HU210668B - Process for production of n-phenyl-pyrazole derivatives - Google Patents

Abstract

The present invention relates to novel N-phenylpyrazole derivatives of formula (I). In which R 1 is halogen, cyano, amino, carbamoyl, carboxy, 1-hydroxyethyl, trifluoromethyl or C 2-7 alkoxycarbonyl, R 2 is hydrogen, thiocyanate, cyano, formyl, C 2-4 alkoxycarbonyl, C 1-4 alkylsulfonyl or trifluoromethylthio, R 3 is hydrogen, amino, cyano or (C 1 -C 4) alkoxycarbonylamino and R4 is in the 2-position with a fluorine, chlorine or bromine, in the 4-position with a haloalkyl of 1-4 carbon atoms or with a C1-4 haloalkoxy group, preferably a trifluoromethyl or trifluoromethoxy group. and optionally phenyl substituted at the 6-position by chlorine or bromine, with various restrictions. The compounds are intermediates for the synthesis of herbicidal agents. (I) EN 210 668 B Scope of the description: 14 pages (including 3 sheets)

Description

The present invention relates to novel N-phenylpyrazole derivatives of formula (I). Wherein R ¹ is halogen, cyano, amino, carbamoyl, carboxy, 1-hydroxyethyl, trifluoromethyl or C 2 -C 7 alkoxycarbonyl,

R ² is hydrogen, thiocyanato, cyano, formyl,

C 2 -C 4 alkoxycarbonyl, C 1 -C 4 alkylsulfonyl or trifluoromethylthio,

R ³ is hydrogen, amino, cyano, or (C 1 -C 4) alkoxy-carbonylamino, and

R ^{4 at} the 2-position is fluoro, chloro or bromo, at the 4-position C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably trifluoromethyl or trifluoromethoxy, and optionally phenyl substituted in the 6-position with chlorine or bromine, except compounds of the formula

R ¹ is halogen or cyano and simultaneously

R ² is C 1-4 alkylsulfonyl or trifluoromethylthio; and

R ³ is hydrogen, amino, or (C 1 -C 4) alkoxy-carbonylamino, and compounds wherein

- R ⁴ is 2,6-dichloro-4- (trifluoromethyl) phenyl, R ¹ and R ² are cyano and R ³ is amino or ethoxycarbonylamino, or

R ¹ is chlorine and R ³ is amino or ethoxycarbonylamino, or

- R * is bromo or iodo or amino or ethoxycarbonyl and R ³ is amino, or

R ¹ is fluoro and R ³ is hydrogen or amino, or

- R ¹ is amino or ethoxycarbonyl and R ³ is hydrogen or

- R ⁴ is 2,4,6-trichlorophenyl, 2-chloro-4- (trifluoromethyl) phenyl or 2,6-dichloro-4- (trifluoromethoxy) phenyl, R ¹ and R ² is cyano and R ³ is amino, or

- R ⁴ is 2,6-dichloro-4- (trifluoromethoxy) phenyl, R ² is cyano, R ¹ is chloro and R ³ is amino, or

- R ⁴ is 2,6-dichloro-4- (trifluoromethyl) phenyl, R ² is carboxycarbamoyl or ethoxycarbonyl and R ³ is amino.

Herbicides containing N-phenyl-prazole derivatives and a process for their preparation are described in HU-B 187 320.

The compounds of formula (I) are useful as intermediates for the synthesis of the herbicidal N-phenylpyrazoles of formula (Ia) (HU-B 203 729). In the compounds of formula (Ia) structurally identical to formula (I), the substituents have the same meaning as given in formula (I), except that

- R ^{2 is} not hydrogen, thiocyanate, formyl, cyano or alkoxycarbonyl,

R * cannot be amino, 1-hydroxyethyl, carboxy, carbamoyl, or alkoxycarbonyl.

A preferred compound of formula I is 5-amino-3-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] pyrazole.

a) Compounds of formula I wherein R ³ is amino, R ² is hydrogen, and R ¹ is cyano can be prepared by diazotizing an aniline of R ⁴ NH ₂ (wherein R ⁴ is as defined above). This is generally carried out in a solution of one molar equivalent of sodium nitrite in a solution of a mineral acid such as concentrated sulfuric acid and acetic acid at a temperature between 0 and 60 ° C, in the presence of an inert solvent such as ethanol and water, and sodium acetate-buffered medium at a temperature between 0 and 50 ° C with a compound of formula XVII wherein R ¹⁸ is C 1-6 alkoxy, preferably ethoxy. Subsequently, slight hydrolysis with a base such as aqueous sodium hydroxide, sodium carbonate or ammonia may be necessary to effect the cyclization.

The variant of the above compound (XVII) in which R ¹⁸ is hydrogen may be used in the form of the alkali enolate salts which are converted to the aldehyde in the acidic medium of the above coupling reaction.

b) Compounds of formula (I) wherein R * is as defined above (i.e., cannot be formyl), R ² is carboxyl, and R ³ is amino can be prepared by hydrolysis of esters of formula (I) wherein R ² is replaced by the -COOR group with the above meaning. The hydrolysis is preferably carried out in a solvent such as an aqueous alcohol with an alkali metal hydroxide between 0 ° C and the reflux temperature of the reaction mixture.

c) Esters of formula I wherein R ² is formyl are prepared by reacting a nitrile wherein R ² is cyano in an inert solvent, preferably tetrahydrofuran, at a temperature between -78 ° C and room temperature, preferably with diisobutylaluminum hydride.

d) Compounds of formula (I) compounds of the general formula wherein ^R1 is carboxy may be prepared from the corresponding ester in which ^R1 is alkoxycarbonyl, e.g., ethoxycarbonyl group, with a base such as sodium hydroxide and a solvent such as aqueous alcohol at 0 ° C to the reflux temperature of the solvent.

For the above reaction, the carboxylic acid ester intermediate wherein R ² is replaced by R ¹⁹ is prepared by reacting an intermediate of formula XXI wherein R and R ² are as defined above and X ⁶ is an easily cleavable intermediate. a group such as chlorine in an inert solvent, preferably ether or tetrahydrofuran, and optionally in the presence of a base such as triethylamine or sodium acetate 2

At a temperature between 0 ° C and the reflux temperature of the reaction mixture, a phenyl hydrazine derivative of formula (V) wherein R ⁴ is as defined above is reacted.

The above carboxylic acid ester intermediate, wherein R ^{2 is} substituted with R ¹⁹ , can also be prepared by reacting a compound of formula II wherein R ⁸ is a -COOR group, wherein R is as defined above. generally a molar amount of ^{R 9} CH ₂ CN, a compound of formula at a temperature between an organic anhydrous inert solvent, and a molar equivalent of a base such as sodium ethoxide in the presence of 0 to 50 ° C - ¹⁹ wherein R is as defined above is reacted.

Compounds of formula (II), intermediates of the formula in which R ⁸ is COOR, known compounds [e.g. _CH3 COCH (C1) COOR] can be prepared by using an ester, a similar method to that of (Π) of the formula We described the preparation of compounds wherein ^R8 is cyano or acetyl.

The halide intermediates of formula (XXI) wherein X ⁶ is chlorine and R and R ² are as defined above may be prepared by reacting a sodium or potassium salt of formula (XXI) wherein X ⁶ is -O'Na ⁺ or -O'K ⁺ - optionally in the presence of an inert solvent such as tetrahydrofuran, at a temperature between 0 ° C and the reflux temperature of the solvent, with a suitable chlorinating agent, preferably phosphorus oxychloride.

The salts (XXI) wherein X ⁶ is -O'Na -O'K or ^{+ +} may be prepared by methods described in the literature in which an R ^ H ^ N active methylene derivative in an inert solvent such as a alcohol such as ethanol in the presence of a metal alkoxide such as sodium ethoxide is reacted with a dialkyl such as diethyl oxalate at a temperature between 25 ° C and the reflux temperature of the solvent.

e) Compounds of formula (I) wherein R * is 1-hydroxyethyl are prepared by reacting an aldehyde of formula (I) wherein R * is formyl and R ³ is hydrogen or amino. in a solvent such as ether or tetrahydrofuran at room temperature to the reflux temperature of the solvent is reacted with a Grignard reagent, preferably a methyl magnesium halide.

f) thiocyano in R ² is wherein R ³ is is the 4-thiocyanato-pyrazole derivatives of formula (I), an amino group, is prepared by treatment of a formula (I) compound wherein R ² is a hydrogen atom, with in an inert organic solvent such as methanol at a temperature between 0 and 100 ° C with a reagent such as an alkali metal or ammonium salt of thiocyanic acid (e.g. NaSCN) and bromine.

g) The diamino esters of formula I wherein R ¹ and R ³ are amino and R ² is C 2 -C 4 straight or branched alkoxycarbonyl may be prepared by appropriately substituted (V). The phenylhydrazine derivative of the formula (III) is reacted with an alkali metal salt of an alkyldicyanoacetate (XXII), preferably potassium ethyldicyanoacetate, at room temperature to the reflux temperature. The potassium salt of alkyl dicyanoacetate can be prepared from the corresponding alkyl chloroformate in tetrahydrofuran at a temperature between 0 ° C and 100 ° C in the presence of potassium hydroxide with malonitrile.

h) The diaminosulfonylpyrazole derivatives of formula I wherein R * and R ³ are amino and R ² is (C 1 -C 4) alkylsulfonyl are prepared in a manner similar to the above reaction: reacting a phenyl hydrazine derivative of the formula wherein R ⁴ is as defined above with an alkylsulfonylmalonitrile of the general formula (ΧΧΙΠ) wherein R ⁵ is a C 1-4 alkyl group.

Compounds of formula (XXIII) may be prepared by methods known in the art.

i () Compounds of formula (I) esters of the formula in which R ¹ is chlorine, bromine, fluorine, a hydrogen atom in the R ² substituent in place and R ³ is an amino group can be prepared by reacting the corresponding compound (I) of formula, wherein R ¹ is an amino group, a sulfuric acid-sodium nitrite solution, fluoroboric acid or its sodium salt in the presence of diazotized and the resulting diazonium fluoroborate derivative is decomposed by art-known methods thermo- or photolysis.

The esters of formula I wherein R ¹ is chloro, bromo, fluoro, R ² is hydrogen and R ³ is amino may also be prepared by reacting a phenyl hydrazine of formula V reacting a derivative wherein R ⁴ is as defined above with an alkali metal salt of a compound of formula XXIV wherein M is potassium or sodium and R is as defined above. The reaction is carried out in an acidic medium, usually dilute sulfuric acid, optionally in the presence of an auxiliary solvent such as ethanol, at a temperature between room temperature and the reflux temperature of the solvent.

The following examples are intended to illustrate the preparation of compounds of formula (I).

Example 1

5-Amino-3-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] pyrazole

A suspension of nitrosyl sulfuric acid (7.0 g) in sodium nitrite and 27.5 ml of concentrated sulfuric acid was diluted with 25 ml of acetic acid and stirred at 25 ° C with mechanical stirring. At 25 to 32 ° C, 21.2 g of 2,6-dichloro-4- (trifluoromethyl) aniline dissolved in 50 ml of acetic acid are added dropwise over 15 minutes. The resulting mixture is heated at 55 'C for 20 minutes and then 14.0 g of ethyl 2,3-dicyanopropionate, 60 ml of acetic acid are added and stirred at 10-20' C.

HU 210 668 Β

125 ml of water. After 15 minutes, 200 mL of water was added and the oily layer was separated. The aqueous solution was extracted with dichloromethane (3 x 70 mL), the extracts were combined with the oil phase and washed with ammonium hydroxide solution until pH = 9. The organic phase is then stirred with 20 ml of ammonium hydroxide solution for 2 hours and the dichloromethane layer is separated. This was washed with water (100 mL) followed by 1N hydrochloric acid (100 mL), dried over anhydrous magnesium sulfate, then filtered and concentrated in vacuo to give an oily solid. Recrystallization from a mixture of toluene and hexane gave the title compound (20.9 g) as a brown crystalline solid; pp. 140-142 'C.

By a similar procedure, but using the appropriately substituted aniline derivative instead of 2,6-dichloro-4- (trifluoromethyl) aniline, the following compounds were obtained:

From 2,6-dichloro-4- (trifluoromethoxy) aniline 5-amino-3-cyano-1- [2,6-dichloro-4- (trifluoromethoxy) phenyl] pyrazole in the form of a light tan solid, m.p. 119-120.5 ° C;

From 2,6-dichloro-4- (trifluoromethoxy) -aniline, 5-amino-3-cyano-1- [2,6-dichloro-4- (trifluoromethoxy) phenyl] pyrazole is first obtained as a solution in dichloromethane. washed with saturated sodium carbonate solution. Recrystallization from toluene gave the title compound as a pale yellow solid, m.p. 120.5122.5 ° C;

From 2-chloro-4- (trifluoromethyl) aniline 5-amino-1- [2-chloro-4- (trifluoromethyl) phenyl] -3-cyanopyrazole in the form of orange crystals, m.p. 133-135 ° C;

2.4.6-Trichloroaniline 5-amino-3-cyano-1- (2,4,6-trichlorophenyl) pyrazole in the form of light brown crystals, m.p. 155-156 ° C;

From 2,6-dibromo-4- (trifluoromethyl) aniline 5-amino-3-cyano-1- [2,6-dibromo-4- (trifluoromethyl) phenyl] pyrazole as a yellow crystalline solid, m.p. 142146 ' C;

From 2-bromo-6-chloro-4- (trifluoromethyl) aniline 5-aminol- [2-bromo-6-chloro-4- (trifluoromethyl) phenyl] -3-cyanopyrazole is a brown crystalline solid. 146-148 ° C;

From 2-bromo-4- (trifluoromethyl) aniline 5-amino-1- [2-bromo-4- (trifluoromethyl) phenyl] -3-cyanopyrazole as a yellow crystalline solid, m.p. 159-162 ' C;

5-Amino-3-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] pyrazole is prepared as follows:

A mixture of 5.8 g of 5-amino-3-chloro-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4- (ethoxycarbonyl) pyrazole and 75 ml of 6N hydrochloric acid in 75 ml of glacial acetic acid was added. After refluxing for 24 hours, cool, concentrate to a small volume, basify to pH 12 with 2N sodium hydroxide, and extract with 3 x 75 mL ether. The ethereal extracts were combined and evaporated in vacuo to give

3.5 g of a yellow gum are obtained in a mixture of 5-amino and 5-acetamidopyrazole. This material was refluxed in a mixture of 30 ml of 6N hydrochloric acid and 60 ml of dioxane for 48 hours. The volatiles were removed in vacuo and the residue was purified by column chromatography with dichloromethane: hexane (4: 1). Evaporation of the eluate containing the main component gives 1.3 g of an off-white solid, m.p. 128129C.

The 5-amino-3-chloro-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4- (ethoxycarbonyl) pyrazole used in the above example was prepared as follows:

50.0 g of 3,5-diamino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4- (ethoxycarbonyl) pyrazole and 21.0 g of copper (II) chloride The reaction mixture was cooled to 0 ° C in acetonitrile (15 ml) and tert-butyl nitrile (15.0 g) was added dropwise with stirring over 10 minutes. The reaction mixture was stirred for 2 hours at 0 ° C, then for 2 hours at room temperature, then concentrated to a small volume and poured into 1500 ml of 5N hydrochloric acid. The resulting solution was extracted with dichloromethane (3 x 600 mL), washed with 2N hydrochloric acid (2 x 600 mL), dried over anhydrous magnesium sulfate and evaporated to give a brown gum. The resin was removed from the product by dry silica gel chromatography, eluting with dichloromethane: hexane (4: 1), followed by column chromatography (60% to 80%) with increasing dichloromethane. 8 g of an orange solid are obtained, m.p. 143-145 ° C.

3,5-Diamino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4- (ethoxycarbonyl) pyrazole used in the above synthesis is prepared as follows:

2,6-Dichloro-4- (trifluoromethyl) phenylhydrazine (g) was suspended in 220 ml of 0.9N hydrochloric acid, 35.2 g of ethyl dicyanoacetate was added with stirring and the reaction mixture was refluxed for 18 hours. The solid was then cooled to precipitate, filtered, triturated with 250 mL of diethyl ether and dried. The resulting 56 g off-white solid was recrystallized from ethyl acetate-hexane to give the title compound as an off-white solid (29.2), m.p. 196-197 ° C.

The potassium salt of ethyl dicyanoacetate is prepared as follows:

To a solution of potassium hydroxide (560 g) in water (2.0 L) was added dropwise with stirring at ambient temperature (40 ° C) over 5 hours (520 g ethyl chloroformate and 330 g malonitrile in 500 ml tetrahydrofuran). The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0 ° C to precipitate the solid, which was then filtered and dried over phosphorus pentoxide.

334.4 g of the title compound are obtained in the form of an off-white solid.

5-Amino-3-bromo-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] pyrazole is prepared as follows:

3.3 g of 5-amino-4-carbethoxy-3-chloro-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] pyrazole and 3.3 g (30 ml of 48%) of hydrogen bromide in 50 ml of glacial acetic acid at reflux for 18 hours. The mixture was concentrated to a small volume, basified with 1N sodium hydroxide solution, filtered and dried. The material (2.9 g) was recrystallized from ethanol / water to give 2.5 g of colorless crystals.

EN 210 668 B, m.p. 132.5-134 ° C.

5-Amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-fluoro-pyrazole is prepared as follows:

1.5 g of 5-amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-fluoro-4-formylpyrazole in a mixture of 40 ml of methanol and 10 ml of 2N hydrochloric acid solution for 24 hours reflux. After concentration in vacuo, water (100 mL) was added and extracted with ether (2 x 100 mL). The extract was washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. Chromatographic purification using dichloromethane as eluent gave the title compound as a white solid, mp 128-129 ° C.

The 5-amino-1- [2,6-dichloro-4-trifluoromethylphenyl] -3-fluoro-4-formylpyrazole used in the above procedure is prepared as follows:

2.2 g of 5-amino-4-cyano [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-fluoro-pyrazole (described in PCT application WO 8703-781-A) Dissolved in 40 ml of anhydrous tetrahydrofuran was treated with 13 ml of a 1M solution of diisobutylaluminum hydride in toluene at -70 ° C under nitrogen. After stirring for 1/2 hour, toluene (25 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2 x 100 mL), the combined organic layers were washed with sodium bicarbonate (20 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting brown material (1.5 g) was chromatographed using 98: 2 toluene / ethyl acetate as eluent. The title compound was obtained as a light yellow solid (1.0 g), m.p. 137-139.5 ° C.

Example 2

3,5-Diamino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole is prepared as follows:

To a mixture of methanesulfonyl malonitrile (30.0 g) and water (150 mL) was added potassium carbonate (11.7 g) in portions, followed by addition of 2,6-dichloro-4-trifluoromethylphenylhydrazine (41.0 g), followed by stirring. overnight at 100 ° C. After cooling, the yellow precipitate was filtered off, washed with water and recrystallized from aqueous methanol. The resulting solid was rinsed thoroughly with ether to give the title compound as a white solid (14.6 g). Mp .: 224-226 'C.

Example 3

3-Amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole is prepared as follows:

6.4 g of 3- (tert-butylcarbonylamino) -1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole in 150 ml of ethanol are dissolved in 20 ml of 50% by volume, hydrochloric acid and the reaction mixture was refluxed for 1 hour. The solvent was evaporated in vacuo, the residue was dissolved in dichloromethane, washed with sodium bicarbonate solution, then water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The product was recrystallized from ethyl acetate-hexane to give 3.0 g of the title compound as a white crystalline solid. Mp .: 222-223 'C.

3- (tert-Butylcarbonylamino) - [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole is prepared as follows:

A mixture of 9.4 g of 3-carboxy-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole, 70 ml of thionyl chloride and 3 drops of Ν, Ν-dimethylformamide Reflux for 2 hours. The solvent was evaporated in vacuo, and toluene (20 mL) was added and the evaporation was repeated. The solid residue was dissolved in 60 ml of anhydrous acetone, stirred at 10-15 ° C, and 2.1 g of sodium azide dissolved in 15 ml of water were added over 5 minutes. After 30 minutes, the mixture was poured into 250 mL of water and extracted with dichloromethane (3 x 80 mL). The combined extracts were washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo at 40 ° C or less to give a pale yellow-brown solid.

The resulting azide was dissolved in 80 mL of duo and refluxed for 0.75 hours with slight evolution of nitrogen. After cooling, the reaction mixture was treated with 15 g of tert-butanol and refluxed for 2 hours. The mixture was allowed to stand at room temperature overnight and then concentrated in vacuo. The resulting brown semi-oil was chromatographed on silica gel (Merck 37-68 µm, 6.8 Nm ² ) eluting with dichloromethane: ethyl acetate (98: 2) to give 6.6 g of the title compound.

3-Carboxy-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] 4-methanesulfonylpyrazole is prepared as follows:

A mixture of 14.0 g of 1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4-methanesulfonylpyrazole and 300 ml of 80% sulfuric acid at 80 ° C. After stirring for 4 hours, allow to stand at room temperature overnight, pour over an excess of ice and filter the precipitated solid. The filtrate was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and evaporated to give the title compound (11.1 g) as a bright solid. Mp .: 215216 'C.

The 1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4-methanesulfonylpyrazole used in the above reaction is prepared as follows:

5-Amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4-methanesulfonylpyrazole (17.1 g) was dissolved in dry tetrahydrofuran (130 ml) at room temperature and while 33 ml of tert-butyl nitrile are added over 2 minutes. The mixture was refluxed for 1.5 hours, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried over anhydrous magnesium sulfate and evaporated to give a yellow solid. This was taken up in toluene and petroleum ether (boiling point 60-80 'C)

Recrystallization from a mixture of B1 210 668 B yields 15.2 g of yellow crystals, m.p. 183-185 ° C.

The 5-amino-1- [2,6-dichloro-4-trifluoromethylphenyl] -3-ethoxycarbonyl-4-methanesulfonylpyrazole used in the above reaction was prepared as follows:

To 20 ml of absolute ethanol cooled in an ice bath was added 0.25 g of sodium hydride (80% oily dispersion), followed by 0.99 g of methanesulfonylacetonitrile and stirred for 1/2 hour. Ethyl chloro [2,6-dichloro-4- (trifluoromethyl) phenyl] hydrazonoacetate (3.0 g) in absolute ethanol (20 ml) was added and stirring was continued for a further 5 hours. The yellow precipitate was filtered off (2.55 g) and recrystallized from ethanol to give the title compound as a colorless solid. Mp .: 255 'C.

Ethyl chloro- [2,6-dichloro-4- (trifluoromethyl) phenyl] hydrazonoacetate is prepared as follows:

To 30 ml of concentrated sulfuric acid was added 3.04 g of sodium nitrite with stirring at 3035C for 15 minutes. After cooling to 20 ° C, the solution was added dropwise over 15 minutes to 9.2 g of 2,6-dichloro-4-trifluoromethylaniline in 90 ml of acetic acid, maintaining the temperature of the mixture at 35 to 40 ° C. The resulting solution was added dropwise to a mixture of 54 g of anhydrous sodium acetate and 7.0 g of ethyl chloroacetoacetate in a mixture of 72 ml of water and 48 ml of ethanol dropwise with stirring at +10 ° C for 45 minutes, while cooling is controlled so that the temperature remains at 10 ° C. After 1 hour at room temperature, the reaction mixture was diluted with water, filtered and the filtrate was dissolved in dichloromethane. The solution was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated in vacuo to give the title compound (11.9 g) as a white solid, m.p. 96-98 ° C.

Example 4

3-Amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-trifluoromethylthio-pyrazole is prepared as follows:

3.45 g of 3- (tert-butoxycarbonylamino) -1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4- (trifluoromethylthio) pyrazole dissolved in 3.50 g of anhydrous acetonitrile are treated with nitrogen. and treated with 2.6 g of iodomethylsilane dropwise under atmosphere. After stirring for 45 minutes, methanol (10 mL) was added, and after a further 15 minutes, the solution was concentrated in vacuo to a dark gum which was dissolved in dichloromethane (100 mL), washed with sodium sulfite (50 mL) and water (50 mL). dried over anhydrous magnesium sulfate. Evaporation of dichloromethane in vacuo gave 2.6 g of an off-white solid, m.p. 130-135 ° C.

The 3- (tert-butoxycarbonylamino) -1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4- (trifluoromethylthio) pyrazole used in the above reaction was prepared as follows:

5.6 g of 1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4- (trifluoromethylthio) pyrazole-3-carboxylic acid are dissolved in 50 ml of anhydrous Ν, Ν-dimethylformamide. 1.33 g of triethylamine are added, followed by cooling to 5 ° C, and 20 ml of 3.63 g of diphenylphosphoryl azide in Ν, Ν-dimethylformamide are added. When the solution has warmed to room temperature, it is heated to 35 ° C and maintained at this temperature for 2 1/2 hours. Concentrate in vacuo at a temperature below 40 ° C, add 5 g of sodium chloride in 100 ml of water and extract with 3 x 100 ml of ether. The combined extracts were washed with water (50 mL), dried over anhydrous magnesium sulfate and evaporated to give 5.4 g of 1- [2,6-dichloro-4-trifluoromethylphenyl] -4- (trifluoromethylthio). The resulting pyrazole-3-carboxylic acid azide is obtained. This was dissolved in 200 ml of anhydrous toluene and refluxed with stirring for 1.5 hours, followed by the addition of tert-butanol (35 ml) and refluxing for 4 hours. After evaporation in vacuo, the residue was purified by silica gel chromatography eluting with dichloromethane to give 3.3 g of the title compound as an off-white solid, m.p. 122-125 ° C.

The 1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4- (trifluoromethylthio) pyrazole-3-carboxylic acid used in the above reaction is prepared as follows:

1- [2,6-Dichloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4-trifluoromethylthio-pyrazole (6.8 g) is suspended in ethanol (70 ml), 73 g of sodium hydroxide are dissolved in 50 ml of water and the reaction mixture is refluxed for 1 1/2 hours. The solvent was evaporated in vacuo, water (250 mL) was added, and concentrated sulfuric acid was added until pH = 1. The product was filtered off, washed with water (100 ml) and dried at 120 ° C in vacuo to give the title compound (5.7 g) as a gray solid. Mp .: 175-177 'C.

1- [2,6-Dichloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4- (trifluoromethylthio) pyrazole used in the above reaction is prepared as follows:

4.0 g of 5-amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4- (trifluoromethylthio) pyrazole in 20 ml of anhydrous dissolved in tetrahydrofuran at room temperature and treated with 5.76 g of tert-butyl nitrile. The reaction mixture was refluxed for 3 hours and then concentrated in vacuo. The resulting yellow solid was purified by silica gel chromatography using petroleum ether / dichloromethane (2: 1) as eluent to give the title compound as an off-white solid, m.p. 122.5126C.

1- [2,6-Dichloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4- (trifluoromethylthio) pyrazole used in the above reaction is prepared as follows:

5-Amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-pyrazole (20.0 g) in dichloromethane (100 ml) was stirred with a magnetic stirrer for 1 hour. A solution of trifluoromethylsulphenyl chloride (10.8 g) in dichloromethane (50 ml) is added dropwise. After stirring overnight at room temperature, the reaction mixture was washed with water (100 mL), dried over magnesium sulfate and concentrated in vacuo. Chromatography affords the title compound as a white solid, m.p. 213-214 ° C.

HU 210 668 B

5-Amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-pyrazole is prepared as follows:

50.0 g of ethyl 3-cyano-2-hydroxyprop-2-enoate sodium salt [C. A. 57: 16604d N. S. Vulfson et al.] Dissolve in 500 ml of cold water and add 2N sulfuric acid with stirring until pH = 1. The solution was extracted with ether (2 x 400 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting yellow oil was dissolved in ethanol (400 mL), treated with 2,6-dichloro-4- (trifluoromethyl) phenylhydrazine (51.1 g), and the reaction mixture was refluxed overnight. After cooling, the solution was concentrated in vacuo to give an orange solid which was recrystallized from toluene / hexane to give 40.2 g of a light tan solid, m.p. 179-181 ° C.

Example 5

5-Amino-3-carbamoyl-1- [2,6-dichloro-4- (trifluoromethoxy) phenyl] -4-methanesulfonylpyrazole is prepared as follows:

5-Amino-3-carboxy-1- [2,6-dichloro-4- (trifluoromethoxy) phenyl] -4-methanesulfonylpyrazole (40.8 g) was suspended in toluene (160 mL) and treated with thionyl chloride (150 mL). reflux for 1 hour. The solution was concentrated in vacuo and the toluene (100 mL) was added and the evaporation was repeated. The acid chloride thus obtained is dissolved in 200 ml of tetrahydrofuran and this solution is added dropwise with stirring to 300 ml of ammonium hydroxide solution over 15 minutes while maintaining the temperature between 5 and 10 ° C. The reaction mixture is allowed to stand overnight and then 250 ml are added. water was added and the solution was extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water (2 x 250 mL), dried over anhydrous magnesium sulfate, and evaporated in vacuo. The resulting solid (34.9 g) was recrystallized from ethyl acetate-hexane to give the title compound (19.3 g) as a white solid. Mp: 219-220'C.

By a similar procedure, but replacing 5-amino-3-carboxy-1- [2,6-dichloro-4- (trifluoromethoxy) phenyl] -4-methanesulfonylpyrazole with 5-amino-1- [2-bromo-6 using chloro-4- (trifluoromethyl) phenyl] -3-carboxy-4-methanesulfonylpyrazole

5-amino-1- [2-bromo-6-chloro-4- (trifluoromethyl) phenyl] 3-carbamoyl-4-methanesulfonylpyrazole is obtained in the form of an off-white powder. Mp .: 250-253 'C.

The starting materials used for the above reaction were prepared as follows:

5-Amino-3-carboxy-1- [2,6-dichloro-4- (trifluoromethoxy) phenyl] -4-methanesulfonylpyrazole in Example 3 was treated with 3-carboxy-1- [2,6-dichloro] Prepared in the same manner as for the preparation of 4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole, except for 1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl. 5-Amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole was substituted for -4-methanesulfonylpyrazole to give a white solid, m.p. 195-196 ° C. .

5-Amino-1- [2-bromo-6-chloro-4- (trifluoromethyl) phenyl] -3-carboxy-4-methanesulfonylpyrazole is prepared as follows:

8.0 g of 5-amino-1- [2-bromo-6-chloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4-methanesulfonylpyrazole in 75 ml of acetic acid 75 ml of 48% of hydrogen bromide at reflux for 3 hours. The reaction mixture was allowed to cool overnight, concentrated in vacuo and triturated with sodium bicarbonate. After drying in vacuo, the title compound is obtained as a gray powder (6.6 g), m.p. 130-133 ° C.

The 5-amino-1- [2-bromo-6-chloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4-methanesulfonylpyrazole used in the above procedure was prepared according to the procedure of Example 3. except that ethyl chloro- [2-bromo-6-chloro-4- (trifluoromethyl) phenyl] is substituted for ethyl chloro [2,6-dichloro-4-trifluoromethylphenyl] hydrazonoacetate ] -hydrazone o-acetate was used. The product is obtained in the form of a light brown solid, m.p.

5-Amino-1- [2-bromo-6-chloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4-methanesulfonylpyrazole is ethyl chloro [2-bromo-6-chloro It can also be prepared from -4- (trifluoromethoxy) phenyl] hydrazonoacetate. It is obtained in the form of a white solid, m.p. 255.5-256.5 ° C.

Ethyl chloro [2,6-dichloro-4-trifluoromethoxy-phenyl] -hydrazono-acetate used in the above procedure was also prepared in the same manner as in Example 3, so that 2,6-dichloro-4- 2,6-dichloro-4- (trifluoromethoxy) aniline is used in place of trifluoromethylaniline. The product is obtained in the form of a brown solid, m.p. 55-58 ° C.

The ethyl chloro [2-bromo-6-chloro-4-trifluoromethoxy-phenyl] -hydrazonoacetate used in the above procedure was similarly prepared from 2-bromo-6-chloro-4- (trifluoromethoxy) aniline. and obtained in the form of a shiny solid, m.p. 116.5-117.5 ° C.

Example 6

5-Amino-3-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-thiocyanato-pyrazole is prepared as follows:

Potassium thiocyanate (4.99 g) was suspended in methanol (75 ml) and, while stirring, at -78 ° C, 0.8 ml of bromine dissolved in 10 ml of methanol was added dropwise over 25 minutes. After a further 20 minutes, 5.0 g of 5-amino-3-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] pyrazole dissolved in 50 ml of methanol are added over 30 minutes. The reaction mixture was stirred at -78 ° C, allowed to stand for 3 hours, and once cooled to room temperature, poured into 250 ml of water. The precipitated solid is filtered off, washed with water and recrystallized from a mixture of toluene and hexane to give 3.1 g of the title compound as a white solid, m.p. 179-182 ° C.

By a similar procedure, however, 5-amino-3-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] pyrazole 5-amino-3-bromo-1- [2,6-dichloro-4 - (trifluoromethyl) phenyl] -pyrazole to give 5-amino-3-bromo-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-thiocyanato-pyrazole as a white solid m.p. 162-163.5 ° C after purification by chromatography and elution with dichloromethane.

HU 210 668 B

5-Amino-3-bromo-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] pyrazole was prepared as described in Example 1.

Example 7

1- [2,6-Dichloro-4- (trifluoromethyl) phenyl] -3- (1-hydroxyethyl) -4- (trifluoromethylthio) pyrazole is prepared as follows:

1.64 g of 1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-formyl-4- (trifluoromethylthio) pyrazole in 20 ml of anhydrous ether are dissolved in 1.35 ml of 3M ether. methyl magnesium iodide solution, which was added dropwise to the reaction mixture under nitrogen. The solution was then refluxed for 1 1/2 hours, cooled, treated with additional 0.2 mL of methyl magnesium iodide solution, then refluxed again for 1 hour, then poured into excess ice, It is diluted with 1 ml of hydrochloric acid and extracted with 2 x 50 ml of food. The extract was washed with 50 ml of sodium bicarbonate solution and 50 ml of water, dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 1.46 g of the title compound as a yellow oil.

Example 8

10.1 g of 2,6-dichloro-4- (trifluoromethyl) phenylhydrazir in 50 ml of tetrahydrofuran are stirred at room temperature and 8.5 g of anhydrous potassium carbonate are added. Then, 11.0 g of ethyl 2-chloro-3-cyano-3- (1-methylethylsulfonyl) -prop-2-enoic acid in 100 ml of tetrahydrofuran are added dropwise at 0 'C. After stirring for 2 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a brown oil. This was triturated with 100 mL of hexane and the resulting 1.7 g of an off-white material was refluxed. After cooling down

8.5 g of 5-amino-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4- (1-methylethylsulfonyl) pyrazole are obtained in the form of white crystals. op: 255.5256.5 ′ C.

Example 9

Ethyl 2-chloro-3-cyano-3- (1-methylethylsulfonyl) -prop-2-enoic acid is prepared as follows:

To 28.5 g of phosphorus oxychloride is added 10.0 g of the sodium salt of 3-cyano-2-hydroxy-3- (1-methylethylsulfonyl) -prop-2-enoic acid at room temperature with stirring. After 3 hours, the mixture was heated to 50 ° C, held at this temperature for 1 hour, and then concentrated in vacuo. After the addition of toluene, the residue was evaporated again to give the title compound as a brown oil.

The sodium salt of 3-cyano-2-hydroxy-3- (1-methylethylsulfonyl) -prop2-enoic acid is prepared as follows:

A solution of sodium ethoxide (4.0 g) in ethanol (80 ml) was treated with propane-2-sulfonylacetonitrile (24.5 g) with stirring. After complete dissolution, 24.8 g of diethyloxalate are added dropwise over 10 minutes, causing vigorous precipitation to occur. The reaction mixture is refluxed for 1 hour, the yellow precipitate is filtered off, washed with hexane and dried in a vacuum dryer. 41.3 g of the title compound are obtained, m.p. 195-197.5'C.

Example 10

3.57 g of 5-carbamoyl-4-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-trifluoromethyl-pyrazole are mixed with 2.82 g of phosphorus pentoxide. Heat to 200 ° C. After 3 hours, the product was cooled, treated with ice and extracted with dichloromethane (3 x 50 mL). The organic solution was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting dry residue was recrystallized from hexane to give 1.8 g of 1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4,5-dicyano-3-trifluoromethylpyrazole as a white crystalline solid, m.p. op: 80 'C

In the above procedure, only 5-carbamoyl-4-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3- (trifluoromethyl) pyrazole is 5-amino-3-carbamoyl-1. - [2,6-Dichloro-4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole 5-amino-3-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole is obtained, m.p.

Example 11

The starting material of Example 10 above, 5-carbamoyl-4-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-trifluoromethyl) pyrazole, is prepared as follows. :

To thionyl chloride (6.0 g) was added 5-carboxy-4-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-trifluoromethyl-pyrazole (6.0 g) and the solution stirred. Reflux for 4 hours. The solvent was evaporated in vacuo and evaporated again with anhydrous toluene (30 mL). The orange oil thus obtained was dissolved in 10 ml of anhydrous ether and added dropwise to 20 ml of a solution of 0.88 g of ammonia, which was stirred and cooled in an ice bath. After stirring overnight, water (150 mL) was added and the mixture was extracted with dichloromethane (3 x 50 mL). The combined organic solutions were washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting white solid (7.0 g) was recrystallized from ethyl acetate / petroleum ether to give 4.3 g of the title compound as a white crystalline solid, m.p. 180-181 ° C.

Similarly, another starting material of Example 10 above, 5-amino-3-carbamoyl-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole, was prepared, except that 5-carboxy Instead of -4-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-trifluoromethyl-pyrazole, 5-amino-3-carboxy-1- [2,6- dichloro-4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole. The title compound is obtained as an off-white solid, m.p. 223-224'C.

The 5-amino-3-carboxy-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -4-methanesulfonylpyrazole used in the above reaction was prepared as follows:

to 80% sulfuric acid (8 ml) with stirring, 8.15 g of 5-amino-1- [2,6-di

Chloro-4- (trifluoromethyl) phenyl] -3-ethoxycarbonyl-4-methanesulfonylpyrazole was added and the mixture was heated at 100 ° C for 5 hours. After cooling, the solution was poured onto ice, the solid filtered and dried in a vacuum desiccator over phosphorus pentoxide. The product was recrystallized from methanol / petroleum ether to give the title compound as a white solid, m.p. 203-205 ° C.

Claims (2)

Patent Claim Point A process for the preparation of N-phenylpyrazole derivatives of formula I wherein R * is halogen, cyano, amino, carbamoyl, carboxy, 1-hydroxyethyl, trifluoromethyl or C 2 -C 7 alkoxy-carbonyl group, R ² is hydrogen, thiocyanato, cyano, formyl, C 2 -C 4 alkoxycarbonyl, C 1 -C 4 alkylsulfonyl or trifluoromethylthio, R ³ is hydrogen, amino, cyano or (C 1 -C 4) alkoxy-carbonylamino, and R ⁴ is at the 2-position with fluoro, chloro or bromo, at the 4-position with C 1-4 haloalkyl - or phenyl substituted with C 1 -C 4 haloalkoxy, preferably trifluoromethyl or trifluoromethoxy and optionally substituted in the 6-position with chlorine or bromine, except for the compounds of formula R ¹ is halogen or cyano and simultaneously R ² is C 1-4 alkylsulfonyl or trifluoromethylthio; and R ³ is hydrogen, amino, or (C 1 -C 4) alkoxy-carbonylamino, and compounds wherein - R ⁴ is 2,6-dichloro-4- (trifluoromethyl) phenyl, R ¹ and R ² are cyano and R ³ is amino or ethoxycarbonylamino, or R ¹ is chlorine and R ³ is amino or ethoxycarbonylamino, or - R ¹ is bromo or iodo or amino or ethoxycarbonyl and R ³ is amino, or R ¹ is fluoro and R ³ is hydrogen or amino, or - R ¹ is amino or ethoxycarbonyl and R ³ is hydrogen or - R ⁴ is 2,4,6-trichlorophenyl, 2-chloro-4- (trifluoromethyl) phenyl or 2,6-dichloro-4- (trifluoromethoxy) phenyl, R ¹ and R ² is cyano and R ³ is amino, or - R ⁴ is 2,6-dichloro-4- (trifluoromethoxy) phenyl, R ² is cyano, R * is chloro and R ³ is amino, or - R ⁴ is 2,6-dichloro-4- (trifluoromethyl) phenyl, R ² is carboxycarbamoyl or ethoxycarbonyl and R ³ is amino, a) For the preparation of compounds of formula I wherein R ³ is amino, R ^{2 is} hydrogen and R ¹ is cyano, an aniline derivative of R ⁴ NH ₂ - R ⁴ is diazotized and the resulting compound is added in the presence of a solvent, reacting a compound of formula XVII, wherein R ¹⁸ is C 1-6 alkoxy, optionally with mild hydrolysis with a base, or b) for the preparation of compounds of formula I wherein R ¹ is cyano or halo, R ^{2 is} hydrogen and R ³ is amino, an ester of formula I wherein R ² is -COOR - wherein R 1 is Is a straight or branched alkyl group of 6 carbon atoms - boiled in an organic solvent in the presence of a strong acid at a temperature between 50 ° C and reflux temperature, or c) for the preparation of compounds of formula I in which R ^{2 is} formyl, a nitrile of formula I in which R ^{2 is} cyano is reacted with a reducing agent, preferably diisobutylaluminum hydride, in an inert solvent at a temperature from -78 ° C to room temperature; obsession d) for the preparation of compounds of formula I wherein R ¹ is carboxyl, the corresponding ester wherein R ¹ is alkoxycarbonyl, preferably ethoxycarbonyl, is a base and a solvent at 0 ° C and the solvent is hydrolyzing at a reflux temperature, or e) (I) formula compounds in which R ¹ is 1-hydroxyethyl group, an aldehyde (I) of formula wherein R ¹ is CHO and R ³ is a hydrogen atom or an amino group, in an inert solvent at room temperature and the solvent at a reflux temperature, with a Grignard reagent, preferably a methyl magnesium halide, or f) for the preparation of 4-thiocyanato-pyrazole derivatives of formula I wherein R ^{2 is} thiocyanate and R ³ is amino, a compound of formula I wherein R ^{2 is} hydrogen in an inert organic solvent at a temperature between 0 and 100 ° C. with a reagent suitable for introducing a thiocyanate group, preferably an alkali metal or ammonium salt of thiocyanic acid, and bromine, or g) for the preparation of compounds of the formula I in which R ¹ and R ³ are amino and R ² is a straight or branched alkoxycarbonyl group containing from ² to 4 carbon atoms, a phenylhydrazine derivative of the formula V using an acid, at room temperature to the reflux temperature, with an alkali metal salt of an alkyl dicyanoacetate of formula (XXII) wherein R is as defined above, preferably potassium ethyl dicyanoacetate, or HU 210 668 B h) for the preparation of diaminosulfonylpyrazole derivatives of formula I wherein R * and R ³ are amino and R ² is C 1-4 alkylsulfonyl, a phenyl hydrazine derivative of formula V - wherein R ⁴ is 5 as above, with an alkylsulfonyl malonitrile of formula (ΧΧΙΠ) wherein R ⁵ is C 1 -C 4 alkyl, or i) for the preparation of compounds of formula I wherein R ¹ is chloro, bromo, fluoro, R ² 10 are hydrogen and R ³ is amino; ii) the corresponding compound of formula I wherein R ¹ is amino, diazotizing and then decomposing the resulting diazonium derivative by known thermal or photolysis techniques, or F2) ^e w (V) phenylhydrazine derivative of the formula - wherein R ⁴ is as defined above - in acidic medium optionally a segéoldószer at room temperature and at a temperature between the reflux temperature of the solvent, an alkali metal salt (XXIV) A compound of general formula - wherein M is potassium or sodium and R is as defined above.