Fluorine-containing isoxazole compound and method for producing same

Abstract

The present invention relates to a fluorine-containing isoxazole compound represented by general formula (A). In general formula (A), R represents a hydrogen atom, or a substituted or unsubstituted hydrocarbon group having 1-12 carbon atoms, X represents a halogen atom,-OA1,-O-NA1A2,-NA1A2,-NA1 (OA2),-NA3-NA1A2,-NA4, or a heterocyclic ring, A1, A2, and A3 each independently represent a substituted or unsubstituted hydrocarbon group or heterocyclic ring having 1-12 carbon atoms, A4 represents an alkylene group represented by = CnH2n, n is an integer of 1-20, and Y1 and Y2 each independently represent N or O and are different from each other. # imgabs0 #

Description

Technical Field

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

[0002] Compounds having an isoxazole ring and an isoxazolone ring as its tautomer are known to have various pharmacological effects. Specifically, as examples of natural products, ibotenic acid and muscimol can be cited. In addition, as examples of pharmaceuticals, as β-lactam antibiotics, oxacillin and floxacillin can be cited, as sulfonamide antibiotics, sulfafurazole and sulfamethoxazole can be cited, as oxazolidinone antibiotics, posizolid can be cited, as antirheumatic drugs, leflunomide and valdecoxib can be cited, as liver disease therapeutic agents, tropifexor can be cited, as anticancer agents, tivozanib can be cited, as antiviral drugs, pleconaril can be cited, as antidepressants, isocarboxazid can be cited, as diabetes therapeutic agents, glisoxepide can be cited, as endometriosis therapeutic agents, danazol and the like can be cited. Furthermore, as examples of pesticides, isoxathion as an insecticide and isoxaben as a herbicide can be cited.

[0003] Against the background of such a wide range of pharmacological effects of isoxazoles, in recent years, interest has been shown in the introduction of heteroatom substituents (substituents having a heteroatom) at the 3-position and / or 5-position. Specifically, in Non-Patent Document 1, it was reported that a compound having an isoxazole ring substituted with a methoxy group at the 3-position and a 1-tetrazolyl group at the 5-position was studied as a therapeutic agent for Alzheimer's disease because it has cholinesterase inhibitory activity.

[0004] In addition, interest has also been shown in the pharmacological effects of compounds having a trifluoromethyl group at the 4-position of the isoxazole ring. Specifically, it was reported in Non-Patent Document 2 that such a compound has agonist activity for the sphingosine-1-phosphate receptor S1P1 and was therefore studied as a therapeutic agent for autoimmune diseases.

[0005] From such a perspective, expecting the usefulness as a therapeutic agent for each disease, it is desired to develop a fluorinated isoxazole compound having a heteroatom substituent not only at the 3-position and / or 5-position of the isoxazole ring but also at the 4-position of the isoxazole ring.

[0006] Prior art documents

[0007] Non-patent documents

[0008] Non-patent document 1: "New Journal Of Chemistry", 2015, Vol. 39, pp. 2028 - 2041;

[0009] Non-patent document 2: "Bioorganic&Medicinal ChemistryLetters", 2016, Vol. 26, pp. 2470 - 2474. Summary of the invention

[0010] Problems to be solved by the invention

[0011] Therefore, the present inventors have found that by reacting specific raw materials, a structure having a trifluoromethyl group at the 4-position of the isoxazole ring and a heteroatom substituent at the 3-position and / or 5-position can be constructed, thereby completing the present invention.

[0012] The present invention provides a novel fluorinated isoxazole compound having a trifluoromethyl group at the 4-position of the isoxazolone ring and a heteroatom substituent at the 3-position and / or 5-position, and a manufacturing method capable of easily manufacturing the fluorinated isoxazole compound.

[0013] Means for solving the problems

[0014] The fluorinated isoxazole compound according to this embodiment is represented by the following general formula (A).

[0015] [Chemical formula 1]

[0016]

[0017] In the above general formula (A), R represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 , -NA 1 A 2 , -NA 4 or a heterocyclic ring, A1 and A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, and A 4 represents an alkylene group represented by =C n H 2n as shown, n is an integer of 1 to 20, and Y 1 and Y 2 each independently represents N or O and are different from each other.

[0018] The method for producing a fluorinated isoxazole compound according to this embodiment includes the following steps:

[0019] (I) React a fluorinated compound selected from fluorinated carbonyl compounds, fluoroisobutene derivatives, and fluoroisobutane derivatives, hydroxylamine or a salt thereof, and an optional compound represented by the following general formula (5) or a salt thereof; or

[0020] (II) React a fluorinated compound selected from fluorinated carbonyl compounds, fluoroisobutene derivatives, and fluoroisobutane derivatives, an amine salt or an amine compound, and an optional compound represented by the following general formula (5) or a salt thereof, thereby synthesizing a fluorinated isoxazole compound represented by the following general formula (A).

[0021] [Chemical formula 2]

[0022]

[0023] In the above general formulas (A) and (5), R represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, and A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, and A 4 represents an alkylene group represented by =C n H 2n as shown, n is an integer of 1 to 20, and Y 1 and Y 2 each independently represents N or O and are different from each other.

[0024] Advantages of the Invention

[0025] The present invention provides novel fluorine-containing isoxazole compounds having a trifluoromethyl group at the 4-position on the isoxazolone ring and a heteroatom substituent at the 3-position and / or 5-position, and a method for easily producing such fluorine-containing isoxazole compounds. Detailed Description of the Invention

[0026] Hereinafter, embodiments of the present invention will be described in detail. However, the scope of the present invention is not limited to the specific examples described below. In addition, the heteroatom substituent is a substituent having a heteroatom, and refers to a functional group containing at least one heteroatom selected from a nitrogen atom (N), a sulfur atom (S), and an oxygen atom (O).

[0027] (Fluorine-containing isoxazole compound)

[0028] The fluorine-containing isoxazole compound in the present embodiment is represented by the following general formula (A), has a trifluoromethyl group at the 4-position on the isoxazole ring, and a heteroatom substituent at the 3-position and / or 5-position.

[0029] [Chemical formula 3]

[0030]

[0031] In the above general formula (A), R represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocyclic ring, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms or a heterocyclic ring, A 4 represents an alkylene group represented by =C n H 2n , n is an integer of 1 to 20, Y 1 and Y 2 each independently represents N or O and are different from each other.

[0032] Y 1 is N, Y 2 is O, and when R is a hydrogen atom, the fluorine-containing isoxazole compound represented by the general formula (A) is represented by the following general formula (1).

[0033] [Chemical formula 4]

[0034]

[0035] In the above general formula (1), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n . n is an integer from 1 to 20.

[0036] Y 1 is N, Y 2 is O, and when R is a hydrocarbon group having 1 to 12 carbon atoms, the fluorine-containing isoxazole compound represented by the general formula (A) is represented by the following general formula (2).

[0037] [Chemical formula 5]

[0038]

[0039] In the above general formula (2), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n . n is an integer from 1 to 20.

[0040] Y 1 is O, Y 2When N is and R is a hydrogen atom, the fluorine-containing isoxazole compound represented by the general formula (A) is represented by the following general formula (3).

[0041] [Chemical formula 6]

[0042]

[0043] In the above general formula (3), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, and n is an integer from 1 to 20.

[0044] Y 1 is O, Y 2 is N, and when R is a hydrocarbon group having 1 to 12 carbon atoms, the fluorine-containing isoxazole compound represented by the general formula (A) is represented by the following general formula (4).

[0045] [Chemical formula 7]

[0046]

[0047] In the above general formula (4), R'represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents =C n H2n The alkylene group shown, where n is an integer from 1 to 20.

[0048] When R and R' are substituted or unsubstituted hydrocarbon groups having 1 to 12 carbon atoms, as long as they are hydrocarbon groups containing carbon atoms and hydrogen atoms with 1 to 12 carbon atoms, there is no particular limitation, and examples include chain hydrocarbon groups, aromatic hydrocarbon groups, alicyclic hydrocarbon groups, etc. For the chain hydrocarbon group, as long as the total number of carbon atoms is 1 to 12, there is no particular limitation, and it can be a straight-chain hydrocarbon group or a branched-chain hydrocarbon group. Additionally, it can be a chain hydrocarbon group with substituents or a chain hydrocarbon group without substituents. When R and R' are aromatic hydrocarbon groups, as long as the total number of carbon atoms is 6 to 12, there is no particular limitation, and it can be an aromatic hydrocarbon group with substituents or an aromatic hydrocarbon group without substituents. Additionally, the aromatic hydrocarbon group can have a fused polycyclic structure. When R and R' are alicyclic hydrocarbon groups, as long as the total number of carbon atoms is 3 to 12, there is no particular limitation, and it can be an alicyclic hydrocarbon group with substituents or an alicyclic hydrocarbon group without substituents. Additionally, the alicyclic hydrocarbon group can have a bridged ring structure.

[0049] As the chain hydrocarbon group, examples include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc.;

[0050] alkenyl groups such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, etc.;

[0051] alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, etc.

[0052] As the aromatic hydrocarbon group, examples include phenyl and naphthyl.

[0053] As the alicyclic hydrocarbon group, examples include saturated or unsaturated cyclic hydrocarbon groups. Examples of the cyclic hydrocarbon group include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, adamantyl, norbornyl, etc.

[0054] When the chain hydrocarbon group has a substituent, one hydrogen atom in the chain hydrocarbon group can be substituted by an alkoxy group or an aralkyl group. As the alkoxy group, it is preferably substituted by an alkoxy group having 1 to 6 carbon atoms. For example, it can include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, etc. As the aralkyl group, it is preferably an alkyl group having 1 to 6 carbon atoms substituted by an aryl group. For example, it can include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, etc.

[0055] When the aromatic hydrocarbon group and the alicyclic hydrocarbon group have substituents, examples of the substituents include the above-mentioned alkyl groups and alkoxy groups having 1 to 6 carbon atoms.

[0056] In X, the halogen atom is F, Cl, Br or I, preferably F or Cl.

[0057] In X, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ) and -NA 3 -NA 1 A 2 The A contained in 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms. X is -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ) or -NA 3 -NA 1 A 2 When, A 1 , A 2 and A 3 can be the same as or different from each other. A 1 , A 2 and A 3 When representing a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 1 , A 2 and A 3 are the same as the hydrocarbon groups having 1 to 12 carbon atoms defined in R and R', and can be, for example, the hydrocarbon groups having 1 to 12 carbon atoms in R and R'. As the hydrocarbon group having 1 to 12 carbon atoms, a chain hydrocarbon group having 1 to 12 carbon atoms is preferred, a chain hydrocarbon group having 1 to 10 carbon atoms is more preferred, an alkyl group having 1 to 10 carbon atoms is further preferred, and an alkyl group having 1 to 4 carbon atoms is particularly preferred.

[0058] In X, the heterocycle is a monocyclic, bicyclic or polycyclic heterocycle that can be arbitrarily substituted, and is a heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom (N), a sulfur atom (S) and an oxygen atom (O) as ring atoms. The heterocyclic group may have a plurality of heteroatoms that are the same or different. In the skeleton of each heterocycle, it is preferable to contain at least one nitrogen atom as a heteroatom. One heteroatom contained in the heterocyclic group, preferably N, is directly bonded to the isoxazole ring of the fluorine-containing isoxazole compound and is substituted by the isoxazole ring as a heteroatom substituent. The heterocycle can be a fused ring, any one of an alicyclic heterocycle and an aromatic heterocycle, or a combination thereof.

[0059] The monocyclic heterocycle is preferably a 3- to 12-membered ring, more preferably a 5- to 9-membered ring. When the heterocycle is a monocyclic heterocycle, it may contain up to 5 heteroatoms. Each heteroatom is independently selected from O, S, and N, and preferably at least one of the heteroatoms is N. Examples of the monocyclic heterocycle include pyrrolidine, pyrroline, pyrrole, pyrazolidine, imidazolidine, pyrazoline, imidazoline, imidazole, pyrazole, triazole, tetrazole, (iso)oxazole, (iso)oxadiazole, (iso)thiazole, thiadiazole, pyridine, pyrrolidine, piperidine, piperazine, pyridazine, pyrimidine, pyrazine, triazine, thienopyridine, piperazinone, morpholine, thiomorpholine, thiomorpholine dioxide, oxazine, thiazine, azocane, azocine, azonane, azonine, and their derivatives.

[0060] The bicyclic heterocycle is preferably a 7- to 14-membered ring, more preferably an 8- to 10-membered ring. In addition, a spiro ring may be included in the bicyclic heterocycle. When the heterocycle is a bicyclic heterocycle, it may contain up to 10 heteroatoms. Each heteroatom is independently selected from O, S, and N, and preferably at least one of the heteroatoms is N. Examples of the bicyclic heterocycle include (iso)indole, azaindole, (aza)indazole, (aza)benzimidazole, (aza)benzotriazole, hydrothienopyridine, (iso)quinoline, hydro(iso)quinoline, hydrofluoropyridine, and their derivatives.

[0061] The polycyclic heterocycle is preferably a 9- to 30-membered ring, more preferably a 12- to 26-membered ring. In addition, a spiro ring may be included in the polycyclic heterocycle. When the heterocycle is a polycyclic heterocycle, it may contain up to 15 heteroatoms. Each heteroatom is independently selected from O, S, and N, and preferably at least one of the heteroatoms is N. Examples of the polycyclic heterocycle include carbazole, phenazine, phenoxazine, phenothiazine, benzindole, pyrroloquinoline, acridine, and their derivatives.

[0062] When the heterocycle has a substituent, examples of the substituent include a halogen atom, C1-C 10The invention also includes hydrocarbon groups, hydroxyl groups, alkoxy groups, carbonyl groups, carboxyl groups and other oxygen-containing substituents, amino groups, cyano groups, nitro groups and other nitrogen-containing substituents, sulfonyl groups, sulfoxy groups, sulfone groups and other sulfur-containing substituents, etc.

[0063] A 1 , A 2 and A 3 When A is a heterocyclic ring, 1 , A 2 and A 3 The same as the heterocycle defined above for X. X is -O-NA 1 A 2 or -NA 1 A 2 When A 1 It may be a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms. 2 It can be a heterocyclic ring. In addition, X is -NA 1 (OA 2 ), it can be A 1 is a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, 2 A 1 A is a heterocyclic ring 2 is a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms. 3 -NA 1 A 2 When 1 and A 3 is a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, 2 A 1 is a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, 2 and A 3 It is a heterocyclic ring.

[0064] X,-NA 4 A contained in 4 =C n H 2n The alkylene group shown in FIG. 1 is an integer of 1 to 20. n H 2n The alkylene group shown may be linear or branched. n is preferably 3-15, more preferably 5-10.

[0065] The fluorine-containing isoxazole compound in the present embodiment has specific substituents (-X, -CF3, -OR or -OR') on the isoxazole ring, and thus can have excellent effects from the viewpoint of structural expandability. In particular, a further improvement in pharmacological activity can be expected. In addition, since the 3-position, 4-position and 5-position on the isoxazole ring can have different substituents respectively, it can be easily derivatized into an asymmetric structure, and the use as an intermediate can also be expected. More specifically, by reacting the fluorine-containing isoxazole compound under acidic conditions, -OR or -OR' can be modified to obtain a derivative. In addition, when the substituent X on the isoxazole ring is a halogen atom, by reacting the fluorine-containing isoxazole compound under basic conditions, the halogen atom can be modified to obtain a derivative. Furthermore, the fluorine-containing isoxazole compound in the present embodiment is also useful in the fields of electronic materials such as organic semiconductors and liquid crystals, for example.

[0066] (Method for producing fluorine-containing isoxazole compound)

[0067] The method for producing the fluorine-containing isoxazole compound in the present embodiment includes the following steps: (I) reacting a fluorine-containing compound selected from a fluorine-containing carbonyl compound, a fluorine-containing isobutene derivative and a fluorine-containing isobutane derivative, hydroxylamine or a salt thereof, and an optional compound of the following general formula (5) or a salt thereof; or, (II) reacting a fluorine-containing compound selected from a fluorine-containing carbonyl compound, a fluorine-containing isobutene derivative and a fluorine-containing isobutane derivative, an amine salt or an amine compound, and an optional compound of the following general formula (5) or a salt thereof, thereby synthesizing a fluorine-containing isoxazole compound represented by the general formula (A).

[0068] [Chemical formula 8]

[0069]

[0070] In the above general formulas (A) and (5), R represents a hydrogen atom, or a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocyclic ring, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocyclic ring having 1 to 12 carbon atoms, and A 4 represents =C n H 2nThe alkylene group shown, n is an integer from 1 to 20, Y 1 and Y 2 each independently represents N or O and are different from each other.

[0071] The fluorine-containing isoxazole compound represented by such a general formula (A) is synthesized, for example, by the following method.

[0072] The first embodiment of manufacturing the fluorine-containing isoxazole compound in this embodiment includes the following steps: (a) reacting a fluorine-containing carbonyl compound represented by the following general formula (6) with hydroxylamine or its salt represented by the following general formula (7) to obtain a fluorine-containing isoxazole compound represented by the following general formula (1).

[0073] [Chemical formula 9]

[0074]

[0075] In the above general formulas (1) and (6), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, Z represents -OA 5 , -O-NA 5 A 6 , -NA 5 A 6 , -NA 5 (OA 6 ), or -NA 7 -NA 5 A 6 , A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer from 1 to 20, A 5 , A 6 and A 7 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and the wavy bond represents a single bond for representing the stereoisomerism of (E) or (Z).

[0076] The second embodiment of manufacturing the fluorine-containing isoxazole compound in the present embodiment includes the following steps: (b) reacting a fluorine-containing carbonyl compound represented by the following general formula (8), a compound represented by the following general formula (5) or a salt thereof, and a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (1).

[0077] [Chemical formula 10]

[0078]

[0079] In the above general formulas (1), (5) and (8), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, Z represents -OA 5 , -O-NA 6 A 7 , -NA 5 A 6 , -NA 5 (OA 6 ), or -NA 7 -NA 5 A 6 , A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer from 1 to 20, A 5 , A 6 and A 7 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0080] The third embodiment of manufacturing the fluorine-containing isoxazole compound in the present embodiment includes the following steps: (c) reacting a fluorine-containing carbonyl compound represented by the following general formula (9) with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then further reacting the obtained reaction product with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (1).

[0081] [Chemical formula 11]

[0082]

[0083] In the above general formulas (1), (5) and (9), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, Z represents -OA 5 , -O-NA 6 A 7 , -NA 5 A 6 , -NA 5 (OA 6 ), or -NA 7 -NA 5 A 6 , A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer from 1 to 20, A 5 , A 6 and A 7 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0084] The fourth embodiment of the method for manufacturing a fluorine-containing isoxazole compound in this embodiment includes the following steps: (d) reacting a fluorine-containing carbonyl compound represented by the following general formula (10) with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) in the presence of a base, and then reacting with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (1).

[0085] [Chemical formula 12]

[0086]

[0087] In the above general formulas (1), (5) and (10), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA1 (OA 2 )、 -NA 3 -NA 1 A 2 、 -NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, n is an integer from 1 to 20, W + represents an ammonium cation, an imidazole cation, a pyridine cation, a quinuclidinium cation or a phosphonium cation.

[0088] The fifth embodiment of the method for manufacturing a fluorinated isoxazole compound in this embodiment includes the following steps: (e) subjecting a fluoroisobutene derivative represented by the following general formula (11) to carbonylation in the presence of a nucleophile, then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (1).

[0089] [Chemical formula 13]

[0090]

[0091] In the above general formulas (1), (5) and (11), R'represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 、 -O-NA 1 A 2 、 -NA 1 A 2 、 -NA 1 (OA 2 )、 -NA 3 -NA 1 A 2 、 -NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, n is an integer from 1 to 20.

[0092] The sixth embodiment of the method for producing a fluorine-containing isoxazole compound in the present embodiment includes the following steps: (f) Carbonylating the compound obtained by the elimination reaction of a fluorine-containing isobutane derivative represented by the following general formula (12) in the presence of a nucleophile, then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (1).

[0093] [Chemical formula 14]

[0094]

[0095] In the above general formulas (1), (5) and (12), R' represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocyclic ring, Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 , m is an integer of 0 to 3, A 1 , A 2 and A 3 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer of 1 to 20, B 1 and B 2 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0096] The seventh embodiment of the method for producing a fluorine-containing isoxazole compound in the present embodiment includes the following steps: (g) Reacting a fluorine-containing carbonyl compound represented by the following general formula (13) with an amine salt or an amine compound, thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (2).

[0097] [Chemical formula 15]

[0098]

[0099] In the above general formulas (2) and (13), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms or a heterocycle, A 4 represents =C n H 2n the alkylene group shown, and n is an integer from 1 to 20. The wavy bond represents a single bond for representing the (E) or (Z) stereoisomer.

[0100] The eighth embodiment of the method for manufacturing a fluorinated isoxazole compound in the present embodiment includes the following steps: (h) reacting a fluorinated carbonyl compound represented by the following general formula (14), an amine salt or an amine compound, and an optional compound represented by the following general formula (5) or a salt thereof to obtain a fluorinated isoxazole compound represented by the following general formula (2).

[0101] [Chemical formula 16]

[0102]

[0103] In the above general formulas (2) and (14), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 (OA 2 ), -NA 1 A 2 , -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, and n is an integer from 1 to 20.

[0104] The ninth embodiment of manufacturing a fluorine-containing isoxazole compound in this embodiment includes the following steps: (i) reacting a fluorine-containing carbonyl compound represented by the following general formula (15) with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting the resulting reaction product with an amine salt or an amine compound to obtain a fluorine-containing isoxazole compound represented by the following general formula (2).

[0105] [Chemical formula 17]

[0106]

[0107] In the above general formulas (2), (5) and (15), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms or a heterocycle, and A 4 represents an alkylene group represented by =C n H 2n , and n is an integer of 1 to 20.

[0108] The tenth embodiment of manufacturing a fluorine-containing isoxazole compound in this embodiment includes the following steps: (j) reacting a fluorine-containing carbonyl compound represented by the following general formula (10) with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting an amine salt or an amine compound to obtain a fluorine-containing isoxazole compound represented by the following general formula (2).

[0109] [Chemical formula 18]

[0110]

[0111] In the above general formulas (2), (5) and (10), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA2 )、 -NA 3 -NA 1 A 2 、 -NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, n is an integer from 1 to 20, W + represents an ammonium cation, an imidazole cation, a pyridine cation, a quininium cation or a phosphonium cation.

[0112] The eleventh embodiment of the method for manufacturing a fluorinated isoxazole compound in this embodiment includes the following steps: (k) subjecting a fluoroisobutene derivative represented by the following general formula (11) to carbonylation in the presence of a nucleophile, then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with an amine salt or an amine compound, thereby obtaining a fluorinated isoxazole compound represented by the following general formula (2).

[0113] [Chemical formula 19]

[0114]

[0115] In the above general formulas (2), (5) and (11), R and R’ each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 、 -O-NA 1 A 2 、 -NA 1 A 2 、 -NA 1 (OA 2 )、 -NA 3 -NA 1 A 2 、 -NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, n is an integer from 1 to 20.

[0116] The twelfth embodiment of manufacturing a fluorine-containing isoxazole compound in the present embodiment includes the following steps: (l) subjecting a compound obtained by an elimination reaction of a fluoro isobutane derivative represented by the following general formula (12) to carbonylation in the presence of a nucleophile, then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with an amine salt or an amine compound, thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (2).

[0117] [Chemical formula 20]

[0118]

[0119] In the above general formulas (2), (5) and (12), R and R' each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 -NA 4 or a heterocyclic ring, Y represents a halogen atom, -OB 1 、-SO m B 1 or -NB 1 B 2 , m is an integer from 0 to 3, A 1 、A 2 and A 3 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer from 1 to 20, B 1 and B 2 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0120] The thirteenth embodiment of manufacturing a fluorine-containing isoxazole compound in the present embodiment includes the following steps: (m) reacting a fluorine-containing carbonyl compound represented by the following general formula (10) with a hydroxylamine or a salt thereof represented by the following general formula (7), and further reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof, thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (3).

[0121] [Chemical formula 21]

[0122]

[0123] In the above general formulas (3), (5) and (10), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents =C n H 2n -represented alkylene group, n is an integer from 1 to 20, W + represents an ammonium cation, an imidazolium cation, a pyridinium cation, a quinuclidinium cation or a phosphonium cation.

[0124] The fourteenth embodiment of the method for producing a fluorine-containing isoxazole compound in the present embodiment includes the following steps: (n) carbonylating a fluoroisobutene derivative represented by the following general formula (11) in the presence of a nucleophile, and then reacting with hydroxylamine or a salt thereof represented by the following general formula (7), and then reacting the obtained reaction product with a compound or a salt thereof represented by the following general formula (5) to obtain a fluorine-containing isoxazole compound represented by the following general formula (3).

[0125] [Chemical formula 22]

[0126]

[0127] In the above general formulas (3), (5) and (11), R'represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A4 represents =C n H 2n The alkylene group shown, where n is an integer from 1 to 20.

[0128] The fifteenth embodiment of the method for manufacturing a fluorine-containing isoxazole compound in this embodiment includes the following steps: (o) Carbonylating a fluorine-containing isobutane derivative represented by the following general formula (12) in the presence of a nucleophile, and then reacting the resulting product with a hydroxylamine or its salt represented by the following general formula (7), and then reacting the resulting reaction product with a compound or its salt represented by the following general formula (5), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (3).

[0129] [Chemical formula 23]

[0130]

[0131] In the above general formulas (3), (5) and (12), R' represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 -NA 4 or a heterocyclic ring, Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 , m is an integer from 0 to 3, A 1 , A 2 and A 3 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n The alkylene group shown, where n is an integer from 1 to 20, B 1 and B 2 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0132] The sixteenth embodiment of the method for manufacturing a fluorine-containing isoxazole compound in this embodiment includes the following steps: (p) Reacting a fluorine-containing isobutene derivative represented by the following general formula (11), a compound or its salt represented by the following general formula (5), and a hydroxylamine or its salt represented by the following general formula (7), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (4).

[0133] [Chemical Formula 24]

[0134]

[0135] In the above general formulas (4), (5) and (11), R’ represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 (OA 2 ), -NA 1 A 2 , -NA 3 , -NA 1 A 2 , -NA 4 , or a heterocyclic ring, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , and n is an integer from 1 to 20.

[0136] The seventeenth embodiment of manufacturing a fluorinated isoxazole compound in the present embodiment includes the following steps: (q) reacting a fluoroisobutene derivative represented by the following general formula (11) with hydroxylamine or its salt represented by the following general formula (7) to obtain a fluorinated isoxazole compound represented by the following general formula (4-1).

[0137] [Chemical Formula 25]

[0138]

[0139] In the above general formulas (4-1) and (11), R’ represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0140] The eighteenth embodiment of manufacturing a fluorinated isoxazole compound in the present embodiment includes the following steps: (r) reacting a fluoroisobutane derivative represented by the following general formula (12), a compound or its salt represented by the following general formula (5), and hydroxylamine or its salt represented by the following general formula (7) to obtain a fluorinated isoxazole compound represented by the following general formula (4).

[0141] [Chemical Formula 26]

[0142]

[0143] In the above general formulas (4), (5) and (12), R' represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocyclic ring, Y represents a halogen atom, -OB 1 、-SO m B 1 or -NB 1 B 2 , m is an integer from 0 to 3, A 1 、A 2 and A 3 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer from 1 to 20, B 1 and B 2 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0144] The nineteenth embodiment of manufacturing the fluorinated isoxazole compound in this embodiment includes the following steps: (s) reacting a fluorinated isobutane derivative represented by the following general formula (12) with hydroxylamine or its salt represented by the following general formula (7) to obtain a fluorinated isoxazole compound represented by the following general formula (4-1).

[0145] [Chemical formula 27]

[0146]

[0147] In the above general formulas (4-1) and (12), R' represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and Y represents a halogen atom, -OB 1 、-SO m B 1 or -NB 1 B 2 , m is an integer from 0 to 3, B 1 and B 2 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0148] Among fluorine-containing compounds, the fluorine-containing carbonyl compounds are preferably the compounds represented by the above general formula (6), (8), (9), (10), (13), (14) or (15), the fluoroisobutene derivatives are preferably the compounds represented by the above general formula (11), and the fluoroisobutane derivatives are preferably the compounds represented by the above general formula (12).

[0149] In the above general formula (5), (6), (13), A 1 , A 2 , A 3 and the heterocycle are the same as those defined in the fluorine-containing isoxazole compounds represented by the above general formula (A), (1) to (4). In addition, in the above general formula (4-1), (11), (12), R' is the same as the group defined in the fluorine-containing isoxazole compound represented by the above general formula (4), and the substituted or unsubstituted hydrocarbon group with 1 to 12 carbon atoms in R' is preferably an alkyl group with 1 to 10 carbon atoms.

[0150] In the above general formula (6), (8), (9), A 5 , A 6 and A 7 are the same as the substituted or unsubstituted hydrocarbon group with 1 to 12 carbon atoms defined in the above R and R', and the substituted or unsubstituted hydrocarbon group with 1 to 12 carbon atoms in A 5 , A 6 and A 7 is preferably an alkyl group with 1 to 10 carbon atoms.

[0151] In the above general formula (12), B 1 and B 2 are the same as the substituted or unsubstituted hydrocarbon group with 1 to 12 carbon atoms defined in the above R and R'.

[0152] In each of the above general formula (12), Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 .

[0153] In Y, the halogen atom is F, Cl, Br or I, preferably F or Cl.

[0154] In Y, -OB 1 , -SO m B 1 contains B 1 which represents a substituted or unsubstituted hydrocarbon group with 1 to 12 carbon atoms, the same as the hydrocarbon group with 1 to 12 carbon atoms defined in the above R and R'. In addition, m is an integer from 0 to 3, preferably an integer from 0 to 2, more preferably an integer from 0 to 1.

[0155] In Y, -NB 1 B 2 The B contained in 1 and B 2 Each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms. B 1 and B 2 May be the same or different from each other. B 1 and B 2 Is the same as the hydrocarbon group having 1 to 12 carbon atoms defined in the above R and R'.

[0156] The overall reaction of (a) in the first embodiment is represented by the following reaction formula (A).

[0157] [Chemical formula 28]

[0158]

[0159] The overall reaction of (b) in the second embodiment is represented by the following reaction formula (B).

[0160] [Chemical formula 29]

[0161]

[0162] The overall reaction of (c) in the third embodiment is represented by the following reaction formula (C).

[0163] [Chemical formula 30]

[0164]

[0165] The overall reaction of (d) in the fourth embodiment is represented by the following reaction formula (D). In the following reaction formula, "WF" represents a salt of cation W + and F - Of

[0166] [Chemical formula 31]

[0167]

[0168] The overall reaction of (e) in the fifth embodiment is represented by the following reaction formula (E). In addition, in the following reaction formula, for convenience, the nucleophile is sometimes represented as "Nu". In addition, "NuR'F" represents a salt of the cation of the nucleophile substituted by R' and F - Of

[0169] [Chemical formula 32]

[0170]

[0171] The overall reaction of (f) in the sixth embodiment is represented by the following reaction formula (F).

[0172] [Chemical formula 33]

[0173]

[0174] The overall reaction of (g) in the seventh embodiment is represented by the following reaction formula (G). In addition, in the following reaction formulas (G) to (O), for convenience, the amine salt or amine compound is sometimes represented as "N compound".

[0175] [Chemical formula 34]

[0176]

[0177] The overall reaction of (h) in the eighth embodiment is represented by the following reaction formula (H). In the reaction of (h), when the compound represented by the general formula (5) or its salt is not used, in the fluorine-containing isoxazole compound represented by the general formula (2), X represents a fluorine atom (F).

[0178] [Chemical formula 35]

[0179]

[0180] The overall reaction of (i) in the ninth embodiment is represented by the following reaction formula (I).

[0181] [Chemical formula 36]

[0182]

[0183] The overall reaction of (j) in the tenth embodiment is represented by the following reaction formula (J).

[0184] [Chemical formula 37]

[0185]

[0186] The overall reaction of (k) in the eleventh embodiment is represented by the following reaction formula (K).

[0187] [Chemical formula 38]

[0188]

[0189] The overall reaction of (l) in the twelfth embodiment is represented by the following reaction formula (L).

[0190] [Chemical formula 39]

[0191]

[0192] The overall reaction of (m) in the thirteenth embodiment is represented by the following reaction formula (M).

[0193] [Chemical formula 40]

[0194]

[0195] The overall reaction of (n) in the fourteenth embodiment is represented by the following reaction formula (N).

[0196] [Chemical formula 41]

[0197]

[0198] The overall reaction of (o) in the fifteenth embodiment is represented by the following reaction formula (O).

[0199] [Chemical formula 42]

[0200]

[0201] The overall reaction of (p) in the sixteenth embodiment is represented by the following reaction formula (P).

[0202] [Chemical formula 43]

[0203]

[0204] The overall reaction of (q) in the seventeenth embodiment is represented by the following reaction formula (Q).

[0205] [Chemical formula 44]

[0206]

[0207] The overall reaction of (r) in the eighteenth embodiment is represented by the following reaction formula (R).

[0208] [Chemical formula 45]

[0209]

[0210] The overall reaction of (s) in the nineteenth embodiment is represented by the following reaction formula (S).

[0211] [Chemical formula 46]

[0212]

[0213] In each of the above reactions, the hydroxylamine represented by the general formula (7) and the compound represented by the general formula (5) may be in the form of salts. When the hydroxylamine represented by the general formula (7) is in the form of a salt, it can be exemplified that the part (-NH2) of the amino group constituting the hydroxylamine is cationized to become (-NH3+ ), in the form of a salt with a counterion. In addition, when the compound represented by the general formula (5) is in the form of a salt, it can be exemplified that the H part of the compound is cationized to become (H + ), in the form of a salt with a counterion. The counterion is not particularly limited as long as it is a monovalent anion, and examples thereof include F - , Cl - , Br - , I - and other halide ions, trifluoroacetate anion, p-toluenesulfonate anion, trifluoromethanesulfonate anion, nonafluorobutanesulfonic acid, bis(trifluoromethylsulfonyl)imide anion, tetrafluoroborate anion, etc.

[0214] In each of the above reactions, when an amine salt or an amine compound is used, as the amine salt and the amine compound, a nitrogen-containing heterocyclic cation in which one amino group (-NH2) is bonded to a nitrogen atom in the heterocycle or a quaternary ammonium cation in which one amino group (-NH2) is bonded to a nitrogen atom and an amine salt of an anion selected from halogens, sulfuric acid, phosphoric acid, sulfonic acid, trifluoroacetic acid, tetrafluoroborate, tetraphenylborate, hexafluoroborate, and sulfimide acid can be exemplified; a primary amine, hydroxylamine, or amine salt having an anionic substituent or anion selected from halogens, sulfuric acid, phosphoric acid, sulfonic acid, and trifluoroacetic acid; or a quaternary ammonium salt substituted with a hydrocarbon group selected from alkyl and aryl groups, etc.

[0215] In the nitrogen-containing heterocyclic cation, at least one nitrogen atom can be included as a heteroatom in the heterocycle and can be optionally substituted. In addition, the nitrogen atom on the nitrogen-containing heterocycle is directly bonded to one amino group (-NH2), and the nitrogen-containing heterocyclic cation is preferably a monocyclic heterocycle. On the nitrogen-containing heterocycle, at least one heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom (O) can be further included as a ring-constituting atom. The nitrogen-containing heterocycle is preferably an aromatic heterocycle, and in addition, the number of ring members is preferably a 5- to 8-membered ring, more preferably a 5- or 6-membered ring. Examples of such a nitrogen-containing heterocycle include pyridine, 4-dimethylaminopyridine, 1-methylimidazole, etc.

[0216] In the quaternary ammonium cation in which one amino group (-NH2) is bonded to a nitrogen atom, the nitrogen atom of the quaternary ammonium cation is preferably bonded to a hydrocarbon group selected from alkyl and aryl groups as other substituents. The alkyl preferably has 1 to 12 carbon atoms and can be linear or branched. Examples of such an alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc. The aryl preferably has 6 to 12 carbon atoms and can also be substituted with methyl or the like. Examples of such an aryl include tolyl and mesityl, etc.

[0217] Among the above-mentioned primary amines, hydroxylamines or amine salts having an anionic substituent or anion, it is preferred that the anionic substituent or anion is directly bonded to the nitrogen atom constituting the amine. Further, among the above-mentioned hydroxylamines having an anionic substituent or anion, it is preferred that the anionic substituent or anion is directly bonded to the oxygen atom (-O-NH2) constituting the hydroxylamine.

[0218] In the quaternary ammonium salt, the nitrogen atom of the quaternary ammonium salt is substituted with a hydrocarbon group selected from alkyl groups and aryl groups and is not bonded to an amino group (-NH2). The alkyl group preferably has 1 to 12 carbon atoms and may be linear or branched. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The aryl group preferably has 6 to 12 carbon atoms and may be substituted with a methyl group or the like. Examples of such aryl groups include tolyl and mesityl.

[0219] Specific examples of the amine salt and the amine compound include 1-aminopyridinium iodide, tetrabutylammonium azide, hydroxylamine-O-sulfonic acid, 1-aminopyridinium mesitylenesulfonate, O-(mesitylenesulfonyl)hydroxylamine, and 1,1,1-trimethylhydrazinium trifluoroacetate and the like.

[0220] In each of the above reactions, when a nucleophile is used, examples of the nucleophile include tertiary amines such as triethylamine, quinuclidine, 1,4-diazabicyclo[2.2.2]octane, imidazole derivatives such as 1-methylimidazole, and pyridine derivatives such as pyridine and 4-dimethylaminopyridine.

[0221] In each of the above reactions, when a base is used, examples of the base include inorganic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium fluoride and potassium fluoride, organic nitrogen derivatives such as pyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, methyltriazabicyclodecene, diazabicyclooctane, and phosphorus derivatives such as phosphazene base.

[0222] In each of the above reactions, when an alcohol (ROH) is used, the type of the alcohol is not particularly limited as long as an ester of the alcohol and 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid can be formed, and it can be appropriately used according to the desired structure of the isoxazole.

[0223] When hydrogen fluoride (HF) is generated in the method for producing the fluorine-containing isoxazole compound in the present embodiment, for example, a hydrogen halide scavenger can be used. By using the hydrogen halide scavenger, the step of recovering hydrogen fluoride can be omitted, and the fluorine-containing isoxazole compound represented by the above general formula (A) can be obtained more simply.

[0224] In the reaction of (a) above, a cyclic isoxazole structure is formed between the amino group of the fluorocarbonyl compound represented by the general formula (6) and the amino group of the hydroxylamine represented by the general formula (7). X and CF3 in the fluorocarbonyl compound represented by the general formula (6) are located at the 3-position and 4-position of the formed isoxazole structure, respectively, and the OH formed due to the formation of the ring structure is located at the 5-position of the isoxazole structure.

[0225] In the reaction of (b) above, a cyclic isoxazole structure is formed between the amino group of the fluorocarbonyl compound represented by the general formula (8) and the amino group of the hydroxylamine represented by the general formula (7), and the compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure. The OH formed due to the formation of the ring structure is located at the 5-position of the isoxazole structure. CF3 in the fluorocarbonyl compound represented by the general formula (8) is located at the 4-position of the formed isoxazole structure.

[0226] In the reaction of (c) above, a cyclic isoxazole structure is formed between the reaction product obtained by reacting the fluorocarbonyl compound represented by the general formula (9) with the compound represented by the general formula (5) in the presence of a base and the amino group of the hydroxylamine represented by the general formula (7), and the compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure. The OH formed due to the formation of the ring structure is located at the 5-position of the isoxazole structure. CF3 in the fluorocarbonyl compound represented by the general formula (9) is located at the 4-position of the formed isoxazole structure.

[0227] In the reaction of (d) above, a cyclic isoxazole structure is formed between the reaction product obtained by reacting the intermediate reaction product obtained by reacting the fluorocarbonyl compound represented by the general formula (10) with an alcohol with the compound represented by the general formula (5) in the presence of a base and the amino group of the hydroxylamine represented by the general formula (7), and the compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure. The OH formed due to the formation of the ring structure is located at the 5-position of the isoxazole structure. CF3 in the fluorocarbonyl compound represented by the general formula (10) is located at the 4-position of the formed isoxazole structure.

[0228] In the reaction of (e) above, the fluoroisobutene derivative represented by the general formula (11) is carbonylated in the presence of a nucleophile, and then reacted with an alcohol. The obtained intermediate reactant is reacted with the compound represented by the general formula (5) in the presence of a base. A cyclic isoxazole structure is formed between the obtained reaction product and the amino group of the hydroxylamine represented by the general formula (7), and the compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure. The OH formed due to the formation of the ring structure is located at the 5-position of the isoxazole structure. CF3 in the fluoroisobutene derivative represented by the general formula (11) is located at the 4-position of the formed isoxazole structure.

[0229] In the reaction of (f) above, a compound obtained by the elimination reaction of a fluoro isobutane derivative represented by the general formula (12) is carbonylated in the presence of a nucleophile, and then reacted with an alcohol. The resulting intermediate reactant is reacted with a compound represented by the general formula (5) in the presence of a base, and a cyclic isoxazole structure is formed between the amino group of the resulting reaction product and the hydroxylamine represented by the general formula (7). The compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure, and the OH formed due to the formation of the ring structure is located at the 5-position of the isoxazole structure. The CF3 of the fluorocarbonyl compound represented by the general formula (12) is located at the 4-position of the formed isoxazole structure.

[0230] In the reaction of (g) above, a cyclic isoxazole structure is formed between the amino group of the fluorocarbonyl compound represented by the general formula (13) and an amine salt or an amine compound. The X, CF3, and OR of the fluorocarbonyl compound represented by the general formula (13) are located at the 3-position, 4-position, and 5-position of the formed isoxazole structure, respectively.

[0231] In the reaction of (h) above, a cyclic isoxazole structure is formed between the amino group of the fluorocarbonyl compound represented by the general formula (14) and an amine salt or an amine compound. The CF3 and OR of the fluorocarbonyl compound represented by the general formula (14) are located at the 4-position and 5-position of the formed isoxazole structure, respectively. When the fluorocarbonyl compound represented by the general formula (14) is further reacted with the compound represented by the general formula (5), the compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure. When the compound represented by the general formula (5) is not used, the F of the fluorocarbonyl compound represented by the general formula (14) is located at the 3-position of the isoxazole structure.

[0232] In the reaction of (i) above, a cyclic isoxazole structure is formed between the amino group of an amine salt or an amine compound and a reaction product obtained by reacting the fluorocarbonyl compound represented by the general formula (15) with the compound represented by the general formula (5) in the presence of a base, and the compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure. The CF3 and OR of the fluorocarbonyl compound represented by the general formula (15) are located at the 4-position and 5-position of the formed isoxazole structure, respectively.

[0233] In the reaction of (j) above, a cyclic isoxazole structure is formed between the amino group of an amine salt or an amine compound and a reaction product obtained by reacting an intermediate reactant obtained by reacting the fluorocarbonyl compound represented by the general formula (10) with an alcohol with the compound represented by the general formula (5) in the presence of a base, and the compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure. The CF3 of the fluorocarbonyl compound represented by the general formula (10) is located at the 4-position of the formed isoxazole structure. The OR of the intermediate reactant obtained by reacting the fluorocarbonyl compound represented by the general formula (10) with an alcohol (ROH) is located at the 5-position of the isoxazole structure.

[0234] In the reaction of (k) above, the fluoroisobutene derivative represented by the general formula (11) is carbonylated in the presence of a nucleophile, and then reacted with an alcohol. The resulting intermediate reactant is reacted with the compound represented by the general formula (5) in the presence of a base to obtain a reaction product. A cyclic isoxazole structure is formed between the reaction product and the amino group of an amine salt or an amine compound, and the compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure. The CF3 of the fluorocarbonyl compound represented by the general formula (11) is located at the 4-position of the formed isoxazole structure. The OR of the intermediate reactant obtained by the reaction of the compound obtained by carbonylating the fluoroisobutene derivative represented by the general formula (11) with an alcohol (ROH) is located at the 5-position of the isoxazole structure.

[0235] In the reaction of (l) above, the compound obtained by the elimination reaction of the fluoroisobutane derivative represented by the general formula (12) is carbonylated in the presence of a nucleophile, and then reacted with an alcohol. The resulting intermediate reactant is reacted with the compound represented by the general formula (5) in the presence of a base. A cyclic isoxazole structure is formed between the obtained reaction product and the amino group of an amine salt or an amine compound, and the compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure. The CF3 of the fluorocarbonyl compound represented by the general formula (12) is located at the 4-position of the formed isoxazole structure. The OR of the intermediate reactant obtained by the reaction of the compound obtained by the elimination reaction of the fluoroisobutene derivative represented by the general formula (12) and then carbonylation with an alcohol (ROH) is located at the 5-position of the isoxazole structure.

[0236] In the reaction of (m) above, a cyclic isoxazole structure is formed between the fluorocarbonyl compound represented by the general formula (10) and the amino group of the hydroxylamine represented by the general formula (7). The compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure, and the OH formed due to the formation of the ring structure is located at the 5-position of the isoxazole structure. The CF3 of the fluorocarbonyl compound represented by the general formula (10) is located at the 4-position of the formed isoxazole structure.

[0237] In the reaction of (n) above, the fluoroisobutene derivative represented by the general formula (11) is carbonylated in the presence of a nucleophile, and then reacted with an alcohol. The resulting intermediate reactant is reacted with the compound represented by the general formula (5) in the presence of a base. A cyclic isoxazole structure is formed between the obtained reaction product and the amino group of the hydroxylamine represented by the general formula (7). The compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure, and the OH formed due to the formation of the ring structure is located at the 5-position of the isoxazole structure. The CF3 of the fluoroisobutene derivative represented by the general formula (11) is located at the 4-position of the formed isoxazole structure.

[0238] In the reaction of (o) above, the compound obtained by the elimination reaction of the fluoroisobutane derivative represented by the general formula (12) is carbonylated in the presence of a nucleophile, and then reacted with an alcohol. The resulting intermediate reactant is reacted with the compound represented by the general formula (5) in the presence of a base to form a cyclic isoxazole structure between the amino group of the resulting reaction product and the hydroxylamine represented by the general formula (7). The compound represented by the general formula (5) is substituted at the 3-position of the isoxazole structure, and the OH formed due to the formation of the ring structure is located at the 5-position of the isoxazole structure. The CF3 of the fluoroisobutene derivative represented by the general formula (12) is located at the 4-position of the formed isoxazole structure.

[0239] In the reaction of (p) above, a cyclic isoxazole structure is formed between the fluoroisobutene derivative represented by the general formula (11) and the amino group of the hydroxylamine represented by the general formula (7), and then the compound represented by the general formula (5) is substituted on the isoxazole structure. The -OR' and CF3 of the fluoroisobutene derivative are located at the 3-position and 4-position of the formed isoxazole structure respectively, and the X of the compound represented by the general formula (5) is located at the 5-position of the isoxazole structure.

[0240] In the reaction of (q) above, a cyclic isoxazole structure is formed between the fluoroisobutene derivative represented by the general formula (11) and the amino group of the hydroxylamine represented by the general formula (7). The -OR', CF3 and F of the fluoroisobutene derivative are located at the 3-position, 4-position and 5-position of the formed isoxazole structure respectively.

[0241] In the reaction of (r) above, a cyclic isoxazole structure is formed between the fluoroisobutane derivative represented by the general formula (12) and the amino group of the hydroxylamine represented by the general formula (7), and then the compound represented by the general formula (5) is substituted on the isoxazole structure. The -OR' and CF3 of the fluoroisobutane derivative are located at the 3-position and 4-position of the formed isoxazole structure respectively, and the X of the compound represented by the general formula (5) is located at the 5-position of the isoxazole structure.

[0242] In the reaction of (s) above, a cyclic isoxazole structure is formed between the fluoroisobutane derivative represented by the general formula (12) and the amino group of the hydroxylamine represented by the general formula (7). The -OR', CF3 and F of the fluoroisobutane derivative are located at the 3-position, 4-position and 5-position of the formed isoxazole structure respectively.

[0243] The hydrogen halide scavenger is a substance having the function of scavenging the generated hydrogen fluoride (HF). Examples of the hydrogen halide scavenger include inorganic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium fluoride and potassium fluoride, organic nitrogen derivatives such as pyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, methyltriazabicyclodecene, diazabicyclooctane, and phosphorus derivatives such as phosphazene base.

[0244] Each of the reactions (a) to (s) above can be carried out in the presence of a fluoride ion scavenger as needed. The fluoride ion scavenger is preferably a salt of a cation of lithium, sodium, magnesium, potassium, calcium or tetramethylammonium and an anion of 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 or tetrakis(pentafluorophenyl)boric acid. Among them, potassium salts or sodium salts are preferably used, and sodium salts are more preferably used. It is considered that the cation from the fluoride ion scavenger captures the free fluoride ions in the reaction and precipitates in the form of a salt with low solubility in the organic solvent, thereby promoting the reaction. Thus, a fluorinated isoxazole compound can be obtained in high yield.

[0245] The reaction temperature in the reactions (a) to (s) above is preferably 0°C to 100°C, more preferably 5°C to 50°C, and further preferably 10°C to 20°C. In addition, the reaction time in the reactions (a) to (s) above is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and further preferably 2 to 12 hours.

[0246] As the solvent used in the reactions (a) to (s) above, organic solvents are preferred. Examples include aprotic polar solvents such as tetrahydrofuran, monoglyme, diglyme, triglyme, tetraglyme, acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 4-methyltetrahydropyran, dimethylpropyleneurea, tetramethylurea, dimethyl sulfoxide and sulfolane, or biphasic solvents such as protic polar solvents such as methanol and water and water-insoluble solvents such as dichloromethane, toluene and diethyl ether. In addition, as the catalyst for the reactions (a) to (s) above, quaternary ammonium halides such as benzyltriethylammonium chloride, quaternary phosphonium halides, crown ethers, etc. can be used arbitrarily.

[0247] Based on the above embodiments, the present invention relates to the following [1] to

[25] .

[0248] [1] A fluorinated isoxazole compound represented by the following general formula (A).

[0249] [Chemical formula 47]

[0250]

[0251] In the above general formula (A), R represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, n is an integer from 1 to 20, Y 1 and Y 2 each independently represents N or O and are different from each other,

[0252] [2] The fluorine-containing isoxazole compound according to [1] above, wherein the fluorine-containing isoxazole compound is a compound represented by the following general formula (1).

[0253] [Chemical formula 48]

[0254]

[0255] In the above general formula (1), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, n is an integer from 1 to 20.

[0256] [3] The fluorine-containing isoxazole compound according to [1] above, wherein the fluorine-containing isoxazole compound is a compound represented by the following general formula (2).

[0257] [Chemical formula 49]

[0258]

[0259] In the above general formula (2), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , and n is an integer from 1 to 20.

[0260] [4] The fluorinated isoxazole compound according to [1] above, wherein the fluorinated isoxazole compound is a compound represented by the following general formula (3).

[0261] [Chemical formula 50]

[0262]

[0263] In the above general formula (3), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , and n is an integer from 1 to 20.

[0264] [5] The fluorinated isoxazole compound according to [1] above, wherein the fluorinated isoxazole compound is a compound represented by the following general formula (4).

[0265] [Chemical formula 51]

[0266]

[0267] In the above general formula (4), R'represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms or a heterocycle, A 4 represents an alkylene group represented by =C n H 2n , and n is an integer from 1 to 20.

[0268] [6] A method for producing a fluorinated isoxazole compound, characterized by comprising the following steps:

[0269] (I) Reacting a fluorine-containing compound selected from fluorine-containing carbonyl compounds, fluoroisobutene derivatives, and fluoroisobutane derivatives, hydroxylamine or a salt thereof, and optionally a compound represented by the following general formula (5) or a salt thereof; or

[0270] (II) Reacting a fluorine-containing compound selected from fluorine-containing carbonyl compounds, fluoroisobutene derivatives, and fluoroisobutane derivatives, an amine salt or an amine compound, and optionally a compound represented by the following general formula (5) or a salt thereof, thereby synthesizing a fluorinated isoxazole compound represented by the following general formula (A).

[0271] [Chemical formula 52]

[0272]

[0273] In the above general formulas (A) and (5), R represents a hydrogen atom, or a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A1 and A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, and A 4 represents =C n H 2n as shown by the alkylene group, n is an integer of 1 to 20, and Y 1 and Y 2 each independently represents N or O and are different from each other.

[0274] [7] The method for producing a fluorinated isoxazole compound according to the above [6], which comprises the following steps: reacting a fluorinated carbonyl compound represented by the following general formula (6) with hydroxylamine or a salt thereof represented by the following general formula (7) to obtain a fluorinated isoxazole compound represented by the following general formula (1).

[0275] [Chemical formula 53]

[0276]

[0277] In the above general formulas (1), (6) and (7), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, Z represents -OA 5 , -O-NA 5 A 6 , -NA 5 A 6 , -NA 5 (OA 6 ) or -NA 7 -NA 5 A 6 , A 1 and A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, and A 4 represents =C n H 2n as shown by the alkylene group, n is an integer of 1 to 20, and A 5 and A 6 and A 7Each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and the wavy bond represents a single bond for representing the (E) or (Z) stereoisomer.

[0278] [8] The method for producing a fluorinated isoxazole compound according to [6] above includes the following steps: reacting a fluorinated carbonyl compound represented by the following general formula (8), a compound represented by the following general formula (5) or a salt thereof, and a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (1).

[0279] [Chemical formula 54]

[0280]

[0281] In the above general formulas (1), (5) and (8), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, Z represents -OA 5 , -O-NA 6 A 7 , -NA 5 A 6 , -NA 5 (OA 6 ) or -NA 7 -NA 5 A 6 , A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer of 1 to 20, A 5 , A 6 and A 7 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0282] [9] The method for producing a fluorine-containing isoxazole compound according to [6] above includes the following steps: reacting a fluorine-containing carbonyl compound represented by the following general formula (9) with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then further reacting the resulting reaction product with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (1).

[0283] [Chemical formula 55]

[0284]

[0285] In the above general formulas (1), (5) and (9), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocyclic ring, Z represents -OA 5 , -O-NA 6 A 7 , -NA 5 A 6 , -NA 5 (OA 6 ), or -NA 7 -NA 5 A 6 , A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocyclic ring having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer from 1 to 20, A 5 , A 6 and A 7 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0286]

[10] The method for producing a fluorine-containing isoxazole compound according to [6] above includes the following steps: reacting a fluorine-containing carbonyl compound represented by the following general formula (10) with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (1).

[0287] [Chemical Formula 56]

[0288]

[0289] In the above general formulas (1), (5) and (10), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer from 1 to 20, and W + represents an ammonium cation, an imidazole cation, a pyridine cation, a quinuclidinium cation or a phosphonium cation.

[0290]

[11] The method for producing a fluorinated isoxazole compound according to [6] above, which comprises the following steps: carbonylating a fluoroisobutene derivative represented by the following general formula (11) in the presence of a nucleophile, then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (1).

[0291] [Chemical Formula 57]

[0292]

[0293] In the above general formulas (1), (5) and (11), R' represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 (OA 2 ), -NA 1 A 2 , -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A3 Each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n and the alkylene group shown, and n is an integer of 1 to 20.

[0294]

[12] The method for producing a fluorinated isoxazole compound according to [6] above includes the following steps: subjecting the compound obtained by the elimination reaction of a fluoroisobutane derivative represented by the following general formula (12) to carbonylation in the presence of a nucleophile, then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (1).

[0295] [Chemical formula 58]

[0296]

[0297] In the above general formulas (1), (5) and (12), R'represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocyclic ring, Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 , m is an integer of 0 to 3, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n and the alkylene group shown, n is an integer of 1 to 20, B 1 and B 2 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0298]

[13] The method for producing a fluorine-containing isoxazole compound according to [6] above includes the following steps: reacting a fluorine-containing carbonyl compound represented by the following general formula (13) with an amine salt or an amine compound to obtain a fluorine-containing isoxazole compound represented by the following general formula (2).

[0299] [Chemical formula 59]

[0300]

[0301] In the above general formulas (2) and (13), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocyclic ring, A 1 , A 2 and A 3 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms or a heterocyclic ring, and A 4 represents an alkylene group represented by =C n H 2n , and n is an integer from 1 to 20. The wavy bond represents a single bond for representing the stereoisomerism of (E) or (Z).

[0302]

[14] The method for producing a fluorine-containing isoxazole compound according to [6] above includes the following steps: reacting a fluorine-containing carbonyl compound represented by the following general formula (14), an amine salt or an amine compound, and an optional compound represented by the following general formula (5) or its salt to obtain a fluorine-containing isoxazole compound represented by the following general formula (2).

[0303] [Chemical formula 60]

[0304]

[0305] In the above general formulas (2), (5) and (14), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 (OA 2 ), -NA 1 A 2 , -NA 3 -NA 1A 2 ,-NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, and n is an integer of 1 to 20.

[0306]

[15] The method for producing a fluorinated isoxazole compound according to the above [6] includes the following steps: reacting a fluorinated carbonyl compound represented by the following general formula (15) with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting the obtained reaction product with an amine salt or an amine compound to obtain a fluorinated isoxazole compound represented by the following general formula (2).

[0307] [Chemical formula 61]

[0308]

[0309] In the above general formulas (2), (5) and (15), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a hydrogen atom, a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms or a heterocycle, A 4 represents =C n H 2n the alkylene group shown, and n is an integer of 1 to 20.

[0310]

[16] The method for producing a fluorinated isoxazole compound according to the above [6] includes the following steps: reacting a fluorinated carbonyl compound represented by the following general formula (10) with an alcohol, and then reacting the obtained reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with an amine salt or an amine compound to obtain a fluorinated isoxazole compound represented by the following general formula (2).

[0311] [Chemical formula 62]

[0312]

[0313] In the above general formulas (2), (5) and (10), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA1, -O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer from 1 to 20, and W + represents an ammonium cation, an imidazolium cation, a pyridinium cation, a quinuclidinium cation or a phosphonium cation.

[0314]

[17] The method for producing a fluorinated isoxazole compound according to the above [6] includes the following steps: carbonylating a fluoroisobutene derivative represented by the following general formula (11) in the presence of a nucleophile, then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with an amine salt or an amine compound to obtain a fluorinated isoxazole compound represented by the following general formula (2).

[0315] [Chemical formula 63]

[0316]

[0317] In the above general formulas (2), (5) and (11), R and R' each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3Each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, and n is an integer of 1 to 20.

[0318]

[18] The method for producing a fluorinated isoxazole compound according to the above [6] includes the following steps: subjecting a compound obtained by an elimination reaction of a fluoroisobutane derivative represented by the following general formula (12) to carbonylation in the presence of a nucleophile, then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with an amine salt or an amine compound, thereby obtaining a fluorinated isoxazole compound represented by the following general formula (2).

[0319] [Chemical formula 64]

[0320]

[0321] In the above general formulas (2), (5) and (12), R and R' each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 -NA 4 or a heterocycle, Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 , m is an integer of 0 to 3, A 1 , A 2 and A 3 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, n is an integer of 1 to 20, B 1 and B 2 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0322]

[19] The method for producing a fluorine-containing isoxazole compound according to [6] above includes the following steps: reacting a fluorine-containing carbonyl compound represented by the following general formula (10) with hydroxylamine or a salt thereof represented by the following general formula (7), and further reacting the resulting reaction product with a compound or a salt thereof represented by the following general formula (5), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (3).

[0323] [Chemical formula 65]

[0324]

[0325] In the above general formulas (3), (5) and (10), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer of 1 to 20, and W + represents an ammonium cation, an imidazole cation, a pyridine cation, a quininium cation or a phosphonium cation.

[0326]

[20] The method for producing a fluorine-containing isoxazole compound according to [6] above includes the following steps: carbonylating a fluorine-containing isobutene derivative represented by the following general formula (11) in the presence of a nucleophile, and then reacting the resulting reaction product with hydroxylamine or a salt thereof represented by the following general formula (7), and further reacting the resulting reaction product with a compound or a salt thereof represented by the following general formula (5), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (3).

[0327] [Chemical formula 66]

[0328]

[0329] In the above general formulas (3), (5) and (11), R'represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, and n is an integer from 1 to 20.

[0330]

[21] The method for producing a fluorinated isoxazole compound according to [6] above, which comprises the following steps: carbonylating a fluoroisobutane derivative represented by the following general formula (12) in the presence of a nucleophile, and then reacting with hydroxylamine or a salt thereof represented by the following general formula (7), and then reacting the resulting reaction product with a compound or a salt thereof represented by the following general formula (5), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (3).

[0331] [Chemical formula 67]

[0332]

[0333] In the above general formulas (3), (5) and (12), R'represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 -NA 4 or a heterocycle, Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 , m is an integer from 0 to 3, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, n is an integer from 1 to 20, B 1 and B 2Each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0334]

[22] According to the method for producing a fluorinated isoxazole compound described in [6] above, the method comprises the following steps: reacting a fluorinated isobutylene derivative represented by the following general formula (11), a compound represented by the following general formula (5) or a salt thereof, and a hydroxylamine represented by the following general formula (7) or a salt thereof, thereby obtaining a fluorinated isoxazole compound represented by the following general formula (4).

[0335] [Chemical formula 68]

[0336]

[0337] In the above general formulae (4), (5) and (11), R' represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 (OA 2 ),-NA 1 A 2 、-NA 3 -NA 1 A 2 、-NA 4 or heterocyclic ring, A 1 , A 2 and A 3 Each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 =C n H 2n In the alkylene group shown, n is an integer of 1 to 20.

[0338]

[23] A method for producing a fluorinated isoxazole compound according to the above-mentioned [6], comprising the following steps: reacting a fluorinated isobutylene derivative represented by the following general formula (11) with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (4-1).

[0339] [Chemical formula 69]

[0340]

[0341] In the above general formulae (4-1) and (11), R' represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0342]

[24] The method for producing a fluorine-containing isoxazole compound according to [6] above includes the following steps: reacting a fluorine-containing isobutane derivative represented by the following general formula (12), a compound represented by the following general formula (5) or a salt thereof, and a hydroxylamine represented by the following general formula (7) or a salt thereof to obtain a fluorine-containing isoxazole compound represented by the following general formula (4).

[0343] [Chemical formula 70]

[0344]

[0345] In the above general formulas (4), (5) and (12), R'represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocyclic ring, Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 , m is an integer from 0 to 3, A 1 , A 2 and A 3 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , n is an integer from 1 to 20, B 1 and B 2 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0346]

[25] The method for producing a fluorine-containing isoxazole compound according to [6] above includes the following steps: reacting a fluorine-containing isobutane derivative represented by the following general formula (12) with a hydroxylamine represented by the following general formula (7) to obtain a fluorine-containing isoxazole compound represented by the following general formula (4-1).

[0347] [Chemical formula 71]

[0348]

[0349] In the above general formulas (4-1) and (12), R’ represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and Y represents a halogen atom, -OB 1 、-SO m B 1 or -NB 1 B 2 , m is an integer from 0 to 3, and B 1 and B 2 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

[0350] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments, and various changes can be made within the scope of the present invention, including all modes included in the concept of the present invention and the claims.

[0351] Examples

[0352] Hereinafter, the examples of the present invention will be described. However, the present invention is not limited to these examples as long as it does not exceed its gist. In addition, the room temperature described below is set in the range of 20°C ± 10°C.

[0353] (Example 1)

[0354] Preparation of 3-Methoxy-4-(trifluoromethyl)-5-hydroxyisoxazole

[0355] Under ice-water cooling, 1.0 g (14 mmol) of hydroxylamine hydrochloride was dissolved in 75 g of methanol. Subsequently, 5.7 g (56 mmol) of triethylamine was added dropwise while maintaining the internal temperature at no more than 10°C. Then, 2.7 g (14 mmol) of methyl 3,3-difluoro-2-(trifluoromethyl)acrylate was added dropwise while maintaining the internal temperature at no more than 10°C, and the mixture was warmed to room temperature. After about 16 hours, 1N hydrochloric acid aqueous solution was added to adjust the pH of the reaction mixture to about 5, and ammonium chloride was added until saturation. After drying the organic phase with sodium sulfate, it was dissolved in a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and purified by silica gel column to obtain 0.2 g of the compound represented by the following formula (16). The isolated yield of the obtained compound was 8%.

[0356] [Chemical formula 72]

[0357]

[0358] The analysis results are as follows.

[0359] Mass spectrometry (APCI, m / z): 183 ([M] + )

[0360] (Example 2)

[0361] Preparation of 3-Ethoxy-4-(trifluoromethyl)-5-hydroxyisoxazole

[0362] Under ice-cooling, 1.0 g (14 mmol) of hydroxylamine hydrochloride was dissolved in 75 g of ethanol. Then, 5.7 g (56 mmol) of triethylamine was added dropwise in such a manner that the internal temperature did not exceed 10°C. Then, 2.7 g (14 mmol) of methyl 3,3-difluoro-2-(trifluoromethyl)acrylate was added dropwise in such a manner that the internal temperature did not exceed 10°C, and the mixture was warmed to room temperature. After about 16 hours, 1N hydrochloric acid aqueous solution was added until the pH of the reaction mixture became about 5, and ammonium chloride was added until saturation. After drying the organic phase with sodium sulfate, it was dissolved with a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3) and purified by silica gel column to obtain 0.4 g of the compound represented by the following formula (17). The isolated yield of the obtained compound was 13%.

[0363] [Chemical formula 73]

[0364]

[0365] The analysis results are as follows.

[0366] Mass spectrometry (APCI, m / z): 197 ([M] + )

[0367] (Example 3)

[0368] Preparation of 3-(Dibenzylamino)-4-(trifluoromethyl)-5-hydroxyisoxazole

[0369] Under ice-cooling, 3.9 g (47 mmol) of 1-methylimidazole was added to 20 g of tetrahydrofuran. Subsequently, 10 g (47 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 8 hours, a reaction mixture containing a salt of 3,3,3-trifluoro-2-(trifluoromethyl)propionate fluoride anion and 1,3-dimethylimidazolium cation was obtained. Under ice-cooling, this reaction mixture was added dropwise in such a manner that the internal temperature did not exceed 10 °C to a mixed solution of 5.6 g (47 mmol) of 2-(2-methoxyethoxy)ethanol and 20 g of tetrahydrofuran, and the temperature was raised to room temperature. After about 8 hours, a reaction mixture containing 2-(2-methoxyethoxy)ethyl 3,3,3-trifluoro-2-(trifluoromethyl)propionate was obtained. Under ice-cooling, this reaction mixture was added dropwise in such a manner that the internal temperature did not exceed 10 °C to a mixed solution of 9.3 g (47 mmol) of dibenzylamine, 9.5 g (94 mmol) of triethylamine and 20 g of tetrahydrofuran, and the temperature was raised to room temperature. After about 16 hours, a reaction mixture containing (E / Z)-2-(2-methoxyethoxy)ethyl 3-(dibenzylamino)-3-fluoro-2-(trifluoromethyl)acrylate was obtained. This reaction mixture was added dropwise in such a manner that the internal temperature did not exceed 10 °C under ice-cooling to a mixed solution of 1.6 g (47 mmol) of hydroxylamine, 9.5 g (94 mmol) of triethylamine and 20 g of tetrahydrofuran, and the temperature was raised to room temperature. After about 16 hours, 1N aqueous hydrochloric acid solution was added until the pH of the reaction mixture became about 5, and ammonium chloride was added until saturation. After drying the organic phase with sodium sulfate, it was dissolved in a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and purified by silica gel column to obtain 0.5 g of the compound represented by the following formula (18). The isolation yield of the obtained compound was 3%.

[0370] [Chemical formula 74]

[0371]

[0372] The analysis results are as follows.

[0373] Mass spectrometry (APCI, m / z): 348 ([M] + )

[0374] (Example 4)

[0375] Preparation of 3-(dibenzylamino)-4-(trifluoromethyl)-5-hydroxyisoxazole using methyl 3,3,3-trifluoro-2-(trifluoromethyl)propionate in place of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene in Example 3

[0376] Under ice-cooling, 1.9 g (9.5 mmol) of dibenzylamine and 1.9 g (19 mmol) of triethylamine were added to 30 g of tetrahydrofuran. Subsequently, 2.0 g (9.5 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propionate was added dropwise in such a manner that the internal temperature did not exceed 10 °C. After about 16 hours, a reaction mixture containing methyl (E / Z)-3-(dibenzylamino)-3-fluoro-2-(trifluoromethyl)acrylate was obtained. The reaction mixture was added dropwise to a mixed solution of 0.3 g (9.5 mmol) of hydroxylamine, 1.9 g (19 mmol) of triethylamine and 30 g of tetrahydrofuran under ice-cooling in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 16 hours, 1N aqueous hydrochloric acid solution was added so that the pH of the reaction mixture became about 5, and ammonium chloride was added until saturation. After drying the organic phase with sodium sulfate, it was dissolved in a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3), and silica gel column purification was carried out. The analysis result was the same as that of the product of Example 3.

[0377] (Example 5)

[0378] Preparation of 3-(1-azacyclononyl)-4-(trifluoromethyl)-5-hydroxyisoxazole

[0379] Under ice-cooling, 3.6 g (30 mmol) of 2-(2-methoxyethoxy)ethanol was added to 30 g of tetrahydrofuran. Subsequently, it was added dropwise to a mixed solution prepared by dissolving 10 g (30 mmol) of the salt of 3,3,3-trifluoro-2-(trifluoromethyl)propionate fluoride anion and 1-methyl-4-dimethylaminopyridinium cation in 30 g of tetrahydrofuran in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 8 hours, a reaction mixture containing 2-(2-methoxyethoxy)ethyl 3,3,3-trifluoro-2-(trifluoromethyl)propionate was obtained. The reaction mixture was added dropwise to a mixed solution of 3.8 g (30 mmol) of octamethylenimine, 6.1 g (60 mmol) of triethylamine and 30 g of tetrahydrofuran under ice-cooling in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 16 hours, the reaction mixture containing (E / Z)-3-(1-azacyclononyl)-3-fluoro-2-(trifluoromethyl)acrylic acid 2-(2-methoxyethoxy)ethyl ester was added dropwise to a mixed solution of 1.0 g (30 mmol) of hydroxylamine, 6.1 g (60 mmol) of triethylamine and 30 g of tetrahydrofuran under ice-cooling in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 16 hours, 1N aqueous hydrochloric acid solution was added so that the pH of the reaction mixture became about 5, and ammonium chloride was added until saturation. After drying the organic phase with sodium sulfate, it was dissolved in a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3), and silica gel column purification was carried out to obtain 0.9 g of the compound represented by the following formula (19). The isolated yield of the obtained compound was 11%.

[0380] [Chemical Formula 75]

[0381]

[0382] The analysis results are as described below.

[0383] Mass spectrometry (APCI, m / z): 278 ([M] + )

[0384] (Example 6)

[0385] Instead of the salt of 3,3,3-trifluoro-2-(trifluoromethyl)propionate fluoride anion and 1-methyl-4-dimethylaminopyridinium cation of Example 5, the preparation of 3-(1-azacyclononyl)-4-(trifluoromethyl)-5-hydroxyisoxazole from methyl (E / Z)-3-(1-azacyclononyl)-3-fluoro-2-(trifluoromethyl)acrylate was used.

[0386] Under ice-water cooling, 1.9 g (27 mmol) of hydroxylamine hydrochloride was dissolved in 60 g of methanol. Then, 8.2 g (81 mmol) of triethylamine was added dropwise while keeping the internal temperature not exceeding 10°C. Then, 5 g (27 mmol) of methyl (E / Z)-3-(1-azacyclononyl)-3-fluoro-2-(trifluoromethyl)acrylate was added dropwise while keeping the internal temperature not exceeding 10°C, and the temperature was raised to room temperature. After about 16 hours, 1N hydrochloric acid aqueous solution was added to make the pH of the reaction mixture about 5, and ammonium chloride was added until saturation. After drying the organic phase with sodium sulfate, it was dissolved in a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and purified by silica gel column. The analysis results were the same as those of the product of Example 5.

[0387] (Example 7)

[0388] Preparation of 3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-4-(trifluoromethyl)-5-hydroxyisoxazole

[0389] Under ice-cooling, 20 g (86 mmol) of 1,1,1,3,3-pentafluoro-methoxy-2-trifluoromethyl-propane was added to 80 g of tetrahydrofuran. Subsequently, 11 g (86 mmol) of diisopropylethylamine was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 8 hours, a reaction mixture containing 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene was obtained. The reaction mixture was added dropwise to a mixed solution of 8.7 g (86 mmol) of triethylamine and 20 g of tetrahydrofuran under ice-cooling in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 8 hours, a reaction mixture containing a salt of 3,3,3-trifluoro-2-(trifluoromethyl)propionate fluoride anion and triethylmethylammonium cation was obtained. Under ice-cooling, the reaction mixture was added dropwise to a mixed solution of 10 g (86 mmol) of 2-(2-methoxyethoxy)ethanol and 20 g of tetrahydrofuran in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 8 hours, a reaction mixture containing 2-(2-methoxyethoxy)ethyl 3,3,3-trifluoro-2-(trifluoromethyl)propionate was obtained. The reaction mixture was added dropwise to a mixed solution of 12 g (86 mmol) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 22 g (172 mmol) of diisopropylethylamine, and 40 g of tetrahydrofuran under ice-cooling in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 16 hours, a reaction mixture containing (E / Z)-2-(2-methoxyethoxy)ethyl 3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-3-fluoro-2-(trifluoromethyl)acrylate was obtained. The reaction mixture was added dropwise to a mixed solution of 2.8 g (86 mmol) of hydroxylamine, 22 g (172 mmol) of diisopropylethylamine, and 30 g of tetrahydrofuran under ice-cooling in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 16 hours, 1N hydrochloric acid aqueous solution was added so that the pH of the reaction mixture became about 5, and ammonium chloride was added until saturation. After drying the organic phase with sodium sulfate, it was dissolved in a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and purified by silica gel column to obtain 0.5 g of the compound represented by the following formula (20). The isolated yield of the obtained compound was 2%.

[0390] [Chemical formula 76]

[0391]

[0392] The analysis results are as follows.

[0393] Mass spectrometry (APCI, m / z): 290 ([M] + )

[0394] (Example 8)

[0395] Preparation of 3-Amino-N,N-dibenzyl-5-methoxy-4-(trifluoromethyl)isoxazole

[0396] Under ice-cooling, 1.1 g (3.0 mmol) of methyl 3-(dibenzylamino)-3-fluoro-2-(trifluoromethyl)-2-propenoate was added to 30 g of tetrahydrofuran, and 0.7 g (3.0 mmol) of 1-aminopyridinium iodide was further dissolved therein. Subsequently, 0.8 g (6.0 mmol) of diisopropylethylamine was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the mixture was then warmed to room temperature. After about 16 hours, the content was dissolved in a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3), and purified by silica gel column chromatography to obtain 0.2 g of the compound represented by the following formula (21). The isolated yield of the obtained compound was 15%.

[0397] [Chemical formula 77]

[0398]

[0399] The analysis results are as follows.

[0400] Mass spectrometry (APCI, m / z): 362 ([M] + )

[0401] 1 1H-NMR (400 MHz, CDCl3) δ ppm: 7.33 - 7.24 (m, 10H), 4.65 (s, 4H), 3.86 (s, 3H)

[0402] (Example 9)

[0403] Preparation of 3-Fluoro-5-methoxy-4-(trifluoromethyl)isoxazole

[0404] Under ice-cooling, 0.6 g (3.0 mmol) of methyl 3,3-difluoro-2-(trifluoromethyl)acrylate was added to 20 g of tetrahydrofuran. Subsequently, a solution prepared by dissolving 0.9 g (3.0 mmol) of tetrabutylammonium azide in 20 g of tetrahydrofuran was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the mixture was then warmed to room temperature. After about 72 hours, the content was dissolved in a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3), and purified by silica gel column chromatography to obtain 0.1 g of the compound represented by the following formula (22). The isolated yield of the obtained compound was 25%.

[0405] [Chemical formula 78]

[0406]

[0407] The analysis results are as follows.

[0408] Mass spectrometry (APCI, m / z): 185 ([M] + )

[0409] (Example 10)

[0410] Preparation of 4-(3-(5-methoxy-4-(trifluoromethyl))isoxazolyl)thiomorpholine 1,1-dioxide

[0411] Under ice-water cooling, 0.3 g (2.0 mmol) of thiomorpholine 1,1-dioxide and 0.5 g (4.0 mmol) of diisopropylethylamine were added to 20 g of tetrahydrofuran. Then, 0.4 g (2.0 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propionate was added dropwise while maintaining the internal temperature at no more than 10 °C, and the temperature was raised to room temperature. After about 16 hours, the content was cooled with ice water, 0.2 g (2.0 mmol) of hydroxylamine-O-sulfonic acid was added while maintaining the internal temperature at no more than 10 °C, then 0.8 g (6.0 mmol) of diisopropylethylamine was added dropwise, and the temperature was raised to room temperature. After about 36 hours, the content was dissolved in a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and purified by silica gel column chromatography to obtain 0.1 g of the compound represented by the following formula (23). The isolated yield of the obtained compound was 9%.

[0412] [Chemical formula 79]

[0413]

[0414] The analysis results are as follows.

[0415] Mass spectrometry (APCI, m / z): 300 ([M] + )

[0416] (Example 11)

[0417] Preparation of 5-ethoxy-3-((4-methoxybenzyl)oxy)-4-(trifluoromethyl)isoxazole

[0418] Under ice-cooling, 0.5 g (10.0 mmol) of ethanol was added to 20 g of tetrahydrofuran. Subsequently, a mixed solution prepared by dissolving 3.0 g (9.0 mmol) of the salt of 3,3,3-trifluoro-2-(trifluoromethyl)propionate fluoride anion and 1-methyl-4-dimethylaminopyridinium cation in 30 g of tetrahydrofuran was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was then raised to room temperature. After about 8 hours, the reaction mixture was cooled with ice-water and added dropwise to a mixed solution of 1.2 g (9.0 mmol) of 4-methoxybenzyl alcohol, 1.8 g (18.0 mmol) of triethylamine, and 30 g of tetrahydrofuran in such a manner that the internal temperature did not exceed 10 °C, and the temperature was then raised to room temperature. After about 16 hours, the reaction mixture was cooled with ice-water, 2.6 g (9.0 mmol) of 1-aminopyridine mesylate was added in such a manner that the internal temperature did not exceed 10 °C, and then 2.3 g (18.0 mmol) of diisopropylethylamine was added dropwise, and the temperature was then raised to room temperature. After about 16 hours, the content was dissolved in a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and purified by silica gel column chromatography to obtain 0.2 g of the compound represented by the following formula (24). The isolated yield of the obtained compound was 8%.

[0419] [Chemical formula 80]

[0420]

[0421] The analysis results are as described below.

[0422] Mass spectrometry (APCI, m / z): 317 ([M] + )

[0423] (Example 12)

[0424] Preparation of 3-amino-5-((2-ethylhexyl)oxy)-N-methyl-N-(3-pyridyl)-4-(trifluoromethyl)isoxazole

[0425] Under ice-cooling, 3.9 g (47.0 mmol) of 1-methylimidazole was added to 20 g of tetrahydrofuran. Subsequently, 10 g (47.0 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was then raised to room temperature. After about 8 hours, a reaction mixture containing a salt of 3,3,3-trifluoro-2-(trifluoromethyl)propionate fluoride anion and 1,3-dimethylimidazolium cation was obtained. The reaction mixture was added dropwise in such a manner that the internal temperature did not exceed 10 °C under ice-cooling to a mixed solution of 6.1 g (47.0 mmol) of 2-ethyl-1-hexanol and 20 g of tetrahydrofuran, and the temperature was then raised to room temperature. After about 8 hours, a reaction mixture containing 2-ethylhexyl 3,3,3-trifluoro-2-(trifluoromethyl)propionate was obtained. The reaction mixture was added dropwise in such a manner that the internal temperature did not exceed 10 °C under ice-cooling to a mixed solution of 5.1 g (47.0 mmol) of 3-(methylamino)pyridine, 9.5 g (94.0 mmol) of triethylamine and 20 g of tetrahydrofuran, and the temperature was then raised to room temperature. After about 16 hours, the reaction mixture was added dropwise in such a manner that the internal temperature did not exceed 10 °C under ice-cooling to a mixed solution of 10 g (47.0 mmol) of o-(mesitylenesulfonyl)hydroxylamine, 9.5 g (94.0 mmol) of triethylamine and 20 g of tetrahydrofuran, and the temperature was then raised to room temperature. After about 16 hours, 1N aqueous hydrochloric acid solution was added to adjust the pH of the reaction mixture to about 5, ammonium chloride was added until saturation, the organic phase was dried over sodium sulfate, dissolved in a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3), and purified by silica gel column chromatography to obtain 0.5 g of the compound represented by the following formula (25). The isolated yield of the obtained compound was 3%.

[0426] [Chemical Formula 81]

[0427]

[0428] The analysis results are as described below.

[0429] Mass spectrometry (APCI, m / z): 371 ([M] + )

[0430] (Example 13)

[0431] Preparation of 4-(3-(5-(2-methoxy)ethoxy-4-(trifluoromethyl))isoxazolyl)-2-piperazinone

[0432] Under ice-cooling, 20 g (86.0 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethyl-propane was added to 80 g of tetrahydrofuran. Subsequently, 11 g (86.0 mmol) of diisopropylethylamine was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was then raised to room temperature. After about 8 hours, a reaction mixture containing 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene was obtained. This reaction mixture was added dropwise under ice-cooling in such a manner that the internal temperature did not exceed 10 °C to a mixed solution of 9.6 g (86.0 mmol) of quinuclidine and 20 g of tetrahydrofuran, and the temperature was then raised to room temperature. After about 8 hours, a reaction mixture containing a salt of the fluoride anion of 3,3,3-trifluoro-2-(trifluoromethyl)propionic acid and the N-methylquinuclidinium cation was obtained. This reaction mixture was added dropwise under ice-cooling in such a manner that the internal temperature did not exceed 10 °C to a mixed solution of 6.5 g (86.0 mmol) of 2-methoxyethanol and 20 g of tetrahydrofuran, and the temperature was then raised to room temperature. After about 8 hours, a reaction mixture containing 2-methoxyethyl 3,3,3-trifluoro-2-(trifluoromethyl)propionate was obtained. This reaction mixture was added dropwise under ice-cooling in such a manner that the internal temperature did not exceed 10 °C to a mixed solution of 8.6 g (86.0 mmol) of piperazinone, 22 g (172.0 mmol) of diisopropylethylamine and 40 g of tetrahydrofuran, and the temperature was then raised to room temperature. After about 16 hours, this reaction mixture was added dropwise under ice-cooling in such a manner that the internal temperature did not exceed 10 °C to a mixed solution of 16 g (86.0 mmol) of 1,1,1-trimethylhydrazinium trifluoroacetate, 22 g (172.0 mmol) of diisopropylethylamine and 30 g of tetrahydrofuran, and the temperature was then raised to room temperature. After about 16 hours, 1N aqueous hydrochloric acid was added so that the pH of the reaction mixture became about 5, and ammonium chloride was added until saturation. After drying the organic phase with sodium sulfate, it was dissolved in a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and silica gel column purification was carried out to obtain 0.5 g of the compound represented by the following formula (26). The isolated yield of the obtained compound was 2%.

[0433] [Chemical formula 82]

[0434]

[0435] The analysis results are as follows.

[0436] Mass spectrometry (APCI, m / z): 309 ([M] + )

[0437] (Example 14)

[0438] Preparation of 5-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(trifluoromethyl)isoxazol-3-ol

[0439] Under ice-cooling, 2 g (6.4 mmol) of hydroxylammonium bis(trifluoromethanesulfonyl)imide was dissolved in 30 g of tetrahydrofuran. Subsequently, a mixed solution prepared by dissolving 1.9 g (6.4 mmol) of the salt of 3,3,3-trifluoro-2-(trifluoromethyl)propionate fluoride anion and N-methylimidazolium cation in 20 g of tetrahydrofuran was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 3 hours, the reaction mixture was cooled with ice water, 0.7 g (6.4 mmol) of triethylamine was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 4 hours, the reaction mixture was cooled in ice water and added dropwise to a mixed solution of 0.8 g (6.4 mmol) of 1,2,3-benzotriazole, 2.3 g (23.0 mmol) of triethylamine and 30 g of tetrahydrofuran in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 16 hours, the content was dissolved in a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3), and purified by silica gel column chromatography to obtain 0.3 g of the compound represented by the following formula (27). The isolated yield of the obtained compound was 17%.

[0440] [Chemical formula 83]

[0441]

[0442] The analysis results are as follows.

[0443] Mass spectrometry (APCI, m / z): 270 ([M] + )

[0444] 1 H-NMR (400 MHz, CDCl3) δ ppm: 8.19 (dd, 1H), 8.12 (dd, 1H), 7.41 (ddd, 1H), 7.33 (ddd, 1H)

[0445] (Example 15)

[0446] Preparation of 5-(10H-spiro[acridine-9,9'-fluorene]-10-yl)-4-(trifluoromethyl)isoxazol-3-ol

[0447] Under ice-cooling, 0.9 g (8.5 mmol) of triethylamine was added to 20 g of acetonitrile. Then, 1.8 g (8.5 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 4 hours, the reaction mixture was added dropwise to a mixed solution of 3.0 g (8.5 mmol) of hydroxylammonium = tetraphenylborate and 20 g of acetonitrile under ice-cooling in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 3 hours, the reaction mixture was cooled with ice water, 0.9 g (8.5 mmol) of triethylamine was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 4 hours, the reaction mixture was added dropwise to a mixed solution of 2.8 g (8.5 mmol) of 10H-spiro[acridine-9,9'-fluorene], 3.0 g (30.0 mmol) of triethylamine and 20 g of acetonitrile under ice-cooling in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 16 hours, the content was dissolved with a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and silica gel column purification was carried out to obtain 0.4 g of the compound represented by the following formula (27). The isolated yield of the obtained compound was 10%.

[0448] [Chemical formula 84]

[0449]

[0450] The analysis results are as described below.

[0451] Mass spectrometry (APCI, m / z): 482 ([M] + )

[0452] (Example 16)

[0453] Preparation of 5-((2,2,4,4-tetramethylpentan-3-ylidene)amino)-4-(trifluoromethyl)isoxazol-3-ol

[0454] Under ice-cooling, 1.1 g (4.8 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethyl-propane was added to 40 g of tetrahydrofuran. Then, 0.6 g (4.8 mmol) of diisopropylethylamine was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 4 hours, the reaction mixture was added dropwise in such a manner that the internal temperature did not exceed 10 °C under ice-cooling to a mixed solution of 0.6 g (4.8 mmol) of 4-dimethylaminopyridine and 15 g of tetrahydrofuran, and the temperature was raised to room temperature. After about 4 hours, under ice-cooling, the reaction mixture was added dropwise in such a manner that the internal temperature did not exceed 10 °C to a mixed solution of 1.5 g (4.8 mmol) of hydroxylammonium bis(trifluoromethanesulfonyl)imide and 20 g of tetrahydrofuran, and the temperature was raised to room temperature. After about 3 hours, the reaction mixture was cooled with ice-water, 0.6 g (4.8 mmol) of diisopropylethylamine was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 4 hours, the reaction mixture was added dropwise in such a manner that the internal temperature did not exceed 10 °C under ice-cooling to a mixed solution of 0.7 g (4.8 mmol) of 2,2,4,4-tetramethyl-3-pentanone imine, 2.8 g (22.0 mmol) of diisopropylethylamine and 20 g of tetrahydrofuran, and the temperature was raised to room temperature. After about 16 hours, the content was dissolved with a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and silica gel column purification was carried out to obtain 0.1 g of the compound represented by the following formula (28). The isolated yield of the obtained compound was 9%.

[0455] [Chemical formula 85]

[0456]

[0457] The analysis results are as described below.

[0458] Mass spectrometry (APCI, m / z): 292 ([M] + )

[0459] (Example 17)

[0460] Preparation of 5-fluoro-3-methoxy-4-trifluoromethylisoxazole

[0461] Under ice-cooling, 3.1 g (10.0 mmol) of hydroxylammonium bis(trifluoromethylsulfonyl)amide and 2.1 g (10.0 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene were added to 75 g of 4-methyltetrahydropyran. Subsequently, a solution prepared by dissolving 4.7 g (20.0 mmol) of tert-butylimino-tris(dimethylamino)phosphorane in 25 g of 4-methyltetrahydropyran was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was then raised to room temperature. After about 16 hours, ice-water cooling was carried out, and then a solution prepared by dissolving 6.1 g (26.0 mmol) of tert-butylimino-tris(dimethylamino)phosphorane in 20 g of 4-methyltetrahydropyran was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was then raised to room temperature. After about 8 hours, the reaction mixture was dissolved in a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3), and purified by silica gel column chromatography to obtain 0.04 g of the compound represented by the following formula (29). The isolated yield of the obtained compound was 2%.

[0462] [Chemical formula 86]

[0463]

[0464] The analysis results are as follows.

[0465] Mass spectrometry (APCI, m / z): 185 ([M] + )

[0466] (Example 18)

[0467] Preparation of 3-methoxy-5-morpholin-4-yl-4-trifluoromethylisoxazole

[0468] Under ice-cooling, 0.7 g (10.0 mmol) of hydroxylamine hydrochloride and 2.1 g (10.0 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene were added to 30 g of methanol. Subsequently, a solution prepared by dissolving 2.0 g (20.0 mmol) of triethylamine in 10 g of methanol was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was then raised to room temperature. After about 16 hours, ice-water cooling was carried out, and then a solution prepared by dissolving 4.5 g (52.0 mmol) of morpholine in 15 g of methanol was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was then raised to room temperature. After about 8 hours, the reaction mixture was dissolved in a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3), and purified by silica gel column chromatography to obtain 0.5 g of the compound represented by the following formula (30). The isolated yield of the obtained compound was 18%.

[0469] [Chemical formula 87]

[0470]

[0471] The analysis results are as described below.

[0472] Mass spectrometry (APCI, m / z): 252 ([M] + )

[0473] 1 1H-NMR (400 MHz, CDCl3) δ ppm: 3.80 (m, 7H), 3.50 (dd, 4H)

[0474] (Example 19)

[0475] Preparation of 5-fluoro-3-methoxy-4-trifluoromethylisoxazole using 1,1,1,3,3-pentafluoro-3-methoxy-trifluoromethyl-propane in place of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene of Example 17

[0476] Under ice-water cooling, 3.1 g (10 mmol) of hydroxylammonium = bis(trifluoromethylsulfonyl)amine and 23 g (10 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-trifluoromethyl-propane were added to 75 g of 4-methyltetrahydropyran. Then, a solution prepared by dissolving 7.1 g (30 mmol) of tert-butylimino-tris(dimethylamino)phosphorane in 25 g of 4-methyltetrahydropyran was added dropwise in such a manner that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature. After about 16 hours, ice-water cooling was carried out, and further, a solution prepared by dissolving 6.1 g (26 mmol) of tert-butylimino-tris(dimethylamino)phosphorane in 20 g of 4-methyltetrahydropyran was added dropwise in such a manner that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature. After about 8 hours, the reaction mixture was dissolved in a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and silica gel column purification was carried out. The analysis results of the obtained compound were the same as those of the product of Example 17.

[0477] In addition, in Example 19, although the isolated yield of the obtained compound was not calculated, due to the possible by-products generated during the process of forming 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene from 1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethyl)-propane in the system, an increase in the types and amounts of impurities was predicted. Therefore, it is considered that the production method of Example 17 has a higher isolated yield of the obtained product compared with the corresponding production method of Example 19.

[0478] (Example 20)

[0479] Preparation of 5-(1-benzimidazolyl)-3-methoxy-4-trifluoromethylisoxazole

[0480] Under ice-cooling, 1.0 g (14 mmol) of hydroxylamine hydrochloride and 3.1 g (14 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene were added to 45 g of methanol. Subsequently, a solution prepared by dissolving 2.9 g (28 mmol) of triethylamine in 20 g of methanol was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 16 hours, ice-water cooling was carried out, and then a solution prepared by dissolving 1.7 g (14 mmol) of benzimidazole and 4.4 g (42 mmol) of triethylamine in 20 g of methanol was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 8 hours, the reaction mixture was dissolved in a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and silica gel column purification was carried out to obtain 0.6 g of the compound represented by the following formula (31). The isolated yield of the obtained compound was 15%.

[0481] [Chemical formula 88]

[0482]

[0483] The analysis results are as follows.

[0484] Mass spectrometry (APCI, m / z): 283 ([M] + )

[0485] 1 1H-NMR (400 MHz, CDCl3) δ ppm: 8.21 (s, 1H), 7.90 (d, 1H), 7.70 (d, 1H), 7.46 (dd, 2H), 4.16 (m, 3H)

[0486] (Example 21)

[0487] Preparation of 3-methoxy-5-(N-methoxymethylamino)-4-trifluoromethylisoxazole

[0488] Under ice-cooling, 1.0 g (14 mmol) of hydroxylamine hydrochloride and 3.1 g (14 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene were added to 45 g of methanol. Subsequently, a solution prepared by dissolving 2.9 g (28 mmol) of triethylamine in 20 g of methanol was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 16 hours, ice-water cooling was carried out, and then a solution prepared by dissolving 1.4 g (14 mmol) of N-methoxymethylamine hydrochloride and 5.8 g (56 mmol) of triethylamine in 20 g of methanol was added dropwise in such a manner that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After about 8 hours, the reaction mixture was dissolved in a mixed solvent of hexane and ethyl acetate (hexane∶ethyl acetate = 7∶3), and silica gel column purification was carried out to obtain 0.3 g of the compound represented by the following formula (32). The isolated yield of the obtained compound was 8%.

[0489] [Chemical Formula 89]

[0490]

[0491] The analysis results are as described below.

[0492] Mass spectrometry (APCI, m / z): 226 ([M] + )

[0493] 1 1H-NMR (400 MHz, CDCl3) δ ppm: 3.98 (s, 3H), 3.74 (s, 3H), 3.21 (s, 3H)

[0494] (Example 22)

[0495] Preparation of 5-[(N-diphenylmethylene)amino]-3-methoxy-4-trifluoromethylisoxazole

[0496] 0.5 g (7.3 mmol) of hydroxylamine hydrochloride and 1.5 g (7.1 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene were added to 14 ml of methanol. Then, after cooling to 0 °C, 1.5 g (14.6 mmol) of triethylamine was added dropwise, and the temperature was raised to room temperature. After about 19 hours, it was cooled to 0 °C, 1.3 g (7.2 mmol) of diphenylketimine and 2.2 g (21.8 mmol) of triethylamine were added dropwise, and the temperature was raised to 60 °C. After about 7 hours, it was cooled, and silica gel column purification was carried out to obtain a trace amount of the compound represented by the following formula (33).

[0497] [Chemical Formula 90]

[0498]

[0499] The analysis results are as described below.

[0500] Mass spectrometry (APCI, m / z): 346 ([M] + )

Claims

1. A fluorinated isoxazole compound represented by the following general formula (A), wherein, [Chemical formula 1] In the above general formula (A), R represents a hydrogen atom, or a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocyclic ring having 1 to 12 carbon atoms A 4 represents =C n H 2n the alkylene group shown n is an integer from 1 to 20, Y 1 and Y 2 each independently represents N or O and are different from each other.

2. The fluoro isoxazole compound according to claim 1, wherein The fluorinated isoxazole compound is a compound represented by the following general formula (1), (2), (3) or (4), [Chemical formula 2] In the above general formula (1), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , and n is an integer from 1 to 20; [Chemical formula 3] In the above general formula (2), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocyclic ring, A 1 , A 2 and A 3 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms or a heterocyclic ring, A 4 represents an alkylene group represented by =C n H 2n , and n is an integer from 1 to 20; [Chemical formula 4] In the above general formula (3), X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents an alkylene group represented by =C n H 2n , and n is an integer from 1 to 20; Or [Chemical formula 5] In the above general formula (4), R' represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom, -OA 1 , -O-NA 1 A 2 , -NA 1 A 2 , -NA 1 (OA 2 ), -NA 3 -NA 1 A 2 , -NA 4 or a heterocyclic ring, A 1 , A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms or a heterocyclic ring, A 4 represents an alkylene group represented by =C n H 2n , and n is an integer from 1 to 20.

3. A method for manufacturing a fluorine-containing isoxazole compound, characterized in that, Comprising the following steps: (I) React a fluorinated compound selected from fluorinated carbonyl compounds, fluoroisobutene derivatives and fluoroisobutane derivatives, hydroxylamine or its salt, and an optional compound or its salt represented by the following general formula (5); or (II) React a fluorinated compound selected from fluorinated carbonyl compounds, fluoroisobutene derivatives and fluoroisobutane derivatives, an amine salt or amine compound, and an optional compound or its salt represented by the following general formula (5), thereby synthesizing a fluorinated isoxazole compound represented by the following general formula (A), [Chemical formula 6] In the above general formulas (A) and (5), R represents a hydrogen atom, or a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocyclic ring having 1 to 12 carbon atoms A 4 represents =C n H 2n the alkylene group shown n is an integer from 1 to 20, Y 1 and Y 2 each independently represents N or O and are different from each other.

4. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: React a fluorinated carbonyl compound represented by the following general formula (6) with hydroxylamine or its salt represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (1), [Chemical formula 7] In the above general formulas (1), (6) and (7), X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, Z represents -OA 5 、 -O-NA 5 A 6 、 -NA 5 A 6 、 -NA 5 (OA 6 ) or -NA 7 -NA 5 A 6 , A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocyclic ring having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer from 1 to 20, A 5 、A 6 and A 7 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, The wavy bond represents a single bond for representing the stereoisomerism of (E) or (Z).

5. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: React a fluorinated carbonyl compound represented by the following general formula (8), a compound or its salt represented by the following general formula (5), and hydroxylamine or its salt represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (1), [Chemical formula 8] In the above general formulas (1), (5) and (8), X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, Z represents -OA 5 、-O-NA 6 A 7 、-NA 5 A 6 、-NA 5 (OA 6 ) or -NA 7 -NA 5 A 6 , A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocycle having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer from 1 to 20, A 5 、A 6 and A 7 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

6. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: React a fluorinated carbonyl compound represented by the following general formula (9) with a compound or its salt represented by the following general formula (5) in the presence of a base, and then further react the obtained reaction product with hydroxylamine or its salt represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (1), [Chemical formula 9] In the above general formulas (1), (5) and (9), X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, Z represents -OA 5 、-O-NA 6 A 7 、-NA 5 A 6 、-NA 5 (OA 6 ) or -NA 7 -NA 5 A 6 , A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocyclic ring having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer from 1 to 20, A 5 、 A 6 and A 7 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

7. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: React a fluorinated carbonyl compound represented by the following general formula (10) with an alcohol, then react the obtained reaction product with a compound or its salt represented by the following general formula (5) in the presence of a base, and then react with hydroxylamine or its salt represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (1), [Chemical formula 10] In the above general formulas (1), (5) and (10), X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocyclic ring having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer from 1 to 20, W + represents an ammonium cation, an imidazolium cation, a pyridinium cation, a quinuclidinium cation or a phosphonium cation.

8. The method for producing a fluorine-containing isoxazole compound according to claim 3, which comprises the following steps: Carbonylating a fluorine-containing isobutene derivative represented by the following general formula (11) in the presence of a nucleophile, then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (1), [Chemical formula 11] In the above general formulas (1), (5) and (11), R' represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 (OA 2 )、-NA 1 A 2 、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer from 1 to 20.

9. The method for producing a fluorine-containing isoxazole compound according to claim 3, which comprises the following steps: Carbonylating a compound obtained by an elimination reaction of a fluorine-containing isobutane derivative represented by the following general formula (12) in the presence of a nucleophile, then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (1), [Chemical formula 12] In the above general formulas (1), (5) and (12), R' represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 , m is an integer from 0 to 3, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer from 1 to 20, B 1 and B 2 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

10. The method for producing a fluorine-containing isoxazole compound according to claim 3, which comprises the following steps: Reacting a fluorine-containing carbonyl compound represented by the following general formula (13) with an amine salt or an amine compound, thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (2), [Chemical formula 13] In the above general formulas (2) and (13), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocyclic ring having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer from 1 to 20, The wavy bond represents a single bond for representing the stereoisomerism of (E) or (Z).

11. The method for producing a fluorine-containing isoxazole compound according to claim 3, which comprises the following steps: Reacting a fluorine-containing carbonyl compound represented by the following general formula (14), an amine salt or an amine compound, and optionally a compound represented by the following general formula (5) or a salt thereof, thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (2), [Chemical formula 14] In the above general formulas (2), (5) and (14), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 (OA 2 )、-NA 1 A 2 、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer from 1 to 20.

12. The method for producing a fluorine-containing isoxazole compound according to claim 3, which comprises the following steps: Reacting a fluorine-containing carbonyl compound represented by the following general formula (15) with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting the resulting reaction product with an amine salt or an amine compound, thereby obtaining a fluorine-containing isoxazole compound represented by the following general formula (2), [Chemical formula 15] In the above general formulas (2), (5) and (15), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 , A 2 and A 3 each independently represents a hydrogen atom, a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, or a heterocyclic ring, A 4 represents =C n H 2n the alkylene group shown n is an integer from 1 to 20.

13. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: Reacting a fluorinated carbonyl compound represented by the following general formula (10) with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with an amine salt or an amine compound, thereby obtaining a fluorinated isoxazole compound represented by the following general formula (2), [Chemical formula 16] In the above general formulas (2), (5) and (10), R represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocyclic ring having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer of 1 to 20, W + represents an ammonium cation, an imidazolium cation, a pyridinium cation, a quinuclidinium cation or a phosphonium cation.

14. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: Carbonylating a fluoroisobutene derivative represented by the following general formula (11) in the presence of a nucleophile, and then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with an amine salt or an amine compound, thereby obtaining a fluorinated isoxazole compound represented by the following general formula (2), [Chemical formula 17] In the above general formulas (2), (5) and (11), R and R' each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms. A 4 represents =C n H 2n the alkylene group shown n is an integer of 1 to 20.

15. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: Carbonylating a compound obtained by an elimination reaction of a fluoroisobutane derivative represented by the following general formula (12) in the presence of a nucleophile, and then reacting with an alcohol, and then reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof in the presence of a base, and then reacting with an amine salt or an amine compound, thereby obtaining a fluorinated isoxazole compound represented by the following general formula (2), [Chemical formula 18] In the above general formulas (2), (5) and (12), R and R' each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 -NA 4 or a heterocycle, Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 , m is an integer of 0 to 3, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer of 1 to 20, B 1 and B 2 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

16. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: Reacting a fluorinated carbonyl compound represented by the following general formula (10) with a hydroxylamine or a salt thereof represented by the following general formula (7), and further reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof, thereby obtaining a fluorinated isoxazole compound represented by the following general formula (3), [Chemical formula 19] In the above general formulas (3), (5) and (10), X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group or heterocyclic ring having 1 to 12 carbon atoms A 4 represents =C n H 2n the alkylene group shown n is an integer of 1 to 20, W + represents an ammonium cation, an imidazolium cation, a pyridinium cation, a quinuclidinium cation or a phosphonium cation.

17. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: Carbonylating a fluoroisobutene derivative represented by the following general formula (11) in the presence of a nucleophile, and then reacting with a hydroxylamine or a salt thereof represented by the following general formula (7), and then further reacting the resulting reaction product with a compound represented by the following general formula (5) or a salt thereof, thereby obtaining a fluorinated isoxazole compound represented by the following general formula (3), [Chemical formula 20] In the above general formulas (3), (5) and (11), R' represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown, n is an integer of 1 to 20.

18. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: Carbonylating a fluoroisobutane derivative represented by the following general formula (12) in the presence of a nucleophile, and then reacting the resulting reaction product with a compound or a salt thereof represented by the following general formula (5) after reacting with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (3). [Chemical formula 21] In the above general formulas (3), (5) and (12), R’ represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms. X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 -NA 4 or a heterocycle, Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 , m is an integer of 0 to 3. A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer of 1 to 20. B 1 and B 2 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

19. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: Reacting a fluoroisobutene derivative represented by the following general formula (11), a compound or a salt thereof represented by the following general formula (5), and a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (4). [Chemical formula 22] In the above general formulas (4), (5) and (11), R’ represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms. X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 (OA 2 )、-NA 1 A 2 、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms A 4 represents =C n H 2n the alkylene group shown, n is an integer of 1 to 20.

20. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: Reacting a fluoroisobutene derivative represented by the following general formula (11) with a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (4-1). [Chemical formula 23] In the above general formulas (4-1) and (11), R’ represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

21. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: Reacting a fluoroisobutane derivative represented by the following general formula (12), a compound or a salt thereof represented by the following general formula (5), and a hydroxylamine or a salt thereof represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (4). [Chemical formula 24] In the above general formulas (4), (5) and (12), R’ represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms. X represents a halogen atom, -OA 1 、-O-NA 1 A 2 、-NA 1 A 2 、-NA 1 (OA 2 )、-NA 3 -NA 1 A 2 、-NA 4 or a heterocycle, Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 , m is an integer of 0 to 3. A 1 、A 2 and A 3 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, A 4 represents =C n H 2n the alkylene group shown n is an integer of 1 to 20. B 1 and B 2 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

22. The method for producing a fluorinated isoxazole compound according to claim 3, which comprises the following steps: Reacting a fluoroisobutane derivative represented by the following general formula (12) with a hydroxylamine represented by the following general formula (7), thereby obtaining a fluorinated isoxazole compound represented by the following general formula (4-1). [Chemical formula 25] In the above general formulas (4-1) and (12), R’ represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms. Y represents a halogen atom, -OB 1 , -SO m B 1 or -NB 1 B 2 , m is an integer of 0 to 3. B 1 and B 2 each independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms.

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