Method for producing fluorine-containing fused triazole derivative

Abstract

To provide a production method that enables the production of a fluorine-containing fused triazole derivative through the use of a fluorine-containing carboxylic acid ester, which has greater stability and safety than trifluoroacetic anhydride or trifluoroacetyl chloride and is easily handled in liquid form at room temperature, as a starting material in a single-step safe reaction.SOLUTION: A method for producing a fluorine-containing fused triazole derivative, the method including a step of reacting a fluorine-containing carboxylic acid ester with a nitrogen-containing heterocyclic compound to provide the fluorine-containing fused triazole derivative.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a fluorine-containing fused ring triazole derivative. [Background technology]

[0002] Fused triazole derivatives, which have a structure in which a nitrogen-containing heteroaromatic ring is fused to a triazole ring, are known to have various pharmacological activities. Specific examples of pharmaceuticals containing fused triazole derivatives include Trapidil, a vasodilator with a triazolopyrimidine partial structure; Filgotinib, an anti-inflammatory drug with a triazolopyridine partial structure; and Vebreltinib, an antitumor drug with a triazolopyridazine partial structure. Similarly, pesticides containing fused triazole derivatives include Tricyclazole, a fungicide with a triazolothiazole partial structure; Penoxsulam, a herbicide with a triazolopyrimidine partial structure; and Iptriazopyrid, a herbicide with a triazolopyridine partial structure. From this perspective, there has been interest in introducing fluorine-containing substituents into fused triazole derivatives in the hope of further improving their pharmacological activity, and an efficient method for producing fluorine-containing fused triazole derivatives has been sought. Specifically, the development of a one-step method in which the introduction of fluorine-containing substituents and the construction of the triazole ring are carried out consecutively has been investigated. Specifically, Non-Patent Document 1 discloses a production method using trifluoroacetic anhydride or trifluoroacetonitrile, Patent Document 1 discloses a production method using trifluoroacetyl chloride, and Non-Patent Document 2 discloses a production method using trifluoroacetohydrazide. On the other hand, Patent Document 2 discloses a multi-step production method using trifluoroacetic acid ethyl ester and hydroxylamine hydrochloride. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 99 / 06404 [Patent Document 2] Chinese Patent Application Publication No. 111635407 [Non-patent literature]

[0004] [Non-Patent Document 1] Journal of Fluorine Chemistry, 1980, Vol. 15, pp. 179-181 [Non-patent document 2] The Journal of Organic Chemistry, 2005, Vol. 70, pp. 2878-2880 Summary of the Invention [Problem to be solved by the invention]

[0005] The trifluoroacetic anhydride used in the production method disclosed in Non-Patent Document 1 and the trifluoroacetyl chloride used in the production method reported in Patent Document 1 decompose violently upon contact with moisture. Therefore, these production methods are not only dangerous to handle but also require a strict anhydrous environment, and therefore simplification of the operation has been desired. It has been reported that trifluoroacetonitrile, used as an alternative method in Non-Patent Document 1, is a gas at room temperature and therefore not only has poor handling and reactivity, but also has a yield inferior to that of a production method using trifluoroacetic anhydride. In the production method reported in Non-Patent Document 2, when the nitrogen-containing heteroaromatic ring compound to be reacted with hydrazide has multiple halogen moieties, the product may further react with hydrazide or the halogen moieties may be hydrolyzed. On the other hand, the production method in Patent Document 2 is a multi-step production method, which not only requires long steps and complicated operations, but also requires the use of a reagent such as phosphorus pentachloride, which is highly corrosive, dangerous, and difficult to handle. From this viewpoint, the present inventors have conducted extensive investigations and have found that it is possible to produce a fluorinated ring-fused triazole derivative from a fluorinated carboxylic acid ester in a safe one-step reaction, thereby completing the present invention. [Means for solving the problem]

[0006] The gist and configuration of the present invention are as follows. [1] A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (2) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (3): [ka] (In the above general formulas (1) to (3), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, W, X 1 , Y 1 and Z 1 are independently CH, CR 2 or N, R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring) [2] A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (4) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (5): [ka] (In the above general formulas (1), (4) and (5), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, W, X 1 , Y 1 and Z 1 are independently CH, CR 2 or N, R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring) [3] A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (6) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (7): [ka] (In the above general formulas (1), (6) and (7), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, X 2 and Y 2 are independently CH, CR 2 , or N, Z 2 NH, NR 2 , O, or S; R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O m CO(O l A 1 ), -Om PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring) [4] A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (8) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (9): [ka] (In the above general formulas (1), (8) and (9), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, X 2 and Y 2 are independently CH, CR 2 , or N, Z 2 NH, NR 2 , O, or S; R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring) [5] A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (10) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (11): [ka] (In the above general formulas (1), (10) and (11), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, X 2 and Y 2 are independently CH, CR 2 , or N, Z 2 NH, NR 2 , O, or S; R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring) [6] A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (12) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (13): [ka] (In the above general formulas (1), (12) and (13), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, X 2 and Y 2 are independently CH, CR 2 , or N, Z 2 NH, NR 2 , O, or S; R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring) [Effects of the Invention]

[0007] The present invention provides a production method capable of producing a fluorinated ring-fused triazole derivative through a safe one-step reaction using a fluorinated carboxylic acid ester as a raw material, which is more stable and safer than trifluoroacetic anhydride or trifluoroacetyl chloride and can be easily handled as a liquid at room temperature. DETAILED DESCRIPTION OF THE INVENTION

[0008] (Method of producing a fluorine-containing fused triazole derivative) In one embodiment, a method for producing a fluorinated ring-fused triazole derivative includes the steps of: (a) A step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (2) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (3). [ka] (In the above general formulas (1) to (3), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, W, X 1 , Y 1 and Z 1 are independently CH, CR 2 , or N, R 2 is a halogen atom, -C jF (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring)

[0009] The reaction in the above step (a), in which a fluorine-containing fused-ring triazole derivative represented by general formula (3) is obtained by reacting a fluorine-containing carboxylic acid ester represented by general formula (1) with a nitrogen-containing heterocyclic compound represented by general formula (2), is represented by the following reaction formula (A1). [ka]

[0010] In the above step (a), a fluorine-containing carboxylic acid ester can be used as a raw material, which is more stable and safer than trifluoroacetic anhydride or trifluoroacetyl chloride and can be easily handled as a liquid at room temperature. In addition, in the above formula (A1), a fluorine-containing ring-fused triazole derivative can be produced in a one-step reaction using a dealcoholized compound as an intermediate. Therefore, the fluorine-containing ring-fused triazole derivative of the above general formula (3) can be easily obtained. In addition, in the reaction of the above step (a), dealcoholization (de-R) is carried out by an ester-amide exchange reaction. 1 OH) occurs, and a dehydration reaction occurs with a dehydrating agent. Then, the triazole ring of the fluorine-containing fused triazole derivative represented by general formula (3) is formed from the fluorine-containing carboxylic acid ester represented by general formula (1) and the amidino group of the nitrogen-containing heterocyclic compound represented by general formula (2). The ester-amide exchange reaction occurs by mixing the fluorine-containing carboxylic acid ester represented by general formula (1) with the nitrogen-containing heterocyclic compound represented by general formula (2) without adding any particular reagent. The ester-amide exchange reaction may be carried out by heating, if necessary. In this case, the temperature for the ester-amide exchange reaction is preferably 0 to 100°C, more preferably 10 to 80°C, and even more preferably 20 to 60°C. The dehydrating agent used in the reaction of step (a) can be a combination of an oxidizing agent and a reducing agent, making it possible to construct a reaction system that is stable to moisture. More specifically, the following substances can be used as dehydrating agents: (i) an oxidizing agent, a reducing agent, and an optional base Examples of oxidizing agents include diethyl azodicarboxylate and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Examples of reducing agents include trialkylphosphines and alkoxydialkylphosphines. When using oxidizing agents that by-produce hydrogen halides, such as carbon tetrabromide and N-chlorosaccharin, a base may be used as needed, such as triethylamine and diisopropylethylamine. (ii) a dehydrating agent and an optional base Examples of the dehydrating agent include phosphorus oxychloride and thionyl chloride. When hydrogen halide is produced as a by-product, a base may be used as needed. Examples of the base include triethylamine and diisopropylethylamine.

[0011] The reaction temperature during the reaction in the above step (a) is preferably 0 to 100° C., more preferably 10 to 80° C., and even more preferably 20 to 60° C. The reaction time during the reaction in the above step (a) is preferably 1 to 48 hours, more preferably 2 to 36 hours, and even more preferably 4 to 24 hours.

[0012] Examples of the solvent used in the reaction of the above step (a) include acetonitrile and dimethoxyethane.

[0013] Another embodiment of the method for producing a fluorine-containing ring-fused triazole derivative includes the following steps: (b) A step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (4) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (5). [ka] (In the above general formulas (1), (4) and (5), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, W, X 1 , Y 1 and Z 1 are independently CH, CR 2 , or N, R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O m CO(O l A 1 ), -Om PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring)

[0014] The reaction in the above step (b) in which a fluorine-containing fused-ring triazole derivative represented by general formula (5) is obtained by reacting a fluorine-containing carboxylic acid ester represented by general formula (1) with a nitrogen-containing heterocyclic compound represented by general formula (4) is represented by the following reaction formula (B1). [ka]

[0015] In the above step (b), a fluorine-containing carboxylic acid ester can be used as a raw material, which is more stable and safer than trifluoroacetic anhydride or trifluoroacetyl chloride and can be easily handled as a liquid at room temperature. In addition, in the above formula (B1), a fluorine-containing ring-fused triazole derivative can be produced in a one-step reaction using a dealcoholized compound as an intermediate. Therefore, a fluorine-containing ring-fused triazole derivative represented by the above general formula (5) can be easily obtained. In addition, in the reaction of the above step (b), dealcoholization (de-R) is achieved by an ester-amide exchange reaction. 1 OH) occurs, and a dehydration reaction occurs with a dehydrating agent. Then, the triazole ring of the fluorine-containing fused triazole derivative represented by general formula (5) is formed from the fluorine-containing carboxylic acid ester represented by general formula (1) and the amidino group of the nitrogen-containing heterocyclic compound represented by general formula (4). The ester-amide exchange reaction occurs by mixing the fluorine-containing carboxylic acid ester represented by general formula (1) with the nitrogen-containing heterocyclic compound represented by general formula (4) without adding any particular reagent. The ester-amide exchange reaction may be carried out by heating, if necessary. In this case, the temperature for the ester-amide exchange reaction is preferably 0 to 100°C, more preferably 10 to 80°C, and even more preferably 20 to 60°C. The dehydrating agent used in the reaction of step (b) can be a combination of an oxidizing agent and a reducing agent, making it possible to construct a reaction system that is stable to moisture. More specifically, the following substances can be used as dehydrating agents: (i) an oxidizing agent, a reducing agent, and an optional base Examples of oxidizing agents include diethyl azodicarboxylate and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Examples of reducing agents include trialkylphosphines and alkoxydialkylphosphines. When using oxidizing agents that by-produce hydrogen halides, such as carbon tetrabromide and N-chlorosaccharin, a base may be used as needed, such as triethylamine and diisopropylethylamine. (ii) a dehydrating agent and an optional base Examples of the dehydrating agent include phosphorus oxychloride and thionyl chloride. When hydrogen halide is produced as a by-product, a base may be used as needed. Examples of the base include triethylamine and diisopropylethylamine.

[0016] The reaction temperature during the reaction in the above step (b) is preferably 0 to 100° C., more preferably 10 to 80° C., and even more preferably 20 to 60° C. The reaction time during the reaction in the above step (b) is preferably 1 to 48 hours, more preferably 2 to 36 hours, and even more preferably 4 to 24 hours.

[0017] Examples of the solvent used in the reaction in the above step (b) include acetonitrile and dimethoxyethane.

[0018] Another embodiment of the method for producing a fluorine-containing ring-fused triazole derivative includes the following steps: (c) A step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (6) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (7). [ka] (In the above general formulas (1), (6) and (7), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, X 2 and Y 2 are independent of each other and are CH and CR 2 , or N, Z 2 NH, NR 2 , O, or S; R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O mCO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring)

[0019] The reaction in the above step (c) in which a fluorine-containing fused-ring triazole derivative represented by general formula (7) is obtained by reacting a fluorine-containing carboxylic acid ester represented by general formula (1) with a nitrogen-containing heterocyclic compound represented by general formula (6) is represented by the following reaction formula (C1). [ka]

[0020] In the above step (c), a fluorine-containing carboxylic acid ester can be used as a raw material, which is more stable and safer than trifluoroacetic anhydride or trifluoroacetyl chloride and can be easily handled as a liquid at room temperature. In addition, in the above formula (C1), a fluorine-containing ring-fused triazole derivative can be produced in a one-step reaction using a dealcoholized compound as an intermediate. Therefore, the fluorine-containing ring-fused triazole derivative represented by the above general formula (7) can be easily obtained. In addition, in the reaction of the above step (c), dealcoholization (de-R) is achieved by an ester-amide exchange reaction. 1 OH) occurs, and a dehydration reaction with a dehydrating agent occurs. Then, the triazole ring of the fluorine-containing fused triazole derivative represented by general formula (7) is formed from the fluorine-containing carboxylic acid ester represented by general formula (1) and the amidino group of the nitrogen-containing heterocyclic compound represented by general formula (6). The ester-amide exchange reaction occurs by mixing the fluorine-containing carboxylic acid ester represented by general formula (1) with the nitrogen-containing heterocyclic compound represented by general formula (6) without adding any particular reagent. The ester-amide exchange reaction may be carried out by heating, if necessary. In this case, the temperature for the ester-amide exchange reaction is preferably 0 to 100°C, more preferably 10 to 80°C, and even more preferably 20 to 60°C. The dehydrating agent used in the reaction of step (c) can be a combination of an oxidizing agent and a reducing agent, making it possible to construct a reaction system that is stable to moisture. More specifically, the following substances can be used as dehydrating agents: (i) an oxidizing agent, a reducing agent, and an optional base Examples of oxidizing agents include diethyl azodicarboxylate and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Examples of reducing agents include trialkylphosphines and alkoxydialkylphosphines. When using oxidizing agents that by-produce hydrogen halides, such as carbon tetrabromide and N-chlorosaccharin, a base may be used as needed, such as triethylamine and diisopropylethylamine. (ii) a dehydrating agent and an optional base Examples of the dehydrating agent include phosphorus oxychloride and thionyl chloride. When hydrogen halide is to be produced as a by-product, a base may be used as needed. Examples of the base include triethylamine and diisopropylethylamine.

[0021] The reaction temperature during the reaction in the above step (c) is preferably 0 to 100° C., more preferably 10 to 80° C., and even more preferably 20 to 60° C. The reaction time during the reaction in the above step (c) is preferably 1 to 48 hours, more preferably 2 to 36 hours, and even more preferably 4 to 24 hours.

[0022] Examples of the solvent used in the reaction in the above step (c) include acetonitrile and dimethoxyethane.

[0023] Another embodiment of the method for producing a fluorine-containing ring-fused triazole derivative includes the following steps: (d) A step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (8) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (9). [ka] (In the above general formulas (1), (8) and (9), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, X 2 and Y 2 are independently CH, CR 2 , or N, Z 2 NH, NR 2 , O, or S; R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O mCO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring)

[0024] The reaction in the above step (d) in which a fluorine-containing fused-ring triazole derivative represented by general formula (9) is obtained by reacting a fluorine-containing carboxylic acid ester represented by general formula (1) with a nitrogen-containing heterocyclic compound represented by general formula (8) is represented by the following reaction formula (D1). [ka]

[0025] In the above step (d), a fluorine-containing carboxylic acid ester can be used as a raw material, which is more stable and safer than trifluoroacetic anhydride or trifluoroacetyl chloride and can be easily handled as a liquid at room temperature. In addition, in the above formula (D1), a fluorine-containing ring-fused triazole derivative can be produced in a one-step reaction using a dealcoholized compound as an intermediate. Therefore, the fluorine-containing ring-fused triazole derivative represented by the above general formula (9) can be easily obtained. In addition, in the reaction of the above step (d), dealcoholization (de-R) is achieved by an ester-amide exchange reaction. 1 OH) occurs, and a dehydration reaction with a dehydrating agent occurs. Then, the triazole ring of the fluorine-containing fused triazole derivative represented by general formula (9) is formed from the fluorine-containing carboxylic acid ester represented by general formula (1) and the amidino group of the nitrogen-containing heterocyclic compound represented by general formula (8). The ester-amide exchange reaction occurs by mixing the fluorine-containing carboxylic acid ester represented by general formula (1) with the nitrogen-containing heterocyclic compound represented by general formula (8) without adding any particular reagent. The ester-amide exchange reaction may be carried out by heating, if necessary. In this case, the temperature for the ester-amide exchange reaction is preferably 0 to 100°C, more preferably 10 to 80°C, and even more preferably 20 to 60°C. The dehydrating agent used in the reaction of step (d) can be a combination of an oxidizing agent and a reducing agent, making it possible to construct a reaction system that is stable to moisture. More specifically, the following substances can be used as dehydrating agents: (i) an oxidizing agent, a reducing agent, and an optional base Examples of oxidizing agents include diethyl azodicarboxylate and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Examples of reducing agents include trialkylphosphines and alkoxydialkylphosphines. When using oxidizing agents that by-produce hydrogen halides, such as carbon tetrabromide and N-chlorosaccharin, a base may be used as needed, such as triethylamine and diisopropylethylamine. (ii) a dehydrating agent and an optional base Examples of the dehydrating agent include phosphorus oxychloride and thionyl chloride. When hydrogen halide is produced as a by-product, a base may be used as needed. Examples of the base include triethylamine and diisopropylethylamine.

[0026] The reaction temperature during the reaction in the above step (d) is preferably 0 to 100° C., more preferably 10 to 80° C., and even more preferably 20 to 60° C. The reaction time during the reaction in the above step (d) is preferably 1 to 48 hours, more preferably 2 to 36 hours, and even more preferably 4 to 24 hours.

[0027] Examples of the solvent used in the reaction in the above step (d) include acetonitrile and dimethoxyethane.

[0028] Another embodiment of the method for producing a fluorine-containing ring-fused triazole derivative includes the following steps: (e) A step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (10) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (11). [ka] (In the above general formulas (1), (10) and (11), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, X 2 and Y 2 are independently CH, CR 2 , or N, Z 2 NH, NR 2 , O, or S; R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -Om CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring)

[0029] The reaction in the above step (e) in which a fluorine-containing fused-ring triazole derivative represented by general formula (11) is obtained by reacting a fluorine-containing carboxylic acid ester represented by general formula (1) with a nitrogen-containing heterocyclic compound represented by general formula (10) is represented by the following reaction formula (E1). [ka]

[0030] In the above step (e), a fluorine-containing carboxylic acid ester can be used as a raw material, which is more stable and safer than trifluoroacetic anhydride or trifluoroacetyl chloride and can be easily handled as a liquid at room temperature. In addition, in the above formula (E1), a fluorine-containing ring-fused triazole derivative can be produced in a one-step reaction using a dealcoholized compound as an intermediate. Therefore, the fluorine-containing ring-fused triazole derivative represented by the above general formula (11) can be easily obtained. In addition, in the reaction of the above step (e), dealcoholization (de-R) is achieved by an ester-amide exchange reaction. 1 OH) occurs, and a dehydration reaction with a dehydrating agent occurs. Then, the triazole ring of the fluorine-containing fused triazole derivative represented by general formula (11) is formed from the fluorine-containing carboxylic acid ester represented by general formula (1) and the amidino group of the nitrogen-containing heterocyclic compound represented by general formula (10). The ester-amide exchange reaction occurs by mixing the fluorine-containing carboxylic acid ester represented by general formula (1) with the nitrogen-containing heterocyclic compound represented by general formula (10) without adding any particular reagent. The ester-amide exchange reaction may be carried out by heating, if necessary. In this case, the temperature for the ester-amide exchange reaction is preferably 0 to 100°C, more preferably 10 to 80°C, and even more preferably 20 to 60°C. The dehydrating agent used in the reaction of step (e) can be a combination of an oxidizing agent and a reducing agent, making it possible to construct a reaction system that is stable to moisture. More specifically, the following substances can be used as dehydrating agents: (i) an oxidizing agent, a reducing agent, and an optional base Examples of oxidizing agents include diethyl azodicarboxylate and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Examples of reducing agents include trialkylphosphines and alkoxydialkylphosphines. When using oxidizing agents that by-produce hydrogen halides, such as carbon tetrabromide and N-chlorosaccharin, a base may be used as needed, such as triethylamine and diisopropylethylamine. (ii) a dehydrating agent and an optional base Examples of the dehydrating agent include phosphorus oxychloride and thionyl chloride. When hydrogen halide is produced as a by-product, a base may be used as needed. Examples of the base include triethylamine and diisopropylethylamine.

[0031] The reaction temperature during the reaction in step (e) is preferably 0 to 100° C., more preferably 10 to 80° C., and even more preferably 20 to 60° C. The reaction time during the reaction in step (e) is preferably 1 to 48 hours, more preferably 2 to 36 hours, and even more preferably 4 to 24 hours.

[0032] Examples of the solvent used in the reaction in the above step (e) include acetonitrile and dimethoxyethane.

[0033] Another embodiment of the method for producing a fluorine-containing ring-fused triazole derivative includes the following steps: (f) A step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (12) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (13). [ka] (In the above general formulas (1), (12) and (13), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, X 2 and Y 2 are independently CH, CR 2 , or N, Z 2 NH, NR 2 , O, or S; R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -Om CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring)

[0034] The reaction in the above step (f), in which a fluorine-containing fused-ring triazole derivative represented by general formula (13) is obtained by reacting a fluorine-containing carboxylic acid ester represented by general formula (1) with a nitrogen-containing heterocyclic compound represented by general formula (12), is represented by the following reaction formula (F1). [ka]

[0035] In the above step (f), a fluorine-containing carboxylic acid ester can be used as a raw material, which is more stable and safer than trifluoroacetic anhydride or trifluoroacetyl chloride and can be easily handled as a liquid at room temperature. In addition, in the above formula (F1), a fluorine-containing ring-fused triazole derivative can be produced in a one-step reaction using a dealcoholized compound as an intermediate. Therefore, the fluorine-containing ring-fused triazole derivative represented by the above general formula (13) can be easily obtained. In the above reaction (f), the dealcoholization (de-R) is carried out by an ester-amide exchange reaction. 1 OH) occurs, and a dehydration reaction with a dehydrating agent occurs. Then, the triazole ring of the fluorine-containing fused triazole derivative represented by general formula (13) is formed from the fluorine-containing carboxylic acid ester represented by general formula (1) and the amidino group of the nitrogen-containing heterocyclic compound represented by general formula (12). The ester-amide exchange reaction occurs by mixing the fluorine-containing carboxylic acid ester represented by general formula (1) with the nitrogen-containing heterocyclic compound represented by general formula (12) without adding any particular reagent. The ester-amide exchange reaction may be carried out by heating, if necessary. In this case, the temperature for the ester-amide exchange reaction is preferably 0 to 100°C, more preferably 10 to 80°C, and even more preferably 20 to 60°C. The dehydrating agent used in the reaction of step (f) can be a combination of an oxidizing agent and a reducing agent, making it possible to construct a reaction system that is stable to moisture. More specifically, the following substances can be used as dehydrating agents: (i) an oxidizing agent, a reducing agent, and an optional base Examples of oxidizing agents include diethyl azodicarboxylate and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Examples of reducing agents include trialkylphosphines and alkoxydialkylphosphines. When using oxidizing agents that by-produce hydrogen halides, such as carbon tetrabromide and N-chlorosaccharin, a base may be used as needed, such as triethylamine and diisopropylethylamine. (ii) a dehydrating agent and an optional base Examples of the dehydrating agent include phosphorus oxychloride and thionyl chloride. When hydrogen halide is produced as a by-product, a base may be used as needed. Examples of the base include triethylamine and diisopropylethylamine.

[0036] The reaction temperature during the reaction in the above step (f) is preferably 0 to 100° C., more preferably 10 to 80° C., and even more preferably 20 to 60° C. The reaction time during the reaction in the above step (f) is preferably 1 to 48 hours, more preferably 2 to 36 hours, and even more preferably 4 to 24 hours.

[0037] Examples of the solvent used in the reaction in the above step (f) include acetonitrile and dimethoxyethane.

[0038] The groups Rf and R in the general formulas (1) to (13) in the steps (a) to (f) above 1 , W, X 1 , Y 1 , Z 1 , X 2 , Y 2 , Z 2 , R 2 , -C j F (2j+1) , -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , -O m B(O l A 2 )(O k A 3 ), A 1 , A 2 , A 3This will be explained in detail below.

[0039] Rf is C n F (2n+1) where n is an integer of 1 to 5, specifically CF3, C2F5, C3F7, C4F9, C5F 11 Examples include: R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, and more specifically, examples thereof include chain hydrocarbon groups, aromatic hydrocarbon groups, and alicyclic hydrocarbon groups having 1 to 10 carbon atoms. Examples of the chain hydrocarbon group include alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl; alkenyl groups such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl; and alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. Examples of the aromatic hydrocarbon group include a phenyl group. The alicyclic hydrocarbon group may be a saturated or unsaturated cyclic hydrocarbon group, and examples of the cyclic hydrocarbon group include a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, and an adamantyl group.

[0040] (a) W, X 1 , Y 1 and Z 1 are independently CH, CR 2 or N, W, X 1 , Y 1 and Z 1 One, two, three, or four of them may be CH, and one, two, three, or four of them may be CR. 2 and one, two, three, or four may be N. (b)X 2 and Y 2 are independent of each other and are CH and CR 2 , or N, Z 2 NH, NR2 , O, or S. X 2 and Y 2 are both CH and CR 2 , or N, and X 2 and Y 2 are CH and CR, respectively. 2 , CH and N, CR 2 and C.H., C.R. 2 and N, N and CH, or N and CR 2 may be.

[0041] R 2 is a halogen atom, -C j F (2j+1) , nitro group (NO2), heterocyclic group, -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring. 2 When R are bonded to each other to form a ring, examples of the group include a heteroaliphatic ring and a heteroaromatic ring. 2Examples of heteroaliphatic rings formed by bonding together include rings containing at least one atom selected from the group consisting of S (sulfur atom), O (oxygen atom), and N (nitrogen atom). This heteroaliphatic ring is fused to the single or double bond indicated by the arrow in the fluorine-containing ring-fused triazole derivatives represented by the following general formulas (3), (5), (7), (9), (11), and (13). In the fluorine-containing ring-fused triazole derivatives represented by the following general formulas (3) and (5), one, two, or three single or double bonds can be fused to the heteroaliphatic rings, as indicated by the arrows. In the fluorine-containing ring-fused triazole derivatives represented by the following general formulas (7), (9), (11), and (13), one or two single or double bonds can be fused to the heteroaliphatic rings, as indicated by the arrows. The heteroaliphatic ring may have a monocyclic structure or a polycyclic structure composed of two or more rings, and the monocyclic structure and the polycyclic structure may further have a substituent. In this case, examples of the substituent include an alkyl group and an aryl group. Specific examples of the heteroaliphatic ring include a pyrrolidine ring and a piperazine ring. R on adjacent ring atoms 2Examples of heteroaromatic rings formed by bonding together include rings containing at least one atom selected from the group consisting of S (sulfur atom), O (oxygen atom), and N (nitrogen atom). This heteroaromatic ring is fused to the single or double bond indicated by the arrow in the fluorine-containing ring-fused triazole derivatives represented by the following general formulae (3), (5), (7), (9), (11), and (13). In the fluorine-containing ring-fused triazole derivatives represented by the following general formulae (3) and (5), one, two, or three single or double bonds can be fused to the heteroaromatic rings, as indicated by the arrows. In the fluorine-containing ring-fused triazole derivatives represented by the following general formulae (7), (9), (11), and (13), one or two single or double bonds can be fused to the heteroaromatic rings, as indicated by the arrows. The heteroaromatic ring may have a monocyclic structure or a polycyclic structure composed of two or more rings, and the monocyclic structure and the polycyclic structure may further have a substituent. In this case, examples of the substituent include an alkyl group, a fluoroalkyl group, an aryl group, etc. Specific examples of the heteroaromatic ring include a pyrrole ring and a pyridine ring. [ka]

[0042] R 2 Examples of halogen atoms in R include F, Cl, Br, and I. 2 -C j F (2j+1) Examples include CF3, C2F5, C3F7, C4F9, and C5F 11 R 2 Examples of the heterocyclic group represented by R include a pyridyl group, a pyrrolyl group, and a pyrazolyl group. One or more ring atoms constituting the heterocyclic group may have a substituent other than a hydrogen atom (e.g., a halogen atom such as F, Cl, Br, or I), or may not have such a substituent. 2 -O m A 1 Examples of R include -OMe and -Ph groups. 2 -Om CO(O l A 1 ) can include groups such as -(CO)Me and -O(CO)OPh. 2 -O m PO(O l A 2 )(O k A 3 ) can include groups such as -(PO)Ph2 and -O(PO)(OEt)2. R 2 -O m SO(O l A 1 ) can include groups such as -(SO)Ph and -O(SO)OPh. 2 -O m SO2(O l A 1 ) can include groups such as -(SO2)Me and -O(SO2)OPh. 2 -O m NA 2 A 3 Examples of R include -NEt2 and -ONPhEt. 2 -O m B(O l A 2 )(O k A 3 ) can include groups such as -BPh2 and -OB(OMe)2. 2 -O m PO(O l A 2 )(O k A 3 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), then A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or one R 2 A that constitutes 2 and A 3 are bonded to each other to form a ring.2 and A 3 When R are bonded to each other to form a ring, examples of the group include a heteroaliphatic ring and a heteroaromatic ring. 2 -O m PO(O l A 2 )(O k A 3 ) and A 2 and A 3 When they are bonded to each other to form a ring, -A 2 -O l -PO k -A 3 A ring having - as a partial structure of the ring is formed. 2 -O m NA 2 A 3 and A 2 and A 3 When they are bonded to each other to form a ring, -A 2 -NA 3 - as a partial structure of the ring. 2 -O m B(O l A 2 )(O k A 3 ) and A 2 and A 3 When they are bonded to each other to form a ring, -A 2 -O l -BO k -A 3 A ring having - as a partial ring structure is formed. The heteroaliphatic ring and heteroaromatic ring can contain at least one atom selected from the group consisting of S (sulfur atom), O (oxygen atom) and N (nitrogen atom) as a ring atom. Typically, the heteroaliphatic ring and heteroaromatic ring have a monocyclic structure. Typically, the heteroaromatic ring has -A 2 -NA 3- as a partial ring structure. Examples of heteroaliphatic rings include a pyrrolidine ring, a piperazine ring, and a morpholine ring. Examples of heteroaromatic rings include a pyrrole ring, a pyridine ring, and a pyrazole ring. The heteroaliphatic ring and the heteroaromatic ring may further have a substituent. In this case, examples of the substituent include an alkyl group and an aryl group. In addition, R 2 is plural and plural R 2 When they bond together to form a ring, one R 2 A that constitutes 2 and A 3 do not bond to each other to form a ring. A 1 , A 2 and A 3 represents a hydrocarbon group having 1 to 10 carbon atoms, for example, 1 Among these, the hydrocarbon group may have 1 to 10 carbon atoms.

[0043] (Fluorine-containing fused triazole derivatives) The fluorine-containing fused-ring triazole derivatives obtained by the method for producing a fluorine-containing fused-ring triazole derivative of the present invention are represented by the following general formulae (3), (5), (7), (9), (11), and (13). [ka] (In the above general formulas (3), (5), (7), (9), (11), and (13), Rf is C n F (2n+1) where n is an integer of 1 to 5, R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, W, X 1 , Y 1 and Z 1 are independently CH, CR 2 or N, X 2 and Y 2 are independent of each other and are CH and CR 2 , or N, Z 2NH, NR 2 , O, or S; R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring, A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring)

[0044] The fluorine-containing ring-fused triazole derivative of the present invention can have activity such as antibacterial activity and antiviral activity. The fluorine-containing ring-fused triazole derivative of one embodiment is also useful in the fields of pharmaceuticals, agricultural chemicals, etc. The groups Rf and R in the general formulas (1) to (13) 1 , W, X 1 , Y 1 , Z 1 , X 2, Y 2 , Z 2 , R 2 , -C j F (2j+1) , -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , -O m B(O l A 2 )(O k A 3 ), A 1 , A 2 , A 3 This will be explained in detail below.

[0045] Rf is C n F (2n+1) where n is an integer of 1 to 5, specifically CF3, C2F5, C3F7, C4F9, C5F 11 Examples include: R 1represents a hydrocarbon group having 1 to 10 carbon atoms, and more specifically, examples thereof include chain hydrocarbon groups, aromatic hydrocarbon groups, and alicyclic hydrocarbon groups having 1 to 10 carbon atoms. Examples of the chain hydrocarbon group include alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl; alkenyl groups such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl; and alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. Examples of the aromatic hydrocarbon group include a phenyl group. The alicyclic hydrocarbon group may be a saturated or unsaturated cyclic hydrocarbon group, and examples of the cyclic hydrocarbon group include a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, and an adamantyl group.

[0046] (a) W, X 1 , Y 1 and Z 1 are independently CH, CR 2 or N, W, X 1 , Y 1 and Z 1 One, two, three, or four of them may be CH, and one, two, three, or four of them may be CR. 2 and one, two, three, or four may be N. (b)X 2 and Y 2 are independent of each other and are CH and CR 2 , or N, Z 2 NH, NR 2 , O, or S. X 2 and Y 2 are both CH and CR 2 , or N, and X 2 and Y 2 are CH and CR, respectively. 2 , CH and N, CR 2 and C.H., C.R.2 and N, N and CH, or N and CR 2 may be.

[0047] R 2 is a halogen atom, -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 2 )(O k A 3 ), -O m SO(O l A 1 ), -O m SO2(O l A 1 ), -O m NA 2 A 3 , or -O m B(O l A 2 )(O k A 3 ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R 2 is plural and plural R 2 are bonded to each other to form a ring. 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, and A 2 and A 3 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A 2 and A 3 are bonded to each other to form a ring. 2 is plural and plural R 2 When they bond together to form a ring, one R 2 A that constitutes 2 and A 3 do not bond to each other to form a ring. 1 , A 2 and A 3 represents a hydrocarbon group having 1 to 10 carbon atoms, for example,1 Among these, the hydrocarbon group may have 1 to 10 carbon atoms.

[0048] Although the embodiments of the present invention have been described above, the present invention is not limited to the above-described embodiments, but includes all aspects encompassed by the concept of the present invention and the scope of the claims, and can be modified in various ways within the scope of the present invention. [Example]

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

[0050] Example 1 Synthesis of 3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine To 15 g of THF, 0.2 g (1.6 mmol) of 2-hydrazinopyridine and 0.4 g (2.1 mmol) of ethyl trifluoroacetate were added to obtain Solution 1. Solution 1 was stirred for approximately 16 hours at room temperature, and the solvent, unreacted ethyl trifluoroacetate, and by-product ethanol were removed by distillation under reduced pressure to obtain a solid. 20 g of MeCN was added to this solid, followed by 0.3 g (1.6 mmol) of carbon tetrachloride, 0.5 g (2.1 mmol) of triphenylphosphine, and 0.3 g (2.1 mmol) of DIPEA to obtain Solution 2. Solution 2 was heated under reflux for approximately 8 hours, after which the solvent was removed by distillation under reduced pressure. The resulting solid was dissolved in ethyl acetate and purified on a silica gel column using a 7:3 hexane-ethyl acetate mixture to obtain 3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine represented by the following formula (A). The yield of the purified product was 0.2 g (42% isolated yield). [ka] The analytical results of the compound of formula (A) obtained are as follows: Mass spectrum (APCI, m / z): 187 ([M] + ) 1H-NMR (400MHz, CDCl3) δppm:8.73(dd,1H), 7.83(dd,1H), 7.60(d,1H), 7.01(d,1H)

[0051] Example 2 Synthesis of 2-(trifluoromethyl)-1,2,4-triazolo[1,5-a]pyridine To 40 g of THF, 0.5 g (1.6 mmol) of 1,2-diaminopyridinium mesitylenesulfonate, 0.2 g (1.6 mmol) of DIPEA, and 0.4 g (2.1 mmol) of ethyl trifluoroacetate were added to obtain solution 3. After stirring solution 3 for approximately 16 hours at room temperature, the solvent, unreacted ethyl trifluoroacetate, and by-product ethanol were removed by distillation under reduced pressure to obtain a solid. 20 g of MeCN was added to this solid, followed by 0.5 g (1.6 mmol) of carbon tetrabromide, 0.5 g (2.1 mmol) of triphenylphosphine, and 0.3 g (2.1 mmol) of DIPEA to obtain solution 4. After heating and refluxing solution 4 for approximately 6 hours, the solvent was removed by distillation under reduced pressure. The resulting solid was dissolved in ethyl acetate and purified on a silica gel column using a 7:3 hexane-ethyl acetate mixed solvent to obtain 2-(trifluoromethyl)-1,2,4-triazolo[1,5-a]pyridine represented by the following formula (B). The amount of purified product obtained was 0.1 g (isolation yield 35%). [ka] The analytical results of the compound of formula (B) obtained are as follows: Mass spectrum (APCI, m / z): 187 ([M] + ) 1 H-NMR (400MHz, CDCl3) δppm:8.70(d,1H), 7.88(d,1H), 7.73(dd,1H), 7.30(dd,1H)

[0052] Example 3 Synthesis of 3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-(trifluoromethyl)[1,2,4]triazolo[4,3-b]-1,2,4,5-tetrazine 0.2 g (1.1 mmol) of 3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-hydrazinyl-1,2,4,5-tetrazine and 0.3 g (1.7 mmol) of isopropyl trifluoroacetate were added to 40 g of 1,2-dimethoxyethane to obtain Solution 5. After stirring Solution 5 for approximately 24 hours at room temperature, the solvent, unreacted isopropyl trifluoroacetate, and by-product isopropyl alcohol were removed by distillation under reduced pressure to obtain a solid. 20 g of 1,2-dimethoxyethane was added to this solid, followed by the addition of 0.5 g (1.6 mmol) of diethyl dibromomalonate, 0.5 g (2.1 mmol) of triphenylphosphine, and 0.2 g (2.1 mmol) of triethylamine to obtain Solution 6. Solution 6 was heated under reflux for approximately 10 hours, and then the solvent was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate and purified using a silica gel column with a 7:3 hexane-ethyl acetate mixed solvent to obtain 3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-(trifluoromethyl)[1,2,4]triazolo[4,3-b]-1,2,4,5-tetrazine, as shown in formula (C). The yield of the purified product was 0.1 g (18% isolated yield). [ka] The analytical results of the compound of formula (C) obtained are as follows: Mass spectrum (APCI, m / z): 284 ([M] + ) 1 H-NMR (400MHz, DMSO-d6) δppm:6.46(s,1H), 2.62(s,3H), 2.34(s,3H)

[0053] Example 4 Synthesis of 2,6-bis(trifluoromethyl)-1H-[1,2,4]triazole[1',5':2,3][1,2,4]triazino[5,6-b]indole To 40 g of THF, 0.4 g (1.5 mmol) of 2-amino-2H-6-trifluoromethyl-1,2,4-triazino[5,6-b]indol-3-amine and 0.4 g (3.1 mmol) of methyl trifluoroacetate were added to obtain Solution 7. After stirring Solution 7 for approximately 24 hours at room temperature, the solvent, unreacted methyl trifluoroacetate, and by-product methanol were removed by distillation under reduced pressure to obtain a solid. To this solid, 20 g of ethyl acetate was added, followed by the addition of 0.3 g (1.6 mmol) of N-chlorosaccharin, 0.4 g (2.1 mmol) of tributylphosphine, and 0.2 g (2.1 mmol) of triethylamine to obtain Solution 8. Solution 8 was heated under reflux for approximately 5 hours, and the solvent was then removed under reduced pressure. The resulting solid was dissolved in ethyl acetate and purified using a silica gel column with a 7:3 hexane-ethyl acetate mixed solvent to obtain 2,6-bis(trifluoromethyl)-1H-[1,2,4]triazole[1',5':2,3][1,2,4]triazino[5,6-b]indole, as shown in formula (D). The yield of the purified product was 0.1 g (15% isolated yield). [ka] The analytical results of the compound of formula (D) obtained are as follows: Mass spectrum (APCI, m / z): 348 ([M] + ) 1 H-NMR (400MHz, DMSO-d6) δppm:8.39(d,1H), 7.91(d,1H), 7.48(dd,1H)

[0054] Example 5 Synthesis of 6-(2,6-dichloro-3-pyridinyl)-3-(trifluoromethyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole 0.5 g (1.8 mmol) of 2-(2,4-dichloro-3-pyridinyl)-5-hydrazino-[1,3,4]thiadiazole and 0.4 g (2.1 mmol) of ethyl trifluoroacetate were added to 40 g of THF to obtain solution 9. After stirring solution 9 for approximately 16 hours at room temperature, the solvent, unreacted ethyl trifluoroacetate, and by-product ethanol were removed by distillation under reduced pressure to obtain a solid. 20 g of MeCN was added to this solid, followed by the addition of 0.4 g (1.6 mmol) of hexachloroacetone, 0.4 g (2.1 mmol) of tributylphosphine, and 0.3 g (2.1 mmol) of DIPEA to obtain solution 10. Solution 10 was heated under reflux for approximately 11 hours, and then the solvent was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate and purified using a silica gel column with a 7:3 hexane-ethyl acetate mixed solvent to obtain 6-(2,6-dichloro-3-pyridinyl)-3-(trifluoromethyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole, as shown in the following formula (E). The yield of the purified product was 0.1 g (23% isolated yield). [ka] The analytical results of the compound of formula (E) obtained are as follows: Mass spectrum (APCI, m / z): 340 ([M] + ) 1 H-NMR (400MHz, DMSO-d6) δppm:8.51(d,1H), 7.76(d,1H)

Claims

1. A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (2) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (3): 【Chemical 1】 (In the above general formulas (1) to (3), Rf is C ｎ F （２ｎ＋１） where n is an integer from 1 to 5; R １ represents a hydrocarbon group having 1 to 10 carbon atoms, W, X １ , Y １ and Z １ are each independently CH, CR ２ or N, R ２ is a halogen atom, -C ｊ F （２ｊ＋１） , a nitro group, a heterocyclic group, —O ｍ A １ , -O ｍ CO(O ｌ A １ ), -O ｍ PO (O ｌ A ２ ) (O ｋ A ３ ), -O ｍ SO (O ｌ A １ ), -O ｍ SO ２ (O ｌ A １ ), -O ｍ N.A. ２ A ３ , or -O ｍ B (O ｌ A ２ ) (O ｋ A ３ ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R ２ is plural and plural R ２ are bonded to each other to form a ring, A １ represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A ２ and A ３ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A ２ and A ３ are bonded to each other to form a ring)

2. A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (4) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (5): 【Chemistry 2】 (In the above general formulas (1), (4) and (5), Rf is C ｎ F （２ｎ＋１） where n is an integer from 1 to 5; R １ represents a hydrocarbon group having 1 to 10 carbon atoms, W, X １ , Y １ and Z １ are each independently CH, CR ２ or N, R ２ is a halogen atom, -C ｊ F （２ｊ＋１） , a nitro group, a heterocyclic group, —O ｍ A １ , -O ｍ CO(O ｌ A １ ), -O ｍ PO (O ｌ A ２ ) (O ｋ A ３ ), -O ｍ SO (O ｌ A １ ), -O ｍ SO ２ (O ｌ A １ ), -O ｍ N.A. ２ A ３ , or -O ｍ B (O ｌ A ２ ) (O ｋ A ３ ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R ２ is plural and plural R ２ are bonded to each other to form a ring, A １ represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A ２ and A ３ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A ２ and A ３ are bonded to each other to form a ring)

3. A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (6) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (7): 【Chemistry 3】 (In the above general formulas (1), (6) and (7), Rf is C ｎ F （２ｎ＋１） where n is an integer from 1 to 5; R １ represents a hydrocarbon group having 1 to 10 carbon atoms, X ２ and Y ２ are each independently CH, CR ２ , or N, Z ２ NH, NR ２ , O, or S; R ２ is a halogen atom, -C ｊ F （２ｊ＋１） , a nitro group, a heterocyclic group, —O ｍ A １ , -O ｍ CO(O ｌ A １ ), -O ｍ PO (O ｌ A ２ ) (O ｋ A ３ ), -O ｍ SO (O ｌ A １ ), -O ｍ SO ２ (O ｌ A １ ), -O ｍ N.A. ２ A ３ , or -O ｍ B (O ｌ A ２ ) (O ｋ A ３ ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R ２ is plural and plural R ２ are bonded to each other to form a ring, A １ represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A ２ and A ３ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A ２ and A ３ are bonded to each other to form a ring)

4. A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (8) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (9): 【Chemistry 4】 (In the above general formulas (1), (8) and (9), Rf is C ｎ F （２ｎ＋１） where n is an integer from 1 to 5; R １ represents a hydrocarbon group having 1 to 10 carbon atoms, X ２ and Y ２ are each independently CH, CR ２ , or N, Z ２ NH, NR ２ , O, or S; R ２ is a halogen atom, -C ｊ F （２ｊ＋１） , a nitro group, a heterocyclic group, —O ｍ A １ , -O ｍ CO(O ｌ A １ ), -O ｍ PO (O ｌ A ２ ) (O ｋ A ３ ), -O ｍ SO (O ｌ A １ ), -O ｍ SO ２ (O ｌ A １ ), -O ｍ N.A. ２ A ３ , or -O ｍ B (O ｌ A ２ ) (O ｋ A ３ ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R ２ is plural and plural R ２ are bonded to each other to form a ring, A １ represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A ２ and A ３ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A ２ and A ３ are bonded to each other to form a ring)

5. A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (10) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (11): 【Chemistry 5】 (In the above general formulas (1), (10) and (11), Rf is C ｎ F （２ｎ＋１） where n is an integer from 1 to 5; R １ represents a hydrocarbon group having 1 to 10 carbon atoms, X ２ and Y ２ are each independently CH, CR ２ , or N, Z ２ NH, NR ２ , O, or S; R ２ is a halogen atom, -C ｊ F （２ｊ＋１） , a nitro group, a heterocyclic group, —O ｍ A １ , -O ｍ CO(O ｌ A １ ), -O ｍ PO (O ｌ A ２ ) (O ｋ A ３ ), -O ｍ SO (O ｌ A １ ), -O ｍ SO ２ (O ｌ A １ ), -O ｍ N.A. ２ A ３ , or -O ｍ B (O ｌ A ２ ) (O ｋ A ３ ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R ２ is plural and plural R ２ are bonded to each other to form a ring, A １ represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A ２ and A ３ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A ２ and A ３ are bonded to each other to form a ring)

6. A method for producing a fluorine-containing ring-fused triazole derivative, comprising a step of reacting a fluorine-containing carboxylic acid ester represented by the following general formula (1) with a nitrogen-containing heterocyclic compound represented by the following general formula (12) to obtain a fluorine-containing ring-fused triazole derivative represented by the following general formula (13): 【Chemistry 6】 (In the above general formulas (1), (12) and (13), Rf is C ｎ F （２ｎ＋１） where n is an integer from 1 to 5; R １ represents a hydrocarbon group having 1 to 10 carbon atoms, X ２ and Y ２ are each independently CH, CR ２ , or N, Z ２ NH, NR ２ , O, or S; R ２ is a halogen atom, -C ｊ F （２ｊ＋１） , a nitro group, a heterocyclic group, —O ｍ A １ , -O ｍ CO(O ｌ A １ ), -O ｍ PO (O ｌ A ２ ) (O ｋ A ３ ), -O ｍ SO (O ｌ A １ ), -O ｍ SO ２ (O ｌ A １ ), -O ｍ N.A. ２ A ３ , or -O ｍ B (O ｌ A ２ ) (O ｋ A ３ ), j represents an integer of 1 to 5, and k, l, and m each independently represent an integer of 0 to 1, or R ２ is plural and plural R ２ are bonded to each other to form a ring, A １ represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A ２ and A ３ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, or A ２ and A ３ are bonded to each other to form a ring)

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