Fluorine-containing pyrazolone compound and method for producing same

Abstract

Provided are: a novel fluorine-containing 1, 2-disubstituted-3-pyrazolone compound which has a trifluoromethyl group at the 4-position and a specific substituent at the 5-position; and a method for producing the fluorine-containing pyrazolone compound in a simple manner without producing an O-substituent as a byproduct. A fluorine-containing pyrazolone compound represented by general formula (1). In general formula (1), X represents a halogen atom,-OA1,-S (Ol) A1,-O-NA1A2,-NA1A2,-NA3-NA1A2, or-N = A4 (where l is an integer of 0-2, Y and Z each independently represent a C1-12 aromatic hydrocarbon group, an alkyl group,-COA1,-COOA1, a benzyl group, or a carbamoyl group, or Y and Z bond to form a ring, and A1, A2, A3, and A4 each independently represent a C1-12 organic group. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a fluorine-containing pyrazolone compound and a method for preparing the same. Background Art

[0002] Compounds containing a pyrazolone ring are known to have various pharmacological effects. Among them, 3-pyrazolone compounds with substituents at the 1- and 2-positions are used in pharmaceuticals and pesticides. Examples of compounds containing a 1,2-disubstituted-3-pyrazolone ring include the anti-inflammatory drugs nifenazone, propyphenazone, dipyrone, antipyrine, and aminopyrine in pharmaceuticals. Furthermore, pesticides include the fungicide fenpyrazamine and the herbicide pinoxaden.

[0003] Against this backdrop, there has been interest in introducing substituents at the 4- and 5-positions of the 1,2-disubstituted-3-pyrazolone ring. In particular, there has been interest in developing methods for synthesizing 1,2-disubstituted-3-pyrazolone compounds having unique substituents such as a trifluoromethyl group at the 4-position and a heteroatom-containing substituent at the 5-position.

[0004] Patent Document 1 (Japanese Patent Application Laid-Open No. 61-118371) discloses a method for producing a 3-pyrazolone compound having a substituent at position 1, a trifluoromethyl group at position 4, and a heteroatom substituent at position 5. Non-Patent Documents 1 and 2 disclose the introduction of a substituent onto the pyrazolone ring of a compound having a pyrazolone ring.

[0005] Prior art literature

[0006] Patent Literature

[0007] Patent Document 1: Japanese Patent Application Laid-Open No. 61-118371.

[0008] Non-patent literature

[0009] Non-patent document 1: Bioorganic & Medicinal Chemistry, 2017, Vol. 25, pp. 5327-5340;

[0010] Non-patent document 2: Journal of Molecular Structure, 2020, Vol. 1215, p. 128272. Summary of the Invention

[0011] Problems to be solved by the invention

[0012] It is believed that the desired 1,2-disubstituted-3-pyrazolone compound can be produced by introducing a substituent at the 2-position of the pyrazolone ring of the compound obtained by the production method disclosed in Patent Document 1. However, Non-Patent Document 1 reports that when a substituent is introduced at the 2-position of the pyrazolone ring of a compound having a 1-substituted 3-pyrazolone ring structure, competition with the introduction of a substituent at the 3-oxygen position of the pyrazolone ring may occur. Similarly, Non-Patent Document 2 reports that when a substituent is introduced at the 1-position of the pyrazolone ring of a compound having a 2-substituted 3-pyrazolone ring structure, competition with the introduction of a substituent at the 3-oxygen position of the pyrazolone ring may also occur. Therefore, according to the disclosures of these documents, if one attempts to obtain a 1,2-disubstituted-3-pyrazolone compound from a 3-pyrazolone compound substituted at the 1- or 2-position, the by-production of a compound in which a substituent is introduced at the 3-oxygen position (O-substituted form) cannot be suppressed, and there is room for research in terms of efficiently producing the desired 1,2-disubstituted-3-pyrazolone compound.

[0013] Therefore, the present inventors discovered that by reacting specific raw materials, 1,2-disubstituted-3-pyrazolone compounds having a trifluoromethyl group at the 4-position and a specific substituent such as a heteroatom-containing substituent at the 5-position can be obtained without producing an O-substituted form as a by-product, thereby completing the present invention. Specifically, an object of the present invention is to provide a previously unknown 1,2-disubstituted-3-pyrazolone compound having a trifluoromethyl group at the 4-position and a specific substituent at the 5-position, as well as a method for producing such a pyrazolone compound in a simple manner without producing an O-substituted form as a by-product.

[0014] Means of solving the problem

[0015] The gist of the present invention is as follows.

[0016] [1] A fluorine-containing pyrazolone compound represented by the following general formula (1), wherein:

[0017] [Chemical Formula 1]

[0018]

[0019] In the above general formula (1), X represents a halogen atom, -OA 1 、-S(O l )A 1 (l is an integer from 0 to 2), -O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A2 or -N=A 4 ,

[0020] Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring,

[0021] A 1 、A 2 、A 3 and A 4 Each independently represents an organic group having 1 to 12 carbon atoms.

[0022] [2] A method for producing a fluorine-containing pyrazolone compound, comprising the following steps:

[0023] The fluorine-containing pyrazolone compound represented by the following general formula (1a) is obtained by reacting a fluoroisobutyryl fluoride derivative represented by the following general formula (2) with a compound represented by the following general formula (6) or a salt thereof.

[0024] [Chemical Formula 2]

[0025]

[0026] In the above general formulae (1a), (2) and (6), Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring,

[0027] A 1 represents an organic group having 1 to 12 carbon atoms,

[0028] W + represents an ammonium cation, an imidazolium cation, a pyridinium cation or a phosphonium cation.

[0029] [3] A method for producing a fluorine-containing pyrazolone compound, comprising the following steps:

[0030] A fluorine-containing pyrazolone compound represented by the following general formula (1b) is obtained by reacting a fluoroisobutyryl fluoride derivative represented by the following general formula (2) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof.

[0031] [Chemical Formula 3]

[0032]

[0033] In the above general formulas (1b), (2), (5) and (6), X1 represents a halogen atom other than a fluorine atom, -OA 1 、-S(O l )A 1 (l is an integer from 0 to 2), -O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 ,

[0034] Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring,

[0035] A 1 、A 2 、A 3 and A 4 each independently represents an organic group having 1 to 12 carbon atoms,

[0036] W + represents an ammonium cation, an imidazolium cation, a pyridinium cation or a phosphonium cation.

[0037] [4] A method for producing a fluorine-containing pyrazolone compound, comprising the following steps:

[0038] The fluorine-containing pyrazolone compound represented by the following general formula (1a) is obtained by reacting a fluoroisobutylene derivative represented by the following general formula (3) with a compound represented by the following general formula (6) or a salt thereof.

[0039] [Chemical Formula 4]

[0040]

[0041] In the above general formulae (1a), (3) and (6), Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring,

[0042] A 1 represents an organic group having 1 to 12 carbon atoms,

[0043] R represents a hydrocarbon group having 1 to 12 carbon atoms.

[0044] [5] A method for producing a fluorine-containing pyrazolone compound, comprising the following steps:

[0045] A fluorine-containing pyrazolone compound represented by the following general formula (1b) is obtained by reacting a fluoroisobutylene derivative represented by the following general formula (3) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof.

[0046] [Chemical Formula 5]

[0047]

[0048] In the above general formulas (1b), (3), (5) and (6), X 1 represents a halogen atom other than a fluorine atom, -OA 1 、-S(O l )A 1 (l is an integer from 0 to 2), -O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 ,

[0049] Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring,

[0050] A 1 、A 2 、A 3 and A 4 each independently represents an organic group having 1 to 12 carbon atoms,

[0051] R represents a hydrocarbon group having 1 to 12 carbon atoms.

[0052] [6] A method for producing a fluorine-containing pyrazolone compound, comprising the following steps:

[0053] By reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (6) or a salt thereof, a fluorine-containing pyrazolone compound represented by the following general formula (1a) is obtained.

[0054] [Chemical Formula 6]

[0055]

[0056] In the above general formulae (1a), (4) and (6), Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring,

[0057] R represents a hydrocarbon group having 1 to 12 carbon atoms,

[0058] V represents a halogen atom, -OA 5 or -SO m A 5 (m is an integer from 0 to 2),

[0059] A 1 and A 5 Each independently represents an organic group having 1 to 12 carbon atoms.

[0060] [7] A method for producing a fluorine-containing pyrazolone compound, comprising the following steps:

[0061] A fluorine-containing pyrazolone compound represented by the following general formula (1b) is obtained by reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof.

[0062] [Chemical Formula 7]

[0063]

[0064] In the above general formulas (1b) and (4) to (6), X 1 represents a halogen atom other than a fluorine atom, -OA 1 、-S(O l )A 1 (l is an integer from 0 to 2), -O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 ,

[0065] Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring,

[0066] R represents a hydrocarbon group having 1 to 12 carbon atoms,

[0067] V represents a halogen atom, -OA 5 or -SO m A 5 (m is an integer from 0 to 2),

[0068] A 1 、A 2 、A 3 、A 4 and A 5 Each independently represents an organic group having 1 to 12 carbon atoms.

[0069] Effects of the Invention

[0070] Provided are a novel fluorinated 1,2-disubstituted-3-pyrazolone compound having a trifluoromethyl group at the 4-position and a unique substituent at the 5-position, and a method for producing the fluorinated 1,2-disubstituted-3-pyrazolone compound in a simple manner without producing an O-substituted form as a by-product. DETAILED DESCRIPTION

[0071] (Fluorine-containing pyrazolone compound)

[0072] The fluorine-containing pyrazolone compound of the present invention is represented by the following general formula (1).

[0073] [Chemical Formula 8]

[0074]

[0075] In the above general formula (1), X represents a halogen atom, -OA 1 、-S(O l )A 1 (l is an integer from 0 to 2), -O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 ,

[0076] Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring,

[0077] A 1 、A 2 、A 3 and A 4 Each independently represents an organic group having 1 to 12 carbon atoms.

[0078] The fluorine-containing pyrazolone compound of the present invention has specific substituents (-CF3, -X) on the 4th and 5th positions of the pyrazolone ring, so from the viewpoint of structural expansibility, it is possible to have excellent effects. In particular, it is possible to expect desired biological activity (such as the inhibitory activity of hormones and enzymes, bactericidal activity, insecticidal activity, and herbicidal activity). In particular, as bactericidal activity, it is possible to enumerate the bactericidal activity of bacteria that have harmful effects on crops such as human body and rice. In addition, since the substituents on the 4th and 5th positions of the pyrazolone ring are different groups (-CF3, -X), these groups can be separated from or reacted and easily derivatized into asymmetric structures, and it is also possible to expect the use as intermediates. More specifically, by reacting the fluorine-containing pyrazolone compound, it is possible to replace -CF3 and obtain derivatives. In addition, by reacting the fluorine-containing pyrazolone compound under alkaline conditions, it is possible to modify -X and obtain derivatives. The fluorine-containing pyrazolone compound of an embodiment is also useful in the field of electronic materials such as organic semiconductors and liquid crystals.

[0079] The group X represents a halogen atom, -OA 1 、-S(O l )A 1 (l is an integer from 0 to 2), -O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 . A 1 、A 2 、A 3 and A 4 Each independently represents an organic group having 1 to 12 carbon atoms, A 1 、A 2 and A 3 is a monovalent group, A 4 A is a divalent group. 1 、A 2 、A 3 and A 4 It only needs to be an organic group with 1 to 12 carbon atoms, and may contain hydrogen atoms, oxygen atoms, sulfur atoms, and nitrogen atoms in addition to carbon atoms. 1 、A 2 and A 3 Examples include chain hydrocarbon groups having 1 to 12 carbon atoms (e.g., alkyl, alkenyl, alkynyl), aromatic hydrocarbon groups (e.g., phenyl), alicyclic hydrocarbon groups (e.g., cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, adamantyl), heterocyclic groups, -COA 6 、-C n H2n -A 7 、-C n H 2n -OA 7 (n is an integer from 1 to 11, A 6 is an organic group with 1 to 11 carbon atoms, A 7 is an organic group having 1 to 12 carbon atoms. 6 , furyl, benzofuranyl, thienyl can be mentioned. 7 , and examples thereof include alkyl groups having 1 to 12 carbon atoms, phenyl groups, pyridyl groups, naphthyl groups, and thienyl groups). The chain hydrocarbon group may be a branched chain hydrocarbon group or an unbranched chain hydrocarbon group. The aromatic hydrocarbon group may be an aromatic hydrocarbon group having a substituent or an aromatic hydrocarbon group without a substituent. In addition, the aromatic hydrocarbon group may have a condensed polycyclic structure. The alicyclic hydrocarbon group may be an alicyclic hydrocarbon group having a substituent or an alicyclic hydrocarbon group without a substituent. In addition, the alicyclic hydrocarbon group may have a bridged ring structure. The heterocyclic group may be a heterocyclic group containing one or more heteroatoms (oxygen atoms, sulfur atoms, nitrogen atoms) as ring atoms, and may have a monocyclic structure or a condensed polycyclic structure. As A 4 , cyclopentylidene, cyclohexylidene, diphenylmethylene, dibutylmethylene, =CN(A 8 )2N(A 9 )2(A 8 and A 9 Each independently represents an alkyl group having 1 to 8 carbon atoms), di(ethoxy)methylene, di(ethylthio)methylene. Group X is preferably a halogen atom, -O-NA 1 A 2 or -NA 1 A 2 As the halogen atom of group X, there can be mentioned fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (I), preferably fluorine atom. 1 、A 2 and A 3 Preferably, alkyl, -COA 6 、-C n H 2n -A 7 or -C n H 2n -OA 7 .

[0080] Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1, benzyl or carbamoyl, or Y and Z are bonded to form a ring. Y and Z are each independently preferably a phenyl group, an alkyl group having 1 to 12 carbon atoms, -COA 1 (A 1 is an alkyl group having 1 to 12 carbon atoms) or -COOA 1 (A 1 is an alkyl group having 1 to 12 carbon atoms), a benzyl group, or Y and Z are bonded to form a ring. When Y and Z are bonded to form a ring, Y and Z together form -C n H 2n -, and the ring structure formed between the nitrogen atoms at positions 1 and 2 of the pyrazolone ring can be mentioned. In this case, a ring having -YZC n H 2n -structured ring. The number of ring atoms forming such a ring is not limited, but the number of ring atoms is preferably 4 to 12, more preferably 5 to 10, and even more preferably 6 to 8. Furthermore, the ring formed by the bonding of Y and Z may or may not have a substituent. When the ring formed by the bonding of Y and Z has a substituent, examples of the substituent include =0, an alkyl group having 1 to 12 carbon atoms, and a halogen atom.

[0081] (Method for producing fluorine-containing pyrazolone compound)

[0082] A method for producing a fluorine-containing pyrazolone compound according to one embodiment includes the following steps:

[0083] (a) A fluorine-containing pyrazolone compound represented by the following general formula (1a) is obtained by reacting a fluoroisobutyryl fluoride derivative represented by the following general formula (2) with a compound represented by the following general formula (6) or a salt thereof.

[0084] [Chemical Formula 9]

[0085]

[0086] In the above general formulae (1a), (2) and (6), Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or, Y and Z are bonded to form a ring, A 1 represents an organic group having 1 to 12 carbon atoms, W + represents an ammonium cation, an imidazolium cation, a pyridinium cation or a phosphonium cation.

[0087] As A 1 , can be set to the same as the above A 1 Same group.

[0088] Examples of the ammonium cation include triethylmethylammonium cation, butyltrimethylammonium cation, and N-methylquinuclium cation.

[0089] Examples of the imidazolium cation include a 1-butyl-3-methylimidazolium cation, a 1,3-dimethylimidazolium cation, and a 1-benzyl-3-methylimidazolium cation.

[0090] Examples of the pyridinium cation include 1-methyl-4-dimethylaminopyridinium cation, 1-methylpyridinium cation, and 1,4-dimethylpyridinium cation.

[0091] Examples of the phosphonium cation include tricyclohexylmethylphosphonium cation, triphenylmethylphosphonium cation, and tributylmethylphosphonium cation.

[0092] Examples of the salt of the compound represented by the general formula (6) include hydrochloride, trifluoroacetate, and p-toluenesulfonate of the compound represented by the general formula (6).

[0093] Preferably, the step (a) of obtaining a fluorine-containing pyrazolone compound is preferably carried out in the presence of a fluoride ion scavenger. It is preferred that the fluoroisobutyryl fluoride derivative represented by the general formula (2) is reacted with the compound represented by the general formula (6) 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 fluoride ions. Examples of fluoride ion scavengers 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 cations derived from the fluoride ion scavenger capture the fluoride ions released from the fluoroisobutyryl fluoride derivative represented by general formula (2) during the reaction and precipitate them as salts with low solubility in organic solvents, thereby promoting the reaction and enabling the fluorine-containing pyrazolone compound represented by general formula (1a) to be obtained in high yield.

[0094] The reaction (a) in which the fluoroisobutyryl fluoride derivative represented by the general formula (2) reacts with the compound represented by the general formula (6) to obtain the fluorine-containing pyrazolone compound represented by the general formula (1a) is represented by the following reaction formula (A).

[0095] [Chemical Formula 10]

[0096]

[0097] In the method for producing a fluorinated pyrazolone compound according to one embodiment, the reaction of (A) can be performed in one stage. Therefore, the fluorinated pyrazolone compound of the general formula (1a) can be easily obtained. In addition, in the reaction of (a), the compound of the general formula (1a) is formed from the fluorinated isobutyryl fluoride derivative represented by the general formula (2) and the compound represented by the general formula (6). -CF3 and -F derived from the fluorinated isobutyryl fluoride derivative are located at positions 4 and 5, respectively, of the pyrazolone structure.

[0098] The reaction of (a) is preferably carried out in the presence of a hydrogen halide scavenger. The hydrogen halide scavenger is a substance having the function of capturing hydrogen fluoride (HF) formed by the hydrogen atom of the compound derived from the general formula (6) and the fluorine atom of the fluoroisobutyryl fluoride derivative derived from the general formula (2) in the reaction formula of (A). As the hydrogen halide scavenger, organic nitrogen derivatives such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium fluoride, potassium fluoride, pyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, methyltriazabicyclodecene, diazabicyclooctane, and phosphazene base can be used.

[0099] The reaction temperature in the reaction (a) is preferably -20°C or higher and lower than the boiling point of the organic solvent, more preferably 0 to 50°C, and even more preferably 10 to 30°C. The reaction time in the reaction (a) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours.

[0100] Examples of the solvent used in the reaction (a) include ethers such as tetrahydrofuran, diethyl ether, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, and tetraethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; nitriles such as acetonitrile; and aprotic polar solvents such as dimethylformamide, dimethylacetamide, methylpyrrolidone, dimethylethylene urea, tetramethylurea, dimethyl sulfoxide, and sulfolane.

[0101] Another embodiment of the method for producing a fluorine-containing pyrazolone compound includes the following steps:

[0102] (b) A fluorine-containing pyrazolone compound represented by the following general formula (1b) is obtained by reacting a fluoroisobutyryl fluoride derivative represented by the following general formula (2) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof.

[0103] [Chemical Formula 11]

[0104]

[0105] In the above general formulas (1b), (2), (5) and (6), X 1represents a halogen atom other than a fluorine atom, -OA 1 、-S(O l )A 1 (l is an integer from 0 to 2), -O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 , Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl, or carbamoyl, or, Y and Z bond to form a ring, A 1 、A 2 、A 3 and A 4 Each independently represents an organic group having 1 to 12 carbon atoms, W + represents an ammonium cation, an imidazolium cation, a pyridinium cation or a phosphonium cation.

[0106] A 1 、A 2 、A 3 and A 4 Can be the same as above A 1 、A 2 、A 3 and A 4 Same group.

[0107] Examples of the salt of the compound represented by the general formula (6) include hydrochloride, trifluoroacetate, and p-toluenesulfonate of the compound represented by the general formula (6).

[0108] Preferably, the step (b) of obtaining the fluorine-containing pyrazolone compound is preferably carried out in the presence of a fluoride ion scavenger. It is preferred that the fluoroisobutyryl fluoride derivative represented by the general formula (2) is reacted with the compound represented by the general formula (5) and the compound represented by the general formula (6) or a salt thereof in the presence of a fluoride ion scavenger. The fluorine ion scavenger is not particularly limited as long as it is a substance having the function of capturing fluoride ions, and the same fluoride ion scavenger as the fluoride ion scavenger used in the above step (a) can be cited. It is believed that the cations derived from the fluoride ion scavenger capture the fluoride ions freed from the fluoroisobutyryl fluoride derivative represented by the general formula (2) during the reaction and precipitate in the form of a salt with low solubility in an organic solvent, thereby promoting the reaction and being able to obtain the fluorine-containing pyrazolone compound represented by the general formula (1b) in a high yield.

[0109] The reaction of the fluoroisobutyryl fluoride derivative represented by the general formula (2) with the compounds represented by the general formulas (5) and (6) in the above-mentioned step (b) is represented by the following reaction formula (B).

[0110] [Chemical Formula 12]

[0111]

[0112] In the method for producing a fluorinated pyrazolone compound according to another embodiment, the reaction of (B) can be carried out in one stage. Therefore, the fluorinated pyrazolone compound of the general formula (1b) can be easily obtained. In addition, in the reaction of (b), a cyclic pyrazolone ring structure is formed between the fluoroisobutyryl fluoride derivative represented by the general formula (2) and the compound of the general formula (6), and -CF3 derived from the fluoroisobutyryl fluoride derivative and -X derived from the compound of the general formula (5) are substituted. 1 They are located at the 4-position and 5-position of the pyrazolone ring structure, respectively.

[0113] The reaction temperature during the reaction (b) is preferably -20°C or higher and lower than the boiling point of the organic solvent, more preferably 0 to 50°C, and even more preferably 10 to 30°C. The reaction time during the reaction (b) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours. In the reaction (b), the same hydrogen halide scavenger and solvent as those for the reaction (a) can be used.

[0114] Another embodiment of the method for producing a fluorine-containing pyrazolone compound includes the following steps:

[0115] (c) A fluorine-containing pyrazolone compound represented by the following general formula (1a) is obtained by reacting a fluoroisobutylene derivative represented by the following general formula (3) with a compound represented by the following general formula (6) or a salt thereof.

[0116] [Chemical Formula 13]

[0117]

[0118] In the above general formulae (1a), (3) and (6), Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or, Y and Z are bonded to form a ring, A 1 represents an organic group having 1 to 12 carbon atoms, and R represents a hydrocarbon group having 1 to 12 carbon atoms.

[0119] As A 1 , can be set to the same as the above A 1 Same group.

[0120] As R, we can cite A 1 A hydrocarbon group having 1 to 10 carbon atoms. More specifically, R includes chain hydrocarbon groups, aromatic hydrocarbon groups, and alicyclic hydrocarbon groups having 1 to 10 carbon atoms. Examples of chain hydrocarbon groups include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl; alkenyl groups such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl; and alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. Examples of aromatic hydrocarbon groups include phenyl. Examples of alicyclic hydrocarbon groups include saturated or unsaturated cyclic hydrocarbon groups. Examples of cyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and adamantyl. Preferably, R is an alkyl group having 1 to 10 carbon atoms. When R is an alkyl group having 1 to 10 carbon atoms, the raw material of the fluorine-containing pyrazolone compound can be easily produced.

[0121] Examples of the salt of the compound represented by the general formula (6) include hydrochloride, trifluoroacetate, and p-toluenesulfonate of the compound represented by the general formula (6).

[0122] The step (c) of obtaining a fluorinated pyrazolone compound is preferably carried out in the presence of a nucleophilic reagent. Examples of the nucleophilic reagent include 1-methylimidazole, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, and triphenylphosphine. By using a nucleophilic reagent, the substituent -R can be effectively separated from the fluorinated isobutylene derivative represented by the general formula (3), thereby promoting the formation of the fluorinated pyrazolone compound represented by the general formula (1a). The step (c) of obtaining a fluorinated pyrazolone compound is preferably carried out in the presence of a fluoride ion scavenger. It is preferred that the fluorinated isobutylene derivative represented by the general formula (3) is reacted with the compound represented by the general formula (6) 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 catching fluoride ions, and examples thereof include the same fluoride ion scavenger as used in the above step (a). It is believed that the cations derived from the fluoride ion scavenger capture the fluoride ions released from the fluoroisobutylene derivative represented by the general formula (3) during the reaction and precipitate them as salts with low solubility in organic solvents, thereby promoting the reaction and enabling the fluorine-containing pyrazolone compound represented by the general formula (1a) to be obtained in high yield.

[0123] The reaction (c) of the fluoroisobutylene derivative represented by the general formula (3) and the compound represented by the general formula (6) in the presence of 1-methylimidazole as a nucleophilic reagent is represented by the following reaction formula (C).

[0124] [Chemical Formula 14]

[0125]

[0126] In other embodiments of the method for producing a fluorinated pyrazolone compound, the reaction (c) can be performed in a single step. Thus, the fluorinated pyrazolone compound of the general formula (1a) can be easily obtained. Furthermore, in the reaction (c), a cyclic pyrazolone ring structure is formed between the fluoroisobutylene derivative of the general formula (3) and the two nitrogen atoms of the compound of the general formula (6), and -CF3 and -F derived from the fluoroisobutylene derivative are located at positions 4 and 5, respectively, of the pyrazolone ring structure.

[0127] The reaction temperature in the reaction (c) is preferably -20°C or higher and lower than the boiling point of the organic solvent, more preferably 0 to 50°C, and even more preferably 10 to 30°C. The reaction time in the reaction (c) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours. In the reaction (c), the same hydrogen halide scavenger and solvent as in the reaction (a) can be used.

[0128] Another embodiment of the method for producing a fluorine-containing pyrazolone compound includes the following steps:

[0129] (d) A fluorine-containing pyrazolone compound represented by the following general formula (1b) is obtained by reacting a fluoroisobutylene derivative represented by the following general formula (3) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof.

[0130] [Chemical Formula 15]

[0131]

[0132] In the above general formulas (1b), (3), (5) and (6), X 1 represents a halogen atom other than a fluorine atom, -OA 1 、-S(O l )A 1 (l is an integer from 0 to 2), -O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 , Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or, Y and Z are bonded to form a ring, A 1 、A 2、A 3 and A 4 Each independently represents an organic group having 1 to 12 carbon atoms, and R represents a hydrocarbon group having 1 to 12 carbon atoms.

[0133] A 1 、A 2 、A 3 and A 4 Can be the same as above A 1 、A 2 、A 3 and A 4 Same group.

[0134] As R, we can cite A 1 、A 2 and A 3 A hydrocarbon group having 1 to 10 carbon atoms. More specifically, R includes chain hydrocarbon groups, aromatic hydrocarbon groups, and alicyclic hydrocarbon groups having 1 to 10 carbon atoms. Examples of chain hydrocarbon groups include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl; alkenyl groups such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl; and alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. Examples of aromatic hydrocarbon groups include phenyl. Examples of alicyclic hydrocarbon groups include saturated or unsaturated cyclic hydrocarbon groups. Examples of cyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and adamantyl. Preferably, R is an alkyl group having 1 to 10 carbon atoms. When R is an alkyl group having 1 to 10 carbon atoms, the raw material of the fluorine-containing pyrazolone compound can be easily produced.

[0135] Examples of the salt of the compound represented by the general formula (6) include hydrochloride, trifluoroacetate, and p-toluenesulfonate of the compound represented by the general formula (6).

[0136] The step (d) of obtaining a fluorinated pyrazolone compound is preferably carried out in the presence of a nucleophilic reagent. Examples of the nucleophilic reagent include 1-methylimidazole, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, and triphenylphosphine. By using a nucleophilic reagent, the substituent -R can be effectively removed from the fluorinated isobutylene derivative represented by the general formula (3), thereby promoting the formation of the fluorinated pyrazolone compound represented by the general formula (1b). Preferably, the step (d) of obtaining a fluorinated pyrazolone compound is preferably carried out in the presence of a fluoride ion scavenger. It is preferred that the fluorinated isobutylene derivative represented by the general formula (3) is reacted with the compound represented by the general formula (5) and the compound represented by the general formula (6) or a salt thereof in the presence of a fluoride ion scavenger. The fluorinated ion scavenger is not particularly limited as long as it is a substance having the function of scavenging fluorinated ions, and examples thereof include the same fluorinated ion scavengers as those used in the step (a). It is believed that the cations derived from the fluoride ion scavenger capture the fluoride ions released from the fluoroisobutylene derivative represented by the general formula (3) during the reaction and precipitate them as salts with low solubility in organic solvents, thereby promoting the reaction and enabling the fluorine-containing pyrazolone compound represented by the general formula (1b) to be obtained in high yield.

[0137] The reaction (d) of the fluoroisobutylene derivative represented by the general formula (3) with the compounds represented by the general formulae (5) and (6) in the presence of 1-methylimidazole as a nucleophile is represented by the following reaction formula (D).

[0138] [Chemical Formula 16]

[0139]

[0140] In the method for producing a fluorinated pyrazolone compound according to another embodiment, the reaction of (D) can be carried out in one stage. Therefore, the fluorinated pyrazolone compound of the general formula (1b) can be easily obtained. In addition, in the reaction of (d), a cyclic pyrazolone ring structure is formed between the fluoroisobutylene derivative of the general formula (3) and the two nitrogen atoms of the compound of the general formula (6), and -CF3 derived from the fluorinated pyrazolone derivative and -X derived from the compound of the general formula (5) are substituted. 1 They are located at the 4-position and 5-position of the pyrazolone ring structure, respectively.

[0141] The reaction temperature in the reaction (d) is preferably -20°C or higher and lower than the boiling point of the organic solvent, more preferably 0°C to 50°C, and even more preferably 10°C to 30°C. The reaction time in the reaction (d) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours. In the reaction (d), the same hydrogen halide scavenger and solvent as in the reaction (a) can be used.

[0142] Another embodiment of the method for producing a fluorine-containing pyrazolone compound includes the following steps:

[0143] (e) A fluorine-containing pyrazolone compound represented by the following general formula (1a) is obtained by reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (6) or a salt thereof.

[0144] [Chemical Formula 17]

[0145]

[0146] In the above general formulae (1a), (4) and (6), Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or, Y and Z bond to form a ring, R represents a hydrocarbon group having 1 to 12 carbon atoms, V represents a halogen atom, -OA 5 or -SO m A 5 (m is an integer from 0 to 2), A 1 and A 5 Each independently represents an organic group having 1 to 12 carbon atoms.

[0147] As A 1 and R, can be set to the same as above A 1 The same group as R.

[0148] V is preferably a halogen atom, more preferably a fluorine atom. 5 , methyl, phenyl and trifluoromethyl can be mentioned.

[0149] Examples of the salt of the compound represented by the general formula (6) include hydrochloride, trifluoroacetate, and p-toluenesulfonate of the compound represented by the general formula (6).

[0150] The step (e) of obtaining a fluorinated pyrazolone compound is preferably carried out in the presence of a nucleophilic reagent. Examples of the nucleophilic reagent include 1-methylimidazole, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, and triphenylphosphine. By using a nucleophilic reagent, the substituent -R can be effectively separated from the fluorinated isobutane derivative represented by the general formula (4), thereby promoting the formation of the fluorinated pyrazolone compound represented by the general formula (1a). Preferably, the step (e) of obtaining a fluorinated pyrazolone compound is preferably carried out in the presence of a fluoride ion scavenger. It is preferred that the fluorinated isobutane derivative represented by the general formula (4) and the compound represented by the general formula (6) or a salt thereof are reacted in the presence of a fluoride ion scavenger. The fluorinated ion scavenger is not particularly limited as long as it is a substance having the function of catching fluorinated ions, and examples thereof include the same fluorinated ion scavenger as used in the above step (a). It is believed that the cations derived from the fluoride ion scavenger capture the fluoride ions released from the fluoroisobutane derivative represented by the general formula (4) during the reaction and precipitate them as salts with low solubility in organic solvents, thereby promoting the reaction and enabling the fluorine-containing pyrazolone compound represented by the general formula (1a) to be obtained in high yield.

[0151] The reaction of the fluoroisobutane derivative represented by the general formula (4) with the compound represented by the general formula (6) in the above step (e) is represented by the following reaction formula (E).

[0152] [Chemical Formula 18]

[0153]

[0154] In other embodiments of the method for producing a fluorinated pyrazolone compound, the reaction (E) can be performed in a single step. Thus, the fluorinated pyrazolone compound of the general formula (1a) can be easily obtained. Furthermore, in the reaction (e), a cyclic pyrazolone ring structure is formed between the fluoroisobutane derivative of the general formula (4) and the two nitrogen atoms derived from the compound of the general formula (6), and -CF3 and -F derived from the fluoroisobutane derivative are located at positions 4 and 5, respectively, of the pyrazolone ring structure.

[0155] The reaction temperature in the reaction (e) is preferably -20°C or higher and lower than the boiling point of the organic solvent, more preferably 0 to 50°C, and even more preferably 10 to 30°C. The reaction time in the reaction (e) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours. In the reaction (e), the same hydrogen halide scavenger and solvent as in the reaction (a) can be used.

[0156] Another embodiment of the method for producing a fluorine-containing pyrazolone compound includes the following steps:

[0157] (f) A fluorine-containing pyrazolone compound represented by the following general formula (1b) is obtained by reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof.

[0158] [Chemical Formula 19]

[0159]

[0160] In the above general formulas (1b) and (4) to (6), X 1 represents a halogen atom other than a fluorine atom, -OA 1 、-S(O l )A 1 (l is an integer from 0 to 2), -O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 , Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or, Y and Z bond to form a ring, R represents a hydrocarbon group having 1 to 12 carbon atoms, V represents a halogen atom, -OA 5 or -SO m A 5 (m is an integer from 0 to 2), A 1 、A 2 、A 3 、A 4 and A 5 Each independently represents an organic group having 1 to 12 carbon atoms.

[0161] A 1 、A 2 、A 3 、A 4 and R can be the same as above A 1 、A 2 、A 3 、A 4 The same group as R.

[0162] V is preferably a halogen atom, more preferably a fluorine atom. 5 , methyl, phenyl and trifluoromethyl can be mentioned.

[0163] Examples of the salt of the compound represented by the general formula (6) include hydrochloride, trifluoroacetate, and p-toluenesulfonate of the compound represented by the general formula (6).

[0164] The step (f) of obtaining a fluorine-containing pyrazolone compound is preferably carried out in the presence of a nucleophilic reagent. Examples of the nucleophilic reagent include 1-methylimidazole, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, and triphenylphosphine. By using a nucleophilic reagent, the substituent -R can be effectively removed from the fluorine-containing pyrazolone compound represented by the general formula (4), thereby promoting the formation of the fluorine-containing pyrazolone compound represented by the general formula (1b). Preferably, the step (f) of obtaining a fluorine-containing pyrazolone compound is preferably carried out in the presence of a fluoride ion scavenger. It is preferred that the fluorine-containing pyrazolone derivative represented by the general formula (4) is reacted with the compound represented by the general formula (5) and the compound represented by the general formula (6) or a salt thereof in the presence of a fluoride ion scavenger. The fluorine ion scavenger is not particularly limited as long as it is a substance having the function of scavenging fluorine ions, and examples thereof include the same fluorine ion scavenger as used in the above step (a). It is believed that the cations derived from the fluoride ion scavenger capture the fluoride ions released from the fluoroisobutane derivative represented by the general formula (4) during the reaction and precipitate them as salts with low solubility in organic solvents, thereby promoting the reaction and enabling the fluorine-containing pyrazolone compound represented by the general formula (1b) to be obtained in high yield.

[0165] The reaction of the fluoroisobutane derivative represented by the general formula (4) with the compounds represented by the general formulas (5) and (6) in the above-mentioned reaction (f) is represented by the following reaction formula (F).

[0166] [Chemical Formula 20]

[0167]

[0168] In the method for producing a fluorinated pyrazolone compound according to another embodiment, the reaction of (F) can be carried out in one stage. Therefore, the fluorinated pyrazolone compound of the general formula (1b) can be easily obtained. In addition, in the reaction of (f), a cyclic pyrazolone ring structure is formed between the fluoroisobutane derivative of the general formula (4) and the two nitrogen atoms of the compound of the general formula (6), and -CF3 derived from the fluoroisobutane derivative and -X derived from the compound of the general formula (5) are substituted. 1 They are located at the 4-position and 5-position of the pyrazolone ring structure, respectively.

[0169] The reaction temperature in the reaction (f) is preferably -20°C or higher and lower than the boiling point of the organic solvent, more preferably 0 to 50°C, and even more preferably 10 to 30°C. The reaction time in the reaction (f) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours. In the reaction (f), the same hydrogen halide scavenger and solvent as in the reaction (a) can be used.

[0170] While the embodiments of the present invention have been described above, the present invention is not limited to the above embodiments, but includes the concept of the present invention and all aspects encompassed by the claims, and various modifications are possible within the scope of the present invention.

[0171] Example

[0172] 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.

[0173] (Example 1)

[0174] Preparation of tert-butyl 5-fluoro-2-isopropyl-3-oxo-4-(trifluoromethyl)-1H-pyrazole-carboxylate

[0175] Under ice-cooling, a solution 1 was prepared by adding 0.70 g (4.0 mmol) of tert-butyl 3-(isopropyl)hydrazinecarboxylate to 30 g of THF. A solution 2 was prepared by dissolving 1.3 g (4.0 mmol) of a salt formed from 3,3,3-trifluoro-2-(trifluoromethyl)propanoyl fluoride anion and 1-methyl-4-dimethylaminopyridinium cation in 30 g of THF. This solution 2 was then added dropwise to solution 1 so that the internal temperature did not exceed 10°C, and the mixture was warmed to room temperature. After approximately 16 hours, the resulting reaction mixture was added dropwise to a mixed solution of 1.0 g (8.0 mmol) of DIPEA and 30 g of THF under ice-cooling so that the internal temperature did not exceed 10°C, and the mixture was warmed to room temperature. After approximately 16 hours, the contents were purified on a silica gel column using a hexane-ethyl acetate = 7:3 mixed solvent to produce tert-butyl 5-fluoro-2-isopropyl-3-oxo-4-(trifluoromethyl)-1H-pyrazole-1-carboxylate represented by the following formula (G). The yield of the compound of the following formula (G) obtained was 0.1 g, and the isolated yield was 9%. In addition, in this example, the salt formed by the 3,3,3-trifluoro-2-(trifluoromethyl)propanoyl fluoride anion and the 1-methyl-4-dimethylaminopyridinium cation and tert-butyl 3-(isopropyl)hydrazinecarboxylate correspond to the fluoroisobutanoyl fluoride derivative of the general formula (2) and the compound of the general formula (6), respectively.

[0176] [Chemical Formula 21]

[0177]

[0178] The analysis results of the obtained target products are as follows.

[0179] Mass spectrum (APCI, m / z): 312 ([M] + ).

[0180] (Example 2)

[0181] Preparation of N-((1-acetyl-5-oxo-2-phenyl-4-trifluoromethyl-1H-pyrazol-3-yl)oxy)-N-methylfuran-2-carboxamide

[0182] Under ice-cooling, dissolve 10 g (43 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethyl-propane in 80 g of THF to obtain a solution. Next, add 6 g (43 mmol) of diisopropylethylamine dropwise to this solution, keeping the internal temperature at 10°C or lower, and warm it to room temperature. After approximately one hour, add the resulting reaction mixture 1 dropwise to a mixed solution of 4.8 g (43 mmol) of quinuclidine and 20 g of THF, also under ice-cooling, keeping the internal temperature at 10°C or lower, and warm it to room temperature. After approximately one hour, add the resulting reaction mixture 2 dropwise to a mixed solution of 5 g (43 mmol) of diethylene glycol monomethyl ether and 20 g of THF, also under ice-cooling, keeping the internal temperature at 10°C or lower, and warm it to room temperature. After approximately 4 hours, the resulting reaction mixture 3 was added dropwise to an ice-cooled mixed solution of 6 g (43 mmol) of N-methylfluorohydroxamic acid, 11 g (86 mmol) of diisopropylethylamine, and 20 g of THF, at an internal temperature not exceeding 10°C, and the mixture was warmed to room temperature. After approximately 16 hours, the resulting reaction mixture 4 was added dropwise to an ice-cooled mixed solution of 7 g (43 mmol) of 1-acetyl-2-phenylhydrazine, 6 g (43 mmol) of diisopropylethylamine, and 20 g of THF, at an internal temperature not exceeding 10°C, and the mixture was warmed to room temperature. After approximately 72 hours, 50 ml of diethyl ether and 50 ml of saturated brine were added to the reaction mixture 5 obtained. The organic phase was dried over sodium sulfate, and the diethyl ether was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate and purified on a silica gel column using a mixed solvent of hexane and ethyl acetate = 7:3 to produce N-((1-acetyl-5-oxo-2-phenyl-4-trifluoromethyl-1H-pyrazol-3-yl)oxy)-N-methylfuran-2-carboxamide represented by the following formula (H). The yield of the compound of the following formula (H) obtained was 0.5 g (isolated yield 3%). In addition, in this example, 1,1,1,3,3-pentafluoro-3-methoxy-trifluoromethyl-propane, N-methylfluorohydroxamic acid, and 1-acetyl-2-phenylhydrazine correspond to the fluoroisobutane derivative of general formula (4), the compound of general formula (5), and the compound of general formula (6), respectively.

[0183] [Chemical Formula 22]

[0184]

[0185] The analysis results of the obtained target products are as follows.

[0186] Mass spectrum (APCI, m / z): 409 ([M] + ).

[0187] (Example 3)

[0188] Preparation of 3-(bis(3-methoxypropyl)amino)-2-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazin-1-one

[0189] To an ice-cooled mixed solution of 3.0 g (30 mmol) of triethylamine and 20 g of THF, 6.4 g (30 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene was added dropwise at an internal temperature of no more than 10°C, and the mixture was warmed to room temperature. After approximately 1 hour, the resulting reaction mixture 1 was added dropwise to an ice-cooled mixed solution of 3.1 g (30 mmol) of 1-hexanol and 20 g of THF, and the mixture was warmed to room temperature. After approximately 4 hours, the resulting reaction mixture 2 was added dropwise to an ice-cooled mixed solution of 4.8 g (30 mmol) of bis(3-methoxypropyl)amine, 6.0 g (60 mmol) of triethylamine, and 20 g of THF, and the mixture was warmed to room temperature, while the internal temperature did not exceed 10°C. Approximately 6 hours later, the resulting reaction mixture 3 was added dropwise to an ice-cooled mixed solution of 4.8 g (30 mmol) of hexahydropyridazine dihydrochloride, 9.0 g (90 mmol) of diisopropylethylamine, and 20 g of methanol, with the internal temperature not exceeding 10°C. The mixture was then warmed to room temperature. Approximately 36 hours later, 50 ml of diethyl ether and 50 ml of saturated brine were added to the resulting reaction mixture 4. The organic phase was dried over sodium sulfate, and the diethyl ether was removed under reduced pressure. The residue was dissolved in ethyl acetate and purified on a silica gel column using a 7:3 hexane / ethyl acetate mixture to produce 3-(bis(3-methoxypropyl)amino)-2-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazin-1-one represented by the following formula (I). The yield of the compound of formula (I) obtained was 0.5 g (isolated yield 5%). In addition, in this embodiment, 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene, bis(3-methoxypropyl)amine and hexahydropyridazine dihydrochloride correspond to the salts of the fluoroisobutylene derivative of general formula (3), the compound of general formula (5) and the compound of general formula (6), respectively.

[0190] [Chemical Formula 23]

[0191]

[0192] The analysis results of the obtained target products are as follows.

[0193] Mass spectrum (APCI, m / z): 365 ([M] + ).

[0194] (Example 4)

[0195] Preparation of 2-(1,7-dioxo-2-(trifluoromethyl)-6,7-dihydro-pyrazolo[1,2-a]pyrazolo-3-yl)-1,1,3,3-tetramethylguanidine

[0196] To a mixed solution of 0.9 g (8.7 mmol) of triethylamine and 31 ml of THF under ice-water cooling, 2.0 g (8.7 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene was added dropwise at an internal temperature not exceeding 10°C, and the mixture was warmed to room temperature. After approximately 1 hour, the resulting reaction mixture 1 was added dropwise to a mixed solution of 0.9 g (8.7 mmol) of 1-hexanol and 2 ml of THF under ice-water cooling at an internal temperature not exceeding 10°C, and the mixture was warmed to room temperature. After approximately 4 hours, the resulting reaction mixture 2 was added dropwise to a mixed solution of 0.5 g (8.7 mmol) of 1,1,3,3-tetramethylguanidine and 0.9 g (8.7 mmol) of triethylamine under ice-water cooling at an internal temperature not exceeding 10°C, and the mixture was warmed to room temperature. After approximately 19 hours, the resulting reaction mixture 3 was cooled with ice water, 1.1 g (8.7 mmol) of 3-pyrazolone hydrochloride and 1.8 g (17.5 mmol) of triethylamine were added, and the mixture was warmed to room temperature. After approximately 71 hours, the resulting reaction mixture 4 was purified on a silica gel column to produce a trace amount of 2-(1,7-dioxo-2-(trifluoromethyl)-6,7-dihydro-pyrazolo[1,2-a]pyrazolo-3-yl)-1,1,3,3-tetramethylguanidine represented by the following formula (J). In this example, 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene, 1,1,3,3-tetramethylguanidine, and 3-pyrazolone hydrochloride correspond to the fluoroisobutylene derivative of general formula (3), the compound of general formula (5), and the compound of general formula (6), respectively.

[0197] [Chemical Formula 24]

[0198]

[0199] The analysis results of the obtained target products are as follows.

[0200] Mass spectrum (APCI, m / z): 319.3 ([M] + ).

[0201] (Example 5)

[0202] Preparation of tert-butyl 2-benzyl-5-(benzyl(propyl)amino)-3-oxo-4-(trifluoromethyl)-pyrazole-1-carboxylate

[0203] Under ice-cooling, prepare Solution 1 by adding 0.5 g (2.1 mmol) of tert-butyl-2-benzylhydrazinecarboxylate to 20 g of THF. Prepare Solution 2 by dissolving 0.6 g (2.1 mmol) of a salt of 3,3,3-trifluoro-2-(trifluoromethyl)propanoyl fluoride anion and 1,3-dimethylimidazolium cation in 20 g of THF. Then, add Solution 2 dropwise to Solution 1 so that the internal temperature does not exceed 10°C, and warm to room temperature. After approximately 16 hours, add the resulting reaction mixture 1 dropwise to a mixed solution of 0.5 g (4.2 mmol) of diisopropylethylamine and 20 g of THF under ice-cooling so that the internal temperature does not exceed 10°C, and warm to room temperature. After approximately 47 hours, 0.3 g (2.1 mmol) of N-benzylpropane-1-amine and 0.3 g (2.1 mmol) of diisopropylethylamine were added dropwise to the reaction mixture 2 obtained at room temperature, and the temperature was raised to 60°C. After approximately 16 hours, the reaction mixture 3 obtained was purified by silica gel column to prepare a trace amount of tert-butyl 2-benzyl-5-(benzyl(propyl)amino)-3-oxo-4-(trifluoromethyl)-pyrazole-1-carboxylate represented by the following formula (K). In addition, in this example, the salt formed by the 3,3,3-trifluoro-2-(trifluoromethyl)propanoyl fluoride anion and the 1,3-dimethylimidazolium cation, N-benzylpropane-1-amine, and tert-butyl-2-benzylhydrazinecarboxylate correspond to the fluoroisobutyryl fluoride derivative of general formula (2), the compound of general formula (5), and the compound of general formula (6), respectively.

[0204] [Chemical Formula 25]

[0205]

[0206] The analysis results of the obtained target products are as follows.

[0207] Mass spectrum (APCI, m / z): 489.7 ([M] + ).

[0208] (Example 6)

[0209] Preparation of 1,2-diethyl-5-(methyl(pyridin-2-ylmethyl)amino)-4-(trifluoromethyl)-pyrazol-3-one

[0210] To an ice-cooled mixed solution of 0.8 g (8.2 mmol) of triethylamine and 29 ml of THF, 1.9 g (8.2 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene was added dropwise at an internal temperature not exceeding 10°C, and the mixture was warmed to room temperature. After approximately 1 hour, the resulting reaction mixture 1 was added dropwise to an ice-cooled mixed solution of 0.8 g (8.2 mmol) of 1-hexanol and 2 ml of THF, and the mixture was warmed to room temperature. After approximately 4 hours, 0.3 g (8.2 mmol) of 3-(methylaminomethyl)pyridine and 0.8 g (8.2 mmol) of triethylamine were added dropwise at an internal temperature not exceeding 10°C, and the mixture was warmed to room temperature. After approximately 17 hours, the resulting reaction mixture 3 was ice-cooled, 1.3 g (8.2 mmol) of 1,2-diethylhydrazine dihydrochloride and 2.5 g (24.5 mmol) of triethylamine were added, and the temperature was raised to 50°C. After approximately 76 hours, the resulting reaction mixture 4 was purified on a silica gel column to produce a trace amount of 1,2-diethyl-5-(methyl(pyridin-2-ylmethyl)amino)-4-(trifluoromethyl)-pyrazol-3-one represented by the following formula (L). Furthermore, in this example, 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene, 3-(methylaminomethyl)pyridine, and 1,2-diethylhydrazine dihydrochloride correspond to salts of the fluoroisobutylene derivative of general formula (3), the compound of general formula (5), and the compound of general formula (6), respectively.

[0211] [Chemical Formula 26]

[0212]

[0213] The analysis results of the obtained target products are as follows.

[0214] Mass spectrum (APCI, m / z): 382.3 ([M] + ).

[0215] (Example 7)

[0216] Preparation of 2-acetyl-5-(2-ethoxyethoxy)-phenyl-4-(trifluoromethyl)-pyrazol-3-one

[0217] Under ice-cooling, dissolve 10 g (43 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethyl-propane in 80 g of THF to obtain a solution. Next, add 6 g (43 mmol) of diisopropylethylamine dropwise to this solution, keeping the internal temperature at 10°C or below, and warm it to room temperature. After approximately one hour, add the resulting reaction mixture 1 dropwise to an ice-cooled mixed solution of 4.8 g (43 mmol) of quinuclidine and 20 g of THF, keeping the internal temperature at 10°C or below, and warm it to room temperature. After approximately one hour, add the resulting reaction mixture 2 dropwise to an ice-cooled mixed solution of 8 g (86 mmol) of 2-ethoxyethanol and 20 g of THF, keeping the internal temperature at 10°C or below, and warm it to room temperature. After approximately 30 minutes, add 11 g (86 mmol) of diisopropylethylamine dropwise to the resulting reaction mixture 3, at room temperature, and warm it to 60°C. Approximately 16 hours later, the resulting reaction mixture 4 was added dropwise to a room temperature mixed solution of 7 g (43 mmol) of 1-acetyl-2-phenylhydrazine, 6 g (43 mmol) of diisopropylethylamine, and 20 g of THF, and the temperature was raised to 60°C. Approximately 72 hours later, 50 ml of diethyl ether and 50 ml of saturated brine were added to the resulting reaction mixture 5. The organic phase was dried over sodium sulfate, and the ether was removed under reduced pressure. The residue was dissolved in ethyl acetate and purified on a silica gel column using a 7:3 hexane / ethyl acetate mixture to produce 2-acetyl-5-(2-ethoxyethoxy)-phenyl-4-(trifluoromethyl)-pyrazol-one represented by the following formula (M). The yield of the compound of formula (M) obtained was 0.3 g (isolated yield 2%). In addition, in this embodiment, 1,1,1,3,3-pentafluoro-3-methoxy-trifluoromethyl-propane, 2-ethoxyethanol and 1-acetyl-2-phenylhydrazine correspond to the fluoroisobutane derivative of general formula (4), the compound of general formula (5) and the compound of general formula (6), respectively.

[0218] [Chemical Formula 27]

[0219]

[0220] The analytical results of the obtained target product are as follows. Mass spectrum (APCI, m / z): 358.3 ([M] + ).

Claims

1. A fluorine-containing pyrazolone compound represented by the following general formula (1), wherein: [Chemical Formula 1] In the above general formula (1), X represents a halogen atom, -OA 1 、-S(O l )A 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 , where l is an integer from 0 to 2, Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring, A 1 、A 2 、A 3 and A 4 Each independently represents an organic group having 1 to 12 carbon atoms.

2. A method for producing a fluorine-containing pyrazolone compound, comprising the following steps: The fluorine-containing pyrazolone compound represented by the following general formula (1a) is obtained by reacting a fluoroisobutyryl fluoride derivative represented by the following general formula (2) with a compound represented by the following general formula (6) or a salt thereof. [Chemical Formula 2] In the above general formulae (1a), (2) and (6), Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring, A 1 represents an organic group having 1 to 12 carbon atoms, W + represents an ammonium cation, an imidazolium cation, a pyridinium cation or a phosphonium cation.

3. A method for producing a fluorine-containing pyrazolone compound, comprising the following steps: A fluorine-containing pyrazolone compound represented by the following general formula (1b) is obtained by reacting a fluoroisobutyryl fluoride derivative represented by the following general formula (2) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof. [Chemical Formula 3] In the above general formulas (1b), (2), (5) and (6), X 1 represents a halogen atom other than a fluorine atom, -OA 1 、-S(O l )A 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 ,in, l is an integer from 0 to 2, Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring, A 1 、A 2 、A 3 and A 4 each independently represents an organic group having 1 to 12 carbon atoms, W + represents an ammonium cation, an imidazolium cation, a pyridinium cation or a phosphonium cation.

4. A method for producing a fluorine-containing pyrazolone compound, comprising the following steps: The fluorine-containing pyrazolone compound represented by the following general formula (1a) is obtained by reacting a fluoroisobutylene derivative represented by the following general formula (3) with a compound represented by the following general formula (6) or a salt thereof. [Chemical Formula 4] In the above general formulae (1a), (3) and (6), Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring, A 1 represents an organic group having 1 to 12 carbon atoms, R represents a hydrocarbon group having 1 to 12 carbon atoms.

5. A method for producing a fluorine-containing pyrazolone compound, comprising the following steps: A fluorine-containing pyrazolone compound represented by the following general formula (1b) is obtained by reacting a fluoroisobutylene derivative represented by the following general formula (3) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof. [Chemical Formula 5] In the above general formulas (1b), (3), (5) and (6), X 1 represents a halogen atom other than a fluorine atom, -OA 1 、-S(O l )A 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 ,in, l is an integer from 0 to 2, Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring, A 1 、A 2 、A 3 and A 4 each independently represents an organic group having 1 to 12 carbon atoms, R represents a hydrocarbon group having 1 to 12 carbon atoms.

6. A method for producing a fluorine-containing pyrazolone compound, comprising the following steps: By reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (6) or a salt thereof, a fluorine-containing pyrazolone compound represented by the following general formula (1a) is obtained. [Chemical Formula 6] In the above general formulae (1a), (4) and (6), Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring, R represents a hydrocarbon group having 1 to 12 carbon atoms, V represents a halogen atom, -OA 5 or -SO m A 5 ,in, m is an integer from 0 to 2, A 1 and A 5 Each independently represents an organic group having 1 to 12 carbon atoms.

7. A method for producing a fluorine-containing pyrazolone compound, comprising the following steps: A fluorine-containing pyrazolone compound represented by the following general formula (1b) is obtained by reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof. [Chemical Formula 7] In the above general formulas (1b) and (4) to (6), X 1 represents a halogen atom other than a fluorine atom, -OA 1 、-S(O l )A 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 3 -NA 1 A 2 or -N=A 4 ,in, l is an integer from 0 to 2, Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 、-COOA 1 , benzyl or carbamoyl, or Y and Z are bonded to form a ring, R represents a hydrocarbon group having 1 to 12 carbon atoms, V represents a halogen atom, -OA 5 or -SO m A 5 , where m is an integer from 0 to 2, A 1 、A 2 、A 3 、A 4 and A 5 Each independently represents an organic group having 1 to 12 carbon atoms.

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