heated with sulphuric acid.
74. 4-Phenyl-1-(3-fluorophenyl)-pyrazolylacetic acid when prepared by the process as claimed in claim 73 or an obvious chemical equivalent thereof.
75. A process as claimed in claim 1, which comprises heating3-bromomethyl-4-phenyl-1-(3-trifluoromethylphenyl)-pyrazole with potassium cyanide in acetonitrile and in the presence of dibenzo-18-coronene-6.
76. 4-Phenyl-1-(3-trifluoromethylphenyl)-pyrazolylacett-onitrile when prepared by the process as claimed in claim 75 or an obvious chemical equivalent thereof.
77. A process as claimed in claim 75, in which the nitrile so obtained is heated with sulphuric acid.
78. 4-Phenyl-1-(3-trifluoromethylphenyl)-pyrazolyl-acetic acid when prepared by the process as claimed in claim 77 or an obvious chemical equivalent thereof.
79. A process as claimed in claim 1, which comprises heating 3-bromomethyl-4-(4-chlorophenyl)-1-phenyl pyrazole with potassium cyanide in acetonitrile and in the presence of dibenzo-18-coronene-6.
80. 4-(4-Chlorophenyl)-l-phenyl-3-pyrazolylacetonitrille when prepared by the process as claimed in claim 79 or an obvious chemical equivalent thereof.
81. A process as claimed in claim 79, in which the nitrile so obtained is heated with sulphuric acid,
82. 4-(4-Chlorophenyl)-1-phenyl-3-pyrazolylacetic acid when prepared by the process as claimed in claim 81 or an obvious chemical equivalent thereof.
83. A process as claimed in claim 1, which comprises heating 3-chloromethyl-4(4-methoxyphenyl)-1-phenyl pyrazole with potassium cyanide in acetonitrile and in the presence of dibenzo-18-coronene-6.
84. 4-(4-Methoxyphenyl)-1-phenyl-3-pyrazolylacetonitriile when prepared by the process as claimed in claim 83 or an obvious chemical equivalent thereof.
85. A process as claimed in claim 83, in which the nitrile so obtained is heated with sulphuric acid.
86. 4-(4-Methoxyphenyl)-1-phenyl-3-pyrazolylacetic acid when prepared by the process as claimed in claim 85 or an obvious chemical equivalent thereof.
87. A process as claimed in claim 1 which comprises reacting 4-(4-nitrophenyl)-1-phenyl-3-pyrazolyl carboxylic acid chloride in dioxane and ether with diazo methane and the product obtained is treated with isoamyl alcohol in the presence silver benzoate and pyridine.
88. 4-(4-Nitrophenyl)-1-phenyl-3-pyrazolylacetic acid isoamyl ester when prepared by the process as claimed in claim 87 or an obvious chemical equivalent thereof.
89. A process as claimed in claim 87, in which the ester is hydrolysed by heating under reflux with isopropanolic potassium hydroxide.
90. 4-(4-Nitrophenyl)-1-phenyl-3-pyrazolylacetic acid when prepared by the process as claimed in claim 89 or an obvious chemical equivalent thereof.
91. A process as claimed in claim 89, in which the acid obtained is hydrogenated in glycol monomethyl ether and in the presence of Raney nickel,
92. 4-(4-Aminophenyl)-1-phenyl-3-pyrazolylacetic acid when prepared by the process as claimed in claim 91 or an obvious chemical equivalent thereof.
93. A process as claimed in claim 1, which comprises heating 3-bromomethyl-4-phenyl-1-(3-chloro-4-fluorophenyl)-pyrazole and the product obtained is hydrolysed by heating with sulphuric acid.
94. 4-Phenyl-1-(3-chloro-4-fluorophenyl)-3-pyrazolyl-acetic acid when prepared by the process as claimed in claim 93 or an obvious chemical equivalent thereof.
95. A process as claimed in claim 1, which comprises heating 3-bromomethyl-4-phenyl-1-(4-trifluoromethylphenyl)-pyrazole and the product obtained is hydrolysed by heating with sulphuric acid.
96. 4-Phenyl-1-(4-trifluoromethyl-phenyl)-3-pyrazolyl-acetic acid when prepared by the process as claimed in claim 95 or an obvious chemical equivalent thereof.
97. A process as claimed in claim 1, which comprises heating 3-bromomethyl-4-(3-methoxyphenyl)-1-phenyl- pyrazole and the product obtained is hydrolysed by heating with sulphuric acid.
98. 4-(3-Methoxyphenyl)-1-phenyl-3-pyrazolylacetic acid when prepared by the process as claimed in claim 97 or an obvious chemical equivalent thereof.
99. A process as claimed in claim 1, which comprises heating 3-bromomethyl-4-(4-chlorophenyl)-1-(4-fluorophenyl)-pyrazole and the product obtained is hydrolysed by heating with sulphuric acid.
100. 4-(4-Chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl--acetic acid when prepared by the process as claimed in claim 99 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA271,158A CA1077049A (en) | 1977-02-07 | 1977-02-07 | Pyrazole derivatives and their manufacture and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA271,158A CA1077049A (en) | 1977-02-07 | 1977-02-07 | Pyrazole derivatives and their manufacture and use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1077049A true CA1077049A (en) | 1980-05-06 |
Family
ID=4107870
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA271,158A Expired CA1077049A (en) | 1977-02-07 | 1977-02-07 | Pyrazole derivatives and their manufacture and use |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1077049A (en) |
-
1977
- 1977-02-07 CA CA271,158A patent/CA1077049A/en not_active Expired
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