WO2004026839A1

WO2004026839A1 - Process for producing arylethynylpyrazole compound

Info

Publication number: WO2004026839A1
Application number: PCT/JP2003/012012
Authority: WO
Inventors: Takao Urata; Naoko Sumitani; Liangyou He
Original assignee: Agro-Kanesho Co.,Ltd.
Priority date: 2002-09-19
Filing date: 2003-09-19
Publication date: 2004-04-01
Also published as: JP2004107264A; AU2003266548A1

Abstract

A method in which the coupling reaction of a halogenated pyrazole compound with an arylacetylene compound is easily conducted using an inexpensive reagent while attaining a satisfactory yield. The process, which is for producing an arylethynylpyrazole compound through the reaction of a halogenated pyrazole compound with an arylacetylene compound, is characterized by conducting the reaction in the presence of a copper halide and a base.

Description

Specification

Method for producing arylethynyl virazoles

The present invention relates to a method for producing an acetylene derivative useful as a medicinal and agricultural chemical, and more particularly, to a method for producing an arylethirubirazole useful as an agricultural chemical. Background art

Halogen compounds, in particular coupling reaction of aromatic halides with acetylenes, it is known to be carried out in the presence of a catalytic component of a copper halide phosphine ligand ZCuI such as Pd compound / PPh ₃ This is generally called the Sonogashira reaction.

This reaction is known to be applicable not only to aromatic halogen compounds but also to heterocyclic aromatic halogen compounds.For example, the coupling reaction between pyrazols and acetylenes is carried out by palladium acetate, PPh ₃ , It is known that the reaction proceeds in the presence of a catalyst component in combination with Cul and a base (see Japanese Patent Publication No. 2001-158704 (pages 8 and 13-14)). However, this way Pd, reaction using a catalyst system comprising a multi-component of PP h ₃ and Cu are industrially from the viewpoint of operation such catalyst removal and reuse after Kos Bok points and the reaction is complicated Not very good. In addition, despite the use of expensive catalysts such as Pd compounds as high as 15 mo 1%, for example, 1-ethyl-4-iodo-3-methylmethylazole-5-yl acetate and 3,5- The yield with the reaction with bistrifluoromethylphenylacetylene (see Synthesis Example 13) is as low as 48.2%, which is insufficient for industrial practice.

Also, the heteroaromatic halogenated compounds, 2-phenylindole and methyl propyl It has been reported that Cu I and PP h ₃ are used as catalyst components in the force-coupling reaction with carbon nanotubes (JCS, Perkin Trans. 1, (1999), p.2669-2670).

). Again, PP h ₃ is essential as a catalyst component, and the yield is as low as 53%, which is insufficient for industrial implementation. DISCLOSURE OF THE INVENTION As described above, in performing a coupling reaction between a heterocyclic aromatic nitrogen compound and aryl acetylene, an expensive Pd catalyst is not used, and a high yield is industrially advantageous. There has been a demand for a reaction method to be carried out. An object of the present invention is to provide a production method for industrially advantageously reacting a halogenated virazole and an arylacetylene in a power coupling reaction. The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that copper coupling and copper halide can be performed without using an expensive Pd compound in the coupling reaction between halogenated virazoles and aryl acetylenes. The present inventors have found that by performing a reaction in the presence of a base, the coupling reaction proceeds under mild conditions, and thus completed the present invention.

That is, the gist of the present invention is characterized in that, when a halogenated pyrazole is reacted with an arylacetylene to produce an arylethyrivazole, the reaction is carried out in the presence of a copper halide and a base. The method for producing arylethynyl bilazoles described above.

Hereinafter, the present invention will be described in detail. BEST MODE FOR CARRYING OUT THE INVENTION

The production method of the present invention is characterized in that a reaction catalyst comprising a copper halide and a base is used in producing an aryl ethynyl virazole by reacting a halogenated pyrazole with an aryl acetylene. Is what you do. (Halogenated pyrazoles)

In the halogenated virazols used in the present invention, the halogen atom may be substituted at any of the 3-, 4- and 5-positions of the pyrazole ring, and a substituent other than the halogen atom is bonded to the pyrazole 璟. May be. Among them, as the halogenated pyrazoles, it is preferable to use a 2- (5-pyrazolyl) acetic acid ester derivative represented by the general formula (1).

R ¹ is a hydrogen atom; a fluorine atom, a chlorine atom, a bromine atom, a halogen atom such as an iodine atom; a methyl group, a chloromethyl group, a bromomethyl group, a odomethyl group, a fluoromethyl group, a difluoromethinole group Trifluoromethyl, 2,2,2-trifluoroethyl, ethyl, methoxymethyl, t-butyl, perfluorobutyl, perfluorooctyl, acetylmethyl, etc. An alkyl group which may be substituted with an active group; an alkenyl group which may be substituted with a group which is inert to the reaction, such as a vinyl group, an aryl group, a 2-butenyl group, and a styryl group; an ethynyl group, —Phenylethynyl group, 2— (p-chlorophenyl) ethynyl group Alkynyl group which may be substituted with a group which is inactive in this reaction such as 2, 2-trimethylsilylethynyl group; a group which is inactive in this reaction such as methoxy group, ethoxy group, benzyloxy group and 2-methoxyethoxy group Or a phenyl group, a naphthyl group, a 4-trifluoromethylphenyl group, a 0-tolyl group, a 4-nitrophenyl group, a 3-cyanophenyl group, a 3,6-di-t It is an aryl group which may be substituted with a group which is inactive in this reaction such as a butyl naphthyl group.

Among them, R ¹ is a methyl group, an ethyl group, a chloromethyl group, a bromomethyl group, a chloromethyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, An alkyl group having 1 to 4 carbon atoms such as a perfluorobutyl group or a haloalkyl group is preferred, a haloalkyl group is more preferred, and a trifluoromethyl group is particularly preferred.

R ² represents a hydrogen atom, an alkyl group, a haloalkyl group, or an optionally substituted aryl group.

Examples of the alkyl group include an alkyl group having 1 to 20 carbon atoms such as a methyl group, an ethyl group, an isopropyl group, a t-butyl group, a cyclohexyl group, an octyl group and a decyl group.

Haloalkyl groups include trifluoromethyl, chloromethyl, dichloromethyl, and perfluorobutyl, etc. Examples are -20 haloalkyl groups.

Examples of the aryl group which may be substituted include phenyl, naphthyl, 4-trifluoromethylphenyl, o-tolyl, 4-nitrophenyl, 3-cyanophenyl, 3, 6 Examples thereof include aryl groups having 6 to 20 carbon atoms, such as —di-t-butyl naphthyl group.

Among them, R ² is preferably a hydrogen atom, an alkyl group or a haloalkyl group, more preferably a hydrogen atom or an alkyl group, particularly, a methyl group, an ethyl group, and a butyl group. An alkyl group having 1 to 4 carbon atoms, such as an alkyl group, is preferred.

R ³ is an alkyl group such as a methyl group, an ethyl group, an isopropyl group, a t-butyl group, a cyclohexyl group, an octyl group, and a decyl group; an aralkyl group such as a penzyl group and a phenyl group; or a phenyl group and a naphthyl group And an aryl group such as a group. Here, the alkyl group preferably has 1 to 20 carbon atoms, the aralkyl group preferably has 7 to 20 carbon atoms, and the aralkyl group preferably has 6 to 12 carbon atoms. . Among these, an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group and a t-butyl group, a benzyl group or a phenyl group is preferable, and a methyl group or an ethyl group is particularly preferable.

X represents a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, of which a bromine atom or an iodine atom is preferable, and an iodine atom is particularly preferable. The 2- (5-pyrazolyl) acetic acid ester derivative represented by the general formula (1) can be synthesized, for example, according to the synthesis method described in Japanese Patent Application Laid-Open No. 2001-158704. it can.

(Aryl acetylenes)

Examples of the arylacetylenes of the present invention include phenylacetylene, substituted phenylacetylene, and naphthylacetylene. Of these, a phenylacetylene derivative represented by the following general formula (2), which is a substituted phenylacetylene, is preferable.

R ⁴ is a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; an alkyl such as a methyl group, an ethyl group, an isopropyl group, a t-butyl group, a cyclohexyl group, a heptyl group, an octyl group, and a cyclooctyl group. Haloalkyl groups such as chloromethyl group, difluoromethyl group, trifluoromethyl group, 2-bromocyclopropyl group, perfluorobutyl group, perfluorooctyl group, 5-pentyl iodide group; methoxy group; Alkoxy groups such as ethoxy group, propoxy group, butoxy group and octoxy group; haloalkoxy groups such as chloromethoxy group, cycloethoxy group, trifluoroethoxy group and the like; alkylthio groups such as methylthio group, ethylthio group and t-butylthio group Group; or trifluoromethylthio group, trifluoroethylthio group, A haloalkylthio group such as a propylthio group.

Of these, the alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio and haloalkylthio groups preferably have 1 to 8 carbon atoms.

Among them, R ⁴ is preferably a halogen atom, a haloalkyl group or a haloalkoxy group, more preferably a halogen atom or a haloalkyl group having 1 to 4 carbon atoms, particularly a fluorine atom or a trifluoromethyl group. Is preferred.

n represents an integer of 0 to 5, preferably 1 or 2.

The phenylacetylene derivative represented by the general formula (2) is described in, for example, J. Org. Chem. 50, 1763 (1985) cited in Japanese Patent Application Laid-Open No. 2001-157870. Was done It can be synthesized according to the synthesis method.

The amount of aryl acetylenes used is usually

It is used in an amount of at least 1 equivalent, preferably at least a small excess of aryl acetylene, specifically at least 1.01 equivalent, more preferably at least 1.1 equivalent. However, too much excess is not desirable in terms of cost and removal of unreacted components.

Usually, it is used in a range of 10 equivalents or less, preferably 5 equivalents or less, more preferably 3 equivalents or less.

(Copper halide)

Copper halide used as a catalyst may be a monovalent copper halide such as cuprous fluoride, cuprous chloride, cuprous bromide, cuprous iodide, cupric chloride, cupric bromide, etc. Examples thereof include divalent copper halides such as copper and cupric iodide. Of these, monovalent copper halide is preferred, and cuprous chloride, cuprous bromide or cuprous iodide is preferred to suppress the dimerization reaction of the acetylene compound itself, and iodide is preferred. Copper (I) is particularly preferred.

The amount of the copper halide to be used is not particularly limited.However, from the viewpoint of economy and simplicity of the treatment after the reaction, the amount is preferably less than 1 equivalent, preferably 0. It is used in an amount of not more than 8 equivalents, more preferably not more than 0.5 equivalent. Although the lower limit depends on the reactivity, it is usually at least 0.1 equivalent, preferably at least 0.1 equivalent. Although copper nodogenide acts as a catalyst, the reaction can be carried out by adding an additive that does not affect the reaction and that forms a complex. Examples of the additive include a nitrogen-containing ligand such as 2,2′-biviridyl and an ammonium salt such as n-butylammonium bromide. (base)

This reaction is performed in the presence of a base. Examples of the base include inorganic substances such as sodium hydroxide, sodium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, cesium carbonate, and potassium phosphate. Bases; or amines such as triethylamine, pyridine and piperidine can be used. Of these, inorganic bases are preferred from the viewpoint of economy, and more preferred are carbonates such as cesium carbonate, potassium carbonate and sodium hydrogen carbonate.

The amount of the base used is 1 equivalent or more based on the halogenated pyrazole. The amount used is determined in terms of economy and reactivity, but can be selected up to 10 equivalents. It can be selected preferably within a range of 5 equivalents or less, more preferably 3 equivalents or less.

(Reaction style)

This reaction may be carried out without a solvent when the substrate is a liquid, but a solvent is usually used. The solvent used in this reaction is not particularly limited as long as it is inert to the reaction, but preferably has a boiling point of 80 ° C. or higher. For example, aprotic polar solvents such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, DMI, HMPA, DMS0, and sulfolane; or hydrocarbon solvents such as heptane, toluene, and xylene Etc. are exemplified. Of these, preferred are polar solvents containing an amide group such as dimethylformamide, dimethylacetamide, and N-methyl-2-pyrrolidone.

The amount of the solvent used is 1 to 100 times, preferably 2 to 100 times, more preferably 5 to 20 times, by volume / weight ratio to the substrate. No. The reaction temperature needs to be 80 ° C. or higher for the reaction to substantially proceed. It is preferably in the range of 90 ° C, more preferably in the range of 100 ° C to 120 ° C. The reaction can be performed in air, but is preferably performed in an atmosphere of an inert gas such as nitrogen or argon to suppress the dimerization reaction of the acetylene compound.

The reaction method is as follows:

(1) a method of mixing an aryl acetylene, a copper halide and a base, adding a predetermined amount of a halogenated pyrazole, and then heating;

(2) A method of mixing aryl acetylenes, phenol, and halogenated copper with a base, heating the mixture to a predetermined temperature, and adding a halogenated virazole,

(3) A method in which aryl acetylenes are added to a mixture of a halogenated pyrazole, a copper halide and a base, and heated to a predetermined temperature.

(4) a method in which a halogenated pyrazole, phenol, copper genogen and a base are mixed and heated to a predetermined temperature, and then a predetermined amount of arylacetylene is added.

Any of the above methods can be used, but aryl acetylenes can react with copper and copper iodide to form copper acetylide, and then react with pyrogenic and pyrogenated pyrogens. From the above, it is preferable to use the above method (1) or (2), which is a method in which aryl acetylenes and copper halide are mixed in advance.

The reaction time is not particularly limited, but is usually 1 hour to 36 hours, preferably 1 to 24 hours.

After completion of the reaction, the reaction can be carried out by a usual post-treatment method. In order to remove the used copper salt, the reaction solution can be washed with an aqueous solution of ammonium chloride and removed to the aqueous layer as a copper-amine complex. Thereafter, extraction and washing operations are performed, and the desired product can be isolated by crystallization, distillation, and column purification. In some cases, it can be used in the next step without isolation. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples. Reference example 1

Synthesis of 3-methyl-1- (3,5-bistrifluoronethylpheninole) -1-butyn-3-ol

3,5-bistrifluoromethylbromobenzene 3. Og (10.24 mmol), triethylamine 2.5 ml, DMF 10 ml In a mixed solution, while supplying nitrogen gas, triphenylphenyl phosphine 53 mg (0.2 mmol) ), 5% Pd / C2 16 mg (0.1 mmol) and copper iodide 38.8 mg (0.2 mmol) were added, and the mixture was stirred at 35 ° C for 30 minutes under a nitrogen atmosphere. The temperature was increased to 80 ° C under a nitrogen atmosphere, and 927 mg (llmmol) of 3-methyl-1-butyne-3-ol was added dropwise at the same temperature over 40 minutes. Stirred. The mixture was cooled to 20 ° C, and unnecessary substances were filtered. Ethyl acetate and ice water were added to the filtrate to carry out liquid separation. The ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solution obtained by removing sodium sulfate by filtration is concentrated, and 3.1 g of crude 3-methyl-1- (3,5-bistrifluoromethylphenyl) -1-butyn-3-ol is pale yellow. Obtained as a solid target. The yield was quantitative.

Mp:.. 74. 5-74 8 ° C ; ^ -NMR (CDC 1 3) d (ppm) = 7 85 (2H, s), 7. 79 (1H, s), 1. 65 (6H, s ^{); 19 F-NMR (CDC1} 3; external standard: C _₆ F ₆₎

24 (CF _3, s). Reference example 2

Synthesis of 3,5-bistrifluoromethylphenylacetylene

Under a nitrogen atmosphere, 10.0 g (33.8 mmol) of 3-methyl-1- (3,5-bistrifluoromethylphenyl) -1-butyn-3-ol was added to a 5-OmL three-necked flask, followed by powdering. 0.9 g (0.46 equiv) of terminal hydroxide hydroxide and 10 mL of liquid paraffin were charged. The heating reaction was continued while removing acetone as a by-product under reduced pressure by setting up a vacuum distillation apparatus. When the reaction was continued for 1 hour while maintaining the oil bath temperature at 85 ° C, no outflow of acetone was observed, and the reaction was terminated at this point.

The effluent was diluted with 5 OmL of gelatin, washed twice with 15 mL of saturated saline, and dried over anhydrous magnesium sulfate. The solution obtained by removing magnesium sulfate by filtration was concentrated, and 6.55 g of 3,5-bistrifluoromethylphenylacetylene was obtained as a clear colorless solution. Isolation yield 81.5%. 92.6% purity (HP LC internal standard method).

Boiling:. 142. 0- 142. 5 ° C ; ^ -NMR (CDC1 3) (^ (ppm) = 7 9 2 (2H, s), 7. 84 (1H, s), 3. 27 (1H, ^{s); 19 F- NMR. (} . 〇 (1 _3; external檫準: 〇) d (ppm) = - 63. 26 (CF 3, s) reference example 3

Synthesis of methyl 1-methyl-4-iod-3-trifluoromethylpyrazole-5-ylacetate

To a 20 Oml four-necked flask were added 10.0 g (39.6 mmol) of iodine, 4.6 g (27 mmo 1) of iodic acid and 1 Oml of water, and the mixture was stirred at room temperature. A mixed solution of 20 g (9 Ommo 1) of methyl 3-trifluoromethylbirazol-5-ylacetate and 6 Oml of acetic acid was added dropwise. Then, it was heated at a temperature of 90 ° C. for 1 hour. After the completion of the reaction, the mixture was cooled to 5 ° C and diluted with 300 ml of ethyl acetate. Then, it was neutralized with 25 Oml of a saturated aqueous solution of sodium carbonate. After removing excess iodine with 2 Oml of a saturated sodium thiosulfate aqueous solution, the layers were separated, and the aqueous layer was extracted twice with 150 ml of ethyl acetate. The organic layers were combined, washed with 200 ml of saturated saline, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the solid obtained was recrystallized by adding 9 Oml of heptane to give 1-methyl-4-chloride. 26.6 g of methyl trifluoromethylpyrazole-5-ylacetate were obtained. 98% purity, 83% yield.

in. p. 64-65. C

_{H-NMR (CDC 1 35 (} Jppm): 3. 96, 3. 80, 3. 77

F-NMR: -62.18 Example 1

Under a nitrogen atmosphere, degassed DMF25 OmL was added with 3,5-bistrifluoromethylphenylacetylene, 14.4 g (60.4 mmol; 1.05 equiv), and then 3.29 g (0.3 equiv) of copper iodide. Was. After stirring for 10 minutes, 9.54 g (1.2 equiv) of lithium carbonate and 20 g (57.5 mmol) of methyl 1-methyl-4-chloride-3-trifluoromethylpyrazole-5-ylacetate were added. The reaction solution was kept at 105 ° C and stirred for 2.5 hours. After cooling to 20, 200 mL of ethyl acetate was added to the reaction solution, and the insoluble matter was filtered. A saturated solution of ammonium chloride was added to the filtrate, and the mixture was separated, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solution obtained by removing magnesium sulfate by filtration was concentrated and 1-methyl-3-trifluoromethyl-4- [3,5-bis (trifluoromethyl) phenylethynyl] pyrazole-5-yl- 28.5 g of crude methyl acetate was obtained as a pale yellow solid. This was recrystallized from ethyl acetate / hexane to obtain 18.9 g (41.2 mmol) of white powder (needle-shaped crystals). Isolation yield 72%. Purity 98.6% (H PLC internal standard method) Melting point:. 148. 4- 148. 7 ° C ; 'H-NMR (CDC1 3) 5 (ppm) = 7 9 0 (2H, s), 7. 83 (1H , s), 3. 93 (3H , s), 3. 88 (2 H, s), 3. 79 (3H, s); 19 F-NMR (CDC1 3; external standard: C _₆ F ₆₎ d ppm ) =-62.24, -63.15. Elemental _{_{_{analysis: C 18 H u F 9 N}}} 2 0 2 Calculated:... C47 18, H2 42, N6 11, F 37. 31. Measurements: C47.86, HI.64, N6.30, F35.70%. Example 2

Under a nitrogen atmosphere, 1.51 g (6.33 mmol) of 3,5-bistrifluoromethylphenylacetylene and then 0.329 g (1.7 mmol) of copper (I) iodide were added to 25 mL of degassed DMF. . After stirring for 15 minutes, 2.25 g (6.9 mmol) of cesium carbonate and 2.0 g (5.75 mmol) of methyl 1-methyl-4-chloride-3-trifluoromethylpyrazole-5-ylacetate were added, and the mixture was reacted. The solution was kept at 105 ° C and stirred for 2 hours. After cooling to 20 ° C, 50 mL of ethyl acetate was added to the reaction solution, and the insoluble matter was filtered. A saturated solution of ammonium chloride was added to the filtrate, and the mixture was separated, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solution obtained by removing magnesium sulfate by filtration was concentrated, and 1-methyl-3-trifluoromethyl-4- [3,5-bis (trifluoromethyl) phenyletinyl] pyrazole-5-y 3.15 g of a crude product of m-methyl acetate was obtained as a pale yellow solid. This was recrystallized from ethyl acetate / hexane to obtain 1.97 g of white powder (needle-shaped crystals). Isolation yield 75%. Purity 98.9% (HPLC internal standard method). Example 3

In a nitrogen atmosphere, 144 mg (0.604 mmol) of 3,5-bistrifluoromethylphenylacetylene was added to 2.5 mL of degassed DMF, followed by 33 mg (0.173 mmol) of copper iodide 0). After stirring for 10 minutes, 90 mg (0.651 mmol) of potassium carbonate and 200 mg (0.575 mmol) of methyl 1-methyl-4-chloride-3-trifluoromethylpyrazole-5-ylacetate were added. The mixture was kept at ° C and stirred for 5 hours. After cooling to 20 ° C, 5 mL of ethyl acetate was added to the reaction solution, and the insoluble matter was filtered. Saturated concentration of ammonium chloride in the filtrate The solution was separated by adding a solution thereof, and then washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solution obtained by removing magnesium sulfate by filtration was concentrated, and 1-methyl-3-trifluoromethyl-4- [3,5-bis (trifluoromethyl) phenyletinyl] birazol-5 was obtained. 280 mg of a crude product of -yl-methyl acetate was obtained as a pale yellow solid. This was recrystallized from ethyl acetate / hexane to obtain 200 mg of white powder (needle-shaped crystals). 76% isolation yield. Example 4

Under a nitrogen atmosphere, 1.51 g (6.33 mmol) of 3,5-bistrifluoromethylphenylacetylene and then 0.17 lg (1.7 mmol) of copper chloride were added to 25 mL of degassed DMF. After stirring for 15 minutes, 0.954 g (6.9 mmol) of potassium carbonate and 2.0 g (5.75 mmol) of methyl 1-methyl-4-chloride-3-trifluoromethylpyrazole-5-ylacetate were added, followed by reaction. The solution was kept at 105 ° C and stirred for 3 hours. After cooling to 20 ° C, 50 mL of ethyl acetate was added to the reaction solution, and the insoluble matter was filtered. A saturated solution of ammonium chloride was added to the filtrate, and the mixture was separated, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solution obtained by removing the magnesium sulfate by filtration was concentrated, and 1-methyl-3-trifluoromethyl-4- [3,5-bis (trifluoromethyl) phenylethynyl] virazol-5-y 3.0 g of a crude product of m-methyl acetate was obtained as a pale yellow solid. As a result of quantification by the HPLC internal standard method, the transfer ratio of the reaction was 92%, and the yield of the desired product was 76%. Example 5

Under a nitrogen atmosphere, 3,5-bistrifluoromethylphenylacetylene 1.51 (6.33 mmol) and then 0.248 g (1.7 mmol) of copper bromide were added to 25 mL of degassed DMF. After stirring for 15 minutes, 0.954 g (6.9 mmol) of potassium carbonate and 1-methyl- 2.0 g (5.75 mniol) of methyl 4-chloride-3-trifluoromethylpyrazole-5-ylacetate was added, and the reaction solution was kept at 105 ° C and stirred for 4 hours. After cooling to 20 ° C, 50 mL of ethyl acetate was added to the reaction solution, and the insoluble matter was filtered. A saturated solution of ammonium chloride was added to the filtrate, and the mixture was separated, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solution obtained by removing magnesium sulfate by filtration was concentrated, and 1-methyl-3-trifluoromethyl-4- [3,5-bis (trifluoromethyl) phenylethinyl] pyrazole-5-inole 2.95 g of crude methyl acetate was obtained as a pale yellow solid. As a result of quantification by the HP LC internal standard method, the conversion of the reaction was 86%, and the yield of the desired product was 61%. Example 6

Degassing under nitrogen atmosphere: DMF 2.5 mL, 2, 2'-Bibiridyl 18 mg (0.12 mmol), 3,5-bis trifluoromethylphenylacetylene 164 mg (0.69 mmol) Subsequently, 22 mg (0.12 mmol) of copper iodide (1) was added. After stirring for 15 minutes, 95 mg (0.69 mmol) of potassium carbonate and 200 mg (0.575 mmol) of methyl 1-methyl-4-oxide-3-trifluoromethylpyrazole-5-ylacetate were added, and the reaction mixture was added. The mixture was kept at 110 ° C and stirred for 4.5 hours. After cooling to 20 ° C, 5 mL of ethyl acetate was added to the reaction solution, and the insoluble matter was filtered. A saturated sodium chloride solution was added to the filtrate, and the mixture was separated, washed with saturated saline and dried over anhydrous magnesium sulfate. The solution obtained by removing magnesium sulfate by filtration was concentrated, and 1-methyl-3-trifluoromethyl-4- [3,5-bis (trifluoromethyl) phenylethinyl] pyrazol-5-yl -290 mg of crude methyl acetate was obtained as a pale yellow solid. As a result of quantification by the HP LC internal standard method, the conversion of the reaction was 91% and the yield of the desired product was 57%. Example 7

In a nitrogen atmosphere, degassed DMF in 2.5 mL was 3,4-bistrifluoromethylphenylacetylene 144 mg (0.604 mmol), followed by n-butylammonium bromide 55 mg (0.173 mmol) and copper iodide 0) 33 mg (0.173 mmol). After stirring for 10 minutes, 88 mg (0.623 mmol) of carbon dioxide lime and 200 mg (0.575 mmol) of methyl 1-methyl-4-oxide-3-trifluoromethylpyrazole-5-ylacetate were added, and the reaction was performed. The solution was kept at 100 ° C and stirred for 7 hours. After cooling to 20 ° C, 5 mL of ethyl acetate was added to the reaction solution, and the insoluble matter was filtered. A saturated sodium chloride solution was added to the filtrate, and the mixture was separated, washed with saturated saline and dried over anhydrous magnesium sulfate. The solution obtained by removing magnesium sulfate by filtration was concentrated and 1-methyl-3-trifluoromethyl-4- [3,5-bis (trifluoromethyl) phenyletinyl] pyrazol-5-y 290 mg of a crude product of m-methyl acetate was obtained as a pale yellow solid. As a result of quantification by the HPLC internal standard method, it was found that the conversion of the reaction was 73% and the yield of the desired product was 55%. Industrial potential

ADVANTAGE OF THE INVENTION According to this invention, coupling reaction of halogenated virazoles and aryl acetylenes can be performed in good yield with simple operation and an inexpensive reagent.

Claims

The scope of the claims

1. In producing an arylethynyl virazole by reacting a halogenated virazole with an aryl acetylene, the reaction is carried out in the presence of a copper halide and a base. A method for producing luetinirubirazoles.

2. The halogenated pyrazoles are 2- (5-virazolyl) acetic acid ester derivatives represented by the following general formula (1), and aryl acetylenes are the phenylacetylenes represented by the following general formula (2). 2. The arylethynyl according to claim 1, wherein the arylethynyl derivative is a 4-acetylarylethylazole derivative represented by the following general formula (3). A method for producing virazoles.

(Wherein R ¹ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted alkoxy group R ² represents a hydrogen atom, an alkyl group, a haloalkyl group, or an optionally substituted aryl group; and R ³ represents an alkyl group, an aralkyl group, or an aryl group. X is a halogen Indicates an atom. )

(In the formula, R ⁴ represents a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a non-alkoxy group, an alkylthio group or a haloalkylthio group, and n represents an integer of 0 to 5.)

(Wherein Ι? Λ R ² , R ³ , R ⁴ and n are the same as above).

3. The method for producing arylethynylpyrazoles described in claim 2, wherein R ¹ is a haloalkyl group.

4. The process for producing arylethynyl virazoles according to claim 2, wherein R ² is an alkyl group.

5. The method according to claim 2, wherein R ³ is an alkyl group.

6. The method for producing arylethynyl virazoles according to claim 2, wherein X is an iodine atom.

7. The method for producing aryletirubirazoles described in claim 2, wherein R ⁴ is a halogen atom, a haloalkyl group or a haloalkoxy group.

8. The method for producing arylethynyl virazoles according to claim 7, wherein n is 1 or 2.

9. R ¹ is a haloalkyl group, R ² is an alkyl group, R ³ is an alkyl group, X is an iodine atom, R ⁴ is a halogen atom, a haloalkyl group or a haloalkoxy group, and 3. The method for producing an arylethynylpyrazole according to claim 2, wherein n is 1 or 2.

10. The method for producing arylethynyl virazoles according to claim 1, wherein the copper halide is a monovalent copper halide.

11. The process for producing arylethynyl virazoles according to claim 1, wherein the amount of copper halide used is less than 1 equivalent relative to aryl acetylenes.

12. The method for producing arylene rubirazoles according to claim 11, wherein the amount of copper halide used is 0.01 to 0.8 equivalents to aryl acetylenes.

13. The method for producing arylethynyl virazoles according to claim 1, wherein the base is a carbonate.

14. The process according to claim 1, wherein the amount of the base used is 1 equivalent or more relative to the halogenated pyrazole.

15. The amount of the base to be used is 1 to 5 equivalents relative to the halogenated pyrazols. Item 14. The process for producing arylethynyl virazoles according to item 14.

16. The process for producing arylethynyl virazoles according to claim 1, wherein the copper halide is a monovalent copper halide, and the base is a carbonate.

17. The claim 16 wherein the amount of copper halide used is less than 1 equivalent to aryl acetylenes and the amount of base used is 1 equivalent or more to halogenated pyrazoles. A method for producing arylethynylpyrazoles of the above.

18. The amount of halogenated copper used is 0.01 to 0.8 equivalents to aryl acetylenes, and the amount of base used is 1 to 5 equivalents to halogenated virazoles. A method for producing an arylethynyl virazole according to claim 17.

19. The process for producing arylene rubirazoles according to claim 1, wherein the aryl acetylenes and the copper halide are mixed in advance, and then the halogenated pyrazoles are added.

2. The method for producing arylethynylpyrazoles according to claim 1, wherein the amount of the arylarylacetylene used is 1.01 to 10 equivalents to the halogenated pyrazoles.