Method for producing fluorine-containing fused imidazole derivative

Abstract

To provide, for example, a novel method for producing a fluorine-containing fused imidazole derivative.SOLUTION: A method for producing a fluorine-containing fused imidazole derivative includes a step of reacting a fluorine-containing carboxylic acid ester represented by General Formula (1) with a nitrogen-containing heteroaromatic compound represented by General Formula (A) to produce a fluorine-containing fused imidazole derivative represented by General Formula (B).SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Fused imidazole derivatives, which have a structure in which a nitrogen-containing heteroaromatic ring is fused to an imidazole ring, are known to have various pharmacological activities.Specifically, examples of pharmaceuticals containing fused imidazole derivatives include temozolomide, an anticancer drug with a partial structure of imidazotetrazine, zolpidem, a hypnotic sedative with a partial structure of imidazopyridine, ponatinib, an anticancer drug with a partial structure of imidazopyridazine, vardenafil, a vasodilator with a partial structure of imidazotriazine, acalabrutinib, an anticancer drug with a partial structure of imidazopyrazine, and quizartinib, an anticancer drug with a partial structure of imidazobenzothiazole.Similarly, examples of pesticides containing fused imidazole derivatives include sulfosulfuron, a herbicide with a partial structure of imidazopyridine, and propylsulfuron, a herbicide with a partial structure of imidazopyridazine.

[0003] In hopes of further improving the pharmacological activity of fused-ring imidazole derivatives, there has been interest in introducing fluorine-containing substituents, and an efficient method for producing fluorine-containing fused-ring imidazole derivatives, which are compounds into which such substituents have been introduced, is desired. That is, the development of a one-step production method in which the introduction of fluorine-containing substituents and the construction of the imidazole ring are carried out consecutively has been considered. For example, Non-Patent Document 1 discloses a production method using trifluoroacetic anhydride or trifluoroacetamide, Non-Patent Document 2 discloses a production method using trifluoroethylamine, and Patent Document 1 discloses a production method using trifluoroacetic acid. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2018 / 118736 [Non-patent literature]

[0005] [Non-Patent Document 1] Organic Letters, 2017, volume 19, pages 6578-6581 [Non-patent document 2] Organic & Biomolecular Chemistry, 2018, Vol. 16, pp. 5653-5660 Summary of the Invention [Problem to be solved by the invention]

[0006] The trifluoroacetic anhydride used in the production method disclosed in Non-Patent Document 1 decomposes violently upon contact with moisture. Therefore, this production method is not only dangerous to handle but also requires a strict anhydrous environment, making simplification of the operation desirable. The production method using trifluoroacetamide reported as an alternative method in Non-Patent Document 1 requires the use of expensive, highly deliquescent cesium carbonate as a base, and requires the use of excess amounts of base and trifluoroacetamide to suppress side reactions. In the production method reported in Non-Patent Document 2, both the raw material trifluoroethylamine and the oxidizing agent iodine are expensive. The trifluoroacetic acid used in the production method reported in Patent Document 1 is not only highly hygroscopic, but also highly volatile, corrosive, and irritating, making it dangerous to handle and leading to complicated operations. From this perspective, the present invention provides a novel method for producing a fluorine-containing ring-fused imidazole derivative. [Means for solving the problem]

[0007] The gist and configuration of the present invention are as follows. [1] A method for producing a fluorine-containing ring-fused imidazole 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 (A) to obtain a fluorine-containing ring-fused imidazole derivative represented by the following general formula (B):

[0008] [ka]

[0009] (In the above general formulas (1), (A), and (B), Rf is C n F (2n+1) wherein n is an integer of 1 to 5; R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, Q is -W=X 1 -Y 1 =Z 1 -, -X 2 =Y 2 -Z 2 - or -Z 2 -Y 2 =X 2 - represents W, X 1 , Y 1 , Z 1 , X 2 , and Y 2 are each independently CR 3 or N, Z 2 is NR 3 , O, or S; R 2 and R 3 are each independently a hydrogen atom, a halogen atom, or -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 ), -Om 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 3 is plural and plural R 3 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.)

[0010] [2] A method for producing the fluorine-containing ring-fused imidazole derivative according to [1], 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 imidazole derivative represented by the following general formula (3):

[0011] [ka]

[0012] (In the above general formulas (1), (2), and (3), Rf, R 1 , R 2 , W, X 1 , Y 1 , and Z 1 is as defined above.)

[0013] [3] A method for producing the fluorine-containing ring-fused imidazole derivative according to [1], 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 imidazole derivative represented by the following general formula (5):

[0014] [ka]

[0015] (In the above general formulas (1), (4), and (5), Rf, R 1 , R 2 , X 2 , Y 2 , and Z 2 is as defined above.)

[0016] [4] A method for producing the fluorine-containing ring-fused imidazole derivative of [1], 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 imidazole derivative represented by the following general formula (7):

[0017] [ka]

[0018] (In the above general formulas (1), (6), and (7), Rf, R 1 , R 2 , X 2 , Y 2 , and Z 2 is as defined above.) [Effects of the Invention]

[0019] According to the present invention, a novel method for producing a fluorine-containing ring-fused imidazole derivative is provided. DETAILED DESCRIPTION OF THE INVENTION

[0020] [Method of producing a fluorine-containing fused ring imidazole derivative] The fluorine-containing ring-fused imidazole derivative is produced by a method 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 (A) to obtain a fluorine-containing ring-fused imidazole derivative represented by the following general formula (B): According to such a method, it is possible to produce the fluorine-containing ring-fused imidazole derivative from a fluorine-containing carboxylic acid ester through a safe one-step reaction.

[0021] [ka]

[0022] (In the above general formulas (1), (A), and (B), Rf is C n F (2n+1) wherein n is an integer of 1 to 5; R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, Q is -W=X 1 -Y 1 =Z 1 -, -X 2 =Y 2 -Z 2 - or -Z 2 -Y 2 =X 2 - represents W, X 1 , Y 1 , Z 1 , X 2 , and Y 2 are each independently CR 3 or N, Z 2 is NR 3 , O, or S; R 2 and R 3 are each independently a hydrogen atom, a halogen atom, or -C j F (2j+1) , nitro group, heterocyclic group, -O m A 1 , -O m CO(O l A1 ), -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 3 is plural and plural R 3 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.)

[0023] The reaction in the above step of obtaining a fluorine-containing ring-fused imidazole derivative represented by general formula (B) by reacting a fluorine-containing carboxylic acid ester represented by general formula (1) with a nitrogen-containing heterocyclic compound represented by general formula (A) is represented, for example, by the following reaction formula:

[0024] [ka]

[0025] In the above process, a fluorine-containing carboxylic acid ester can be used as a raw material, which is more stable and safer than trifluoroacetic anhydride and can be easily handled as a liquid at room temperature. In addition, in the above process, a fluorine-containing ring-fused imidazole derivative can be produced in a one-step reaction using a dealcoholized compound as an intermediate. The by-product in the synthesis of the intermediate is an alcohol (R 1 Since only the hydroxyl group (OH) is present, the next step can be carried out by simple vacuum distillation, making this a one-step process. 1 OH) occurs, and a dehydration reaction occurs with the dehydrating agent. Then, the fluorine-containing carboxylic acid ester represented by general formula (1) and the nitrogen-containing heterocyclic compound represented by general formula (A) are reacted with each other to form -C(CH(NH)(R 2 ))=N--, ​​the imidazole ring of the fluorine-containing ring-fused imidazole derivative represented by general formula (B) is formed from the group represented by the formula (B).

[0026] The ester-amide exchange reaction may be carried out by mixing the fluorine-containing carboxylic acid ester represented by general formula (1) with the nitrogen-containing heterocyclic compound represented by general formula (A) without adding any particular reagent. Furthermore, the ester-amide exchange reaction may be carried out by heating, if necessary. In this case, the temperature of 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.

[0027] The dehydrating agent used in the reaction of the above step is not particularly limited. For example, a reaction system stable to moisture may be constructed by using a combination of an oxidizing agent and a reducing agent. Examples of dehydrating agents include the following. However, the dehydrating agents that can be used in the above step are not limited to the following.

[0028] (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, triphenylphosphine, alkoxydialkylphosphines, and phenoxydiphenylphosphine. Oxidizing agents that by-produce hydrogen halides, such as carbon tetrachloride, carbon tetrabromide, bromine-1,4-dioxane complex, halogenated succinimides, and N-chlorosaccharin, may be used together with a base, if necessary. Examples of the base include triethylamine and N,N-diisopropylethylamine.

[0029] (ii) Other dehydrating agents and any base Other dehydrating agents include, for example, phosphorus oxychloride and thionyl chloride. If hydrogen halide is produced as a by-product, a base may be additionally used as needed. Examples of the base include triethylamine and N,N-diisopropylethylamine.

[0030] The reaction temperature during the reaction in the above step 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.

[0031] Examples of the solvent used in the reaction of the above step include acetonitrile and dimethoxyethane.

[0032] Q is -W=X 1 -Y 1 =Z 1 When - represents, the above step is 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 imidazole derivative represented by the following general formula (3):

[0033] [ka]

[0034] (In the above general formulas (1), (2), and (3), Rf, R 1 , R 2 , W, X 1 , Y 1 , and Z 1 is as defined above.)

[0035] Q is -X 2 =Y 2 -Z 2 When - represents, the above step is 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 imidazole derivative represented by the following general formula (5):

[0036] [ka]

[0037] (In the above general formulas (1), (4), and (5), Rf, R 1 , R 2 , X 2 , Y 2 , and Z 2 is as defined above.)

[0038] Q is -Z 2 -Y 2 =X 2 When - represents, the above step is 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 imidazole derivative represented by the following general formula (7):

[0039] [ka]

[0040] (In the above general formulas (1), (6), and (7), Rf, R 1 , R 2 , X 2 , Y 2 , and Z 2 is as defined above.)

[0041] The groups Rf and R in the general formulae of the above steps 1 , W, X 1 , Y 1 , Z 1 , X 2 , Y 2 , Z 2 , R 2 , R 3 , -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 , and A 3 This will be explained in detail below.

[0042] Rf is C n F (2n+1) where n is an integer of 1 to 5, specifically CF3, C2F5, C3F7, C4F9, C5F 11In one embodiment, Rf is CF3, C2F5, C3F7, or C4F9. In one embodiment, Rf is CF3, C2F5, or C3F7. In one embodiment, Rf is CF3 or C2F5. In one embodiment, Rf is CF3.

[0043] 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. The chain hydrocarbon group may be linear or branched. Examples of the chain hydrocarbon group include alkyl groups, alkenyl groups, and alkynyl groups. Examples of the alkyl group include methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, t-butyl groups, pentyl groups, hexyl groups, heptyl groups, octyl groups, nonyl groups, and decyl groups. Examples of the alkenyl group include ethenyl groups, propenyl groups, butenyl groups, pentenyl groups, hexenyl groups, heptenyl groups, octenyl groups, nonenyl groups, and decenyl groups. Examples of the alkynyl group include an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a heptynyl group, an octynyl group, a nonynyl group, and a decynyl group. Examples of the aromatic hydrocarbon group include a phenyl group. The phenyl group can be formed by the reaction of R 1 The alicyclic hydrocarbon group may be substituted with one or more hydrocarbon groups, so long as the carbon number of R is 10 or less. Examples of the alicyclic hydrocarbon group include saturated or unsaturated cyclic hydrocarbon groups. Examples of the cyclic hydrocarbon group include a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, and an adamantyl group. The alicyclic hydrocarbon group is 1 may be substituted with one or more hydrocarbon groups, so long as the number of carbon atoms is 10 or less.

[0044] W, X 1 , Y 1 , and Z 1 are each independently CR 3or N, W, X 1 , Y 1 , and Z 1 One, two, three, or four of the 3 and one, two, three, or four may be N.

[0045] X 2 and Y 2 are each independently CR 3 or N, Z 2 is NR 3 , O, or S. X 2 and Y 2 Both are CR 3 X may be 2 and Y 2 may both be N, and X 2 is CR 3 And Y 2 may be N, and X 2 is N and Y 2 is CR 3 may be.

[0046] R 2 and R 3 are each independently a hydrogen atom, a halogen atom, or -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. R 3 If there are multiple R 3 may be bonded to each other to form a ring. 3 The ring formed by bonding together may have, for example, 20 or less carbon atoms, 15 or less carbon atoms, 10 or less carbon atoms, 8 or less carbon atoms, 7 or less carbon atoms, or 6 or less carbon atoms. 3 The ring formed by bonding together may have at least one heteroatom selected from the group consisting of S (sulfur atom), O (oxygen atom), and N (nitrogen atom) as a ring atom, for example, 5 or less, 4 or less, 3 or less, 2 or less, or even 1. 3 When these are bonded to each other to form a ring, examples of the group include an aliphatic ring, a heteroaliphatic ring, an aromatic ring, and a heteroaromatic ring.

[0047] R on adjacent ring atoms 3Examples of the aliphatic ring or heteroaliphatic ring formed by bonding together include a ring that may contain at least one heteroatom selected from the group consisting of S (sulfur atom), O (oxygen atom), and N (nitrogen atom). Such an aliphatic ring or heteroaliphatic ring is fused to the single or double bond indicated by the arrow in the fluorine-containing ring-fused imidazole derivative represented by the following general formulas (3), (5), and (7). In the fluorine-containing ring-fused imidazole derivative represented by the following general formula (3), one, two, or three single or double bonds can be fused with the aliphatic ring or heteroaliphatic ring, as indicated by the arrow. In the fluorine-containing ring-fused imidazole derivative represented by the following general formulas (5) and (7), one or two single or double bonds can be fused with the aliphatic ring or heteroaliphatic ring, as indicated by the arrow. The aliphatic ring or heteroaliphatic ring may have a monocyclic structure or a polycyclic structure composed of two or more rings, and the monocyclic structure or polycyclic structure may further have one, two, three, or four or more substituents. In this case, examples of the substituent include an alkyl group, a fluoroalkyl group, an aryl group, etc. Specific examples of the heteroaliphatic ring include a pyrrolidine ring and a piperazine ring.

[0048] [ka]

[0049] R on adjacent ring atoms 3Examples of aromatic or heteroaromatic rings formed by bonding together include rings that may contain at least one atom selected from the group consisting of S (sulfur atom), O (oxygen atom), and N (nitrogen atom). Such aromatic or heteroaromatic rings are fused to the single or double bonds indicated by arrows in the fluorine-containing ring-fused imidazole derivatives represented by the above general formulas (3), (5), and (7). In the fluorine-containing ring-fused imidazole derivatives represented by the above general formula (3), aromatic or heteroaromatic rings can be fused to one, two, or three single or double bonds as indicated by the arrows. In the fluorine-containing ring-fused imidazole derivatives represented by the above general formulas (5) and (7), aromatic or heteroaromatic rings can be fused to one or two single or double bonds as indicated by the arrows. The aromatic ring or heteroaromatic ring may have a monocyclic structure or a polycyclic structure composed of two or more rings, and the monocyclic structure or polycyclic structure may further have one, two, three, or four or more substituents. 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.

[0050] R 2 or R 3 Examples of halogen atoms in R include F, Cl, Br, and I. 2 or R 3 -C j F (2j+1) Examples include CF3, C2F5, C3F7, C4F9, and C5F 11 R 2 or R 3 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 or R 3 -O m A 1Examples of R include -Me, -Et, -OMe, -OEt, and -Ph. 2 or R 3 -O m CO(O l A 1 ) can include groups such as -(CO)Me and -O(CO)OPh. 2 or R 3 -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 or R 3 -O m SO(O l A 1 ) can include groups such as -(SO)Ph and -O(SO)OPh. 2 or R 3 -O m SO2(O l A 1 ) can include groups such as -(SO2)Me and -O(SO2)OPh. R 2 or R 3 -O m NA 2 A 3 Examples of R include groups such as -NEt2 and -ONPhEt. 2 or R 3 -O m B(O l A 2 )(O k A 3 ) can include groups such as -BPh2, -OB(OMe)2, etc.

[0051] R 2 or R 3 -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 or R 3 A that constitutes 2 and A 3 are bonded to each other to form a ring. 2 and A 3 The ring formed by bonding together may have, for example, 20 or less, 15 or less, 10 or less, 8 or less, 7 or less, or 6 or less carbon atoms. 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 or R 3 -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 or R 3 -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 A3 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. In addition, 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, for example, 5 or less, 4 or less, 3 or less, 2 or less, or 1. Typically, the heteroaliphatic ring and heteroaromatic ring have a monocyclic structure. In addition, 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 one, two, three, or four or more substituents. In this case, examples of the substituents include an alkyl group and an aryl group. In addition, R 3 is plural and plural R 3 When they bond together to form a ring, one R 3 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, the above-mentioned R 1 The hydrocarbon group can be selected from the hydrocarbon groups having 1 to 10 carbon atoms mentioned in the description of 1.

[0052] [Fluorine-containing fused imidazole derivatives] The fluorine-containing ring-fused imidazole derivatives obtained by the above method are represented by the following general formulae (3), (5), and (7).

[0053] [ka]

[0054] (In the above general formulas (3), (5), and (7), Rf is C n F (2n+1) wherein n is an integer of 1 to 5; W, X 1 , Y 1 , Z 1 , X 2 , and Y 2 are each independently CR 3 or N, Z 2 is NR 3 , O, or S; R 2 and R 3 are each independently a hydrogen atom, a halogen atom, or -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 3 is plural and plural R 3 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 2and A 3 are bonded to each other to form a ring.)

[0055] The groups Rf and R in the general formulas of the above steps 1 , W, X 1 , Y 1 , Z 1 , X 2 , Y 2 , Z 2 , R 2 , R 3 , -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 , and A 3 The above description of the manufacturing method is applicable to this.

[0056] These fluorine-containing ring-fused imidazole derivatives can have activity such as antiviral activity. In one embodiment, the fluorine-containing ring-fused triazole derivatives are also useful in the fields of, for example, pharmaceuticals and agricultural chemicals. In addition, in one embodiment, the fluorine-containing ring-fused triazole derivatives can also be used in the field of, for example, organic electronic materials.

[0057] The above describes the embodiments of the present invention, but the present invention is not limited to the above embodiments, and 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]

[0058] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0059] Example 1 [Synthesis of 3-(trifluoromethyl)imidazo[1,5-a]pyridine] 0.2 g (1.4 mmol) of 2-pyridinemethanamine and 0.3 g (1.8 mmol) of ethyl trifluoroacetate were added to 10 g of tetrahydrofuran to obtain Solution 1. Solution 1 was stirred at room temperature for approximately 16 hours, and the solvent and by-product ethanol were removed by distillation under reduced pressure to obtain a solid. 25 g of acetonitrile 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 N,N-diisopropylethylamine 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)imidazo[1,5-a]pyridine, as shown below. The yield of the purified product was 0.1 g (isolation yield 39%).

[0060] [ka]

[0061] The analysis results were as follows: Mass spectrum (APCI, m / z): 186 ([M] + )

[0062] Example 2 [Synthesis of 3-methyl-5-(trifluoromethyl)imidazo[5,1-b]thiazole] 0.2 g (1.3 mmol) of 2-(4-methyl-1,3-thiazolyl)methanamine and 0.2 g (1.7 mmol) of ethyl trifluoroacetate were added to 10 g of tetrahydrofuran to obtain Solution 1. After stirring Solution 1 for approximately 16 hours at room temperature, the solvent and by-product ethanol were removed by distillation under reduced pressure to obtain a solid. 25 g of acetonitrile was added to this solid, followed by 0.4 g (1.5 mmol) of bromine-1,4-dioxane complex, 0.6 g (2.0 mmol) of phenoxydiphenylphosphine, and 0.5 g (4.2 mmol) of N,N-diisopropylethylamine to obtain Solution 2. Solution 2 was heated under reflux for approximately 6 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-methyl-5-(trifluoromethyl)imidazo[5,1-b]thiazole, as shown below. The amount of purified product obtained was 0.1 g (isolation yield 42%).

[0063] [ka]

[0064] The analysis results were as follows: Mass spectrum (APCI, m / z): 206 ([M] + ) 1 H-NMR(400MHz,CDCl3) δppm:7.17(s,1H),6.56(d,1H),2.48(br,3H)

Claims

1. A method for producing a fluorine-containing ring-fused imidazole 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 (A) to obtain a fluorine-containing ring-fused imidazole derivative represented by the following general formula (B): 【Chemical 1】 (In the above general formulas (1), (A), and (B), Rf is C ｎ F （２ｎ＋１） wherein n is an integer of 1 to 5; R １ represents a hydrocarbon group having 1 to 10 carbon atoms, Q is -W=X １ -Y １ =Z １ -, -X ２ = Y ２ -Z ２ - or -Z ２ -Y ２ =X ２ represents -, W, X １ , Y １ , Z １ , X ２ , and Y ２ are each independently CR ３ or N, Z ２ is NR ３ , O, or S; R ２ and R ３ are each independently a hydrogen atom, a halogen atom, or —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 ３ is plural and plural R ３ 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. 2. A method for producing a fluorine-containing ring-fused imidazole derivative according to claim 1, 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 imidazole derivative represented by the following general formula (3): 【Chemistry 2】 (In the above general formulas (1), (2), and (3), Rf, R １ , R ２ , W, X １ , Y １ , and Z １ is as defined in claim 1)

3. 2. A method for producing a fluorine-containing ring-fused imidazole derivative according to claim 1, 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 imidazole derivative represented by the following general formula (5): 【Chemistry 3】 (In the above general formulas (1), (4), and (5), Rf, R １ , R ２ , X ２ , Y ２ , and Z ２ is as defined in claim 1)

4. 2. A method for producing a fluorine-containing ring-fused imidazole derivative according to claim 1, 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 imidazole derivative represented by the following general formula (7): 【Chemistry 4】 (In the above general formulas (1), (6), and (7), Rf, R １ , R ２ , X ２ , Y ２ , and Z ２ is as defined in claim 1)

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