Fluorine-containing pyrazole compound and method for producing same

Abstract

Provided are: a novel fluorine-containing pyrazole compound having a halogen atom, an oxygen-containing substituent, or a nitrogen-containing substituent at the 3-position, a trifluoromethyl group at the 4-position, and an oxygen-containing substituent at the 5-position; and a production method by which said fluorine-containing pyrazole compound can be simply produced.Provided are: a novel fluorine-containing pyrazole compound having a halogen atom, an oxygen-containing substituent, or a nitrogen-containing substituent at the 3-position, a trifluoromethyl group at the 4-position, and an oxygen-containing substituent at the 5-position; and a production method by which said fluorine-containing pyrazole compound can be simply produced.　The fluorine-containing pyrazole compound is represented by general formula (1). (In general formula (1), R represents a C1-C12 hydrocarbon group, X represents a halogen atom, a heterocyclic group containing, as a ring atom, at least one heteroatom selected from the group consisting of nitrogen and oxygen, -OA1, or -NA1A2, and A1 and A2 each independently represent a hydrogen atom or a C1-C10 organic group)

Description

[Technical field]

[0001] The present invention relates to a fluorine-containing pyrazole compound and a method for producing the same. [Background technology]

[0002] It has been reported that fluorine-containing pyrazole compounds have various biological activities. In particular, compounds having a nitrogen-containing substituent at the 3-position of the pyrazole ring and a methoxy group at the 5-position are expected to be used in the pharmaceutical and agricultural chemical fields. Specifically, Non-Patent Document 1 reports that compounds having a 3-heteroarylamino-5-methoxy-pyrazole structure have inhibitory activity against Janus kinases JAK2 and JAK3, and Non-Patent Document 2 reports that compounds having an inhibitory activity against tropomyosin receptor kinase A. In addition, Patent Document 1 reports a method for producing a compound having a nitrogen-containing substituent at the 3-position of the pyrazole ring, a trifluoromethyl group at the 4-position, and a hydroxyl group at the 5-position.

[0003] From the above viewpoints, there has been interest in developing compounds having a halogen atom, an oxygen-containing substituent, or a nitrogen-containing substituent at the 3-position of the pyrazole ring, a trifluoromethyl group at the 4-position, and an oxygen-containing substituent at the 5-position, in the hope of further improving activity. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 61-118371 [Non-patent literature]

[0005] [Non-Patent Document 1] Bioorganic & Medicinal Chemistry Letters, 2013, Vol. 23, pp. 3105-3110 [Non-Patent Document 2] ACS Medicinal Chemistry Letters, 2012, Vol. 3, pp. 705-709 Summary of the Invention [Problem to be solved by the invention]

[0006] There has been no report of a reaction example in which a trifluoromethyl group is introduced at the 4th position of a compound having a halogen atom, an oxygen-containing substituent, or a nitrogen-containing substituent at the 3rd position of a pyrazole ring and an oxygen-containing substituent at the 5th position. This is because the control of the reactivity of the substrate and the selectivity of the reaction becomes an issue in the process of introducing the trifluoromethyl group. On the other hand, it is considered that the substituent at the 5th position is converted to a methoxy group by reacting a methylating agent with a compound having a nitrogen-containing substituent at the 3rd position of a pyrazole ring, a trifluoromethyl group at the 4th position, and a hydroxyl group at the 5th position, as reported in Patent Document 1. In such a reaction, it is expected that a methyl group will also be introduced at the 1st or 2nd position of the pyrazole ring, and there is room for further improvement in terms of reaction efficiency, such as selectivity.

[0007] Therefore, the present inventors discovered that a pyrazole compound having a halogen atom, an oxygen-containing substituent, or a nitrogen-containing substituent at the 3-position of the pyrazole ring, a trifluoromethyl group at the 4-position, and an oxygen-containing substituent at the 5-position can be synthesized by reacting specific raw materials, and have completed the present invention. That is, an object of the present invention is to provide a novel fluorine-containing pyrazole compound having a halogen atom, an oxygen-containing substituent, or a nitrogen-containing substituent at the 3-position, a trifluoromethyl group at the 4-position, and an oxygen-containing substituent at the 5-position, which has not been known in the past, and a production method capable of easily producing the fluorine-containing pyrazole compound. [Means for solving the problem]

[0008] The gist and configuration of the present invention are as follows. [1] A fluorine-containing pyrazole compound represented by the following general formula (1): [ka] (In the above general formula (1), R represents a hydrocarbon group having 1 to 12 carbon atoms, X is a heterocyclic group containing at least one heteroatom selected from the group consisting of halogen atoms, nitrogen and oxygen as a ring atom; 1 , or -NA 1 A 2 represents A 1 , A 2 each independently represents a hydrogen atom or an organic group having 1 to 10 carbon atoms. [2] A step of reacting a fluoroisobutylene derivative represented by the following general formula (2) with a compound represented by the following general formula (3) or a salt thereof to obtain a fluorine-containing pyrazole compound represented by the following general formula (4): [ka] (In the above general formulas (2) to (4), R represents a hydrocarbon group having 1 to 12 carbon atoms.) The present invention relates to a method for producing a fluorine-containing pyrazole compound. [3] A step of reacting a fluoroisobutylene derivative represented by the following general formula (2) with a compound represented by the following general formula (3) or a salt thereof, and a compound represented by the following general formula (5) to obtain a fluorine-containing pyrazole compound represented by the following general formula (1): [ka] (In the above general formulas (1) to (3) and (5), R represents a hydrocarbon group having 1 to 12 carbon atoms, X is a heterocyclic group containing at least one heteroatom selected from the group consisting of halogen atoms, nitrogen and oxygen as a ring atom; 1 , or -NA 1 A 2 represents A 1 , A 2 each independently represents a hydrogen atom or an organic group having 1 to 10 carbon atoms. The present invention relates to a method for producing a fluorine-containing pyrazole compound. [4] A step of reacting a fluoroisobutane derivative represented by the following general formula (6) with a compound represented by the following general formula (3) or a salt thereof to obtain a fluorine-containing pyrazole compound represented by the following general formula (4): [ka] (In the above general formulas (3), (4) and (6), R represents a hydrocarbon group having 1 to 12 carbon atoms, Y is a halogen atom, -OA 3 , -SO m A 3 (m is an integer from 0 to 3), or -NA 3 A 4 represents A 3 , A 4 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. The present invention relates to a method for producing a fluorine-containing pyrazole compound. [5] A step of reacting a fluoroisobutane derivative represented by the following general formula (6) with a compound represented by the following general formula (3) or a salt thereof, and a compound represented by the following general formula (5) to obtain a fluorine-containing pyrazole compound represented by the following general formula (1): [ka] (In the above general formulas (1), (3), (5), and (6), R represents a hydrocarbon group having 1 to 12 carbon atoms, X is a heterocyclic group containing at least one heteroatom selected from the group consisting of halogen atoms, nitrogen and oxygen as a ring atom; 1 , or -NA 1 A 2 represents A 1 , A 2 each independently represents a hydrogen atom or an organic group having 1 to 10 carbon atoms, Y is a halogen atom, -OA 3 , -SO m A 3 (m is an integer from 0 to 3), or -NA 3 A 4represents A 3 , A 4 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. The present invention relates to a method for producing a fluorine-containing pyrazole compound. Effect of the Invention

[0009] The present invention provides a novel fluorine-containing pyrazole compound having a halogen atom, an oxygen-containing substituent, or a nitrogen-containing substituent at the 3-position, a trifluoromethyl group at the 4-position, and an oxygen-containing substituent at the 5-position, and a production method by which the fluorine-containing pyrazole compound can be simply produced. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] (Fluorine-containing pyrazole compound) The fluorine-containing pyrazole compound of the present invention is represented by the following general formula (1). [ka] (In the above general formula (1), R represents a hydrocarbon group having 1 to 12 carbon atoms, X is a heterocyclic group containing at least one heteroatom selected from the group consisting of halogen atoms, nitrogen and oxygen as a ring atom; 1 , or -NA 1 A 2 represents A 1 , A 2 each independently represents a hydrogen atom or an organic group having 1 to 10 carbon atoms.

[0011] The fluorine-containing pyrazole compound of the present invention has specific substituents (-X, -CF 3, -OR), it can have an excellent effect from the viewpoint of structure expandability. In particular, it can be expected to have a desired biological activity (for example, hormone or enzyme inhibitory activity, fungicidal activity, insecticidal activity, herbicidal activity). In particular, the fungicidal activity can be exemplified by the fungicidal activity against bacteria that have harmful effects on the human body and agricultural crops such as rice. In addition, since the substituents on the 3rd and 5th positions of the pyrazole ring are different groups (-X and -OR), these groups can be easily derivatized into an asymmetric structure by elimination or reaction, and it can be expected to be used as an intermediate. More specifically, it is possible to obtain a derivative by modifying -OR by reacting a fluorine-containing pyrazole compound under acidic conditions. It is also possible to obtain a derivative by modifying -X by reacting a fluorine-containing pyrazole compound under basic conditions. The fluorine-containing pyrazole compound of one embodiment is also useful in the field of electronic materials such as organic semiconductors and liquid crystals.

[0012] R is not particularly limited as long as it is a hydrocarbon group having 1 to 12 carbon atoms and composed of carbon atoms and hydrogen atoms, and examples thereof include a chain hydrocarbon group, an aromatic hydrocarbon group, and an alicyclic hydrocarbon group. The chain hydrocarbon group is not particularly limited as long as it has a total carbon number of 1 to 12, and may be a branched chain hydrocarbon group or an unbranched chain hydrocarbon group. The aromatic hydrocarbon group is not particularly limited as long as it has a total carbon number of 5 to 12, and may be an aromatic hydrocarbon group having a substituent or an aromatic hydrocarbon group having no substituent. The aromatic hydrocarbon group may have a condensed polycyclic structure. The alicyclic hydrocarbon group is not particularly limited as long as it has a total carbon number of 3 to 12, and may be an alicyclic hydrocarbon group having a substituent or an alicyclic hydrocarbon group having no substituent. The alicyclic hydrocarbon group may have a bridged ring structure.

[0013] Examples of the chain hydrocarbon group include alkyl groups such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, and a dodecyl group; alkenyl groups such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, and dodecenyl groups; Examples of the alkynyl group include an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a heptynyl group, an octynyl group, a nonynyl group, a decynyl group, an undecynyl group, and a dodecynyl group.

[0014] Examples of the aromatic hydrocarbon group include a phenyl group and a naphthyl group.

[0015] The alicyclic hydrocarbon group may be a saturated or unsaturated cyclic hydrocarbon group, and examples of the cyclic hydrocarbon group include a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, an adamantyl group, and a norbornyl group.

[0016] R is preferably an alkyl group having 1 to 10 carbon atoms. When R is an alkyl group having 1 to 10 carbon atoms, the fluoroisobutylene derivative of general formula (2) and the fluoroisobutane derivative of general formula (6), which are raw materials for the fluorine-containing pyrazole compound, can be easily prepared.

[0017] The group X is a heterocyclic group containing at least one heteroatom selected from the group consisting of halogen atoms, nitrogen and oxygen as a ring atom, -OA 1 , or -NA 1 A 2 A stands for 1 , A 2each independently represents a hydrogen atom or an organic group having 1 to 10 carbon atoms. When the group X is a halogen atom, examples of the atom include a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), and an iodine atom (I), and a fluorine atom is preferred. When the group X is a heterocyclic group, the heterocyclic group contains nitrogen, oxygen, or both nitrogen and oxygen as ring atoms. The number of ring atoms of at least one heteroatom selected from the group consisting of nitrogen and oxygen is not particularly limited as long as it is 1 or more, and may be 1 or 2 or more, and for example, the number of ring atoms of the heteroatom may be 1, 2, 3, or 4. The number of ring atoms constituting the heterocyclic group as the group X is not particularly limited, and the number of ring atoms is preferably 3 to 14, more preferably 4 to 10, and even more preferably 5 to 6. The heterocyclic group as the group X may be a monocyclic structure or a polycyclic structure, and may be an aromatic heterocyclic group or an alicyclic heterocyclic group. The heterocyclic group as the group X may or may not have a substituent bonded to a ring atom, and desired properties can be imparted to the fluorine-containing pyrazole compound depending on the number and type of heteroatoms, the size of the ring, the number of ring atoms, and the number, type and presence or absence of substituents.

[0018] More specifically, examples of the heterocyclic group represented by the group X include a pyrrolyl group, a pyridyl group, an oxazolyl group, an isoxazolyl group, an imidazolyl group, a pyrazolyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a benzofuranyl group, an isobenzofuranyl group, an indolyl group, an isoindolyl group, a quinolinyl group, an isoquinolinyl group, a benzimidazolyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a phthalazinyl group, a carbazolyl group, a xanthenyl group, a phenanthridinyl group, a phenoxazinyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an indolinyl group, an isoindolinyl group, an azonanyl group, a thiazolyl group, and a phenothiazinyl group. A substituent may or may not be bonded to a ring atom in the heterocyclic group which is the group X. Examples of the substituent bonded to a ring atom include a halogen atom, a hydrocarbon group, an oxygen-containing substituent, a nitrogen-containing substituent, and a sulfur-containing substituent.

[0019] The group X is -OA 1 A included in 1 represents a hydrogen atom or an organic group having 1 to 10 carbon atoms. 1 A 2 A included in 1 , A 2 Each independently represents a hydrogen atom or an organic group having 1 to 10 carbon atoms. 1 , A 2 When represents an organic group having 1 to 10 carbon atoms, A 1 , A 2 may have atoms other than carbon and hydrogen atoms, and A 1 , A 2 Examples of R include a hydrocarbon group having 1 to 10 carbon atoms, a heterocyclic group, and an oxygen-containing substituent. Examples of the hydrocarbon group having 1 to 10 carbon atoms include an aromatic hydrocarbon group and an alkyl group. More specifically, A 1 , A 2 Examples of the alkyl group include an oxanyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenylalkyl group, an alkoxyalkyl group, a hydroxyalkyl group, and a thiazolyl group.

[0020] Specific examples of the fluorine-containing pyrazole compound represented by the general formula (1) include the following compounds. [ka]

[0021] (Method of producing fluorine-containing pyrazole compound) A method for producing a fluorine-containing pyrazole compound according to one embodiment includes the steps of: (a) A step of reacting a fluoroisobutylene derivative represented by the following general formula (2) with a compound represented by the following general formula (3) or a salt thereof to obtain a fluorine-containing pyrazole compound represented by the following general formula (4). [ka] (In the above general formulas (2) to (4), R represents a hydrocarbon group having 1 to 12 carbon atoms.) The step (a) of obtaining a fluorine-containing pyrazole compound is preferably carried out in the presence of a fluoride ion scavenger. The fluoroisobutylene derivative represented by the general formula (2) is preferably reacted with the compound represented by the general formula (3) or a salt thereof in the presence of a fluoride ion scavenger. The fluoride ion scavenger is not particularly limited as long as it is a substance having the function of capturing fluorine ions, and examples of the fluoride ion scavenger include lithium, sodium, magnesium, potassium, calcium, tetramethylammonium, trifluoroacetic acid, heptafluorobutyric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, nonafluorobutanesulfonic acid, bis(trifluoromethanesulfonyl)imide, bis(nonafluorobutanesulfonyl)imide, N,N-hexafluoropropane-1,3-disulfonylimide, tetraphenylboric acid, tetrakis[3,5-bis(trifluoromethyl)phenyl]boric acid, and tetrakis(pentafluorophenyl)borate. It is believed that the cation derived from the fluoride ion scavenger captures the fluorine ion liberated from the fluoroisobutylene derivative represented by general formula (2) during the reaction and precipitates it as a salt with low solubility in organic solvents, thereby accelerating the reaction and enabling the fluorine-containing pyrazole compound represented by general formula (4) to be obtained in high yield. R in general formulas (2) and (4) preferably represents an alkyl group having 1 to 10 carbon atoms.

[0022] The above reaction (a) between the fluoroisobutylene derivative represented by general formula (2) and the compound represented by general formula (3) is represented by the following reaction formula (A). [ka]

[0023] In the above reaction formula (A), the compound of general formula (3) may be in the form of a salt. When it is in the form of a salt, the amino moiety (-NH 2 ) is cationized (-NH 3 + ) and forms a salt with the counter ion. The counter ion is not particularly limited as long as it is a monovalent anion, and for example, F - , Cl - , Br - , I - Examples of the halide ions include:

[0024] In one embodiment of the method for producing a fluorine-containing pyrazole compound, the reaction (A) can be carried out in one step. Therefore, the fluorine-containing pyrazole compound of the general formula (4) can be easily obtained. In the reaction (a) above, a cyclic pyrazole structure is formed between the fluoroisobutylene derivative of the general formula (2) and the amidino group of the compound of the general formula (3). The pyrazole structure has F, CF, and CF3 derived from the fluoroisobutylene derivative at the 3rd, 4th, and 5th positions, respectively. 3 , and -OR are located.

[0025] The reaction (a) is preferably carried out in the presence of a hydrogen halide scavenger. The hydrogen halide scavenger is a substance that has the function of scavenging hydrogen fluoride (HF) formed from the hydrogen atom derived from the amidino group in the compound of general formula (3) in the reaction formula (A) above and the fluorine atom derived from the fluoroisobutylene derivative of general formula (2). As the hydrogen halide scavenger, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium fluoride, potassium fluoride, pyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, methyltriazabicyclodecene, diazabicyclooctane, phosphazene base, or other organic nitrogen derivatives can be used.

[0026] The reaction temperature during the above reaction (a) is preferably 0 to 100° C., more preferably 5 to 80° C., and even more preferably 10 to 40° C. The reaction time during the above reaction (a) is preferably 1 to 36 hours, more preferably 2 to 24 hours, and even more preferably 4 to 18 hours.

[0027] Examples of the solvent used in the reaction (a) above include aprotic polar solvents such as tetrahydrofuran, monoglyme, diglyme, triglyme, tetraglyme, acetonitrile, dimethylformamide, dimethylacetamide, methylpyrrolidone, dimethylethyleneurea, tetramethylurea, dimethylsulfoxide, and sulfolane, and two-phase solvents of a protic polar solvent such as water and a non-aqueous solvent such as dichloromethane, toluene, and diethyl ether. In addition, examples of the catalyst used in the reaction (a) above include quaternary ammonium halides such as benzyltriethylammonium chloride, quaternary phosphonium halides, and crown ethers.

[0028] In another embodiment, a method for producing a fluorine-containing pyrazole compound includes the steps of: (b) A step of reacting a fluoroisobutylene derivative represented by the following general formula (2) with a compound represented by the following general formula (3) or a salt thereof, and a compound represented by the following general formula (5) to obtain a fluorine-containing pyrazole compound represented by the following general formula (1). [ka] (In the above general formulas (1) to (3) and (5), R represents a hydrocarbon group having 1 to 12 carbon atoms, X is a heterocyclic group containing at least one heteroatom selected from the group consisting of halogen atoms, nitrogen and oxygen as a ring atom; 1 , or -NA 1 A 2 represents A 1 , A 2 each independently represents a hydrogen atom or an organic group having 1 to 10 carbon atoms. Preferably, the step (b) of obtaining the fluorine-containing pyrazole compound is carried out in the presence of a fluoride ion trapping agent. The fluoroisobutylene derivative represented by the above general formula (2) is preferably reacted with the compound represented by the above general formula (3) or its salt and the compound represented by the above general formula (5) in the presence of a fluoride ion trapping agent. The fluoride ion trapping agent is not particularly limited as long as it is a substance having a function of trapping fluorine ions, and may be the same fluoride ion trapping agent as the fluoride ion trapping agent used in the above step (a). The cation derived from the fluoride ion trapping agent traps the fluorine ion liberated from the fluoroisobutylene derivative represented by the general formula (2) during the reaction and precipitates it as a salt with low solubility in an organic solvent, which is considered to promote the reaction and to obtain the fluorine-containing pyrazole compound represented by the above general formula (1) in high yield. R in the above general formulas (1) and (2) preferably represents an alkyl group having 1 to 10 carbon atoms.

[0029] The above reaction (b) of the fluoroisobutylene derivative represented by general formula (2) with the compounds represented by general formulas (3) and (5) is represented by the following reaction formula (B). [ka]

[0030] In the above reaction formula (B), the compound of general formula (3) may be in the form of a salt. When it is in the form of a salt, the amino moiety (-NH 2 ) is cationized (-NH 3 + ) and forms a salt with the counter ion. The counter ion is not particularly limited as long as it is a monovalent anion, and for example, F - , Cl - , Br - , I - Examples of the halide ions include:

[0031] When the group X is a halogen atom, examples of the group include a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), and an iodine atom (I), with a fluorine atom being preferred. When the group X is a heterocyclic group, the heterocyclic group contains nitrogen, oxygen, or both nitrogen and oxygen as ring atoms. The number of ring atoms of at least one heteroatom selected from the group consisting of nitrogen and oxygen is not particularly limited as long as it is 1 or more, and may be 1 or 2 or more, and for example, the number of ring atoms of the heteroatom may be 1, 2, 3, or 4. The number of ring atoms constituting the heterocyclic group which is the group X is not particularly limited, and the number of ring atoms is preferably 3 to 14, more preferably 4 to 10, and even more preferably 5 to 6. The heterocyclic group which is the group X may be a monocyclic structure or a polycyclic structure, and may be an aromatic heterocyclic group or an alicyclic heterocyclic group. The -OA group which is the group X 1 A included in 1 represents a hydrogen atom or an organic group having 1 to 10 carbon atoms. 1 A 2 A included in 1 , A 2 Each independently represents a hydrogen atom or an organic group having 1 to 10 carbon atoms. 1 , A 2 When represents an organic group having 1 to 10 carbon atoms, A 1 , A 2 may have atoms other than carbon and hydrogen atoms, and A 1 , A 2 Examples of R include a hydrocarbon group, a heterocyclic group, and an oxygen-containing substituent having 1 to 10 carbon atoms, and examples of the hydrocarbon group having 1 to 10 carbon atoms include an aromatic hydrocarbon group and an alkyl group.

[0032] In another embodiment of the method for producing a fluorine-containing pyrazole compound, the reaction (B) can be carried out in one step. Therefore, the fluorine-containing pyrazole compound of the general formula (1) can be easily obtained. In the reaction (b) above, a cyclic pyrazole structure is formed between the fluoroisobutylene derivative of the general formula (2) and the amidino group of the compound of the general formula (3). At the 3rd, 4th, and 5th positions of the pyrazole structure, X derived from the compound represented by the general formula (5), CF derived from the fluoroisobutylene derivative, and the like are respectively attached. 3 , and -OR are located.

[0033] The reaction temperature in the above reaction (b) is preferably 0 to 100° C., more preferably 5 to 80° C., and even more preferably 10 to 40° C. The reaction time in the above reaction (b) is preferably 1 to 36 hours, more preferably 2 to 24 hours, and even more preferably 4 to 18 hours. In the above reaction (b), the same hydrogen halide scavenger and solvent as in the above reaction (a) can be used.

[0034] In another embodiment, a method for producing a fluorine-containing pyrazole compound includes the steps of: (c) A step of reacting a fluoroisobutane derivative represented by the following general formula (6) with a compound represented by the following general formula (3) or a salt thereof to obtain a fluorine-containing pyrazole compound represented by the following general formula (4). [ka] (In the above general formulas (3), (4) and (6), R represents a hydrocarbon group having 1 to 12 carbon atoms, Y is a halogen atom, -OA 3 , -SO m A 3 (m is an integer from 0 to 3), or -NA 3 A 4 represents A 3 , A 4 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. Preferably, the step (c) of obtaining a fluorine-containing pyrazole compound is carried out in the presence of a fluoride ion scavenger. It is preferable to react the fluoroisobutane derivative represented by the general formula (6) with the compound represented by the general formula (3) or a salt thereof in the presence of a fluoride ion scavenger. The fluoride ion trapping agent is not particularly limited as long as it is a substance having a function of trapping fluorine ions, and examples of the fluoride ion trapping agent include lithium, sodium, magnesium, potassium, calcium, tetramethylammonium, trifluoroacetic acid, heptafluorobutyric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, nonafluorobutanesulfonic acid, bis(trifluoromethanesulfonyl)imide, bis(nonafluorobutanesulfonyl)imide, N,N-hexafluoropropane-1,3-disulfonylimide, tetraphenylboric acid, tetrakis[3,5-bis(trifluoromethyl)phenyl]boric acid, and tetrakis(pentafluorophenyl)borate. The cation derived from the fluoride ion trapping agent traps the fluorine ion liberated from the fluoroisobutane derivative represented by the general formula (6) during the reaction, and precipitates it as a salt with low solubility in an organic solvent, thereby promoting the reaction, and it is considered that the fluorine-containing pyrazole compound represented by the general formula (4) can be obtained in high yield. In the compounds of the general formulae (4) and (6) in the above step (c), R preferably represents an alkyl group having 1 to 10 carbon atoms.

[0035] The above reaction (c) of the fluoroisobutane derivative represented by the general formula (6) with the compound represented by the general formula (3) is represented by the following reaction formula (C). [ka]

[0036] In the above reaction formula (C), the compound of general formula (3) may be in the form of a salt. When it is in the form of a salt, the amino moiety (-NH 2 ) is cationized (-NH3 + ) and forms a salt with the counter ion. The counter ion is not particularly limited as long as it is a monovalent anion, and for example, F - , Cl - , Br - , I - Examples of the halide ions include:

[0037] Examples of halogen atoms represented by Y include F, Cl, Br, and I. Y is -OA. 3 , -SO m A 3 (m is an integer from 0 to 3) 3 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. Y is -NA 3 A 4 A included in 3 , A 4 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 3 , A 4 When represents a hydrocarbon group having 1 to 10 carbon atoms, for example, the above R can be a hydrocarbon group having 1 to 10 carbon atoms.

[0038] In another embodiment of the method for producing a fluorine-containing pyrazole compound, the reaction (C) can be carried out in one step. Therefore, the fluorine-containing pyrazole compound of the general formula (4) can be easily obtained. In the reaction (c) above, a cyclic pyrazole structure is formed between the fluoroisobutane derivative of the general formula (6) and the amidino group of the compound of the general formula (3). The pyrazole structure has F, CF, and CF3 derived from the fluoroisobutane derivative at the 3rd, 4th, and 5th positions, respectively. 3 , and -OR are located.

[0039] The reaction temperature in the above reaction (c) is preferably 0 to 100° C., more preferably 5 to 80° C., and even more preferably 10 to 40° C. The reaction time in the above reaction (c) is preferably 1 to 36 hours, more preferably 2 to 24 hours, and even more preferably 4 to 18 hours. In the above reaction (c), the same hydrogen halide scavenger and solvent as in the above reaction (a) can be used.

[0040] In another embodiment, a method for producing a fluorine-containing pyrazole compound includes the steps of: (d) A step of reacting a fluoroisobutane derivative represented by the following general formula (6) with a compound represented by the following general formula (3) or a salt thereof, and a compound represented by the following general formula (5) to obtain a fluorine-containing pyrazole compound represented by the following general formula (1). [ka] (In the above general formulas (1), (3), (5), and (6), R represents a hydrocarbon group having 1 to 12 carbon atoms, X is a heterocyclic group containing at least one heteroatom selected from the group consisting of halogen atoms, nitrogen and oxygen as a ring atom; 1 , or -NA 1 A 2 represents A 1 , A 2 each independently represents a hydrogen atom or an organic group having 1 to 10 carbon atoms, Y is a halogen atom, -OA 3 , -SO m A 3 (m is an integer from 0 to 3), or -NA 3 A 4 represents A 3 , A 4 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. Preferably, the step of obtaining the fluorine-containing pyrazole compound in (d) is carried out in the presence of a fluoride ion trapping agent. The fluoroisobutane derivative represented by the general formula (6) is preferably reacted with the compound represented by the general formula (3) or its salt and the compound represented by the general formula (5) in the presence of a fluoride ion trapping agent. The fluoride ion trapping agent is not particularly limited as long as it is a substance having a function of trapping fluorine ions, and examples of the fluoride ion trapping agent include the same fluoride ion trapping agent as the fluoride ion trapping agent used in (c) above. It is considered that the cation derived from the fluoride ion trapping agent traps the fluorine ion liberated from the fluoroisobutane derivative represented by the general formula (6) during the reaction and precipitates it as a salt with low solubility in an organic solvent, thereby accelerating the reaction and allowing the fluorine-containing pyrazole compound represented by the general formula (1) to be obtained in high yield. It is preferable that R in the compounds of the general formulas (1) and (6) in the step (d) above represents an alkyl group having 1 to 10 carbon atoms.

[0041] The above reaction (d) of the fluoroisobutane derivative represented by the general formula (6) with the compounds represented by the general formulas (3) and (5) is represented by the following reaction formula (D). [ka]

[0042] In the above reaction formula (D), the compound of general formula (3) may be in the form of a salt. When it is in the form of a salt, the amino moiety (-NH 2 ) is cationized (-NH 3 + ) and forms a salt with the counter ion. The counter ion is not particularly limited as long as it is a monovalent anion, and for example, F - , Cl - , Br - , I - Examples of the halide ions include:

[0043] When the group X is a halogen atom, examples of the group include a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), and an iodine atom (I), with a fluorine atom being preferred. When the group X is a heterocyclic group, the heterocyclic group contains nitrogen, oxygen, or both nitrogen and oxygen as ring atoms. The number of ring atoms of at least one heteroatom selected from the group consisting of nitrogen and oxygen is not particularly limited as long as it is 1 or more, and may be 1 or 2 or more, and for example, the number of ring atoms of the heteroatom may be 1, 2, 3, or 4. The number of ring atoms constituting the heterocyclic group which is the group X is not particularly limited, and the number of ring atoms is preferably 3 to 14, more preferably 4 to 10, and even more preferably 5 to 6. The heterocyclic group which is the group X may be a monocyclic structure or a polycyclic structure, and may be an aromatic heterocyclic group or an alicyclic heterocyclic group. The -OA group which is the group X 1 A included in 1 represents a hydrogen atom or an organic group having 1 to 10 carbon atoms. 1 A 2 A included in 1 , A 2 Each independently represents a hydrogen atom or an organic group having 1 to 10 carbon atoms. 1 , A 2 When represents an organic group having 1 to 10 carbon atoms, A 1 , A 2 may have atoms other than carbon and hydrogen atoms, and A 1 , A 2 Examples of R include a hydrocarbon group, a heterocyclic group, and an oxygen-containing substituent having 1 to 10 carbon atoms, and examples of the hydrocarbon group having 1 to 10 carbon atoms include an aromatic hydrocarbon group and an alkyl group.

[0044] Examples of halogen atoms represented by Y include F, Cl, Br, and I. Y is -OA. 3 , -SO m A 3 (m is an integer from 0 to 3) 3 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. Y is -NA 3 A 4 A included in 3 , A4 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 3 , A 4 When represents a hydrocarbon group having 1 to 10 carbon atoms, for example, the above R can be a hydrocarbon group having 1 to 10 carbon atoms.

[0045] In another embodiment of the method for producing a fluorine-containing pyrazole compound, the reaction (D) can be carried out in one step. Therefore, the fluorine-containing pyrazole compound of the general formula (1) can be easily obtained. In the reaction (d) above, a cyclic pyrazole structure is formed between the fluoroisobutane derivative of the general formula (6) and the amidino group of the compound of the general formula (3). At the 3rd, 4th, and 5th positions of the pyrazole structure, X derived from the compound represented by the general formula (5), CF derived from the fluoroisobutane derivative, and the like are respectively attached. 3 , and -OR are located.

[0046] The reaction temperature in the above reaction (d) is preferably 0 to 100° C., more preferably 5 to 80° C., and even more preferably 10 to 40° C. The reaction time in the above reaction (d) is preferably 1 to 36 hours, more preferably 2 to 24 hours, and even more preferably 4 to 18 hours. In the above reaction (d), the same hydrogen halide scavenger as in the above reaction (a) can be used.

[0047] In the above reaction (d), the same solvent and catalyst as in the above reaction (c) can be used.

[0048] Although the embodiment of the present invention has been described above, the present invention is not limited to the above embodiment, and includes all aspects included in the concept of the present invention and the scope of the claims, and can be modified in various ways within the scope of the present invention. EXAMPLES

[0049] Next, in order to further clarify the effects of the present invention, examples will be described, but the present invention is not limited to these examples.

[0050] Example 1 Preparation of 5-methoxy-3-(4-morpholyl)-4-trifluoromethylpyrazole Under ice-water cooling, 2.0g (19mmol) of hydrazine dihydrochloride and 4.0g (19mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene were added to 30g of MeOH to obtain solution 1. Subsequently, solution 2 in which 5.4g (42mmol) of diisopropylethylamine was dissolved in 15g of MeOH was dropped into solution 1 so that the internal temperature did not exceed 10°C, and the resulting mixed solution was warmed to room temperature. After about 16 hours, the mixture was cooled with ice water, and solution 3 in which 9.1g (105mmol) of morpholine was dissolved in 20g of MeOH was dropped into the mixed solution, and the temperature was raised to room temperature. After about 8 hours, the reaction mixture was purified with a silica gel column using a mixed solvent of hexane-ethyl acetate = 7:3 to isolate 1.2g of 5-methoxy-3-(4-morpholyl)-4-trifluoromethylpyrazole represented by the following formula (E). The isolated yield of 5-methoxy-3-(4-morpholyl)-4-trifluoromethylpyrazole was 25%. [ka]

[0051] The analytical results of the obtained target substance are as follows: Mass spectrum (APCl, m / z): 251 ([M] + ) 1 H-NMR (400 MHz, CDCl 3 ) δppm:3.91(s,3H), 3.81(dd,4H), 3.14(dd,4H)

[0052] Example 2 Preparation of 3-fluoro-5-methoxy-4-trifluoromethylpyrazole Under ice-water cooling, 2.0g (19mmol) of hydrazine dihydrochloride and 4.0g (19mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene were added to 30g of THF to obtain solution 1. Subsequently, solution 2, in which 14g (105mmol) of diisopropylethylamine was dissolved in 30g of THF, was added dropwise to solution 1 so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature. After about 16 hours, the reaction mixture was purified with a silica gel column using a hexane-ethyl acetate=7:3 mixed solvent, and 70mg of 3-fluoro-5-methoxy-4-trifluoromethylpyrazole represented by the following formula (F) was isolated. The isolation yield of 3-fluoro-5-methoxy-4-trifluoromethylpyrazole was 2%. [ka]

[0053] The analytical results of the obtained target substance are as follows: Mass spectrum (APCl, m / z): 184 ([M] + )

[0054] Example 3 Preparation of 5-methoxy-3-(4-morpholyl)-4-trifluoromethylpyrazole using 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethyl-propane instead of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene in Example 1 Under ice-water cooling, 2.0g (19mmol) of hydrazine dihydrochloride and 4.4g (19mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethyl-propane were added to 30g of MeOH to obtain solution 1. Subsequently, solution 2 in which 8.1g (63mmol) of diisopropylethylamine was dissolved in 20g of MeOH was dropped into solution 1 so that the internal temperature did not exceed 10°C, and the resulting mixed solution was warmed to room temperature. After about 16 hours, the mixture was cooled with ice-water, and solution 3 in which 9.1g (105mmol) of morpholine was dissolved in 20g of MeOH was dropped into the mixed solution, and the temperature was raised to room temperature. After about 8 hours, the reaction mixture was purified with a silica gel column using a mixed solvent of hexane-ethyl acetate = 7:3 to isolate 5-methoxy-3-(4-morpholyl)-4-trifluoromethylpyrazole. The analytical results of the obtained target product were similar to those of the product in Example 1.

[0055] Example 4 Preparation of 5-methoxy-3-(1-pyrazolyl)-4-trifluoromethylpyrazole Under ice-water cooling, 2.0g (19mmol) of hydrazine dihydrochloride and 4.0g (19mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene were added to 30g of MeOH to obtain solution 1. Then, solution 2 in which 3.8g (38mmol) of triethylamine was dissolved in 15g of MeOH was added dropwise to solution 1 so that the internal temperature did not exceed 10°C, and the resulting mixed solution was warmed to room temperature. After about 16 hours, the mixture was cooled with ice-water, and solution 3 in which 1.3g (19mmol) of pyrazole and 8.5g (84mmol) of triethylamine were dissolved in 30g of MeOH was added dropwise to the mixed solution, and the temperature was raised to room temperature. After about 8 hours, the reaction mixture was purified with a silica gel column using a mixed solvent of hexane-ethyl acetate = 7:3 to isolate 0.2 g of 5-methoxy-3-(1-pyrazolyl)-4-trifluoromethylpyrazole represented by the following formula (G). The isolated yield of 5-methoxy-3-(1-pyrazolyl)-4-trifluoromethylpyrazole was 5%. [ka]

[0056] The analytical results of the obtained target substance are as follows: Mass spectrum (APCl, m / z): 232 ([M] + ) 1 H-NMR (400 MHz, CDCl 3 ) δppm:7.90(d,1H), 7.78(d,1H), 6.52(dd,1H), 4.03(s,3H)

[0057] Example 5 Preparation of 1-(3-methoxy-4-trifluoromethyl-1H-pyrazol-5-yl)azonane 0.5g (4.8mmol) of hydrazine dihydrochloride was dissolved in 13ml of methanol and cooled to 0°C, and then 1.0g (4.7mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene and 1.0g (9.6mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. The resulting solution was stirred for 16 hours, cooled to 0°C, and 3.1g (24.0mmol) of octamethyleneimine was added so as not to exceed room temperature, and the temperature was raised to room temperature. Next, after stirring the solution for 8 hours, the resulting reaction mixture was purified using a silica gel column with a hexane-ethyl acetate mixed solvent, and 0.6g (1.9mmol) of 1-(3-methoxy-4-trifluoromethyl-1H-pyrazol-5-yl)azonane represented by the following formula (H) was isolated. The isolation yield of 1-(3-methoxy-4-trifluoromethyl-1H-pyrazol-5-yl)azonane was 41%. [ka]

[0058] The analytical results of the obtained target substance are as follows: Mass spectrum (APCl, m / z): 292.6 ([M+H] + ) 1 H-NMR (400 MHz, CDCl 3) δppm:3.90(s,3H),3.25-3.32(m,4H),1.62-1.72(m,8H),1.49-1.59(m,4H)

[0059] Example 6 Preparation of 3-methoxy-N-(oxan-4-yl)-4-trifluoromethyl-1H-pyrazol-5-amine 0.5g (4.8mmol) of hydrazine dihydrochloride was dissolved in 13ml of methanol and cooled to 0°C, and then 1.0g (4.7mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene and 1.0g (9.7mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. The resulting solution was stirred for 16 hours, cooled to 0°C, and 0.7g (4.8mmol) of 4-aminotetrahydropyran hydrochloride and 2.4g (23.9mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. Next, after stirring the solution for 8 hours, the resulting reaction mixture was purified using a silica gel column with a hexane-ethyl acetate mixed solvent, and 0.1g (0.5mmol) of 3-methoxy-N-(oxan-4-yl)-4-trifluoromethyl-1H-pyrazol-5-amine represented by the following formula (I) was isolated. The isolated yield of 3-methoxy-N-(oxan-4-yl)-4-trifluoromethyl-1H-pyrazol-5-amine was 10%. [ka]

[0060] The analytical results of the obtained target substance are as follows: Mass spectrum (APCl, m / z): 266.5 ([M+H] + ) 1 H-NMR (400 MHz, CDCl 3) δppm:4.11-4.16(m,1H),4.00(ddd,J=11.9,3.7,3.3Hz,2H),3.90(s,3H),3.47(ddd ,J=11.9,11.3,2.1Hz,2H),3.28-3.39(m,1H),1.95-2.02(m,2H),1.51-1.62(m,2H)

[0061] Example 7 Preparation of N,N-bis[(2,4-dimethoxyphenyl)methyl]-3-methoxy-4-trifluoromethyl-1H-pyrazol-5-amine 0.5g (4.8mmol) of hydrazine dihydrochloride was dissolved in 13ml of methanol and cooled to 0°C, and then 1.0g (4.7mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene and 1.0g (9.6mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. The resulting solution was stirred for 16 hours, cooled to 0°C, and 1.5g (4.8mmol) of bis(2,4-dimethoxybenzyl)amine and 1.9g (19.1mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. Next, after stirring the solution for 8 hours, the resulting reaction mixture was purified using a silica gel column with a hexane-ethyl acetate mixed solvent, and 0.3g (0.6mmol) of N,N-bis[(2,4-dimethoxyphenyl)methyl]-3-methoxy-4-trifluoromethyl-1H-pyrazol-5-amine represented by the following formula (J) was isolated. The isolated yield of N,N-bis[(2,4-dimethoxyphenyl)methyl]-3-methoxy-4-trifluoromethyl-1H-pyrazol-5-amine was 13%. [ka]

[0062] The analytical results of the obtained target substance are as follows: Mass spectrum (APCl, m / z): 483.0 ([M+H] + ) 1 H-NMR (400 MHz, CDCl 3) δppm:9.19(br,1H),7.15(d,J=8.3Hz,2H),6.42-6.48(m,4H),4.24(s,3H),3.87(s,3H),3.80(s,1H)

[0063] Example 8 Preparation of 3-methoxy-N-(4-methoxyphenyl)-N-methyl-4-trifluoromethyl-1H-pyrazol-5-amine 0.5g (4.8mmol) of hydrazine dihydrochloride was dissolved in 13ml of methanol and cooled to 0°C, and then 1.0g (4.7mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene and 1.0g (9.8mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. The resulting solution was stirred for 16 hours, cooled to 0°C, and 0.7g (4.8mmol) of N-methyl-p-anisidine and 1.9g (19.3mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. Next, after stirring the solution for 8 hours, the resulting reaction mixture was purified with a silica gel column using a hexane-ethyl acetate mixed solvent to obtain 0.1g of a mixture of 3-methoxy-N-(4-methoxyphenyl)-N-methyl-4-trifluoromethyl-1H-pyrazol-5-amine represented by the following formula (K). [ka]

[0064] The analytical results of the obtained target substance are as follows: Mass spectrum (APCl, m / z): 302.6 ([M+H] + )

[0065] Example 9 Preparation of 3-methoxy-5-(4-methoxypiperidin-1-yl)-4-trifluoromethyl-1H-pyrazole 0.5g (4.8mmol) of hydrazine dihydrochloride was dissolved in 13ml of methanol, cooled to 0°C, and then 1.0g (4.7mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene and 1.0g (9.7mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. The resulting solution was stirred for 17 hours, cooled to 0°C, and 0.6g (4.8mmol) of 4-methoxypiperidine and 1.9g (19.2mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. Next, after stirring the solution for 8 hours, the resulting reaction mixture was purified with a silica gel column using a hexane-ethyl acetate mixed solvent to obtain 0.2g of a mixture of 3-methoxy-5-(4-methoxypiperidin-1-yl)-4-trifluoromethyl-1H-pyrazole represented by the following formula (L). [ka]

[0066] The analytical results of the obtained target substance are as follows: Mass spectrum (APCl, m / z): 280.8 ([M+H] + ) 19 F-NMR (400 MHz, CDCl 3 ) δppm:-55.85(s,3F)

[0067] Example 10 Preparation of N,N-bis(2-ethoxyethyl)-3-methoxy-4-trifluoromethyl-1H-pyrazol-5-amine 0.5g (4.8mmol) of hydrazine dihydrochloride was dissolved in 13ml of methanol, cooled to 0°C, and then 1.0g (4.7mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene and 1.0g (9.6mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. The resulting solution was stirred for 16 hours, cooled to 0°C, and 0.8g (4.9mmol) of bis(2-ethoxyethyl)amine and 2.0g (19.4mmol) were added so as not to exceed room temperature, and the temperature was raised to room temperature. Next, after stirring the solution for 8 hours, the resulting reaction mixture was purified with a silica gel column using a hexane-ethyl acetate mixed solvent to obtain 0.1g of a mixture of N,N-bis(2-ethoxyethyl)-3-methoxy-4-trifluoromethyl-1H-pyrazol-5-amine represented by the following formula (M). [ka]

[0068] The analytical results of the obtained target substance are as follows: Mass spectrum (APCl, m / z): 327.0 ([M+H] + ) 1 H-NMR (400 MHz, CDCl 3 ) δppm:10.38(br,1H),3.90(s,1H),3.61(t,J=4.7Hz,4H),3.53(q,J=7.0Hz,4H),3.46(t,J=4.9Hz,4H),1.23(t,J=7.0Hz,6H)

[0069] Example 11 Preparation of 4-[butyl(3-methoxy-4-trifluoromethyl-1H-pyrazol-5-yl)amino]-1-butanol 0.5g (4.8mmol) of hydrazine dihydrochloride was dissolved in 13ml of methanol, cooled to 0°C, and then 1.0g (4.7mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene and 1.0g (9.7mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. The resulting solution was stirred for 16 hours, cooled to 0°C, and 0.7g (5.0mmol) of 4-(butylamino)-1-butanol and 1.9g (19.2mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. Next, after stirring the solution for 8 hours, the resulting reaction mixture was purified with a silica gel column using a hexane-ethyl acetate mixed solvent to obtain 0.1g of a mixture of 4-[butyl(3-methoxy-4-trifluoromethyl-1H-pyrazol-5-yl)amino]-1-butanol represented by the following formula (N). [ka]

[0070] The analytical results of the obtained target substance are as follows: Mass spectrum (APCl, m / z): 311.0 ([M+H] + ) 19 F-NMR (400 MHz, CDCl 3 ) δppm:-54.59(s,3F)

[0071] Example 12 Preparation of N-(3-methoxy-4-trifluoromethyl-1H-pyrazol-5-yl)-N-methyl-2-thiazolamine 0.5g (4.8mmol) of hydrazine dihydrochloride was dissolved in 13ml of methanol, cooled to 0°C, and then 1.0g (4.7mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene and 1.0g (9.5mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. The resulting solution was stirred for 17 hours, cooled to 0°C, and 0.5g (4.7mmol) of N-methyl-2-thiazolamine and 1.9g (19.2mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to reflux. Next, the solution was stirred for 8 hours, and then air-cooled to room temperature, and the resulting reaction mixture was purified using a silica gel column with a hexane-ethyl acetate mixed solvent to obtain 0.03g of a mixture of N-(3-methoxy-4-trifluoromethyl-1H-pyrazol-5-yl)-N-methyl-2-thiazolamine represented by the following formula (O). [ka]

[0072] The analytical results of the obtained target substance are as follows: Mass spectrum (APCl, m / z): 279.8 ([M+H] + )

[0073] (Example 13) Preparation of 2-(ethylthio)-10-(3-methoxy-4-trifluoromethyl-1H-pyrazol-5-yl)-10H-phenothiazine 0.5g (4.8mmol) of hydrazine dihydrochloride was dissolved in 13ml of methanol, cooled to 0°C, and then 1.0g (4.7mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene and 1.0g (9.6mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. The resulting solution was stirred for 16 hours, cooled to 0°C, and 1.2g (4.8mmol) of 2-ethylthiophenothiazine and 1.9g (19.1mmol) of triethylamine were added so as not to exceed room temperature, and the temperature was raised to room temperature. Next, the solution was stirred for 25 hours, and the resulting reaction mixture was purified with a silica gel column using a hexane-ethyl acetate mixed solvent to obtain 0.02g of a mixture of 2-(ethylthio)-10-(3-methoxy-4-trifluoromethyl-1H-pyrazol-5-yl)-10H-phenothiazine represented by the following formula (P). [ka]

[0074] The analytical results of the obtained target substance are as follows: Mass spectrum (EI, m / z): 423.1 ([M] + )

[0075] Evaluation test against rice blast disease (500ppm) The fluorine-containing pyrazole compounds prepared in Examples 2 and 9 were each dissolved in DMSO (dimethyl sulfoxide) to a concentration of 50,000 ppm to obtain a DMSO solution. 30 μL of the DMSO solution containing the fluorine-containing pyrazole prepared in Examples 2 or 9 and DMSO were added to 3 mL of dissolved PDA medium, stirred with a pipette, and placed in a well of a 6-well plate to solidify (each of the fluorine-containing pyrazole compounds prepared in Examples 2 and 9 was placed in three wells). Rice blast fungus (Pyricularia oryzae, MAFF101511) grown in PDA medium was cut out together with the medium using a Seiken punch with a diameter of 0.4 cm, and these were placed in the center of the PDA medium of a 6-well plate containing the fluorine-containing pyrazole compound of Example 2 or 9, and grown at 27° C. The diameter of the hyphae was measured after 3 days. Separately, rice blast fungus was grown on three PDA media containing DMSO in the same manner as above, except that no treatment with the fluorinated pyrazole compounds of Examples 2 and 9 was performed, and the diameter of the hyphae was measured after three days. The average value of the three hyphae elongations thus obtained was designated as the "average hyphae elongation length of untreated fungal cultures." The inhibition rate (%) of mycelial growth was calculated as follows: Inhibition rate = {(average hyphal elongation length of untreated - average hyphal elongation length of treated with the fluorine-containing pyrazole compound prepared in Example 2 or 9) / average hyphal elongation length of untreated} x 100

[0076] [Table 1]

[0077] The inhibition rates of the fluorinated pyrazole compounds prepared in Examples 2 and 9 are shown in Table 1. As shown in Table 1, high inhibition rates were observed when the fluorinated pyrazole compounds of Examples 2 and 9 were used, and it can be said that these fluorinated pyrazole compounds have excellent fungicidal activity against rice blast.

Claims

1. A fluorine-containing pyrazole compound represented by the following general formula (1): 【Chemistry 1】 (In the above general formula (1), R represents a hydrocarbon group having 1 to 12 carbon atoms, X is a heterocyclic group containing at least one heteroatom selected from the group consisting of a halogen atom, nitrogen, and oxygen as a ring atom; １ , or -NA １ A ２ represents the heterocycle is an alicyclic heterocycle, an aromatic heterocycle having five ring atoms, or an aromatic heterocycle having a heterocyclic structure having one, two, three, or four heteroatom ring atoms, A １ , A ２ each independently represents a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a heterocyclic group, or an oxygen-containing substituent.

2. A step of reacting a fluoroisobutylene derivative represented by the following general formula (2) with a compound represented by the following general formula (3) or a salt thereof to obtain a fluorine-containing pyrazole compound represented by the following general formula (4): 【Chemistry 2】 (In the above general formulas (2) to (4), R represents a hydrocarbon group having 1 to 12 carbon atoms.) The present invention relates to a method for producing a fluorine-containing pyrazole compound.

3. A step of reacting a fluoroisobutylene derivative represented by the following general formula (2) with a compound represented by the following general formula (3) or a salt thereof, and a compound represented by the following general formula (5) to obtain a fluorine-containing pyrazole compound represented by the following general formula (1): 【Chemistry 3】 (In the above general formulas (1) to (3) and (5), R represents a hydrocarbon group having 1 to 12 carbon atoms, X is a heterocyclic group containing at least one heteroatom selected from the group consisting of a halogen atom, nitrogen, and oxygen as a ring atom; １ , or -NA １ A ２ represents A １ , A ２ each independently represents a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a heterocyclic group, or an oxygen-containing substituent. The present invention relates to a method for producing a fluorine-containing pyrazole compound.

4. A step of reacting a fluoroisobutane derivative represented by the following general formula (6) with a compound represented by the following general formula (3) or a salt thereof to obtain a fluorine-containing pyrazole compound represented by the following general formula (4): 【Chemistry 4】 (In the above general formulas (3), (4), and (6), R represents a hydrocarbon group having 1 to 12 carbon atoms, Y is a halogen atom, -OA ３ , -SO ｍ A ３ (m is an integer from 0 to 3), or -NA ３ A ４ represents A ３ , A ４ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. The present invention relates to a method for producing a fluorine-containing pyrazole compound.

5. A step of reacting a fluoroisobutane derivative represented by the following general formula (6) with a compound represented by the following general formula (3) or a salt thereof, and a compound represented by the following general formula (5) to obtain a fluorine-containing pyrazole compound represented by the following general formula (1): 【Chemistry 5】 (In the above general formulas (1), (3), (5), and (6), R represents a hydrocarbon group having 1 to 12 carbon atoms, X is a heterocyclic group containing at least one heteroatom selected from the group consisting of a halogen atom, nitrogen, and oxygen as a ring atom; １ , or -NA １ A ２ represents A １ , A ２ each independently represents a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a heterocyclic group, or an oxygen-containing substituent; Y is a halogen atom, -OA ３ , -SO ｍ A ３ (m is an integer from 0 to 3), or -NA ３ A ４ represents A ３ , A ４ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. The present invention relates to a method for producing a fluorine-containing pyrazole compound.

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