WO2014103812A1 - Method for producing crystals of pyrazole compound - Google Patents

Method for producing crystals of pyrazole compound Download PDF

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Publication number
WO2014103812A1
WO2014103812A1 PCT/JP2013/083807 JP2013083807W WO2014103812A1 WO 2014103812 A1 WO2014103812 A1 WO 2014103812A1 JP 2013083807 W JP2013083807 W JP 2013083807W WO 2014103812 A1 WO2014103812 A1 WO 2014103812A1
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pyrazole compound
organic solvent
water
compound
formula
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PCT/JP2013/083807
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French (fr)
Japanese (ja)
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匡哉 谷本
広田　将司
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住友化学株式会社
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Priority to BR112015015120A priority Critical patent/BR112015015120A2/en
Publication of WO2014103812A1 publication Critical patent/WO2014103812A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to a method for producing a crystal of a pyrazole compound.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a methyl group, a monofluoromethyl group, a difluoromethyl group, or a trifluoromethyl group.
  • Patent Document 1 a solid containing a pyrazole compound represented by the formula (I) in which R 1 is a hydrogen atom and R 2 is a difluoromethyl group is represented by the formula (I) by recrystallization from toluene. A method for producing crystals of pyrazole compounds is described.
  • An object of the present invention is to provide a method for industrially advantageously producing a crystal of a pyrazole compound represented by the formula (I).
  • the present inventor has intensively studied to develop a method for producing a crystal of a pyrazole compound represented by the formula (I) in an industrially advantageous manner, and has reached the present invention.
  • the present invention is as follows.
  • Formula (I) (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a methyl group, a monofluoromethyl group, a difluoromethyl group, or a trifluoromethyl group.)
  • a crystal of the pyrazole compound represented by formula (I) is precipitated by removing the organic solvent from a mixture of a solution in which the pyrazole compound represented by formula (I) is dissolved in an organic solvent and water. The manufacturing method of the crystal
  • [2] A solution in which a pyrazole compound represented by the formula (I) is dissolved in an organic solvent and water are mixed, and the organic solvent is removed from the obtained mixture to thereby remove the pyrazole compound represented by the formula (I).
  • [4] The production method according to any one of [1] to [3], wherein the solution in which the pyrazole compound represented by the formula (I) is dissolved in an organic solvent contains a dispersant.
  • crystals of the pyrazole compound represented by the formula (I) can be produced industrially advantageously.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a methyl group, a monofluoromethyl group, or a difluoromethyl group. Or represents a trifluoromethyl group.
  • the pyrazole compound (I) has the formula (IR) (In the formula, R 1 and R 2 have the same meaning as described above.) R-form (hereinafter sometimes abbreviated as pyrazole compound (1-R)) and formula (IS) (In the formula, R 1 and R 2 have the same meaning as described above.) S-form (hereinafter sometimes abbreviated as pyrazole compound (1-S)) is present, but pyrazole compound (I) may be pyrazole compound (IR) or pyrazole. Compound (IS) may be sufficient, and the mixture which contains both in arbitrary ratios may be sufficient.
  • the pyrazole compound (I) may be a racemate or an optically active substance.
  • the present invention provides a pyrazole compound (I) characterized by precipitating crystals of a pyrazole compound (I) by removing the organic solvent from a mixture of a solution in which the pyrazole compound (I) is dissolved in an organic solvent and water. ) Crystal production method.
  • the organic solvent is an organic solvent that can dissolve the pyrazole compound (I), and an organic solvent having a lower boiling point than water or an organic solvent that can be azeotroped with water is easy to remove the organic solvent. From the viewpoint, it is preferable.
  • Such an organic solvent may be a water-miscible organic solvent or a water-immiscible organic solvent.
  • the water-miscible organic solvent include alcohol solvents having 1 to 3 carbon atoms such as methanol, ethanol, propanol and isopropanol, water-soluble cyclic ether solvents such as tetrahydrofuran and dioxane, acetonitrile, acetone and methyl cellosolve.
  • a water-immiscible organic solvent is an organic solvent that can form two layers of an aqueous layer and an organic layer when mixed with water, specifically, an aliphatic hydrocarbon solvent such as pentane, hexane, cyclohexane, etc.
  • Aromatic hydrocarbon solvents such as toluene, xylene and ethylbenzene, halogenated aliphatic hydrocarbon solvents such as dichloromethane, chloroform and 1,2-dichloroethane, halogenated aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene and trichlorobenzene, Water-insoluble ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether and cyclohexyl methyl ether, water-insoluble ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, water-insoluble with 4 or more carbon atoms such as butanol and pentyl alcohol Alcohol solvent, methyl acetate Ethyl acetate, water-insoluble ester solvents such as propyl acetate.
  • Aromatic hydrocarbon solvents such as toluene, xy
  • At least one selected from the group consisting of an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, a halogenated aromatic hydrocarbon solvent, and an alcohol solvent having 1 to 3 carbon atoms is preferable.
  • the aromatic hydrocarbon solvent and the carbon number More preferred is at least one selected from the group consisting of 1 to 3 alcohol solvents.
  • the organic solvent preferably contains an alcohol solvent having 1 to 3 carbon atoms.
  • the concentration of the pyrazole compound (I) in the solution in which the pyrazole compound (I) is dissolved in the organic solvent varies depending on the kind of the pyrazole compound (I) and the kind of the organic solvent, but is preferably 5% by weight to 70% by weight, More preferably, it is 60% by weight.
  • a solution can be prepared, for example, by subjecting the reaction mixture obtained by the method for producing the pyrazole compound (I) described later to post-treatment such as washing and concentration.
  • the solution in which pyrazole compound (I) is dissolved in an organic solvent, water, or both may contain a dispersant.
  • Dispersants include alkyl sulfate, alkyl sulfonate, alkyl aryl sulfonate, dialkyl sulfo succinate, polyoxyethylene alkyl ether sulfate, polyoxyethylene alkyl aryl ether phosphate, naphthalene sulfonate Formalin condensate, polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene block copolymer, sorbidan fatty acid ester, polyoxysorbidic fatty acid ester, polyhydric alcohol ester, etc. An activator is mentioned.
  • the amount of the dispersant used is usually 0.005 to 0.05 parts by weight with respect to 1 part by weight of the pyrazole compound (I).
  • a solution in which the pyrazole compound (I) is dissolved in an organic solvent is mixed with water, and the organic solvent is removed from the resulting mixture to precipitate crystals of the pyrazole compound (I). Crystals of pyrazole compound (I) may be precipitated by removing the organic solvent while adding a solution of (I) dissolved in the organic solvent to water.
  • a method for precipitating crystals of the pyrazole compound (I) by mixing a solution of the pyrazole compound (I) dissolved in an organic solvent and water and removing the organic solvent from the obtained mixture will be described below.
  • the solution and water are mixed by a method of adding the solution to water. Alternatively, it may be carried out by adding water to the solution.
  • the mixing temperature is usually in the range of room temperature to the low temperature of the boiling point of the organic solvent or water, preferably 20 ° C. to 80 ° C., more preferably 25 ° C. to 65 ° C.
  • the mixing time is usually 1 minute to 24 hours.
  • the amount of water used is preferably 0.5 to 100 parts by weight, more preferably 1 to 20 parts by weight with respect to 1 part by weight of the pyrazole compound (I).
  • Stirring is usually performed by stirring means such as an anchor blade, paddle blade, turbine blade, swept blade, and bull margin blade.
  • the mixture obtained by mixing a solution in which the pyrazole compound (I) is dissolved in an organic solvent and water is preferably a mixture in which the solution is dispersed in water.
  • the removal of the organic solvent from the mixture may be performed under reduced pressure conditions or normal pressure conditions.
  • the pyrazole compound (I) is thermally unstable or when the boiling point of the organic solvent is higher than that of water, it is preferable to remove the organic solvent under reduced pressure conditions.
  • seed crystals may be added to the mixture.
  • the removal of the organic solvent is preferably carried out in the range of 20 ° C. to 90 ° C., more preferably in the range of 25 ° C. to 75 ° C.
  • the removal time is usually 1 minute to 30 hours.
  • water When water is removed together with the organic solvent such as when the organic solvent forms an azeotrope with water, water is added to the mixture from the viewpoint of improving the slurry properties of the mixture in which crystals of the pyrazole compound (I) are precipitated. While adding, it is preferable to remove the organic solvent. In this case, the water removed together with the organic solvent may be condensed to separate the organic solvent and water, and the separated water may be added to the mixture.
  • the removal of the organic solvent is preferably performed while stirring, and the stirring is usually performed by stirring means such as an anchor blade, paddle blade, turbine blade, swept blade, and bull margin blade.
  • This method is preferable in that the maximum volume of the mixture of the solution and water can be reduced.
  • seed crystals may be added to water.
  • the amount of water used is preferably 0.5 to 100 parts by weight, more preferably 1 to 20 parts by weight, with respect to 1 part by weight of the pyrazole compound (I).
  • the addition of the solution in which the pyrazole compound (I) is dissolved in an organic solvent to water may be performed under reduced pressure conditions or under normal pressure conditions.
  • the pyrazole compound (I) is thermally unstable or when the boiling point of the organic solvent is higher than the boiling point of water, it is preferable to add the solution to water under reduced pressure conditions.
  • the addition of the solution in which the pyrazole compound (I) is dissolved in the organic solvent to the water is performed at a temperature higher than the temperature at which the organic solvent can be distilled out by evaporation.
  • an azeotrope is formed, it is carried out at or above the azeotropic temperature.
  • the reaction is preferably performed at 20 ° C to 90 ° C, more preferably 25 ° C to 75 ° C.
  • the time for adding the solution in which the pyrazole compound (I) is dissolved in the organic solvent to the water is preferably substantially the same as the time for removing the organic solvent.
  • water When water is removed together with the organic solvent such as when the organic solvent forms an azeotrope with water, water is added to the mixture from the viewpoint of improving the slurry properties of the mixture in which crystals of the pyrazole compound (I) are precipitated. While adding, it is preferable to remove the organic solvent. In this case, the water removed together with the organic solvent may be condensed to separate the organic solvent and water, and the separated water may be added to the mixture.
  • the removal of the organic solvent is preferably performed while stirring, and the stirring is usually performed by stirring means such as an anchor blade, paddle blade, turbine blade, swept blade, and bull margin blade.
  • the precipitated crystals of the pyrazole compound (I) can be taken out by cooling the obtained slurry as necessary, followed by separation treatment such as filtration and decantation.
  • the temperature for the separation treatment is preferably 0 ° C. to 50 ° C., more preferably 5 ° C. to 40 ° C.
  • the extracted crystals of pyrazole compound (I) may be washed with water or the like, if necessary.
  • the drying may be performed under normal pressure conditions or under reduced pressure conditions, and the temperature is usually 20 ° C. to 80 ° C.
  • the pyrazole compound (I) can be produced, for example, by the following production method 1 or 2.
  • chlorinating agents examples include thionyl chloride, oxalyl chloride and phosgene.
  • the amount of the chlorinating agent to be used is generally 1 mol-2 mol, preferably 1 mol-1.5 mol, per 1 mol of compound (II).
  • the reaction between the compound (II) and the chlorinating agent can be carried out in the presence of a tertiary amine or amide.
  • Tertiary amines or amides include pyridine, picoline, N, N-dimethylformamide and N-methyl-N-phenylformamide.
  • the amount of the tertiary amine or amide to be used is generally 0.001 mol to 0.05 mol, preferably 0.003 mol to 0.03 mol, per 1 mol of compound (II).
  • the reaction between the compound (II) and the chlorinating agent is usually performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it is inert to the reaction, and is an aliphatic hydrocarbon solvent such as pentane, hexane, heptane, and cyclohexane, an aromatic hydrocarbon solvent such as toluene, xylene, and ethylbenzene, dichloromethane, chloroform, 1, 2 -Halogenated aliphatic hydrocarbon solvents such as dichloroethane and carbon tetrachloride, halogenated aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene and trichlorobenzene, and diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclohexyl methyl ether And ether solvents such as dioxane, aromatic hydrocarbon solvents and halogenated aromatic hydro
  • the reaction between the compound (II) and the chlorinating agent is usually carried out in the range of 10 ° C. to 100 ° C., preferably in the range of 40 ° C. to 80 ° C., and the reaction time is usually 0.1 hour to 24 hours.
  • the compound (III) can be taken out by concentrating the obtained reaction mixture.
  • the obtained compound (III) may be purified by distillation or the like.
  • the reaction between compound (III) and compound (IV) is carried out in the presence of a base.
  • a base include alkali metal carbonates such as sodium carbonate and potassium carbonate, tertiary amines such as triethylamine and diisopropylethylamine, and nitrogen-containing aromatic compounds such as pyridine and 4-dimethylaminopyridine.
  • the amount of the base to be used is generally a catalyst amount to 5 mol, preferably 1 mol to 3 mol, per 1 mol of compound (IV).
  • Compound (IV) may be a salt such as hydrochloride or hydrobromide.
  • the amount of compound (III) to be used is generally 0.5 mol to 1.5 mol, preferably 0.8 mol to 1.3 mol, per 1 mol of compound (IV).
  • the reaction between compound (III) and compound (IV) is usually performed in the presence of a solvent.
  • the solvent is not particularly limited as long as it is inert to the reaction, and is an aliphatic hydrocarbon solvent such as pentane, hexane, heptane, and cyclohexane, an aromatic hydrocarbon solvent such as toluene, xylene, and ethylbenzene, dichloromethane, chloroform, 1, Halogenated aliphatic hydrocarbon solvents such as 2-dichloroethane and carbon tetrachloride, halogenated aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene and trichlorobenzene, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclohexyl methyl ether, Examples include ether solvents such as tetrahydrofuran and dioxane, ester solvents such as
  • Aromatic hydrocarbon solvents Preferably, toluene, xylene, ethylbenzene, chlorobenzene and tetrahydrofuran is more preferable. Two or more solvents may be used in combination.
  • the amount of the solvent used is preferably 1 to 20 parts by weight, more preferably 2 to 10 parts by weight, relative to 1 part by weight of compound (IV).
  • reaction between compound (III) and compound (IV) is usually carried out in the range of ⁇ 20 ° C. to 80 ° C., preferably 0 ° C. to 60 ° C., more preferably 20 ° C. to 55 ° C. 1 to 24 hours.
  • a solution containing compound (I) can be obtained by mixing an aqueous acid solution and then separating the solution into an organic layer and an aqueous layer.
  • the obtained solution is preferably water, an aqueous solution of sodium bicarbonate, an aqueous solution of sodium carbonate, an aqueous solution of ammonium chloride, an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid. Washed. Such washing is usually performed at 0 to 70 ° C., preferably 20 to 60 ° C.
  • the obtained solution can be used in the present invention as it is.
  • dehydrating condensing agent examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, carbodiimide compounds such as 1,3-dicyclohexylcarbodiimide, and (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium. Hexafluorophosphate is mentioned.
  • the amount of the dehydrating condensing agent used is usually 1 mol to 5 mol with respect to 1 mol of the compound (II).
  • the amount of compound (IV) to be used is generally 0.5 mol to 3 mol with respect to 1 mol of compound (II).
  • solvents include ether solvents such as tetrahydrofuran, ethylene glycol dimethyl ether and tert-butyl methyl ether, aliphatic hydrocarbon solvents such as hexane, heptane and octane, aromatic hydrocarbon solvents such as toluene and xylene, and halogenated carbonization such as chlorobenzene.
  • Hydrogen solvents such as butyl acetate and ethyl acetate, nitrile solvents such as acetonitrile, acid amide solvents such as N, N-dimethylformamide, sulfoxide solvents such as dimethyl sulfoxide, and nitrogen-containing aromatic compound solvents such as pyridine Can be mentioned. Two or more solvents may be used in combination. The amount of the solvent used is usually 1 part by weight to 20 parts by weight with respect to 1 part by weight of the compound (II).
  • reaction between compound (II) and compound (IV) is usually carried out in the range of ⁇ 20 ° C. to 140 ° C., and the reaction time is usually 1 hour to 24 hours.
  • the resulting mixture can be filtered to take out the pyrazole compound (I) and the solid does not precipitate.
  • the pyrazole compound (I) can be taken out by extracting the obtained mixture with an organic solvent, separating the organic layer, and concentrating.
  • the obtained organic layer can be used in the present invention as it is or after washing.
  • an optically active substance of pyrazole compound (I) By using an optically active substance as compound (IV), an optically active substance of pyrazole compound (I) can be obtained.
  • a solution prepared by dissolving the obtained 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride in 9.36 g of toluene was subjected to (R) -1,1,3- at 45 ° C. to 50 ° C.
  • a solution prepared by mixing 9.29 g of trimethyl-4-aminoindane (optical purity: 95.2% ee), 5.81 g of triethylamine and 28.03 g of toluene was added dropwise over 1 hour. After completion of the dropwise addition, the obtained mixture was stirred at 45 ° C. to 50 ° C. for 2 hours. After mixing the obtained reaction mixture and water, the organic layer was separated.
  • the obtained 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride was subjected to (R) -1,1,3-trimethyl-4-aminoindane (optical purity: 90.2) at 0 ° C. to 5 ° C. % Ee) was added dropwise over 1 hour to a solution prepared by mixing 20.03 g, 12.52 g of triethylamine and 110.04 g of toluene. After completion of the dropwise addition, the obtained mixture was stirred at 0 ° C. to 5 ° C. for 1 hour, then heated to 20 ° C. to 25 ° C. and stirred at the same temperature for 2 hours. After mixing the obtained reaction mixture and water, the organic layer was separated.
  • Example 1 A 500-mL flask equipped with a stirrer equipped with three receding blades, a baffle, a condenser tube, and a thermometer was kept warm with warm water adjusted to 62 ° C. A flask was charged with 84.4 g of a toluene solution (concentration: 50 wt%) of pyrazole compound (a) (optical purity: 90.4% ee) and 0.3 g of sodium bis (2-ethylhexyl) sulfosuccinate. While stirring, 295.3 g of water was added to the obtained mixture.
  • the mixture in the flask was in a state where the toluene solution of the pyrazole compound (a) was uniformly dispersed in water. While stirring the mixture, the pressure in the flask was reduced to 30.3 kPa, and toluene was removed over 5 hours. While removing toluene, the temperature of the warm water was raised to 75 ° C. over 4 hours, and water was added so that the amount of liquid in the flask did not decrease. In order to promote crystallization of the pyrazole compound (a), 0.4 g of seed crystals were added.
  • Example 2 A 300-mL flask equipped with a stirrer equipped with three receding blades, a baffle, a condenser, and a thermometer was kept warm with warm water adjusted to 60 ° C. A flask was charged with 43.3 g of a toluene solution (concentration: 50 wt%) of pyrazole compound (a) (optical purity: 95.4% ee) and 0.06 g of sodium bis (2-ethylhexyl) sulfosuccinate. While stirring, 64.9 g of water was added to the resulting mixture. While stirring the obtained mixture, the pressure in the flask was reduced to 30.3 kPa, and toluene was removed over 3 hours.
  • a toluene solution
  • Example 3 303.5 g of water and 1 g of seed crystals were charged into a 500-mL flask equipped with a stirrer equipped with three blades, a baffle, a cooling tube, and a thermometer. The flask was kept warm with warm water adjusted to 43 ° C. While stirring the mixture in the flask, the pressure in the flask was reduced to 7.3 kPa, and the mixture was refluxed. The temperature of the mixture in the flask at this time was 40.6 ° C.
  • Example 4 300.3 g of water and 1 g of seed crystals were charged into a 500-mL flask equipped with a stirrer equipped with three blades, a baffle, a cooling tube, and a thermometer. The flask was kept warm with warm water adjusted to 45 ° C. While stirring the mixture in the flask, the pressure in the flask was reduced to 5.3 kPa, and the mixture was refluxed. The temperature of the mixture in the flask at this time was 35 ° C.
  • crystals of a pyrazole compound exhibiting a controlling effect against plant diseases can be produced industrially advantageously.

Abstract

A method for producing crystals of a pyrazole compound represented by formula (I), said method being characterized by comprising removing an organic solvent from a mixture of water and a solution, which is a solution prepared by dissolving the pyrazole compound represented by formula (I) in the organic solvent, to thereby cause crystals of the pyrazole compound represented by formula (I) to be precipitated.

Description

ピラゾール化合物の結晶の製造方法Method for producing crystal of pyrazole compound
　本発明は、ピラゾール化合物の結晶の製造方法に関する。 The present invention relates to a method for producing a crystal of a pyrazole compound.
　式（Ｉ）
Figure JPOXMLDOC01-appb-I000002
（式中、Ｒ１は水素原子またはメチル基を表わし、Ｒ２はメチル基、モノフルオロメチル基、ジフルオロメチル基またはトリフルオロメチル基を表わす。）
で示されるピラゾール化合物が植物病害に対して防除効力を示すことが知られている（特許文献１および特許文献２）。 Formula (I)
Figure JPOXMLDOC01-appb-I000002
(In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a methyl group, a monofluoromethyl group, a difluoromethyl group, or a trifluoromethyl group.)
It is known that the pyrazole compound represented by (1) exhibits a controlling effect against plant diseases (Patent Document 1 and Patent Document 2).
　特許文献１には、Ｒ１が水素原子であり、Ｒ２がジフルオロメチル基である式（Ｉ）で示されるピラゾール化合物を含む固体を、トルエンから再結晶することにより、式（Ｉ）で示されるピラゾール化合物の結晶の製造方法が記載されている。 In Patent Document 1, a solid containing a pyrazole compound represented by the formula (I) in which R 1 is a hydrogen atom and R 2 is a difluoromethyl group is represented by the formula (I) by recrystallization from toluene. A method for producing crystals of pyrazole compounds is described.
国際公開第９２／１２９７０号パンフレットInternational Publication No. 92/12970 Pamphlet 特開２０１２−２５７３５号公報JP 2012-25735 A
　本発明は、式（Ｉ）で示されるピラゾール化合物の結晶を、工業的に有利に製造する方法を提供することを課題とする。 An object of the present invention is to provide a method for industrially advantageously producing a crystal of a pyrazole compound represented by the formula (I).
　本発明者は、工業的に有利に、式（Ｉ）で示されるピラゾール化合物の結晶を製造する方法を開発すべく、鋭意検討し、本発明に至った。 The present inventor has intensively studied to develop a method for producing a crystal of a pyrazole compound represented by the formula (I) in an industrially advantageous manner, and has reached the present invention.
　すなわち、本発明は、以下のとおりである。
［１］式（Ｉ）
（式中、Ｒ１は水素原子またはメチル基を表わし、Ｒ２はメチル基、モノフルオロメチル基、ジフルオロメチル基またはトリフルオロメチル基を表わす。）
で示されるピラゾール化合物が有機溶媒に溶解した溶液と水との混合物から、該有機溶媒を除去することにより式（Ｉ）で示されるピラゾール化合物の結晶を析出させることを特徴とする式（Ｉ）で示されるピラゾール化合物の結晶の製造方法。
［２］式（Ｉ）で示されるピラゾール化合物が有機溶媒に溶解した溶液と水とを混合し、得られた混合物から該有機溶媒を除去することにより、式（Ｉ）で示されるピラゾール化合物の結晶を析出させる［１］に記載の製造方法。
［３］式（Ｉ）で示されるピラゾール化合物が有機溶媒に溶解した溶液を水に加えながら、該有機溶媒を除去する［１］に記載の製造方法。
［４］式（Ｉ）で示されるピラゾール化合物が有機溶媒に溶解した溶液が分散剤を含む［１］~［３］のいずれかに記載の製造方法。
［５］有機溶媒が、芳香族炭化水素溶媒およびアルコール溶媒からなる群から選ばれる少なくとも一つである［１］~［４］のいずれかに記載の製造方法。
［６］有機溶媒が、アルコール溶媒を含む［１］~［５］のいずれかに記載の製造方法。
［７］式（Ｉ）で示されるピラゾール化合物が光学活性体である［１］~［６］のいずれかに記載の製造方法。 That is, the present invention is as follows.
[1] Formula (I)
(In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a methyl group, a monofluoromethyl group, a difluoromethyl group, or a trifluoromethyl group.)
A crystal of the pyrazole compound represented by formula (I) is precipitated by removing the organic solvent from a mixture of a solution in which the pyrazole compound represented by formula (I) is dissolved in an organic solvent and water. The manufacturing method of the crystal | crystallization of the pyrazole compound shown by these.
[2] A solution in which a pyrazole compound represented by the formula (I) is dissolved in an organic solvent and water are mixed, and the organic solvent is removed from the obtained mixture to thereby remove the pyrazole compound represented by the formula (I). The production method according to [1], wherein crystals are precipitated.
[3] The production method according to [1], wherein the organic solvent is removed while adding a solution in which the pyrazole compound represented by the formula (I) is dissolved in an organic solvent to water.
[4] The production method according to any one of [1] to [3], wherein the solution in which the pyrazole compound represented by the formula (I) is dissolved in an organic solvent contains a dispersant.
[5] The production method according to any one of [1] to [4], wherein the organic solvent is at least one selected from the group consisting of an aromatic hydrocarbon solvent and an alcohol solvent.
[6] The production method according to any one of [1] to [5], wherein the organic solvent includes an alcohol solvent.
[7] The production method according to any one of [1] to [6], wherein the pyrazole compound represented by the formula (I) is an optically active substance.
　本発明によれば、式（Ｉ）で示されるピラゾール化合物の結晶を、工業的に有利に製造することができる。 According to the present invention, crystals of the pyrazole compound represented by the formula (I) can be produced industrially advantageously.
参考例１で得られたピラゾール化合物（ａ）の白色結晶のＸＲＤチャートである。3 is an XRD chart of white crystals of a pyrazole compound (a) obtained in Reference Example 1.
　式（Ｉ）
Figure JPOXMLDOC01-appb-I000004
で示されるピラゾール化合物（以下、ピラゾール化合物（Ｉ）と略記する場合がある。）の式中、Ｒ１は水素原子またはメチル基を表わし、Ｒ２はメチル基、モノフルオロメチル基、ジフルオロメチル基またはトリフルオロメチル基を表わす。 Formula (I)
Figure JPOXMLDOC01-appb-I000004
Wherein R 1 represents a hydrogen atom or a methyl group, and R 2 represents a methyl group, a monofluoromethyl group, or a difluoromethyl group. Or represents a trifluoromethyl group.
　ピラゾール化合物（Ｉ）には、式（Ｉ−Ｒ）
Figure JPOXMLDOC01-appb-I000005
（式中、Ｒ１およびＲ２は前記と同じ意味を表わす。）
で示されるＲ体（以下、ピラゾール化合物（１−Ｒ）と略記する場合がある。）と式（Ｉ−Ｓ）
Figure JPOXMLDOC01-appb-I000006
（式中、Ｒ１およびＲ２は前記と同じ意味を表わす。）
で示されるＳ体（以下、ピラゾール化合物（１−Ｓ）と略記する場合がある。）が存在するが、ピラゾール化合物（Ｉ）は、ピラゾール化合物（Ｉ−Ｒ）であってもよいし、ピラゾール化合物（Ｉ−Ｓ）であってもよいし、その両者を任意の割合で含む混合物であってもよい。ピラゾール化合物（Ｉ）は、ラセミ体であってもよいし、光学活性体であってもよい。 The pyrazole compound (I) has the formula (IR)
Figure JPOXMLDOC01-appb-I000005
(In the formula, R 1 and R 2 have the same meaning as described above.)
R-form (hereinafter sometimes abbreviated as pyrazole compound (1-R)) and formula (IS)
Figure JPOXMLDOC01-appb-I000006
(In the formula, R 1 and R 2 have the same meaning as described above.)
S-form (hereinafter sometimes abbreviated as pyrazole compound (1-S)) is present, but pyrazole compound (I) may be pyrazole compound (IR) or pyrazole. Compound (IS) may be sufficient, and the mixture which contains both in arbitrary ratios may be sufficient. The pyrazole compound (I) may be a racemate or an optically active substance.
　ピラゾール化合物（Ｉ）としては、
Ｒ１が水素原子であるピラゾール化合物（Ｉ）、
Ｒ１がメチル基であるピラゾール化合物（Ｉ）、
Ｒ２がメチル基であるピラゾール化合物（Ｉ）、
Ｒ２がモノフルオロメチル基であるピラゾール化合物（Ｉ）、
Ｒ２がジフルオロメチル基であるピラゾール化合物（Ｉ）、
Ｒ２がトリフルオロメチル基であるピラゾール化合物（Ｉ）、
Ｒ１がメチル基であり、Ｒ２がメチル基であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、Ｒ２がモノフルオロメチル基であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、Ｒ２がジフルオロメチル基であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、Ｒ２がトリフルオロメチル基であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であるピラゾール化合物（Ｉ−Ｒ）、
Ｒ１がメチル基であるピラゾール化合物（Ｉ−Ｒ）、
Ｒ２がメチル基であるピラゾール化合物（Ｉ−Ｒ）、
Ｒ２がモノフルオロメチル基であるピラゾール化合物（Ｉ−Ｒ）、
Ｒ２がジフルオロメチル基であるピラゾール化合物（Ｉ−Ｒ）、
Ｒ２がトリフルオロメチル基であるピラゾール化合物（Ｉ−Ｒ）、
Ｒ１がメチル基であり、Ｒ２がメチル基であるピラゾール化合物（Ｉ−Ｒ）、
Ｒ１が水素原子であり、Ｒ２がモノフルオロメチル基であるピラゾール化合物（Ｉ−Ｒ）、
Ｒ１が水素原子であり、Ｒ２がジフルオロメチル基であるピラゾール化合物（Ｉ−Ｒ）、Ｒ１が水素原子であり、Ｒ２がトリフルオロメチル基であるピラゾール化合物（Ｉ−Ｒ）、
Ｒ１が水素原子であるピラゾール化合物（Ｉ−Ｓ）、
Ｒ１がメチル基であるピラゾール化合物（Ｉ−Ｓ）、
Ｒ２がメチル基であるピラゾール化合物（Ｉ−Ｓ）、
Ｒ２がモノフルオロメチル基であるピラゾール化合物（Ｉ−Ｓ）、
Ｒ２がジフルオロメチル基であるピラゾール化合物（Ｉ−Ｓ）、
Ｒ２がトリフルオロメチル基であるピラゾール化合物（Ｉ−Ｓ）、
Ｒ１がメチル基であり、Ｒ２がメチル基であるピラゾール化合物（Ｉ−Ｓ）、
Ｒ１が水素原子であり、Ｒ２がモノフルオロメチル基であるピラゾール化合物（Ｉ−Ｓ）、
Ｒ１が水素原子であり、Ｒ２がジフルオロメチル基であるピラゾール化合物（Ｉ−Ｓ）、Ｒ１が水素原子であり、Ｒ２がトリフルオロメチル基であるピラゾール化合物（Ｉ−Ｓ）、
エナンチオマー比（Ｒ体／Ｓ体）が８０／２０以上であるピラゾール化合物（Ｉ）、
エナンチオマー比（Ｒ体／Ｓ体）が９０／１０以上であるピラゾール化合物（Ｉ）、
エナンチオマー比（Ｒ体／Ｓ体）が９５／５以上であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、エナンチオマー比（Ｒ体／Ｓ体）が８０／２０以上であるピラゾール化合物（Ｉ）、
Ｒ１がメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が８０／２０以上であるピラゾール化合物（Ｉ）、
Ｒ２がメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が８０／２０以上であるピラゾール化合物（Ｉ）、
Ｒ２がモノフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が８０／２０以上であるピラゾール化合物（Ｉ）、
Ｒ２がジフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が８０／２０以上であるピラゾール化合物（Ｉ）、
Ｒ２がトリフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が８０／２０以上であるピラゾール化合物（Ｉ）、
Ｒ１がメチル基であり、Ｒ２がメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が８０／２０以上であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、Ｒ２がモノフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が８０／２０以上であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、Ｒ２がジフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が８０／２０以上であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、Ｒ２がトリフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が８０／２０以上であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、エナンチオマー比（Ｒ体／Ｓ体）が９０／１０以上であるピラゾール化合物（Ｉ）、
Ｒ１がメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９０／１０以上であるピラゾール化合物（Ｉ）、
Ｒ２がメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９０／１０以上であるピラゾール化合物（Ｉ）、
Ｒ２がモノフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９０／１０以上であるピラゾール化合物（Ｉ）、
Ｒ２がジフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９０／１０以上であるピラゾール化合物（Ｉ）、
Ｒ２がトリフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９０／１０以上であるピラゾール化合物（Ｉ）、
Ｒ１がメチル基であり、Ｒ２がメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９０／１０以上であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、Ｒ２がモノフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９０／１０以上であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、Ｒ２がジフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９０／１０以上であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、Ｒ２がトリフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９０／１０以上であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、エナンチオマー比（Ｒ体／Ｓ体）が９５／５以上であるピラゾール化合物（Ｉ）、
Ｒ１がメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９５／５以上であるピラゾール化合物（Ｉ）、
Ｒ２がメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９５／５以上であるピラゾール化合物（Ｉ）、
Ｒ２がモノフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９５／５以上であるピラゾール化合物（Ｉ）、
Ｒ２がジフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９５／５以上であるピラゾール化合物（Ｉ）、
Ｒ２がトリフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９５／５以上であるピラゾール化合物（Ｉ）、
Ｒ１がメチル基であり、Ｒ２がメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９５／５以上であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、Ｒ２がモノフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９５／５以上であるピラゾール化合物（Ｉ）、
Ｒ１が水素原子であり、Ｒ２がジフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９５／５以上であるピラゾール化合物（Ｉ）、および、
Ｒ１が水素原子であり、Ｒ２がトリフルオロメチル基であり、エナンチオマー比（Ｒ体／Ｓ体）が９５／５以上であるピラゾール化合物（Ｉ）が挙げられる。 As the pyrazole compound (I),
Pyrazole compound (I) wherein R 1 is a hydrogen atom,
Pyrazole compound (I) wherein R 1 is a methyl group,
Pyrazole compound (I) wherein R 2 is a methyl group,
Pyrazole compound (I) wherein R 2 is a monofluoromethyl group,
Pyrazole compound (I) wherein R 2 is a difluoromethyl group,
Pyrazole compound (I) wherein R 2 is a trifluoromethyl group,
A pyrazole compound (I) wherein R 1 is a methyl group and R 2 is a methyl group;
A pyrazole compound (I) wherein R 1 is a hydrogen atom and R 2 is a monofluoromethyl group,
A pyrazole compound (I) wherein R 1 is a hydrogen atom and R 2 is a difluoromethyl group,
A pyrazole compound (I) wherein R 1 is a hydrogen atom and R 2 is a trifluoromethyl group,
A pyrazole compound (IR) in which R 1 is a hydrogen atom;
A pyrazole compound (IR) wherein R 1 is a methyl group,
A pyrazole compound (IR) wherein R 2 is a methyl group,
A pyrazole compound (IR) wherein R 2 is a monofluoromethyl group,
A pyrazole compound (IR) wherein R 2 is a difluoromethyl group,
A pyrazole compound (IR) wherein R 2 is a trifluoromethyl group,
A pyrazole compound (IR) wherein R 1 is a methyl group and R 2 is a methyl group;
A pyrazole compound (IR) wherein R 1 is a hydrogen atom and R 2 is a monofluoromethyl group,
R 1 is a hydrogen atom, a pyrazole compound wherein R 2 is a difluoromethyl group (I-R), R 1 is a hydrogen atom, a pyrazole compound wherein R 2 is a trifluoromethyl group (I-R),
A pyrazole compound (IS) in which R 1 is a hydrogen atom;
A pyrazole compound (IS) in which R 1 is a methyl group,
A pyrazole compound (IS) in which R 2 is a methyl group,
A pyrazole compound (IS) wherein R 2 is a monofluoromethyl group,
A pyrazole compound (IS) wherein R 2 is a difluoromethyl group,
A pyrazole compound (IS) in which R 2 is a trifluoromethyl group,
A pyrazole compound (IS) in which R 1 is a methyl group and R 2 is a methyl group;
A pyrazole compound (IS) in which R 1 is a hydrogen atom and R 2 is a monofluoromethyl group;
R 1 is a hydrogen atom, a pyrazole compound wherein R 2 is a difluoromethyl group (I-S), R 1 is a hydrogen atom, a pyrazole compound wherein R 2 is a trifluoromethyl group (I-S),
A pyrazole compound (I) having an enantiomeric ratio (R-form / S-form) of 80/20 or more,
A pyrazole compound (I) having an enantiomeric ratio (R-form / S-form) of 90/10 or more,
A pyrazole compound (I) having an enantiomeric ratio (R-form / S-form) of 95/5 or more,
A pyrazole compound (I) in which R 1 is a hydrogen atom and the enantiomeric ratio (R-form / S-form) is 80/20 or more;
A pyrazole compound (I) wherein R 1 is a methyl group and the enantiomeric ratio (R-form / S-form) is 80/20 or more,
A pyrazole compound (I) wherein R 2 is a methyl group and the enantiomeric ratio (R-form / S-form) is 80/20 or more,
A pyrazole compound (I) wherein R 2 is a monofluoromethyl group and the enantiomeric ratio (R isomer / S isomer) is 80/20 or more;
A pyrazole compound (I) wherein R 2 is a difluoromethyl group and the enantiomeric ratio (R isomer / S isomer) is 80/20 or more;
A pyrazole compound (I) wherein R 2 is a trifluoromethyl group and the enantiomeric ratio (R-form / S-form) is 80/20 or more,
A pyrazole compound (I) in which R 1 is a methyl group, R 2 is a methyl group, and the enantiomeric ratio (R-form / S-form) is 80/20 or more;
A pyrazole compound (I) in which R 1 is a hydrogen atom, R 2 is a monofluoromethyl group, and the enantiomeric ratio (R-form / S-form) is 80/20 or more;
A pyrazole compound (I) in which R 1 is a hydrogen atom, R 2 is a difluoromethyl group, and the enantiomeric ratio (R-form / S-form) is 80/20 or more,
A pyrazole compound (I) in which R 1 is a hydrogen atom, R 2 is a trifluoromethyl group, and the enantiomeric ratio (R-form / S-form) is 80/20 or more;
A pyrazole compound (I) in which R 1 is a hydrogen atom and the enantiomeric ratio (R-form / S-form) is 90/10 or more,
A pyrazole compound (I) wherein R 1 is a methyl group and the enantiomeric ratio (R-form / S-form) is 90/10 or more,
A pyrazole compound (I) wherein R 2 is a methyl group and the enantiomeric ratio (R-form / S-form) is 90/10 or more,
A pyrazole compound (I) wherein R 2 is a monofluoromethyl group and the enantiomeric ratio (R-form / S-form) is 90/10 or more,
A pyrazole compound (I) wherein R 2 is a difluoromethyl group and the enantiomeric ratio (R-form / S-form) is 90/10 or more,
A pyrazole compound (I) in which R 2 is a trifluoromethyl group and the enantiomeric ratio (R isomer / S isomer) is 90/10 or more,
A pyrazole compound (I) in which R 1 is a methyl group, R 2 is a methyl group, and the enantiomeric ratio (R-form / S-form) is 90/10 or more;
A pyrazole compound (I) in which R 1 is a hydrogen atom, R 2 is a monofluoromethyl group, and the enantiomeric ratio (R-form / S-form) is 90/10 or more;
A pyrazole compound (I) in which R 1 is a hydrogen atom, R 2 is a difluoromethyl group, and the enantiomeric ratio (R isomer / S isomer) is 90/10 or more;
A pyrazole compound (I) wherein R 1 is a hydrogen atom, R 2 is a trifluoromethyl group, and the enantiomeric ratio (R isomer / S isomer) is 90/10 or more,
A pyrazole compound (I) wherein R 1 is a hydrogen atom and the enantiomeric ratio (R-form / S-form) is 95/5 or more,
A pyrazole compound (I) wherein R 1 is a methyl group and the enantiomeric ratio (R-form / S-form) is 95/5 or more,
A pyrazole compound (I) wherein R 2 is a methyl group and the enantiomeric ratio (R-form / S-form) is 95/5 or more,
A pyrazole compound (I) wherein R 2 is a monofluoromethyl group and the enantiomeric ratio (R isomer / S isomer) is 95/5 or more,
A pyrazole compound (I) wherein R 2 is a difluoromethyl group and the enantiomeric ratio (R-form / S-form) is 95/5 or more,
A pyrazole compound (I) wherein R 2 is a trifluoromethyl group and the enantiomeric ratio (R-form / S-form) is 95/5 or more,
A pyrazole compound (I) in which R 1 is a methyl group, R 2 is a methyl group, and the enantiomeric ratio (R-form / S-form) is 95/5 or more;
A pyrazole compound (I) in which R 1 is a hydrogen atom, R 2 is a monofluoromethyl group, and the enantiomeric ratio (R isomer / S isomer) is 95/5 or more;
A pyrazole compound (I) in which R 1 is a hydrogen atom, R 2 is a difluoromethyl group, and an enantiomeric ratio (R-form / S-form) is 95/5 or more; and
Examples thereof include a pyrazole compound (I) in which R 1 is a hydrogen atom, R 2 is a trifluoromethyl group, and the enantiomeric ratio (R isomer / S isomer) is 95/5 or more.
　本発明は、ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液と水との混合物から、該有機溶媒を除去することによりピラゾール化合物（Ｉ）の結晶を析出させることを特徴とするピラゾール化合物（Ｉ）の結晶の製造方法である。 The present invention provides a pyrazole compound (I) characterized by precipitating crystals of a pyrazole compound (I) by removing the organic solvent from a mixture of a solution in which the pyrazole compound (I) is dissolved in an organic solvent and water. ) Crystal production method.
　該有機溶媒としては、ピラゾール化合物（Ｉ）を溶解し得る有機溶媒であって、水よりも沸点が低い有機溶媒または水と共沸し得る有機溶媒が、該有機溶媒の除去が容易であるという観点から、好ましい。かかる有機溶媒は、水に混和性の有機溶媒であってもよいし、水に非混和性の有機溶媒であってもよい。水に混和性の有機溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール等の炭素数１~３のアルコール溶媒、テトラヒドロフラン、ジオキサン等の水溶性の環状エーテル溶媒、アセトニトリル、アセトンおよびメチルセロソルブが挙げられる。水に非混和性の有機溶媒は、水と混合したときに水層と有機層の二層を形成し得る有機溶媒であり、具体的には、ペンタン、ヘキサン、シクロヘキサン等の脂肪族炭化水素溶媒、トルエン、キシレン、エチルベンゼン等の芳香族炭化水素溶媒、ジクロロメタン、クロロホルム、１，２−ジクロロエタン等のハロゲン化脂肪族炭化水素溶媒、クロロベンゼン、ジクロロベンゼン、トリクロロベンゼン等のハロゲン化芳香族炭化水素溶媒、ジエチルエーテル、ジイソプロピルエーテル、ｔｅｒｔ−ブチルメチルエーテル、シクロヘキシルメチルエーテル等の非水溶性エーテル溶媒、メチルエチルケトン、メチルイソブチルケトン等の非水溶性ケトン溶媒、ブタノール、ペンチルアルコール等の炭素数４以上の非水溶性アルコール溶媒、酢酸メチル、酢酸エチル、酢酸プロピル等の非水溶性エステル溶媒が挙げられる。なかでも、脂肪族炭化水素溶媒、芳香族炭化水素溶媒、ハロゲン化芳香族炭化水素溶媒および炭素数１~３のアルコール溶媒からなる群から選ばれる少なくとも一種が好ましく、芳香族炭化水素溶媒および炭素数１~３のアルコール溶媒からなる群から選ばれる少なくとも一種がより好ましい。有機溶媒は、炭素数１~３のアルコール溶媒を含むことが好ましい。 The organic solvent is an organic solvent that can dissolve the pyrazole compound (I), and an organic solvent having a lower boiling point than water or an organic solvent that can be azeotroped with water is easy to remove the organic solvent. From the viewpoint, it is preferable. Such an organic solvent may be a water-miscible organic solvent or a water-immiscible organic solvent. Examples of the water-miscible organic solvent include alcohol solvents having 1 to 3 carbon atoms such as methanol, ethanol, propanol and isopropanol, water-soluble cyclic ether solvents such as tetrahydrofuran and dioxane, acetonitrile, acetone and methyl cellosolve. A water-immiscible organic solvent is an organic solvent that can form two layers of an aqueous layer and an organic layer when mixed with water, specifically, an aliphatic hydrocarbon solvent such as pentane, hexane, cyclohexane, etc. , Aromatic hydrocarbon solvents such as toluene, xylene and ethylbenzene, halogenated aliphatic hydrocarbon solvents such as dichloromethane, chloroform and 1,2-dichloroethane, halogenated aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene and trichlorobenzene, Water-insoluble ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether and cyclohexyl methyl ether, water-insoluble ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, water-insoluble with 4 or more carbon atoms such as butanol and pentyl alcohol Alcohol solvent, methyl acetate Ethyl acetate, water-insoluble ester solvents such as propyl acetate. Among these, at least one selected from the group consisting of an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, a halogenated aromatic hydrocarbon solvent, and an alcohol solvent having 1 to 3 carbon atoms is preferable. The aromatic hydrocarbon solvent and the carbon number More preferred is at least one selected from the group consisting of 1 to 3 alcohol solvents. The organic solvent preferably contains an alcohol solvent having 1 to 3 carbon atoms.
　ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液中のピラゾール化合物（Ｉ）の濃度は、ピラゾール化合物（Ｉ）の種類および有機溶媒の種類により異なるが、５重量％~７０重量％が好ましく、２０重量％~６０重量％がより好ましい。かかる溶液は、例えば、後述するピラゾール化合物（Ｉ）の製造方法により得られた反応混合物に、洗浄、濃縮等の後処理を施すことにより調製することができる。 The concentration of the pyrazole compound (I) in the solution in which the pyrazole compound (I) is dissolved in the organic solvent varies depending on the kind of the pyrazole compound (I) and the kind of the organic solvent, but is preferably 5% by weight to 70% by weight, More preferably, it is 60% by weight. Such a solution can be prepared, for example, by subjecting the reaction mixture obtained by the method for producing the pyrazole compound (I) described later to post-treatment such as washing and concentration.
　ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液、水またはその両方は、分散剤を含んでいてもよい。分散剤としては、アルキル硫酸エステル塩、アルキルスルホン酸塩、アルキルアリールスルホン酸塩、ジアルキルスルホこはく酸塩、ポリオキシエチレンアルキルエーテル硫酸エステル塩、ポリオキシエチレンアルキルアリールエーテルリン酸エステル塩、ナフタレンスルホン酸ホルマリン縮合物、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンアルキルアリールエーテル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンポリオキシプロピレンブロックコポリマー、ソルビダン脂肪酸エステル、ポリオキシソルビダン脂肪酸エステル、多価アルコールエステル等の界面活性剤が挙げられる。分散剤の使用量は、ピラゾール化合物（Ｉ）１重量部に対して、通常０．００５重量部~０．０５重量部である。 The solution in which pyrazole compound (I) is dissolved in an organic solvent, water, or both may contain a dispersant. Dispersants include alkyl sulfate, alkyl sulfonate, alkyl aryl sulfonate, dialkyl sulfo succinate, polyoxyethylene alkyl ether sulfate, polyoxyethylene alkyl aryl ether phosphate, naphthalene sulfonate Formalin condensate, polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene block copolymer, sorbidan fatty acid ester, polyoxysorbidic fatty acid ester, polyhydric alcohol ester, etc. An activator is mentioned. The amount of the dispersant used is usually 0.005 to 0.05 parts by weight with respect to 1 part by weight of the pyrazole compound (I).
　ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液と水とを混合し、得られた混合物から該有機溶媒を除去することにより、ピラゾール化合物（Ｉ）の結晶を析出させてもよいし、ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液を水に加えながら、該有機溶媒を除去することにより、ピラゾール化合物（Ｉ）の結晶を析出させてもよい。 A solution in which the pyrazole compound (I) is dissolved in an organic solvent is mixed with water, and the organic solvent is removed from the resulting mixture to precipitate crystals of the pyrazole compound (I). Crystals of pyrazole compound (I) may be precipitated by removing the organic solvent while adding a solution of (I) dissolved in the organic solvent to water.
　ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液と水とを混合し、得られた混合物から該有機溶媒を除去することにより、ピラゾール化合物（Ｉ）の結晶を析出させる方法について、以下説明する。 A method for precipitating crystals of the pyrazole compound (I) by mixing a solution of the pyrazole compound (I) dissolved in an organic solvent and water and removing the organic solvent from the obtained mixture will be described below.
　ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液と水とを混合し、得られた混合物から該有機溶媒を除去する場合、該溶液と水との混合は、水に該溶液を加える方法により行なってもよいし、該溶液に水を加える方法により行なってもよい。混合温度は、通常室温~有機溶媒または水の沸点の内の低い温度の範囲であり、好ましくは２０℃~８０℃であり、より好ましくは２５℃~６５℃である。混合時間は、通常１分~２４時間である。水の使用量は、ピラゾール化合物（Ｉ）１重量部に対して、好ましくは０．５重量部~１００重量部であり、より好ましくは１重量部~２０重量部である。 When a solution in which the pyrazole compound (I) is dissolved in an organic solvent and water are mixed and the organic solvent is removed from the resulting mixture, the solution and water are mixed by a method of adding the solution to water. Alternatively, it may be carried out by adding water to the solution. The mixing temperature is usually in the range of room temperature to the low temperature of the boiling point of the organic solvent or water, preferably 20 ° C. to 80 ° C., more preferably 25 ° C. to 65 ° C. The mixing time is usually 1 minute to 24 hours. The amount of water used is preferably 0.5 to 100 parts by weight, more preferably 1 to 20 parts by weight with respect to 1 part by weight of the pyrazole compound (I).
　混合は、攪拌しながら行われることが好ましい。撹拌は、通常、アンカー翼、パドル翼、タービン翼、後退翼、ブルマージン翼等の攪拌手段により行われる。 Mixing is preferably performed while stirring. Stirring is usually performed by stirring means such as an anchor blade, paddle blade, turbine blade, swept blade, and bull margin blade.
　ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液と水とを混合することにより得られる混合物は、該溶液が水中に分散している混合物であることが好ましい。 The mixture obtained by mixing a solution in which the pyrazole compound (I) is dissolved in an organic solvent and water is preferably a mixture in which the solution is dispersed in water.
　前記混合物からの有機溶媒の除去は、減圧条件下で行ってもよいし、常圧条件下で行ってもよい。ピラゾール化合物（Ｉ）が熱的に不安定である場合や有機溶媒の沸点が水の沸点よりも高い場合には、減圧条件下で有機溶媒を除去することが好ましい。 The removal of the organic solvent from the mixture may be performed under reduced pressure conditions or normal pressure conditions. When the pyrazole compound (I) is thermally unstable or when the boiling point of the organic solvent is higher than that of water, it is preferable to remove the organic solvent under reduced pressure conditions.
　ピラゾール化合物（Ｉ）の結晶の析出を促すため、該混合物に種晶を添加してもよい。 In order to promote precipitation of crystals of pyrazole compound (I), seed crystals may be added to the mixture.
　有機溶媒の除去は、好ましくは２０℃~９０℃の範囲で、より好ましくは２５℃~７５℃の範囲で実施される。除去時間は、通常１分~３０時間である。 The removal of the organic solvent is preferably carried out in the range of 20 ° C. to 90 ° C., more preferably in the range of 25 ° C. to 75 ° C. The removal time is usually 1 minute to 30 hours.
　有機溶媒が水と共沸混合物を形成するとき等の有機溶媒と共に水が除去される場合、ピラゾール化合物（Ｉ）の結晶が析出する混合物のスラリー性状の改善の観点で、水を該混合物中に加えながら、有機溶媒を除去することが好ましい。この場合、有機溶媒と共に除去された水を凝縮させ、有機溶媒と水とを分離し、分離した水を混合物中に加えてもよい。 When water is removed together with the organic solvent such as when the organic solvent forms an azeotrope with water, water is added to the mixture from the viewpoint of improving the slurry properties of the mixture in which crystals of the pyrazole compound (I) are precipitated. While adding, it is preferable to remove the organic solvent. In this case, the water removed together with the organic solvent may be condensed to separate the organic solvent and water, and the separated water may be added to the mixture.
　有機溶媒の除去は、攪拌しながら行われることが好ましく、撹拌は、通常、アンカー翼、パドル翼、タービン翼、後退翼、ブルマージン翼等の攪拌手段により行われる。 The removal of the organic solvent is preferably performed while stirring, and the stirring is usually performed by stirring means such as an anchor blade, paddle blade, turbine blade, swept blade, and bull margin blade.
　続いて、ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液を水に加えながら、該有機溶媒を除去することにより、ピラゾール化合物（Ｉ）の結晶を析出させる方法について説明する。 Subsequently, a method for precipitating crystals of the pyrazole compound (I) by removing the organic solvent while adding a solution in which the pyrazole compound (I) is dissolved in an organic solvent to water will be described.
　かかる方法は、該溶液と水との混合物の最大容積を小さくすることができるという点で好ましい。 This method is preferable in that the maximum volume of the mixture of the solution and water can be reduced.
　ピラゾール化合物（Ｉ）の結晶の析出を促すため、水に種晶を添加してもよい。 In order to promote precipitation of crystals of pyrazole compound (I), seed crystals may be added to water.
　水の使用量は、ピラゾール化合物（Ｉ）１重量部に対して、好ましくは０．５重量部~１００重量部であり、より好ましくは１重量部~２０重量部である。 The amount of water used is preferably 0.5 to 100 parts by weight, more preferably 1 to 20 parts by weight, with respect to 1 part by weight of the pyrazole compound (I).
　ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液の水への添加は、減圧条件下で行ってもよいし、常圧条件下で行ってもよい。ピラゾール化合物（Ｉ）が熱的に不安定である場合や有機溶媒の沸点が水の沸点よりも高い場合には、減圧条件下で、前記溶液を水に添加することが好ましい。 The addition of the solution in which the pyrazole compound (I) is dissolved in an organic solvent to water may be performed under reduced pressure conditions or under normal pressure conditions. When the pyrazole compound (I) is thermally unstable or when the boiling point of the organic solvent is higher than the boiling point of water, it is preferable to add the solution to water under reduced pressure conditions.
　ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液の水への添加は、該有機溶媒が蒸発により系外へ留去され得る温度以上で行なわれ、通常、有機溶媒の沸点以上、有機溶媒が水と共沸混合物を形成する場合には、その共沸温度以上で行なわれる。好ましくは２０℃~９０℃、より好ましくは２５℃~７５℃で行なわれる。 The addition of the solution in which the pyrazole compound (I) is dissolved in the organic solvent to the water is performed at a temperature higher than the temperature at which the organic solvent can be distilled out by evaporation. When an azeotrope is formed, it is carried out at or above the azeotropic temperature. The reaction is preferably performed at 20 ° C to 90 ° C, more preferably 25 ° C to 75 ° C.
　ピラゾール化合物（Ｉ）が有機溶媒に溶解した溶液を水へ添加する時間は、有機溶媒の除去時間と略同一であることが好ましい。 The time for adding the solution in which the pyrazole compound (I) is dissolved in the organic solvent to the water is preferably substantially the same as the time for removing the organic solvent.
　有機溶媒が水と共沸混合物を形成するとき等の有機溶媒と共に水が除去される場合、ピラゾール化合物（Ｉ）の結晶が析出する混合物のスラリー性状の改善の観点で、水を該混合物中に加えながら、有機溶媒を除去することが好ましい。この場合、有機溶媒と共に除去された水を凝縮させ、有機溶媒と水とを分離し、分離した水を混合物中に加えてもよい。 When water is removed together with the organic solvent such as when the organic solvent forms an azeotrope with water, water is added to the mixture from the viewpoint of improving the slurry properties of the mixture in which crystals of the pyrazole compound (I) are precipitated. While adding, it is preferable to remove the organic solvent. In this case, the water removed together with the organic solvent may be condensed to separate the organic solvent and water, and the separated water may be added to the mixture.
　有機溶媒の除去は、攪拌しながら行われることが好ましく、撹拌は、通常、アンカー翼、パドル翼、タービン翼、後退翼、ブルマージン翼等の攪拌手段により行われる。 The removal of the organic solvent is preferably performed while stirring, and the stirring is usually performed by stirring means such as an anchor blade, paddle blade, turbine blade, swept blade, and bull margin blade.
　析出したピラゾール化合物（Ｉ）の結晶は、得られたスラリーを、必要に応じて冷却した後、濾過、デカンテーション等の分離処理することにより取り出すことができる。分離処理の温度は、好ましくは０℃~５０℃であり、より好ましくは５℃~４０℃である。取り出したピラゾール化合物（Ｉ）の結晶は、必要に応じて、水等で洗浄してもよい。ピラゾール化合物（Ｉ）の結晶を乾燥する場合、乾燥は、常圧条件下で行ってもよいし、減圧条件下で行ってもよく、また、その温度が、通常２０℃~８０℃である。 The precipitated crystals of the pyrazole compound (I) can be taken out by cooling the obtained slurry as necessary, followed by separation treatment such as filtration and decantation. The temperature for the separation treatment is preferably 0 ° C. to 50 ° C., more preferably 5 ° C. to 40 ° C. The extracted crystals of pyrazole compound (I) may be washed with water or the like, if necessary. When the crystals of the pyrazole compound (I) are dried, the drying may be performed under normal pressure conditions or under reduced pressure conditions, and the temperature is usually 20 ° C. to 80 ° C.
　最後に、ピラゾール化合物（Ｉ）の製造方法について説明する。ピラゾール化合物（Ｉ）は、例えば、下記製造方法１または２により製造することができる。 Finally, a method for producing the pyrazole compound (I) will be described. The pyrazole compound (I) can be produced, for example, by the following production method 1 or 2.
［製造方法１］
　製造方法１では、式（ＩＩ）で示される化合物（以下、化合物（ＩＩ）と略記する場合がある。）と塩素化剤とを反応させて、式（ＩＩＩ）で示される化合物（以下、化合物（ＩＩＩ）と略記する場合がある。）を得、得られた化合物（ＩＩＩ）と式（ＩＶ）で示される化合物（以下、化合物（ＩＶ）と略記する場合がある。）とを、塩基の存在下に反応させることにより、ピラゾール化合物（Ｉ）が得られる。
Figure JPOXMLDOC01-appb-I000007
（式中、Ｒ１およびＲ２は前記と同じ意味を表わす。） [Production Method 1]
In the production method 1, a compound represented by the formula (III) (hereinafter referred to as the compound (II)) and a chlorinating agent are reacted with each other to react with a compound represented by the formula (III) (hereinafter referred to as the compound). (III) may be abbreviated), and the obtained compound (III) and the compound represented by the formula (IV) (hereinafter sometimes abbreviated as compound (IV)) are converted into a base. Pyrazole compound (I) is obtained by reacting in the presence.
Figure JPOXMLDOC01-appb-I000007
(In the formula, R 1 and R 2 have the same meaning as described above.)
　塩素化剤としては、塩化チオニル、塩化オキサリルおよびホスゲンが挙げられる。塩素化剤の使用量は、化合物（ＩＩ）１モルに対して、通常１モル~２モル、好ましくは１モル~１．５モルである。 Examples of chlorinating agents include thionyl chloride, oxalyl chloride and phosgene. The amount of the chlorinating agent to be used is generally 1 mol-2 mol, preferably 1 mol-1.5 mol, per 1 mol of compound (II).
　化合物（ＩＩ）と塩素化剤との反応は、第三級アミンまたはアミドの存在下で行うことができる。第三級アミンまたはアミドとしては、ピリジン、ピコリン、Ｎ，Ｎ−ジメチルホルムアミドおよびＮ−メチル−Ｎ−フェニルホルムアミドが挙げられる。第三級アミンまたはアミドの使用量は、化合物（ＩＩ）１モルに対して、通常０．００１モル~０．０５モル、好ましくは０．００３モル~０．０３モルである。 The reaction between the compound (II) and the chlorinating agent can be carried out in the presence of a tertiary amine or amide. Tertiary amines or amides include pyridine, picoline, N, N-dimethylformamide and N-methyl-N-phenylformamide. The amount of the tertiary amine or amide to be used is generally 0.001 mol to 0.05 mol, preferably 0.003 mol to 0.03 mol, per 1 mol of compound (II).
　化合物（ＩＩ）と塩素化剤との反応は、通常、溶媒の存在下で行われる。溶媒としては前記反応に不活性なものであればよく、ペンタン、ヘキサン、ヘプタン、シクロヘキサン等の脂肪族炭化水素溶媒、トルエン、キシレン、エチルベンゼン等の芳香族炭化水素溶媒、ジクロロメタン、クロロホルム、１，２−ジクロロエタン、四塩化炭素等のハロゲン化脂肪族炭化水素溶媒、クロロベンゼン、ジクロロベンゼン、トリクロロベンゼン等のハロゲン化芳香族炭化水素溶媒、および、ジエチルエーテル、ジイソプロピルエーテル、ｔｅｒｔ−ブチルメチルエーテル、シクロヘキシルメチルエーテル、ジオキサン等のエーテル溶媒が挙げられ、芳香族炭化水素溶媒およびハロゲン化芳香族炭化水素溶媒が好ましく、トルエン、キシレン、エチルベンゼンおよびクロロベンゼンがより好ましい。二種以上の溶媒を組み合わせて用いてもよい。溶媒の使用量は、化合物（ＩＩ）１重量部に対して、０．５重量部~２０重量部が好ましく、１重量部~１０重量部がより好ましい。 The reaction between the compound (II) and the chlorinating agent is usually performed in the presence of a solvent. The solvent is not particularly limited as long as it is inert to the reaction, and is an aliphatic hydrocarbon solvent such as pentane, hexane, heptane, and cyclohexane, an aromatic hydrocarbon solvent such as toluene, xylene, and ethylbenzene, dichloromethane, chloroform, 1, 2 -Halogenated aliphatic hydrocarbon solvents such as dichloroethane and carbon tetrachloride, halogenated aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene and trichlorobenzene, and diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclohexyl methyl ether And ether solvents such as dioxane, aromatic hydrocarbon solvents and halogenated aromatic hydrocarbon solvents are preferred, and toluene, xylene, ethylbenzene and chlorobenzene are more preferred. Two or more solvents may be used in combination. The amount of the solvent used is preferably 0.5 to 20 parts by weight, more preferably 1 to 10 parts by weight with respect to 1 part by weight of compound (II).
　化合物（ＩＩ）と塩素化剤との反応は、通常１０℃~１００℃の範囲、好ましくは４０℃~８０℃の範囲で行なわれ、反応時間は通常０．１時間~２４時間である。 The reaction between the compound (II) and the chlorinating agent is usually carried out in the range of 10 ° C. to 100 ° C., preferably in the range of 40 ° C. to 80 ° C., and the reaction time is usually 0.1 hour to 24 hours.
　反応終了後、例えば、得られた反応混合物を濃縮することにより、化合物（ＩＩＩ）を取り出すことができる。得られた化合物（ＩＩＩ）は蒸留等により精製してもよい。 After completion of the reaction, for example, the compound (III) can be taken out by concentrating the obtained reaction mixture. The obtained compound (III) may be purified by distillation or the like.
　化合物（ＩＩＩ）と化合物（ＩＶ）との反応は、塩基の存在下に実施される。塩基としては、炭酸ナトリウム、炭酸カリウム等のアルカリ金属炭酸塩、トリエチルアミン、ジイソプロピルエチルアミン等の第三級アミンおよびピリジン、４−ジメチルアミノピリジン等の含窒素芳香族化合物が挙げられる。塩基の使用量は、化合物（ＩＶ）１モルに対して、通常、触媒量~５モル、好ましくは１モル~３モルである。 The reaction between compound (III) and compound (IV) is carried out in the presence of a base. Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, tertiary amines such as triethylamine and diisopropylethylamine, and nitrogen-containing aromatic compounds such as pyridine and 4-dimethylaminopyridine. The amount of the base to be used is generally a catalyst amount to 5 mol, preferably 1 mol to 3 mol, per 1 mol of compound (IV).
　化合物（ＩＶ）は、塩酸塩、臭化水素酸塩等の塩であってもよい。 Compound (IV) may be a salt such as hydrochloride or hydrobromide.
　化合物（ＩＩＩ）の使用量は、化合物（ＩＶ）１モルに対して、通常０．５モル~１．５モル、好ましくは０．８モル~１．３モルである。 The amount of compound (III) to be used is generally 0.5 mol to 1.5 mol, preferably 0.8 mol to 1.3 mol, per 1 mol of compound (IV).
　化合物（ＩＩＩ）と化合物（ＩＶ）との反応は、通常溶媒の存在下で行われる。溶媒としては、前記反応に不活性なものであればよく、ペンタン、ヘキサン、ヘプタン、シクロヘキサン等の脂肪族炭化水素溶媒、トルエン、キシレン、エチルベンゼン等の芳香族炭化水素溶媒、ジクロロメタン、クロロホルム、１，２−ジクロロエタン、四塩化炭素等のハロゲン化脂肪族炭化水素溶媒、クロロベンゼン、ジクロロベンゼン、トリクロロベンゼン等のハロゲン化芳香族炭化水素溶媒、ジエチルエーテル、ジイソプロピルエーテル、ｔｅｒｔ−ブチルメチルエーテル、シクロヘキシルメチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル溶媒、酢酸エチル、酢酸ブチル等のエステル溶媒、および、アセトニトリル等のニトリル溶媒が挙げられ、芳香族炭化水素溶媒、ハロゲン化芳香族炭化水素溶媒およびエーテル溶媒が好ましく、トルエン、キシレン、エチルベンゼン、クロロベンゼンおよびテトラヒドロフランがより好ましい。二種以上の溶媒を組み合わせて用いてもよい。溶媒の使用量は、化合物（ＩＶ）１重量部に対して、１重量部~２０重量部が好ましく、２重量部~１０重量部がより好ましい。 The reaction between compound (III) and compound (IV) is usually performed in the presence of a solvent. The solvent is not particularly limited as long as it is inert to the reaction, and is an aliphatic hydrocarbon solvent such as pentane, hexane, heptane, and cyclohexane, an aromatic hydrocarbon solvent such as toluene, xylene, and ethylbenzene, dichloromethane, chloroform, 1, Halogenated aliphatic hydrocarbon solvents such as 2-dichloroethane and carbon tetrachloride, halogenated aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene and trichlorobenzene, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclohexyl methyl ether, Examples include ether solvents such as tetrahydrofuran and dioxane, ester solvents such as ethyl acetate and butyl acetate, and nitrile solvents such as acetonitrile. Aromatic hydrocarbon solvents, halogenated aromatic hydrocarbon solvents, and ether solvents. Preferably, toluene, xylene, ethylbenzene, chlorobenzene and tetrahydrofuran is more preferable. Two or more solvents may be used in combination. The amount of the solvent used is preferably 1 to 20 parts by weight, more preferably 2 to 10 parts by weight, relative to 1 part by weight of compound (IV).
　化合物（ＩＩＩ）と化合物（ＩＶ）との反応は、通常−２０℃~８０℃、好ましくは０℃~６０℃、より好ましくは２０℃~５５℃の範囲で行なわれ、反応時間は通常０．１時間~２４時間である。 The reaction between compound (III) and compound (IV) is usually carried out in the range of −20 ° C. to 80 ° C., preferably 0 ° C. to 60 ° C., more preferably 20 ° C. to 55 ° C. 1 to 24 hours.
　反応終了後、例えば、得られた反応混合物と、水、炭酸水素ナトリウム水溶液、炭酸ナトリウム水溶液、塩化アンモニウム水溶液、水酸化ナトリウム水溶液、水酸化カリウム水溶液、または、塩酸、硫酸、リン酸、酢酸等の酸の水溶液とを混合した後、有機層と水層とに分液することにより、化合物（Ｉ）を含む溶液を得ることができる。得られた溶液は、好ましくは、水、炭酸水素ナトリウム水溶液、炭酸ナトリウム水溶液、塩化アンモニウム水溶液、水酸化ナトリウム水溶液、水酸化カリウム水溶液、または、塩酸、硫酸、リン酸、酢酸等の酸の水溶液で洗浄される。かかる洗浄は、通常０~７０℃、好ましくは２０~６０℃で行われる。得られた溶液は、そのまま本発明に用いることができる。 After completion of the reaction, for example, the obtained reaction mixture and water, aqueous sodium hydrogen carbonate solution, aqueous sodium carbonate solution, aqueous ammonium chloride solution, aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, etc. A solution containing compound (I) can be obtained by mixing an aqueous acid solution and then separating the solution into an organic layer and an aqueous layer. The obtained solution is preferably water, an aqueous solution of sodium bicarbonate, an aqueous solution of sodium carbonate, an aqueous solution of ammonium chloride, an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid. Washed. Such washing is usually performed at 0 to 70 ° C., preferably 20 to 60 ° C. The obtained solution can be used in the present invention as it is.
［製造方法２］
　製造方法２では、化合物（ＩＩ）と化合物（ＩＶ）とを、脱水縮合剤の存在下に反応させることにより、ピラゾール化合物（Ｉ）が得られる。
Figure JPOXMLDOC01-appb-I000008
（式中、Ｒ１およびＲ２は前記と同じ意味を表わす。） [Production Method 2]
In production method 2, pyrazole compound (I) is obtained by reacting compound (II) with compound (IV) in the presence of a dehydrating condensation agent.
Figure JPOXMLDOC01-appb-I000008
(In the formula, R 1 and R 2 have the same meaning as described above.)
　脱水縮合剤としては、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩、１，３−ジシクロヘキシルカルボジイミド等のカルボジイミド化合物、および、（ベンゾトリアゾール−１−イルオキシ）トリス（ジメチルアミノ）ホスホニウムヘキサフルオロホスフェートが挙げられる。 Examples of the dehydrating condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, carbodiimide compounds such as 1,3-dicyclohexylcarbodiimide, and (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium. Hexafluorophosphate is mentioned.
　脱水縮合剤の使用量は、化合物（ＩＩ）１モルに対して、通常１モル~５モルである。 The amount of the dehydrating condensing agent used is usually 1 mol to 5 mol with respect to 1 mol of the compound (II).
　化合物（ＩＶ）の使用量は、化合物（ＩＩ）１モルに対して、通常０．５モル~３モルである。 The amount of compound (IV) to be used is generally 0.5 mol to 3 mol with respect to 1 mol of compound (II).
　化合物（ＩＩ）と化合物（ＩＶ）との反応は、通常、該反応に不活性な溶媒の存在下で行われる。溶媒としては、テトラヒドロフラン、エチレングリコールジメチルエーテル、ｔｅｒｔ−ブチルメチルエーテル等のエーテル溶媒、ヘキサン、ヘプタン、オクタン等の脂肪族炭化水素溶媒、トルエン、キシレン等の芳香族炭化水素溶媒、クロロベンゼン等のハロゲン化炭化水素溶媒、酢酸ブチル、酢酸エチル等のエステル溶媒、アセトニトリル等のニトリル溶媒、Ｎ，Ｎ−ジメチルホルムアミド等の酸アミド溶媒、ジメチルスルホキシド等のスルホキシド溶媒、および、ピリジン等の含窒素芳香族化合物溶媒が挙げられる。二種以上の溶媒を組み合わせて用いてもよい。溶媒の使用量は、化合物（ＩＩ）１重量部に対して、通常１重量部~２０重量部である。 The reaction between compound (II) and compound (IV) is usually carried out in the presence of a solvent inert to the reaction. Solvents include ether solvents such as tetrahydrofuran, ethylene glycol dimethyl ether and tert-butyl methyl ether, aliphatic hydrocarbon solvents such as hexane, heptane and octane, aromatic hydrocarbon solvents such as toluene and xylene, and halogenated carbonization such as chlorobenzene. Hydrogen solvents, ester solvents such as butyl acetate and ethyl acetate, nitrile solvents such as acetonitrile, acid amide solvents such as N, N-dimethylformamide, sulfoxide solvents such as dimethyl sulfoxide, and nitrogen-containing aromatic compound solvents such as pyridine Can be mentioned. Two or more solvents may be used in combination. The amount of the solvent used is usually 1 part by weight to 20 parts by weight with respect to 1 part by weight of the compound (II).
　化合物（ＩＩ）と化合物（ＩＶ）との反応は、通常−２０℃~１４０℃の範囲で実施され、反応時間は通常１時間~２４時間である。 The reaction between compound (II) and compound (IV) is usually carried out in the range of −20 ° C. to 140 ° C., and the reaction time is usually 1 hour to 24 hours.
　反応終了後、例えば、得られた反応混合物と水とを混合し、固体が析出した場合は、得られた混合物を濾過することにより、ピラゾール化合物（Ｉ）を取り出すことができ、固体が析出しない場合は、得られた混合物を有機溶媒で抽出し、有機層を分離し、濃縮することにより、ピラゾール化合物（Ｉ）を取り出すことができる。得られた有機層をそのままもしくは洗浄した後、本発明に用いることができる。 After completion of the reaction, for example, when the obtained reaction mixture and water are mixed and a solid is precipitated, the resulting mixture can be filtered to take out the pyrazole compound (I) and the solid does not precipitate. In the case, the pyrazole compound (I) can be taken out by extracting the obtained mixture with an organic solvent, separating the organic layer, and concentrating. The obtained organic layer can be used in the present invention as it is or after washing.
　化合物（ＩＶ）として、光学活性体を用いることにより、ピラゾール化合物（Ｉ）の光学活性体を得ることができる。 By using an optically active substance as compound (IV), an optically active substance of pyrazole compound (I) can be obtained.
　以下、実施例により、本発明をさらに詳しく説明する。 Hereinafter, the present invention will be described in more detail with reference to examples.
［参考製造例１］
　窒素雰囲気下、室温で、１−メチル−３−ジフルオロメチルピラゾール−４−カルボン酸９．３４ｇとトルエン１８．９０ｇとを混合し、さらに、Ｎ，Ｎ−ジメチルホルムアミド０．２０ｇを加えた。得られた混合物を５０℃~５５℃に加熱した後、塩化チオニル６．９５ｇを５時間かけて滴下した。滴下終了後、得られた混合物を５０℃~５５℃で２時間攪拌しながら保持した。得られた反応混合物から、減圧条件下で、塩化チオニルおよびトルエンを留去することにより、褐色の１−メチル−３−ジフルオロメチルピラゾール−４−カルボン酸クロライドを得た。 [Reference Production Example 1]
Under a nitrogen atmosphere, at room temperature, 9.34 g of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid and 18.90 g of toluene were mixed, and 0.20 g of N, N-dimethylformamide was further added. The obtained mixture was heated to 50 ° C. to 55 ° C., and 6.95 g of thionyl chloride was added dropwise over 5 hours. After completion of the dropwise addition, the obtained mixture was held at 50 ° C. to 55 ° C. with stirring for 2 hours. From the resulting reaction mixture, thionyl chloride and toluene were distilled off under reduced pressure to obtain brown 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride.
　得られた１−メチル−３−ジフルオロメチルピラゾール−４−カルボン酸クロライドをトルエン９．０７ｇに溶解させることにより調製した溶液を、０~５℃で、（Ｒ）−１，１，３−トリメチル−４−アミノインダン（光学純度：９５．２％ｅｅ）９．０７ｇ、トリエチルアミン５．８４ｇおよびトルエン２７．３２ｇを混合して調製した溶液に、１時間かけて滴下した。滴下終了後、得られた混合物を、０℃~５℃で１時間攪拌した後、４５℃~５０℃に加熱し、同温度で２時間攪拌した。得られた反応混合物と水とを混合した後、有機層を分離した。有機層を、１０重量％塩酸、水、１０重量％水酸化ナトリウム水溶液、水で順次洗浄した後、減圧条件下で濃縮して、（Ｒ）−（−）−Ｎ−（１，１，３−トリメチルインダン−４−イル）−１−メチル−３−ジフルオロメチルピラゾール−４−カルボン酸アミド（以下、ピラゾール化合物（ａ）と略記する場合がある。）１６．５８ｇを得た。収率：９６．０％、光学純度：９５．４％ｅｅ。 A solution prepared by dissolving the obtained 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride in 9.07 g of toluene was subjected to (R) -1,1,3-trimethyl at 0 to 5 ° C. -4-Aminoindane (optical purity: 95.2% ee) 9.07 g, triethylamine 5.84 g and toluene 27.32 g were mixed and added dropwise over 1 hour. After completion of dropping, the obtained mixture was stirred at 0 ° C. to 5 ° C. for 1 hour, then heated to 45 ° C. to 50 ° C. and stirred at the same temperature for 2 hours. After mixing the obtained reaction mixture and water, the organic layer was separated. The organic layer was washed successively with 10% by weight hydrochloric acid, water, 10% by weight sodium hydroxide aqueous solution and water, and then concentrated under reduced pressure to give (R)-(−)-N- (1,1,3 -Trimethylindan-4-yl) -1-methyl-3-difluoromethylpyrazole-4-carboxylic acid amide (hereinafter sometimes abbreviated as pyrazole compound (a)) 16.58 g was obtained. Yield: 96.0%, optical purity: 95.4% ee.
［参考製造例２］
　窒素雰囲気下、室温で、１−メチル−３−ジフルオロメチルピラゾール−４−カルボン酸９．３４ｇとトルエン１８．８４ｇとを混合した。得られた混合物を７５℃~７８℃に加熱した後、塩化チオニル６．９８ｇをトルエン４．７５ｇに溶解させることにより調製した溶液を５時間かけて滴下した。滴下終了後、得られた混合物を７５℃~７８℃で２時間攪拌した後、４０℃まで冷却した。得られた反応混合物から、減圧条件下で、塩化チオニルおよびトルエンを留去することにより、褐色の１−メチル−３−ジフルオロメチルピラゾール−４−カルボン酸クロライドを得た。 [Reference Production Example 2]
In a nitrogen atmosphere, 9.34 g of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid and 18.84 g of toluene were mixed at room temperature. The obtained mixture was heated to 75 ° C. to 78 ° C., and then a solution prepared by dissolving 6.98 g of thionyl chloride in 4.75 g of toluene was added dropwise over 5 hours. After completion of dropping, the obtained mixture was stirred at 75 ° C. to 78 ° C. for 2 hours, and then cooled to 40 ° C. From the resulting reaction mixture, thionyl chloride and toluene were distilled off under reduced pressure to obtain brown 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride.
　得られた１−メチル−３−ジフルオロメチルピラゾール−４−カルボン酸クロライドをトルエン９．３６ｇに溶解させることにより調製した溶液を、４５℃~５０℃で、（Ｒ）−１，１，３−トリメチル−４−アミノインダン（光学純度：９５．２％ｅｅ）９．２９ｇ、トリエチルアミン５．８１ｇおよびトルエン２８．０３ｇを混合して調製した溶液に１時間かけて滴下した。滴下終了後、得られた混合物を、４５℃~５０℃で２時間攪拌した。得られた反応混合物と水とを混合した後、有機層を分離した。有機層を、１０重量％塩酸、水、１０重量％水酸化ナトリウム水溶液、水で順次洗浄した後、減圧条件下で濃縮して、ピラゾール化合物（ａ）１７．１５ｇを得た。収率：９７．０％、光学純度：９５．４％ｅｅ。 A solution prepared by dissolving the obtained 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride in 9.36 g of toluene was subjected to (R) -1,1,3- at 45 ° C. to 50 ° C. A solution prepared by mixing 9.29 g of trimethyl-4-aminoindane (optical purity: 95.2% ee), 5.81 g of triethylamine and 28.03 g of toluene was added dropwise over 1 hour. After completion of the dropwise addition, the obtained mixture was stirred at 45 ° C. to 50 ° C. for 2 hours. After mixing the obtained reaction mixture and water, the organic layer was separated. The organic layer was washed successively with 10% by weight hydrochloric acid, water, 10% by weight sodium hydroxide aqueous solution and water and then concentrated under reduced pressure to obtain 17.15 g of pyrazole compound (a). Yield: 97.0%, optical purity: 95.4% ee.
［参考製造例３］
　窒素雰囲気下、室温で、１−メチル−３−ジフルオロメチルピラゾール−４−カルボン酸２０．１５ｇとトルエン４０．６０ｇとを混合し、さらに、Ｎ，Ｎ−ジメチルホルムアミド０．４２ｇを加えた。得られた混合物を７０℃~７５℃に加熱した後、塩化チオニル２０．４２ｇを１時間かけて滴下した。滴下終了後、得られた混合物を、７０℃~７５℃で１時間攪拌した後、１００℃に加熱し、同温度で２時間攪拌した後、４０℃まで冷却した。得られた反応混合物から、減圧条件下で、塩化チオニルおよびトルエンを留去して、褐色の１−メチル−３−ジフルオロメチルピラゾール−４−カルボン酸クロライドを得た。 [Reference Production Example 3]
Under a nitrogen atmosphere, 20.15 g of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid and 40.60 g of toluene were mixed at room temperature, and 0.42 g of N, N-dimethylformamide was further added. The obtained mixture was heated to 70 ° C. to 75 ° C., and then 20.42 g of thionyl chloride was added dropwise over 1 hour. After completion of the dropwise addition, the obtained mixture was stirred at 70 ° C. to 75 ° C. for 1 hour, then heated to 100 ° C., stirred at the same temperature for 2 hours, and then cooled to 40 ° C. From the resulting reaction mixture, thionyl chloride and toluene were distilled off under reduced pressure to obtain brown 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride.
　得られた１−メチル−３−ジフルオロメチルピラゾール−４−カルボン酸クロライドを、０℃~５℃で、（Ｒ）−１，１，３−トリメチル−４−アミノインダン（光学純度：９０．２％ｅｅ）２０．０３ｇ、トリエチルアミン１２．５２ｇおよびトルエン１１０．０４ｇを混合することにより調製した溶液に、１時間かけて滴下した。滴下終了後、得られた混合物を、０℃~５℃で１時間攪拌した後、２０℃~２５℃に加熱し、同温度で２時間攪拌した。得られた反応混合物と水とを混合した後、有機層を分離した。有機層を、１０重量％塩酸、水、１０重量％水酸化ナトリウム水溶液、水で順次洗浄した後、減圧条件下で濃縮することにより、ピラゾール化合物（ａ）３５．４８ｇを得た。収率：９３．２％、光学純度：９０．４％ｅｅ。 The obtained 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride was subjected to (R) -1,1,3-trimethyl-4-aminoindane (optical purity: 90.2) at 0 ° C. to 5 ° C. % Ee) was added dropwise over 1 hour to a solution prepared by mixing 20.03 g, 12.52 g of triethylamine and 110.04 g of toluene. After completion of the dropwise addition, the obtained mixture was stirred at 0 ° C. to 5 ° C. for 1 hour, then heated to 20 ° C. to 25 ° C. and stirred at the same temperature for 2 hours. After mixing the obtained reaction mixture and water, the organic layer was separated. The organic layer was washed successively with 10% by weight hydrochloric acid, water, 10% by weight sodium hydroxide aqueous solution and water, and then concentrated under reduced pressure to obtain 35.48 g of a pyrazole compound (a). Yield: 93.2%, optical purity: 90.4% ee.
［実施例１］
　３枚後退翼付の攪拌装置、バッフル、冷却管および温度計を備えた内容積５００ｍＬのフラスコを、６２℃に調節した温水で保温した。フラスコに、ピラゾール化合物（ａ）（光学純度：９０．４％ｅｅ）のトルエン溶液（濃度：５０重量％）８４．４ｇとビス（２−エチルヘキシル）スルホコハク酸ナトリウム０．３ｇとを仕込んだ。得られた混合物に、攪拌しながら、水２９５．３ｇを加えた。フラスコ内の混合物は、ピラゾール化合物（ａ）のトルエン溶液が水に一様に分散した状態であった。混合物を攪拌しながら、フラスコ内の圧力を３０．３ｋＰａまで減圧し、５時間かけてトルエンを除去した。トルエンを除去している間、前記温水の温度を、４時間かけて７５℃に昇温すると共に、フラスコ内の液量が減少しないように、水を添加した。また、ピラゾール化合物（ａ）の結晶化を促すために、種晶０．４ｇを添加した。 [Example 1]
A 500-mL flask equipped with a stirrer equipped with three receding blades, a baffle, a condenser tube, and a thermometer was kept warm with warm water adjusted to 62 ° C. A flask was charged with 84.4 g of a toluene solution (concentration: 50 wt%) of pyrazole compound (a) (optical purity: 90.4% ee) and 0.3 g of sodium bis (2-ethylhexyl) sulfosuccinate. While stirring, 295.3 g of water was added to the obtained mixture. The mixture in the flask was in a state where the toluene solution of the pyrazole compound (a) was uniformly dispersed in water. While stirring the mixture, the pressure in the flask was reduced to 30.3 kPa, and toluene was removed over 5 hours. While removing toluene, the temperature of the warm water was raised to 75 ° C. over 4 hours, and water was added so that the amount of liquid in the flask did not decrease. In order to promote crystallization of the pyrazole compound (a), 0.4 g of seed crystals were added.
　トルエンの除去終了後、ピラゾール化合物（ａ）の結晶が水中に一様に分散したスラリーが得られ、該スラリーの流動性は良好であった。得られたスラリーを濾過し、得られた結晶を減圧乾燥して、ピラゾール化合物（ａ）の粒状結晶４１．８ｇを得た。回収率：９９．１％、光学純度：９０．４％ｅｅ。 After removal of toluene, a slurry in which crystals of the pyrazole compound (a) were uniformly dispersed in water was obtained, and the fluidity of the slurry was good. The obtained slurry was filtered, and the obtained crystal was dried under reduced pressure to obtain 41.8 g of a granular crystal of the pyrazole compound (a). Recovery rate: 99.1%, optical purity: 90.4% ee.
［実施例２］
　３枚後退翼付の攪拌装置、バッフル、冷却管および温度計を備えた内容積３００ｍＬのフラスコを、６０℃に調節した温水で保温した。フラスコに、ピラゾール化合物（ａ）（光学純度：９５．４％ｅｅ）のトルエン溶液（濃度：５０重量％）４３．３ｇとビス（２−エチルヘキシル）スルホコハク酸ナトリウム０．０６ｇとを仕込んだ。得られた混合物に、撹拌しながら、水６４．９ｇを添加した。得られた混合物を攪拌しながら、フラスコ内の圧力を３０．３ｋＰａまで減圧し、３時間かけてトルエンを除去した。トルエンを除去している間、前記温水の温度を、２．５時間かけて７５℃に昇温すると共に、フラスコ内の液量が減少しないように、水を添加した。また、ピラゾール化合物（ａ）の結晶化を促すために、種晶０．２ｇを添加した。 [Example 2]
A 300-mL flask equipped with a stirrer equipped with three receding blades, a baffle, a condenser, and a thermometer was kept warm with warm water adjusted to 60 ° C. A flask was charged with 43.3 g of a toluene solution (concentration: 50 wt%) of pyrazole compound (a) (optical purity: 95.4% ee) and 0.06 g of sodium bis (2-ethylhexyl) sulfosuccinate. While stirring, 64.9 g of water was added to the resulting mixture. While stirring the obtained mixture, the pressure in the flask was reduced to 30.3 kPa, and toluene was removed over 3 hours. While removing toluene, the temperature of the warm water was raised to 75 ° C. over 2.5 hours, and water was added so that the amount of liquid in the flask did not decrease. In order to promote crystallization of the pyrazole compound (a), 0.2 g of seed crystals was added.
　トルエンの除去終了後、ピラゾール化合物（ａ）の結晶が水中に一様に分散したスラリーが得られ、該スラリーの流動性は良好であった。得られたスラリーを濾過し、得られた結晶を減圧乾燥して、ピラゾール化合物（ａ）の粒状結晶２１．４ｇを得た。回収率：９８．７％、光学純度：９５．４％ｅｅ。 After removal of toluene, a slurry in which crystals of the pyrazole compound (a) were uniformly dispersed in water was obtained, and the fluidity of the slurry was good. The obtained slurry was filtered, and the obtained crystal was dried under reduced pressure to obtain 21.4 g of a granular crystal of the pyrazole compound (a). Recovery rate: 98.7%, optical purity: 95.4% ee.
［実施例３］
　３枚後退翼付の攪拌装置、バッフル、冷却管および温度計を備えた内容積５００ｍＬのフラスコに、水３０３．５ｇと種晶１ｇとを仕込んだ。フラスコを、４３℃に調節した温水で保温した。フラスコ内の混合物を攪拌しながら、フラスコ内の圧力を７．３ｋＰａまで減圧し、該混合物を還流させた。この時のフラスコ内の混合物の温度は４０．６℃であった。還流している混合物中に、ピラゾール化合物（ａ）（光学純度：９５．４％ｅｅ）のトルエン／メタノール溶液（濃度：２０重量％、トルエン／メタノール重量比＝１／９）３０２．６ｇを、１１時間かけて加えながら、同時に、トルエンとメタノールとを除去した。トルエンとメタノールとを除去している間、フラスコ内の液量が減少しないように、水を添加した。 [Example 3]
303.5 g of water and 1 g of seed crystals were charged into a 500-mL flask equipped with a stirrer equipped with three blades, a baffle, a cooling tube, and a thermometer. The flask was kept warm with warm water adjusted to 43 ° C. While stirring the mixture in the flask, the pressure in the flask was reduced to 7.3 kPa, and the mixture was refluxed. The temperature of the mixture in the flask at this time was 40.6 ° C. In a refluxing mixture, 302.6 g of a toluene / methanol solution (concentration: 20 wt%, toluene / methanol weight ratio = 1/9) of the pyrazole compound (a) (optical purity: 95.4% ee) While adding over 11 hours, toluene and methanol were simultaneously removed. While removing toluene and methanol, water was added so that the amount of liquid in the flask did not decrease.
　トルエンとメタノールの除去終了後、ピラゾール化合物（ａ）の結晶が水中に一様に分散したスラリーが得られ、該スラリーの流動性は良好であった。得られたスラリーを濾過し、得られた結晶を減圧乾燥して、ピラゾール化合物（ａ）の粉状結晶５９．９ｇを得た。回収率：９９．０％、光学純度：９５．４％ｅｅ。 After the removal of toluene and methanol, a slurry in which crystals of the pyrazole compound (a) were uniformly dispersed in water was obtained, and the fluidity of the slurry was good. The obtained slurry was filtered, and the obtained crystal was dried under reduced pressure to obtain 59.9 g of a powdery crystal of the pyrazole compound (a). Recovery rate: 99.0%, optical purity: 95.4% ee.
［実施例４］
　３枚後退翼付の攪拌装置、バッフル、冷却管および温度計を備えた内容積５００ｍＬのフラスコに、水３００．３ｇと種晶１ｇとを仕込んだ。フラスコを、４５℃に調節した温水で保温した。フラスコ内の混合物を攪拌しながら、フラスコ内の圧力を５．３ｋＰａまで減圧し、該混合物を還流させた。この時のフラスコ内の混合物の温度は３５℃であった。還流している混合物中に、ピラゾール化合物（ａ）（光学純度：９０．４％ｅｅ）のトルエン／メタノール溶液（濃度：２０重量％、トルエン／メタノール重量比＝１／９）１００．４ｇを、５時間かけて加えながら、同時に、トルエンとメタノールとを除去した。
トルエンとメタノールとを除去している間、フラスコ内の液量が減少しないように、水を添加した。 [Example 4]
300.3 g of water and 1 g of seed crystals were charged into a 500-mL flask equipped with a stirrer equipped with three blades, a baffle, a cooling tube, and a thermometer. The flask was kept warm with warm water adjusted to 45 ° C. While stirring the mixture in the flask, the pressure in the flask was reduced to 5.3 kPa, and the mixture was refluxed. The temperature of the mixture in the flask at this time was 35 ° C. In a refluxing mixture, 100.4 g of a toluene / methanol solution (concentration: 20% by weight, toluene / methanol weight ratio = 1/9) of the pyrazole compound (a) (optical purity: 90.4% ee) While adding over 5 hours, toluene and methanol were simultaneously removed.
While removing toluene and methanol, water was added so that the amount of liquid in the flask did not decrease.
　トルエンとメタノールの除去終了後、ピラゾール化合物（ａ）の結晶が水中に一様に分散したスラリーが得られ、該スラリーの流動性は良好であった。得られたスラリーを濾過し、得られた結晶を減圧乾燥して、ピラゾール化合物（ａ）の粉状結晶１９．９ｇを得た。回収率：９８．９％、光学純度９０．４％ｅｅ。 After the removal of toluene and methanol, a slurry in which crystals of the pyrazole compound (a) were uniformly dispersed in water was obtained, and the fluidity of the slurry was good. The obtained slurry was filtered, and the obtained crystal was dried under reduced pressure to obtain 19.9 g of a powdery crystal of the pyrazole compound (a). Recovery rate: 98.9%, optical purity 90.4% ee.
［参考例１］
　窒素雰囲気下、室温で、ピラゾール化合物（ａ）（光学純度：９０．４％ｅｅ）のキシレン溶液（濃度：３９．８重量％）３７．７ｇとヘプタン２２．８ｇとを混合した。得られた混合物を６５℃に加熱した。得られた均一溶液を５９℃まで冷却した後、種晶０．０２ｇを添加し、５９℃で１時間攪拌した。その後、冷却速度５℃／時で５℃まで冷却し、５℃で３時間攪拌した。得られた混合物を濾過し、得られた固体を、氷冷したヘプタン１５．０ｇで洗浄した後、減圧乾燥して、ピラゾール化合物（ａ）の白色結晶１４．３ｇを得た。回収率：９５．２％、光学純度：９０．６％ｅｅ。
　得られたピラゾール化合物（ａ）の白色結晶のＸＲＤチャートを図１に示す。なお、ＸＲＤの測定条件は、以下のとおりである。
Ｘ線回折装置：Ｘ’Ｐｅｒｔ　ＰＲＯ　ＭＰＤ（スペクトリス）
ターゲット：Ｃｕ
Ｘ線管電流：４０ｍＡ
Ｘ線管電圧：４５ｋＶ
走査範囲：２θ＝４．０~４０．０°
ステップ：２θ＝０．０１６７１°
平均時間／ステップ：１０．１６０ｓ
固定発散スリット：１／２°
前処理：めのう製乳鉢による粉砕 [Reference Example 1]
Under a nitrogen atmosphere, 37.7 g of a xylene solution (concentration: 39.8 wt%) of pyrazole compound (a) (optical purity: 90.4% ee) and 22.8 g of heptane were mixed at room temperature. The resulting mixture was heated to 65 ° C. The obtained homogeneous solution was cooled to 59 ° C., 0.02 g of seed crystals were added, and the mixture was stirred at 59 ° C. for 1 hour. Then, it cooled to 5 degreeC with the cooling rate of 5 degree-C / hr, and stirred at 5 degreeC for 3 hours. The obtained mixture was filtered, and the obtained solid was washed with 15.0 g of ice-cooled heptane and then dried under reduced pressure to obtain 14.3 g of white crystals of the pyrazole compound (a). Recovery rate: 95.2%, optical purity: 90.6% ee.
An XRD chart of white crystals of the obtained pyrazole compound (a) is shown in FIG. The measurement conditions for XRD are as follows.
X-ray diffractometer: X'Pert PRO MPD (Spectris)
Target: Cu
X-ray tube current: 40 mA
X-ray tube voltage: 45 kV
Scanning range: 2θ = 4.0-40.0 °
Step: 2θ = 0.01671 °
Average time / step: 10.160 s
Fixed divergence slit: 1/2 °
Pretreatment: grinding with agate mortar
［参考例２］
　窒素雰囲気下、室温で、ピラゾール化合物（ａ）（光学純度：９０．４％ｅｅ）３４．２ｇと酢酸エチル２５．６ｇとを混合した。得られた混合物を６１℃まで加熱した。得られた均一溶液を２５℃まで冷却した後、種晶０．０３ｇを添加した。その後、ヘキサン１０６．１ｇを３０分かけて滴下した後、得られた混合物を２５℃で３０分攪拌した。その後、冷却速度１０℃／時で５℃まで冷却し、５℃で２時間攪拌した。得られた混合物を濾過し、得られた固体を、氷冷したヘキサン３４．２ｇで洗浄した後、減圧乾燥して、ピラゾール化合物（ａ）の白色結晶３２．２ｇを得た。回収率：９４．２％、光学純度：９０．６％ｅｅ。 [Reference Example 2]
Under a nitrogen atmosphere, 34.2 g of pyrazole compound (a) (optical purity: 90.4% ee) and 25.6 g of ethyl acetate were mixed at room temperature. The resulting mixture was heated to 61 ° C. After cooling the obtained uniform solution to 25 ° C., 0.03 g of seed crystals was added. Thereafter, 106.1 g of hexane was added dropwise over 30 minutes, and the resulting mixture was stirred at 25 ° C. for 30 minutes. Then, it cooled to 5 degreeC with the cooling rate of 10 degree-C / hr, and stirred at 5 degreeC for 2 hours. The obtained mixture was filtered, and the obtained solid was washed with 34.2 g of ice-cooled hexane and dried under reduced pressure to obtain 32.2 g of white crystals of the pyrazole compound (a). Recovery rate: 94.2%, optical purity: 90.6% ee.
　本発明によれば、植物病害に対して防除効力を示すピラゾール化合物の結晶を、工業的に有利に製造することができる。 According to the present invention, crystals of a pyrazole compound exhibiting a controlling effect against plant diseases can be produced industrially advantageously.

Claims (7)

  1. 　式（Ｉ）
    Figure JPOXMLDOC01-appb-I000001
    （式中、Ｒ１は水素原子またはメチル基を表わし、Ｒ２はメチル基、モノフルオロメチル基、ジフルオロメチル基またはトリフルオロメチル基を表わす。）
    で示されるピラゾール化合物が有機溶媒に溶解した溶液と水との混合物から、該有機溶媒を除去することにより式（Ｉ）で示されるピラゾール化合物の結晶を析出させることを特徴とする式（Ｉ）で示されるピラゾール化合物の結晶の製造方法。     Formula (I)
    Figure JPOXMLDOC01-appb-I000001
    (In the formula, R 1 represents a hydrogen atom or a methyl group, and R 2 represents a methyl group, a monofluoromethyl group, a difluoromethyl group, or a trifluoromethyl group.)
    A crystal of the pyrazole compound represented by formula (I) is precipitated by removing the organic solvent from a mixture of a solution in which the pyrazole compound represented by formula (I) is dissolved in an organic solvent and water. The manufacturing method of the crystal | crystallization of the pyrazole compound shown by these.
  2. 　式（Ｉ）で示されるピラゾール化合物が有機溶媒に溶解した溶液と水とを混合し、得られた混合物から該有機溶媒を除去することにより、式（Ｉ）で示されるピラゾール化合物の結晶を析出させる請求項１に記載の製造方法。 A solution in which a pyrazole compound represented by the formula (I) is dissolved in an organic solvent is mixed with water, and the organic solvent is removed from the resulting mixture to precipitate crystals of the pyrazole compound represented by the formula (I). The manufacturing method of Claim 1.
  3. 　式（Ｉ）で示されるピラゾール化合物が有機溶媒に溶解した溶液を水に加えながら、該有機溶媒を除去する請求項１に記載の製造方法。 The method according to claim 1, wherein the organic solvent is removed while adding a solution in which the pyrazole compound represented by the formula (I) is dissolved in an organic solvent to water.
  4. 　式（Ｉ）で示されるピラゾール化合物が有機溶媒に溶解した溶液、水またはその両方が分散剤を含む請求項１~３のいずれかに記載の製造方法。 The method according to any one of claims 1 to 3, wherein a solution in which the pyrazole compound represented by the formula (I) is dissolved in an organic solvent, water, or both contain a dispersant.
  5. 　有機溶媒が、芳香族炭化水素溶媒および炭素数１~３のアルコール溶媒からなる群から選ばれる少なくとも一つである請求項１~４のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 4, wherein the organic solvent is at least one selected from the group consisting of an aromatic hydrocarbon solvent and an alcohol solvent having 1 to 3 carbon atoms.
  6. 　有機溶媒が、炭素数１~３のアルコール溶媒を含む請求項１~５のいずれかに記載の製造方法。 6. The production method according to claim 1, wherein the organic solvent contains an alcohol solvent having 1 to 3 carbon atoms.
  7. 　式（Ｉ）で示されるピラゾール化合物が光学活性体である請求項１~６のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 6, wherein the pyrazole compound represented by the formula (I) is an optically active substance.
PCT/JP2013/083807 2012-12-25 2013-12-11 Method for producing crystals of pyrazole compound WO2014103812A1 (en)

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US9765032B2 (en) 2014-02-07 2017-09-19 Sumitomo Chemical Company, Limited Method for producing (R)-1,1,3-trimethyl-4-aminoindane
WO2021085263A1 (en) * 2019-11-01 2021-05-06 住友化学株式会社 Crystal of 3-(difluoromethyl)-1-methyl-n-(1,1,3-trimethyl-2,3-dihydro-1h-inden-4-yl)-1h-pyrazole-4-carboxamide

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US9765032B2 (en) 2014-02-07 2017-09-19 Sumitomo Chemical Company, Limited Method for producing (R)-1,1,3-trimethyl-4-aminoindane
WO2021085263A1 (en) * 2019-11-01 2021-05-06 住友化学株式会社 Crystal of 3-(difluoromethyl)-1-methyl-n-(1,1,3-trimethyl-2,3-dihydro-1h-inden-4-yl)-1h-pyrazole-4-carboxamide

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